WO2012165398A1 - Cycloalkyloxybiaryl compound - Google Patents

Cycloalkyloxybiaryl compound Download PDF

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Publication number
WO2012165398A1
WO2012165398A1 PCT/JP2012/063693 JP2012063693W WO2012165398A1 WO 2012165398 A1 WO2012165398 A1 WO 2012165398A1 JP 2012063693 W JP2012063693 W JP 2012063693W WO 2012165398 A1 WO2012165398 A1 WO 2012165398A1
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group
phenyl
amino
compound
oxy
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PCT/JP2012/063693
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French (fr)
Japanese (ja)
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芳一 宇都
裕 森
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound having a specific chemical structure having an excellent acylcoenzyme A: diacylglycerol acyltransferase (hereinafter also referred to as DGAT) inhibitory activity and an excellent feeding inhibitory activity, Relates to acceptable salts.
  • DGAT diacylglycerol acyltransferase
  • triglyceride triacylglycerol or triglyceride, hereinafter also referred to as TG
  • TG triglyceride
  • TG ingested by the meal is broken down into free fatty acids and monoacylglycerol by the action of bile acids and pancreatic lipase in the lumen of the small intestine.
  • Micelles composed of free fatty acid, monoacylglycerol and bile acid are absorbed into small intestinal epithelial cells, and in the endoplasmic reticulum by the action of acylcoenzyme A synthase (hereinafter referred to as ACS), acylcoenzyme A: monoacylglycerol acyltransferase and DGAT.
  • ACS acylcoenzyme A synthase
  • TG in combination with phospholipids, cholesterol and apolipoprotein, is secreted into the gastrointestinal lymphatic vessels as kilomicrons. Furthermore, TG is secreted into the blood via the lymph main duct and transported to the periphery for use.
  • TG is synthesized from glycerol 3-phosphate and free fatty acids by the action of ACS, glycerol 3-phosphate acyltransferase, lysophosphatidic acid acyltransferase, and DGAT (Non-patent Document 2).
  • ACS glycerol 3-phosphate acyltransferase
  • DGAT Non-patent Document 2
  • DGAT is an enzyme that is present in the endoplasmic reticulum in the cell and catalyzes the most important final step reaction in the TG synthesis pathway, that is, the reaction of transferring the acyl group of acylcoenzyme A to the 3-position of 1,2-diacylglycerol.
  • Non-Patent Documents 3 to 5 It has been reported that DGAT has two types of isozymes DGAT1 (Non-patent document 6) and DGAT2 (Non-patent document 7).
  • DGAT1 is highly expressed in the small intestine and adipose tissue
  • DGAT2 is highly expressed in the liver and adipose tissue, respectively
  • DGAT1 is mainly used for fat absorption from the small intestine and fat accumulation
  • DGAT2 is used for TG synthesis or VLDL in the liver. (Very low density lipoproteins) secretion and fat accumulation in adipose tissue.
  • DGAT1 and DGAT2 has not yet been clarified in detail, the relationship between DGAT and obesity, lipid metabolism, sugar metabolism, etc. has been suggested (Non-patent Document 8).
  • DGAT is a key enzyme for TG synthesis in gastrointestinal epithelial cells and adipose tissue, and a drug that inhibits DGAT suppresses fat absorption in the gastrointestinal tract and fat accumulation in adipose tissue by suppressing TG synthesis, and obesity , Obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, diabetes, non-alcoholic steatohepatitis, or obesity-induced hyperlipidemia, hypertriglyceridemia, lipid metabolism It is expected to be useful as a therapeutic or prophylactic agent for abnormal diseases, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis, hypertension, arteriosclerosis, cerebrovascular disorder, coronary artery disease, etc. 9 to 13).
  • An appetite suppressant directly or indirectly regulates the appetite control system, but its mechanism of action is roughly divided into central and peripheral.
  • An appetite suppressant acting centrally acts on the hypothalamic nervous system where the feeding center and satiety center exist and the monoamine nervous system in the brain that regulates the nervous system, thereby directly suppressing appetite.
  • an appetite suppressant that acts on the periphery acts on a mechanism that senses and transmits the intake of nutrients and the accumulation of surplus energy, and indirectly suppresses appetite.
  • Non-patent Document 14 gastrointestinal hormones secreted in close association with the digestion and absorption of food (Non-Patent Document 14) and from fat cells according to the energy accumulation (fat mass)
  • Non-patent Document 15 The mechanism by which secreted leptin (Non-patent Document 15) or the like transmits a signal that regulates appetite from the periphery to the center in a hormonal or neurological manner has been clarified.
  • These new appetite suppressants associated with peripheral signals are expected to be more effective and less effective for the treatment of obesity.
  • Patent Document 1 discloses that a [5- (4- ⁇ [(substituted phenyl) carbamoyl] amino ⁇ phenyl) pyrimidin-2-yl] oxy group and a carboxylic acid are bonded via an alkylene group. And a compound in which an [5- (4- ⁇ [(substituted phenyl) carbamoyl] amino ⁇ phenyl) pyrimidin-2-yl] oxy group and a cyclopentanecarboxylic acid are bonded via an alkylene group.
  • Patent Document 2 describes a compound having (2,3′-bipyridin-6′-yloxy) cyclohexanecarboxylic acid.
  • Non-Patent Document 16 describes a compound in which a 4 '-[(substituted anilinocarbonyl) amino] biphenyl-4-yl group and a cyclopentanecarboxylic acid are bonded via a carbonyl group.
  • this compound is obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral Neuropathy, including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic Hyperlipidemia, hypertriglyceridemia, lipid metabolism resulting from obesity or as an active ingredient of a medicament for the prevention and / or treatment of a disease selected from the group consisting of arteriosclerosis, ischemic heart disease and bulimia Abnormal diseases, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, Gynecologic diabetes, nonalcoholic steatohepatitis, polycystic ova
  • the present invention comprises (1) general formula (I)
  • R is a phenyl group which may be independently substituted with a group selected from the substituent group A, and may be independently substituted with 1 to 3 groups independently selected from a group selected from the substituent group A;
  • Q represents a nitrogen atom or a group represented by the formula —CH ⁇
  • U represents a nitrogen atom or a group represented by the formula —CH ⁇
  • V represents a nitrogen atom or a group represented by the formula —CH ⁇
  • m represents 0 or 1
  • n represents 0 or 1
  • Substituent group A includes a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 halogenated alkoxy group, (C 1 -C 6 alkoxy)-(C 1 -
  • a compound in which the general formula (I) is the general formula (Ia), the general formula (Ib), the general formula (Ic), the general formula (Id), the general formula (Ie) or the general formula (If) or a pharmacologically acceptable salt thereof Salt.
  • R is a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3- Methoxyphenyl group, 4-methoxyphenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-3-methylphenyl group, 2-fluoro-4-methylphenyl group, 2,4-dimethylphenyl group, 2- A compound having a methoxy-5-methylphenyl group or a 2,4,5-trifluorophenyl group, or a pharmacologically acceptable salt thereof.
  • General Formula (I) is General Formula (Ia), General Formula (Ib), General Formula (Ic), General Formula (Id), General Formula (Ie), or General Formula (If), and R is a substituent.
  • a compound or a pharmacologically acceptable salt thereof which is a phenyl group which may be independently substituted with 1 to 5 groups selected from Group A.
  • General Formula (I) is General Formula (Ia), General Formula (Ib), General Formula (Ic), General Formula (Id), General Formula (Ie), or General Formula (If), and R is (fluorine A compound or a pharmacologically acceptable salt thereof which is a phenyl group which may be independently substituted with 1 to 3 groups independently selected from a group selected from an atom, a chlorine atom, a methyl group and a methoxy group.
  • General Formula (I) is General Formula (Ia), General Formula (Ib), General Formula (Ic), General Formula (Id), General Formula (Ie), or General Formula (If), and R is a phenyl group 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4 -Methoxyphenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-3-methylphenyl group, 2-fluoro-4-methylphenyl group, 2,4-dimethylphenyl group, 2-methoxy-5-methyl
  • the general formula (I) is the general formula (Ia), and R is a phenyl optionally substituted with 1 to 3 groups independently selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group) Or a pharmacologically acceptable salt thereof.
  • the general formula (I) is the general formula (Ia), and R is a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group.
  • An acyl coenzyme A diacylglycerol acyltransferase inhibitor comprising as an active ingredient the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition inhibits acyl coenzyme A: diacylglycerol acyltransferase, inhibits the synthesis of triglyceride, and suppresses the absorption of triglyceride, thereby treating, improving, reducing and / or preventing symptoms.
  • the pharmaceutical composition inhibits acylcoenzyme A: diacylglycerol acyltransferase and inhibits the synthesis of triglyceride, thereby treating and / or treating diseases in which symptoms are treated, ameliorated, reduced and / or prevented.
  • the pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceride disease, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, false The pharmaceutical composition according to (19) for the treatment and / or prevention of blood heart disease or bulimia.
  • the pharmaceutical composition is obesity-induced hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension (19)
  • composition according to (19), wherein the pharmaceutical composition is for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.
  • Obesity obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetes Retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, non-alcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease or The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in the treatment and / or prevention of bulimia.
  • the pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, false
  • the use according to (35) which is a pharmaceutical composition for the treatment and / or prevention of blood heart disease or bulimia.
  • Hyperlipidemia hypertriglycerideemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic kidney) , Including diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension
  • diabetes diabetes
  • diabetic complications diabetic peripheral neuropathy, diabetic kidney
  • Including diabetic retinopathy, diabetic macroangiopathy cataract
  • gestational diabetes nonalcoholic steatohepatitis
  • polycystic ovary syndrome arteriosclerosis
  • atherosclerosis diabetic arteriosclerosis
  • hypertension which is a pharmaceutical composition for the treatment and / or prevention of cerebrovascular disorder, coronary artery disease, fatty liver, respiratory disorder, low back pain, knee osteoarthritis, gout or cholelithiasis.
  • the pharmaceutical composition is a pharmaceutical composition for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity .
  • Acyl coenzyme A diacylglycerol for administering a pharmacologically effective amount of the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof to a warm-blooded animal Acyltransferase inhibition method.
  • Diseases are obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy , Including diabetic retinopathy, diabetic macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart
  • the method according to (46) which is a disease or bulimia.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a fluorine atom or a chlorine atom Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
  • the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Preferred is a linear or branched alkyl group having 1 to 4 carbon atoms (C 1 -C 4 alkyl group), and more preferred is a methyl group or an ethyl group (C 1 -C 2 alkyl group). And even more preferably a methyl group.
  • the “C 1 -C 6 halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkyl group”.
  • a trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl or 2-fluoroethyl group is there.
  • the same or different 1 to 5 “halogen atoms” are groups bonded to the “C 1 -C 4 alkyl group” (C 1 -C 4 halogenated alkyl group), more preferably A group (C 1 -C 2 halogenated alkyl group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 2 alkyl group”, and even more preferably, A fluoromethyl group;
  • the “C 1 -C 6 alkoxy group” is a group in which the “C 1 -C 6 alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, 2-methylbutoxy, 3-ethylpropoxy, hexyloxy or 2,3-dimethylbutoxy group.
  • Preferred is a linear or branched alkoxy group having 1 to 4 carbon atoms (C 1 -C 4 alkoxy group), and more preferred is a methoxy group or an ethoxy group (C 1 -C 2 alkoxy group). And even more preferably a methoxy group.
  • the “C 1 -C 6 halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkoxy group”.
  • the same or different 1 to 5 “halogen atoms” are groups bonded to the “C 1 -C 4 alkoxy group” (C 1 -C 4 halogenated alkoxy group), and more preferably A group (C 1 -C 2 halogenated alkoxy group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 2 alkoxy group”, and even more preferably, A fluoromethoxy group;
  • the “(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group” means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 alkyl group”. It is a group bonded to For example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, s-butoxymethyl, t-butoxymethyl, 2-methoxyethyl or 3-isopropoxypropyl group.
  • a group ((C 1 -C 4 alkoxy)-(C 1 -C 4 alkyl) in which one said “C 1 -C 4 alkoxy group” is bonded to the above “C 1 -C 4 alkyl group” a group), more preferably, one group wherein the "C 1 -C 2 alkoxy group” attached to the "C 1 -C 2 alkyl group” ((C 1 -C 2 alkoxy) - (C 1- C 2 alkyl) group), and even more preferably a methoxymethyl group.
  • the “C 1 -C 6 alkylthio group” is a group in which the “C 1 -C 6 alkyl group” is bonded to a sulfur atom, and is a linear or branched alkylthio group having 1 to 6 carbon atoms. It is. For example, a methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio or hexylthio group.
  • the “C 1 -C 6 alkylsulfinyl group” is a group in which the “C 1 -C 6 alkyl group” is bonded to a sulfinyl group, and is a straight chain or branched alkyl group having 1 to 6 carbon atoms. It is a sulfinyl group.
  • Preferred is a linear or branched alkylsulfinyl group having 1 to 4 carbon atoms (C 1 -C 4 alkylsulfinyl group), and more preferred is a methylsulfinyl group or an ethylsulfinyl group (C 1 -C 2 alkylsulfinyl group), and more preferably a methylsulfinyl group.
  • a “C 2 -C 7 alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a carbonyl group.
  • a carbonyl group For example, an acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group.
  • one of the above “C 1 -C 4 alkyl group” is a group (C 2 -C 5 alkylcarbonyl group) bonded to a carbonyl group, and more preferably an acetyl group or a propionyl group (C 2 a -C 3 alkylcarbonyl group), still more preferably, an acetyl group.
  • a “C 2 -C 7 alkoxycarbonyl group” is a group in which one of the above “C 1 -C 6 alkoxy groups” is bonded to a carbonyl group.
  • one of the above “C 1 -C 4 alkoxy groups” is a group (C 2 -C 5 alkoxycarbonyl group) bonded to a carbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group ( C 2 -C 3 alkoxycarbonyl group), and more preferably a methoxycarbonyl group.
  • the “mono-C 1 -C 6 alkylamino group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to an amino group.
  • one said “C 1 -C 4 alkyl group” is a group bonded to an amino group (mono-C 1 -C 4 alkylamino group), more preferably a methylamino group or ethylamino group Group (mono-C 1 -C 2 alkylamino group), still more preferably a methylamino group.
  • the “di- (C 1 -C 6 alkyl) amino group” is a group in which two identical or different “C 1 -C 6 alkyl groups” are bonded to an amino group.
  • two identical or different “C 1 -C 4 alkyl groups” are groups bonded to an amino group (di- (C 1 -C 4 alkyl) amino group), more preferably dimethyl amino group, a diethylamino group or an N- ethyl
  • the “mono-C 2 -C 7 alkylcarbonylamino group” is a group in which one carbonyl group bonded to the “C 1 -C 6 alkyl group” is bonded to an amino group.
  • an acetamide, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino or isobutylcarbonylamino group is a group in which one carbonyl group bonded to the “C 1 -C 6 alkyl group” is bonded to an amino group.
  • a one of said "C 1 -C 4 alkyl group” is a carbonyl group attached is attached to an amino group group (mono--C 2 -C 5 alkylcarbonylamino group), more preferably, the An acetamide group or an ethylcarbonylamino group (mono-C 2 -C 3 alkylcarbonylamino group), and even more preferably an acetamide group.
  • "mono--C 1 -C 6 alkylsulfonylamino group” one of the sulfonyl group "C 1 -C 6 alkyl group” is bonded is a group attached to an amino group.
  • a sulfonyl group to which one said “C 1 -C 4 alkyl group” is bonded is a group bonded to an amino group (mono-C 1 -C 4 alkylsulfonylamino group), more preferably a methylsulfonylamino group or an ethylsulfonylamino group (mono--C 1 -C 2 alkylsulfonylamino group), more preferably more, a methylsulfonylamino group.
  • the “C 3 -C 6 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and preferably a cyclohexyl group.
  • the “phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” is independently 1 to 5 groups with a phenyl group or a group selected from the substituent group A. This is a phenyl group that is substituted.
  • a phenyl group which may be independently substituted with 1 to 3 groups independently selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group), more preferably a phenyl group, 2- Fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl Group, 2-chloro-4-fluorophenyl group, 2-fluoro-3-methylphenyl group, 2-fluoro-4-methylphenyl group, 2,4-dimethylphenyl group, 2-methoxy-5-methylphenyl group or 2,4,5-trifluorophenyl group.
  • 1 to 3 groups independently selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group), more preferably a phenyl group,
  • the “pyridyl group optionally substituted by 1 to 3 groups independently selected from the substituent group A” refers to 1 to 3 groups independently selected from the pyridyl group or the substituent group A. It is a pyridyl group substituted one by one. A 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group is preferred.
  • preferred general formula (I) is general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id), general formula (Ie) or general formula (If). More preferred general formula (I) is general formula (Ia).
  • preferred R is a phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A, and more preferred R is (fluorine atom, chlorine atom, methyl group).
  • Q is preferably a nitrogen atom.
  • preferred U is a nitrogen atom.
  • preferred V is a group represented by the formula —CH ⁇ .
  • m is preferably 1.
  • n is preferably 1.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (diastereoisomers, optical isomers, rotational isomers, etc.).
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom exists in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
  • an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.
  • the compound represented by the general formula (Ia) or a pharmacologically acceptable salt thereof is more preferable than the compound represented by the general formulas (Ib) to (If) or a pharmacologically acceptable salt thereof.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the pharmacologically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicine.
  • the compound represented by the general formula (I) of the present invention can be converted into a salt by reacting with an acid when it has a basic group, or by reacting with a base when it has an acidic group. can do.
  • Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate Organic acids such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine salt, lysine salt, Examples thereof include amino acid salts such as arginine salt, ornithine salt, glutamate salt and aspartate salt.
  • hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide
  • examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt.
  • Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salt
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is taken in the air or recrystallized to take in water molecules, Such hydrates are also encompassed by the salts of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present. Included in the salts of the invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action and feeding inhibitory action, and is a warm-blooded animal (preferably a mammal, Diseases (including humans): obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis , A disease selected from the group consisting of ischemic heart disease and bulimia, or hyperlipidemia, hypertriglycerideemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, sugar caused by obesity Urinary disease, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic
  • novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action, and is a warm-blooded animal (preferably a mammalian animal). And is useful as an active ingredient of a medicament for the prevention and / or treatment of the above-mentioned diseases (including humans). Suitably, it can be used as a medicament for the treatment of the above-mentioned diseases.
  • the compound represented by the general formula (I) of the present invention can be produced according to the methods A to C described below.
  • solvent used in the reaction of each step of the following methods A to C is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example.
  • Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as -2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; methanol, ethanol, n-propanol, i -Propanol, n-butanol,
  • the base used in the reaction of each step of the following methods A to C is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide and lithium hydroxide; alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium Alkali metal alcohols such as t-butoxide Cids; alkali metal trialkylsiloxides such as sodium trimethylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; N-methylmorpholine, triethyl
  • the palladium catalyst used in the reaction in each step of the following methods A to C is, for example, tetrakis (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II).
  • reaction temperature varies depending on the solvent, starting material, reagent, and the like
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
  • each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent.
  • an immiscible organic solvent such as ethyl acetate
  • the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.
  • a target compound insoluble in a solvent the obtained solid crude product can be purified by washing with a solvent.
  • the target compound in each step can be directly used in the next reaction without purification.
  • R, Q, U, V, m, and n have the same meaning as described above in the reaction of each step of the following methods A to C.
  • X represents a halogen atom (preferably a bromine atom or an iodine atom, more preferably a bromine atom), and Y represents a protecting group for a carboxy group used in the field of synthetic organic chemistry ( Preferred is a C 1 -C 6 alkyl group, and more preferred is a methyl group.
  • R a is an amino group, hydroxy group and / or carboxy group which may be protected as an amino group, hydroxy group and / or carboxy group contained as a substituent in the R group, and in the definition of the R group. A group similar to the group is shown.
  • Method A is a method for producing a compound represented by the general formula (I). (Method A)
  • Step AI comprises reacting a compound represented by the general formula (II) with a compound represented by the general formula (III) in a solvent in the presence of a Mitsunobu reagent. It is a process of manufacturing the compound represented by these.
  • the compound represented by the general formula (II) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the compound represented by the general formula (III) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably aromatic hydrocarbons or ethers, and more preferably toluene or tetrahydrofuran.
  • the Mitsunobu reagent used in this step is preferably an azodicarboxylic acid diester or (cyanomethylene) phosphorane reagent, more preferably diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or ( Cyanomethylene) tributylphosphorane (CMBP).
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • CMBP Cyanomethylene tributylphosphorane
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 180 ° C., preferably 0 ° C. to 120 ° C.
  • the reaction time in this step is usually 0.5 hours to 72 hours, preferably 2 hours to 24 hours.
  • Step A-II This step is represented by the general formula (VI) by reacting the compound represented by the general formula (IV) with the compound (V) in the presence of a palladium catalyst and a base in a solvent. This is a process for producing a compound.
  • the solvent used in this step is preferably a mixed solvent of ethers or amides and water, more preferably a mixed solvent of tetrahydrofuran, dioxane or N, N-dimethylacetamide and water.
  • the palladium catalyst used in this step is preferably a zero-valent palladium catalyst, and more preferably tetrakis (triphenylphosphine) palladium (0).
  • the base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
  • the reaction temperature in this step is usually 20 ° C. to 180 ° C., preferably 60 ° C. to 120 ° C.
  • the reaction time in this step is usually 0.5 hours to 72 hours, preferably 2 hours to 24 hours.
  • Step A-III In this step, the compound represented by the general formula (VIII) is reacted with the compound represented by the general formula (VII) in a solvent to react the compound represented by the general formula (VIII). It is a manufacturing process.
  • the compound represented by the general formula (VII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
  • the reaction temperature in this step is usually ⁇ 78 ° C. to 180 ° C., preferably 0 ° C. to 80 ° C.
  • the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
  • Step A-IV This step is based on a known method (for example, “Protective Groups in Organic Synthesis” (the method described in Theodora W. Greene, Peter GMWuts, 1999, published by Wiley-Interscience Publication), etc.).
  • the protecting group of the amino group, hydroxy group and / or carboxy group in R a is optionally removed, thereby being represented by the general formula (I).
  • This is a process for producing a compound.
  • Y is a C 1 -C 6 alkyl group is shown below.
  • the solvent used in this step is preferably an ether or an alcohol, and more preferably tetrahydrofuran, dioxane or methanol.
  • the base used in this step is preferably a quaternary ammonium salt, and more preferably tetrabutylammonium hydroxide.
  • the reaction temperature in this step is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time in this reaction is usually 0.5 to 24 hours, preferably 1 to 10 hours.
  • Method B is a method for producing a compound represented by the general formula (VIII) used in the A-IV step of Method A. (Method B)
  • Step BI the compound represented by the general formula (VI) is reacted with the compound (IX) in the presence of a base in a solvent, and further the general formula (X) in the presence of a base in a solvent. ) To produce a compound represented by the general formula (VIII).
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the base used in this step is preferably an organic base, and more preferably triethylamine.
  • the reaction temperature in this step is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
  • Method C is a method for producing a compound represented by the general formula (VIII) used in Step A-IV of Method A. (Method C)
  • Step CI This step is a step for producing a compound represented by the general formula (XII) by reacting a compound represented by the general formula (VI) with a compound (XI) in a solvent.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the reaction temperature in this step is usually ⁇ 78 ° C. to 120 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
  • Step C-II In this step, the compound represented by the general formula (VIII) is reacted with the compound represented by the general formula (X) in a solvent to react the compound represented by the general formula (VIII). It is a manufacturing process.
  • the solvent used in this step is preferably an ether, nitrile, nitro compound, amide or hydrocarbon, and more preferably tetrahydrofuran, acetonitrile, nitrobenzene, N, N-dimethylacetamide or Hexane.
  • the reaction temperature in this step is usually ⁇ 78 ° C. to 180 ° C., preferably 0 ° C. to 120 ° C.
  • the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
  • the protecting group of “amino group that may be protected”, “hydroxy group that may be protected” and / or “carboxy group that may be protected” in the definition of R a is hydrogenolysis, hydrolysis,
  • the “protecting group” of the “hydroxy group that may be protected” in the definition of R a is not particularly limited as long as it is a protecting group for a hydroxy group used in the field of synthetic organic chemistry.
  • Substituted ethyl groups such as 1-ethoxyethyl, alkoxyethyl groups such as 1- (isopropoxy) ethyl, and halogenated ethyl groups such as 2,2,2-trichloroethyl; benzyl , ⁇ -naphthylmethyl, alkyl groups substituted with 1 to 3 aryl groups such as ⁇ -naphthylmethyl, diphenylmethyl, triphenylmethyl, ⁇ -naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6 -Trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl
  • An “aralkyl group” such as an alkyl group substituted with (an
  • the “protecting group” of the “carboxy group that may be protected” in the definition of R a is not particularly limited as long as it is a protecting group for a carboxy group used in the field of synthetic organic chemistry.
  • An “alkynyl group” such as propynyl; the aforementioned “C 1 -C 6 halogenated alkyl group”; a hydroxyalkyl group such as hydroxymethyl, 2-hydroxyethyl; an alkylcarbonylalkyl group such as acetylmethyl; Group ”; or the above-mentioned“ silyl group ”, preferably a C 1 -C 6 alkyl group or an aralkyl group.
  • protecting group of the "protected or an amino group” in the definition of R a is not particularly limited as long as it is a protecting group for amino groups used in the field of organic synthetic chemistry, for example, the “Alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; “silyl group”; “aralkyl group”; “alkenyloxycarbonyl group”; or “aralkyloxycarbonyl group” N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) ) “Substituted methylene groups forming Schiff bases” such as phenylmethylene And preferably an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, and more
  • the compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms.
  • the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration).
  • These various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. as main ingredients in accordance with conventional methods. It can be formulated with the resulting adjuvant.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; disintegrators such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as starch
  • the tablet which gave the normal coating for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
  • excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.
  • a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.
  • solutions, emulsions or suspensions When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
  • the solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.
  • the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.
  • the amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.
  • the amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.
  • the solvent specified in each example was used at the specified ratio. (Or, the ratio was changed as necessary.)
  • the abbreviations used in the examples have the following significance. mg: milligram, g: gram, mL: milliliter, MHz: megahertz.
  • 1 H NMR nuclear magnetic resonance
  • MS Mass spectrometry
  • the reaction mixture was diluted with ethyl acetate, washed with water and concentrated.
  • the residue was purified by chromatography (automatic chromatography apparatus, dichloromethane / ethyl acetate 100: 0 ⁇ 85: 15) to obtain 1.59 g (92%) of the title compound as a yellow solid.
  • Example (1c) 198 mg (84%) of urea was obtained as a white solid from the compound (171 mg) obtained in Example (1b) and 4-methylphenyl isocyanate (0.082 mL). .
  • This urea compound (198 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 155 mg (81%) of the title compound as a white solid.
  • Example (1c) 130 mg (94%) of urea was obtained as a white solid from the compound (102 mg) obtained in Example (1b) and phenyl isocyanate (0.042 mL). This urea compound (85 mg) was hydrolyzed in the same way as in Example (1d) to obtain 58 mg (71%) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 89 mg (94%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 3-fluorophenyl isocyanate (0.029 mL). .
  • This urea compound (89 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 66 mg (76%) of the title compound as a white solid.
  • Example (1c) 85 mg (90%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 4-fluorophenyl isocyanate (0.029 mL). .
  • This urea compound (85 mg) was hydrolyzed in the same way as in Example (1d) to obtain 58 mg (71%) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 83 mg (88%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 2-methylphenyl isocyanate (0.032 mL). .
  • This urea compound (83 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 63 mg (78%) of the title compound as a white solid.
  • Example (1c) 90 mg (95%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 3-methylphenyl isocyanate (0.032 mL). .
  • This urea compound (90 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 77 mg (88%) of the title compound as a white solid.
  • Example (1c) 51 mg (52%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 2-methoxyphenyl isocyanate (0.035 mL). .
  • This urea compound (51 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 48 mg (quantitative yield) of the title compound as a yellow solid.
  • Example (1c) 91 mg (93%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 3-methoxyphenyl isocyanate (0.034 mL). .
  • This urea compound (91 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 40 mg (45%) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 86 mg (88%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 4-methoxyphenyl isocyanate (0.034 mL). .
  • This urea compound (86 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 68 mg (82%) of the title compound as a white solid.
  • urea compound 250 mg, 97%) was obtained from Compound (171 mg) obtained in Example (1b) and 2,4,5-trifluorophenyl isocyanate (0.079 mL). Obtained as a white solid.
  • This urea compound (250 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 241 mg (99%) of the title compound as a white solid.
  • Example (1c) 504 mg of urea compound (quantitative yield) was obtained from the compound (341 mg) obtained in Example (1b) and 2-methoxy-5-methylphenyl isocyanate (424 mL). Obtained as a white solid.
  • This urea compound (504 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 489 mg (quantitative yield) of the title compound as a white solid.
  • Example (13b) (cis-4- ⁇ [5- (4-Aminophenyl) pyrazin-2-yl] oxy ⁇ cyclohexyl) acetic acid methyl ester obtained in Example (13a) in a manner similar to Example (1b) From the compound (633 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (421 mg), the title compound 324 mg (49%) was pale brown Obtained as a solid.
  • Example (14b) (cis-4- ⁇ [5- (4-Aminophenyl) pyridin-2-yl] oxy ⁇ cyclohexyl) acetic acid methyl ester obtained in Example (14a) in the same manner as in Example (1b) From the compound (2.76 g) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.84 g), 2.37 g (83%) of the title compound was pale yellow Obtained as a solid.
  • Example (1c) In the same manner as in Example (1c), 571 mg (99%) of a urea compound was obtained as a white solid from the compound (413 mg) obtained in Example (14b) and 4-methylphenyl isocyanate (0.20 mL). .
  • This urea compound (571 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 538 mg (97%) of the title compound as a pale yellow solid.
  • Example (1c) In the same manner as in Example (1c), 460 mg (89%) of a urea compound was obtained as a brown solid from the compound (383 mg) obtained in Example (14b) and phenyl isocyanate (0.179 mL). This urea compound (460 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 419 mg (94%) of the title compound as a yellow solid.
  • urea compound (206 mg, 84%) was obtained as a pale yellow solid from the compound (170 mg) obtained in Example (14b) and 2,4-dimethylphenyl isocyanate (0.092 mL). Got as.
  • This urea compound (206 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 190 mg (96%) of the title compound as a white solid.
  • Example (18b) (cis-4- ⁇ [5- (4- ⁇ [(2-Chloro-4-fluorophenyl) carbamoyl] amino ⁇ phenyl) pyridin-2-yl] oxy ⁇ cyclohexyl) acetic acid
  • Example (18a) The obtained compound (193 mg) was hydrolyzed in the same way as in Example (1d) to obtain 141 mg (75%) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 66 mg (72%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (19b) and phenyl isocyanate (0.028 mL). This urea compound (66 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 61 mg (95%) of the title compound as a white solid.
  • Example (1c) 68 mg (71%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (19b) and 4-methylphenyl isocyanate (0.033 mL). .
  • This urea compound (68 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 58 mg (89%) of the title compound as an off-white solid.
  • urea compound 222 mg (90%) was converted into white solid from compound (171 mg) obtained in Example (1b) and 2-fluoro-3-methylaniline (63 mg). Obtained.
  • This urea compound (222 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 206 mg (95%) of the title compound as a white solid.
  • urea compound (207 mg, 84%) was obtained as a white solid from the compound (171 mg) obtained in Example (1b) and 2-fluoro-4-methylaniline (63 mg). Obtained.
  • This urea compound (207 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 191 mg (95%) of the title compound as a white solid.
  • Example (1c) 146 mg of urea compound (quantitative yield) was obtained as a white solid from the compound (102 mg) obtained in Example (1b) and 2,4-dimethylphenyl isocyanate (0.11 mL). Got as.
  • This urea compound (146 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 115 mg (81%) of the title compound as a white solid.
  • Example (25b) (trans-4- ⁇ [5- (4-aminophenyl) pyridin-2-yl] oxy ⁇ cyclohexyl) acetic acid methyl ester obtained in Example (25a) in a manner similar to Example (1b) From the compound (1.47 g) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (980 mg), the title compound 897 mg (59%) was obtained as a brown solid Got as.
  • Example (1c) In the same manner as in Example (1c), 244 mg of urea compound (quantitative yield) was off-white from the compound (170 mg) obtained in Example (25b) and 2,4-dimethylphenyl isocyanate (0.092 mL). Obtained as a colored solid.
  • This urea compound (244 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 224 mg (95%) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 233 mg of urea compound (quantitative yield) was obtained as a white solid from the compound (164 mg) obtained in Example (27b) and 2-fluorophenyl isocyanate (0.073 mL). It was. This urea compound (233 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 226 mg (quantitative yield) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 231 mg (99%) of a urea compound was obtained as a white solid from the compound (164 mg) obtained in Example (29b) and 2-fluorophenyl isocyanate (0.073 mL). .
  • This urea compound (231 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 212 mg (95%) of the title compound as a white solid.
  • urea compound 203 mg (88%) was obtained as a white solid from the compound (253 mg) obtained in Example (31a) and 4-aminopyridine (47 mg). .
  • This urea compound (203 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 194 mg (99%) of the title compound as a white solid.
  • Example (31b) In the same manner as in the first half of Example (31b), 198 mg (86%) of urea was obtained as a white solid from the compound (253 mg) obtained in Example (31a) and 2-aminopyridine (47 mg). .
  • This urea compound (198 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 182 mg (95%) of the title compound as a pale yellow solid.
  • Example (34c) trans-4-[(5- ⁇ 4-[(anilinocarbonyl) amino] phenyl ⁇ pyrimidin-2-yl) oxy] cyclohexanecarboxylic acid
  • Example (34b) The urea compound 134 mg (98%) was obtained as a light brown solid from the compound (100 mg) obtained in (1) and phenyl isocyanate (0.046 mL). This urea compound (129 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 117 mg (94%) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 144 mg of urea (quantitative yield) was obtained as a light brown solid from the compound (100 mg) obtained in Example (34b) and 2-fluorophenyl isocyanate (0.048 mL). Obtained. This urea compound (138 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 121 mg (91%) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 135 mg (96%) of urea was obtained as a white solid from the compound (100 mg) obtained in Example (34b) and 4-methylphenyl isocyanate (0.054 mL). .
  • This urea compound (128 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 122 mg (98%) of the title compound as a white solid.
  • urea compound 220 mg (94%) was obtained as a white solid from the compound (253 mg) obtained in Example (31a) and aminocyclohexane (50 mg).
  • This urea compound (219 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 204 mg (96%) of the title compound as a white solid.
  • Example (1c) In the same manner as in Example (1c), 1.33 g (93%) of the urea compound as a white solid was obtained from the compound (980 mg) obtained in Example (29b) and 2,4-dimethylphenyl isocyanate (0.44 mL). Obtained. This urea compound (1.32 g) was hydrolyzed in the same manner as in Example (1d) to obtain 305 mg (24%) of the title compound as a white solid.
  • Example (1c) 860 mg (55%) of the urea compound was pale orange from the compound (1.07 g) obtained in Example (27b) and 2,4-dimethylphenyl isocyanate (0.48 mL). Obtained as a solid.
  • This urea compound (860 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 290 mg (35%) of the title compound as a white solid.
  • reaction stop solution 70 ⁇ l
  • isopropanol / 1-heptane / water 80: 20: 2, v / v / v
  • water 30 ⁇ l
  • 1-heptane 100 ⁇ l
  • a 1-heptane layer 50 ⁇ l was spotted on a TLC plate and developed with a developing solvent consisting of 1-hexane / diethyl ether / acetic acid (85: 15: 1, v / v / v).
  • the radioactivity of the triglyceride fraction was quantified with a BAS2000 bioimage analyzer (Fuji Film), and the inhibitory activity of the test compound was calculated by the following formula by comparing with the control. The unreacted (0 minute incubation) radioactivity was used as the background.
  • Inhibition rate 100 ⁇ [(radioactivity at the time of addition of test compound) ⁇ (background)] / [(radioactivity of control) ⁇ (background)] ⁇ 100
  • the compound of Example 1-42 showed an inhibition rate of 50% or more at a test compound concentration of 1 ⁇ g / ml.
  • the DGAT inhibitory activity test is not limited to the above method.
  • microsomes prepared from the small intestine, adipose tissue, or liver of animals such as rats and mice may be used as the DGAT enzyme.
  • microsomes prepared from cultured cells (3T3-L1 adipocytes, primary cultured adipocytes, Caco2 cells, HepG2 cells, etc.) or cultured cells highly expressing DGAT can also be used as the DGAT enzyme.
  • a flash plate PerkinElmer in which the extraction operation is omitted can be used.
  • the compound of the present invention has excellent DGAT1 inhibitory biological activity.
  • the DGAT1 enzyme is important for digestion and absorption of neutral fat, and when small intestine DGAT1 is inhibited, the absorption of neutral fat is suppressed.
  • the biological activity of the DGAT1 inhibitory action was evaluated using as an index the inhibition of neutral fat absorption after neutral fat loading.
  • Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) fasted overnight were assigned to Vehicle Group 1, Vehicle Group 2 and each test compound group, respectively vehicle (0.5% Methylcellulose) Alternatively, each test compound (1 to 10 mg / kg) suspended in the vehicle was orally administered (5 mL / kg).
  • Lipoprotein lipase inhibitor (Pluronic-F127: Sigma-Aldrich Co., Ltd., 1 g / kg, dissolved in physiological saline at 20% by weight) was intraperitoneally administered (5 mL / kg) Distilled water was orally administered to Vehicle Group 1 and 20% neutral fat-containing emulsion (Intralipid 20%: Terumo Corporation) was orally administered (0.2 mL / mouse) to Vehicle Group 2 and Compound Group.
  • Neutral fat absorption inhibitory activity (%) 100-[(Neutral fat concentration of each test compound group)-(Neutral fat concentration of Vehicle group 1)] / [(Neutral fat concentration of Vehicle group 2)-( Vehicle group 1 neutral fat concentration)] ⁇ 100
  • the compounds of Examples 1-30 and 34-42 showed neutral fat absorption inhibitory activity of 60% or more at a dose of 3 mg / kg or less.
  • the compound of the present invention has excellent neutral fat absorption inhibitory activity.
  • mice Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) are bred individually and fed with a high fat diet (fat content 45 kcal%: Research Diet D12451) for over a week. I got used to it. Allocate the animals evenly to the experimental groups based on the amount of food consumed during the period, fast overnight and then each vehicle (0.5% Methylcellulose) or test compound (1-10 mg / kg) suspended in the vehicle. The group was orally administered (10 mL / kg). A high fat diet was fed 30 minutes after the administration, and the amount of food intake was measured 6 hours after the start of feeding. The feeding inhibitory activity of each test compound was calculated based on the following formula.
  • Feeding inhibitory activity (%) [(food consumption of vehicle group) ⁇ (food consumption of each test compound group)] / [(food consumption of vehicle group)] ⁇ 100
  • the compound of Example 1-2 exhibited an antifeedant activity of 25% or more at a dose of 10 mg / kg or less.
  • the compound of the present invention has an excellent antifeedant action.
  • the high-fat diet used for the feed is not limited to the above-mentioned high-fat diet, and for example, a rodent feed containing 45 to 60% neutral fat as calories can be used.
  • Formulation Example 1 Capsule 50 mg of the compound of Example 1 or 2 Lactose 128mg Corn starch 70mg Magnesium stearate 2mg -------------- 250mg After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.
  • Formulation Example 2 Tablet Example 1 or 2 compound 50 mg Lactose 126mg Corn starch 23mg Magnesium stearate 1mg -------------- 200mg
  • the powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action and antifeeding action and is useful as a medicine.

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Abstract

The present invention relates to a compound having an excellent DGAT inhibitory activity and an anti-feeding activity or a pharmacologically acceptable salt thereof. A compound represented by general formula (I) [wherein R represents a phenyl group which may be substituted by 1-5 groups independently selected from substituent group (A), or the like; Q represents a nitrogen atom, or a group represented by the formula -CH=; U represents a nitrogen atom, or a group represented by the formula -CH=; V represents a nitrogen atom, or a group represented by the formula -CH=; m represents 0 or 1; and n represents 0 or 1; wherein the substituent group (A) consists of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group and so on], or a pharmacologically acceptable salt thereof.

Description

シクロアルキルオキシビアリール型化合物Cycloalkyloxybiaryl type compounds
　本発明は、優れたアシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼ（Acyl-CoA:diacylglycerol acyltransferase、以下、ＤＧＡＴともいう）阻害作用及び優れた摂食抑制作用を有する特定の化学構造を有する化合物又はその薬理上許容される塩に関する。 The present invention relates to a compound having a specific chemical structure having an excellent acylcoenzyme A: diacylglycerol acyltransferase (hereinafter also referred to as DGAT) inhibitory activity and an excellent feeding inhibitory activity, Relates to acceptable salts.
　肥満は、消費エネルギーに比較して摂取エネルギーが過剰な状態が持続することにより、脂肪細胞において中性脂肪（トリアシルグリセロールまたはトリグリセライド、以下、ＴＧともいう）が蓄積し、その結果として体重が標準体重に比較して著しく増加した状態である（非特許文献１）。肥満は、高脂血症、高ＴＧ血症、糖尿病、高血圧症、動脈硬化症などの生活習慣病、脳血管障害、冠動脈疾患、呼吸異常、腰痛、変形性膝関節症、痛風、胆石症などをもたらし、肥満のうちこれらの合併症を有するもの、あるいは将来これらの合併症を生じる可能性があるものは、肥満症と定義され、一つの疾患として扱われている。 In obesity, triglyceride (triacylglycerol or triglyceride, hereinafter also referred to as TG) accumulates in adipocytes due to the persistence of excess energy compared to energy consumption, resulting in standard weight gain. It is in a state of significantly increasing compared to body weight (Non-Patent Document 1). Obesity is hyperlipidemia, hyperTGemia, diabetes, hypertension, lifestyle-related diseases such as arteriosclerosis, cerebrovascular disorder, coronary artery disease, respiratory abnormalities, low back pain, knee osteoarthritis, gout, cholelithiasis, etc. Any obesity that has these complications or that may cause these complications in the future is defined as obesity and is treated as a disease.
　動物および植物は、脂質を不溶性のＴＧとして蓄え、必要に応じて、ＴＧを分解してエネルギーを産生する。食事により摂取されたＴＧは、小腸内腔で胆汁酸および膵リパーゼの作用により、遊離脂肪酸およびモノアシルグリセロールに分解される。遊離脂肪酸、モノアシルグリセロールおよび胆汁酸からなるミセルは、小腸上皮細胞に吸収され、小胞体でアシルコエンザイムＡ合成酵素（以下、ＡＣＳという）、アシルコエンザイムＡ：モノアシルグリセロールアシルトランスフェラーゼおよびＤＧＡＴの作用により、新たにＴＧが合成される。ＴＧは、リン脂質、コレステロールおよびアポリポタンパクと組み合わされて、キロミクロンとして胃腸のリンパ管に分泌される。さらに、ＴＧは、リンパ主管を経て血中に分泌され、末梢に運ばれて利用される。一方、脂肪組織においても、グリセロール３－リン酸および遊離脂肪酸からＡＣＳ、グリセロール３－リン酸アシルトランスフェラーゼ、リゾホスファチジン酸アシルトランスフェラーゼおよびＤＧＡＴの作用により、ＴＧが合成される（非特許文献２）。このように過剰に摂取されたＴＧは、脂肪組織に蓄積され、その結果として肥満が生じる。 Animals and plants store lipid as insoluble TG, and decompose TG as necessary to produce energy. TG ingested by the meal is broken down into free fatty acids and monoacylglycerol by the action of bile acids and pancreatic lipase in the lumen of the small intestine. Micelles composed of free fatty acid, monoacylglycerol and bile acid are absorbed into small intestinal epithelial cells, and in the endoplasmic reticulum by the action of acylcoenzyme A synthase (hereinafter referred to as ACS), acylcoenzyme A: monoacylglycerol acyltransferase and DGAT. TG is newly synthesized. TG, in combination with phospholipids, cholesterol and apolipoprotein, is secreted into the gastrointestinal lymphatic vessels as kilomicrons. Furthermore, TG is secreted into the blood via the lymph main duct and transported to the periphery for use. On the other hand, in adipose tissue, TG is synthesized from glycerol 3-phosphate and free fatty acids by the action of ACS, glycerol 3-phosphate acyltransferase, lysophosphatidic acid acyltransferase, and DGAT (Non-patent Document 2). Thus, TG ingested excessively accumulates in adipose tissue, resulting in obesity.
　ＤＧＡＴは、細胞内の小胞体に存在する酵素であり、ＴＧ合成経路の最も重要な最終ステップの反応、すなわちアシルコエンザイムＡのアシル基を１，２－ジアシルグリセロールの３位へ転移する反応を触媒する酵素である（非特許文献３乃至５）。ＤＧＡＴには、２種類のアイソザイムＤＧＡＴ１（非特許文献６）およびＤＧＡＴ２（非特許文献７）が存在することが報告されている。ＤＧＡＴ１は小腸および脂肪組織に、ＤＧＡＴ２は肝臓および脂肪組織にそれぞれ高発現していることから、ＤＧＡＴ１は主として小腸からの脂肪吸収および脂肪組織での脂肪蓄積に、ＤＧＡＴ２は肝臓でのＴＧ合成もしくはＶＬＤＬ（very low density lipoproteins）分泌、および脂肪組織での脂肪蓄積に関与していると考えられている。ＤＧＡＴ１およびＤＧＡＴ２の役割の違いはまだ詳細には明らかにされていないが、ＤＧＡＴと肥満、脂質代謝、糖代謝などとの関連性が示唆されている（非特許文献８）。ＤＧＡＴは、消化管上皮細胞および脂肪組織におけるＴＧ合成の鍵酵素であり、ＤＧＡＴを阻害する薬剤は、ＴＧ合成を抑制することにより、消化管における脂肪吸収および脂肪組織における脂肪蓄積を抑制し、肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、糖尿病、非アルコール性脂肪肝炎、または、肥満に起因する高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、糖尿病、非アルコール性脂肪肝炎、高血圧症、動脈硬化症、脳血管障害、もしくは、冠動脈疾患などの治療剤もしくは予防剤として有用であると期待される（非特許文献９乃至１３）。 DGAT is an enzyme that is present in the endoplasmic reticulum in the cell and catalyzes the most important final step reaction in the TG synthesis pathway, that is, the reaction of transferring the acyl group of acylcoenzyme A to the 3-position of 1,2-diacylglycerol. (Non-Patent Documents 3 to 5). It has been reported that DGAT has two types of isozymes DGAT1 (Non-patent document 6) and DGAT2 (Non-patent document 7). Since DGAT1 is highly expressed in the small intestine and adipose tissue, and DGAT2 is highly expressed in the liver and adipose tissue, respectively, DGAT1 is mainly used for fat absorption from the small intestine and fat accumulation, and DGAT2 is used for TG synthesis or VLDL in the liver. (Very low density lipoproteins) secretion and fat accumulation in adipose tissue. Although the difference in the roles of DGAT1 and DGAT2 has not yet been clarified in detail, the relationship between DGAT and obesity, lipid metabolism, sugar metabolism, etc. has been suggested (Non-patent Document 8). DGAT is a key enzyme for TG synthesis in gastrointestinal epithelial cells and adipose tissue, and a drug that inhibits DGAT suppresses fat absorption in the gastrointestinal tract and fat accumulation in adipose tissue by suppressing TG synthesis, and obesity , Obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, diabetes, non-alcoholic steatohepatitis, or obesity-induced hyperlipidemia, hypertriglyceridemia, lipid metabolism It is expected to be useful as a therapeutic or prophylactic agent for abnormal diseases, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis, hypertension, arteriosclerosis, cerebrovascular disorder, coronary artery disease, etc. 9 to 13).
　食欲抑制薬は、直接あるいは間接的に食欲制御系を調節するものであるが、その作用メカニズムは中枢性と末梢性に大別される。中枢性に作用する食欲抑制薬は摂食中枢及び満腹中枢の存在する視床下部神経系や同神経系を調節する脳内モノアミン神経系に作用して食欲を直接的に抑制する。一方、末梢性に作用する食欲抑制薬は食事による栄養摂取や余剰エネルギーの蓄積状態を、感知し伝達する機構に作用して間接的に食欲を抑制する。 An appetite suppressant directly or indirectly regulates the appetite control system, but its mechanism of action is roughly divided into central and peripheral. An appetite suppressant acting centrally acts on the hypothalamic nervous system where the feeding center and satiety center exist and the monoamine nervous system in the brain that regulates the nervous system, thereby directly suppressing appetite. On the other hand, an appetite suppressant that acts on the periphery acts on a mechanism that senses and transmits the intake of nutrients and the accumulation of surplus energy, and indirectly suppresses appetite.
　近年、食物の消化・吸収と密接に関連して分泌される消化管ホルモン（ＣＣＫ、ＧＬＰ－１、ＰＹＹなど）(非特許文献１４)や、エネルギー蓄積量（脂肪量）に応じて脂肪細胞から分泌されるレプチン(非特許文献１５)などが、ホルモン性あるいは神経性に末梢から中枢へ食欲を調節するシグナルを伝えるメカニズムが明らかになってきている。これら末梢性シグナルに関連する新しい食欲抑制薬はより効果的で副作用の少ない肥満症治療薬になることが期待されている。 In recent years, gastrointestinal hormones (CCK, GLP-1, PYY, etc.) secreted in close association with the digestion and absorption of food (Non-Patent Document 14) and from fat cells according to the energy accumulation (fat mass) The mechanism by which secreted leptin (Non-patent Document 15) or the like transmits a signal that regulates appetite from the periphery to the center in a hormonal or neurological manner has been clarified. These new appetite suppressants associated with peripheral signals are expected to be more effective and less effective for the treatment of obesity.
　ＤＧＡＴ阻害作用を有する化合物として、特許文献１には、［５－（４－｛［（置換フェニル）カルバモイル］アミノ｝フェニル）ピリミジン－２－イル］オキシ基とカルボン酸がアルキレン基で結合している化合物、［５－（４－｛［（置換フェニル）カルバモイル］アミノ｝フェニル）ピリミジン－２－イル］オキシ基とシクロペンタンカルボン酸がアルキレン基で結合している化合物が記載されている。特許文献２には、（２，３’－ビピリジン－６’－イルオキシ）シクロヘキサンカルボン酸を有する化合物が記載されている。また、非特許文献１６には、４’－［（置換アニリノカルボニル）アミノ］ビフェニル－４－イル基とシクロペンタンカルボン酸がカルボニル基で結合している化合物が記載されている。 As a compound having a DGAT inhibitory action, Patent Document 1 discloses that a [5- (4-{[(substituted phenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy group and a carboxylic acid are bonded via an alkylene group. And a compound in which an [5- (4-{[(substituted phenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy group and a cyclopentanecarboxylic acid are bonded via an alkylene group. Patent Document 2 describes a compound having (2,3′-bipyridin-6′-yloxy) cyclohexanecarboxylic acid. Non-Patent Document 16 describes a compound in which a 4 '-[(substituted anilinocarbonyl) amino] biphenyl-4-yl group and a cyclopentanecarboxylic acid are bonded via a carbonyl group.
ＷＯ２００９／０１１２８５号公報WO2009 / 011285 ＷＯ２０１１／０３１６２８号公報WO2011 / 031628
　発明者らは、ＤＧＡＴ阻害作用及び摂食抑制作用を有する化合物について鋭意研究を行った結果、特定の化学構造を有する化合物が、優れたＤＧＡＴ阻害作用を有しており、特にＤＧＡＴ１に対して高い阻害作用を有することを見出した。また、本発明者らは、この化合物が、優れた摂食抑制作用を有していることを見出した。更に、本発明者らは、この化合物が、肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患及び過食症からなる群から選ばれる疾患の予防及び／又は治療のための医薬の有効成分として、又は肥満に起因する高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、高血圧症、脳血管障害、冠動脈疾患、脂肪肝、呼吸異常、腰痛、変形性膝関節症、痛風、及び胆石症からなる群から選ばれる疾患の治療及び／又は予防のための医薬の有効成分として有用であることを見出した。 As a result of intensive studies on compounds having a DGAT inhibitory action and an antifeedant action, the inventors have found that a compound having a specific chemical structure has an excellent DGAT inhibitory action, particularly high for DGAT1. It was found to have an inhibitory effect. The present inventors have also found that this compound has an excellent antifeeding action. Furthermore, the present inventors have found that this compound is obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral Neuropathy, including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic Hyperlipidemia, hypertriglyceridemia, lipid metabolism resulting from obesity or as an active ingredient of a medicament for the prevention and / or treatment of a disease selected from the group consisting of arteriosclerosis, ischemic heart disease and bulimia Abnormal diseases, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, Gynecologic diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformity It was found useful as an active ingredient of a medicament for the treatment and / or prevention of a disease selected from the group consisting of knee arthropathy, gout, and cholelithiasis.
　本発明は、（１）一般式（Ｉ） The present invention comprises (1) general formula (I)
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
［式中、
Ｒは、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基、置換基群Ａから選択される基で独立に１乃至３個置換されていてもよいピリジル基又はＣ３－Ｃ６シクロアルキル基を示し、
Ｑは、窒素原子又は式－ＣＨ＝で表わされる基を示し、
Ｕは、窒素原子又は式－ＣＨ＝で表わされる基を示し、
Ｖは、窒素原子又は式－ＣＨ＝で表わされる基を示し、
ｍは、０又は１を示し、
ｎは、０又は１を示し、
置換基群Ａは、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロゲン化アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６ハロゲン化アルコキシ基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、Ｃ１－Ｃ６アルキルチオ基、Ｃ１－Ｃ６アルキルスルフィニル基、カルボキシ基、Ｃ２－Ｃ７アルキルカルボニル基、Ｃ２－Ｃ７アルコキシカルボニル基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、モノ－Ｃ２－Ｃ７アルキルカルボニルアミノ基、モノ－Ｃ１－Ｃ６アルキルスルホニルアミノ基、シアノ基、ニトロ基及びヒドロキシ基からなる群を示す。］で表される化合物又はその薬理上許容される塩に関する。 [Where:
R is a phenyl group which may be independently substituted with a group selected from the substituent group A, and may be independently substituted with 1 to 3 groups independently selected from a group selected from the substituent group A; A pyridyl group or a C 3 -C 6 cycloalkyl group,
Q represents a nitrogen atom or a group represented by the formula —CH═,
U represents a nitrogen atom or a group represented by the formula —CH═,
V represents a nitrogen atom or a group represented by the formula —CH═,
m represents 0 or 1,
n represents 0 or 1,
Substituent group A includes a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 halogenated alkoxy group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfinyl group, carboxy group, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group Group, amino group, mono-C 1 -C 6 alkylamino group, di- (C 1 -C 6 alkyl) amino group, mono-C 2 -C 7 alkylcarbonylamino group, mono-C 1 -C 6 alkylsulfonyl A group consisting of an amino group, a cyano group, a nitro group and a hydroxy group is shown. Or a pharmacologically acceptable salt thereof.
　本発明において、好適には、
　（２）　（１）において、
　一般式（Ｉ）が、一般式（Ｉａ）、一般式（Ｉｂ）、一般式（Ｉｃ）、一般式（Ｉｄ）、一般式（Ｉｅ）又は一般式（Ｉｆ）である化合物又はその薬理上許容される塩。 In the present invention, preferably,
(2) In (1),
A compound in which the general formula (I) is the general formula (Ia), the general formula (Ib), the general formula (Ic), the general formula (Id), the general formula (Ie) or the general formula (If) or a pharmacologically acceptable salt thereof Salt.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　（３）　（１）において、
　一般式（Ｉ）が、一般式（Ｉａ）である化合物又はその薬理上許容される塩。 (3) In (1),
The compound or its pharmacologically acceptable salt whose general formula (I) is general formula (Ia).
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　（４）　（１）乃至（３）から選択されるいずれか一項において、
　Ｒが、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基である化合物又はその薬理上許容される塩。 (4) In any one item selected from (1) to (3),
A compound or a pharmacologically acceptable salt thereof, wherein R is a phenyl group which may be independently substituted with 1 to 5 groups selected from substituent group A.
　（５）　（１）乃至（３）から選択されるいずれか一項において、
　Ｒが、（フッ素原子、塩素原子、メチル基及びメトキシ基）から選択される基で独立に１乃至３個置換されていてもよいフェニル基である化合物又はその薬理上許容される塩。 (5) In any one item selected from (1) to (3),
A compound or a pharmacologically acceptable salt thereof, wherein R is a phenyl group optionally independently substituted by 1 to 3 groups selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group).
　（６）　（１）乃至（３）から選択されるいずれか一項において、
　Ｒが、フェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－メチルフェニル基、３－メチルフェニル基、４－メチルフェニル基、２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基、２－クロロ－４－フルオロフェニル基、２－フルオロ－３－メチルフェニル基、２－フルオロ－４－メチルフェニル基、２，４－ジメチルフェニル基、２－メトキシ－５－メチルフェニル基又は２，４，５－トリフルオロフェニル基である化合物又はその薬理上許容される塩。 (6) In any one item selected from (1) to (3),
R is a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3- Methoxyphenyl group, 4-methoxyphenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-3-methylphenyl group, 2-fluoro-4-methylphenyl group, 2,4-dimethylphenyl group, 2- A compound having a methoxy-5-methylphenyl group or a 2,4,5-trifluorophenyl group, or a pharmacologically acceptable salt thereof.
　（７）　（１）において、
　一般式（Ｉ）が、一般式（Ｉａ）、一般式（Ｉｂ）、一般式（Ｉｃ）、一般式（Ｉｄ）、一般式（Ｉｅ）又は一般式（Ｉｆ）であり、Ｒが、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基である化合物又はその薬理上許容される塩。 (7) In (1),
General Formula (I) is General Formula (Ia), General Formula (Ib), General Formula (Ic), General Formula (Id), General Formula (Ie), or General Formula (If), and R is a substituent. A compound or a pharmacologically acceptable salt thereof which is a phenyl group which may be independently substituted with 1 to 5 groups selected from Group A.
　（８）　（１）において、
　一般式（Ｉ）が、一般式（Ｉａ）、一般式（Ｉｂ）、一般式（Ｉｃ）、一般式（Ｉｄ）、一般式（Ｉｅ）又は一般式（Ｉｆ）であり、Ｒが、（フッ素原子、塩素原子、メチル基及びメトキシ基）から選択される基で独立に１乃至３個置換されていてもよいフェニル基である化合物又はその薬理上許容される塩。 (8) In (1),
General Formula (I) is General Formula (Ia), General Formula (Ib), General Formula (Ic), General Formula (Id), General Formula (Ie), or General Formula (If), and R is (fluorine A compound or a pharmacologically acceptable salt thereof which is a phenyl group which may be independently substituted with 1 to 3 groups independently selected from a group selected from an atom, a chlorine atom, a methyl group and a methoxy group.
　（９）　（１）において、
　一般式（Ｉ）が、一般式（Ｉａ）、一般式（Ｉｂ）、一般式（Ｉｃ）、一般式（Ｉｄ）、一般式（Ｉｅ）又は一般式（Ｉｆ）であり、Ｒが、フェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－メチルフェニル基、３－メチルフェニル基、４－メチルフェニル基、２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基、２－クロロ－４－フルオロフェニル基、２－フルオロ－３－メチルフェニル基、２－フルオロ－４－メチルフェニル基、２，４－ジメチルフェニル基、２－メトキシ－５－メチルフェニル基又は２，４，５－トリフルオロフェニル基である化合物又はその薬理上許容される塩。 (9) In (1),
General Formula (I) is General Formula (Ia), General Formula (Ib), General Formula (Ic), General Formula (Id), General Formula (Ie), or General Formula (If), and R is a phenyl group 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4 -Methoxyphenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-3-methylphenyl group, 2-fluoro-4-methylphenyl group, 2,4-dimethylphenyl group, 2-methoxy-5-methyl A compound which is a phenyl group or a 2,4,5-trifluorophenyl group or a pharmacologically acceptable salt thereof.
　（１０）　（１）において、
　一般式（Ｉ）が、一般式（Ｉａ）であり、Ｒが、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基である化合物又はその薬理上許容される塩。 (10) In (1),
A compound in which the general formula (I) is the general formula (Ia), and R is a phenyl group which may be independently substituted with a group selected from the substituent group A or a pharmacologically acceptable compound thereof Salt.
　（１１）　（１）において、
　一般式（Ｉ）が、一般式（Ｉａ）であり、Ｒが、（フッ素原子、塩素原子、メチル基及びメトキシ基）から選択される基で独立に１乃至３個置換されていてもよいフェニル基である化合物又はその薬理上許容される塩。 (11) In (1),
The general formula (I) is the general formula (Ia), and R is a phenyl optionally substituted with 1 to 3 groups independently selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group) Or a pharmacologically acceptable salt thereof.
　（１２）　（１）において、
　一般式（Ｉ）が、一般式（Ｉａ）であり、Ｒが、フェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－メチルフェニル基、３－メチルフェニル基、４－メチルフェニル基、２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基、２－クロロ－４－フルオロフェニル基、２－フルオロ－３－メチルフェニル基、２－フルオロ－４－メチルフェニル基、２，４－ジメチルフェニル基、２－メトキシ－５－メチルフェニル基又は２，４，５－トリフルオロフェニル基である化合物又はその薬理上許容される塩。 (12) In (1),
The general formula (I) is the general formula (Ia), and R is a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group. 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-3-methylphenyl group, 2-fluoro-4 A compound which is a methylphenyl group, 2,4-dimethylphenyl group, 2-methoxy-5-methylphenyl group or 2,4,5-trifluorophenyl group, or a pharmacologically acceptable salt thereof.
　（１３）　(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
{cis-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸、
(cis-4-{[5-(4-{[(3-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(4-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(3-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(3-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(4-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2,4,5-トリフルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-メトキシ-5-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸、
{cis-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリジン-2-イル)オキシ]シクロヘキシル}酢酸、
(cis-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-クロロ-4-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸、
(trans-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
{trans-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸、
(trans-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-フルオロ-3-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-フルオロ-4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
{trans-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリジン-2-イル)オキシ]シクロヘキシル}酢酸、
(trans-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸、
{trans-3-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロペンチル}酢酸、
[trans-3-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロペンチル]酢酸、
{cis-3-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロペンチル}酢酸、又は、
[cis-3-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロペンチル]酢酸
である化合物又はその薬理上許容される塩。 (13) (cis-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(4-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
{cis-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid,
(cis-4-{[5- (4-{[(3-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(4-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(3-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(3-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(4-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2,4,5-trifluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(4-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid,
{cis-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyridin-2-yl) oxy] cyclohexyl} acetic acid,
(cis-4-{[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid,
(trans-4-{[5- (4-{[(2-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
{trans-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid,
(trans-4-{[5- (4-{[(4-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-fluoro-3-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-fluoro-4-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
{trans-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyridin-2-yl) oxy] cyclohexyl} acetic acid,
(trans-4-{[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid,
{trans-3-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclopentyl} acetic acid,
[trans-3-{[5- (4-{[(2-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclopentyl] acetic acid,
{cis-3-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclopentyl} acetic acid, or
[cis-3-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclopentyl] acetic acid or a pharmacologically acceptable salt thereof.
　（１４）　（１３）に記載してある化合物又はその薬理上許容される塩のうちの化合物。 (14) A compound described in (13) or a pharmacologically acceptable salt thereof.
　（１５）　(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
{cis-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸、
(cis-4-{[5-(4-{[(3-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(4-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(3-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(3-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(4-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2,4,5-トリフルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-メトキシ-5-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-フルオロ-3-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
(cis-4-{[5-(4-{[(2-フルオロ-4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、又は、
(cis-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸
である化合物又はその薬理上許容される塩。 (15) (cis-4-{[5- (4-{[(2-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(4-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
{cis-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid,
(cis-4-{[5- (4-{[(3-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(4-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(3-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(3-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(4-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2,4,5-trifluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-fluoro-3-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(2-fluoro-4-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid, or
(cis-4-{[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid or a pharmacologically acceptable salt thereof .
　（１６）　（１５）に記載してある化合物又はその薬理上許容される塩のうちの化合物。 (16) A compound described in (15) or a pharmacologically acceptable salt thereof.
　（１７）　（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有するアシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼ阻害剤。 (17) An acyl coenzyme A: diacylglycerol acyltransferase inhibitor comprising as an active ingredient the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof.
　（１８）　（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有する摂食抑制剤及び／又は食欲抑制剤。 (18) An eating inhibitor and / or an appetite suppressant containing as an active ingredient the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof.
　（１９）　（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 (19) A pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof.
　（２０）　医薬組成物が、アシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼ阻害作用を有する（１９）に記載の医薬組成物。 (20) The pharmaceutical composition according to (19), wherein the pharmaceutical composition has an inhibitory action on acylcoenzyme A: diacylglycerol acyltransferase.
　（２１）　医薬組成物が、摂食抑制作用及び／又は食欲抑制作用を有する（１９）に記載の医薬組成物。 (21) The pharmaceutical composition according to (19), wherein the pharmaceutical composition has an antifeedant action and / or an appetite suppressive action.
　（２２）　医薬組成物が、アシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼ阻害作用により、治療及び／又は予防される疾病の治療及び／又は予防のための（１９）に記載の医薬組成物。 (22) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is used for treatment and / or prevention of a disease that is treated and / or prevented by acylcoenzyme A: diacylglycerol acyltransferase inhibitory action.
　（２３）　医薬組成物が、アシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼ活性の亢進に起因する疾病の治療及び／又は予防のための（１９）に記載の医薬組成物。 (23) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is for the treatment and / or prevention of a disease caused by enhancement of acylcoenzyme A: diacylglycerol acyltransferase activity.
　（２４）　医薬組成物が、アシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼを阻害させ、トリグリセライドの合成を阻害し、トリグリセライドの吸収が抑制されることにより、症状の治療、改善、軽減及び／又は予防がなされる疾病の治療及び／又は予防のための（１９）に記載の医薬組成物。 (24) The pharmaceutical composition inhibits acyl coenzyme A: diacylglycerol acyltransferase, inhibits the synthesis of triglyceride, and suppresses the absorption of triglyceride, thereby treating, improving, reducing and / or preventing symptoms. The pharmaceutical composition according to (19) for the treatment and / or prevention of a disease.
　（２５）　医薬組成物が、アシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼを阻害させ、トリグリセライドの合成が阻害されることにより、症状の治療、改善、軽減及び／又は予防がなされる疾病の治療及び／又は予防のための（１９）に記載の医薬組成物。 (25) The pharmaceutical composition inhibits acylcoenzyme A: diacylglycerol acyltransferase and inhibits the synthesis of triglyceride, thereby treating and / or treating diseases in which symptoms are treated, ameliorated, reduced and / or prevented. The pharmaceutical composition according to (19) for prevention.
　（２６）　医薬組成物が、肥満、肥満症、高脂血症、高トリグリセライド症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患又は過食症の治療及び／又は予防のための（１９）に記載の医薬組成物。 (26) The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceride disease, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, false The pharmaceutical composition according to (19) for the treatment and / or prevention of blood heart disease or bulimia.
　（２７）　医薬組成物が、肥満又は肥満症の治療及び／又は予防のための（１９）に記載の医薬組成物。 (27) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is for the treatment and / or prevention of obesity or obesity.
　（２８）　医薬組成物が、糖尿病の治療及び／又は予防のための（１９）に記載の医薬組成物。 (28) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is for the treatment and / or prevention of diabetes.
　（２９）　医薬組成物が、肥満に起因する高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、高血圧症、脳血管障害、冠動脈疾患、脂肪肝、呼吸異常、腰痛、変形性膝関節症、痛風又は胆石症の治療及び／又は予防のための（１９）に記載の医薬組成物。 (29) When the pharmaceutical composition is obesity-induced hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension (19) The pharmaceutical composition for treatment and / or prevention of symptom, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory disorder, low back pain, knee osteoarthritis, gout or cholelithiasis.
　（３０）　医薬組成物が、肥満に起因する高脂血症、高トリグリセライド血症、糖尿病、動脈硬化症又は高血圧症の治療及び／又は予防のための（１９）に記載の医薬組成物。 (30) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.
　（３１）　医薬組成物が、小腸からの脂肪吸収を抑制するための（１９）に記載の医薬組成物。 (31) The pharmaceutical composition according to (19), wherein the pharmaceutical composition suppresses fat absorption from the small intestine.
　（３２）　肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患又は過食症の治療及び／又は予防で使用するための、（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩。 (32) Obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetes Retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, non-alcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease or The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in the treatment and / or prevention of bulimia.
　（３３）　肥満又は肥満症の治療及び／又は予防で使用するための、（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩。 (33) The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in the treatment and / or prevention of obesity or obesity.
　（３４）　糖尿病の治療及び／又は予防で使用するための、（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩。 (34) The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in the treatment and / or prevention of diabetes.
　（３５）　医薬組成物を製造するための、（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の使用。 (35) Use of the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
　（３６）　医薬組成物がアシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼを阻害するための医薬組成物である（３５）に記載の使用。 (36) The use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for inhibiting acylcoenzyme A: diacylglycerol acyltransferase.
　（３７）　医薬組成物が摂食及び／又は食欲を抑制するための医薬組成物である（３５）に記載の使用。 (37) Use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for suppressing eating and / or appetite.
　（３８）　医薬組成物が肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患又は過食症の治療及び／又は予防のための医薬組成物である（３５）に記載の使用。 (38) The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, false The use according to (35), which is a pharmaceutical composition for the treatment and / or prevention of blood heart disease or bulimia.
　（３９）　医薬組成物が肥満又は肥満症の治療及び／又は予防のための医薬組成物である（３５）に記載の使用。 (39) The use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and / or prevention of obesity or obesity.
　（４０）　医薬組成物が糖尿病の治療及び／又は予防のための医薬組成物である（３５）に記載の使用。 (40) The use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and / or prevention of diabetes.
　（４１）　医薬組成物が肥満に起因する高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、高血圧症、脳血管障害、冠動脈疾患、脂肪肝、呼吸異常、腰痛、変形性膝関節症、痛風又は胆石症の治療及び／又は予防のための医薬組成物である（３５）に記載の使用。 (41) Hyperlipidemia, hypertriglycerideemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic kidney) , Including diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension The use according to (35), which is a pharmaceutical composition for the treatment and / or prevention of cerebrovascular disorder, coronary artery disease, fatty liver, respiratory disorder, low back pain, knee osteoarthritis, gout or cholelithiasis.
　（４２）　医薬組成物が肥満に起因する高脂血症、高トリグリセライド血症、糖尿病、動脈硬化症又は高血圧症の治療及び／又は予防のための医薬組成物である（３５）に記載の使用。 (42) Use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity .
　（４３）　医薬組成物が小腸からの脂肪吸収を抑制するための医薬組成物である（３５）に記載の使用。 (43) Use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for inhibiting fat absorption from the small intestine.
　（４４）　（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与するアシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼ阻害方法。 (44) Acyl coenzyme A: diacylglycerol for administering a pharmacologically effective amount of the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof to a warm-blooded animal Acyltransferase inhibition method.
　（４５）　（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与する摂食抑制及び／又は食欲抑制方法。 (45) Feeding suppression and / or administration of a pharmacologically effective amount of the compound or pharmacologically acceptable salt thereof described in any one of (1) to (16) to a warm-blooded animal Appetite suppression method.
　（４６）　（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与する疾病の治療及び／又は予防方法。 (46) Treatment of diseases and / or diseases in which a pharmacologically effective amount of the compound described in any one of (1) to (16) or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal Prevention method.
　（４７）　疾病が肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患又は過食症である（４６）に記載の方法。 (47) Diseases are obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy , Including diabetic retinopathy, diabetic macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart The method according to (46), which is a disease or bulimia.
　（４８）　疾病が肥満又は肥満症である（４６）に記載の方法。 (48) The method according to (46), wherein the disease is obesity or obesity.
　（４９）　疾病が糖尿病である（４６）に記載の方法。 (49) The method according to (46), wherein the disease is diabetes.
　（５０）　疾病が肥満に起因する高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、高血圧症、脳血管障害、冠動脈疾患、脂肪肝、呼吸異常、腰痛、変形性膝関節症、痛風又は胆石症である（４６）に記載の方法。 (50) Hyperlipidemia caused by obesity, hypertriglyceridemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension, brain (46) The method according to (46), which is vascular disorder, coronary artery disease, fatty liver, respiratory disorder, low back pain, knee osteoarthritis, gout or gallstone disease.
　（５１）　疾病が肥満に起因する高脂血症、高トリグリセライド血症、糖尿病、動脈硬化症又は高血圧症である（４６）に記載の方法。 (51) The method according to (46), wherein the disease is hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.
　（５２）　（１）乃至（１６）から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与する小腸からの脂肪吸収を抑制する方法。 (52) Absorption of fat from the small intestine in which a pharmacologically effective amount of the compound described in any one of (1) to (16) or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal. How to suppress.
　（５３）　温血動物がヒトである（４４）乃至（５２）から選択されるいずれか一項に記載の方法
である。 (53) The method according to any one of (44) to (52), wherein the warm-blooded animal is a human.
　本発明において、「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又は沃素原子である。好適には、フッ素原子又は塩素原子であり、より好適には、フッ素原子である。 In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
　本発明において、「Ｃ１－Ｃ６アルキル基」は、炭素数１乃至６個の直鎖又は分枝鎖アルキル基である。例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓ－ブチル、ｔ－ブチル、ペンチル、イソペンチル、２－メチルブチル、ネオペンチル、１－エチルプロピル、ヘキシル、イソヘキシル又は４－メチルペンチル基である。好適には、炭素数１乃至４個の直鎖又は分枝鎖アルキル基（Ｃ1－Ｃ４アルキル基）であり、より好適には、メチル基又はエチル基（Ｃ1－Ｃ２アルキル基）であり、更により好適には、メチル基である。 In the present invention, the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl or 4-methylpentyl group. Preferred is a linear or branched alkyl group having 1 to 4 carbon atoms (C 1 -C 4 alkyl group), and more preferred is a methyl group or an ethyl group (C 1 -C 2 alkyl group). And even more preferably a methyl group.
　本発明において、「Ｃ１－Ｃ６ハロゲン化アルキル基」は、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、トリフルオロメチル、トリクロロメチル、ジフルオロメチル、ジクロロメチル、ジブロモメチル、フルオロメチル、２，２，２－トリフルオロエチル、２，２，２－トリクロロエチル、２－ブロモエチル又は２－フルオロエチル基である。好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ1－Ｃ４アルキル基」に結合した基（Ｃ１－Ｃ４ハロゲン化アルキル基）であり、より好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ1－Ｃ２アルキル基」に結合した基（Ｃ１－Ｃ２ハロゲン化アルキル基）であり、更により好適には、トリフルオロメチル基である。 In the present invention, the “C 1 -C 6 halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkyl group”. For example, with a trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl or 2-fluoroethyl group is there. Preferably, the same or different 1 to 5 “halogen atoms” are groups bonded to the “C 1 -C 4 alkyl group” (C 1 -C 4 halogenated alkyl group), more preferably A group (C 1 -C 2 halogenated alkyl group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 2 alkyl group”, and even more preferably, A fluoromethyl group;
　本発明において、「Ｃ１－Ｃ６アルコキシ基」は、前記「Ｃ１－Ｃ６アルキル基」が酸素原子に結合した基であり、炭素数１乃至６個の直鎖又は分枝鎖アルコキシ基である。例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓ－ブトキシ、ｔ－ブトキシ、ペントキシ、２－メチルブトキシ、３－エチルプロポキシ、ヘキシルオキシ又は２，３－ジメチルブトキシ基である。好適には、炭素数１乃至４個の直鎖又は分枝鎖アルコキシ基（Ｃ１－Ｃ４アルコキシ基）であり、より好適には、メトキシ基又はエトキシ基（Ｃ1－Ｃ２アルコキシ基）であり、更により好適には、メトキシ基である。 In the present invention, the “C 1 -C 6 alkoxy group” is a group in which the “C 1 -C 6 alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, 2-methylbutoxy, 3-ethylpropoxy, hexyloxy or 2,3-dimethylbutoxy group. Preferred is a linear or branched alkoxy group having 1 to 4 carbon atoms (C 1 -C 4 alkoxy group), and more preferred is a methoxy group or an ethoxy group (C 1 -C 2 alkoxy group). And even more preferably a methoxy group.
　本発明において、「Ｃ１－Ｃ６ハロゲン化アルコキシ基」は、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ６アルコキシ基」に結合した基である。例えば、トリフルオロメトキシ、トリクロロメトキシ、ジフルオロメトキシ、ジクロロメトキシ、ジブロモメトキシ、フルオロメトキシ、２，２，２－トリフルオロエトキシ、２，２，２－トリクロロエトキシ又はペンタフルオロエトキシ基である。好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ１－Ｃ４アルコキシ基」に結合した基（Ｃ１－Ｃ４ハロゲン化アルコキシ基）であり、より好適には、同一又は異なる１乃至５個の前記「ハロゲン原子」が前記「Ｃ1－Ｃ２アルコキシ基」に結合した基（Ｃ１－Ｃ２ハロゲン化アルコキシ基）であり、更により好適には、トリフルオロメトキシ基である。 In the present invention, the “C 1 -C 6 halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkoxy group”. For example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy or pentafluoroethoxy group. Preferably, the same or different 1 to 5 “halogen atoms” are groups bonded to the “C 1 -C 4 alkoxy group” (C 1 -C 4 halogenated alkoxy group), and more preferably A group (C 1 -C 2 halogenated alkoxy group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 2 alkoxy group”, and even more preferably, A fluoromethoxy group;
　本発明において、「（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基」は、１個の前記「Ｃ１－Ｃ６アルコキシ基」が前記「Ｃ１－Ｃ６アルキル基」に結合した基である。例えば、メトキシメチル、エトキシメチル、プロポキシメチル、イソプロポキシメチル、ブトキシメチル、ｓ－ブトキシメチル、ｔ－ブトキシメチル、２－メトキシエチル又は３－イソプロポキシプロピル基である。好適には、１個の前記「Ｃ１－Ｃ４アルコキシ基」が前記「Ｃ１－Ｃ４アルキル基」に結合した基（（Ｃ１－Ｃ４アルコキシ）－（Ｃ１－Ｃ４アルキル）基）であり、より好適には、１個の前記「Ｃ１－Ｃ２アルコキシ基」が前記「Ｃ１－Ｃ２アルキル基」に結合した基（（Ｃ１－Ｃ２アルコキシ）－（Ｃ１－Ｃ２アルキル）基）であり、更により好適には、メトキシメチル基である。 In the present invention, the “(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group” means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 alkyl group”. It is a group bonded to For example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, s-butoxymethyl, t-butoxymethyl, 2-methoxyethyl or 3-isopropoxypropyl group. Preferably, a group ((C 1 -C 4 alkoxy)-(C 1 -C 4 alkyl) in which one said “C 1 -C 4 alkoxy group” is bonded to the above “C 1 -C 4 alkyl group” a group), more preferably, one group wherein the "C 1 -C 2 alkoxy group" attached to the "C 1 -C 2 alkyl group" ((C 1 -C 2 alkoxy) - (C 1- C 2 alkyl) group), and even more preferably a methoxymethyl group.
　本発明において、「Ｃ１－Ｃ６アルキルチオ基」は、前記「Ｃ１－Ｃ６アルキル基」が硫黄原子に結合した基であり、炭素数１乃至６個の直鎖又は分枝鎖アルキルチオ基である。例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、ペンチルチオ又はヘキシルチオ基である。好適には、炭素数１乃至４個の直鎖又は分枝鎖アルキルチオ基（Ｃ1－Ｃ４アルキルチオ基）であり、より好適には、メチルチオ基又はエチルチオ基（Ｃ1－Ｃ２アルキルチオ基）であり、更により好適には、メチルチオ基である。 In the present invention, the “C 1 -C 6 alkylthio group” is a group in which the “C 1 -C 6 alkyl group” is bonded to a sulfur atom, and is a linear or branched alkylthio group having 1 to 6 carbon atoms. It is. For example, a methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio or hexylthio group. Preferred is a linear or branched alkylthio group having 1 to 4 carbon atoms (C 1 -C 4 alkylthio group), and more preferred is a methylthio group or an ethylthio group (C 1 -C 2 alkylthio group). And even more preferably a methylthio group.
　本発明において、「Ｃ１－Ｃ６アルキルスルフィニル基」は、前記「Ｃ１－Ｃ６アルキル基」がスルフィニル基に結合した基であり、炭素数１乃至６個の直鎖又は分枝鎖アルキルスルフィニル基である。例えば、メチルスルフィニル、エチルスルフィニル、プロピルスルフィニル、イソプロピルスルフィニル、ブチルスルフィニル、ペンチルスルフィニル又はヘキシルスルフィニル基である。好適には、炭素数１乃至４個の直鎖又は分枝鎖アルキルスルフィニル基（Ｃ1－Ｃ４アルキルスルフィニル基）であり、より好適には、メチルスルフィニル基又はエチルスルフィニル基（Ｃ1－Ｃ２アルキルスルフィニル基）であり、更により好適には、メチルスルフィニル基である。 In the present invention, the “C 1 -C 6 alkylsulfinyl group” is a group in which the “C 1 -C 6 alkyl group” is bonded to a sulfinyl group, and is a straight chain or branched alkyl group having 1 to 6 carbon atoms. It is a sulfinyl group. For example, a methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl or hexylsulfinyl group. Preferred is a linear or branched alkylsulfinyl group having 1 to 4 carbon atoms (C 1 -C 4 alkylsulfinyl group), and more preferred is a methylsulfinyl group or an ethylsulfinyl group (C 1 -C 2 alkylsulfinyl group), and more preferably a methylsulfinyl group.
　本発明において、「Ｃ２－Ｃ７アルキルカルボニル基」は、１個の前記「Ｃ１－Ｃ６アルキル基」がカルボニル基に結合した基である。例えば、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ピバロイル又はバレリル基である。好適には、１個の前記「Ｃ1－Ｃ４アルキル基」がカルボニル基に結合した基（Ｃ２－Ｃ５アルキルカルボニル基）であり、より好適には、アセチル基又はプロピオニル基（Ｃ２－Ｃ３アルキルカルボニル基）であり、更により好適には、アセチル基である。 In the present invention, a “C 2 -C 7 alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a carbonyl group. For example, an acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group. Preferably, one of the above “C 1 -C 4 alkyl group” is a group (C 2 -C 5 alkylcarbonyl group) bonded to a carbonyl group, and more preferably an acetyl group or a propionyl group (C 2 a -C 3 alkylcarbonyl group), still more preferably, an acetyl group.
　本発明において、「Ｃ２－Ｃ７アルコキシカルボニル基」は、１個の前記「Ｃ１－Ｃ６アルコキシ基」がカルボニル基に結合した基である。例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｓ－ブトキシカルボニル又はｔ－ブトキシカルボニル基である。好適には、１個の前記「Ｃ１－Ｃ４アルコキシ基」がカルボニル基に結合した基（Ｃ２－Ｃ５アルコキシカルボニル基）であり、より好適には、メトキシカルボニル基又はエトキシカルボニル基（Ｃ２－Ｃ３アルコキシカルボニル基）であり、更により好適には、メトキシカルボニル基である。 In the present invention, a “C 2 -C 7 alkoxycarbonyl group” is a group in which one of the above “C 1 -C 6 alkoxy groups” is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl group. Preferably, one of the above “C 1 -C 4 alkoxy groups” is a group (C 2 -C 5 alkoxycarbonyl group) bonded to a carbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group ( C 2 -C 3 alkoxycarbonyl group), and more preferably a methoxycarbonyl group.
　本発明において、「モノ－Ｃ１－Ｃ６アルキルアミノ基」は、１個の前記「Ｃ１－Ｃ６アルキル基」がアミノ基に結合した基である。例えば、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ブチルアミノ、イソブチルアミノ、ｔ－ブチルアミノ、ペンチルアミノ、ネオペンチルアミノ又はヘキシルアミノ基である。好適には、１個の前記「Ｃ１－Ｃ４アルキル基」がアミノ基に結合した基（モノ－Ｃ１－Ｃ４アルキルアミノ基）であり、より好適には、メチルアミノ基又はエチルアミノ基（モノ－Ｃ１－Ｃ２アルキルアミノ基）であり、更により好適には、メチルアミノ基である。 In the present invention, the “mono-C 1 -C 6 alkylamino group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to an amino group. For example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, t-butylamino, pentylamino, neopentylamino or hexylamino group. Preferably, one said “C 1 -C 4 alkyl group” is a group bonded to an amino group (mono-C 1 -C 4 alkylamino group), more preferably a methylamino group or ethylamino group Group (mono-C 1 -C 2 alkylamino group), still more preferably a methylamino group.
　本発明において、「ジ－（Ｃ１－Ｃ６アルキル）アミノ基」は、同一又は異なる２個の前記「Ｃ１－Ｃ６アルキル基」がアミノ基に結合した基である。例えば、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジイソプロピルアミノ、ジブチルアミノ、Ｎ－エチル－Ｎ－メチルアミノ、Ｎ－メチル－Ｎ－プロピルアミノ、Ｎ－イソプロピル－Ｎ－メチルアミノ、Ｎ－ブチル－Ｎ－メチルアミノ、Ｎ－エチル－Ｎ－プロピルアミノ又はＮ－エチル－Ｎ－イソペンチルアミノ基である。好適には、同一又は異なる２個の前記「Ｃ１－Ｃ４アルキル基」がアミノ基に結合した基（ジ－（Ｃ１－Ｃ４アルキル）アミノ基）であり、より好適には、ジメチルアミノ基、ジエチルアミノ基又はＮ－エチル－Ｎ－メチルアミノ基（ジ－（Ｃ１－Ｃ２アルキル）アミノ基）であり、更により好適には、ジメチルアミノ基である。 In the present invention, the “di- (C 1 -C 6 alkyl) amino group” is a group in which two identical or different “C 1 -C 6 alkyl groups” are bonded to an amino group. For example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-methylamino, N-butyl-N— A methylamino, N-ethyl-N-propylamino or N-ethyl-N-isopentylamino group; Preferably, two identical or different “C 1 -C 4 alkyl groups” are groups bonded to an amino group (di- (C 1 -C 4 alkyl) amino group), more preferably dimethyl amino group, a diethylamino group or an N- ethyl -N- methylamino group - a (di (C 1 -C 2 alkyl) amino group), even more preferably more, a dimethylamino group.
　本発明において、「モノ－Ｃ２－Ｃ７アルキルカルボニルアミノ基」は、１個の前記「Ｃ１－Ｃ６アルキル基」が結合したカルボニル基がアミノ基に結合した基である。例えば、アセトアミド、エチルカルボニルアミノ、プロピルカルボニルアミノ、イソプロピルカルボニルアミノ、ブチルカルボニルアミノ又はイソブチルカルボニルアミノ基である。好適には、１個の前記「Ｃ１－Ｃ４アルキル基」が結合したカルボニル基がアミノ基に結合した基（モノ－Ｃ２－Ｃ５アルキルカルボニルアミノ基）であり、より好適には、アセトアミド基又はエチルカルボニルアミノ基（モノ－Ｃ２－Ｃ３アルキルカルボニルアミノ基）であり、更により好適には、アセトアミド基である。 In the present invention, the “mono-C 2 -C 7 alkylcarbonylamino group” is a group in which one carbonyl group bonded to the “C 1 -C 6 alkyl group” is bonded to an amino group. For example, an acetamide, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino or isobutylcarbonylamino group. Preferably a one of said "C 1 -C 4 alkyl group" is a carbonyl group attached is attached to an amino group group (mono--C 2 -C 5 alkylcarbonylamino group), more preferably, the An acetamide group or an ethylcarbonylamino group (mono-C 2 -C 3 alkylcarbonylamino group), and even more preferably an acetamide group.
　本発明において、「モノ－Ｃ１－Ｃ６アルキルスルホニルアミノ基」は、１個の前記「Ｃ１－Ｃ６アルキル基」が結合したスルホニル基がアミノ基に結合した基である。例えば、メチルスルホニルアミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、イソプロピルスルホニルアミノ、ブチルスルホニルアミノ、ｔ－ブチルスルホニルアミノ又は２－エチルブチルスルホニルアミノ基である。好適には、１個の前記「Ｃ１－Ｃ４アルキル基」が結合したスルホニル基がアミノ基に結合した基（モノ－Ｃ１－Ｃ４アルキルスルホニルアミノ基）であり、より好適には、メチルスルホニルアミノ基又はエチルスルホニルアミノ基（モノ－Ｃ１－Ｃ２アルキルスルホニルアミノ基）であり、更により好適には、メチルスルホニルアミノ基である。 In the present invention, "mono--C 1 -C 6 alkylsulfonylamino group", one of the sulfonyl group "C 1 -C 6 alkyl group" is bonded is a group attached to an amino group. For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, t-butylsulfonylamino or 2-ethylbutylsulfonylamino group. Preferably, a sulfonyl group to which one said “C 1 -C 4 alkyl group” is bonded is a group bonded to an amino group (mono-C 1 -C 4 alkylsulfonylamino group), more preferably a methylsulfonylamino group or an ethylsulfonylamino group (mono--C 1 -C 2 alkylsulfonylamino group), more preferably more, a methylsulfonylamino group.
　本発明において、「Ｃ３－Ｃ６シクロアルキル基」は、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基であり、好適には、シクロヘキシル基である。 In the present invention, the “C 3 -C 6 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and preferably a cyclohexyl group.
　本発明において、「置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基」は、フェニル基又は置換基群Ａから選択される基で独立に１乃至５個置換されているフェニル基である。好適には、（フッ素原子、塩素原子、メチル基及びメトキシ基）から選択される基で独立に１乃至３個置換されていてもよいフェニル基であり、より好適には、フェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－メチルフェニル基、３－メチルフェニル基、４－メチルフェニル基、２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基、２－クロロ－４－フルオロフェニル基、２－フルオロ－３－メチルフェニル基、２－フルオロ－４－メチルフェニル基、２，４－ジメチルフェニル基、２－メトキシ－５－メチルフェニル基又は２，４，５－トリフルオロフェニル基である。 In the present invention, the “phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” is independently 1 to 5 groups with a phenyl group or a group selected from the substituent group A. This is a phenyl group that is substituted. Preferred is a phenyl group which may be independently substituted with 1 to 3 groups independently selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group), more preferably a phenyl group, 2- Fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl Group, 2-chloro-4-fluorophenyl group, 2-fluoro-3-methylphenyl group, 2-fluoro-4-methylphenyl group, 2,4-dimethylphenyl group, 2-methoxy-5-methylphenyl group or 2,4,5-trifluorophenyl group.
　本発明において、「置換基群Ａから選択される基で独立に１乃至３個置換されていてもよいピリジル基」は、ピリジル基又は置換基群Ａから選択される基で独立に１乃至３個置換されているピリジル基である。好適には、２－ピリジル基、３－ピリジル基又は４－ピリジル基である。 In the present invention, the “pyridyl group optionally substituted by 1 to 3 groups independently selected from the substituent group A” refers to 1 to 3 groups independently selected from the pyridyl group or the substituent group A. It is a pyridyl group substituted one by one. A 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group is preferred.
　本発明において、好適な一般式（I）は、一般式（Ｉａ）、一般式（Ｉｂ）、一般式（Ｉｃ）、一般式（Ｉｄ）、一般式（Ｉｅ）又は一般式（Ｉｆ）であり、より好適な一般式（I）は、一般式（Iａ）である。 In the present invention, preferred general formula (I) is general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id), general formula (Ie) or general formula (If). More preferred general formula (I) is general formula (Ia).
　本発明において、好適なＲは、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基であり、より好適なＲは、（フッ素原子、塩素原子、メチル基及びメトキシ基）から選択される基で独立に１乃至３個置換されていてもよいフェニル基であり、更により好適なＲは、フェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－メチルフェニル基、３－メチルフェニル基、４－メチルフェニル基、２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基、２－クロロ－４－フルオロフェニル基、２－フルオロ－３－メチルフェニル基、２－フルオロ－４－メチルフェニル基、２，４－ジメチルフェニル基、２－メトキシ－５－メチルフェニル基又は２，４，５－トリフルオロフェニル基である。 In the present invention, preferred R is a phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A, and more preferred R is (fluorine atom, chlorine atom, methyl group). A phenyl group which may be independently substituted with 1 to 3 groups independently selected from a group selected from a group and a methoxy group, and even more preferred R is a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-chloro-4-fluorophenyl Group, 2-fluoro-3-methylphenyl group, 2-fluoro-4-methylphenyl group, 2,4-dimethylphenyl group, 2-methoxy-5-methylphenyl group or 2 4,5-trifluorophenyl group.
　本発明において、好適なＱは、窒素原子である。 In the present invention, Q is preferably a nitrogen atom.
　本発明において、好適なＵは、窒素原子である。 In the present invention, preferred U is a nitrogen atom.
　本発明において、好適なＶは、式－ＣＨ＝で表わされる基である。 In the present invention, preferred V is a group represented by the formula —CH═.
　本発明において、好適なｍは、１である。 In the present invention, m is preferably 1.
　本発明において、好適なｎは、１である。 In the present invention, n is preferably 1.
　本発明の一般式（Ｉ）で表される化合物又はその薬理上許容される塩は、全ての異性体（ジアステレオ異性体、光学異性体、回転異性体等）を有する。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (diastereoisomers, optical isomers, rotational isomers, etc.).
　本発明の一般式（Ｉ）で表される化合物又はその薬理上許容される塩は、その分子内に不斉炭素原子が存在するので、種々の異性体を有する。本発明の化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式（Ｉ）で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含むものである。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom exists in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
　上記のような立体異性体は、光学活性な原料化合物を用いるか、又は不斉合成若しくは不斉誘導の手法を用いて本発明に係る化合物を合成するか、或いは合成した本発明に係る化合物を所望により通常の光学分割法又は分離法を用いて単離することにより得ることができる。 For the stereoisomer as described above, an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.
　一般式（Ｉａ）で表される化合物又はその薬理上許容される塩は、一般式（Ｉｂ）乃至（Ｉｆ）で表される化合物又はその薬理上許容される塩より好適である。 The compound represented by the general formula (Ia) or a pharmacologically acceptable salt thereof is more preferable than the compound represented by the general formulas (Ib) to (If) or a pharmacologically acceptable salt thereof.
　本発明の化合物は、このような化合物を構成する原子の１以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素（２Ｈ）、トリチウム（３Ｈ）、ヨウ素－125（１２５Ｉ）又は炭素－14（１４Ｃ）などが挙げられる。また、前記化合物は、例えば、トリチウム（３Ｈ）、ヨウ素－125（１２５Ｉ）又は炭素－14（１４Ｃ）などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like. The compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
　「その薬理上許容される塩」とは、著しい毒性を有さず、医薬として使用され得る塩をいう。本発明の一般式（Ｉ）で表される化合物は、塩基性の基を有する場合には酸と反応させることにより、又、酸性の基を有する場合には塩基と反応させることにより、塩にすることができる。 “The pharmacologically acceptable salt” refers to a salt that has no significant toxicity and can be used as a medicine. The compound represented by the general formula (I) of the present invention can be converted into a salt by reacting with an acid when it has a basic group, or by reacting with a base when it has an acidic group. can do.
　塩基性基に基づく塩としては、例えば、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のようなアルキルスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリ－ルスルホン酸塩、酢酸塩、りんご酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、シュウ酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate Organic acids such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine salt, lysine salt, Examples thereof include amino acid salts such as arginine salt, ornithine salt, glutamate salt and aspartate salt.
　一方、酸性基に基づく塩としては、例えば、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金属塩；アンモニウム塩のような無機塩、ｔ－オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ－メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’－ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ－ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 On the other hand, examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt. Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.
　本発明の一般式（Ｉ）で表される化合物又はその薬理上許容される塩は、大気中に放置したり、又は、再結晶したりすることにより、水分子を取り込んで、水和物となる場合があり、そのような水和物も本発明の塩に包含される。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is taken in the air or recrystallized to take in water molecules, Such hydrates are also encompassed by the salts of the present invention.
　本発明の一般式（Ｉ）で表される化合物又はその薬理上許容される塩は、他のある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の塩に包含される。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present. Included in the salts of the invention.
　本発明の一般式（I）で表される化合物又はその薬理上許容される塩は、優れたＤＧＡＴ阻害作用及び摂食抑制作用を有しており、温血動物（好ましくは哺乳類動物であり、ヒトを含む）における下記の疾患：肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患及び過食症からなる群から選ばれる疾患、又は肥満に起因する高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、高血圧症、脳血管障害、冠動脈疾患、脂肪肝、呼吸異常、腰痛、変形性膝関節症、痛風、及び胆石症からなる群から選ばれる疾患の予防及び／又は治療のための医薬として有用である。また、本発明により提供される一般式（I）で表される新規な化合物またはその薬理上許容される塩は、優れたＤＧＡＴ阻害作用を有しており、温血動物（好ましくは哺乳類動物であり、ヒトを含む）における上記の疾患の予防及び／又は治療のための医薬の有効成分として有用である。好適には、上記の疾患の治療のための医薬として用いることができる。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action and feeding inhibitory action, and is a warm-blooded animal (preferably a mammal, Diseases (including humans): obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis , A disease selected from the group consisting of ischemic heart disease and bulimia, or hyperlipidemia, hypertriglycerideemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, sugar caused by obesity Urinary disease, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis Disease selected from the group consisting of infectious disease, atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout, and cholelithiasis It is useful as a medicament for the prevention and / or treatment. Further, the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action, and is a warm-blooded animal (preferably a mammalian animal). And is useful as an active ingredient of a medicament for the prevention and / or treatment of the above-mentioned diseases (including humans). Suitably, it can be used as a medicament for the treatment of the above-mentioned diseases.
　本発明の一般式（Ｉ）で表される化合物は、以下に記載するＡ法乃至Ｃ法に従って製造することができる。 The compound represented by the general formula (I) of the present invention can be produced according to the methods A to C described below.
　下記Ａ法乃至Ｃ法の各工程の反応において使用される溶媒は、反応を阻害せず、出発原料をある程度溶解するものであれば特に限定はなく、例えば、下記溶媒群より選択される。溶媒群は、ペンタン、ヘキサン、オクタン、石油エーテル、リグロイン、シクロヘキサンのような炭化水素類；ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ-メチル-２-ピロリドン、Ｎ－メチル－２－ピロリジノン、ヘキサメチルリン酸トリアミドのようなアミド類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテル、シクロペンチルメチルエーテルのようなエーテル類；メタノール、エタノール、n-プロパノール、ｉ-プロパノール、ｎ-ブタノール、２-ブタノール、２-メチル-１-プロパノール、t-ブタノール、イソアミルアルコール、ジエチレングリコール、グリセリン、オクタノール、シクロヘキサノール、メチルセロソルブのようなアルコール類；ジメチルスルホキシドのようなスルホキシド類；スルホランのようなスルホン類；アセトニトリル、プロピオニトリル、ブチロニトリル、イソブチロニトリルのようなニトリル類；蟻酸エチル、酢酸エチル、酢酸プロピル、酢酸ブチル、炭酸ジエチルのようなエステル類；アセトン、メチルエチルケトン、４-メチル-２-ペンタノン、メチルイソブチルケトン、イソホロン、シクロヘキサノンのようなケトン類；ニトロエタン、ニトロベンゼンのようなニトロ化合物類；ジクロロメタン、１，２－ジクロロエタン、クロロベンゼン、ジクロロベンゼン、クロロホルム、四塩化炭素のようなハロゲン化炭化水素類；ベンゼン、トルエン、キシレンのような芳香族炭化水素類；Ｎ－メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ－メチルピペリジン、ピリジン、２，６－ルチジン、４－ピロリジノピリジン、ピコリン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ（ｔ－ブチル）－４－メチルピリジン、キノリン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、ピペリジンのようなアミン類；水；及び、これらの混合溶媒からなる。 The solvent used in the reaction of each step of the following methods A to C is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example. Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as -2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; methanol, ethanol, n-propanol, i -Propanol, n-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, Alcohols such as methyl cellosolve; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, Esters such as butyl acetate and diethyl carbonate; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; N-methylmorpholine, tri Tylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (T-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, 4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), amines such as piperidine; water; and mixtures thereof It consists of a solvent.
　下記Ａ法乃至Ｃ法の各工程の反応において使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム、炭酸リチウム、炭酸セシウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウムのようなアルカリ金属炭酸水素塩類；酢酸ナトリウム、酢酸カリウム、酢酸リチウム、酢酸セシウムのようなアルカリ金属酢酸塩類；水素化リチウム、水素化ナトリウム、水素化カリウムのようなアルカリ金属水素化物類；水酸化ナトリウム、水酸化カリウム、水酸化リチウムのようなアルカリ金属水酸化物類；弗化ナトリウム、弗化カリウムのようなアルカリ金属弗化物類；ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム－ｔ－ブトキシド、カリウム－ｔ－ブトキシドのようなアルカリ金属アルコキシド類；ナトリウムトリメチルシロキシド、カリウムトリメチルシロキシド、リチウムトリメチルシロキシドのようなアルカリ金属トリアルキルシロキシド類；Ｎ－メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ－メチルピペリジン、ピリジン、２，６－ルチジン、コリジン、４－ピロリジノピリジン、ピコリン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ（ｔ－ブチル）－４－メチルピリジン、キノリン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）のような有機塩基類；リチウムジイソプロピルアミド、リチウム　ビス（トリメチルシリル）アミドのような有機金属塩基類；又は、プロリンのようなアミノ酸である。 The base used in the reaction of each step of the following methods A to C is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide and lithium hydroxide; alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium Alkali metal alcohols such as t-butoxide Cids; alkali metal trialkylsiloxides such as sodium trimethylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N- Methylpiperidine, pyridine, 2,6-lutidine, collidine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane ( DABCO), 1,8-diazabicyclo [5 4.0] organic bases such as undec-7-ene (DBU); organometallic bases such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide; or an amino acid such as proline.
　下記Ａ法乃至Ｃ法の各工程の反応において使用されるパラジウム触媒は、例えば、テトラキス（トリフェニルホスフィン）パラジウム（０）、パラジウム－活性炭素、酢酸パラジウム（ＩＩ）、トリフルオロ酢酸パラジウム（ＩＩ）、パラジウム黒、臭化パラジウム（ＩＩ）、塩化パラジウム（ＩＩ）、沃化パラジウム（ＩＩ）、シアン化パラジウム（ＩＩ）、硝酸パラジウム（ＩＩ）、酸化パラジウム（ＩＩ）、硫酸パラジウム（ＩＩ）、ジクロロビス（アセトニトリル）パラジウム（ＩＩ）、ジクロロビス（ベンゾニトリル）パラジウム（ＩＩ）、ジクロロ（１,５－シクロオクタジエン）パラジウム（ＩＩ）、アセチルアセトンパラジウム（ＩＩ）、硫化パラジウム（ＩＩ）、［１，１′－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド、トリス（ジベンジリデンアセトン）ジパラジウム（０）、テトラキス（アセトニトリル）パラジウム（ＩＩ）テトラフルオロボレート又は塩化アリールパラジウムダイマーのような２価のパラジウム触媒又は０価のパラジウム触媒である。 The palladium catalyst used in the reaction in each step of the following methods A to C is, for example, tetrakis (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II). , Palladium black, palladium (II) bromide, palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, dichlorobis (Acetonitrile) palladium (II), dichlorobis (benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), acetylacetone palladium (II), palladium (II) sulfide, [1,1 ' -Bis (diphenylphosphino) ferrocene] A divalent palladium catalyst such as palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (acetonitrile) palladium (II) tetrafluoroborate or arylpalladium chloride dimer, or a zerovalent palladium catalyst. .
　下記Ａ法乃至Ｃ法の各工程の反応において、反応温度は、溶媒、出発原料、試薬等により異なり、反応時間は、溶媒、出発原料、試薬、反応温度等により異なる。 In the reaction of each step of Method A to Method C below, the reaction temperature varies depending on the solvent, starting material, reagent, and the like, and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
　下記Ａ法乃至Ｃ法の各工程の反応において、反応終了後、各目的化合物は常法に従って、反応混合物から採取される。例えば、反応混合物を適宜中和し、又、不溶物が存在する場合には濾過により除去した後、水と酢酸エチルのような混和しない有機溶媒を加え、目的化合物を含む有機層を分離し、水等で洗浄後、無水硫酸マグネシウム、無水硫酸ナトリウム等で乾燥、ろ過後、溶剤を留去することによって得られる。得られた目的化合物は必要ならば、常法、例えば再結晶、再沈殿等の通常、有機化合物の分離精製に慣用されている方法を適宜組合せ、クロマトグラフィーを応用し、適切な溶離剤で溶出することによって分離、精製することができる。溶媒に不溶の目的化合物では、得られた固体の粗生成物を溶媒で洗浄して、精製することができる。また、各工程の目的化合物は精製することなくそのまま次の反応に使用することもできる。 In the reaction of each step of Method A to Method C below, after completion of the reaction, each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified. For a target compound insoluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. In addition, the target compound in each step can be directly used in the next reaction without purification.
　下記Ａ法乃至Ｃ法の各工程の反応において、Ｒ、Ｑ、Ｕ、Ｖ、ｍ及びｎは、前述したものと同意義を示す。Ｘは、ハロゲン原子（好適には、臭素原子又はヨウ素原子であり、より好適には、臭素原子である。）を示し、Ｙは、有機合成化学の分野で使用されるカルボキシ基の保護基（好適には、Ｃ１－Ｃ６アルキル基であり、より好適には、メチル基である。）を示す。Ｒａは、Ｒの基に置換基として含まれるアミノ基、ヒドロキシ基及び／又はカルボキシ基が、保護されてもよいアミノ基、ヒドロキシ基及び／又はカルボキシ基である他、Ｒの基の定義における基と同様の基を示す。 R, Q, U, V, m, and n have the same meaning as described above in the reaction of each step of the following methods A to C. X represents a halogen atom (preferably a bromine atom or an iodine atom, more preferably a bromine atom), and Y represents a protecting group for a carboxy group used in the field of synthetic organic chemistry ( Preferred is a C 1 -C 6 alkyl group, and more preferred is a methyl group. R a is an amino group, hydroxy group and / or carboxy group which may be protected as an amino group, hydroxy group and / or carboxy group contained as a substituent in the R group, and in the definition of the R group. A group similar to the group is shown.
　Ａ法は、一般式（Ｉ）で表される化合物を製造する方法である。
（Ａ法） Method A is a method for producing a compound represented by the general formula (I).
(Method A)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　Ａ－Ｉ工程
　本工程は、溶媒中、光延試薬の存在下、一般式（ＩＩ）で表される化合物を、一般式（ＩＩＩ）で表される化合物と反応させることにより、一般式（ＩＶ）で表される化合物を製造する工程である。 Step AI This step comprises reacting a compound represented by the general formula (II) with a compound represented by the general formula (III) in a solvent in the presence of a Mitsunobu reagent. It is a process of manufacturing the compound represented by these.
　本工程において使用される一般式（ＩＩ）で表される化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。 The compound represented by the general formula (II) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
　本工程において使用される一般式（ＩＩＩ）で表される化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。 The compound represented by the general formula (III) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
　本工程において使用される溶媒は、好適には、芳香族炭化水素類又はエーテル類であり、より好適には、トルエン又はテトラヒドロフランである。 The solvent used in this step is preferably aromatic hydrocarbons or ethers, and more preferably toluene or tetrahydrofuran.
　本工程において使用される光延試薬は、好適には、アゾジカルボン酸ジエステル又は（シアノメチレン）ホスホラン試薬であり、より好適には、アゾジカルボン酸ジエチル（DEAD）、アゾジカルボン酸ジイソプロピル（DIAD）又は（シアノメチレン）トリブチルホスホラン（CMBP）である。 The Mitsunobu reagent used in this step is preferably an azodicarboxylic acid diester or (cyanomethylene) phosphorane reagent, more preferably diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or ( Cyanomethylene) tributylphosphorane (CMBP).
　本工程における反応温度は、通常、－２０℃乃至１８０℃であり、好適には、０℃乃至１２０℃である。 The reaction temperature in this step is usually −20 ° C. to 180 ° C., preferably 0 ° C. to 120 ° C.
　本工程における反応時間は、通常、０．５時間乃至７２時間であり、好適には、２時間乃至２４時間である。 The reaction time in this step is usually 0.5 hours to 72 hours, preferably 2 hours to 24 hours.
　Ａ－ＩＩ工程
　本工程は、溶媒中、パラジウム触媒及び塩基の存在下、一般式（ＩＶ）で表される化合物を、化合物（Ｖ）と反応させることにより、一般式（ＶＩ）で表される化合物を製造する工程である。 Step A-II This step is represented by the general formula (VI) by reacting the compound represented by the general formula (IV) with the compound (V) in the presence of a palladium catalyst and a base in a solvent. This is a process for producing a compound.
　本工程において使用される溶媒は、好適には、エーテル類又はアミド類と水の混合溶媒であり、より好適には、テトラヒドロフラン、ジオキサン又はＮ，Ｎ－ジメチルアセトアミドと水の混合溶媒である。 The solvent used in this step is preferably a mixed solvent of ethers or amides and water, more preferably a mixed solvent of tetrahydrofuran, dioxane or N, N-dimethylacetamide and water.
　本工程において使用されるパラジウム触媒は、好適には、０価のパラジウム触媒であり、より好適には、テトラキス（トリフェニルホスフィン）パラジウム（０）である。 The palladium catalyst used in this step is preferably a zero-valent palladium catalyst, and more preferably tetrakis (triphenylphosphine) palladium (0).
　本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウムである。 The base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
　本工程における反応温度は、通常、２０℃乃至１８０℃であり、好適には、６０℃乃至１２０℃である。 The reaction temperature in this step is usually 20 ° C. to 180 ° C., preferably 60 ° C. to 120 ° C.
　本工程における反応時間は、通常、０．５時間乃至７２時間であり、好適には、２時間乃至２４時間である。 The reaction time in this step is usually 0.5 hours to 72 hours, preferably 2 hours to 24 hours.
　Ａ－ＩＩＩ工程
　本工程は、溶媒中、一般式（ＶＩ）で表される化合物を、一般式（ＶＩＩ）で表される化合物と反応させることにより、一般式（ＶＩＩＩ）で表される化合物を製造する工程である。 Step A-III In this step, the compound represented by the general formula (VIII) is reacted with the compound represented by the general formula (VII) in a solvent to react the compound represented by the general formula (VIII). It is a manufacturing process.
　本工程において使用される一般式（ＶＩＩ）で表される化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。 The compound represented by the general formula (VII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
　本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、テトラヒドロフランである。 The solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
　本工程における反応温度は、通常、－７８℃乃至１８０℃であり、好適には、０℃乃至８０℃である。 The reaction temperature in this step is usually −78 ° C. to 180 ° C., preferably 0 ° C. to 80 ° C.
　本工程における反応時間は、通常、０．１時間乃至７２時間であり、好適には、０．５時間乃至２４時間である。 The reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
　Ａ－ＩＶ工程
　本工程は、既知の方法（例えば、”Protective Groups in Organic Synthesis” (Theodora W. Greene、Peter G. M.Wuts著、 1999年、Wiley-Interscience Publication発行)等に記載の方法）に準じて、一般式（ＶＩＩＩ）で表される化合物を反応させた後、所望によりＲａにおけるアミノ基、ヒドロキシ基及び／又はカルボキシ基の保護基を除去することにより、一般式（Ｉ）で表される化合物を製造する工程である。例えば、ＹがＣ１－Ｃ６アルキル基の場合を下記に示す。 Step A-IV This step is based on a known method (for example, “Protective Groups in Organic Synthesis” (the method described in Theodora W. Greene, Peter GMWuts, 1999, published by Wiley-Interscience Publication), etc.). , After reacting the compound represented by the general formula (VIII), the protecting group of the amino group, hydroxy group and / or carboxy group in R a is optionally removed, thereby being represented by the general formula (I). This is a process for producing a compound. For example, the case where Y is a C 1 -C 6 alkyl group is shown below.
　本工程において使用される溶媒は、好適には、エーテル類又はアルコール類であり、より好適には、テトラヒドロフラン、ジオキサン又はメタノールである。 The solvent used in this step is preferably an ether or an alcohol, and more preferably tetrahydrofuran, dioxane or methanol.
　本工程において使用される塩基は、好適には、四級アンモニウム塩類であり、より好適には、水酸化テトラブチルアンモニウムである。 The base used in this step is preferably a quaternary ammonium salt, and more preferably tetrabutylammonium hydroxide.
　本工程における反応温度は、通常、０℃乃至１５０℃であり、好適には２０℃乃至１００℃である。 The reaction temperature in this step is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
　本反応における反応時間は、通常、０．５時間乃至２４時間であり、好適には１時間乃至１０時間である。 The reaction time in this reaction is usually 0.5 to 24 hours, preferably 1 to 10 hours.
　Ｂ法は、前記Ａ法のＡ－ＩＶ工程で用いる一般式（ＶＩＩＩ）で表される化合物を製造する方法である。
（Ｂ法） Method B is a method for producing a compound represented by the general formula (VIII) used in the A-IV step of Method A.
(Method B)
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　Ｂ－Ｉ工程
　本工程は、溶媒中、塩基の存在下、一般式（ＶＩ）で表される化合物を、化合物（ＩＸ）と反応させ、更に、溶媒中、塩基の存在下、一般式（Ｘ）で表される化合物と反応させることにより、一般式（ＶＩＩＩ）で表される化合物を製造する工程である。 Step BI In this step, the compound represented by the general formula (VI) is reacted with the compound (IX) in the presence of a base in a solvent, and further the general formula (X) in the presence of a base in a solvent. ) To produce a compound represented by the general formula (VIII).
　本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。 The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
　本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、トリエチルアミンである。 The base used in this step is preferably an organic base, and more preferably triethylamine.
　本工程における反応温度は、通常、－７８℃乃至１００℃であり、好適には、０℃乃至４０℃である。 The reaction temperature in this step is usually −78 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
　本工程における反応時間は、通常、０．１時間乃至７２時間であり、好適には、０．５時間乃至２４時間である。 The reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
　Ｃ法は、前記Ａ法のＡ－ＩＶ工程で用いる一般式（ＶＩＩＩ）で表される化合物を製造する方法である。
（Ｃ法） Method C is a method for producing a compound represented by the general formula (VIII) used in Step A-IV of Method A.
(Method C)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　Ｃ－Ｉ工程
　本工程は、溶媒中、一般式（ＶＩ）で表される化合物を、化合物（ＸＩ）と反応させることにより、一般式（ＸＩＩ）で表される化合物を製造する工程である。 Step CI This step is a step for producing a compound represented by the general formula (XII) by reacting a compound represented by the general formula (VI) with a compound (XI) in a solvent.
　本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。 The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
　本工程における反応温度は、通常、－７８℃乃至１２０℃であり、好適には、０℃乃至４０℃である。 The reaction temperature in this step is usually −78 ° C. to 120 ° C., preferably 0 ° C. to 40 ° C.
　本工程における反応時間は、通常、０．１時間乃至７２時間であり、好適には、０．５時間乃至２４時間である。 The reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
　Ｃ－ＩＩ工程
　本工程は、溶媒中、一般式（ＸＩＩ）で表される化合物を、一般式（Ｘ）で表される化合物と反応させることにより、一般式（ＶＩＩＩ）で表される化合物を製造する工程である。 Step C-II In this step, the compound represented by the general formula (VIII) is reacted with the compound represented by the general formula (X) in a solvent to react the compound represented by the general formula (VIII). It is a manufacturing process.
　本工程において使用される溶媒は、好適には、エーテル類、ニトリル類、ニトロ化合物類、アミド類又は炭化水素類であり、より好適には、テトラヒドロフラン、アセトニトリル、ニトロベンゼン、Ｎ，Ｎ－ジメチルアセトアミド又はヘキサンである。 The solvent used in this step is preferably an ether, nitrile, nitro compound, amide or hydrocarbon, and more preferably tetrahydrofuran, acetonitrile, nitrobenzene, N, N-dimethylacetamide or Hexane.
　本工程における反応温度は、通常、－７８℃乃至１８０℃であり、好適には、０℃乃至１２０℃である。 The reaction temperature in this step is usually −78 ° C. to 180 ° C., preferably 0 ° C. to 120 ° C.
　本工程における反応時間は、通常、０．１時間乃至７２時間であり、好適には、０．５時間乃至２４時間である。 The reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
　上記において、Ｒａの定義における「保護されてもよいアミノ基」、「保護されてもよいヒドロキシ基」及び／又は「保護されてもよいカルボキシ基」の保護基とは、加水素分解、加水分解、電気分解、光分解のような化学的方法により開裂し得る保護基をいい、有機合成化学で一般的に用いられる保護基を示す（例えば、T. W. Greeneら，Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. （1999年）参照）。 In the above, the protecting group of “amino group that may be protected”, “hydroxy group that may be protected” and / or “carboxy group that may be protected” in the definition of R a is hydrogenolysis, hydrolysis, A protecting group that can be cleaved by chemical methods such as decomposition, electrolysis, and photolysis, and indicates a protecting group commonly used in organic synthetic chemistry (eg, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition , John Wiley & Sons, Inc. (1999)).
　上記において、Ｒａの定義における「保護されてもよいヒドロキシ基」の「保護基」は、有機合成化学の分野で使用されるヒドロキシ基の保護基であれば特に限定はされないが、例えば、ホルミル基、前記「Ｃ２－Ｃ７アルキルカルボニル基」、クロロアセチル、ジクロロアセチル、トリクロロアセチル、トリフルオロアセチルのようなハロゲン化アルキルカルボニル基、メトキシアセチルのようなアルコキシアルキルカルボニル基、アクリロイル、プロピオロイル、メタクリロイル、クロトノイル、イソクロトノイル、（Ｅ）－２－メチル－２－ブテノイルのような不飽和アルキルカルボニル基等の「アルキルカルボニル基」；ベンゾイル、α－ナフトイル、β－ナフトイルのようなアリールカルボニル基、２－ブロモベンゾイル、４－クロロベンゾイルのようなハロゲン化アリールカルボニル基、２，４，６－トリメチルベンゾイル、４－トルオイルのようなアルキル化アリ－ルカルボニル基、４－アニソイルのようなアルコキシ化アリールカルボニル基、４－ニトロベンゾイル、２－ニトロベンゾイルのようなニトロ化アリールカルボニル基、２－（メトキシカルボニル）ベンゾイルのようなアルコキシカルボニル化アリールカルボニル基、４－フェニルベンゾイルのようなアリール化アリールカルボニル基等の「アリールカルボニル基」；前記「Ｃ２－Ｃ７アルコキシカルボニル基」、２，２，２－トリクロロエトキシカルボニル、２－トリメチルシリルエトキシカルボニルのようなハロゲン又はトリアルキルシリル基で置換されたアルコキシカルボニル基等の「アルコキシカルボニル基」；テトラヒドロピラン－２－イル、３－ブロモテトラヒドロピラン－２－イル、４－メトキシテトラヒドロピラン－４－イル、テトラヒドロチオピラン－２－イル、４－メトキシテトラヒドロチオピラン－４－イルのような「テトラヒドロピラニル又はテトラヒドロチオピラニル基」；テトラヒドロフラン－２－イル、テトラヒドロチオフラン－２－イルのような「テトラヒドロフラニル又はテトラヒドロチオフラニル基」；トリメチルシリル、トリエチルシリル、イソプロピルジメチルシリル、ｔ－ブチルジメチルシリル、メチルジイソプロピルシリル、メチルジ－ｔ－ブチルシリル、トリイソプロピルシリルのようなトリアルキルシリル基、ジフェニルメチルシリル、ジフェニルブチルシリル、ジフェニルイソプロピルシリル、フェニルジイソプロピルシリルのようなアルキルジアリールシリル又はジアルキルアリールシリル基等の「シリル基」；メトキシメチル、１，１－ジメチル－１－メトキシメチル、エトキシメチル、プロポキシメチル、イソプロポキシメチル、ブトキシメチル、ｔ－ブトキシメチルのようなアルコキシメチル基、２－メトキシエトキシメチルのようなアルコキシアルコキシメチル基、２，２，２－トリクロロエトキシメチル、ビス（２－クロロエトキシ）メチルのようなハロゲン化アルコキシメチル等の「アルコキシメチル基」；１－エトキシエチル、１－（イソプロポキシ）エチルのようなアルコキシエチル基、２，２，２－トリクロロエチルのようなハロゲン化エチル基等の「置換エチル基」；ベンジル、α－ナフチルメチル、β－ナフチルメチル、ジフェニルメチル、トリフェニルメチル、α－ナフチルジフェニルメチル、９－アンスリルメチルのような１乃至３個のアリール基で置換されたアルキル基、４－メチルベンジル、２，４，６－トリメチルベンジル、３，４，５－トリメチルベンジル、４－メトキシベンジル、４－メトキシフェニルジフェニルメチル、２－ニトロベンジル、４－ニトロベンジル、４－クロロベンジル、４－ブロモベンジル、４－シアノベンジルのような（アルキル、アルコキシ、ニトロ、ハロゲン、シアノ基でアリール環が置換された１乃至３個のアリール基）で置換されたアルキル基等の「アラルキル基」；ビニルオキシカルボニル、アリルオキシカルボニルのような「アルケニルオキシカルボニル基」；ベンジルオキシカルボニル、４－メトキシベンジルオキシカルボニル、３，４－ジメトキシベンジルオキシカルボニル、２－ニトロベンジルオキシカルボニル、４－ニトロベンジルオキシカルボニルのような、１又は２個のアルコキシ又はニトロ基でアリール環が置換されていてもよい「アラルキルオキシカルボニル基」であり、好適には、アルキルカルボニル基、シリル基又はアラルキル基である。 In the above, the “protecting group” of the “hydroxy group that may be protected” in the definition of R a is not particularly limited as long as it is a protecting group for a hydroxy group used in the field of synthetic organic chemistry. Group, the aforementioned “C 2 -C 7 alkylcarbonyl group”, halogenated alkylcarbonyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, alkoxyalkylcarbonyl group such as methoxyacetyl, acryloyl, propioroyl, methacryloyl , “Alkylcarbonyl groups” such as unsaturated alkylcarbonyl groups such as crotonoyl, isocrotonoyl, (E) -2-methyl-2-butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, 2- Bromobenzoyl, 4- Halogenated arylcarbonyl groups such as lolobenzoyl, 2,4,6-trimethylbenzoyl, alkylated arylcarbonyl groups such as 4-toluoyl, alkoxylated arylcarbonyl groups such as 4-anisoyl, 4-nitrobenzoyl "Arylcarbonyl groups" such as 2-nitrobenzoyl nitrated arylcarbonyl groups, 2- (methoxycarbonyl) benzoyl alkoxycarbonylated arylcarbonyl groups, 4-phenylbenzoyl arylated arylcarbonyl groups, etc. The “C 2 -C 7 alkoxycarbonyl group”, “alkoxycarbonyl group substituted with halogen or trialkylsilyl group such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl” Xyloxycarbonyl group "; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl “Tetrahydropyranyl or tetrahydrothiopyranyl group” such as “tetrahydrofuranyl or tetrahydrothiofuranyl group” such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl , T-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, trialkylsilyl groups such as triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropyl “Silyl groups” such as alkyldiarylsilyl or dialkylarylsilyl groups such as silyl, phenyldiisopropylsilyl; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, alkoxymethyl group such as t-butoxymethyl, alkoxyalkoxymethyl group such as 2-methoxyethoxymethyl, halogenated alkoxymethyl such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, etc. “Substituted ethyl groups” such as 1-ethoxyethyl, alkoxyethyl groups such as 1- (isopropoxy) ethyl, and halogenated ethyl groups such as 2,2,2-trichloroethyl; benzyl , Α-naphthylmethyl, alkyl groups substituted with 1 to 3 aryl groups such as β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6 -Trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl An “aralkyl group” such as an alkyl group substituted with (an aryl group substituted with an aryl ring with an alkyl, alkoxy, nitro, halogen, cyano group) such as vinyloxycarbonyl, allyloxycarbonyl "Alkenyloxycarbonyl group"; benzyloxycarbonyl, The aryl ring is substituted with one or two alkoxy or nitro groups, such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl. Or an “aralkyloxycarbonyl group”, preferably an alkylcarbonyl group, a silyl group or an aralkyl group.
　上記において、Ｒａの定義における「保護されてもよいカルボキシ基」の「保護基」は、有機合成化学の分野で使用されるカルボキシ基の保護基であれば特に限定はされないが、例えば、前記「Ｃ１－Ｃ６アルキル基」；エテニル、１－プロペニル、２－プロペニル、１－メチル－２－プロペニルのような「アルケニル基」；エチニル、１－プロピニル、２－プロピニル、１－メチル－２－プロピニルのような「アルキニル基」；前記「Ｃ１－Ｃ６ハロゲン化アルキル基」；ヒドロキシメチル、２－ヒドロキシエチルのようなヒドロキシアルキル基；アセチルメチルのようなアルキルカルボニルアルキル基；前記「アラルキル基」；又は前記「シリル基」であり、好適には、Ｃ１－Ｃ６アルキル基又はアラルキル基である。 In the above, the “protecting group” of the “carboxy group that may be protected” in the definition of R a is not particularly limited as long as it is a protecting group for a carboxy group used in the field of synthetic organic chemistry. “C 1 -C 6 alkyl group”; “alkenyl group” such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl; ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2 An “alkynyl group” such as propynyl; the aforementioned “C 1 -C 6 halogenated alkyl group”; a hydroxyalkyl group such as hydroxymethyl, 2-hydroxyethyl; an alkylcarbonylalkyl group such as acetylmethyl; Group ”; or the above-mentioned“ silyl group ”, preferably a C 1 -C 6 alkyl group or an aralkyl group.
　上記において、Ｒａの定義における「保護されてもよいアミノ基」の「保護基」は、有機合成化学の分野で使用されるアミノ基の保護基であれば特に限定はされないが、例えば、前記「ヒドロキシ基の保護基」における、「アルキルカルボニル基」；「アリールカルボニル基」；「アルコキシカルボニル基」；「シリル基」；「アラルキル基」；「アルケニルオキシカルボニル基」；又は「アラルキルオキシカルボニル基」と同様な基を示すか或いはＮ，Ｎ－ジメチルアミノメチレン、ベンジリデン、４－メトキシベンジリデン、４－ニトロベンジリデン、サリシリデン、５－クロロサリシリデン、ジフェニルメチレン、（５－クロロ－２－ヒドロキシフェニル）フェニルメチレンのような「シッフ塩基を形成する置換されたメチレン基」であり、好適には、アルキルカルボニル基、アリールカルボニル基又はアルコキシカルボニル基であり、より好適には、アルコキシカルボニル基である。 In the above, "protecting group" of the "protected or an amino group" in the definition of R a is not particularly limited as long as it is a protecting group for amino groups used in the field of organic synthetic chemistry, for example, the “Alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; “silyl group”; “aralkyl group”; “alkenyloxycarbonyl group”; or “aralkyloxycarbonyl group” N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) ) “Substituted methylene groups forming Schiff bases” such as phenylmethylene And preferably an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, and more preferably an alkoxycarbonyl group.
　保護・脱保護が必要な工程は、既知の方法（例えば、”Protective Groups in Organic Synthesis” (Theodora W. Greene、Peter G. M.Wuts著、 1999年、Wiley-Interscience Publication発行)等に記載の方法）に準じて行われる。 Processes that require protection / deprotection are described in known methods (for example, “Protective Groups in Organic Synthesis” (written by Theodora W. Greene, Peter G. M.Wuts, 1999, published by Wiley-Interscience Publication)). Method).
　本発明の化合物又はその薬理上許容される塩は、種々の形態で投与することができる。その投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、乳剤、丸剤、散剤、シロップ剤（液剤）等による経口投与、または注射剤（静脈内、筋肉内、皮下または腹腔内投与）、点滴剤、坐剤（直腸投与）等による非経口投与を挙げることができる。これらの各種製剤は、常法に従って主薬に賦形剤、結合剤、崩壊剤、滑沢剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤等の医薬の製剤技術分野において通常使用し得る補助剤を用いて製剤化することができる。 The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration). These various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. as main ingredients in accordance with conventional methods. It can be formulated with the resulting adjuvant.
　錠剤として使用する場合、担体として、例えば、乳糖、白糖、塩化ナトリウム、グルコース、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤；水、エタノール、プロパノール、単シロップ、グルコース液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤；乾燥デンプン、アルギン酸ナトリウム、寒天末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖等の崩壊剤；白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤；第４級アンモニウム塩類、ラウリル硫酸ナトリウム等の吸収促進剤；グリセリン、デンプン等の保湿剤；デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤；精製タルク、ステアリン酸塩、硼酸末、ポリエチレングリコール等の潤沢剤等を使用することができる。また、必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。 When used as a tablet, as a carrier, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; disintegrators such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Use of lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can do. Moreover, it can be set as the tablet which gave the normal coating as needed, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
　丸剤として使用する場合、担体として、例えば、グルコース、乳糖、カカオバター、デンプン、硬化植物油、カオリン、タルク等の賦形剤；アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤；ラミナラン、寒天等の崩壊剤等を使用することができる。 When used as pills, as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.
　坐剤として使用する場合、担体としてこの分野で従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオバター、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセリド等を挙げることができる。 When used as a suppository, a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.
　注射剤として使用する場合、液剤、乳剤または懸濁剤として使用することができる。これらの液剤、乳剤または懸濁剤は、滅菌され、血液と等張であることが好ましい。これら液剤、乳剤または懸濁剤の製造に用いる溶媒は、医療用の希釈剤として使用できるものであれば特に限定はなく、例えば、水、エタノール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。なお、この場合、等張性の溶液を調製するのに充分な量の食塩、グルコースまたはグリセリンを製剤中に含んでいてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を含んでいてもよい。 When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.
　また、上記の製剤には、必要に応じて、着色剤、保存剤、香料、風味剤、甘味剤等を含めることもでき、更に、他の医薬品を含めることもできる。 In addition, the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.
　上記製剤に含まれる有効成分化合物の量は、特に限定されず広範囲に適宜選択されるが、通常、全組成物中０．５乃至７０重量％、好ましくは１乃至３０重量％含む。 The amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.
　その使用量は患者（温血動物、特に人間）の症状、年齢等により異なるが、経口投与の場合には、１日あたり、上限として２０００ｍｇ（好ましくは１００ｍｇ）であり、下限として０．１ｍｇ（好ましくは１ｍｇ、さらに好ましくは１０ｍｇ）を成人に対して、１日当り１乃至６回症状に応じて投与することが望ましい。 The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.
　以下、実施例および試験例を挙げて、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.
　実施例のカラムクロマトグラフィーにおける溶出はTLC(Thin Layer Chromatography,薄層クロマトグラフィー)による観察下に行われた。TLC観察においては、TLCプレートとしてメルク（Merck)社製のシリカゲル60F254を、展開溶媒としてはカラムクロマトグラフィーで溶出溶媒として用いられた溶媒を、検出法としてUV検出器を採用した。カラム用シリカゲルは同じくメルク社製のシリカゲルSK-85(230～400メッシュ)、もしくは富士シリシア化学　Chromatorex NH（200 - 350メッシュ)を用いた。通常のカラムクロマトグラフィーの他に、昭光サイエンティフィック社の自動クロマトグラフィー装置（Purif-α2　もしくは　Purif-espoir2　)を適宜使用した。溶出溶媒は各実施例で指定した溶媒を指定された比率で用いた。（もしくは適宜必要に応じて比率を変化させた。）尚、実施例で用いる略号は、次のような意義を有する。
mg : ミリグラム，g : グラム，mL: ミリリットル，MHz : メガヘルツ。 Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, silica gel 60F 254 manufactured by Merck was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. As silica gel for the column, silica gel SK-85 (230-400 mesh) manufactured by Merck Co., Ltd. or Fuji Silysia Chemical Chromatorex NH (200-350 mesh) was used. In addition to ordinary column chromatography, an automatic chromatography apparatus (Purif-α2 or Purif-espoir2) manufactured by Shoko Scientific was used as appropriate. As the elution solvent, the solvent specified in each example was used at the specified ratio. (Or, the ratio was changed as necessary.) The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz.
　以下の実施例において、核磁気共鳴（以下、1H NMR)スペクトルは、テトラメチルシランを標準物質として、ケミカルシフト値をδ値(ppm)にて記載した。***パターンは一重線をs、二重線をd、三重線をt、四重線をq、多重線をm、ブロードをbrで示した。 In the following examples, nuclear magnetic resonance (hereinafter, 1 H NMR) spectra are described with chemical shift values expressed as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, m for multiple lines, and br for broad lines.
　質量分析（以下、MS)は、EI(Electron Ionization)法、ESI（Electron Spray Ionization)法、もしくはFAB(Fast Atom Bombardment)法で行った。 Mass spectrometry (hereinafter referred to as MS) was performed by EI (Electron Ionization) method, ESI (Electron Spray Ionization) method, or FAB (Fast Atom Bombardment) method.
　(実施例１)
(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 1)
(cis-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　（１ａ）　{cis-4-[(5-ブロモピリミジン-2-イル)オキシ]シクロヘキシル}酢酸メチルエステル
　(trans-4-ヒドロキシシクロヘキシル) 酢酸メチルエステル　（WO2009119534）（2.58 g）と5-ブロモピリミジン-2-オール（1.74 g）のトルエン（30 mL）溶液にシアノメチレントリブチルホスホラン（CMBP）（3.93 mL）を室温で加えた。反応混合物を120℃で9時間加熱し、室温に冷却し、飽和塩化アンモニウム水溶液で希釈し、そして酢酸エチルで抽出した。有機層を水で洗浄し、濃縮した。残渣物をクロマトグラフィーで精製し（自動クロマトグラフィー装置、ヘキサン／酢酸エチル　100:0→80:20）、標記化合物 1.67 g（51%）を薄黄色オイルとして得た。
1H NMR (500MHz, CDCl3)：δ(ppm) = 8.51 (2H, s), 5.23-5.18 (1H, m), 3.67 (3H, s), 2.28 (2H, d, J = 6.8 Hz), 2.09-1.89 (3H, m), 1.69-1.43 (6H, m)。 (1a) {cis-4-[(5-Bromopyrimidin-2-yl) oxy] cyclohexyl} acetic acid methyl ester (trans-4-hydroxycyclohexyl) acetic acid methyl ester (WO2009119534) (2.58 g) and 5-bromopyrimidine- Cyanomethylenetributylphosphorane (CMBP) (3.93 mL) was added to a toluene (30 mL) solution of 2-ol (1.74 g) at room temperature. The reaction mixture was heated at 120 ° C. for 9 hours, cooled to room temperature, diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The residue was purified by chromatography (automatic chromatography apparatus, hexane / ethyl acetate 100: 0 → 80: 20) to give 1.67 g (51%) of the title compound as a pale yellow oil.
1 H NMR (500MHz, CDCl 3 ): δ (ppm) = 8.51 (2H, s), 5.23-5.18 (1H, m), 3.67 (3H, s), 2.28 (2H, d, J = 6.8 Hz), 2.09-1.89 (3H, m), 1.69-1.43 (6H, m).
　（１ｂ）　(cis-4-{[5-(4-アミノフェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸メチルエステル
　実施例(１ａ)で得た化合物（1.67 g)、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（1.11 g)、テトラキス(トリフェニルホスフィン)パラジウム(0)（295 mg)、そして炭酸カリウム（1.41 g)の1,4-ジオキサン／水（7:3, 30 mL)溶液を80 ℃で2時間加熱した。反応混合物を酢酸エチルで希釈し、水で洗浄し、そして濃縮した。残渣物をクロマトグラフィー（自動クロマトグラフィー装置、ジクロロメタン／酢酸エチル 100:0→85:15)で精製し、標記化合物 1.59 g（92%)を黄色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.64(2H, s), 7.32(2H, d, J=8.6Hz), 6.79(2H, d, J=8.2Hz), 5.29(1H, brs), 3.80(2H, brs), 3.68(3H, s), 2.29(2H, d, J=7.0Hz), 2.13-2.09(2H, m), 1.97-1.91(1H, m), 1.72-1.55(6H, m)。 (1b) (cis-4-{[5- (4-Aminophenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid methyl ester Compound (1.67 g) obtained in Example (1a) (4- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.11 g), tetrakis (triphenylphosphine) palladium (0) (295 mg), and potassium carbonate (1.41 g) A 1,4-dioxane / water (7: 3, 30 mL) solution was heated at 80 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and concentrated. The residue was purified by chromatography (automatic chromatography apparatus, dichloromethane / ethyl acetate 100: 0 → 85: 15) to obtain 1.59 g (92%) of the title compound as a yellow solid.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.64 (2H, s), 7.32 (2H, d, J = 8.6Hz), 6.79 (2H, d, J = 8.2Hz), 5.29 (1H, brs), 3.80 (2H, brs), 3.68 (3H, s), 2.29 (2H, d, J = 7.0Hz), 2.13-2.09 (2H, m), 1.97-1.91 (1H, m), 1.72-1.55 (6H, m).
　（１ｃ）　(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸メチルエステル
　実施例（１ｂ）で得た化合物（205 mg）のテトラヒドロフラン（6 mL）溶液に２－フルオロフェニルイソシアナート（0.088 mL）を室温で加えた。反応混合物を一晩撹拌し濃縮した。残渣物をカラムクロマトグラフィー（自動クロマトグラフィー装置、ジクロロメタン／酢酸エチル 100:0→75:25）で精製し、標記化合物 251 mg（87%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=9.28(1H, brs), 8.88(2H, s), 8.65(1H, brs), 8.16(1H, dt, J=11.7 and 4.1Hz), 7.67(2H, d, J=8.6Hz), 7.58(2H, d, J=9.0Hz), 7.29-7.23(1H, m), 7.18-7.14(1H, m), 7.06-7.00(1H, m), 5.22-5.21(1H, m), 3.60(3H, s), 2.30(2H, d, J=7.0Hz), 1.98-1.93(2H, m), 1.89-1.83(1H, m), 1.72-1.63(2H, m), 1.59-1.55(2H, m), 1.42-1.34(2H, m)。 (1c) (cis-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid methyl ester obtained in Example (1b) To a solution of the compound (205 mg) in tetrahydrofuran (6 mL) was added 2-fluorophenyl isocyanate (0.088 mL) at room temperature. The reaction mixture was stirred overnight and concentrated. The residue was purified by column chromatography (automatic chromatography apparatus, dichloromethane / ethyl acetate 100: 0 → 75: 25) to obtain 251 mg (87%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 9.28 (1H, brs), 8.88 (2H, s), 8.65 (1H, brs), 8.16 (1H, dt, J = 11.7 and 4.1Hz ), 7.67 (2H, d, J = 8.6Hz), 7.58 (2H, d, J = 9.0Hz), 7.29-7.23 (1H, m), 7.18-7.14 (1H, m), 7.06-7.00 (1H, m), 5.22-5.21 (1H, m), 3.60 (3H, s), 2.30 (2H, d, J = 7.0Hz), 1.98-1.93 (2H, m), 1.89-1.83 (1H, m), 1.72 -1.63 (2H, m), 1.59-1.55 (2H, m), 1.42-1.34 (2H, m).
　（１ｄ）　(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸
　実施例（１ｃ)で得た化合物（251 mg)の１，４－ジオキサン（6 mL)溶液に、水酸化テトラブチルアンモニウム（1 mol/L 水溶液、1.1 mL)を室温で加えた。一晩撹拌後、反応混合物を濃縮し、1 N 塩酸水溶液（1.1 mL)で中和した。混合物に酢酸エチルとイソプロピルエーテルを加え、激しく撹拌し、そしてろ取した。得られた固体を減圧下乾燥し、標記化合物 229 mg (94%) を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.29(1H, s), 8.88(2H, s), 8.66(1H, s), 8.16(1H, dt, J=11.6 and 4.2Hz), 7.67(2H, d, J=9.0Hz), 7.58(2H, d, J=9.0Hz), 7.28-7.23(1H, m), 7.16(1H, dt, J=10.9 and 3.9Hz), 7.06-7.00(1H, m), 5.22-5.20(1H, m), 2.18(2H, d, J=7.0Hz), 1.98-1.93(2H, m), 1.87-1.80(1H, m), 1.72-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.34(2H, m).
MS(ESI) m/z:465 (M + H)+。 (1d) (cis-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid Compound (1) obtained in Example (1c) ( To a solution of 251 mg) of 1,4-dioxane (6 mL), tetrabutylammonium hydroxide (1 mol / L aqueous solution, 1.1 mL) was added at room temperature. After stirring overnight, the reaction mixture was concentrated and neutralized with 1 N aqueous hydrochloric acid (1.1 mL). Ethyl acetate and isopropyl ether were added to the mixture, stirred vigorously and collected by filtration. The obtained solid was dried under reduced pressure to obtain 229 mg (94%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.29 (1H, s), 8.88 (2H, s), 8.66 (1H, s), 8.16 (1H, dt , J = 11.6 and 4.2Hz), 7.67 (2H, d, J = 9.0Hz), 7.58 (2H, d, J = 9.0Hz), 7.28-7.23 (1H, m), 7.16 (1H, dt, J = 10.9 and 3.9Hz), 7.06-7.00 (1H, m), 5.22-5.20 (1H, m), 2.18 (2H, d, J = 7.0Hz), 1.98-1.93 (2H, m), 1.87-1.80 (1H , m), 1.72-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.34 (2H, m).
MS (ESI) m / z: 465 (M + H) <+> .
　（実施例２）
(cis-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 2)
(cis-4-{[5- (4-{[(4-Methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（171 mg）と４－メチルフェニルイソシアナート（0.082 mL）からウレア体 198 mg（84%）を白色固体として得た。このウレア体（198 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 155 mg（81%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.87(2H, s), 8.83(1H, s), 8.66(1H, s), 7.64(2H, d, J=9.0Hz), 7.57(2H, d, J=9.0Hz), 7.35(2H, d, J=8.6Hz), 7.10(2H, d, J=8.2Hz), 5.22-5.20(1H, m), 2.25(3H, s), 2.19(2H, d, J=7.1Hz), 1.97-1.93(2H, m), 1.86-1.81(1H, m), 1.71-1.63(2H, m), 1.60-1.56(2H, m), 1.43-1.32(2H, m).
MS(ESI) m/z:461 (M + H)+。 In the same manner as in Example (1c), 198 mg (84%) of urea was obtained as a white solid from the compound (171 mg) obtained in Example (1b) and 4-methylphenyl isocyanate (0.082 mL). . This urea compound (198 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 155 mg (81%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.87 (2H, s), 8.83 (1H, s), 8.66 (1H, s), 7.64 (2H, d , J = 9.0Hz), 7.57 (2H, d, J = 9.0Hz), 7.35 (2H, d, J = 8.6Hz), 7.10 (2H, d, J = 8.2Hz), 5.22-5.20 (1H, m ), 2.25 (3H, s), 2.19 (2H, d, J = 7.1Hz), 1.97-1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H, m), 1.60- 1.56 (2H, m), 1.43-1.32 (2H, m).
MS (ESI) m / z: 461 (M + H) <+> .
　（実施例３）
{cis-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸 (Example 3)
{cis-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（102 mg）とフェニルイソシアナート（0.042 mL）からウレア体 130 mg（94%）を白色固体として得た。このウレア体（85 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 58 mg（71%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, s), 8.87(2H, s), 8.87(1H, s), 8.76(1H, s), 7.65(2H, d, J=8.6Hz), 7.58(2H, d, J=9.0Hz), 7.47(2H, d, J=7.4Hz), 7.30(2H, dd, J=8.0 and 8.0Hz), 6.98(1H, dd, J=7.4 and 7.4Hz), 5.22-5.20(1H, m), 2.20-2.18(2H, m), 1.98-1.93(2H, m), 1.86-1.81(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:447 (M + H)+。 In the same manner as in Example (1c), 130 mg (94%) of urea was obtained as a white solid from the compound (102 mg) obtained in Example (1b) and phenyl isocyanate (0.042 mL). This urea compound (85 mg) was hydrolyzed in the same way as in Example (1d) to obtain 58 mg (71%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, s), 8.87 (2H, s), 8.87 (1H, s), 8.76 (1H, s), 7.65 (2H, d , J = 8.6Hz), 7.58 (2H, d, J = 9.0Hz), 7.47 (2H, d, J = 7.4Hz), 7.30 (2H, dd, J = 8.0 and 8.0Hz), 6.98 (1H, dd , J = 7.4 and 7.4Hz), 5.22-5.20 (1H, m), 2.20-2.18 (2H, m), 1.98-1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H , m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 447 (M + H) <+> .
　（実施例４）
(cis-4-{[5-(4-{[(3-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 Example 4
(cis-4-{[5- (4-{[(3-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（68 mg）と３－フルオロフェニルイソシアナート（0.029 mL）からウレア体 89 mg（94%）を白色固体として得た。このウレア体（89 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 66 mg（76%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.12(1H, brs), 9.05(1H, brs), 8.87(2H, s), 7.66(2H, d, J=8.6Hz), 7.59(2H, d, J=9.0Hz), 7.53-7.49(1H, m), 7.32(1H, dd, J=15.1 and 8.1Hz), 7.16-7.14(1H, m), 6.80(1H, dt, J=12.5 and 4.2Hz), 5.22-5.20(1H, m), 2.18(2H, d, J=7.0Hz), 1.97-1.93(2H, m), 1.88-1.80(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:465 (M + H)+。 In the same manner as in Example (1c), 89 mg (94%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 3-fluorophenyl isocyanate (0.029 mL). . This urea compound (89 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 66 mg (76%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.12 (1H, brs), 9.05 (1H, brs), 8.87 (2H, s), 7.66 (2H, d , J = 8.6Hz), 7.59 (2H, d, J = 9.0Hz), 7.53-7.49 (1H, m), 7.32 (1H, dd, J = 15.1 and 8.1Hz), 7.16-7.14 (1H, m) , 6.80 (1H, dt, J = 12.5 and 4.2Hz), 5.22-5.20 (1H, m), 2.18 (2H, d, J = 7.0Hz), 1.97-1.93 (2H, m), 1.88-1.80 (1H , m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 465 (M + H) <+> .
　（実施例５）
(cis-4-{[5-(4-{[(4-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 5)
(cis-4-{[5- (4-{[(4-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（68 mg）と４－フルオロフェニルイソシアナート（0.029 mL）からウレア体 85 mg（90%）を白色固体として得た。このウレア体（85 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 58 mg（71%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.94(1H, brs), 8.87(2H, s), 8.86(1H, brs), 7.65(2H, d, J=8.6Hz), 7.58(2H, d, J=9.0Hz), 7.48(2H, dd, J=9.2 and 4.9Hz), 7.14(2H, dd, J=8.8 and 8.8Hz), 5.22-5.20(1H, m), 2.19-2.18(2H, m), 1.97-1.93(2H, m), 1.87-1.80(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:465 (M + H)+。 In the same manner as in Example (1c), 85 mg (90%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 4-fluorophenyl isocyanate (0.029 mL). . This urea compound (85 mg) was hydrolyzed in the same way as in Example (1d) to obtain 58 mg (71%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.94 (1H, brs), 8.87 (2H, s), 8.86 (1H, brs), 7.65 (2H, d , J = 8.6Hz), 7.58 (2H, d, J = 9.0Hz), 7.48 (2H, dd, J = 9.2 and 4.9Hz), 7.14 (2H, dd, J = 8.8 and 8.8Hz), 5.22-5.20 (1H, m), 2.19-2.18 (2H, m), 1.97-1.93 (2H, m), 1.87-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m) , 1.43-1.33 (2H, m).
MS (ESI) m / z: 465 (M + H) <+> .
　（実施例６）
(cis-4-{[5-(4-{[(2-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 6)
(cis-4-{[5- (4-{[(2-Methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（68 mg）と２－メチルフェニルイソシアナート（0.032 mL）からウレア体 83 mg（88%）を白色固体として得た。このウレア体（83 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 63 mg（78%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.25(1H, brs), 8.88(2H, s), 8.05(1H, brs), 7.85(1H, d, J=8.3Hz), 7.66(2H, d, J=8.6Hz), 7.60(2H, d, J=9.0Hz), 7.20(1H, d, J=8.6Hz), 7.17(1H, dd, J=7.8 and 7.8Hz), 6.97(1H, dd, J=7.6 and 7.6Hz), 5.22-5.20(1H, m), 2.26(3H, s), 2.18(2H, d, J=7.1Hz), 1.98-1.93(2H, m), 1.86-1.80(1H, m), 1.71-1.63(2H, m), 1.61-1.57(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:461 (M + H)+。 In the same manner as in Example (1c), 83 mg (88%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 2-methylphenyl isocyanate (0.032 mL). . This urea compound (83 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 63 mg (78%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.25 (1H, brs), 8.88 (2H, s), 8.05 (1H, brs), 7.85 (1H, d , J = 8.3Hz), 7.66 (2H, d, J = 8.6Hz), 7.60 (2H, d, J = 9.0Hz), 7.20 (1H, d, J = 8.6Hz), 7.17 (1H, dd, J = 7.8 and 7.8Hz), 6.97 (1H, dd, J = 7.6 and 7.6Hz), 5.22-5.20 (1H, m), 2.26 (3H, s), 2.18 (2H, d, J = 7.1Hz), 1.98 -1.93 (2H, m), 1.86-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 461 (M + H) <+> .
　（実施例７）
(cis-4-{[5-(4-{[(3-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 7)
(cis-4-{[5- (4-{[(3-Methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（68 mg）と３－メチルフェニルイソシアナート（0.032 mL）からウレア体 90 mg（95%）を白色固体として得た。このウレア体（90 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 77 mg（88%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.91(1H, brs), 8.88(2H, s), 8.74(1H, brs), 7.66(2H, d, J=8.6Hz), 7.58(2H, d, J=8.6Hz), 7.32(1H, s), 7.25(1H, d, J=8.6Hz), 7.17(1H, dd, J=7.8 and 7.9Hz), 6.81(1H, d, J=7.8Hz), 5.22-5.20(1H, m), 2.29(3H, s), 2.19(2H, d, J=7.0Hz), 1.98-1.93(2H, m), 1.88-1.80(1H, m), 1.72-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:461 (M + H)+。 In the same manner as in Example (1c), 90 mg (95%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 3-methylphenyl isocyanate (0.032 mL). . This urea compound (90 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 77 mg (88%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.1 (1H, brs), 8.91 (1H, brs), 8.88 (2H, s), 8.74 (1H, brs), 7.66 (2H, d, J = 8.6Hz), 7.58 (2H, d, J = 8.6Hz), 7.32 (1H, s), 7.25 (1H, d, J = 8.6Hz), 7.17 (1H, dd, J = 7.8 and 7.9Hz) , 6.81 (1H, d, J = 7.8Hz), 5.22-5.20 (1H, m), 2.29 (3H, s), 2.19 (2H, d, J = 7.0Hz), 1.98-1.93 (2H, m), 1.88-1.80 (1H, m), 1.72-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 461 (M + H) +.
　（実施例８）
(cis-4-{[5-(4-{[(2-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 8)
(cis-4-{[5- (4-{[(2-Methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（68 mg）と2-メトキシフェニルイソシアナート（0.035 mL）からウレア体 51 mg（52%）を白色固体として得た。このウレア体（51 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 48 mg（定量的収量）を黄色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.48(1H, brs), 8.87(2H, s), 8.28(1H, brs), 8.14(1H, dd, J=7.8 and 2.0Hz), 7.66(2H, d, J=9.0Hz), 7.58(2H, d, J=9.0Hz), 7.04(1H, dd, J=7.8 and 1.6Hz), 6.96(1H, dt, J=10.8 and 3.9Hz), 6.91(1H, dt, J=10.7 and 3.8Hz), 5.22-5.20(1H, m), 3.89(3H, s), 2.19(2H, d, J=7.0Hz), 1.98-1.93(2H, m), 1.87-1.80(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:477 (M + H)+。 In the same manner as in Example (1c), 51 mg (52%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 2-methoxyphenyl isocyanate (0.035 mL). . This urea compound (51 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 48 mg (quantitative yield) of the title compound as a yellow solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.48 (1H, brs), 8.87 (2H, s), 8.28 (1H, brs), 8.14 (1H, dd , J = 7.8 and 2.0Hz), 7.66 (2H, d, J = 9.0Hz), 7.58 (2H, d, J = 9.0Hz), 7.04 (1H, dd, J = 7.8 and 1.6Hz), 6.96 (1H , dt, J = 10.8 and 3.9Hz), 6.91 (1H, dt, J = 10.7 and 3.8Hz), 5.22-5.20 (1H, m), 3.89 (3H, s), 2.19 (2H, d, J = 7.0 Hz), 1.98-1.93 (2H, m), 1.87-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 477 (M + H) <+> .
　（実施例９）
(cis-4-{[5-(4-{[(3-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 Example 9
(cis-4-{[5- (4-{[(3-Methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（68 mg）と3-メトキシフェニルイソシアナート（0.034 mL）からウレア体 91 mg（93%）を白色固体として得た。このウレア体（91 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 40 mg（45%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.19(1H, brs), 9.09(1H, brs), 8.87(2H, s), 7.65(2H, d, J=8.7Hz), 7.59(2H, d, J=8.6Hz), 7.22(1H, dd, J=2.4 and 2.4Hz), 7.18(1H, dd, J=8.0 and 8.0Hz), 6.99-6.96(1H, m), 6.57-6.54(1H, m), 5.22-5.20(1H, m), 3.74(3H, s), 2.17(2H, d, J=7.0Hz), 1.97-1.93(2H, m), 1.87-1.82(1H, m), 1.70-1.63(2H, m), 1.61-1.57(2H, m), 1.42-1.34(2H, m).
MS(ESI) m/z:477 (M + H)+。 In the same manner as in Example (1c), 91 mg (93%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 3-methoxyphenyl isocyanate (0.034 mL). . This urea compound (91 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 40 mg (45%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.19 (1H, brs), 9.09 (1H, brs), 8.87 (2H, s), 7.65 (2H, d , J = 8.7Hz), 7.59 (2H, d, J = 8.6Hz), 7.22 (1H, dd, J = 2.4 and 2.4Hz), 7.18 (1H, dd, J = 8.0 and 8.0Hz), 6.99-6.96 (1H, m), 6.57-6.54 (1H, m), 5.22-5.20 (1H, m), 3.74 (3H, s), 2.17 (2H, d, J = 7.0Hz), 1.97-1.93 (2H, m ), 1.87-1.82 (1H, m), 1.70-1.63 (2H, m), 1.61-1.57 (2H, m), 1.42-1.34 (2H, m).
MS (ESI) m / z: 477 (M + H) <+> .
　（実施例１０）
(cis-4-{[5-(4-{[(4-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 10)
(cis-4-{[5- (4-{[(4-Methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（68 mg）と4-メトキシフェニルイソシアナート（0.034 mL）からウレア体 86 mg（88%）を白色固体として得た。このウレア体（86 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 68 mg（82%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.87(2H, s), 8.79(1H, brs), 8.57(1H, brs), 7.64(2H, d, J=9.0Hz), 7.57(2H, d, J=8.6Hz), 7.37(2H, d, J=9.4Hz), 6.88(2H, d, J=9.0Hz), 5.21-5.20(1H, m), 3.72(3H, s), 2.19(2H, d, J=7.1Hz), 1.97-1.93(2H, m), 1.86-1.81(1H, m), 1.71-1.63(2H, m), 1.60-1.56(2H, m), 1.42-1.33(2H, m).
MS(ESI) m/z:477 (M + H)+。 In the same manner as in Example (1c), 86 mg (88%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (1b) and 4-methoxyphenyl isocyanate (0.034 mL). . This urea compound (86 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 68 mg (82%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.87 (2H, s), 8.79 (1H, brs), 8.57 (1H, brs), 7.64 (2H, d , J = 9.0Hz), 7.57 (2H, d, J = 8.6Hz), 7.37 (2H, d, J = 9.4Hz), 6.88 (2H, d, J = 9.0Hz), 5.21-5.20 (1H, m ), 3.72 (3H, s), 2.19 (2H, d, J = 7.1Hz), 1.97-1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H, m), 1.60- 1.56 (2H, m), 1.42-1.33 (2H, m).
MS (ESI) m / z: 477 (M + H) <+> .
　（実施例１１）
(cis-4-{[5-(4-{[(2,4,5-トリフルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 11)
(cis-4-{[5- (4-{[(2,4,5-trifluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（171 mg）と2,4,5-トリフルオロフェニルイソシアナート（0.079 mL）からウレア体 250 mg（97%）を白色固体として得た。このウレア体（250 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 241 mg（99%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.32(1H, s), 8.88(2H, s), 8.86(1H, s), 8.24-8.17(1H, m), 7.68(2H, d, J=9.0Hz), 7.65-7.62(1H, m), 7.58(2H, d, J=9.0Hz), 5.22-5.20(1H, m), 2.18(2H, d, J=7.0Hz), 1.97-1.93(2H, m), 1.86-1.81(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:501 (M + H)+。 In the same manner as in Example (1c), urea compound (250 mg, 97%) was obtained from Compound (171 mg) obtained in Example (1b) and 2,4,5-trifluorophenyl isocyanate (0.079 mL). Obtained as a white solid. This urea compound (250 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 241 mg (99%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.32 (1H, s), 8.88 (2H, s), 8.86 (1H, s), 8.24-8.17 (1H , m), 7.68 (2H, d, J = 9.0Hz), 7.65-7.62 (1H, m), 7.58 (2H, d, J = 9.0Hz), 5.22-5.20 (1H, m), 2.18 (2H, d, J = 7.0Hz), 1.97-1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 501 (M + H) <+> .
　（実施例１２）
(cis-4-{[5-(4-{[(2-メトキシ-5-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 12)
(cis-4-{[5- (4-{[(2-Methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（341 mg）と2-メトキシ-5-メチルフェニルイソシアナート（424 mL）からウレア体 504 mg（定量的収量）を白色固体として得た。このウレア体（504 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 489 mg（定量的収量）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=9.48(1H, s), 8.87(2H, s), 8.22(1H, s), 8.00(1H, d, J=2.0Hz), 7.65(2H, d, J=9.0Hz), 7.57(2H, d, J=8.6Hz), 6.91(1H, d, J=8.2Hz), 6.76(1H, dd, J=8.2 and 1.5Hz), 5.21-5.20(1H, m), 3.85(3H, s), 2.24(3H, s), 2.19(2H, d, J=7.0Hz), 1.97-1.93(2H, m), 1.86-1.81(1H, m), 1.70-1.64(2H, m), 1.60-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:491 (M + H)+。 In the same manner as in Example (1c), 504 mg of urea compound (quantitative yield) was obtained from the compound (341 mg) obtained in Example (1b) and 2-methoxy-5-methylphenyl isocyanate (424 mL). Obtained as a white solid. This urea compound (504 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 489 mg (quantitative yield) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 9.48 (1H, s), 8.87 (2H, s), 8.22 (1H, s), 8.00 (1H, d, J = 2.0 Hz), 7.65 (2H, d, J = 9.0Hz), 7.57 (2H, d, J = 8.6Hz), 6.91 (1H, d, J = 8.2Hz), 6.76 (1H, dd, J = 8.2 and 1.5Hz), 5.21-5.20 (1H, m), 3.85 (3H, s), 2.24 (3H, s), 2.19 (2H, d, J = 7.0Hz), 1.97-1.93 (2H, m), 1.86-1.81 (1H, m), 1.70-1.64 (2H, m), 1.60-1.56 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 491 (M + H) <+> .
　（実施例１３）
(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピラジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 13)
(cis-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrazin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　（１３ａ）　{cis-4-[(5-ブロモピラジン-2-イル)オキシ]シクロヘキシル}酢酸メチルエステル
　実施例（１ａ）と同様の方法で、(trans-4-ヒドロキシシクロヘキシル) 酢酸メチルエステル　（WO2009119534）（694 mg）と5-ブロモピラジン-2-オール（470 mg）、シアノメチレントリブチルホスホラン（CMBP）（1.1 mL）から、標記化合物 633 mg（72%）を白色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.16(1H, d, J=1.6Hz), 7.99(1H, d, J=1.1Hz), 5.21-5.20(1H, m), 3.69(3H, s), 2.29(2H, d, J=7.1Hz), 2.03-1.99(2H, m), 1.96-1.91(1H, m), 1.69-1.55(4H, m), 1.48-1.38(2H, m)。 (13a) {cis-4-[(5-Bromopyrazin-2-yl) oxy] cyclohexyl} acetic acid methyl ester (trans-4-hydroxycyclohexyl) acetic acid methyl ester in the same manner as in Example (1a) (WO2009119534 ) (694 mg), 5-bromopyrazin-2-ol (470 mg), and cyanomethylenetributylphosphorane (CMBP) (1.1 mL), 633 mg (72%) of the title compound was obtained as a white solid.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.16 (1H, d, J = 1.6 Hz), 7.99 (1H, d, J = 1.1 Hz), 5.21-5.20 (1H, m), 3.69 ( 3H, s), 2.29 (2H, d, J = 7.1Hz), 2.03-1.99 (2H, m), 1.96-1.91 (1H, m), 1.69-1.55 (4H, m), 1.48-1.38 (2H, m).
　（１３ｂ）　(cis-4-{[5-(4-アミノフェニル)ピラジン-2-イル]オキシ}シクロヘキシル)酢酸メチルエステル
　実施例（１ｂ）と同様の方法で、実施例（１３ａ）で得た化合物（633 mg）と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（421 mg)から、標記化合物 324 mg（49%）を薄褐色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.39(1H, d, J=1.6Hz), 8.20(1H, d, J=1.6Hz), 7.72(2H, d, J=8.6Hz), 6.78(2H, d, J=8.6Hz), 5.27-5.25(1H, m), 3.82(2H, brs), 3.69(3H, s), 2.31(2H, d, J=7.4Hz), 2.07-2.03(2H, m), 1.98-1.92(1H, m), 1.72-1.58(4H, m), 1.53-1.46(2H, m)。 (13b) (cis-4-{[5- (4-Aminophenyl) pyrazin-2-yl] oxy} cyclohexyl) acetic acid methyl ester obtained in Example (13a) in a manner similar to Example (1b) From the compound (633 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (421 mg), the title compound 324 mg (49%) was pale brown Obtained as a solid.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.39 (1 H, d, J = 1.6 Hz), 8.20 (1 H, d, J = 1.6 Hz), 7.72 (2 H, d, J = 8.6 Hz) , 6.78 (2H, d, J = 8.6Hz), 5.27-5.25 (1H, m), 3.82 (2H, brs), 3.69 (3H, s), 2.31 (2H, d, J = 7.4Hz), 2.07- 2.03 (2H, m), 1.98-1.92 (1H, m), 1.72-1.58 (4H, m), 1.53-1.46 (2H, m).
　（１３ｃ）　(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピラジン-2-イル]オキシ}シクロヘキシル)酢酸
　実施例（１ｃ）と同様の方法で、実施例（１３ｂ）で得た化合物（102 mg）と2-フルオロフェニルイソシアナート（0.044 mL）からウレア体 131 mg（92%）を白色固体として得た。このウレア体（131 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 92 mg（73%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, s), 9.28(1H, s), 8.72(1H, d, J=1.2Hz), 8.64(1H, s), 8.31(1H, d, J=1.2Hz), 8.17(1H, dt, J=11.5 and 4.1Hz), 7.97(2H, d, J=9.0Hz), 7.58(2H, d, J=8.6Hz), 7.28-7.23(1H, m), 7.16(1H, dd, J=7.8 and 7.8Hz), 7.06-7.00(1H, m), 5.25-5.21(1H, m), 2.19(2H, d, J=7.1Hz), 1.97-1.92(2H, m), 1.86-1.80(1H, m), 1.71-1.65(2H, m), 1.61-1.56(2H, m), 1.43-1.34(2H, m).
MS(ESI) m/z:465 (M + H)+。 (13c) (cis-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrazin-2-yl] oxy} cyclohexyl) acetic acid In the same manner as in Example (1c) From the compound (102 mg) obtained in Example (13b) and 2-fluorophenyl isocyanate (0.044 mL), 131 mg (92%) of urea was obtained as a white solid. This urea compound (131 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 92 mg (73%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, s), 9.28 (1H, s), 8.72 (1H, d, J = 1.2 Hz), 8.64 (1H, s), 8.31 (1H, d, J = 1.2Hz), 8.17 (1H, dt, J = 11.5 and 4.1Hz), 7.97 (2H, d, J = 9.0Hz), 7.58 (2H, d, J = 8.6Hz), 7.28-7.23 (1H, m), 7.16 (1H, dd, J = 7.8 and 7.8Hz), 7.06-7.00 (1H, m), 5.25-5.21 (1H, m), 2.19 (2H, d, J = 7.1 Hz), 1.97-1.92 (2H, m), 1.86-1.80 (1H, m), 1.71-1.65 (2H, m), 1.61-1.56 (2H, m), 1.43-1.34 (2H, m).
MS (ESI) m / z: 465 (M + H) <+> .
　（実施例１４）
(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 14)
(cis-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　（１４ａ）　{cis-4-[(5-ブロモピリジン-2-イル)オキシ]シクロヘキシル}酢酸メチルエステル
　実施例（１ａ）と同様の方法で、(trans-4-ヒドロキシシクロヘキシル)酢酸メチルエステル　（WO2009119534）（2.58 g）と5-ブロモピリジン-2-オール（1.74 g）、シアノメチレントリブチルホスホラン（CMBP）（3.93 mL）から、標記化合物 2.76 g（84%）を無色オイルとして得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.16(1H, d, J=2.7Hz), 7.62(1H, dd, J=8.8 and 2.5Hz), 6.64(1H, d, J=8.6Hz), 5.20-5.18(1H, m), 3.68(3H, s), 2.28(2H, d, J=7.5Hz), 2.02-1.96(2H, m), 1.95-1.88(1H, m), 1.67-1.54(4H, m), 1.48-1.38(2H, m)。 (14a) {cis-4-[(5-Bromopyridin-2-yl) oxy] cyclohexyl} acetic acid methyl ester (trans-4-hydroxycyclohexyl) acetic acid methyl ester (WO2009119534) in the same manner as in Example (1a) ) (2.58 g), 5-bromopyridin-2-ol (1.74 g), and cyanomethylenetributylphosphorane (CMBP) (3.93 mL), 2.76 g (84%) of the title compound was obtained as a colorless oil.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.16 (1H, d, J = 2.7 Hz), 7.62 (1H, dd, J = 8.8 and 2.5 Hz), 6.64 (1H, d, J = 8.6 Hz), 5.20-5.18 (1H, m), 3.68 (3H, s), 2.28 (2H, d, J = 7.5Hz), 2.02-1.96 (2H, m), 1.95-1.88 (1H, m), 1.67 -1.54 (4H, m), 1.48-1.38 (2H, m).
　（１４ｂ）　(cis-4-{[5-(4-アミノフェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸メチルエステル
　実施例（１ｂ）と同様の方法で、実施例（１４ａ）で得た化合物（2.76 g）と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（1.84 g)から、標記化合物 2.37 g（83%）を淡黄色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.30(1H, d, J=1.9Hz), 7.72(1H, dd, J=8.4 and 2.5Hz), 7.33(2H, d, J=8.7Hz), 6.77-6.74(1H, m), 6.76(2H, d, J=8.6Hz), 5.27-5.26(1H, m), 3.75(2H, brs), 3.69(3H, s), 2.30(2H, d, J=7.5Hz), 2.07-2.02(2H, m), 1.97-1.90(1H, m), 1.70-1.44(6H, m)。 (14b) (cis-4-{[5- (4-Aminophenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid methyl ester obtained in Example (14a) in the same manner as in Example (1b) From the compound (2.76 g) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.84 g), 2.37 g (83%) of the title compound was pale yellow Obtained as a solid.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.30 (1 H, d, J = 1.9 Hz), 7.72 (1 H, dd, J = 8.4 and 2.5 Hz), 7.33 (2 H, d, J = 8.7 Hz), 6.77-6.74 (1H, m), 6.76 (2H, d, J = 8.6Hz), 5.27-5.26 (1H, m), 3.75 (2H, brs), 3.69 (3H, s), 2.30 (2H , d, J = 7.5 Hz), 2.07-2.02 (2H, m), 1.97-1.90 (1H, m), 1.70-1.44 (6H, m).
　（１４ｃ）　(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸
　実施例（１ｃ）と同様の方法で、実施例（１４ｂ）で得た化合物（170 mg）と2-フルオロフェニルイソシアナート（0.073 mL）からウレア体 221 mg（93%）を白色固体として得た。このウレア体（221 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 202 mg（94%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.20(1H, s), 8.61(1H, d, J=2.4Hz), 8.43(1H, d, J=2.8Hz), 8.17(1H, dt, J=11.5 and 4.1Hz), 7.96(1H, dd, J=8.6 and 2.7Hz), 7.60(2H, d, J=9.0Hz), 7.55(2H, d, J=9.0Hz), 7.28-7.23(1H, m), 7.16(1H, dd, J=7.6 and 7.6Hz), 7.05-6.99(1H, m), 6.86(1H, d, J=8.6Hz), 5.23-5.22(1H, m), 2.18(2H, d, J=7.4Hz), 1.94-1.90(2H, m), 1.85-1.79(1H, m), 1.68-1.64(2H, m), 1.61-1.54(2H, m), 1.42-1.33(2H, m).
MS(ESI) m/z:464 (M + H)+。 (14c) (cis-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid In the same manner as in Example (1c) From the compound (170 mg) obtained in Example (14b) and 2-fluorophenyl isocyanate (0.073 mL), 221 mg (93%) of urea was obtained as a white solid. This urea compound (221 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 202 mg (94%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.20 (1H, s), 8.61 (1H, d, J = 2.4 Hz), 8.43 (1H, d, J = 2.8Hz), 8.17 (1H, dt, J = 11.5 and 4.1Hz), 7.96 (1H, dd, J = 8.6 and 2.7Hz), 7.60 (2H, d, J = 9.0Hz), 7.55 (2H, d , J = 9.0Hz), 7.28-7.23 (1H, m), 7.16 (1H, dd, J = 7.6 and 7.6Hz), 7.05-6.99 (1H, m), 6.86 (1H, d, J = 8.6Hz) , 5.23-5.22 (1H, m), 2.18 (2H, d, J = 7.4Hz), 1.94-1.90 (2H, m), 1.85-1.79 (1H, m), 1.68-1.64 (2H, m), 1.61 -1.54 (2H, m), 1.42-1.33 (2H, m).
MS (ESI) m / z: 464 (M + H) <+> .
　（実施例１５）
(cis-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 15)
(cis-4-{[5- (4-{[(4-Methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　実施例（１ｃ）と同様の方法で、実施例（１４ｂ）で得た化合物（413 mg）と4-メチルフェニルイソシアナート（0.20 mL）からウレア体 571 mg（99%）を白色固体として得た。このウレア体（571 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 538 mg（97%）を淡黄色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=8.81(1H, s), 8.66(1H, s), 8.42(1H, d, J=3.1Hz), 7.96(1H, dd, J=8.6 and 2.7Hz), 7.59-7.52(4H, m), 7.35(2H, d, J=8.6Hz), 7.10(2H, d, J=7.9Hz), 6.86(1H, d, J=8.6Hz), 5.23-5.21(1H, m), 2.25(3H, s), 2.18(2H, d, J=7.0Hz), 1.94-1.90(2H, m), 1.85-1.79(1H, m), 1.67-1.63(2H, m), 1.60-1.54(2H, m), 1.42-1.32(2H, m).
MS(ESI) m/z:460 (M + H)+。 In the same manner as in Example (1c), 571 mg (99%) of a urea compound was obtained as a white solid from the compound (413 mg) obtained in Example (14b) and 4-methylphenyl isocyanate (0.20 mL). . This urea compound (571 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 538 mg (97%) of the title compound as a pale yellow solid.
1 H NMR (400MHz, DMSO- d 6): δ (ppm) = 8.81 (1H, s), 8.66 (1H, s), 8.42 (1H, d, J = 3.1Hz), 7.96 (1H, dd, J = 8.6 and 2.7Hz), 7.59-7.52 (4H, m), 7.35 (2H, d, J = 8.6Hz), 7.10 (2H, d, J = 7.9Hz), 6.86 (1H, d, J = 8.6Hz ), 5.23-5.21 (1H, m), 2.25 (3H, s), 2.18 (2H, d, J = 7.0Hz), 1.94-1.90 (2H, m), 1.85-1.79 (1H, m), 1.67- 1.63 (2H, m), 1.60-1.54 (2H, m), 1.42-1.32 (2H, m).
MS (ESI) m / z: 460 (M + H) <+> .
　（実施例１６）
{cis-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリジン-2-イル)オキシ]シクロヘキシル}酢酸 (Example 16)
{cis-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyridin-2-yl) oxy] cyclohexyl} acetic acid
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　実施例（１ｃ）と同様の方法で、実施例（１４ｂ）で得た化合物（383 mg）とフェニルイソシアナート（0.179 mL）からウレア体 460 mg（89%）を褐色固体として得た。このウレア体（460 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 419 mg（94%）を黄色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.0(1H, brs), 8.81(1H, s), 8.73(1H, s), 8.43(1H, d, J=2.8Hz), 7.96(1H, dd, J=8.6 and 2.8Hz), 7.60-7.54(4H, m), 7.47(2H, d, J=7.8Hz), 7.30(2H, dd, J=7.8 and 7.8Hz), 6.98(1H, dd, J=7.4 and 7.5Hz), 6.86(1H, d, J=8.6Hz), 5.23-5.23(1H, m), 2.18(2H, d, J=7.1Hz), 1.94-1.90(2H, m), 1.86-1.80(1H, m), 1.68-1.64(2H, m), 1.61-1.54(2H, m), 1.42-1.33(2H, m).
MS(ESI) m/z:446 (M + H)+。 In the same manner as in Example (1c), 460 mg (89%) of a urea compound was obtained as a brown solid from the compound (383 mg) obtained in Example (14b) and phenyl isocyanate (0.179 mL). This urea compound (460 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 419 mg (94%) of the title compound as a yellow solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.0 (1H, brs), 8.81 (1H, s), 8.73 (1H, s), 8.43 (1H, d, J = 2.8 Hz), 7.96 (1H, dd, J = 8.6 and 2.8Hz), 7.60-7.54 (4H, m), 7.47 (2H, d, J = 7.8Hz), 7.30 (2H, dd, J = 7.8 and 7.8Hz), 6.98 (1H, dd, J = 7.4 and 7.5Hz), 6.86 (1H, d, J = 8.6Hz), 5.23-5.23 (1H, m), 2.18 (2H, d, J = 7.1Hz), 1.94-1.90 ( 2H, m), 1.86-1.80 (1H, m), 1.68-1.64 (2H, m), 1.61-1.54 (2H, m), 1.42-1.33 (2H, m).
MS (ESI) m / z: 446 (M + H) <+> .
　（実施例１７）
(cis-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 17)
(cis-4-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　実施例（１ｃ）と同様の方法で、実施例（１４ｂ）で得た化合物（170 mg）と2,4-ジメチルフェニルイソシアナート（0.092 mL）からウレア体 206 mg（84%）を淡黄色固体として得た。このウレア体（206 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 190 mg（96%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.10(1H, s), 8.42(1H, d, J=3.1Hz), 7.95(1H, dd, J=8.6 and 2.7Hz), 7.93(1H, s), 7.67(1H, d, J=8.2Hz), 7.59-7.53(4H, m), 7.00(1H, s), 6.96(1H, d, J=8.6Hz), 6.85(1H, d, J=8.6Hz), 5.23-5.21(1H, m), 2.23(3H, s), 2.21(3H, s), 2.17(2H, d, J=7.1Hz), 1.94-1.89(2H, m), 1.85-1.79(1H, m), 1.67-1.63(2H, m), 1.60-1.54(2H, m), 1.42-1.32(2H, m).
MS(ESI) m/z:474 (M + H)+。 In the same manner as in Example (1c), urea compound (206 mg, 84%) was obtained as a pale yellow solid from the compound (170 mg) obtained in Example (14b) and 2,4-dimethylphenyl isocyanate (0.092 mL). Got as. This urea compound (206 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 190 mg (96%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.10 (1H, s), 8.42 (1H, d, J = 3.1 Hz), 7.95 (1H, dd, J = 8.6 and 2.7Hz), 7.93 (1H, s), 7.67 (1H, d, J = 8.2Hz), 7.59-7.53 (4H, m), 7.00 (1H, s), 6.96 (1H, d, J = 8.6Hz), 6.85 (1H, d, J = 8.6Hz), 5.23-5.21 (1H, m), 2.23 (3H, s), 2.21 (3H, s), 2.17 (2H, d, J = 7.1Hz) , 1.94-1.89 (2H, m), 1.85-1.79 (1H, m), 1.67-1.63 (2H, m), 1.60-1.54 (2H, m), 1.42-1.32 (2H, m).
MS (ESI) m / z: 474 (M + H) <+> .
　（実施例１８）
(cis-4-{[5-(4-{[(2-クロロ-4-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 18)
(cis-4-{[5- (4-{[(2-Chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　（１８ａ）　(cis-4-{[5-(4-{[(2-クロロ-4-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸メチルエステル
　トリホスゲン（59 mg）のジクロロメタン（4 mL）溶液に、実施例（１４ｂ）で得た化合物（170 mg）とトリエチルアミン（0.15 mL）のジクロロメタン（4 mL）溶液を室温で加えた。この混合物に2-クロロ-4-フルオロアニリン（73 mg）とトリエチルアミン（0.15 mL）のジクロロメタン（4 mL）溶液を室温で加えた。反応混合物を室温で一晩撹拌し、濃縮した。残渣物をカラムクロマトグラフィー（自動クロマトグラフィー装置、ジクロロメタン／酢酸エチル 100:0→85:15）で精製し、標記化合物 193 mg（75%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=9.45(1H, s), 8.43(1H, d, J=2.0Hz), 8.34(1H, s), 8.13(1H, dd, J=9.2 and 5.7Hz), 7.96(1H, dd, J=8.6 and 2.7Hz), 7.60(2H, d, J=8.6Hz), 7.55(2H, d, J=9.0Hz), 7.50(1H, dd, J=8.6 and 3.1Hz), 7.23(1H, dt, J=12.5 and 4.4Hz), 6.85(1H, d, J=8.6Hz), 5.23-5.22(1H, m), 3.60(3H, s), 2.28(2H, d, J=7.0Hz), 1.94-1.90(2H, m), 1.87-1.82(1H, m), 1.68-1.60(2H, m), 1.57-1.52(2H, m), 1.43-1.33(2H, m)。 (18a) (cis-4-{[5- (4-{[(2-Chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid methyl ester triphosgene (59 mg ) In dichloromethane (4 mL) was added a solution of the compound obtained in Example (14b) (170 mg) and triethylamine (0.15 mL) in dichloromethane (4 mL) at room temperature. To this mixture was added a solution of 2-chloro-4-fluoroaniline (73 mg) and triethylamine (0.15 mL) in dichloromethane (4 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography (automatic chromatography apparatus, dichloromethane / ethyl acetate 100: 0 → 85: 15) to obtain 193 mg (75%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 9.45 (1H, s), 8.43 (1H, d, J = 2.0 Hz), 8.34 (1H, s), 8.13 (1H, dd, J = 9.2 and 5.7Hz), 7.96 (1H, dd, J = 8.6 and 2.7Hz), 7.60 (2H, d, J = 8.6Hz), 7.55 (2H, d, J = 9.0Hz), 7.50 (1H, dd , J = 8.6 and 3.1Hz), 7.23 (1H, dt, J = 12.5 and 4.4Hz), 6.85 (1H, d, J = 8.6Hz), 5.23-5.22 (1H, m), 3.60 (3H, s) , 2.28 (2H, d, J = 7.0Hz), 1.94-1.90 (2H, m), 1.87-1.82 (1H, m), 1.68-1.60 (2H, m), 1.57-1.52 (2H, m), 1.43 -1.33 (2H, m).
　（１８ｂ）　(cis-4-{[5-(4-{[(2-クロロ-4-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸
　実施例（１８ａ）で得た化合物（193 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 141 mg（75%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.48(1H, s), 8.43(1H, d, J=2.8Hz), 8.37(1H, s), 8.13(1H, dd, J=9.4 and 5.9Hz), 7.96(1H, dd, J=8.6 and 2.8Hz), 7.61-7.54(4H, m), 7.50(1H, dd, J=8.6 and 3.1Hz), 7.26-7.21(1H, m), 6.86(1H, d, J=9.0Hz), 5.24-5.22(1H, m), 2.18(2H, d, J=7.0Hz), 1.94-1.89(2H, m), 1.86-1.79(1H, m), 1.67-1.63(2H, m), 1.60-1.54(2H, m), 1.42-1.32(2H, m).
MS(ESI) m/z:498 (M + H)+。 (18b) (cis-4-{[5- (4-{[(2-Chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid In Example (18a) The obtained compound (193 mg) was hydrolyzed in the same way as in Example (1d) to obtain 141 mg (75%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.48 (1H, s), 8.43 (1H, d, J = 2.8 Hz), 8.37 (1H, s), 8.13 (1H, dd, J = 9.4 and 5.9Hz), 7.96 (1H, dd, J = 8.6 and 2.8Hz), 7.61-7.54 (4H, m), 7.50 (1H, dd, J = 8.6 and 3.1Hz) , 7.26-7.21 (1H, m), 6.86 (1H, d, J = 9.0Hz), 5.24-5.22 (1H, m), 2.18 (2H, d, J = 7.0Hz), 1.94-1.89 (2H, m ), 1.86-1.79 (1H, m), 1.67-1.63 (2H, m), 1.60-1.54 (2H, m), 1.42-1.32 (2H, m).
MS (ESI) m / z: 498 (M + H) <+> .
　（実施例１９）
(trans-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 19)
(trans-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
　（１９ａ）　{trans-4-[(5-ブロモピリミジン-2-イル)オキシ]シクロヘキシル}酢酸メチルエステル
　実施例（１ａ）と同様の方法で、(cis-4-ヒドロキシシクロヘキシル) 酢酸メチルエステル　（WO2009119534）（1.48 g）と5-ブロモピリミジン-2-オール（1.00 g）から、標記化合物 0.62 g（33%）を無色固体として得た。
1H NMR (500MHz, CDCl3)：δ(ppm) = 8.50 (2H, s), 4.87-4.84 (1H, m), 3.68 (3H, s), 2.25-2.16 (3H, m), 1.99-1.82 (4H, m), 1.58-1.42 (2H, m), 1.18 (2H, q, J = 4.7 Hz).
MS(ESI) m/z:330 (M + H)+。 (19a) {trans-4-[(5-Bromopyrimidin-2-yl) oxy] cyclohexyl} acetic acid methyl ester (cis-4-hydroxycyclohexyl) acetic acid methyl ester in the same manner as in Example (1a) (WO2009119534 ) (1.48 g) and 5-bromopyrimidin-2-ol (1.00 g), 0.62 g (33%) of the title compound was obtained as a colorless solid.
1 H NMR (500 MHz, CDCl 3 ): δ (ppm) = 8.50 (2H, s), 4.87-4.84 (1H, m), 3.68 (3H, s), 2.25-2.16 (3H, m), 1.99-1.82 (4H, m), 1.58-1.42 (2H, m), 1.18 (2H, q, J = 4.7 Hz).
MS (ESI) m / z: 330 (M + H) <+> .
　（１９ｂ）　(trans-4-{[5-(4-アミノフェニル)ピリミジン-2-イル]オキシ}シクロヘキシル酢酸)メチル
　実施例(１ｂ)と同様の方法で、実施例（１９ａ）で得た化合物（475 mg)と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（321 mg)から標記化合物 449 mg（91%)を淡黄色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.63(2H, s), 7.32(2H, d, J=8.6Hz), 6.78(2H, d, J=8.6Hz), 4.99-4.91(1H, m), 3.80(2H, brs), 3.69(3H, s), 2.26(2H, d, J=6.6Hz), 2.23-2.20(2H, m), 1.92-1.85(3H, m), 1.65-1.55(2H, m), 1.26-1.18(2H, m)。 (19b) (trans-4-{[5- (4-aminophenyl) pyrimidin-2-yl] oxy} cyclohexyl acetic acid) methyl Compound obtained in Example (19a) in the same manner as in Example (1b) (475 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (321 mg) to 449 mg (91%) of the title compound as a pale yellow solid Obtained.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.63 (2H, s), 7.32 (2H, d, J = 8.6Hz), 6.78 (2H, d, J = 8.6Hz), 4.99-4.91 ( 1H, m), 3.80 (2H, brs), 3.69 (3H, s), 2.26 (2H, d, J = 6.6Hz), 2.23-2.20 (2H, m), 1.92-1.85 (3H, m), 1.65 -1.55 (2H, m), 1.26-1.18 (2H, m).
　（１９ｃ）　(trans-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸
　実施例（１ｃ）と同様の方法で、実施例（１９ｂ）で得た化合物（68 mg）と2-フルオロフェニルイソシアナート（0.03 mL）からウレア体 86 mg（90%）を白色固体として得た。このウレア体（86 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 73 mg（88%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.24(1H, s), 8.89(2H, s), 8.61(1H, d, J=2.4Hz), 8.19-8.14(1H, m), 7.67(2H, d, J=9.0Hz), 7.58(2H, d, J=8.6Hz), 7.28-7.23(1H, m), 7.16(1H, dd, J=7.8 and 7.8Hz), 7.05-7.00(1H, m), 4.95-4.87(1H, m), 2.16-2.15(2H, m), 2.13-2.10(2H, m), 1.83-1.80(1H, m), 1.76-1.70(2H, m), 1.52-1.42(2H, m), 1.20-1.09(2H, m).
MS(ESI) m/z:465 (M + H)+。 (19c) (trans-4-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid In the same manner as in Example (1c) From a compound (68 mg) obtained in Example (19b) and 2-fluorophenyl isocyanate (0.03 mL), 86 mg (90%) of urea was obtained as a white solid. This urea compound (86 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 73 mg (88%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.24 (1H, s), 8.89 (2H, s), 8.61 (1H, d, J = 2.4 Hz), 8.19-8.14 (1H, m), 7.67 (2H, d, J = 9.0Hz), 7.58 (2H, d, J = 8.6Hz), 7.28-7.23 (1H, m), 7.16 (1H, dd, J = 7.8 and 7.8Hz), 7.05-7.00 (1H, m), 4.95-4.87 (1H, m), 2.16-2.15 (2H, m), 2.13-2.10 (2H, m), 1.83-1.80 (1H, m) , 1.76-1.70 (2H, m), 1.52-1.42 (2H, m), 1.20-1.09 (2H, m).
MS (ESI) m / z: 465 (M + H) <+> .
　（実施例２０）
{trans-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸 (Example 20)
{trans-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　実施例（１ｃ）と同様の方法で、実施例（１９ｂ）で得た化合物（68 mg）とフェニルイソシアナート（0.028 mL）からウレア体 66 mg（72%）を白色固体として得た。このウレア体（66 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 61 mg（95%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.88(1H, brs), 8.88(2H, s), 8.78(1H, brs), 7.65(2H, d, J=9.0Hz), 7.58(2H, d, J=8.7Hz), 7.47(2H, dd, J=8.6 and 1.2Hz), 7.29(2H, dd, J=8.0 and 8.0Hz), 6.98(1H, dd, J=7.4 and 7.5Hz), 4.93-4.88(1H, m), 2.15(2H, d, J=6.7Hz), 2.13-2.10(2H, m), 1.84-1.79(2H, m), 1.75-1.70(1H, m), 1.51-1.42(2H, m), 1.20-1.09(2H, m).
MS(ESI) m/z:447 (M + H)+。 In the same manner as in Example (1c), 66 mg (72%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (19b) and phenyl isocyanate (0.028 mL). This urea compound (66 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 61 mg (95%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.88 (1H, brs), 8.88 (2H, s), 8.78 (1H, brs), 7.65 (2H, d , J = 9.0Hz), 7.58 (2H, d, J = 8.7Hz), 7.47 (2H, dd, J = 8.6 and 1.2Hz), 7.29 (2H, dd, J = 8.0 and 8.0Hz), 6.98 (1H , dd, J = 7.4 and 7.5Hz), 4.93-4.88 (1H, m), 2.15 (2H, d, J = 6.7Hz), 2.13-2.10 (2H, m), 1.84-1.79 (2H, m), 1.75-1.70 (1H, m), 1.51-1.42 (2H, m), 1.20-1.09 (2H, m).
MS (ESI) m / z: 447 (M + H) <+> .
　（実施例２１）
(trans-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 21)
(trans-4-{[5- (4-{[(4-Methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　実施例（１ｃ）と同様の方法で、実施例（１９ｂ）で得た化合物（68 mg）と4-メチルフェニルイソシアナート（0.033 mL）からウレア体 68 mg（71%）を白色固体として得た。このウレア体（68 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 58 mg（89%）をオフホイト色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.88(2H, s), 8.81(1H, brs), 8.64(1H, brs), 7.64(2H, d, J=9.0Hz), 7.57(2H, d, J=8.7Hz), 7.35(2H, d, J=8.2Hz), 7.10(2H, d, J=8.2Hz), 4.95-4.87(1H, m), 2.25(3H, s), 2.16(2H, d, J=7.0Hz), 2.14-2.10(2H, m), 1.84-1.79(2H, m), 1.76-1.69(1H, m), 1.52-1.41(2H, m), 1.20-1.09(2H, m).
MS(ESI) m/z:461 (M + H)+。 In the same manner as in Example (1c), 68 mg (71%) of urea was obtained as a white solid from the compound (68 mg) obtained in Example (19b) and 4-methylphenyl isocyanate (0.033 mL). . This urea compound (68 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 58 mg (89%) of the title compound as an off-white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.88 (2H, s), 8.81 (1H, brs), 8.64 (1H, brs), 7.64 (2H, d , J = 9.0Hz), 7.57 (2H, d, J = 8.7Hz), 7.35 (2H, d, J = 8.2Hz), 7.10 (2H, d, J = 8.2Hz), 4.95-4.87 (1H, m ), 2.25 (3H, s), 2.16 (2H, d, J = 7.0Hz), 2.14-2.10 (2H, m), 1.84-1.79 (2H, m), 1.76-1.69 (1H, m), 1.52- 1.41 (2H, m), 1.20-1.09 (2H, m).
MS (ESI) m / z: 461 (M + H) +.
　（実施例２２）
(cis-4-{[5-(4-{[(2-フルオロ-3-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 22)
(cis-4-{[5- (4-{[(2-Fluoro-3-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　実施例（１８ａ）と同様の方法で、実施例（１ｂ）で得た化合物（171 mg）と2-フルオロ-3-メチルアニリン（63 mg）からウレア体 222 mg（90%）を白色固体として得た。このウレア体（222 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 206 mg（95%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.24(1H, brs), 8.88(2H, s), 8.54(1H, d, J=2.8Hz), 7.99(1H, dd, J=8.0 and 8.0Hz), 7.67(2H, d, J=9.0Hz), 7.58(2H, d, J=9.0Hz), 7.03(1H, dd, J=7.8 and 7.8Hz), 6.90(1H, dd, J=7.1 and 7.1Hz), 5.22-5.20(1H, m), 2.26(3H, d, J=2.0Hz), 2.19(2H, d, J=7.0Hz), 1.98-1.93(2H, m), 1.86-1.81(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:479 (M + H)+。 In the same manner as in Example (18a), urea compound 222 mg (90%) was converted into white solid from compound (171 mg) obtained in Example (1b) and 2-fluoro-3-methylaniline (63 mg). Obtained. This urea compound (222 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 206 mg (95%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.24 (1H, brs), 8.88 (2H, s), 8.54 (1H, d, J = 2.8 Hz), 7.99 (1H, dd, J = 8.0 and 8.0Hz), 7.67 (2H, d, J = 9.0Hz), 7.58 (2H, d, J = 9.0Hz), 7.03 (1H, dd, J = 7.8 and 7.8Hz ), 6.90 (1H, dd, J = 7.1 and 7.1Hz), 5.22-5.20 (1H, m), 2.26 (3H, d, J = 2.0Hz), 2.19 (2H, d, J = 7.0Hz), 1.98 -1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 479 (M + H) <+> .
　（実施例２３）
(cis-4-{[5-(4-{[(2-フルオロ-4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 23)
(cis-4-{[5- (4-{[(2-Fluoro-4-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　実施例（１８ａ）と同様の方法で、実施例（１ｂ）で得た化合物（171 mg）と2-フルオロ-4-メチルアニリン（63 mg）からウレア体 207 mg（84%）を白色固体として得た。このウレア体（207 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 191 mg（95%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.16(1H, brs), 8.87(2H, s), 8.48(1H, d, J=2.4Hz), 7.99(1H, dd, J=8.4 and 8.4Hz), 7.66(2H, d, J=9.0Hz), 7.57(2H, d, J=9.0Hz), 7.08(1H, dd, J=12.1 and 1.5Hz), 6.97(1H, d, J=7.8Hz), 5.22-5.20(1H, m), 2.27(3H, s), 2.19(2H, d, J=7.0Hz), 1.97-1.93(2H, m), 1.87-1.80(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.42-1.33(2H, m).
MS(ESI) m/z:479 (M + H)+。 In the same manner as in Example (18a), urea compound (207 mg, 84%) was obtained as a white solid from the compound (171 mg) obtained in Example (1b) and 2-fluoro-4-methylaniline (63 mg). Obtained. This urea compound (207 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 191 mg (95%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.16 (1H, brs), 8.87 (2H, s), 8.48 (1H, d, J = 2.4 Hz), 7.99 (1H, dd, J = 8.4 and 8.4Hz), 7.66 (2H, d, J = 9.0Hz), 7.57 (2H, d, J = 9.0Hz), 7.08 (1H, dd, J = 12.1 and 1.5Hz ), 6.97 (1H, d, J = 7.8Hz), 5.22-5.20 (1H, m), 2.27 (3H, s), 2.19 (2H, d, J = 7.0Hz), 1.97-1.93 (2H, m) , 1.87-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.42-1.33 (2H, m).
MS (ESI) m / z: 479 (M + H) <+> .
　（実施例２４）
(cis-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 24)
(cis-4-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　実施例（１ｃ）と同様の方法で、実施例（１ｂ）で得た化合物（102 mg）と2,4-ジメチルフェニルイソシアナート（0.11 mL）からウレア体 146 mg（定量的収量）を白色固体として得た。このウレア体（146 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 115 mg（81%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.16(1H, brs), 8.87(2H, s), 8.48(1H, d, J=2.4Hz), 7.99(1H, dd, J=8.4 and 8.4Hz), 7.66(2H, d, J=9.0Hz), 7.57(2H, d, J=9.0Hz), 7.08(1H, dd, J=12.1 and 1.5Hz), 6.97(1H, d, J=7.8Hz), 5.22-5.20(1H, m), 2.27(3H, s), 2.19(2H, d, J=7.0Hz), 1.97-1.93(2H, m), 1.87-1.80(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.42-1.33(2H, m).
MS(ESI) m/z:479 (M + H)+。 In the same manner as in Example (1c), 146 mg of urea compound (quantitative yield) was obtained as a white solid from the compound (102 mg) obtained in Example (1b) and 2,4-dimethylphenyl isocyanate (0.11 mL). Got as. This urea compound (146 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 115 mg (81%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.16 (1H, brs), 8.87 (2H, s), 8.48 (1H, d, J = 2.4 Hz), 7.99 (1H, dd, J = 8.4 and 8.4Hz), 7.66 (2H, d, J = 9.0Hz), 7.57 (2H, d, J = 9.0Hz), 7.08 (1H, dd, J = 12.1 and 1.5Hz ), 6.97 (1H, d, J = 7.8Hz), 5.22-5.20 (1H, m), 2.27 (3H, s), 2.19 (2H, d, J = 7.0Hz), 1.97-1.93 (2H, m) , 1.87-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.42-1.33 (2H, m).
MS (ESI) m / z: 479 (M + H) <+> .
　（実施例２５）
{trans-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリジン-2-イル)オキシ]シクロヘキシル}酢酸 (Example 25)
{trans-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyridin-2-yl) oxy] cyclohexyl} acetic acid
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　（２５ａ）　{trans-4-[(5-ブロモピリジン-2-イル)オキシ]シクロヘキシル}酢酸メチルエステル
　実施例（１ａ）と同様の方法で、(cis-4-ヒドロキシシクロヘキシル) 酢酸メチルエステル　（WO2009119534）（3.43 g）と5-ブロモピリジン-2-オール（2.78 g）、シアノメチレントリブチルホスホラン（CMBP）（6.3 mL）から、標記化合物 2.65 g（50%）を白色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.15(1H, d, J=3.1Hz), 7.62(1H, dd, J=8.8 and 2.5Hz), 6.60(1H, d, J=8.2Hz), 4.93-4.85(1H, m), 3.68(3H, s), 2.24(2H, d, J=6.6Hz), 2.16-2.12(2H, m), 1.89-1.78(3H, m), 1.50-1.40(2H, m), 1.23-1.13(2H, m)。 (25a) {trans-4-[(5-Bromopyridin-2-yl) oxy] cyclohexyl} acetic acid methyl ester (cis-4-hydroxycyclohexyl) acetic acid methyl ester (WO2009119534) in the same manner as in Example (1a) ) (3.43 g), 5-bromopyridin-2-ol (2.78 g), and cyanomethylenetributylphosphorane (CMBP) (6.3 mL), 2.65 g (50%) of the title compound was obtained as a white solid.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.15 (1H, d, J = 3.1 Hz), 7.62 (1H, dd, J = 8.8 and 2.5 Hz), 6.60 (1H, d, J = 8.2 Hz), 4.93-4.85 (1H, m), 3.68 (3H, s), 2.24 (2H, d, J = 6.6Hz), 2.16-2.12 (2H, m), 1.89-1.78 (3H, m), 1.50 -1.40 (2H, m), 1.23-1.13 (2H, m).
　（２５ｂ）　(trans-4-{[5-(4-アミノフェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸メチルエステル
　実施例（１ｂ）と同様の方法で、実施例（２５ａ）で得た化合物（1.47 g）と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（980 mg)から、標記化合物 897 mg（59%）を茶色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.29(1H, d, J=2.4Hz), 7.71(1H, dd, J=8.6 and 2.8Hz), 7.33(2H, d, J=8.6Hz), 6.76(2H, d, J=8.6Hz), 6.72(1H, d, J=8.6Hz), 5.01-4.94(1H, m), 3.74(2H, brs), 3.69(3H, s), 2.25(2H, d, J=6.6Hz), 2.21-2.17(2H, m), 1.88-1.85(3H, m), 1.55-1.44(2H, m), 1.26-1.16(2H, m)。 (25b) (trans-4-{[5- (4-aminophenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid methyl ester obtained in Example (25a) in a manner similar to Example (1b) From the compound (1.47 g) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (980 mg), the title compound 897 mg (59%) was obtained as a brown solid Got as.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.29 (1H, d, J = 2.4Hz), 7.71 (1H, dd, J = 8.6 and 2.8Hz), 7.33 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 8.6Hz), 6.72 (1H, d, J = 8.6Hz), 5.01-4.94 (1H, m), 3.74 (2H, brs), 3.69 (3H, s), 2.25 (2H, d, J = 6.6Hz), 2.21-2.17 (2H, m), 1.88-1.85 (3H, m), 1.55-1.44 (2H, m), 1.26-1.16 (2H, m).
　（２５ｃ）　{trans-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリジン-2-イル)オキシ]シクロヘキシル}酢酸
　実施例（１ｃ）と同様の方法で、実施例（２５ｂ）で得た化合物（358 mg）とフェニルイソシアナート（0.15 mL）からウレア体 483 mg（定量的収量）を白色固体として得た。このウレア体（483 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 437 mg（94%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.79(1H, brs), 8.71(1H, brs), 8.43(1H, d, J=3.1Hz), 7.95(1H, dd, J=8.7 and 2.8Hz), 7.59-7.53(2H, m), 7.56(2H, d, J=7.8Hz), 7.47(2H, dd, J=8.7 and 1.1Hz), 7.29(2H, dd, J=7.8 and 7.8Hz), 6.98(1H, dd, J=7.4 and 7.4Hz), 6.82(1H, d, J=8.7Hz), 4.98-4.92(1H, m), 2.15(2H, d, J=7.1Hz), 2.12-2.08(2H, m), 1.82-1.78(1H, m), 1.73-1.67(2H, m), 1.46-1.36(2H, m), 1.19-1.09(2H, m).
MS(ESI) m/z:446 (M + H)+。 (25c) {trans-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyridin-2-yl) oxy] cyclohexyl} acetic acid In the same manner as in Example (1c), From the compound (358 mg) obtained in 25b) and phenyl isocyanate (0.15 mL), 483 mg (quantitative yield) of the urea compound was obtained as a white solid. This urea compound (483 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 437 mg (94%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.79 (1H, brs), 8.71 (1H, brs), 8.43 (1H, d, J = 3.1 Hz), 7.95 (1H, dd, J = 8.7 and 2.8Hz), 7.59-7.53 (2H, m), 7.56 (2H, d, J = 7.8Hz), 7.47 (2H, dd, J = 8.7 and 1.1Hz), 7.29 (2H, dd, J = 7.8 and 7.8Hz), 6.98 (1H, dd, J = 7.4 and 7.4Hz), 6.82 (1H, d, J = 8.7Hz), 4.98-4.92 (1H, m), 2.15 ( 2H, d, J = 7.1Hz), 2.12-2.08 (2H, m), 1.82-1.78 (1H, m), 1.73-1.67 (2H, m), 1.46-1.36 (2H, m), 1.19-1.09 ( 2H, m).
MS (ESI) m / z: 446 (M + H) <+> .
　（実施例２６）
(trans-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキシル)酢酸 (Example 26)
(trans-4-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexyl) acetic acid
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　実施例（１ｃ）と同様の方法で、実施例（２５ｂ）で得た化合物（170 mg）と2,4-ジメチルフェニルイソシアナート（0.092 mL）からウレア体 244 mg（定量的収量）をオフホワイト色固体として得た。このウレア体（244 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 224 mg（95%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.05(1H, brs), 8.43(1H, d, J=2.0Hz), 7.95(1H, dd, J=8.6 and 2.4Hz), 7.89(1H, brs), 7.67(1H, d, J=7.9Hz), 7.58(2H, d, J=9.0Hz), 7.54(2H, d, J=9.0Hz), 7.00(1H, s), 6.97(1H, d, J=8.6Hz), 6.81(1H, d, J=9.0Hz), 4.98-4.91(1H, m), 2.23(3H, s), 2.21(3H, s), 2.15(2H, d, J=6.7Hz), 2.12-2.08(2H, m), 1.82-1.78(1H, m), 1.73-1.67(2H, m), 1.46-1.36(2H, m), 1.19-1.09(2H, m).
MS(ESI) m/z:474 (M + H)+。 In the same manner as in Example (1c), 244 mg of urea compound (quantitative yield) was off-white from the compound (170 mg) obtained in Example (25b) and 2,4-dimethylphenyl isocyanate (0.092 mL). Obtained as a colored solid. This urea compound (244 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 224 mg (95%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.05 (1H, brs), 8.43 (1H, d, J = 2.0 Hz), 7.95 (1H, dd, J = 8.6 and 2.4Hz), 7.89 (1H, brs), 7.67 (1H, d, J = 7.9Hz), 7.58 (2H, d, J = 9.0Hz), 7.54 (2H, d, J = 9.0Hz), 7.00 (1H, s), 6.97 (1H, d, J = 8.6Hz), 6.81 (1H, d, J = 9.0Hz), 4.98-4.91 (1H, m), 2.23 (3H, s), 2.21 (3H , s), 2.15 (2H, d, J = 6.7Hz), 2.12-2.08 (2H, m), 1.82-1.78 (1H, m), 1.73-1.67 (2H, m), 1.46-1.36 (2H, m ), 1.19-1.09 (2H, m).
MS (ESI) m / z: 474 (M + H) <+> .
　（実施例２７）
{trans-3-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロペンチル}酢酸 (Example 27)
{trans-3-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclopentyl} acetic acid
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　（２７ａ）　trans-{3-[(5-ブロモピリミジン-2-イル)オキシ]シクロペンチル}酢酸メチルエステル
　実施例（１ａ）と同様の方法で、cis-(3-ヒドロキシシクロペンチル)酢酸メチルエステル　（WO2009119534）（1.91 g）と5-ブロモピリミジン-2-オール（1.75 g）から、標記化合物 1.70 g（54%）を無色透明オイルとして得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.63(2H, s), 7.32(2H, d, J=8.6Hz), 6.78(2H, dd, J=6.2 and 2.0Hz), 5.48-5.43(1H, m), 3.80(2H, brs), 3.67(3H, s), 2.71-2.63(1H, m), 2.39(2H, d, J=7.1Hz), 2.26-2.15(2H, m), 2.13-2.07(1H, m), 1.97-1.88(1H, m), 1.67-1.60(1H, m), 1.35-1.25(1H, m)。 (27a) trans- {3-[(5-Bromopyrimidin-2-yl) oxy] cyclopentyl} acetic acid methyl ester In the same manner as in Example (1a), cis- (3-hydroxycyclopentyl) acetic acid methyl ester (WO2009119534 ) (1.91 g) and 5-bromopyrimidin-2-ol (1.75 g), 1.70 g (54%) of the title compound was obtained as a colorless transparent oil.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.63 (2H, s), 7.32 (2H, d, J = 8.6Hz), 6.78 (2H, dd, J = 6.2 and 2.0Hz), 5.48- 5.43 (1H, m), 3.80 (2H, brs), 3.67 (3H, s), 2.71-2.63 (1H, m), 2.39 (2H, d, J = 7.1Hz), 2.26-2.15 (2H, m) 2.13-2.07 (1H, m), 1.97-1.88 (1H, m), 1.67-1.60 (1H, m), 1.35-1.25 (1H, m).
　（２７ｂ）　trans-(3-{[5-(4-アミノフェニル)ピリミジン-2-イル]オキシ}シクロペンチル)酢酸メチルエステル
　実施例(１ｂ)と同様の方法で、実施例（２７ａ）で得た化合物（1.70 g)と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（1.18 g)から標記化合物 1.46 g（83%)を淡黄色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.51(2H, s), 5.39-5.36(1H, m), 3.67(3H, s), 2.70-2.58(1H, m), 2.38(2H, dd, J=7.4 and 1.9Hz), 2.23-2.06(3H, m), 1.93-1.84(1H, m), 1.65-1.59(1H, m), 1.34-1.24(1H, m)。 (27b) trans- (3-{[5- (4-aminophenyl) pyrimidin-2-yl] oxy} cyclopentyl) acetic acid methyl ester obtained in Example (27a) in a manner similar to Example (1b) From the compound (1.70 g) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.18 g), 1.46 g (83%) of the title compound was obtained as a pale yellow solid Got as.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.51 (2H, s), 5.39-5.36 (1H, m), 3.67 (3H, s), 2.70-2.58 (1H, m), 2.38 (2H , dd, J = 7.4 and 1.9Hz), 2.23-2.06 (3H, m), 1.93-1.84 (1H, m), 1.65-1.59 (1H, m), 1.34-1.24 (1H, m).
　（２７ｃ）　{trans-3-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロペンチル}酢酸
　実施例（１ｃ）と同様の方法で、実施例（２７ｂ）で得た化合物（144 mg）とフェニルイソシアナート（0.062 mL）からウレア体 145 mg（74%）を白色固体として得た。このウレア体（145 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 127 mg（91%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.90(1H, brs), 8.88(2H, s), 8.79(1H, brs), 7.66(1H, d, J=9.0Hz), 7.58(2H, d, J=8.6Hz), 7.47(2H, dd, J=8.8 and 1.0Hz), 7.31(2H, d, J=7.4Hz), 6.99(2H, d, J=7.4Hz), 5.42-5.38(1H, m), 2.46-2.40(1H, m), 2.30(2H, dd, J=7.2 and 3.0Hz), 2.22-2.13(1H, m), 2.04-1.93(2H, m), 1.78-1.70(1H, m), 1.63-1.56(1H, m), 1.34-1.21(1H, m).
MS(ESI) m/z:433 (M + H)+。 (27c) {trans-3-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclopentyl} acetic acid In the same manner as in Example (1c), From the compound (144 mg) obtained in 27b) and phenyl isocyanate (0.062 mL), 145 mg (74%) of urea was obtained as a white solid. This urea compound (145 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 127 mg (91%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.90 (1H, brs), 8.88 (2H, s), 8.79 (1H, brs), 7.66 (1H, d , J = 9.0Hz), 7.58 (2H, d, J = 8.6Hz), 7.47 (2H, dd, J = 8.8 and 1.0Hz), 7.31 (2H, d, J = 7.4Hz), 6.99 (2H, d , J = 7.4Hz), 5.42-5.38 (1H, m), 2.46-2.40 (1H, m), 2.30 (2H, dd, J = 7.2 and 3.0Hz), 2.22-2.13 (1H, m), 2.04- 1.93 (2H, m), 1.78-1.70 (1H, m), 1.63-1.56 (1H, m), 1.34-1.21 (1H, m).
MS (ESI) m / z: 433 (M + H) <+> .
　（実施例２８）
[trans-3-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロペンチル]酢酸 (Example 28)
[trans-3-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclopentyl] acetic acid
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　実施例（１ｃ）と同様の方法で、実施例（２７ｂ）で得た化合物（164 mg）と2-フルオロフェニルイソシアナート（0.073 mL）からウレア体 233 mg（定量的収量）を白色固体として得た。このウレア体（233 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 226 mg（定量的収量）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.23(1H, brs), 8.89(2H, s), 8.61(1H, d, J=2.4Hz), 8.17(1H, m), 7.68(2H, d, J=9.0Hz), 7.58(2H, d, J=8.6Hz), 7.28-7.23(1H, m), 7.16(1H, dd, J=7.8 and 7.8Hz), 7.05-7.00(1H, m), 5.42-5.38(1H, m), 2.46-2.40(1H, m), 2.30(2H, dd, J=7.2 and 2.6Hz), 2.22-2.13(1H, m), 2.03-1.93(2H, m), 1.79-1.70(1H, m), 1.63-1.56(1H, m), 1.31-1.21(1H, m).
MS(ESI) m/z:451 (M + H)+。 In the same manner as in Example (1c), 233 mg of urea compound (quantitative yield) was obtained as a white solid from the compound (164 mg) obtained in Example (27b) and 2-fluorophenyl isocyanate (0.073 mL). It was. This urea compound (233 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 226 mg (quantitative yield) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.23 (1H, brs), 8.89 (2H, s), 8.61 (1H, d, J = 2.4 Hz), 8.17 (1H, m), 7.68 (2H, d, J = 9.0Hz), 7.58 (2H, d, J = 8.6Hz), 7.28-7.23 (1H, m), 7.16 (1H, dd, J = 7.8 and 7.8Hz), 7.05-7.00 (1H, m), 5.42-5.38 (1H, m), 2.46-2.40 (1H, m), 2.30 (2H, dd, J = 7.2 and 2.6Hz), 2.22-2.13 (1H , m), 2.03-1.93 (2H, m), 1.79-1.70 (1H, m), 1.63-1.56 (1H, m), 1.31-1.21 (1H, m).
MS (ESI) m / z: 451 (M + H) <+> .
　（実施例２９）
{cis-3-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロペンチル}酢酸 (Example 29)
{cis-3-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclopentyl} acetic acid
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　（２９ａ）　cis-{3-[(5-ブロモピリミジン-2-イル)オキシ]シクロペンチル}酢酸メチルエステル
　実施例（１ａ）と同様の方法で、trans-(3-ヒドロキシシクロペンチル)酢酸メチルエステル　（WO2009119534）（899 mg）と5-ブロモピリミジン-2-オール（875 mg）から、標記化合物 812 mg（51%）を無色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.51(2H, s), 5.36-5.31(1H, m), 3.67(3H, s), 2.49-2.33(2H, m), 2.46(2H, dd, J=7.2 and 3.0Hz), 2.00-1.88(3H, m), 1.57-1.48(2H, m)。 (29a) cis- {3-[(5-Bromopyrimidin-2-yl) oxy] cyclopentyl} acetic acid methyl ester In the same manner as in Example (1a), trans- (3-hydroxycyclopentyl) acetic acid methyl ester (WO2009119534 ) (899 mg) and 5-bromopyrimidin-2-ol (875 mg) gave 812 mg (51%) of the title compound as a colorless solid.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.51 (2H, s), 5.36-5.31 (1H, m), 3.67 (3H, s), 2.49-2.33 (2H, m), 2.46 (2H , dd, J = 7.2 and 3.0 Hz), 2.00-1.88 (3H, m), 1.57-1.48 (2H, m).
　（２９ｂ）　cis-(3-{[5-(4-アミノフェニル)ピリミジン-2-イル]オキシ}シクロペンチル)酢酸メチルエステル
　実施例(１ｂ)と同様の方法で、実施例（２９ａ）で得た化合物（812 mg)と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（564 mg)から標記化合物 624 mg（74%)を薄褐色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.63(2H, s), 7.32(2H, d, J=8.6Hz), 6.78(2H, dd, J=6.2 and 2.0Hz), 5.44-5.39(1H, m), 3.80(2H, brs), 3.67(3H, s), 2.51-2.34(2H, m), 2.03-1.98(2H, m), 1.95-1.89(3H, m), 1.59-1.51(2H, m)。 (29b) cis- (3-{[5- (4-Aminophenyl) pyrimidin-2-yl] oxy} cyclopentyl) acetic acid methyl ester obtained in Example (29a) in a manner similar to Example (1b) Compound (812 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (564 mg) were used to obtain 624 mg (74%) of the title compound as a light brown solid Got as.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.63 (2H, s), 7.32 (2H, d, J = 8.6Hz), 6.78 (2H, dd, J = 6.2 and 2.0Hz), 5.44- 5.39 (1H, m), 3.80 (2H, brs), 3.67 (3H, s), 2.51-2.34 (2H, m), 2.03-1.98 (2H, m), 1.95-1.89 (3H, m), 1.59- 1.51 (2H, m).
　（２９ｃ）　{cis-3-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロペンチル}酢酸
　実施例（１ｃ）と同様の方法で、実施例（２９ｂ）で得た化合物（122 mg）とフェニルイソシアナート（0.052 mL）からウレア体 166 mg（定量的収量）を白色固体として得た。このウレア体（166 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 154 mg（定量的収量）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.88(2H, s), 8.84(1H, brs), 8.74(1H, brs), 7.66(2H, d, J=9.0Hz), 7.58(2H, d, J=8.6Hz), 7.47(2H, dd, J=8.6 and 1.2Hz), 7.30(2H, dd, J=8.0 and 8.0Hz), 6.99(1H, dd, J=7.5 and 7.5Hz), 5.37-5.32(1H, m), 2.41-2.33(3H, m), 2.29-2.22(1H, m), 2.02-1.94(1H, m), 1.90-1.80(2H, m), 1.47-1.37(2H, m).
MS(ESI) m/z:433 (M + H)+。 (29c) {cis-3-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclopentyl} acetic acid In the same manner as in Example (1c), From the compound (122 mg) obtained in 29b) and phenyl isocyanate (0.052 mL), 166 mg of urea compound (quantitative yield) was obtained as a white solid. This urea compound (166 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 154 mg (quantitative yield) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.88 (2H, s), 8.84 (1H, brs), 8.74 (1H, brs), 7.66 (2H, d , J = 9.0Hz), 7.58 (2H, d, J = 8.6Hz), 7.47 (2H, dd, J = 8.6 and 1.2Hz), 7.30 (2H, dd, J = 8.0 and 8.0Hz), 6.99 (1H , dd, J = 7.5 and 7.5Hz), 5.37-5.32 (1H, m), 2.41-2.33 (3H, m), 2.29-2.22 (1H, m), 2.02-1.94 (1H, m), 1.90-1.80 (2H, m), 1.47-1.37 (2H, m).
MS (ESI) m / z: 433 (M + H) <+> .
　（実施例３０）
[cis-3-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロペンチル]酢酸 (Example 30)
[cis-3-{[5- (4-{[(2-Fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclopentyl] acetic acid
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　実施例（１ｃ）と同様の方法で、実施例（２９ｂ）で得た化合物（164 mg）と2-フルオロフェニルイソシアナート（0.073 mL）からウレア体 231 mg（99%）を白色固体として得た。このウレア体（231 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 212 mg（95%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 9.23(1H, brs), 8.89(2H, s), 8.61(1H, d, J=2.7Hz), 8.19-8.14(1H, m), 7.68(2H, d, J=8.6Hz), 7.58(2H, d, J=9.0Hz), 7.28-7.23(1H, m), 7.16(1H, dd, J=7.8 and 7.8Hz), 7.05-7.00(1H, m), 5.37-5.32(1H, m), 2.41-2.33(3H, m), 2.29-2.22(1H, m), 2.01-1.94(1H, m), 1.90-1.80(2H, m), 1.45-1.37(2H, m).
MS(ESI) m/z:451 (M + H)+。 In the same manner as in Example (1c), 231 mg (99%) of a urea compound was obtained as a white solid from the compound (164 mg) obtained in Example (29b) and 2-fluorophenyl isocyanate (0.073 mL). . This urea compound (231 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 212 mg (95%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 9.23 (1H, brs), 8.89 (2H, s), 8.61 (1H, d, J = 2.7 Hz), 8.19-8.14 (1H, m), 7.68 (2H, d, J = 8.6Hz), 7.58 (2H, d, J = 9.0Hz), 7.28-7.23 (1H, m), 7.16 (1H, dd, J = 7.8 and 7.8Hz), 7.05-7.00 (1H, m), 5.37-5.32 (1H, m), 2.41-2.33 (3H, m), 2.29-2.22 (1H, m), 2.01-1.94 (1H, m) , 1.90-1.80 (2H, m), 1.45-1.37 (2H, m).
MS (ESI) m / z: 451 (M + H) <+> .
　（実施例３１）
{cis-4-[(5-{4-[(ピリジン-3-イルカルバモイル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸 (Example 31)
{cis-4-[(5- {4-[(Pyridin-3-ylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　（３１ａ）　(cis-4-{[5-(4-{[(4-ニトロフェノキシ)カルボニル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸メチルエステル
　実施例（１ｂ）で得た化合物（1.36 g）とピリジン（0.34 mL）のジクロロメタン溶液（10 mL）を4-ニトロフェニル クロロカルボナート（8.06 g）のジクロロメタン溶液（10 mL）に0℃でゆっくりと滴下した。反応混合物を室温に温め１時間撹拌し、濃縮した。残渣物をイソプロピルエーテル／水（１：１）中で激しく撹拌し、ろ取し、減圧下乾燥し、標記化合物 1.87 g（93%）を淡黄色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.70(2H, s), 8.32(2H, d, J=9.4Hz), 7.59(2H, d, J=8.6Hz), 7.53(2H, d, J=8.6Hz), 7.43(2H, d, J=9.4Hz), 7.12(1H, brs), 5.32-5.31(1H, m), 3.68(3H, s), 2.29(2H, d, J=7.0Hz), 2.14-2.09(2H, m), 1.99-1.91(1H, m), 1.74-1.56(6H, m)。 (31a) (cis-4-{[5- (4-{[(4-Nitrophenoxy) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid methyl ester obtained in Example (1b) A dichloromethane solution (10 mL) of the compound (1.36 g) and pyridine (0.34 mL) was slowly added dropwise at 0 ° C. to a dichloromethane solution (10 mL) of 4-nitrophenyl chlorocarbonate (8.06 g). The reaction mixture was warmed to room temperature, stirred for 1 hour and concentrated. The residue was vigorously stirred in isopropyl ether / water (1: 1), collected by filtration and dried under reduced pressure to give 1.87 g (93%) of the title compound as a pale yellow solid.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.70 (2H, s), 8.32 (2H, d, J = 9.4Hz), 7.59 (2H, d, J = 8.6Hz), 7.53 (2H, d, J = 8.6Hz), 7.43 (2H, d, J = 9.4Hz), 7.12 (1H, brs), 5.32-5.31 (1H, m), 3.68 (3H, s), 2.29 (2H, d, J = 7.0 Hz), 2.14-2.09 (2H, m), 1.99-1.91 (1H, m), 1.74-1.56 (6H, m).
　（３１ｂ）　{cis-4-[(5-{4-[(ピリジン-3-イルカルバモイル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸
　実施例（３１ａ）で得た化合物（253 mg）と3-アミノピリジン（47 mg）のアセトニトリル（6 mL）溶液を１時間加熱還流した。反応混合物を室温に冷却し濃縮した。残渣物をカラムクロマトグラフィー（自動クロマトグラフィー装置、ジクロロメタン／メタノール 100:0→85:15）で精製しウレア体 231  mg（定量的収量）を白色固体として得た。 (31b) {cis-4-[(5- {4-[(Pyridin-3-ylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid Compound (253) obtained in Example (31a) mg) and 3-aminopyridine (47 mg) in acetonitrile (6 mL) were heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (automatic chromatography apparatus, dichloromethane / methanol 100: 0 → 85: 15) to obtain 231 mg of urea compound (quantitative yield) as a white solid.
　このウレア体（231 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 223 mg（99%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=9.67(1H, brs), 9.40(1H, brs), 8.98(1H, d, J=2.0Hz), 8.89(2H, s), 8.43(1H, d, J=5.1Hz), 8.25(1H, d, J=9.4Hz), 7.77(1H, dd, J=8.4 and 5.2Hz), 7.69(2H, d, J=8.6Hz), 7.61(2H, d, J=9.0Hz), 5.22-5.21(1H, m), 2.19(2H, d, J=7.0Hz), 1.98-1.93(2H, m), 1.87-1.80(1H, m), 1.71-1.64(2H, m), 1.61-1.57(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:448 (M + H)+。 This urea compound (231 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 223 mg (99%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 9.67 (1H, brs), 9.40 (1H, brs), 8.98 (1H, d, J = 2.0 Hz), 8.89 (2H, s), 8.43 (1H, d, J = 5.1Hz), 8.25 (1H, d, J = 9.4Hz), 7.77 (1H, dd, J = 8.4 and 5.2Hz), 7.69 (2H, d, J = 8.6Hz), 7.61 (2H, d, J = 9.0Hz), 5.22-5.21 (1H, m), 2.19 (2H, d, J = 7.0Hz), 1.98-1.93 (2H, m), 1.87-1.80 (1H, m) , 1.71-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 448 (M + H) <+> .
　（実施例３２）
{cis-4-[(5-{4-[(ピリジン-4-イルカルバモイル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸 (Example 32)
{cis-4-[(5- {4-[(Pyridin-4-ylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　実施例（３１ｂ）の前半と同様の方法で、実施例（３１ａ）で得た化合物（253 mg）と4-アミノピリジン（47 mg）からウレア体 203 mg（88%）を白色固体として得た。このウレア体（203 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 194 mg（99%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.0(1H, brs), 10.9(1H, brs), 9.89(1H, brs), 8.90(2H, s), 8.61(2H, d, J=7.1Hz), 7.91(2H, d, J=7.0Hz), 7.73(2H, d, J=9.0Hz), 7.63(2H, d, J=8.6Hz), 5.22-5.21(1H, m), 2.19(2H, d, J=7.0Hz), 1.98-1.93(2H, m), 1.86-1.81(1H, m), 1.72-1.64(2H, m), 1.61-1.57(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:448 (M + H)+。 In the same manner as in the first half of Example (31b), urea compound 203 mg (88%) was obtained as a white solid from the compound (253 mg) obtained in Example (31a) and 4-aminopyridine (47 mg). . This urea compound (203 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 194 mg (99%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.0 (1H, brs), 10.9 (1H, brs), 9.89 (1H, brs), 8.90 (2H, s), 8.61 (2H, d , J = 7.1Hz), 7.91 (2H, d, J = 7.0Hz), 7.73 (2H, d, J = 9.0Hz), 7.63 (2H, d, J = 8.6Hz), 5.22-5.21 (1H, m ), 2.19 (2H, d, J = 7.0Hz), 1.98-1.93 (2H, m), 1.86-1.81 (1H, m), 1.72-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 448 (M + H) <+> .
　（実施例３３）
{cis-4-[(5-{4-[(ピリジン-2-イルカルバモイル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸 (Example 33)
{cis-4-[(5- {4-[(Pyridin-2-ylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　実施例（３１ｂ）の前半と同様の方法で、実施例（３１ａ）で得た化合物（253 mg）と2-アミノピリジン（47 mg）からウレア体 198 mg（86%）を白色固体として得た。このウレア体（198 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 182 mg（95%）を淡黄色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 10.6(1H, s), 9.5(1H, s), 8.89(2H, s), 8.89-8.32(1H, m), 7.80-7.75(1H, m), 7.70(2H, d, J=9.0Hz), 7.66(2H, d, J=9.0Hz), 7.52(1H, d, J=8.7Hz), 7.05-7.02(1H, m), 5.22-5.20(1H, m), 2.19(2H, d, J=7.0Hz), 1.98-1.93(2H, m), 1.86-1.80(1H, m), 1.71-1.63(2H, m), 1.61-1.56(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:448 (M + H)+。 In the same manner as in the first half of Example (31b), 198 mg (86%) of urea was obtained as a white solid from the compound (253 mg) obtained in Example (31a) and 2-aminopyridine (47 mg). . This urea compound (198 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 182 mg (95%) of the title compound as a pale yellow solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 10.6 (1H, s), 9.5 (1H, s), 8.89 (2H, s), 8.89-8.32 (1H , m), 7.80-7.75 (1H, m), 7.70 (2H, d, J = 9.0Hz), 7.66 (2H, d, J = 9.0Hz), 7.52 (1H, d, J = 8.7Hz), 7.05 -7.02 (1H, m), 5.22-5.20 (1H, m), 2.19 (2H, d, J = 7.0Hz), 1.98-1.93 (2H, m), 1.86-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 448 (M + H) <+> .
　（実施例３４）
trans-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキサンカルボン酸 (Example 34)
trans-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexanecarboxylic acid
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　（３４ａ）　trans-4-[(5-ブロモピリミジン-2-イル)オキシ] シクロヘキサンカルボン酸メチルエステル
　実施例（１ａ）と同様の方法で、cis-4-ヒドロキシシクロヘキサンカルボン酸メチルエステル　（WO2009119534）（1.13 g）と5-ブロモピリミジン-2-オール（1.00 g）から、標記化合物 0.665 g（37%）を無色オイルとして得た。
1H NMR(500MHz,CDCl3):δ(ppm)=8.50(2H, s), 4.95-4.89(1H, m), 3.69(3H, s), 2.40-2.34(1H, m), 2.23-2.19(2H, m), 2.12-2.07(2H, m), 1.68-1.53(4H, m)。 (34a) trans-4-[(5-Bromopyrimidin-2-yl) oxy] cyclohexanecarboxylic acid methyl ester In the same manner as in Example (1a), cis-4-hydroxycyclohexanecarboxylic acid methyl ester (WO2009119534) ( From 1.13 g) and 5-bromopyrimidin-2-ol (1.00 g), 0.665 g (37%) of the title compound was obtained as a colorless oil.
1 H NMR (500 MHz, CDCl 3 ): δ (ppm) = 8.50 (2H, s), 4.95-4.89 (1H, m), 3.69 (3H, s), 2.40-2.34 (1H, m), 2.23-2.19 (2H, m), 2.12-2.07 (2H, m), 1.68-1.53 (4H, m).
　（３４ｂ）　trans-4-{[5-(4-アミノフェニル)ピリミジン-2-イル]オキシ}シクロヘキサンカルボン酸メチルエステル
　実施例（１ｂ）と同様の方法で、実施例（３４ａ）で得た化合物（341 mg）と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（240 mg)から、標記化合物 273 mg（77%）を無色固体として得た。
1H NMR(500MHz,CDCl3):δ(ppm)=8.62(2H, s), 7.31(2H, d, J=8.3Hz), 6.78(2H, d, J=8.3Hz), 5.03-4.97(1H, m), 3.80(2H, brs), 3.69(3H, s), 2.42-2.36(1H, m), 2.28-2.25(2H, m), 2.13-2.09(2H, m), 1.70-1.57(4H, m)。 (34b) trans-4-{[5- (4-Aminophenyl) pyrimidin-2-yl] oxy} cyclohexanecarboxylic acid methyl ester Compound obtained in Example (34a) in the same manner as in Example (1b) (341 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (240 mg) gave 273 mg (77%) of the title compound as a colorless solid Obtained.
1 H NMR (500 MHz, CDCl 3 ): δ (ppm) = 8.62 (2H, s), 7.31 (2H, d, J = 8.3 Hz), 6.78 (2H, d, J = 8.3 Hz), 5.03-4.97 ( 1H, m), 3.80 (2H, brs), 3.69 (3H, s), 2.42-2.36 (1H, m), 2.28-2.25 (2H, m), 2.13-2.09 (2H, m), 1.70-1.57 ( 4H, m).
　（３４ｃ）　trans-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキサンカルボン酸
　実施例（１ｃ）と同様の方法で、実施例（３４ｂ）で得た化合物（100 mg）とフェニルイソシアナート（0.046 mL）からウレア体 134 mg（98%）を薄茶色固体として得た。このウレア体（129 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 117 mg（94%）を白色固体として得た。
1H NMR(500MHz,DMSO-d6):δ(ppm)=12.15(1H, brs), 8.88(2H, s), 8.82(1H, s), 8.71(1H, s), 7.65(2H, d, J=8.8Hz), 7.57(2H, d, J=8.8Hz), 7.47(2H, d, J=8.3Hz), 7.29(2H, t, J=7.9Hz), 6.98(1H, t, J=7.4Hz), 4.96-4.90(1H, m), 2.33-2.27(1H, m), 2.16-2.12(2H, m), 2.01-1.97(2H, m), 1.55-1.43(4H, m)。 (34c) trans-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexanecarboxylic acid In the same manner as in Example (1c), Example (34b) The urea compound 134 mg (98%) was obtained as a light brown solid from the compound (100 mg) obtained in (1) and phenyl isocyanate (0.046 mL). This urea compound (129 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 117 mg (94%) of the title compound as a white solid.
1 H NMR (500 MHz, DMSO-d 6 ): δ (ppm) = 12.15 (1H, brs), 8.88 (2H, s), 8.82 (1H, s), 8.71 (1H, s), 7.65 (2H, d , J = 8.8Hz), 7.57 (2H, d, J = 8.8Hz), 7.47 (2H, d, J = 8.3Hz), 7.29 (2H, t, J = 7.9Hz), 6.98 (1H, t, J = 7.4Hz), 4.96-4.90 (1H, m), 2.33-2.27 (1H, m), 2.16-2.12 (2H, m), 2.01-1.97 (2H, m), 1.55-1.43 (4H, m).
　（実施例３５）
trans-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキサンカルボン酸 (Example 35)
trans-4-{[5- (4-{[(2-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexanecarboxylic acid
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　実施例（１ｃ）と同様の方法で、実施例（３４ｂ）で得た化合物（100 mg）と2-フルオロフェニルイソシアナート（0.048 mL）からウレア体 144 mg（定量的収量）を薄茶色固体として得た。このウレア体（138 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 121 mg（91%）を白色固体として得た。
1H-NMR (400 MHz, DMSO-d6) : δ (ppm) = 12.14 (1H, s), 9.04 (1H, s), 8.43 (1H, s), 7.95 (1H, d, J = 8.4 Hz), 7.88 (1H, s), 7.67 (1H, d, J = 8.3 Hz), 7.59-7.53 (3H, m), 7.00 (1H, s), 6.96 (1H, d, J = 7.5 Hz), 6.82 (1H, d, J = 8.6 Hz), 4.99-4.93 (1H, m), 2.31-2.27 (1H, m), 2.23 (3H, s), 2.21 (3H, s), 2.16-2.10 (2H, m), 2.00-1.95 (2H, m), 1.54-1.42 (4H, m)
　（実施例３６）
trans-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキサンカルボン酸 In the same manner as in Example (1c), 144 mg of urea (quantitative yield) was obtained as a light brown solid from the compound (100 mg) obtained in Example (34b) and 2-fluorophenyl isocyanate (0.048 mL). Obtained. This urea compound (138 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 121 mg (91%) of the title compound as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.14 (1H, s), 9.04 (1H, s), 8.43 (1H, s), 7.95 (1H, d, J = 8.4 Hz ), 7.88 (1H, s), 7.67 (1H, d, J = 8.3 Hz), 7.59-7.53 (3H, m), 7.00 (1H, s), 6.96 (1H, d, J = 7.5 Hz), 6.82 (1H, d, J = 8.6 Hz), 4.99-4.93 (1H, m), 2.31-2.27 (1H, m), 2.23 (3H, s), 2.21 (3H, s), 2.16-2.10 (2H, m ), 2.00-1.95 (2H, m), 1.54-1.42 (4H, m)
(Example 36)
trans-4-{[5- (4-{[(4-Methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexanecarboxylic acid
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　実施例（１ｃ）と同様の方法で、実施例（３４ｂ）で得た化合物（100 mg）と4-メチルフェニルイソシアナート（0.054 mL）からウレア体 135 mg（96%）を白色固体として得た。このウレア体（128 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 122 mg（98%）を白色固体として得た。
1H NMR(500MHz,DMSO-d6):δ(ppm)=12.14(1H, brs), 8.88(2H, s), 8.78(1H, s), 8.61(1H, s), 7.64(2H, d, J=8.3Hz), 7.56(2H, d, J=8.8Hz), 7.35(2H, d, J=8.3Hz), 7.09(2H, d, J=8.8Hz), 4.96-4.90(1H, m), 2.33-2.27(1H, m), 2.25(3H, s), 2.16-2.12(2H, m), 2.01-1.96(2H, m), 1.55-1.45(4H, m)。 In the same manner as in Example (1c), 135 mg (96%) of urea was obtained as a white solid from the compound (100 mg) obtained in Example (34b) and 4-methylphenyl isocyanate (0.054 mL). . This urea compound (128 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 122 mg (98%) of the title compound as a white solid.
1 H NMR (500 MHz, DMSO-d 6 ): δ (ppm) = 12.14 (1H, brs), 8.88 (2H, s), 8.78 (1H, s), 8.61 (1H, s), 7.64 (2H, d , J = 8.3Hz), 7.56 (2H, d, J = 8.8Hz), 7.35 (2H, d, J = 8.3Hz), 7.09 (2H, d, J = 8.8Hz), 4.96-4.90 (1H, m ), 2.33-2.27 (1H, m), 2.25 (3H, s), 2.16-2.12 (2H, m), 2.01-1.96 (2H, m), 1.55-1.45 (4H, m).
　（実施例３７）
trans-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキサンカルボン酸 (Example 37)
trans-4-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexanecarboxylic acid
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　（３７ａ）　trans-4-{[5-(4-アミノフェニル)ピリジン-2-イル]オキシ}シクロヘキサンカルボン酸メチルエステル
　実施例（１ａ）と同様の方法で、cis-4-ヒドロキシシクロヘキサンカルボン酸メチルエステル　（WO2009119534）（1.00 g）と5-ブロモピリジン-2-オール（1.16 g）から、エーテル体 889 mg（45%）を黄色オイルとして得た。 (37a) trans-4-{[5- (4-Aminophenyl) pyridin-2-yl] oxy} cyclohexanecarboxylic acid methyl ester In the same manner as in Example (1a), methyl cis-4-hydroxycyclohexanecarboxylate From the ester (WO2009119534) (1.00 g) and 5-bromopyridin-2-ol (1.16 g), 889 mg (45%) of an ether form was obtained as a yellow oil.
　実施例（１ｂ）と同様の方法で、エーテル体（885 mg）と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（617 mg)から、標記化合物 757 mg（82%）を薄茶色固体として得た。
1H NMR(500MHz,CDCl3):δ(ppm)=8.29(1H, d, J=2.4Hz), 7.71(1H, dd, J=8.1 and 2.2Hz), 7.32(2H, d, J=8.3Hz), 6.76(2H, d, J=8.3Hz), 6.71(1H, d, J=8.8Hz), 5.05-4.99(1H, m), 3.74(2H, brs), 3.69(3H, s), 2.39-2.33(1H, m), 2.27-2.21(2H, m), 2.10-2.05(2H, m), 1.71-1.63(2H, m), 1.53-1.45(2H, m)。 From the ether form (885 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (617 mg) in the same manner as in Example (1b) , 757 mg (82%) of the title compound was obtained as a light brown solid.
1 H NMR (500 MHz, CDCl 3 ): δ (ppm) = 8.29 (1 H, d, J = 2.4 Hz), 7.71 (1 H, dd, J = 8.1 and 2.2 Hz), 7.32 (2 H, d, J = 8.3 Hz), 6.76 (2H, d, J = 8.3Hz), 6.71 (1H, d, J = 8.8Hz), 5.05-4.99 (1H, m), 3.74 (2H, brs), 3.69 (3H, s), 2.39-2.33 (1H, m), 2.27-2.21 (2H, m), 2.10-2.05 (2H, m), 1.71-1.63 (2H, m), 1.53-1.45 (2H, m).
　（３７ｂ）　trans-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキサンカルボン酸
　実施例（１ｃ）と同様の方法で、実施例（３７ａ）で得た化合物（100 mg）と2,4-ジメチルフェニルイソシアナート（0.070 mL）からウレア体 145 mg（100%）を薄茶色固体として得た。このウレア体（143 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 106 mg（76%）を白色固体として得た。
1H NMR(400MHz,CDCl3):δ(ppm)=8.29(1H, d, J=2.4Hz), 7.71(1H, dd, J=8.1 and 2.2Hz), 7.32(2H, d, J=8.3Hz), 6.76(2H, d, J=8.3Hz), 6.71(1H, d, J=8.8Hz), 5.05-4.99(1H, m), 3.74(2H, brs), 3.69(3H, s), 2.39-2.33(1H, m), 2.27-2.21(2H, m), 2.10-2.05(2H, m), 1.71-1.63(2H, m), 1.53-1.45(2H, m)。 (37b) trans-4-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexanecarboxylic acid The same method as in Example (1c) Thus, 145 mg (100%) of urea was obtained as a light brown solid from the compound (100 mg) obtained in Example (37a) and 2,4-dimethylphenyl isocyanate (0.070 mL). This urea compound (143 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 106 mg (76%) of the title compound as a white solid.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 8.29 (1H, d, J = 2.4Hz), 7.71 (1H, dd, J = 8.1 and 2.2Hz), 7.32 (2H, d, J = 8.3 Hz), 6.76 (2H, d, J = 8.3Hz), 6.71 (1H, d, J = 8.8Hz), 5.05-4.99 (1H, m), 3.74 (2H, brs), 3.69 (3H, s), 2.39-2.33 (1H, m), 2.27-2.21 (2H, m), 2.10-2.05 (2H, m), 1.71-1.63 (2H, m), 1.53-1.45 (2H, m).
　（実施例３８）
[cis-4-({4'-[(アニリノカルボニル)アミノ]ビフェニル-4-イル}オキシ)シクロヘキシル]酢酸 (Example 38)
[cis-4-({4 '-[(anilinocarbonyl) amino] biphenyl-4-yl} oxy) cyclohexyl] acetic acid
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　（３８ａ）　[cis-4-(4-ブロモフェノキシ)シクロヘキシル]酢酸メチルエステル
　実施例（１ａ）と同様の方法で、(trans-4-ヒドロキシシクロヘキシル) 酢酸メチルエステル　（WO2009119534）（2.07 g）と4-ブロモフェノール（1.73 g）から、標記化合物 2.07 g（63%）を淡黄色オイルとして得た。
1H NMR(400MHz,CDCl3):δ(ppm)=7.36(2H, d, J=9.0Hz), 6.79(2H, d, J=9.0Hz), 4.48-4.47(1H, m), 3.68(3H, s), 2.27(2H, d, J=7.4Hz), 2.01-1.97(2H, m), 1.94-1.87(1H, m), 1.63-1.54(4H, m), 1.49-1.39(2H, m)。 (38a) [cis-4- (4-Bromophenoxy) cyclohexyl] acetic acid methyl ester (trans-4-hydroxycyclohexyl) acetic acid methyl ester (WO2009119534) (2.07 g) and 4 in the same manner as in Example (1a) -From bromophenol (1.73 g), 2.07 g (63%) of the title compound was obtained as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 7.36 (2H, d, J = 9.0 Hz), 6.79 (2H, d, J = 9.0 Hz), 4.48-4.47 (1H, m), 3.68 ( 3H, s), 2.27 (2H, d, J = 7.4Hz), 2.01-1.97 (2H, m), 1.94-1.87 (1H, m), 1.63-1.54 (4H, m), 1.49-1.39 (2H, m).
　（３８ｂ）　{cis-4-[(4'-アミノビフェニル-4-イル)オキシ]シクロヘキシル}酢酸メチルエステル
　実施例(１ｂ)と同様の方法で、実施例（３８ａ）で得た化合物（2.07 g)と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（1.39 g)から標記化合物 1.14 g（53%)を茶色オイルとして得た。
1H NMR(400MHz,CDCl3):δ(ppm)=7.44(2H, d, J=9.0Hz), 7.36(2H, d, J=8.6Hz), 6.94(2H, d, J=8.7Hz), 6.75(2H, d, J=8.6Hz), 4.55-4.54(1H, m), 3.71(3H, s), 3.68(2H, brs), 2.29(2H, d, J=7.5Hz), 2.06-2.02(2H, m), 1.95-1.88(1H, m), 1.65-1.45(6H, m)。 (38b) {cis-4-[(4′-Aminobiphenyl-4-yl) oxy] cyclohexyl} acetic acid methyl ester Compound (2.07 g) obtained in Example (38a) in the same manner as in Example (1b) ) And 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.39 g) gave 1.14 g (53%) of the title compound as a brown oil.
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 7.44 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 8.6 Hz), 6.94 (2H, d, J = 8.7 Hz) , 6.75 (2H, d, J = 8.6Hz), 4.55-4.54 (1H, m), 3.71 (3H, s), 3.68 (2H, brs), 2.29 (2H, d, J = 7.5Hz), 2.06- 2.02 (2H, m), 1.95-1.88 (1H, m), 1.65-1.45 (6H, m).
　（３８ｃ）　[cis-4-({4'-[(アニリノカルボニル)アミノ]ビフェニル-4-イル}オキシ)シクロヘキシル]酢酸
　実施例（１ｃ）と同様の方法で、実施例（３８ｂ）で得た化合物（280 mg）とフェニルイソシアナート（0.12 mL）からウレア体 333 mg（88%）をオフホワイト色固体として得た。このウレア体（333 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 306 mg（95%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.0(1H, brs), 8.74(1H, brs), 8.70(1H, brs), 7.55-7.46(8H, m), 7.29(2H, dd, J=7.6 and 7.6Hz), 7.02-6.96(3H, m), 4.61-4.60(1H, m), 2.17(2H, d, J=7.0Hz), 1.91-1.87(2H, m), 1.84-1.78(1H, m), 1.63-1.60(2H, m), 1.56-1.52(2H, m), 1.41-1.32(2H, m).
MS(ESI) m/z:445 (M + H)+。 (38c) [cis-4-({4 '-[(anilinocarbonyl) amino] biphenyl-4-yl} oxy) cyclohexyl] acetic acid obtained in the same manner as in Example (1c) and in Example (38b) From the compound (280 mg) and phenyl isocyanate (0.12 mL), 333 mg (88%) of the urea compound was obtained as an off-white solid. This urea compound (333 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 306 mg (95%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.0 (1H, brs), 8.74 (1H, brs), 8.70 (1H, brs), 7.55-7.46 (8H, m), 7.29 (2H , dd, J = 7.6 and 7.6Hz), 7.02-6.96 (3H, m), 4.61-4.60 (1H, m), 2.17 (2H, d, J = 7.0Hz), 1.91-1.87 (2H, m), 1.84-1.78 (1H, m), 1.63-1.60 (2H, m), 1.56-1.52 (2H, m), 1.41-1.32 (2H, m).
MS (ESI) m / z: 445 (M + H) <+> .
　（実施例３９）
{cis-4-[(5-{4-[(シクロヘキシルカルバモイル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸 (Example 39)
{cis-4-[(5- {4-[(cyclohexylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　実施例（３１ｂ）の前半と同様の方法で、実施例（３１ａ）で得た化合物（253 mg）とアミノシクロヘキサン（50 mg）からウレア体 220 mg（94%）を白色固体として得た。このウレア体（219 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 204 mg（96%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, brs), 8.84(2H, s), 8.46(1H, s), 7.59(2H, d, J=9.0Hz), 7.49(2H, d, J=8.6Hz), 6.13(1H, d, J=7.4Hz), 5.22-5.18(1H, m), 3.50-3.44(1H, m), 2.19(2H, d, J=7.0Hz), 1.97-1.92(2H, m), 1.83-1.79(3H, m), 1.69-1.56(7H, m), 1.42-1.27(4H, m), 1.22-1.15(3H, m).
MS(ESI) m/z:453 (M + H)+。
（実施例４０）
cis-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキサンカルボン酸 In the same manner as in the first half of Example (31b), urea compound 220 mg (94%) was obtained as a white solid from the compound (253 mg) obtained in Example (31a) and aminocyclohexane (50 mg). This urea compound (219 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 204 mg (96%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, brs), 8.84 (2H, s), 8.46 (1H, s), 7.59 (2H, d, J = 9.0 Hz), 7.49 (2H, d, J = 8.6Hz), 6.13 (1H, d, J = 7.4Hz), 5.22-5.18 (1H, m), 3.50-3.44 (1H, m), 2.19 (2H, d, J = 7.0Hz), 1.97-1.92 (2H, m), 1.83-1.79 (3H, m), 1.69-1.56 (7H, m), 1.42-1.27 (4H, m), 1.22-1.15 (3H, m).
MS (ESI) m / z: 453 (M + H) <+> .
(Example 40)
cis-4-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexanecarboxylic acid
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
（４０ａ）　cis-4-{[5-(4-アミノフェニル)ピリジン-2-イル]オキシ}シクロヘキサンカルボン酸メチルエステル
　実施例（１ａ）と同様の方法で、trans-4-ヒドロキシシクロヘキサンカルボン酸メチルエステル　（WO2009119534）（1.00 g）と5-ブロモピリジン-2-オール（1.15 g）から、エーテル体 1.38 g（70%）を薄黄色オイルとして得た。 (40a) cis-4-{[5- (4-Aminophenyl) pyridin-2-yl] oxy} cyclohexanecarboxylic acid methyl ester In the same manner as in Example (1a), methyl trans-4-hydroxycyclohexanecarboxylate From the ester (WO2009119534) (1.00 g) and 5-bromopyridin-2-ol (1.15 g), 1.38 g (70%) of the ether form was obtained as a pale yellow oil.
　実施例（１ｂ）と同様の方法で、エーテル体（500 mg）と4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン（350 mg)から、標記化合物 519 mg（83%）を薄茶色固体として得た。
1H NMR(500MHz,CDCl3):δ(ppm)=8.28(1H, d, J=2.0Hz), 7.71(1H, dd, J=8.5 and 2.8Hz), 7.32(2H, d, J=8.7Hz), 6.75(3H, d, J=8.3Hz), 5.27-5.21(1H, m), 3.74(2H, s), 3.70(3H, s), 2.47-2.41(1H, m), 2.07-1.93(4H, m), 1.82-1.76(2H, m), 1.73-1.66(2H, m).
　（４０ｂ）　cis-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロヘキサンカルボン酸
　実施例（１ｃ）と同様の方法で、実施例（４０ａ）で得た化合物（110 mg）と2,4-ジメチルフェニルイソシアナート（0.080 mL）からウレア体を得た。このウレア体（54 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 45 mg(28%、２工程)を白色固体として得た。
1H-NMR (400 MHz, DMSO-d6) : δ (ppm) = 12.1 (1H, s), 9.08 (1H, s), 8.41 (1H, s), 7.95 (1H, d, J = 8.6 Hz), 7.90 (1H, s), 7.67 (1H, d, J = 8.1 Hz), 7.59-7.53 (3H, m), 6.99 (1H, s), 6.95 (1H, d, J = 8.2 Hz), 6.85 (1H, d, J = 8.4 Hz), 5.21-5.15 (1H, m), 2.41-2.36 (1H, m), 2.23 (3H, s), 2.21 (3H, s), 1.92-1.60 (8H, m).
MS(ESI) m/z:460 (M + H)+。
（実施例４１）
 [cis-3-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロペンチル]酢酸 In the same manner as in Example (1b), ether (500 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (350 mg) were used. 519 mg (83%) of the title compound was obtained as a light brown solid.
1 H NMR (500 MHz, CDCl 3 ): δ (ppm) = 8.28 (1H, d, J = 2.0 Hz), 7.71 (1H, dd, J = 8.5 and 2.8 Hz), 7.32 (2H, d, J = 8.7 Hz), 6.75 (3H, d, J = 8.3Hz), 5.27-5.21 (1H, m), 3.74 (2H, s), 3.70 (3H, s), 2.47-2.41 (1H, m), 2.07-1.93 (4H, m), 1.82-1.76 (2H, m), 1.73-1.66 (2H, m).
(40b) cis-4-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclohexanecarboxylic acid Method similar to Example (1c) Thus, a urea compound was obtained from the compound (110 mg) obtained in Example (40a) and 2,4-dimethylphenyl isocyanate (0.080 mL). This urea compound (54 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 45 mg (28%, 2 steps) of the title compound as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 12.1 (1H, s), 9.08 (1H, s), 8.41 (1H, s), 7.95 (1H, d, J = 8.6 Hz ), 7.90 (1H, s), 7.67 (1H, d, J = 8.1 Hz), 7.59-7.53 (3H, m), 6.99 (1H, s), 6.95 (1H, d, J = 8.2 Hz), 6.85 (1H, d, J = 8.4 Hz), 5.21-5.15 (1H, m), 2.41-2.36 (1H, m), 2.23 (3H, s), 2.21 (3H, s), 1.92-1.60 (8H, m ).
MS (ESI) m / z: 460 (M + H) <+> .
(Example 41)
[cis-3-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclopentyl] acetic acid
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　実施例（１ｃ）と同様の方法で、実施例（２９ｂ）で得た化合物（980 mg）と2,4-ジメチルフェニルイソシアナート（0.44 mL）からウレア体 1.33 g（93%）を白色固体として得た。このウレア体（1.32 g）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 305 mg（24%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.1(1H, s), 9.06(1H, s), 8.44(1H, d, J=2.7Hz), 7.95(1H, dd, J=8.8 and 2.5Hz), 7.89(1H, s), 7.68(1H, d, J=8.2Hz), 7.59(2H, d, J=9.0Hz), 7.55(2H, d, J=9.0Hz), 7.01(1H, s), 6.97(1H, d, J=8.2Hz), 6.83(1H, d, J=8.6Hz), 5.37-5.33(1H, m), 2.39-2.33(3H, m), 2.28-2.24(1H, m), 2.24(3H, s), 2.22(3H, s), 2.00-1.92(1H, m), 1.86-1.76(2H, m), 1.43-1.33(2H, m).
MS(ESI) m/z:458 (M - H)+。
（実施例４２）
 [trans-3-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリジン-2-イル]オキシ}シクロペンチル]酢酸 In the same manner as in Example (1c), 1.33 g (93%) of the urea compound as a white solid was obtained from the compound (980 mg) obtained in Example (29b) and 2,4-dimethylphenyl isocyanate (0.44 mL). Obtained. This urea compound (1.32 g) was hydrolyzed in the same manner as in Example (1d) to obtain 305 mg (24%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.1 (1H, s), 9.06 (1H, s), 8.44 (1H, d, J = 2.7 Hz), 7.95 (1H, dd, J = 8.8 and 2.5Hz), 7.89 (1H, s), 7.68 (1H, d, J = 8.2Hz), 7.59 (2H, d, J = 9.0Hz), 7.55 (2H, d, J = 9.0Hz), 7.01 (1H, s), 6.97 (1H, d, J = 8.2Hz), 6.83 (1H, d, J = 8.6Hz), 5.37-5.33 (1H, m), 2.39-2.33 (3H, m), 2.28- 2.24 (1H, m), 2.24 (3H, s), 2.22 (3H, s), 2.00-1.92 (1H, m), 1.86-1.76 (2H, m), 1.43-1.33 (2H, m).
MS (ESI) m / z: 458 (M-H) <+> .
(Example 42)
[trans-3-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} cyclopentyl] acetic acid
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　実施例（１ｃ）と同様の方法で、実施例（２７ｂ）で得た化合物（1.07g）と2,4-ジメチルフェニルイソシアナート（0.48 mL）からウレア体 860 mg（55%）を薄オレンジ色固体として得た。このウレア体（860 mg）を実施例（１ｄ）と同様の方法で加水分解し、標記化合物 290 mg（35%）を白色固体として得た。
1H NMR(400MHz,DMSO-d6):δ(ppm)=12.0(1H, brs), 9.09(1H, s), 8.43(1H, d, J=1.9Hz), 7.95(1H, dd, J=8.6 and 2.4Hz), 7.92(1H, s), 7.67(1H, d, J=8.2Hz), 7.59(2H, d, J=8.9Hz), 7.55(2H, d, J=9.0Hz), 7.00(1H, s), 6.97(1H, d, J=8.2Hz), 6.83(1H, d, J=8.3Hz), 5.43-5.38(1H, m), 2.46-2.38(1H, m), 2.32-2.26(2H, m), 2.23(1H, s), 2.21(3H, s), 2.18-2.11(3H, m), 1.99-1.91(1H, m), 1.75-1.67(2H, m), 1.61-1.53(1H, m), 1.61-1.53(1H, m).
MS(ESI) m/z:460 (M + H)+。 In the same manner as in Example (1c), 860 mg (55%) of the urea compound was pale orange from the compound (1.07 g) obtained in Example (27b) and 2,4-dimethylphenyl isocyanate (0.48 mL). Obtained as a solid. This urea compound (860 mg) was hydrolyzed in the same manner as in Example (1d) to obtain 290 mg (35%) of the title compound as a white solid.
1 H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.0 (1H, brs), 9.09 (1H, s), 8.43 (1H, d, J = 1.9 Hz), 7.95 (1H, dd, J = 8.6 and 2.4Hz), 7.92 (1H, s), 7.67 (1H, d, J = 8.2Hz), 7.59 (2H, d, J = 8.9Hz), 7.55 (2H, d, J = 9.0Hz), 7.00 (1H, s), 6.97 (1H, d, J = 8.2Hz), 6.83 (1H, d, J = 8.3Hz), 5.43-5.38 (1H, m), 2.46-2.38 (1H, m), 2.32- 2.26 (2H, m), 2.23 (1H, s), 2.21 (3H, s), 2.18-2.11 (3H, m), 1.99-1.91 (1H, m), 1.75-1.67 (2H, m), 1.61- 1.53 (1H, m), 1.61-1.53 (1H, m).
MS (ESI) m / z: 460 (M + H) <+> .
　（試験例１）
（１）DGAT1酵素の調製
　ＵＳ２００７／０２４９６２０号公報に記載されている方法に従って、DGAT1酵素を調整、保存した。
（２）DGAT１阻害活性試験
　以下の組成の反応液［175 mM Tris-HCl (pH 8.0)、8 mM MgCl2、1 mg/ml BSA、0.3 mM 1,2-dioleoyl-sn-glycerol（10倍濃度のEtOH溶液を10％添加）、10μM [14C]-oleoyl-CoA (約50 mCi/mmol)、0.5% triton X-100（ダウケミカル）、試験例１（１）で得られるDGAT1酵素(10μg)、試験化合物またはビークル（DMSO/MeOH, 7:3溶液、5％添加）、総容量50μl］を室温（23℃）で30分間インキュベーションした。反応液にイソプロパノール／１－ヘプタン／水（80:20:2, v/v/v）からなる反応停止液（70μl）を加えて撹拌し、次いで、水（30μl）および１－ヘプタン（100μl）を加えて撹拌した。１－ヘプタン層（50μl）をTLCプレートにスポットして、１－ヘキサン／ジエチルエーテル／酢酸（85:15:1, v/v/v）からなる展開溶媒にて展開した。BAS2000バイオイメージアナライザ（富士フィルム）によりトリグリセライド画分の放射活性を定量して、コントロールと比較することにより試験化合物の阻害活性を以下の式により算出した。なお、未反応（0分間インキュベーション）の放射活性をバックグラウンドとした。 (Test Example 1)
(1) Preparation of DGAT1 enzyme The DGAT1 enzyme was prepared and stored in accordance with the method described in US2007 / 0249620.
(2) DGAT1 inhibitory activity test Reaction solution [175 mM Tris-HCl (pH 8.0), 8 mM MgCl 2 , 1 mg / ml BSA, 0.3 mM 1,2-dioleoyl-sn-glycerol (10-fold concentration) 10% EtOH solution), 10 μM [ 14 C] -oleoyl-CoA (about 50 mCi / mmol), 0.5% triton X-100 (Dow Chemical), DGAT1 enzyme obtained in Test Example 1 (1) (10 μg) ), Test compound or vehicle (DMSO / MeOH, 7: 3 solution, 5% added), total volume 50 μl] was incubated at room temperature (23 ° C.) for 30 minutes. To the reaction mixture was added a reaction stop solution (70 μl) consisting of isopropanol / 1-heptane / water (80: 20: 2, v / v / v) and stirred, then water (30 μl) and 1-heptane (100 μl) Was added and stirred. A 1-heptane layer (50 μl) was spotted on a TLC plate and developed with a developing solvent consisting of 1-hexane / diethyl ether / acetic acid (85: 15: 1, v / v / v). The radioactivity of the triglyceride fraction was quantified with a BAS2000 bioimage analyzer (Fuji Film), and the inhibitory activity of the test compound was calculated by the following formula by comparing with the control. The unreacted (0 minute incubation) radioactivity was used as the background.
　阻害率　＝　100－[(試験化合物添加時の放射活性)－(バックグラウンド)]／[(コントロールの放射活性)－(バックグラウンド)]×100
　実施例１－４２の化合物は、試験化合物濃度1 μg／mlにおいて50％以上の阻害率を示した。 Inhibition rate = 100 − [(radioactivity at the time of addition of test compound) − (background)] / [(radioactivity of control) − (background)] × 100
The compound of Example 1-42 showed an inhibition rate of 50% or more at a test compound concentration of 1 μg / ml.
　なお、DGAT阻害活性試験は上記の方法に限定されず、例えば、ラット、マウス等の動物の小腸、脂肪組織または肝臓から調製したミクロソームをDGAT酵素として使用してもよい。また、培養細胞（3T3-L1脂肪細胞、初代培養脂肪細胞、Caco2細胞、HepG2細胞等）またはDGATを高発現させた培養細胞から調製したミクロソームをDGAT酵素として使用することもできる。さらに、多数の試験化合物を短時間で効率よく評価するためには、抽出操作を省略したフラッシュプレート（PerkinElmer）を使用することができる。 The DGAT inhibitory activity test is not limited to the above method. For example, microsomes prepared from the small intestine, adipose tissue, or liver of animals such as rats and mice may be used as the DGAT enzyme. Alternatively, microsomes prepared from cultured cells (3T3-L1 adipocytes, primary cultured adipocytes, Caco2 cells, HepG2 cells, etc.) or cultured cells highly expressing DGAT can also be used as the DGAT enzyme. Furthermore, in order to efficiently evaluate a large number of test compounds in a short time, a flash plate (PerkinElmer) in which the extraction operation is omitted can be used.
　上記の結果から、本発明の化合物は、優れたDGAT1阻害生物活性を有する。 From the above results, the compound of the present invention has excellent DGAT1 inhibitory biological activity.
　（試験例２）
　DGAT1酵素は中性脂肪の消化吸収に重要であり、小腸DGAT1が阻害されると中性脂肪の吸収が抑制される。中性脂肪負荷後の中性脂肪吸収抑制を指標として、DGAT1阻害作用の生物活性を評価した。１晩絶食させた雄性C57BL/6Nマウス（7-12週齡、体重17-25 g、日本チャールズリバー)をVehicle群1、Vehicle群2および各試験化合物群に割り付け、それぞれvehicle（0.5% Methylcellulose）またはvehicleに懸濁させた各試験化合物（1乃至10 mg/kg）を経口投与（5 mL/kg）した。一定時間後にリポプロテインリパーゼ阻害剤（Pluronic-F127：シグマアルドリッチ（株）、1 g/kg、重量比20%で生理食塩水に溶解）を腹腔内投与（5 mL/kg）し、直後に、Vehicle群1には蒸留水を、Vehicle群2および化合物群には20%中性脂肪含有エマルジョン (イントラリピッド20%：テルモ（株）)を経口投与（0.2 mL/マウス）した。投与後1乃至4時間の一定時間後に、尾静脈または右心室より採血を行い、速やかに血漿を分離回収した後、血漿中の中性脂肪濃度を市販のキット (トリグリセライド E テスト ワコー：和光純薬工業（株）)を用いて測定した。本法ではリポプロテインリパーゼ阻害剤の投与により血中に流入した中性脂肪の分解が抑制され、中性脂肪は血中に蓄積するが、その由来は消化管にて吸収された外因性のものと肝臓より放出された内因性のものに二分される。各試験化合物の中性脂肪吸収抑制活性は下記計算式に基づき、内因性中性脂肪の影響を除いて算出した。なお、各試験化合物が内因性中性脂肪濃度に影響しないことは別途確認されている。 (Test Example 2)
The DGAT1 enzyme is important for digestion and absorption of neutral fat, and when small intestine DGAT1 is inhibited, the absorption of neutral fat is suppressed. The biological activity of the DGAT1 inhibitory action was evaluated using as an index the inhibition of neutral fat absorption after neutral fat loading. Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) fasted overnight were assigned to Vehicle Group 1, Vehicle Group 2 and each test compound group, respectively vehicle (0.5% Methylcellulose) Alternatively, each test compound (1 to 10 mg / kg) suspended in the vehicle was orally administered (5 mL / kg). Lipoprotein lipase inhibitor (Pluronic-F127: Sigma-Aldrich Co., Ltd., 1 g / kg, dissolved in physiological saline at 20% by weight) was intraperitoneally administered (5 mL / kg) Distilled water was orally administered to Vehicle Group 1 and 20% neutral fat-containing emulsion (Intralipid 20%: Terumo Corporation) was orally administered (0.2 mL / mouse) to Vehicle Group 2 and Compound Group. After 1 to 4 hours after administration, blood is collected from the tail vein or right ventricle, and plasma is promptly separated and collected, and then the neutral fat concentration in the plasma is measured using a commercially available kit (Triglyceride E Test Wako: Wako Pure Chemical Industries, Ltd.) (Industry Co., Ltd.). In this method, the administration of lipoprotein lipase inhibitor suppresses the degradation of neutral fat flowing into the blood, and neutral fat accumulates in the blood, but its origin is exogenous absorbed in the digestive tract And it is divided into endogenous ones released from the liver. The neutral fat absorption inhibitory activity of each test compound was calculated based on the following formula, excluding the influence of endogenous neutral fat. It has been separately confirmed that each test compound does not affect the endogenous triglyceride concentration.
　中性脂肪吸収抑制活性（％）＝100－[（各試験化合物群の中性脂肪濃度）－（Vehicle群1の中性脂肪濃度）]/[（Vehicle群2の中性脂肪濃度）－（Vehicle群1の中性脂肪濃度）]×100
　実施例１－３０、３４－４２の化合物は、3 mg/kg以下の用量で60％以上の中性脂肪吸収抑制活性を示した。 Neutral fat absorption inhibitory activity (%) = 100-[(Neutral fat concentration of each test compound group)-(Neutral fat concentration of Vehicle group 1)] / [(Neutral fat concentration of Vehicle group 2)-( Vehicle group 1 neutral fat concentration)] × 100
The compounds of Examples 1-30 and 34-42 showed neutral fat absorption inhibitory activity of 60% or more at a dose of 3 mg / kg or less.
　上記の結果から、本発明の化合物は、優れた中性脂肪吸収抑制活性を有する。 From the above results, the compound of the present invention has excellent neutral fat absorption inhibitory activity.
　（試験例３）
　雄性C57BL/6Nマウス (7-12週齢、体重17-25 g、日本チャールズリバー)を個体別に飼育し、高脂肪食（脂肪含有率 45 kcal%：リサーチダイエット社D12451)を1週間以上給餌して馴化させた。期間中の摂餌量に基づいて実験群に動物を均等に割り付け、一晩絶食させた後、vehicle (0.5% Methylcellulose)またはvehicleに懸濁させた試験化合物（1乃至10 mg/kg）を各群に経口投与(10 mL/kg)した。投与30分後に高脂肪食を給餌し、給餌開始後6時間での摂餌量を測定した。各試験化合物の摂食抑制活性は下記計算式に基づき算出した。 (Test Example 3)
Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) are bred individually and fed with a high fat diet (fat content 45 kcal%: Research Diet D12451) for over a week. I got used to it. Allocate the animals evenly to the experimental groups based on the amount of food consumed during the period, fast overnight and then each vehicle (0.5% Methylcellulose) or test compound (1-10 mg / kg) suspended in the vehicle. The group was orally administered (10 mL / kg). A high fat diet was fed 30 minutes after the administration, and the amount of food intake was measured 6 hours after the start of feeding. The feeding inhibitory activity of each test compound was calculated based on the following formula.
　摂食抑制活性（％）＝[（Vehicle群の摂餌量）－（各試験化合物群の摂餌量）]/[（Vehicle群の摂餌量）]×100
　実施例１－２の化合物は、10 mg/kg以下の用量で25％以上の摂食抑制活性を示した。 Feeding inhibitory activity (%) = [(food consumption of vehicle group) − (food consumption of each test compound group)] / [(food consumption of vehicle group)] × 100
The compound of Example 1-2 exhibited an antifeedant activity of 25% or more at a dose of 10 mg / kg or less.
　上記の結果から、本発明の化合物は、優れた摂食抑制作用を有する。 From the above results, the compound of the present invention has an excellent antifeedant action.
　なお、餌に使用する高脂肪食は上記の高脂肪食に限定されず、例えば、カロリーとして45乃至60％の中性脂肪を含有するげっ歯類用飼料を使用することができる。 Note that the high-fat diet used for the feed is not limited to the above-mentioned high-fat diet, and for example, a rodent feed containing 45 to 60% neutral fat as calories can be used.
　製剤例１：カプセル剤
実施例１又は２の化合物　　５０ｍｇ
乳糖　　　　　　　　　　１２８ｍｇ
トウモロコシデンプン　　　７０ｍｇ
ステアリン酸マグネシウム　　２ｍｇ
－－－－－－－－－－－－－－－－－
　　　　　　　　　　　　２５０ｍｇ
上記処方の粉末を混合し、６０メッシュのふるいを通した後、この粉末を２５０ｍｇのゼラチンカプセルに入れ、カプセル剤とする。 Formulation Example 1: Capsule 50 mg of the compound of Example 1 or 2
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
-----------------
250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.
　製剤例２：錠剤
実施例１又は２の化合物　　５０ｍｇ
乳糖　　　　　　　　　　１２６ｍｇ
トウモロコシデンプン　　　２３ｍｇ
ステアリン酸マグネシウム　　１ｍｇ
－－－－－－－－－－－－－－－－－
　　　　　　　　　　　　２００ｍｇ
上記処方の粉末を混合し、トウモロコシデンプン糊を用いて造粒、乾燥した後、打錠機により打錠して、１錠２００ｍｇの錠剤とする。この錠剤は必要に応じて糖衣を施すことができる。 Formulation Example 2: Tablet Example 1 or 2 compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
-----------------
200mg
The powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.
　本発明の一般式（I）で表される化合物又はその薬理上許容される塩は、優れたＤＧＡＴ阻害作用及び摂食抑制作用を有し、医薬として有用である。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action and antifeeding action and is useful as a medicine.

Claims (23)

  1. 　一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
    ［式中、
    　Ｒは、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基、置換基群Ａから選択される基で独立に１乃至３個置換されていてもよいピリジル基又はＣ３－Ｃ６シクロアルキル基を示し、
    　Ｑは、窒素原子又は式－ＣＨ＝で表わされる基を示し、
    　Ｕは、窒素原子又は式－ＣＨ＝で表わされる基を示し、
    　Ｖは、窒素原子又は式－ＣＨ＝で表わされる基を示し、
    　ｍは、０又は１を示し、
    　ｎは、０又は１を示し、
    　置換基群Ａは、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６ハロゲン化アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６ハロゲン化アルコキシ基、（Ｃ１－Ｃ６アルコキシ）－（Ｃ１－Ｃ６アルキル）基、Ｃ１－Ｃ６アルキルチオ基、Ｃ１－Ｃ６アルキルスルフィニル基、カルボキシ基、Ｃ２－Ｃ７アルキルカルボニル基、Ｃ２－Ｃ７アルコキシカルボニル基、アミノ基、モノ－Ｃ１－Ｃ６アルキルアミノ基、ジ－（Ｃ１－Ｃ６アルキル）アミノ基、モノ－Ｃ２－Ｃ７アルキルカルボニルアミノ基、モノ－Ｃ１－Ｃ６アルキルスルホニルアミノ基、シアノ基、ニトロ基及びヒドロキシ基からなる群を示す。］で表される化合物又はその薬理上許容される塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    R is a phenyl group which may be independently substituted with a group selected from the substituent group A, and may be independently substituted with 1 to 3 groups independently selected from a group selected from the substituent group A; A pyridyl group or a C 3 -C 6 cycloalkyl group,
    Q represents a nitrogen atom or a group represented by the formula —CH═,
    U represents a nitrogen atom or a group represented by the formula —CH═,
    V represents a nitrogen atom or a group represented by the formula —CH═,
    m represents 0 or 1,
    n represents 0 or 1,
    Substituent group A includes a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 halogenated alkoxy group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfinyl group, carboxy group, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group Group, amino group, mono-C 1 -C 6 alkylamino group, di- (C 1 -C 6 alkyl) amino group, mono-C 2 -C 7 alkylcarbonylamino group, mono-C 1 -C 6 alkylsulfonyl A group consisting of an amino group, a cyano group, a nitro group and a hydroxy group is shown. Or a pharmacologically acceptable salt thereof.
  2. 　請求項１において、一般式（Ｉ）が、一般式（Ｉａ）、一般式（Ｉｂ）、一般式（Ｉｃ）、一般式（Ｉｄ）、一般式（Ｉｅ）又は一般式（Ｉｆ）である化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000002
         The compound according to claim 1, wherein the general formula (I) is the general formula (Ia), the general formula (Ib), the general formula (Ic), the general formula (Id), the general formula (Ie), or the general formula (If). Or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000002
  3. 　請求項１において、一般式（Ｉ）が、一般式（Ｉａ）である化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000003
         The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (Ia).
    Figure JPOXMLDOC01-appb-C000003
  4. 　請求項１乃至３から選択されるいずれか一項において、Ｒが、置換基群Ａから選択される基で独立に１乃至５個置換されていてもよいフェニル基である化合物又はその薬理上許容される塩。 The compound or pharmacologically acceptable compound thereof according to any one of claims 1 to 3, wherein R is a phenyl group which may be independently substituted with 1 to 5 groups independently selected from the substituent group A. Salt.
  5. 　請求項１乃至３から選択されるいずれか一項において、Ｒが、（フッ素原子、塩素原子、メチル基及びメトキシ基）から選択される基で独立に１乃至３個置換されていてもよいフェニル基である化合物又はその薬理上許容される塩。 4. The phenyl according to any one of claims 1 to 3, wherein R is independently substituted with 1 to 3 groups independently selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group). Or a pharmacologically acceptable salt thereof.
  6. 　請求項１乃至３から選択されるいずれか一項において、Ｒが、フェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－メチルフェニル基、３－メチルフェニル基、４－メチルフェニル基、２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基、２－クロロ－４－フルオロフェニル基、２－フルオロ－３－メチルフェニル基、２－フルオロ－４－メチルフェニル基、２，４－ジメチルフェニル基、２－メトキシ－５－メチルフェニル基又は２，４，５－トリフルオロフェニル基である化合物又はその薬理上許容される塩。 4. The method according to claim 1, wherein R is a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-methylphenyl group, or a 3-methylphenyl group. 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-3-methylphenyl group, 2-fluoro-4 A compound which is a methylphenyl group, 2,4-dimethylphenyl group, 2-methoxy-5-methylphenyl group or 2,4,5-trifluorophenyl group, or a pharmacologically acceptable salt thereof.
  7. 　(cis-4-{[5-(4-{[(2-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    {cis-4-[(5-{4-[(アニリノカルボニル)アミノ]フェニル}ピリミジン-2-イル)オキシ]シクロヘキシル}酢酸、
    (cis-4-{[5-(4-{[(3-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(4-フルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(2-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(3-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(2-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(3-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(4-メトキシフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(2,4,5-トリフルオロフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(2-メトキシ-5-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(2-フルオロ-3-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、
    (cis-4-{[5-(4-{[(2-フルオロ-4-メチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸、又は、
    (cis-4-{[5-(4-{[(2,4-ジメチルフェニル)カルバモイル]アミノ}フェニル)ピリミジン-2-イル]オキシ}シクロヘキシル)酢酸
    である化合物又はその薬理上許容される塩。     (cis-4-{[5- (4-{[(2-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(4-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    {cis-4-[(5- {4-[(anilinocarbonyl) amino] phenyl} pyrimidin-2-yl) oxy] cyclohexyl} acetic acid,
    (cis-4-{[5- (4-{[(3-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(4-fluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(2-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(3-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(2-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(3-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(4-methoxyphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(2,4,5-trifluorophenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(2-fluoro-3-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
    (cis-4-{[5- (4-{[(2-fluoro-4-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid, or
    (cis-4-{[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid or a pharmacologically acceptable salt thereof .
  8. 　請求項１乃至７から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有するアシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼ阻害剤。 An acyl coenzyme A: diacylglycerol acyltransferase inhibitor containing the compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof as an active ingredient.
  9. 　請求項１乃至７から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有する摂食抑制剤及び／又は食欲抑制剤。 An antifeedant and / or an appetite suppressant comprising the compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof as an active ingredient.
  10. 　請求項１乃至７から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof as an active ingredient.
  11. 　医薬組成物が、アシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼ阻害作用を有する請求項１０に記載の医薬組成物。 The pharmaceutical composition according to claim 10, which has an acylcoenzyme A: diacylglycerol acyltransferase inhibitory action.
  12. 　医薬組成物が、摂食抑制作用及び／又は食欲抑制作用を有する請求項１０に記載の医薬組成物。 The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition has an antifeedant action and / or an appetite suppressive action.
  13. 　医薬組成物が、アシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼを阻害させ、トリグリセライドの合成を阻害し、トリグリセライドの吸収が抑制されることにより、症状の治療、改善、軽減及び／又は予防がなされる疾病の治療及び／又は予防のための請求項１０に記載の医薬組成物。 The pharmaceutical composition inhibits acylcoenzyme A: diacylglycerol acyltransferase, inhibits the synthesis of triglyceride, and suppresses the absorption of triglyceride, thereby preventing the treatment, amelioration, reduction and / or prevention of symptoms. The pharmaceutical composition according to claim 10 for treatment and / or prevention.
  14. 　医薬組成物が、アシルコエンザイムＡ：ジアシルグリセロールアシルトランスフェラーゼを阻害させ、トリグリセライドの合成が阻害されることにより、症状の治療、改善、軽減及び／又は予防がなされる疾病の治療及び／又は予防のための請求項１０に記載の医薬組成物。 For the treatment and / or prevention of a disease in which the pharmaceutical composition inhibits acylcoenzyme A: diacylglycerol acyltransferase and the synthesis of triglyceride is inhibited, thereby treating, ameliorating, reducing and / or preventing symptoms. The pharmaceutical composition according to claim 10.
  15. 　医薬組成物が、肥満、肥満症、高脂血症、高トリグリセライド症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患又は過食症の治療及び／又は予防のための請求項１０に記載の医薬組成物。 The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceride disease, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, non-alcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease Or the pharmaceutical composition of Claim 10 for the treatment and / or prevention of bulimia.
  16. 　医薬組成物が、肥満又は肥満症の治療及び／又は予防のための請求項１０に記載の医薬組成物。 The pharmaceutical composition according to claim 10 for treating and / or preventing obesity or obesity.
  17. 　医薬組成物が、糖尿病の治療及び／又は予防のための請求項１０に記載の医薬組成物。 The pharmaceutical composition according to claim 10 for treating and / or preventing diabetes.
  18. 　肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患又は過食症の治療及び／又は予防で使用するための、請求項１乃至７から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩。 Obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy Cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease or bulimia The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7 for use in therapy and / or prevention.
  19. 　医薬組成物を製造するための、請求項１乃至７から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の使用。 Use of the compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
  20. 　医薬組成物が肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患又は過食症の治療及び／又は予防のための医薬組成物である請求項１９に記載の使用。 If the pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, non-alcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease The use according to claim 19, which is a pharmaceutical composition for the treatment and / or prevention of bulimia.
  21. 　請求項１乃至７から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与する疾病の治療及び／又は予防方法。 A method for treating and / or preventing a disease, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof.
  22. 　疾病が肥満、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、インスリン抵抗性症候群、耐糖能異常、糖尿病、糖尿病合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む）、白内障、妊娠糖尿病、非アルコール性脂肪肝炎、多嚢胞卵巣症候群、動脈硬化症、アテローム性動脈硬化症、糖尿病性動脈硬化症、虚血性心疾患又は過食症である請求項２１に記載の方法。 Diseases are obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic Retinopathy, including diabetic macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease or binge eating The method according to claim 21, which is a symptom.
  23. 　温血動物がヒトである請求項２１又は２２に記載の方法。 The method according to claim 21 or 22, wherein the warm-blooded animal is a human.
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Citations (4)

* Cited by examiner, † Cited by third party
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JP2007191471A (en) * 2005-12-21 2007-08-02 Sankyo Co Ltd Medicine containing urea derivative
WO2009011285A1 (en) * 2007-07-13 2009-01-22 Taisho Pharmaceutical Co., Ltd. Heteroarylbenzene compounds
WO2011024932A1 (en) * 2009-08-28 2011-03-03 第一三共株式会社 Novel tetrahydroisoquinoline compounds
JP2011507823A (en) * 2007-12-20 2011-03-10 アストラゼネカ アクチボラグ Carbamoyl compounds 190 as DGAT1 inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007191471A (en) * 2005-12-21 2007-08-02 Sankyo Co Ltd Medicine containing urea derivative
WO2009011285A1 (en) * 2007-07-13 2009-01-22 Taisho Pharmaceutical Co., Ltd. Heteroarylbenzene compounds
JP2011507823A (en) * 2007-12-20 2011-03-10 アストラゼネカ アクチボラグ Carbamoyl compounds 190 as DGAT1 inhibitors
WO2011024932A1 (en) * 2009-08-28 2011-03-03 第一三共株式会社 Novel tetrahydroisoquinoline compounds

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