WO2014003124A1 - Novel amide derivative and salt thereof - Google Patents

Novel amide derivative and salt thereof Download PDF

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WO2014003124A1
WO2014003124A1 PCT/JP2013/067668 JP2013067668W WO2014003124A1 WO 2014003124 A1 WO2014003124 A1 WO 2014003124A1 JP 2013067668 W JP2013067668 W JP 2013067668W WO 2014003124 A1 WO2014003124 A1 WO 2014003124A1
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group
optionally substituted
compound
benzamide
biphenyl
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PCT/JP2013/067668
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French (fr)
Japanese (ja)
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潤一 横谷
洋一 谷口
有弘 高鳥
崇良 仲
泰子 小幡
加藤　寛
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富士フイルム株式会社
富山化学工業株式会社
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    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
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    • 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
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    • A61P13/00—Drugs for disorders of the urinary system
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    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a novel amide derivative having a collagen production inhibitory action or a salt thereof.
  • Fibrosis in which extracellular matrix including collagen is produced is a mechanism of wound healing. However, if the damage is prolonged, it deviates from the normal process and the extracellular matrix is excessively deposited over a wide area, resulting in fibrosis. Fibrosis is a disease state with a poor prognosis leading to organ failure due to a combination of damage to the tissue itself due to the causative disease and subsequent dysfunction due to fibrosis. Although fibrosis is found in various organs, the origin of extracellular matrix-producing cells is thought to be common, and the origin is endogenous fibroblasts, epithelial cells and fibrocytes that have transitioned to epithelial-mesenchymal cells (non- Patent Document 1).
  • Non-Patent Document 2 a Non-Patent Document 2
  • Pirfenidone trade name: Pirrespa Tablets 200 mg
  • the efficacy observed in clinical trials was only suppression of the decrease in vital capacity, and in addition, side effects such as photosensitivity were observed in 87.9% (Non-patent Document 3).
  • N-acyl anthranilic acid derivatives have a matrix metalloproteinase-13 production inhibitory action and a collagen production inhibitory action (Patent Document 1).
  • a treatment agent for preventing or treating diseases that have collagen production inhibitory activity and involve excessive production of collagen is desired.
  • R 1 represents an aryl group which may be substituted with one or more groups selected from substituent group ⁇ , and a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group ⁇ A formula group or an optionally substituted bicyclic heterocyclic group;
  • R 2 and R 3 has the general formula —X 1 —R 6 wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 An alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6 is an optionally substituted aryl group, A heterocyclic group or an optionally substituted C 3-8 cycloalkyl group ”.
  • R 2 and R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an optionally substituted aryl group, or A group represented by the general formula -X 1 -R 6 , wherein X 1 and R 6 have the same meaning as described above;
  • X 2 represents an optionally substituted C 1-6 alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond;
  • Z 1 and Z 2 may be the same or different and each represents a nitrogen atom or a general formula C—R 7 wherein R 7 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or a substituted A C 1-6 alkoxy group which may optionally be represented by the formula:
  • Y represents —N ⁇ N—, —S (O) —O—, —C (O)
  • Substituent group ⁇ a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • R 2 has the general formula —X 1 —R 6 wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 alkylene group, An optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6 is an optionally substituted aryl group, an optionally substituted heterocycle A cyclic group or an optionally substituted C 3-8 cycloalkyl group ”, a group represented by R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or a substituted group;
  • R 1 is an aryl group which may be substituted with one or more groups selected from substituent group ⁇ or a monocyclic group which may be substituted with one or more groups selected from substituent group ⁇
  • Substituent group ⁇ a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • Z 1 and Z 2 are the same or different and have the general formula C—R 7 wherein R 7 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or a substituted group. It indicates a C 1-6 alkoxy group optionally. a group represented by "(1) a compound or salt thereof according to any one of the - (5).
  • R 2 has the general formula —X 1 —R 6a “wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 alkylene group, An optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6a represents an optionally substituted aryl group.
  • R 2 is a group represented by the general formula —X 1d —R 6a, wherein R 1a represents a bond; R 6a represents an optionally substituted aryl group, R 3
  • X 2 is a C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group or a bond.
  • R 1 is an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted C 1
  • R 1 is an aryl group which may be substituted with one or more groups selected from substituent group ⁇ or a monocyclic group which may be substituted with one or more groups selected from substituent group ⁇
  • Substituent group ⁇ a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 ., which may be the same or different, a hydrogen atom or a substituted showing a C 1-6 alkyl group optionally group (13) represented by "R 1 annular optionally substituted amino group or the formula - Aryl substituted with a group represented by NR 4 R 5 wherein R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • the compound is 4- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (piperidin-1-yl) -N- ( 4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole) -3-yl) biphenyl-3-yl) benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl)- 2- (piperidin-1-yl) isonicotinamide, 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro- 1,2,4-oxadiazole-3-
  • Substituent group ⁇ 1 a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, C 1-6 alkoxy group which may be substituted, C 3-8 cycloalkyl group which may be substituted, heterocyclic group which may be substituted, cyclic amino group which may be substituted and general formula A group represented by: —NR 4 R 5 wherein R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. (28) The compound or a salt thereof according to (27), wherein X 2 is a bond.
  • a pharmaceutical composition comprising the compound or salt thereof according to (27) or (28).
  • a collagen production inhibitor containing the compound or salt thereof according to (27) or (28).
  • the present invention also provides the following.
  • a compound represented by the general formula [1] defined above or a salt thereof for use as a medicament (B) a compound represented by the general formula [1] for use in treatment such as prevention or treatment of a disease associated with overproduction of collagen, preferably for treatment such as prevention or treatment of fibrosis, or Its salt.
  • B a compound represented by the general formula [1] for use in treatment such as prevention or treatment of a disease associated with overproduction of collagen, preferably for treatment such as prevention or treatment of fibrosis, or Its salt.
  • C A pharmaceutical composition comprising a compound represented by the general formula [1] or a salt thereof and a pharmacologically acceptable additive.
  • D A method of using a compound represented by the general formula [1] or a salt thereof for treatment such as prevention or treatment of a disease associated with overproduction of collagen, which is represented by the general formula [1].
  • Administering a therapeutically effective amount of a compound or salt thereof to a subject (mammal, including humans).
  • E Use of the compound according to any one of (1) to (23) or a salt thereof for the production of a pharmaceutical composition.
  • (F) Use of the compound or salt thereof according to any one of (1) to (23) for the production of a collagen production inhibitor.
  • G Use of the compound according to any one of (1) to (23) or a salt thereof for the manufacture of a therapeutic agent for a disease involving excessive production of collagen.
  • novel amide derivative of the present invention or a salt thereof has a collagen production inhibitory action and is excellent in safety and kinetics, for example, overproduction of collagen such as pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis It is useful for treatments such as prevention or treatment of diseases in which is involved. Furthermore, the compound of the present invention has excellent metabolic stability.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the C 1-6 alkyl group is a linear or branched C 1-6 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups.
  • An alkyl group is meant.
  • the C 2-6 alkenyl group is a linear or branched C 2-6 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups.
  • the C 2-6 alkynyl group means a linear or branched C 2-6 alkynyl group such as ethynyl, 2-propynyl and 2-butynyl groups.
  • the C 3-8 cycloalkyl group is a C 3-8 cyclo which may have an unsaturated bond in the molecule such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl groups.
  • An alkyl group is meant.
  • An aryl group means a partially saturated aryl group such as phenyl, naphthyl, dihydronaphthyl and tetrahydronaphthyl groups.
  • the ar C 1-6 alkyl group means a benzyl, diphenylmethyl, trityl, phenethyl or naphthylmethyl group or the like.
  • the C 1-6 alkylene group means a linear or branched C 1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene groups.
  • the C 2-6 alkenylene group means a linear or branched C 2-6 alkenylene group such as vinylene, propenylene, 1-butenylene and 2-butenylene groups.
  • the C 2-6 alkynylene group means a linear or branched C 2-6 alkynylene group such as ethynylene, propynylene, 1-butynylene and 2-butynylene groups.
  • the C 1-6 alkoxy group means a linear or branched C 1 -1 group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.
  • 6 means an alkyloxy group.
  • the C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyloxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
  • Al C 1-6 alkoxy C 1-6 alkyl group means an al C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl groups.
  • the C 2-12 alkanoyl group means a linear or branched C 2-12 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
  • An aroyl group means a benzoyl or naphthoyl group.
  • the heterocyclic carbonyl group means nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.
  • the ( ⁇ -substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, tryptophan, proline and hydroxyproline, etc.) means the N-terminus derived from ( ⁇ -substituted) aminoacetyl group which may be protected.
  • amino acid glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, try
  • Acyl group means formyl group, succinyl group, glutaryl group, maleoyl group, phthaloyl group, C 2-12 alkanoyl group, aroyl group, heterocyclic carbonyl group or ( ⁇ -substituted) aminoacetyl group.
  • the C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 alkyloxy group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and 1,1-dimethylpropoxycarbonyl group.
  • the al C 1-6 alkoxycarbonyl group means a benzyloxycarbonyl or phenethyloxycarbonyl group.
  • An aryloxycarbonyl group means a phenyloxycarbonyl or naphthyloxycarbonyl group.
  • An acyl C 1-6 alkyl group means an acetylmethyl, benzoylmethyl or 1-benzoylethyl group.
  • the C 2-6 alkanoyloxy group means a linear or branched C 2-6 alkanoyloxy group such as acetyloxy and propionyloxy groups.
  • An aroyloxy group means a benzoyloxy or naphthoyloxy group.
  • the acyloxy group means a C 2-6 alkanoyloxy or aroyloxy group.
  • the acyloxy C 1-6 alkyl group means an acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, benzoyloxymethyl or 1- (benzoyloxy) ethyl group.
  • the C 1-6 alkylamino group means a mono (C 1-6 alkyl) amino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino and pentylamino groups.
  • DiC 1-6 alkylamino group means dimethylamino, diethylamino, dipropylamino, dibutylamino, (ethyl) (methyl) amino, (methyl) (propyl) amino, (butyl) (methyl) amino and (methyl) It means a di (C 1-6 alkyl) amino group such as (pentyl) amino group.
  • the C 1-6 alkylsulfonyl group means a methylsulfonyl, ethylsulfonyl, propylsulfonyl group or the like.
  • the arylsulfonyl group means benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.
  • the C 1-6 alkylsulfonyloxy group means a methylsulfonyloxy or ethylsulfonyloxy group.
  • An arylsulfonyloxy group means a benzenesulfonyloxy or p-toluenesulfonyloxy group.
  • the C 1-6 alkylsulfonylamino group means a methylsulfonylamino or ethylsulfonylamino group.
  • a silyl group means a trimethylsilyl, triethylsilyl, or tributylsilyl group.
  • the oxygen-containing heterocyclic group means a 2-tetrahydropyranyl or 2-tetrahydrofuranyl group.
  • the sulfur-containing heterocyclic group means tetrahydrothiopyranyl and the like.
  • the heterocyclic oxycarbonyl group means a 2-furfuryloxycarbonyl or 8-quinolyloxycarbonyl group.
  • the nitrogen-containing heterocyclic alkyl group means a phthalimidomethyl or succinimidomethyl group.
  • Monocyclic heterocyclic groups include azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperazinyl, azepanyl, diazepanyl, octahydroazosinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, A monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a hetero atom forming the ring, such as imidazolinyl, imidazolidinyl, pyrazolinyl and pyrazolidinyl groups; hetero rings forming the ring such as tetrahydrofuranyl, furanyl and pyranyl groups A monocyclic oxygen-containing heterocyclic group containing only an
  • Bicyclic heterocyclic groups include indolyl, indolinyl, 2-oxoindolinyl, isoindolyl, indolizinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinolidinyl, Condensed or bridged rings containing only a nitrogen atom as a hetero atom forming the ring, such as isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, quinuclidinyl and 2,3-dihydrobenzopyrrolyl groups
  • a bicyclic nitrogen-containing heterocyclic group represented by: benzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochro
  • a heterocyclic group is a monocyclic heterocyclic group; a bicyclic heterocyclic group; or thiantenyl, xanthenyl, phenoxathinyl, carbazolyl, ⁇ -carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenidinyl It means a tricyclic heterocyclic group such as nantrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl.
  • Cyclic amino groups are azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, imidazolidinyl, piperazinyl, homopiperazinyl, morpholinyl, oxazepanyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzomorpholinyl, dihydropyridoxazinyl and quinuclidinyl
  • Amino protecting groups include all groups that can be used as protecting groups for ordinary amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group.
  • the imino protecting group includes all groups that can be used as protecting groups for ordinary imino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group.
  • C 1-6 alkylamino protecting groups include protecting groups similar to imino protecting groups.
  • Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 16-366, 2007, John Wiley & Sons (John Wiley & Sons, INC.).
  • a C 1-6 alkyl group a C 2-6 alkenyl group, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an ar C 1-6 alkoxy C 1- 1 6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, al C 1-6 alkoxycarbonyl group, C 1-6 alkylsulfonyl group, arylsulfonyl group, silyl group, tetrahydrofuranyl group or tetrahydropyranyl group .
  • the carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis 4th Edition, pp. 533-646, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, a C 1-6 alkyl group, a C 2-6 alkenyl group, an aryl group, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an ar C 1-6 alkoxy C 1 Examples include a -6 alkyl group, an acyl C 1-6 alkyl group, an acyloxy C 1-6 alkyl group, and a silyl group.
  • Acidic imino protecting groups are 1H-tetrazol-5-yl group, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl group, 5-oxo-4,5-dihydro Means a protecting group for acidic imino group such as -1,2,4-thiadiazol-3-yl group, 5-thiooxo-4,5-dihydro-1,2,4-oxadiazol-3-yl group, For example, W.W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 872-894, 2007, John Wiley & Sons, INC.).
  • acyl group C 1-6 alkoxycarbonyl group, al C 1-6 alkyloxycarbonyl group, aryloxycarbonyl group, al C 1-6 alkyl group, acyl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, arylsulfonyl group, silyl group and the like can be mentioned.
  • Examples of the leaving group include a halogen atom, a C 1-6 alkylsulfonyloxy group, an arylsulfonyloxy group, and the like.
  • Alcohols include methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
  • Aromatic hydrocarbons include benzene, toluene or xylene.
  • amides include N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone.
  • halogenated hydrocarbons include methylene chloride, chloroform or dichloroethane.
  • ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.
  • Ketones include acetone, 2-butanone or 4-methyl-2-pentanone.
  • Esters include methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
  • Aliphatic hydrocarbons include pentane, hexane or cyclohexane.
  • Palladium catalysts include palladium-carbon and metal black such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium.
  • metal catalyst examples include palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metals such as Raney nickel and platinum salts such as platinum oxide.
  • the ligand examples include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trimethylphosphite, triethyl Trialkyl phosphites such as phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1,3-bis (2,4,6 Imidazolium salts such as trimethylphenyl) imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; , Amines such as triethylamine, tripropy
  • diseases involving excessive production of collagen include pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis, and pulmonary fibrosis is preferred.
  • Examples of the salt of the compound represented by the general formula [1] include salts that are generally known in basic groups such as amino groups or acidic groups such as phenolic hydroxyl groups or carboxyl groups.
  • Salts in basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrogen bromide and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and Examples thereof include salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.
  • salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine and N, N′-dibenzylethylenediamine Can be mentioned. Furthermore, among the above salts, preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.
  • Amino group is halogen atom, cyano group, nitro group, acyl group, acyloxy group, sulfo group, phosphoryl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino group, acetamide group, carbamoyl group, oxo group ,
  • the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group of substituent group ⁇ 1 Group, heterocyclic group and cyclic amino group are a halogen atom, cyano group, nitro group, acyl group, acyloxy group, sulfo group, phosphoryl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino group, An acetamido group, a carbamoyl group, an oxo group, an optionally protected carboxyl group, an optionally protected amino group, an optionally protected C 1-6 alkylamino group, an optionally protected hydroxyl group, C 1-6 alkyl groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 alkoxy group, di C 1-6 alkylamino group,
  • the bicyclic heterocyclic group of R 1 is a halogen atom, cyano group, nitro group, acyl group, acyloxy group, sulfo group, phosphoryl group, C 1-6 alkyl.
  • the C 1-6 alkyl group, C 1-6 alkoxy group and aryl group of R 2 or R 3 are each a halogen atom, a cyano group, a nitro group, an acyl group, an acyloxy group, A sulfo group, a phosphoryl group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfonylamino group, an acetamide group, a carbamoyl group, an oxo group, an optionally protected carboxyl group, an optionally protected amino group, A protected C 1-6 alkylamino group, an optionally protected hydroxyl group, a C 1-6 alkyl group optionally substituted with one or more groups selected from substituent group ⁇ , substituent group one or more optionally substituted C 2-6 alkenyl group with a group selected from the beta, optionally substituted with one or more groups selected from substituent group beta C 2- 6 alkyn
  • the C 1-6 alkyl group of R 4 or R 5 is a hydroxyl group, an optionally protected carboxyl group, an optionally protected amino group, or an protected group.
  • C 1-6 alkylamino group, optionally substituted with one or more groups selected from substituent group ⁇ C 1-6 alkyl group, optionally substituted with one or more groups selected from substituent group ⁇ C 2-6 alkenyl group which may be substituted with one or more groups selected from substituent group ⁇ may be substituted with one or more groups selected from C 2-6 alkynyl group which may be substituted, or substituent group ⁇
  • the aryl group, heterocyclic group and C 3-8 cycloalkyl group of R 6 are each a halogen atom, a cyano group, a nitro group, an acyl group, an acyloxy group, a sulfo group, a phosphoryl group.
  • the C 1-6 alkyl group and the C 1-6 alkoxy group of R 7 are a hydroxyl group, an optionally protected carboxyl group, an optionally protected amino group, C 1-6 alkylamino group which is protected, C 1-6 alkyl group which may be substituted with one or more groups selected from substituent group ⁇ , one or more groups selected from substituent group ⁇ One or more selected from a C 2-6 alkynyl group optionally substituted with one or more groups selected from substituent group ⁇ and a C 2-6 alkenyl group optionally substituted with substituent group ⁇
  • the C 1-6 alkylene group, C 2-6 alkenylene group and C 2-6 alkynylene group of X 1 are each a halogen atom, a cyano group, a hydroxyl group and a C 1-6 alkoxy group. It may be substituted with one or more groups selected from the group.
  • the C 1-6 alkylene group, C 2-6 alkenylene group and C 2-6 alkynylene group of X 2 are one or more selected from a halogen atom and a substituent group ⁇ .
  • a C 1-6 alkyl group optionally substituted with a group, a phenyl group optionally substituted with one or more groups selected from substituent group ⁇ , and one or more groups selected from substituent group ⁇ It may be substituted with one or more groups selected from an optionally substituted cyclic amino group and one or more heterocyclic groups optionally substituted with one or more groups selected from substituent group ⁇ .
  • Substituent group ⁇ a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group and a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • Substituent group ⁇ 1 a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, C 1-6 alkoxy group which may be substituted, C 3-8 cycloalkyl group which may be substituted, heterocyclic group which may be substituted, cyclic amino group which may be substituted and general formula A group represented by: —NR 4 R 5 wherein R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • Substituent group ⁇ 2 a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a cyclic amino group optionally substituted with one or more C 1-6 alkyl groups, and a general formula —NR 4a R 5a A group represented by the formula: wherein R 4a and R 5a are the same or different and each represents a C 1-6 alkyl group.
  • Substituent group ⁇ halogen atom, cyano group, amino group which may be protected, hydroxyl group which may be protected, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group An aryl group, a heterocyclic group and an oxo group.
  • R 1 is an aryl group which may be substituted with one or more groups selected from substituent group ⁇ or a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group ⁇ A compound which is a formula group is preferable, and an aryl group substituted with one or more groups selected from substituent group ⁇ or a monocyclic heterocyclic ring substituted with one or more groups selected from substituent group ⁇ A compound which is a formula group is more preferable, and may be a cyclic amino group which may be substituted or a general formula —NR 4 R 5 , wherein R 4 and R 5 have the same meaning as described above.
  • R 1 is an aryl group which may be substituted with one or more groups selected from substituent group ⁇ 1, or a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group ⁇ 1
  • a compound which is a formula group is preferable, and an aryl group substituted with one or more groups selected from substituent group ⁇ 1 or a monocyclic heterocyclic ring substituted with one or more groups selected from substituent group ⁇ 1
  • a compound which is a formula group is more preferable, and may be a cyclic amino group which may be substituted or a general formula —NR 4 R 5 , wherein R 4 and R 5 have the same meaning as described above.
  • R 1 is a group represented by the following general formulas (I) to (VI), and is a group represented by the following general formula (I), (III) or (V) Compounds are most preferred.
  • Z 3 represents a nitrogen atom or C—H;
  • R 4a , R 4b , R 5a and R 5b are the same or different and represent a C 1-6 alkyl group;
  • R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , R 9c and R 9d are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group;
  • m1 and m2 represent an integer of 0 to 3 ”
  • a compound in which m1 and m2 are integers of 1 to 3 is preferable, and a compound in which integers of 1 to 2 are more preferable.
  • R 2 is a group represented by the general formula —X 1 —R 6 , wherein X 1 and R 6 have the same meaning as described above is preferable, and the general formula —X 1 —R is preferable.
  • 6a “wherein X 1 and R 6a have the same meaning as described above” is more preferable, and a compound represented by the general formula —X 1d —R 6a “wherein X 1d and R 6a Has the same meaning as described above. ”Is more preferable.
  • R 2 is more preferably a compound represented by the general formula —X 1d —R 6b , wherein R 6b represents an aryl group; X 1d has the same meaning as described above. Most preferred are compounds that are phenyl groups.
  • R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or an optionally substituted aryl group is preferred, A compound that is a hydrogen atom is more preferable.
  • R 2 is a group represented by the general formula —X 1 —R 6 , wherein X 1 and R 6 have the same meaning as described above, and R 3 is a hydrogen atom, a halogen atom or a substituted group
  • R 2 is more preferably a group represented by the general formula —X 1 —R 6a wherein “X 1 and R 6a have the same meaning as described above”, and R 3 is a hydrogen atom. .
  • R 2 is a group represented by the general formula —X 1d —R 6a , wherein X 1d and R 6a have the same meanings as described above, and R 3 is a hydrogen atom.
  • R 2 is a group represented by the general formula —X 1d —R 6b , wherein X 1d and R 6b have the same meaning as described above, and a compound in which R 3 is a hydrogen atom is more preferable. Most preferred is a compound wherein R 2 is a phenyl group and R 3 is a hydrogen atom.
  • the compound which is a group represented is more preferable.
  • Y is —N ⁇ N—, —C (O) —O—, —C (O) —S— or —C (S) —O— (where the bond on the left side of each group is bonded to NH) Is preferred).
  • a compound in which Y is —N ⁇ N—, —C (O) —O— or —C (O) —S— (wherein the bond on the left side of each group is bonded to NH). Is more preferable.
  • a compound in which X 2 is a C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group or a bond is preferable, and a compound in which X 2 is a bond is more preferable.
  • R 1 is an aryl group which may be substituted with one or more groups selected from substituent group ⁇ or a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group ⁇
  • R 1 is an aryl group which may be substituted with one or more groups selected from substituent group ⁇ 1, or a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group ⁇ 1
  • preferred compounds include the following compounds. 4- (Piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (piperidin-1-yl) -N- (4- (1H- Tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- (piperidine- 1-yl) isonicotinamide, 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (5-oxo-4,5-d
  • the group represented by the following general formula [T] includes tautomers represented by the following formulas [t1] to [t6].
  • the present invention also includes these tautomers.
  • the present invention when isomers (for example, optical isomers and geometric isomers, etc.) exist, the present invention includes those isomers, and also includes solvates, water Including hydrates and crystals of various shapes.
  • the compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.
  • R a represents a hydrogen atom or a C 1-6 alkyl group
  • R b represents an optionally substituted alkylene group
  • L 1 represents a leaving group
  • R 1 , R 3 , R 6 , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
  • Examples of the compound of the general formula [3a] include pyridine-3-boronic acid, 3- (methanesulfonamido) phenylboronic acid, thiophene-2-boronic acid, benzofuran-2-boronic acid, and 3-methoxyphenylboronic acid. It has been known.
  • the compounds of the general formulas [3a] and [3b] are described in, for example, JP-A-2003-206290 and The Journal of Organic Chemistry, 1995, Vol. 60, p. According to the method described in .7508 to 7510, etc., it can be produced from the corresponding halogeno compound.
  • the compound of general formula [1a] is a compound of general formula [2] in the presence or absence of (1) a base, (2) in the presence of a palladium catalyst, and (3) in the presence or absence of a ligand.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers examples include ketones, acetonitrile, esters, dimethyl sulfoxide, and the like, and these may be used as a mixture.
  • Examples of the base optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and 1,8-diazabicyclo [5.4.0] -7- And organic bases such as undecene, triethylamine and N, N-diisopropylethylamine.
  • the amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [2].
  • the amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
  • the amount of the ligand used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
  • the amount of the compound of general formula [3a] or [3b] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [2].
  • This reaction is preferably carried out at 40 to 170 ° C. for 1 minute to 96 hours in an inert gas (eg, nitrogen, argon) atmosphere. This reaction may be carried out under pressure at 100 to 250 ° C. for 1 minute to 1 hour.
  • the compound of the general formula [1b] can be produced by reacting the compound of the general formula [4] with the compound of the general formula [3a] or [3b] according to the production method 1.
  • the compound of the general formula [5a] for example, aniline, phenol, thiophenol and the like are known. Moreover, the compound of general formula [5a] can be manufactured by a conventional method from the corresponding halogeno compound, for example.
  • the compound of the general formula [1c] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [5a] according to the production method 1.
  • the compound of the general formula [1d] can be produced by reacting the compound of the general formula [4] with the compound of the general formula [5a] according to the production method 1.
  • X 1b represents an optionally substituted alkenylene group or an optionally substituted alkynylene group
  • X 1c represents an optionally substituted alkylene group
  • R 1 , R 3 , R 6 , L 1 , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
  • the compound of the general formula [5b] for example, styrene, allylbenzene, 4-phenyl-1-butene, vinylcyclohexane and allylcyclohexane are known. Further, the compound of the general formula [5b] can be produced, for example, by the method described in Experimental Chemistry Course, 4th edition, volume 19, pages 298-361, 1992, Maruzen or a method analogous thereto. .
  • the compound of the general formula [1e] is (1) in the presence or absence of a base, (2) in the presence or absence of a phase transfer catalyst, (3) It can be produced by reacting a compound of general formula [2] with a compound of general formula [5b] in the presence or absence of a ligand and (4) in the presence of a palladium catalyst.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Bases optionally used in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and 1,8-diazabicyclo [5.4.0] -7-undecene, And organic bases such as triethylamine and N, N-diisopropylethylamine.
  • phase transfer catalysts optionally used in this reaction include, for example, tetramethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate and trioctylmethylammonium.
  • Quaternary ammonium salts such as chloride; N-laurylpyridinium chloride, N-lauryl-4-picolinium chloride, N-laurylpicolinium chloride, N-benzylpicolinium chloride, and the like.
  • the amount of the phase transfer catalyst used may be 0.01 to 50 times mol, preferably 0.1 to 5 times mol, of the compound of the general formula [2].
  • the amount of the ligand used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
  • the amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
  • the amount of the compound of general formula [5b] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [2].
  • This reaction is usually carried out at 40 to 170 ° C. for 1 minute to 24 hours in an inert gas (eg, nitrogen, argon) atmosphere.
  • This reaction may be carried out under pressure at 100 to 250 ° C. for 1 minute to 1 hour.
  • the compound of the general formula [1e] is (1) in the presence or absence of a base, (2) in the presence or absence of a copper catalyst, and (3 ) It can be produced by reacting the compound of the general formula [2] with the compound of the general formula [5b] in the presence of a palladium catalyst.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers examples include ketones, acetonitrile, esters, dimethyl sulfoxide, and the like, and these may be used as a mixture.
  • Examples of the base optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and 1,8-diazabicyclo [5.4.0] -7- And organic bases such as undecene, triethylamine and N, N-diisopropylethylamine.
  • the amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [2].
  • Copper catalysts optionally used in this reaction include copper bromide and copper iodide. The amount of the copper catalyst used may be 0.01 to 50 times mol, preferably 0.1 to 5 times mol, of the compound of the general formula [2].
  • the amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
  • the amount of the compound of general formula [5b] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [2].
  • This reaction is usually carried out at 10 to 170 ° C. for 1 minute to 24 hours in an inert gas (eg, nitrogen, argon) atmosphere. This reaction may be carried out under pressure at 100 to 250 ° C. for 1 minute to 1 hour.
  • the compound of the general formula [1f] can be produced by reducing the compound of the general formula [1e].
  • the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, Acetonitrile, ketones, esters, acetic acid, pyridine and the like can be mentioned, and these may be used as a mixture.
  • the amount of the metal catalyst used may be 0.001 to 1 times (mass ratio), preferably 0.01 to 0.5 times (mass ratio) with respect to the compound of the general formula [1e].
  • Examples of the hydrogen source include hydrogen; formates such as formic acid, sodium formate, ammonium formate and triethylammonium formate; cyclohexene and cyclohexadiene.
  • the amount of the hydrogen source to be used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [1e]. This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.
  • the compound of the general formula [1g] is produced by reacting the compound of the general formula [4] with the compound of the general formula [5b] according to the method described in the above (5-1A) and (5-1B). can do.
  • the compound of the general formula [1h] can be produced by reducing the compound of the general formula [1g] according to the method described in the above (5-2).
  • the compound of the general formula [7] can be produced by acylating the compound of the general formula [6].
  • Specific examples include a method using an acid halide in the presence or absence of a base.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • amides, halogenated hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, ketones examples thereof include esters, sulfolane and dimethyl sulfoxide, and these may be used in combination.
  • the acid halide used in this reaction is represented by the general formula [8]. It can be produced by reacting a compound represented by “wherein R 1 and X 2 have the same meaning as described above” with thionyl chloride or oxalyl chloride.
  • the amount of the acid halide used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [6].
  • Examples of the compound of the general formula [8] include 3- (dimethylamino) benzoic acid, 4- (dimethylamino) benzoic acid, 3- (diethylamino) benzoic acid, 4- (diethylamino) benzoic acid and 2-chloro-5.
  • -(Piperidin-1-yl) benzoic acid and the like are known.
  • Examples of the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5. 4.0] -7-undecene, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, N, N-diisopropylethylamine and organic bases such as pyridine.
  • the amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [6]. This reaction is usually carried out at ⁇ 78 to 100 ° C., preferably 0 to 80 ° C., for 10 minutes to 24 hours.
  • the compound of general formula [1] can be produced by deprotecting the compound of general formula [7].
  • W.W. W. Greene et al. Protective Groups in Organic Synthesis, 4th edition, pp. 872-894, 2007, John Wiley & Sons, INC.
  • Specific examples include a hydrolysis reaction using an acid or a base, a dealkylation reaction using a salt, a reductive dealkylation reaction including a catalytic hydrogenation reaction using a metal catalyst.
  • examples of the acid used include formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, aluminum chloride, and trimethylsilyl iodide.
  • the amount of the acid used may be 1 to 100000 times mol, preferably 1 to 1000 times mol, of the compound of the general formula [7].
  • examples of the base used include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate; sodium methoxide, sodium ethoxide and potassium tert- And organic bases such as butoxide; and tetrabutylammonium fluoride.
  • the amount of the base used may be 1 to 1000 times mol, preferably 1 to 50 times mol, of the compound of the general formula [7].
  • examples of the salt used include lithium iodide and sodium chloride.
  • the amount of the salt used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [7].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, Acetonitrile, ketones, esters and the like can be mentioned, and these may be used in combination.
  • the solvent used is not particularly limited as long as it does not adversely affect the reaction.
  • water, alcohols, amides, halogenated hydrocarbons, aromatics examples thereof include hydrocarbons, ethers, acetonitrile, ketones, esters, acetic acid and pyridine, and these may be used as a mixture.
  • the amount of the metal catalyst used may be 0.001 to 5 times (mass ratio), preferably 0.01 to 1 times (mass ratio) with respect to the compound of the general formula [7].
  • Examples of the hydrogen source include hydrogen; formic acid; formate salts such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene; and cyclohexadiene.
  • the amount of the hydrogen source to be used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [7]. This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.
  • the compound of the general formula [1] is obtained by deprotecting the compound of the general formula [6] according to the method described in the above (7-2) and then according to the method described in the above (7-1). It can also be produced by reacting with a compound of general formula [8] or an acid halide thereof.
  • the compound of the general formula [1i] can be produced, for example, by the method described in Kodansha, or a method similar to that described in Kodansha, New Edition of Heterocyclic Compound Application, pages 98 to 100, 2004. Specifically, it can be produced by reacting the compound of the general formula [9] with an azide in the presence or absence of a salt.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, dimethyl sulfoxide and aliphatic Hydrocarbons etc. are mentioned, and these may be used as a mixture.
  • the azide used include sodium azide and trimethylsilyl azide.
  • the amount of azide used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of general formula [9].
  • Examples of salts used as desired in this reaction include ammonium chloride and triethylamine hydrochloride.
  • the amount of the salt used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [9].
  • This reaction is usually carried out at ⁇ 78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours. This reaction may be carried out under pressure at 60 to 200 ° C. for 1 minute to 1 hour
  • the compound of the general formula [10] can be produced by reacting the compound of the general formula [9] with hydroxylamine or a salt thereof in the presence or absence of a base.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers examples include ketones, esters, dimethyl sulfoxide, and aliphatic hydrocarbons, and these may be used as a mixture.
  • the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5.
  • the amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [9].
  • the hydroxylamine salt include hydrochloride and sulfate.
  • the amount of hydroxylamine or a salt thereof used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [9].
  • This reaction is usually carried out at ⁇ 78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours. This reaction may be carried out under pressure at 40 to 150 ° C. for 1 minute to 1 hour.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, ketones, acetonitrile examples thereof include esters, dimethyl sulfoxide and aliphatic hydrocarbons, and these may be used as a mixture.
  • the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5.
  • the amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [10].
  • the active carbonyl compound include 1,1′-carbonyldiimidazole, methyl chlorocarbonate and ethyl chlorocarbonate.
  • the amount of the active carbonyl compound used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [10]. This reaction is usually carried out at ⁇ 78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, ketones, acetonitrile examples thereof include esters, dimethyl sulfoxide and aliphatic hydrocarbons, and these may be used as a mixture.
  • the amount of boron trifluoride diethyl ether complex used may be 1 to 100 times mol, preferably 3 to 10 times mol, of the compound of general formula [10]. This reaction is usually carried out at ⁇ 78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, ketones, acetonitrile examples thereof include esters, dimethyl sulfoxide and aliphatic hydrocarbons, and these may be used as a mixture.
  • the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5.
  • -7-undecene sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, N, N-diisopropylethylamine and organic bases such as pyridine.
  • the amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [10].
  • the amount of 1,1′-thiocarbonyldiimidazole used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of general formula [10]. This reaction is usually carried out at ⁇ 78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, ketones, acetonitrile examples thereof include esters, dimethyl sulfoxide and aliphatic hydrocarbons, and these may be used as a mixture.
  • the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5.
  • the amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [10].
  • the amount of thionyl chloride to be used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of general formula [10]. This reaction is usually carried out at ⁇ 78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.
  • the compound of the general formula [11] can be produced by reacting the compound of the general formula [12] with azide or the like according to production method 8 or 9.
  • the compound of the general formula [6a] can be produced by reacting the compound of the general formula [11] with the compound of the general formula [3a] or [3b] according to the production method 1.
  • the compound of the general formula [13] can be produced by reacting the compound of the general formula [12] with the compound of the general formula [3a] or [3b] according to the production method 1.
  • the compound of the general formula [9a] is produced by reacting the compound of the general formula [13] with the compound of the general formula [8] or an acid halide thereof according to the method described in (7-1) above. be able to.
  • the compound of the general formula [14] can be produced, for example, by reacting the compound of the general formula [12] with the compound of the general formula [3a] or [3b] according to the production method 1.
  • the compound of the general formula [15] can be produced by reacting the compound of the general formula [14] with azide or the like according to production method 8 or 9.
  • the compound of the general formula [6b] can be produced by protecting the acidic imino group of the compound of the general formula [15].
  • the compound of the general formula [6b] can be produced by protecting the acidic imino group of the compound of the general formula [15].
  • W.W. W. Greene et al. Protective Groups in Organic Synthesis, 4th edition, pp. 872-894, 2007, John Wiley & Sons, INC.
  • the compound of the general formula [16] is produced by reacting the compound of the general formula [12] with the compound of the general formula [8] or an acid halide thereof according to the method described in the above (7-1). be able to.
  • the compound of the general formula [2a] can be produced by reacting the compound of the general formula [16] with azide or the like according to production method 8 or 9.
  • the compound of the general formula [4a] can be produced by reacting the compound of the general formula [18] with azide or the like according to the production method 8 or 9.
  • a compound that can take the form of a salt can also be used as a salt.
  • examples of such salts include the same salts as the salts of the compound of the general formula [1].
  • the compound obtained by the above-described production method or a salt thereof is subjected to a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or those reactions.
  • a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or those reactions.
  • additives When the compound of the present invention is used as a medicine, usually pharmacologically acceptable additives may be appropriately mixed.
  • the additive include an excipient, a disintegrant, a binder, a lubricant, a corrigent, a coloring agent, a flavoring agent, a surfactant, a coating agent, and a plasticizer.
  • Excipients include sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and glucose; ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl ⁇ - Cyclodextrins such as cyclodextrin and sulfobutyl ether ⁇ -cyclodextrin sodium; celluloses such as crystalline cellulose and microcrystalline cellulose; and starches such as corn starch, potato starch and pregelatinized starch.
  • sugar alcohols such as erythritol, mannitol, xylitol and sorbitol
  • sugars such as sucrose, powdered sugar, lactose and glucose
  • Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, and partially pregelatinized starch.
  • Examples of the binder include hydroxypropylcellulose, carmellose sodium and methylcellulose.
  • Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, light anhydrous silicic acid, and sucrose fatty acid ester.
  • Examples of the corrigent include aspartame, saccharin, stevia, thaumatin and acesulfame potassium.
  • Examples of the colorant include titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, food red No. 102, food yellow No. 4, and food yellow No. 5.
  • Flavoring agents include, for example, essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, Powder fragrances such as peach micron, strawberry micron and orange micron; vanillin; and ethyl vanillin.
  • Examples of the surfactant include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate and polyoxyethylene hydrogenated castor oil.
  • the coating agent examples include hydroxypropyl methylcellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S.
  • the plasticizer include triethyl citrate, macrogol, triacetin, and propylene glycol. These additives may be used alone or in combination of two or more.
  • the blending amount is not particularly limited, and may be blended appropriately so that the effect is sufficiently exhibited according to each purpose.
  • tablets These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection.
  • the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg daily may be divided into 1 to several doses. Good.
  • Test Example 1 Type I Collagen ⁇ 1 Chain mRNA Expression Inhibition Test
  • Human fetal lung fibroblast cell line WI-38 cells were suspended in Dulbecco's modified Eagle's medium containing 10% fetal calf serum, and seeded 7.0 ⁇ 10 4 in a 12-well plate. Cultured for days. After the cells became subconfluent, the cells were replaced with Dulbecco's modified Eagle's medium containing 0.4% fetal bovine serum and 50 ⁇ g / mL ascorbic acid, and further cultured for 24 hours. Thereafter, a test compound was added, and after 1 hour, TGF- ⁇ 1 was added to a final concentration of 1 ng / mL.
  • a PCR reaction was performed using the diluted cDNA as a template and a primer specific for the type I collagen ⁇ 1 chain gene or the GAPDH gene as an internal standard, and the reaction product was measured.
  • the PCR reaction was carried out for 40 cycles of incubation at 95 ° C. for 10 seconds, denaturation at 95 ° C. for 1 second, and annealing / extension at 60 ° C. for 20 seconds.
  • the expression level of type I collagen ⁇ 1 chain mRNA was corrected by GAPDH, and expressed as a relative value when the expression level obtained in the absence of the test compound was taken as 100%. The results are shown in Table 1-1 and Table 1-2.
  • the compound used in the present invention showed an excellent collagen production inhibitory action.
  • Test Example 2 Rat Bleomycin-Induced Pulmonary Fibrosis Seven week old male SD rats (Japan SLC) were used. Bleomycin (Nippon Kayaku) was dissolved in physiological saline, and 10 mg / kg was administered into rat trachea using Microsprayer (Microsprayer model IA-IC, Penn-Century) to induce pulmonary fibrosis. The test compound was dissolved or suspended in water, and 5 mg / kg (in the form of free form in the case of a salt) was orally administered twice a day from 28 days to 42 days after induction. In the control group, water was similarly administered. Lungs were collected 42 days after induction, homogenates were prepared, and hydroxyproline was quantified.
  • the mixture was incubated with 6N hydrochloric acid at 110 ° C. for 16 hours, distilled using a centrifugal concentrator, and the dried product was dissolved in distilled water to obtain a measurement sample.
  • a chloramine T solution was added to the measurement sample, incubated at room temperature for 20 minutes, then a perchloric acid solution was added, incubated at room temperature for 5 minutes, further added with p-dimethylaminobenzaldehyde solution, and incubated at 60 ° C. for 20 minutes.
  • the reaction was cooled and the absorbance at 570 nm was measured using a microplate reader.
  • the amount of hydroxyproline in the measurement sample was calculated by creating a calibration curve from the absorbance of the hydroxyproline standard solution.
  • Formula Inhibition rate (%) (1 ⁇ Lung hydroxyproline amount in test compound administration group / Lung hydroxyproline amount in control group) ⁇ 100
  • the amount of pulmonary hydroxyproline in the group administered with the sodium salt of Example 26, the sodium salt of Example 41 and the sodium salt of Example 62 was 20% or more lower than that of the control group.
  • Test Example 3 Reactive Metabolite Using pooled human liver microsomes (Celsis In Vitro Technologies), the test compound is reacted for a certain period of time, the amount of adduct product with radiolabeled glutathione is calculated, and the extent to which reactive metabolite is produced Evaluated.
  • reaction solution was allowed to stand on ice to stop the reaction, and added to a solid phase extraction column (OASIS HLB, 10 mg; Waters).
  • OASIS HLB 10 mg
  • the adduct product of the reactive metabolite and radiolabeled glutathione was retained on the column, washed with distilled water, and eluted with methanol / acetonitrile.
  • the radioactivity in the eluate was measured with a liquid scintillation counter (PerkinElmer), and the amount of adduct product was calculated.
  • Example 3 Example 14, Example 16, Example 26, Example 33, Example 39, Example 41, Example 49, Example 55, Example 62, Example 64, Example 70, Example 71, Example 88, Example 91, Example 92, Example 98, Example 102, Example 103, Example 108, Example 110, Example 112, Example 113, Example 122, Example 127,
  • the amount of adduct produced with glutathione was 10 pmol or less, and it was difficult to produce a reactive metabolite.
  • the compounds of the present invention showed excellent metabolic stability.
  • the mixing ratio in the eluent is a volume ratio.
  • “eluent: 97-60% hexane / ethyl acetate” means that the eluent of 97% hexane / 3% ethyl acetate was finally changed to the eluent of 60% hexane / 40% ethyl acetate.
  • the carrier in silica gel column chromatography is Fuji Silysia Chemical Ltd., Purif-Pack SI (60 ⁇ m). In each example, each abbreviation has the following meaning.
  • the solvent was distilled off under reduced pressure, 10 mL of tetrahydrofuran was added, and then added to a 5.0 mL solution of benzylamine 0.99 mL in tetrahydrofuran, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference example 4 0.02 mL of N, N-dimethylformamide and 0.034 mL of oxalyl chloride were sequentially added to a solution of 0.053 g of 3- (dimethylamino) benzoic acid in 2 mL of tetrahydrofuran and stirred at room temperature for 40 minutes. 0.034 mL of oxalyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and toluene was added. The solvent was distilled off under reduced pressure, and 2 mL of tetrahydrofuran was added.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-60% hexane / ethyl acetate], and white solid N- (4-cyanobiphenyl-3 0.030 g of -yl) -3- (dimethylamino) benzamide was obtained.
  • the reaction mixture was cooled to room temperature, 10% aqueous citric acid solution and ethyl acetate were added, insoluble materials were filtered off, and water and ethyl acetate were added.
  • the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-50% hexane / ethyl acetate], and a pale yellow solid N- (4-cyanobiphenyl- 0.065 g of 3-yl) -3- (4-methylpiperidin-1-yl) benzamide was obtained.
  • N- (4-cyanobiphenyl-3 0.51 g of -yl) -3- (ethylamino) benzamide was obtained.
  • N-dimethylacetamide (1 mL) was added potassium carbonate (0.079 g) and methyl iodide (0.036 mL) at room temperature. For 6 hours.
  • N- (4-cyanobiphenyl-3-yl) -3- (piperidin-4-yl) benzamide hydrochloride 0.15 g in tetrahydrofuran 4.0 mL triethylamine 0.060 mL, 37% formaldehyde aqueous solution 0.035 mL, Acetic acid 0.041 mL and sodium triacetoxyborohydride 0.19 g were sequentially added, and the mixture was stirred at room temperature for 1 hour. Water, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture.
  • Reference Example 42 0.50 g of 3-bromobenzonitrile, 30 mL of toluene, 1.6 mL of 2-methylpiperidine, 3.6 g of cesium carbonate, 0.050 g of tris (dibenzylideneacetone) dipalladium (0), 2-dicyclohexylphosphino-2 ′, 4 ′, 6 '-Triisopropylbiphenyl (0.13 g) and palladium (II) acetate (0.025 g) were added, and the mixture was heated to reflux for 8 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and water and ethyl acetate were added.
  • the reaction mixture was cooled to room temperature, adjusted to pH 4 with 1 mol / L hydrochloric acid, and water and chloroform were added.
  • the organic layer was separated and the aqueous layer was extracted with chloroform.
  • the obtained organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [eluent: 98-70% chloroform / methanol] to give 3-((2R, 6S) -2,6-dimethylpiperidin-1-yl) benzoic acid as a brown solid. 0.029 g of acid was obtained.
  • reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure.
  • -4-yl) benzoate was obtained.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane / ethyl acetate] to give a colorless oily methyl 3- (ethyl (propyl) ) 0.21 g of amino) benzoate was obtained.
  • silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane / ethyl acetate]
  • Reference Example 60 0.20 g 2-amino-4-chloro-5-methylbenzonitrile, 0.18 g phenylboronic acid, 0.40 g potassium carbonate, 1.6 mL dioxane, 0.40 mL water and bis (di-tert-butyl (4-dimethylaminophenyl) Phosphine) palladium (II) dichloride (5.0 mg) was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and the solvent was distilled off under reduced pressure.
  • the solvent was distilled off under reduced pressure, and 0.10 mL of 1-methyl-2-pyrrolidone, 1.0 mL of acetonitrile, and 2.0 mL of acetonitrile of 36 mg of 4-amino-6-chlorobiphenyl-3-carbonitrile were sequentially added, and the mixture was stirred at room temperature for 2 hours. Stir.
  • the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and white solid N- (2-chloro-5- 5 34 mg of cyanobiphenyl-4-yl) -3- (piperidin-1-yl) benzamide were obtained.
  • the reaction mixture was adjusted to pH 4 with concentrated hydrochloric acid, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid was collected by filtration. The obtained solid was washed with 50% aqueous methanol solution to obtain 1.6 g of light yellow solid N- (4-cyanobiphenyl-3-yl) -3-hydroxybenzamide.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-80% hexane / ethyl acetate] to give a colorless oily methyl 3- (diethylamino)- 4-Methylbenzoate was obtained.
  • silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-80% hexane / ethyl acetate] to give a colorless oily methyl 3- (diethylamino)- 4-Methylbenzoate was obtained.
  • To the obtained methyl 3- (diethylamino) -4-methylbenzoate, 4.0 mL of methanol and 3.0 mL of a 2 mol / L aqueous sodium hydroxide solution were added, and the mixture was stirred at 70 ° C
  • reaction mixture was cooled to room temperature, adjusted to pH 4 with 2 mol / L hydrochloric acid, and the solvent was distilled off under reduced pressure.
  • Ethyl acetate was added to the obtained residue, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.30 g of white solid 3- (diethylamino) -4-methylbenzoic acid.
  • Reference Example 76 1.0 mL of sulfuric acid was added to a 3.0 mL methanol suspension of 0.50 g of 3-amino-5-methoxybenzoic acid, and the mixture was stirred at 70 ° C. for 4 hours. The reaction mixture was cooled to room temperature, adjusted to pH 10 with 2 mol / L aqueous sodium hydroxide under ice cooling, the solvent was evaporated under reduced pressure, and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-80% hexane / ethyl acetate] to give a colorless oily methyl 3- (diethylamino)- 5-Methoxybenzoate was obtained.
  • silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-80% hexane / ethyl acetate]
  • the reaction mixture was cooled to room temperature, adjusted to pH 4 with 2 mol / L hydrochloric acid, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, the insoluble material was filtered off, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and white solid 3- (diethylamino) -5-methoxybenzoic acid 0.38 g Got.
  • the solvent was distilled off under reduced pressure, water was added, the pH was adjusted to 4 with a 2 mol / L aqueous sodium hydroxide solution, and the solvent was distilled off under reduced pressure.
  • Ethyl acetate was added to the obtained residue, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Water was added to the obtained residue, and the pH was adjusted to 5.5 with a saturated aqueous sodium hydrogen carbonate solution.
  • the solid was collected by filtration, and 50 mg of white solid 3-methyl-5- (piperidin-1-yl) benzoic acid was added. Obtained.
  • the solvent was distilled off under reduced pressure, water was added, the pH was adjusted to 4 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was distilled off under reduced pressure.
  • Ethyl acetate was added to the obtained residue, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 75-0% hexane / ethyl acetate] to give a pale yellow solid of 3- (diethylamino) -5- 0.19 g of methylbenzoic acid was obtained.
  • Reference Example 106 4-Bromo-5-methoxy-2-nitrobenzonitrile (0.77 g), ethylene glycol dimethyl ether (4.0 mL), phenylboronic acid (0.44 g), potassium carbonate (0.99 g), water (1.0 mL) and bis (di-tert-butyl (4-dimethylaminophenyl) ) Phosphine) palladium (II) dichloride (10 mg) was added, and the mixture was stirred at 110 ° C. for 10 minutes under microwave irradiation. Water and ethyl acetate were added to the reaction mixture.
  • the organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-90% chloroform / methanol] to give 4-bromo-5-methoxy-2-nitrobenzamide. Obtained.
  • Example 1 To a solution of 0.11 g of 3- (2-methylpiperidin-1-yl) benzoic acid in 3 mL of tetrahydrofuran were sequentially added N, N-dimethylformamide 0.010 mL and oxalyl chloride 0.053 mL, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 0.030 mL of oxalyl chloride was added and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and toluene was added.
  • Example 13 To a solution of 0.086 g of 3- (dipropylamino) benzoic acid in 2 mL of tetrahydrofuran were sequentially added 0.010 mL of N, N-dimethylformamide and 0.039 mL of oxalyl chloride, and the mixture was stirred at room temperature for 20 minutes. 0.039 mL of oxalyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and toluene was added.
  • Example 18 To a mixed solution of 0.050 g of 3- (3-aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one in tetrahydrofuran and 0.021 mL of pyridine was added 0.025 mL of benzoyl chloride at room temperature. Stir for 3 hours. To the reaction mixture was added 0.025 mL of benzoyl chloride, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the solid was collected by filtration.
  • Example 26 3- (piperidin-1-yl) benzoic acid 0.11 g, 4- (1-benzyl-1H-tetrazol-5-yl) biphenyl-3-amine 0.15 g, acetonitrile 2.0 mL and N, N-dimethylformamide 0.010 mL
  • thionyl chloride was added at 60 ° C., and the mixture was stirred at the same temperature for 1 hour 30 minutes.
  • 0.010 mL of thionyl chloride was added at 60 ° C., and the mixture was stirred at the same temperature for 1 hour. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added.
  • Example 27 To a solution of 0.10 g of N- (4-cyanobiphenyl-3-yl) -3- (diethylamino) benzamide in 0.30 mL of 1-methyl-2-pyrrolidone, 0.075 g of triethylamine hydrochloride and 0.035 g of sodium azide were sequentially added. Stir at 1 ° C. for 1 hour. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the pH was adjusted to 5.0 with 10% aqueous citric acid solution. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 40 N- (4- (1-benzyl-1H-tetrazol-5-yl) biphenyl-3-yl) -3- (1-methylpiperidin-4-yl) benzamide (0.045 g) in a mixture of methanol (20 mL) and ethyl acetate (10 mL) 0.045 g of 10% palladium-carbon was added, and the mixture was stirred at 40 ° C. for 4 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid was collected by filtration.
  • Example 41 To a solution of 0.10 g of N- (4-cyanobiphenyl-3-yl) -3- (diethylamino) benzamide in 2 mL of tetrahydrofuran was added 0.14 mL of a 50% aqueous hydroxylamine solution, and the mixture was stirred at 60 ° C. for 30 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solid was collected by filtration to obtain 3- (diethylamino) -N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide as a pale yellow solid.
  • Example 62 To a solution of N- (4-cyanobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide (0.10 g) in N, N-dimethylformamide (0.50 mL) was added 50% hydroxylamine aqueous solution (0.087 mL) at 60 ° C. Stir for 2 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give 0.11 g of N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide as a white solid. Obtained.
  • Example 63 To a mixture of 4- (diethylamino) benzoic acid (0.10 g) with acetonitrile (1 mL), 1-methyl-2-pyrrolidone (0.10 mL) and N, N-dimethylformamide (0.010 mL) was added thionyl chloride (0.044 mL) at room temperature, and the mixture was stirred at the same temperature for 10 minutes. . To the reaction mixture was added a solution of 0.10 g of 3- (3-aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one in 0.30 mL of 1-methyl-2-pyrrolidone under water cooling. And stirred at room temperature for 2 hours.
  • Example 67 To a mixture of 3-nitro-N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide (0.39 g) in tetrahydrofuran (30 mL) and methanol (5.0 mL) was added 10% palladium-carbon (0.078 g) under a hydrogen atmosphere. And stirred at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (0.078 g) was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-95% chloroform / methanol] to give a pale yellow solid of 3-amino-N- (4- 0.23 g of (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide was obtained.
  • Example 68 A mixture of 0.50 g of N- (4-cyanobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide in 2.5 mL of tetrahydrofuran and 0.10 mL of 50% aqueous hydroxylamine was stirred at 50 ° C. for 1 hour. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. 2-Propanol was added to the obtained residue, and the solid was collected by filtration to obtain N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide.
  • Example 70 To a solution of 0.31 g of N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide in 3.1 mL of tetrahydrofuran was added 0.16 g of 1,1′-thiocarbonyldiimidazole, For 30 minutes. Chloroform and water were added to the reaction mixture, and the solid was collected by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 72 N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide 0.50 g in tetrahydrofuran 10 mL, 1-methyl-2-pyrrolidone 5.0 mL, acetonitrile 5.0 mL and pyridine 0.29 mL Under ice cooling, 0.097 mL of thionyl chloride was added, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 0.097 mL of thionyl chloride, and the mixture was stirred at room temperature for 20 minutes.
  • Example 74 To a 2.0 mL tetrahydrofuran solution of 90 mg of N- (2-cyano-5-phenoxyphenyl) -3- (diethylamino) benzamide was added 0.075 mL of a 50% aqueous hydroxylamine solution, and the mixture was stirred at 55 ° C. for 1 hour. To the reaction mixture, 0.075 mL of 50% aqueous hydroxylamine solution was added, and the mixture was stirred at 55 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure to obtain 3- (diethylamino) -N- (2- (hydroxyamidino) -5-phenoxyphenyl) benzamide.
  • Example 76 In the same manner as in Example 74, the following compound was obtained. N- (2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -5-((E) -2-phenylvinyl) phenyl) -3- (piperidine -1-yl) benzamide 1 H-NMR (DMSO-d 6 ) ⁇ value: 13.10-12.80 (broad, 1H), 10.46 (s, 1H), 8.50 (s, 1H), 7.76-7.60 (m, 4H), 7.54-7.28 (m , 8H), 7.24-7.15 (m, 1H), 3.30-3.20 (m, 4H), 1.70-1.52 (m, 6H).
  • Example 78 To 60 mg of N- (5-cyano-2-methylbiphenyl-4-yl) -3- (piperidin-1-yl) benzamide, 0.50 mL of tetrahydrofuran, 0.10 mL of 1-methyl-2-pyrrolidone, 23 mg of hydroxylamine hydrochloride and 1 , 8-diazabicyclo [5.4.0] -7-undecene (0.10 mL) was added, and the mixture was stirred at 90 ° C. for 4 minutes under microwave irradiation. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour.
  • Example 79 In the same manner as in Example 78, the following compound was obtained. N- (2-chloro-5- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl) Benzamide 1 H-NMR (DMSO-d 6 ) ⁇ value: 10.72-10.58 (broad, 1H), 8.64 (s, 1H), 7.83 (s, 1H), 7.56-7.44 (m, 6H), 7.43-7.36 (m , 1H), 7.35-7.29 (m, 1H), 7.25-7.16 (m, 1H), 3.30-3.22 (m, 4H), 1.70-1.53 (m, 6H).
  • Example 80 In the same manner as in Example 78, the following compound was obtained. N- (6-Methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide 1 H-NMR (DMSO-d 6 ) ⁇ value: 13.07-12.80 (broad, 1H), 10.38 (s, 1H), 8.15 (s, 1H), 7.68 (s, 1H), 7.55-7.40 (m, 6H) ), 7.39-7.32 (m, 1H), 7.32-7.26 (m, 1H), 7.21-7.14 (m, 1H), 3.28-3.20 (m, 4H), 2.28 (s, 3H), 1.70-1.52 (m , 6H).
  • Example 81 In the same manner as in Example 78, the following compound was obtained. N- (3-Methyl-5- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl) Benzamide 1 H-NMR (DMSO-d 6 ) ⁇ value: 12.78-12.70 (broad, 1H), 9.94 (s, 1H), 7.92-7.76 (m, 4H), 7.57-7.40 (m, 4H), 7.37-7.29 (m, 2H), 7.19-7.10 (m, 1H), 3.26-3.18 (m, 4H), 2.35 (s, 3H), 1.70-1.52 (m, 6H).
  • Example 103 Add 0.063 mL of thionyl chloride to a mixture of 2.0 mL of acetonitrile, 0.14 g of 3- (diethylamino) -4-methylbenzoic acid, 0.10 mL of 1-methyl-2-pyrrolidone, and 0.010 mL of N, N-dimethylformamide, and then at room temperature for 30 minutes Stir. 0.031 mL of thionyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
  • the obtained solid was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-30% hexane / ethyl acetate], and white solid 3- (diethylamino) -4-methyl 61 mg of —N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide was obtained.
  • Example 104 In the same manner as in Example 103, the compounds shown in Table 16 were obtained.
  • Example 106 To a mixed solution of 0.12 g of 4-chloro-3- (piperidin-1-yl) benzoic acid in 2.0 mL of acetonitrile and 0.010 mL of N, N-dimethylformamide was added 0.051 mL of oxalyl chloride, and the mixture was stirred at room temperature for 30 minutes. 0.051 mL of oxalyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
  • Example 107-117 In the same manner as in Example 106, the compounds shown in Table 17 were obtained.
  • Example 120 To a 1.0 mL tetrahydrofuran solution of 22 mg 2-chloro-N- (4-cyanobiphenyl-3-yl) -3- (diethylamino) benzamide was added 0.014 mL of a 50% aqueous hydroxylamine solution, and the mixture was at 50-60 ° C. for 1 hour 30 minutes. Stir. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solvent was distilled off under reduced pressure to obtain 2-chloro-3- (diethylamino) -N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide.
  • Example 122 To a suspension of 0.97 g of 3-bromo-N- (4-cyanobiphenyl-3-yl) benzamide in 10 mL of tetrahydrofuran was added 0.51 mL of a 50% aqueous hydroxylamine solution, and the mixture was stirred at 60 ° C. for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solid matter was collected by filtration to give 3-bromo-N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide as a white solid.
  • Example 124 To a mixture of 2-chloro-N- (4-cyanobiphenyl-3-yl) -5- (piperidin-1-yl) benzamide (0.10 g) with 1-methyl-2-pyrrolidone (0.10 mL) and tetrahydrofuran (0.50 mL), hydroxylamine hydrochloride 23 mg and 1,8-diazabicyclo [5.4.0] -7-undecene (0.10 mL) were added, and the mixture was stirred at 90 ° C. for 4 minutes under microwave irradiation. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 30 minutes.
  • Example 125 To a suspension of 0.31 g of N- (4-cyanobiphenyl-3-yl) -3-hydroxybenzamide, 0.65 g of 1- (2-hydroxyethyl) piperidine and 1.3 g of triphenylphosphine in 10 mL of tetrahydrofuran was added diisopropyl azodicarboxyl. 1.0 g of Lat was added and stirred at room temperature for 30 minutes.
  • the obtained solid was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-90% chloroform / methanol], and white solid N- (4- (5-oxo- 10 mg of 4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (2- (piperidin-1-yl) ethoxy) benzamide was obtained.
  • Example 126 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide (0.10 g), furan-3-boronic acid (50 mg), potassium acetate (88 mg), butanol (1 mL), water (0.3 mL) and bis (di-tert -Butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (10 mg) was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water and ethyl acetate were added.
  • Example 127 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide (0.10 g), 3-fluorophenylboronic acid (50 mg), potassium carbonate (0.10 g), dioxane (0.80 mL), water (0.20 mL) and bis (di -Tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 5 minutes under microwave irradiation.
  • Example 148 To 0.10 g of N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide, 53 mg of 2-methylphenylboronic acid, 0.10 g of potassium carbonate, 0.80 mL of dioxane, 0.20 mL of water and bis (di -Tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation.
  • Example 158 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide (0.10 g), 4-methylphenylboronic acid (49 mg), potassium carbonate (0.10 g), dioxane (0.80 mL), water (0.20 mL) and bis (di -Tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 5 minutes under microwave irradiation.
  • the organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (4-cyano-4′-methylbiphenyl).
  • -3-yl) -3- (piperidin-1-yl) benzamide was obtained.
  • Example 203 N- (5-chloro-2-cyanophenyl) -3- (diethylamino) benzamide 98 mg, 3-fluorophenylboronic acid 54 mg, potassium carbonate 0.10 g, dioxane 0.50 mL, water 0.10 mL and bis (di-tert-butyl ( 4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation.
  • the organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (4-cyano-3′-fluorobiphenyl -3-yl) -3- (diethylamino) benzamide was obtained.
  • silica gel column chromatography silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate]
  • N- (4-cyano-3′-fluorobiphenyl -3-yl) -3- (diethylamino) benzamide was obtained.
  • 2.0 mL of tetrahydrofuran and 0.10 mL of 50% hydroxylamine aqueous solution were added, and the mixture was stirred at 60 ° C.
  • Example 206 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide (0.20 g), 1-cyclohexeneboronic acid (98 mg), potassium carbonate (0.20 g), dioxane (1.60 mL), water (0.40 mL) and bis (di- 10 mg of tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation.
  • the organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (2-cyano-5- (cyclohexene- 1-yl) phenyl) -3- (piperidin-1-yl) benzamide was obtained.
  • N- (2-cyano-5- (cyclohexen-1-yl) phenyl) -3- (piperidin-1-yl) benzamide was added 18 mg of 10% palladium-carbon.
  • Examples 208-215 In the same manner as in Example 207, the compounds shown in Table 23 were obtained.
  • Example 216 To 0.10 g of N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide, 53 mg of 2-methylphenylboronic acid, 0.10 g of potassium carbonate, 0.80 mL of dioxane, 0.20 mL of water and bis (di -Tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation.
  • the organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (4-cyano-2′-methylbiphenyl). -3-yl) -3- (piperidin-1-yl) benzamide was obtained.
  • Example 238 A suspension of 0.050 g of N- (2-cyano-5-phenoxyphenyl) -3- (piperidin-1-yl) benzamide, 0.084 g of triethylamine hydrochloride and 0.040 g of sodium azide in 0.50 mL of 1-methyl-2-pyrrolidone was stirred at 150 ° C. for 10 minutes under microwave irradiation. To the reaction mixture, 0.084 g of triethylamine hydrochloride and 0.040 g of sodium azide were added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation.
  • Example 239 In the same manner as in Example 238, the following compound was obtained. N- (6-Methyl-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide 1 H-NMR (DMSO-d 6 ) ⁇ value: 11.56 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 7.83-7.70 (m, 1H), 7.59-7.30 (m, 8H) ), 3.40-3.32 (m, 4H), 2.32 (s, 3H), 1.78-1.68 (m, 4H), 1.65-1.56 (m, 2H).
  • Example 246 In the same manner as in Example 238, the following compound was obtained. N- (5-phenyl-2- (1H-tetrazol-5-yl) pyridin-3-yl) -3- (piperidin-1-yl) benzamide 1 H-NMR (DMSO-d 6 + D 2 O) ⁇ value: 9.40-9.35 (m, 1H), 8.86-8.82 (m, 1H), 7.86-7.80 (m, 2H), 7.71-7.66 (m, 1H), 7.64-7.57 (m, 2H), 7.57-7.51 (m, 1H), 7.49-7.42 (m, 2H), 7.29-7.22 (m, 1H), 3.35-3.28 (m, 4H), 1.71- 1.63 (m, 4H), 1.63-1.55 (m, 2H).
  • Example 247 (E) -N- (5-chloro-2-cyanophenyl) -3- (3- (diethylamino) phenyl) acrylamide 0.11 g, 2-fluorophenylboronic acid 84 mg, potassium carbonate 0.10 g, dioxane 0.80 mL, water 0.20 mL and 5 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride were added and stirred at 150 ° C. for 10 minutes under microwave irradiation.
  • the organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and (E) -N- (4-cyano-2 '-Fluorobiphenyl-3-yl) -3- (3- (diethylamino) phenyl) acrylamide was obtained.
  • Example 254 (E) -N- (5-chloro-2-cyanophenyl) -3- (3- (diethylamino) phenyl) acrylamide 0.11 g, 2-methylphenylboronic acid 82 mg, potassium carbonate 0.10 g, dioxane 0.80 mL, water 0.20 mL and 5 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride were added and stirred at 150 ° C. for 10 minutes under microwave irradiation.
  • the organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and (E) -N- (4-cyano-2 '-Methylbiphenyl-3-yl) -3- (3- (diethylamino) phenyl) acrylamide was obtained.
  • Example 255 In the same manner as in Example 254, the following compound was obtained.
  • Example 256 In the same manner as in Example 122, the following compound was obtained. N- (2-Fluoro-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl) Benzamide 1 H-NMR (DMSO-d 6 ) ⁇ value: 12.94-12.65 (broad, 1H), 10.53-10.37 (broad, 1H), 7.87-7.78 (m, 2H), 7.63-7.57 (m, 2H), 7.57 -7.50 (m, 2H), 7.49-7.43 (m, 1H), 7.42-7.39 (m, 1H), 7.38-7.32 (m, 1H), 7.28-7.23 (m, 1H), 7.20-7.15 (m, 1H), 3.27-3.18 (m, 4H), 1.70-1.61 (m, 4H), 1.61-1.52 (m, 2H).
  • Example 257 In the same manner as in Example 122, the following compound was obtained. N- (6-Methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide 1 H-NMR (DMSO-d 6 ) ⁇ value: 10.35-10.26 (broad, 1H), 8.16 (s, 1H), 7.58-7.53 (m, 2H), 7.50-7.32 (m, 6H), 7.32-7.26 (m, 1H), 7.19-7.13 (m, 1H), 3.85 (s, 3H), 3.27-3.20 (m, 4H), 1.68-1.61 (m, 4H), 1.60-1.53 (m, 2H).
  • Example 262 To a solution of 0.055 g of 3- (3- (piperidin-1-yl) phenyl) propiolic acid in 3 mL of methylene chloride, 0.10 mL of N, N-diisopropylethylamine, 0.14 g of bromotris (pyrrolidino) phosphonium hexafluorophosphate and 3- (3- Aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one (0.062 g) was sequentially added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added.
  • Example 263 In the same manner as in Example 262, the following compound was obtained. 3- (3- (Diethylamino) phenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) propioramide 1 H-NMR (DMSO-d 6 + D 2 O) ⁇ value: 8.13-8.08 (m, 1H), 7.78-7.69 (m, 4H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.31-7.23 (m, 1H), 6.88-6.80 (m, 3H), 3.40-3.31 (m, 4H), 1.13-1.07 (m, 6H).
  • novel amide derivative of the present invention or a salt thereof has a collagen production inhibitory action and is excellent in safety and kinetics, for example, overproduction of collagen such as pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis It is useful for treatments such as prevention or treatment of diseases in which is involved. Furthermore, the compound of the present invention has excellent metabolic stability.

Abstract

The compound represented by formula (1) or a salt thereof has a collagen production-inhibiting effect, and is thus useful for use in the prevention, treatment, or the like of diseases associated with overproduction of collagen such as pulmonary fibrosis, scleroderma, nephrosclerosis, and cirrhosis. In formula (1): R1 represents an aryl group or the like that may be substituted with one or more groups selected from the substituent group (α); one of R2 or R3 represents a group represented by the formula -X1-R6 (in the formula, X1 represents an oxygen atom, a bond, or the like, and R6 represents an aryl group of the like that may be substituted; the other of R2 or R3 represents a hydrogen atom or a halogen atom; Z1 and Z2 may be identical or different, and represent either a nitrogen atom or the group represented by the formula C-R7 (in the formula, R7 represents a hydrogen atom or a halogen atom); and Y represents -N=N-, -S(O)-O-, -C(O)-O-, -C(O)-S-, or -C(S)-O- (wherein the bond to the left of each group is a bond that bonds to NH).

Description

新規なアミド誘導体またはその塩Novel amide derivative or salt thereof
　本発明は、コラーゲン産生阻害作用を有する新規なアミド誘導体またはその塩に関する。 The present invention relates to a novel amide derivative having a collagen production inhibitory action or a salt thereof.
　コラーゲンをはじめとする細胞外マトリクスが産生される線維形成は、創傷治癒のメカニズムである。しかし、損傷が遷延化すると通常のプロセスを逸脱し、細胞外マトリクスが広範囲にわたって過剰に沈着し、線維症となる。線維症は原因疾患による組織自体の損傷とそれに続く線維化よる機能障害が相まって臓器不全に至る予後不良な病態である。線維症は様々な臓器で認められるが、細胞外マトリクス産生細胞の起源は共通と考えられており、その起源は内在性の線維芽細胞、上皮間葉転換した上皮細胞および線維細胞である（非特許文献１）。
　これまでに線維症の治療として炎症応答の抑制が試みられてきた。線維化の制御因子であるＴＧＦ（Transforming growth factor）－β１、ＶＥＧＦ（Vascular Endothelial Growth Factor）、ＰＤＧＦ（Platelet-Derived Growth Factor）およびアンジオテンシンII（angiotensin II）などを標的として抗線維化薬の研究が行われている（非特許文献２）。
　ピルフェニドン（商品名：ピレスパ錠200ｍｇ）は特発性肺線維症の適応をもつ唯一の抗線維化薬である。しかし、臨床試験において認められた有効性は肺活量低下の抑制のみであり、加えて、光線過敏症などの副作用が87.9％に認められた（非特許文献３）。
　線維化において過剰沈着する細胞外マトリクスの主成分はコラーゲンであり、その中でも最も豊富に存在するのがI型コラーゲンである。したがって、コラーゲンの産生を阻害する物質は線維化病変を伴う疾患の予防または治療に有用である。
　これまでに、Ｎ－アシルアントラニル酸誘導体が、マトリクスメタロプロテアーゼ－13産生阻害作用を有し、コラーゲン産生抑制作用を有することが知られている（特許文献１）。 Fibrosis in which extracellular matrix including collagen is produced is a mechanism of wound healing. However, if the damage is prolonged, it deviates from the normal process and the extracellular matrix is excessively deposited over a wide area, resulting in fibrosis. Fibrosis is a disease state with a poor prognosis leading to organ failure due to a combination of damage to the tissue itself due to the causative disease and subsequent dysfunction due to fibrosis. Although fibrosis is found in various organs, the origin of extracellular matrix-producing cells is thought to be common, and the origin is endogenous fibroblasts, epithelial cells and fibrocytes that have transitioned to epithelial-mesenchymal cells (non- Patent Document 1).
To date, attempts have been made to suppress the inflammatory response as a treatment for fibrosis. Research on anti-fibrotic drugs targeting TGF (Transforming growth factor) -β1, VEGF (Vascular Endothelial Growth Factor), PDGF (Platelet-Derived Growth Factor), angiotensin II (angiotensin II), etc. (Non-Patent Document 2).
Pirfenidone (trade name: Pirrespa Tablets 200 mg) is the only antifibrotic drug that is indicated for idiopathic pulmonary fibrosis. However, the efficacy observed in clinical trials was only suppression of the decrease in vital capacity, and in addition, side effects such as photosensitivity were observed in 87.9% (Non-patent Document 3).
The main component of the extracellular matrix that is excessively deposited during fibrosis is collagen. Among them, type I collagen is the most abundant. Therefore, substances that inhibit collagen production are useful for the prevention or treatment of diseases associated with fibrotic lesions.
So far, it has been known that N-acyl anthranilic acid derivatives have a matrix metalloproteinase-13 production inhibitory action and a collagen production inhibitory action (Patent Document 1).
国際公開第２０１０／０８７４３０号パンフレットInternational Publication No. 2010/087430 Pamphlet
　コラーゲン産生阻害作用を有し、コラーゲンの過剰産生が関与する疾患の予防または治療などの処置剤が望まれている。 A treatment agent for preventing or treating diseases that have collagen production inhibitory activity and involve excessive production of collagen is desired.
　このような状況下において、本発明者らは鋭意検討を行った結果、下記の一般式［１］で表される化合物またはその塩がコラーゲン産生阻害作用を有し、コラーゲンの過剰産生が関与する疾患の予防または治療などの処置に有用であることを見出し、本発明を完成した。 Under such circumstances, as a result of intensive studies, the present inventors have found that a compound represented by the following general formula [1] or a salt thereof has a collagen production inhibitory action, and overproduction of collagen is involved. It was found useful for treatment such as prevention or treatment of diseases, and the present invention was completed.
　本発明は、下記を提供する。
（１）一般式[１]
Figure JPOXMLDOC01-appb-C000002
 「式中、
Ｒ１は、置換基群αから選ばれる１つ以上の基で置換されていてもよいアリール基、置換基群αから選ばれる１つ以上の基で置換されていてもよい単環の複素環式基または置換されていてもよい二環式の複素環式基を；
Ｒ２およびＲ３の一方は、一般式－Ｘ１－Ｒ６「式中、Ｘ１は、酸素原子、硫黄原子、保護されていてもよいイミノ基、置換されていてもよいＣ１－６アルキレン基、置換されていてもよいＣ２－６アルケニレン基、置換されていてもよいＣ２－６アルキニレン基または結合手を；Ｒ６は、置換されていてもよいアリール基、置換されていてもよい複素環式基または置換されていてもよいＣ３－８シクロアルキル基を示す。」で表される基を；
Ｒ２およびＲ３の他方は、水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよいアリール基または一般式－Ｘ１－Ｒ６「式中、Ｘ１およびＲ６は、前記と同様な意味を有する。」で表される基を；
Ｘ２は、置換されていてもよいＣ１－６アルキレン基、置換されていてもよいＣ２－６アルケニレン基、置換されていてもよいＣ２－６アルキニレン基または結合手を；
Ｚ１およびＺ２は、同一または異なって、窒素原子または一般式Ｃ－Ｒ７「式中、Ｒ７は、水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基または置換されていてもよいＣ１－６アルコキシ基を示す。」で表される基を；
Ｙは、－Ｎ＝Ｎ－、－Ｓ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｓ－または－Ｃ（Ｓ）－Ｏ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）を示す。
但し、Ｒ３が一般式－Ｘ１－Ｒ６「式中、Ｘ１およびＲ６は前記と同様な意味を有する。」で表される基であるとき、Ｙは、－Ｓ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｓ－または－Ｃ（Ｓ）－Ｏ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）であり、かつ、Ｘ２は結合手である。」で表される化合物またはその塩。
置換基群α：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基または一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基
（２）Ｙが－Ｎ＝Ｎ－、－Ｃ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｓ－または－Ｃ（Ｓ）－Ｏ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）である（１）に記載の化合物またはその塩。
（３）Ｒ２が一般式－Ｘ１－Ｒ６「式中、Ｘ１は、酸素原子、硫黄原子、保護されていてもよいイミノ基、置換されていてもよいＣ１－６アルキレン基、置換されていてもよいＣ２－６アルケニレン基、置換されていてもよいＣ２－６アルキニレン基または結合手を；Ｒ６は、置換されていてもよいアリール基、置換されていてもよい複素環式基または置換されていてもよいＣ３－８シクロアルキル基を示す。」で表される基、Ｒ３が水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基または置換されていてもよいアリール基である（１）または（２）に記載の化合物またはその塩。
（４）Ｒ１が置換基群αから選ばれる１つ以上の基で置換されていてもよいアリール基または置換基群αから選ばれる１つ以上の基で置換されていてもよい単環の複素環式基である（１）～（３）のいずれか一に記載の化合物またはその塩。
置換基群α：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基または一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基
（５）Ｙが－Ｎ＝Ｎ－、－Ｃ（Ｏ）－Ｏ－または－Ｃ（Ｏ）－Ｓ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）である（１）～（４）のいずれか一に記載の化合物またはその塩。
（６）Ｚ１およびＺ２が、同一または異なって、一般式Ｃ－Ｒ７「式中、Ｒ７は、水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基または置換されていてもよいＣ１－６アルコキシ基を示す。」で表される基である（１）～（５）のいずれか一に記載の化合物またはその塩。
（７）Ｒ２が一般式－Ｘ１－Ｒ６ａ「式中、Ｘ１は、酸素原子、硫黄原子、保護されていてもよいイミノ基、置換されていてもよいＣ１－６アルキレン基、置換されていてもよいＣ２－６アルケニレン基、置換されていてもよいＣ２－６アルキニレン基または結合手を；Ｒ６ａは、置換されていてもよいアリール基を示す。」で表される基、Ｒ３が水素原子である（１）～（６）のいずれか一に記載の化合物またはその塩。
（８）Ｒ２が一般式－Ｘ１ｄ－Ｒ６ａ「式中、Ｘ１ｄは、結合手を；Ｒ６ａは、置換されていてもよいアリール基を示す。」で表される基、Ｒ３が水素原子である（１）～（７）のいずれか一に記載の化合物またはその塩。
（９）Ｘ２がＣ１－６アルキレン基、Ｃ２－６アルケニレン基、Ｃ２－６アルキニレン基または結合手である（１）～（８）のいずれか一に記載の化合物またはその塩。
（１０）Ｒ１が置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基で置換されているアリール基または置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されている単環の複素環式基である（１）～（９）のいずれか一に記載の化合物またはその塩。
（１１）Ｘ２が結合手である（１）～（１０）のいずれか一に記載の化合物またはその塩。
（１２）Ｒ１が置換基群αから選ばれる１つ以上の基で置換されていてもよいアリール基または置換基群αから選ばれる１つ以上の基で置換されていてもよい単環の複素環式基、Ｘ２が結合手である（１）～（９）のいずれか一に記載の化合物またはその塩。
置換基群α：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基または一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基
（１３）Ｒ１が置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基で置換されているアリール基または置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されている単環の複素環式基、Ｘ２が結合手である（１）～（１２）のいずれか一に記載の化合物またはその塩。
（１４）化合物が４－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド、３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド、３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（ピペリジン－１－イル）イソニコチンアミド、３－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド、４－（ジメチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドおよび３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドから選ばれる化合物である（１）に記載の化合物またはその塩。
（１５）４－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。
（１６）３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。
（１７）３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。
（１８）Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（ピペリジン－１－イル）イソニコチンアミドまたはその塩。
（１９）３－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。
（２０）Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドまたはその塩。
（２１）４－（ジメチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。
（２２）Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドまたはその塩。
（２３）３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。
（２４）（１）～（２３）のいずれか一に記載の化合物またはその塩を含有する医薬組成物。
（２５）（１）～（２３）のいずれか一に記載の化合物またはその塩を含有するコラーゲン産生阻害剤。
（２６）（１）～（２３）のいずれか一に記載の化合物またはその塩を含有するコラーゲンの過剰産生が関与する疾患の処置剤。
（２７）置換基群αが置換基群α１である（１）～（９）のいずれか一に記載の化合物またはその塩。
　置換基群α１：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよいＣ３－８シクロアルキル基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基および一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基。
（２８）Ｘ２が結合手である（２７）に記載の化合物またはその塩。
（２９）（２７）または（２８）に記載の化合物またはその塩を含有する医薬組成物。
（３０）（２７）または（２８）に記載の化合物またはその塩を含有するコラーゲン産生阻害剤。
（３１）（２７）または（２８）に記載の化合物またはその塩を含有するコラーゲンの過剰産生が関与する疾患の処置剤。 The present invention provides the following.
(1) General formula [1]
Figure JPOXMLDOC01-appb-C000002
 "In the formula,
R 1 represents an aryl group which may be substituted with one or more groups selected from substituent group α, and a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group α A formula group or an optionally substituted bicyclic heterocyclic group;
One of R 2 and R 3 has the general formula —X 1 —R 6 wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 An alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6 is an optionally substituted aryl group, A heterocyclic group or an optionally substituted C 3-8 cycloalkyl group ”.
The other of R 2 and R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an optionally substituted aryl group, or A group represented by the general formula -X 1 -R 6 , wherein X 1 and R 6 have the same meaning as described above;
X 2 represents an optionally substituted C 1-6 alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond;
Z 1 and Z 2 may be the same or different and each represents a nitrogen atom or a general formula C—R 7 wherein R 7 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or a substituted A C 1-6 alkoxy group which may optionally be represented by the formula:
Y represents —N═N—, —S (O) —O—, —C (O) —O—, —C (O) —S— or —C (S) —O— (in each group It is assumed that the bond on the left side is bonded to NH.)
However, when R 3 is a group represented by the general formula —X 1 —R 6 , wherein X 1 and R 6 have the same meanings as described above, Y represents —S (O) — O—, —C (O) —O—, —C (O) —S— or —C (S) —O— (provided that the bond on the left side of each group is bonded to NH) And X 2 is a bond. Or a salt thereof.
Substituent group α: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ”The group (2) Y represented by , -C (O) -S- or -C (S) -O- (wherein the bond on the left side of each group is bonded to NH) or a compound thereof salt.
(3) R 2 has the general formula —X 1 —R 6 wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 alkylene group, An optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6 is an optionally substituted aryl group, an optionally substituted heterocycle A cyclic group or an optionally substituted C 3-8 cycloalkyl group ”, a group represented by R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or a substituted group; The compound or a salt thereof according to (1) or (2), which is a C 1-6 alkoxy group which may be substituted or an aryl group which may be substituted.
(4) R 1 is an aryl group which may be substituted with one or more groups selected from substituent group α or a monocyclic group which may be substituted with one or more groups selected from substituent group α The compound or a salt thereof according to any one of (1) to (3), which is a heterocyclic group.
Substituent group α: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ”(5) Y represented by —N—N—, —C (O) —O— Or a compound or a salt thereof according to any one of (1) to (4), which is —C (O) —S— (wherein the bond on the left side of each group is bonded to NH). .
(6) Z 1 and Z 2 are the same or different and have the general formula C—R 7 wherein R 7 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or a substituted group. It indicates a C 1-6 alkoxy group optionally. a group represented by "(1) a compound or salt thereof according to any one of the - (5).
(7) R 2 has the general formula —X 1 —R 6a “wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 alkylene group, An optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6a represents an optionally substituted aryl group. The compound or a salt thereof according to any one of (1) to (6), wherein the group, R 3 is a hydrogen atom.
(8) R 2 is a group represented by the general formula —X 1d —R 6a, wherein R 1a represents a bond; R 6a represents an optionally substituted aryl group, R 3 The compound or a salt thereof according to any one of (1) to (7), wherein is a hydrogen atom.
(9) The compound or a salt thereof according to any one of (1) to (8), wherein X 2 is a C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group or a bond.
(10) R 1 is an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted C 1 An aryl group substituted with a group represented by “ -6 alkyl group” or an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same as defined above; The compound or a salt thereof according to any one of (1) to (9), which is a monocyclic heterocyclic group substituted with a group represented by:
(11) The compound or a salt thereof according to any one of (1) to (10), wherein X 2 is a bond.
(12) R 1 is an aryl group which may be substituted with one or more groups selected from substituent group α or a monocyclic group which may be substituted with one or more groups selected from substituent group α The compound or a salt thereof according to any one of (1) to (9), wherein the heterocyclic group, X 2 is a bond.
Substituent group α: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 ., which may be the same or different, a hydrogen atom or a substituted showing a C 1-6 alkyl group optionally group (13) represented by "R 1 annular optionally substituted amino group or the formula - Aryl substituted with a group represented by NR 4 R 5 wherein R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. Group or may be substituted 4 R 5 "wherein, R 4 and R 5 are the a. Have the meanings similar" Jo amino or the general formula -NR monocyclic heterocyclic group substituted with a group represented by, X The compound or a salt thereof according to any one of (1) to (12), wherein 2 is a bond.
(14) The compound is 4- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (piperidin-1-yl) -N- ( 4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole) -3-yl) biphenyl-3-yl) benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl)- 2- (piperidin-1-yl) isonicotinamide, 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro- 1,2,4-oxadiazole-3- L) biphenyl-3-yl) benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- ( Piperidin-1-yl) benzamide, 4- (dimethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl ) Benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide and 3 (1) is a compound selected from-(diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) benzamide Listed compounds A salt thereof.
(15) 4- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide or a salt thereof.
(16) 3- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide or a salt thereof.
(17) 3- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide or a salt thereof.
(18) N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- (piperidin-1-yl) iso Nicotinamide or a salt thereof.
(19) 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole- 3-yl) biphenyl-3-yl) benzamide or a salt thereof.
(20) N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide Or its salt.
(21) 4- (Dimethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide or a salt thereof .
(22) N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide or its salt.
(23) 3- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) benzamide or a salt thereof.
(24) A pharmaceutical composition comprising the compound or a salt thereof according to any one of (1) to (23).
(25) A collagen production inhibitor comprising the compound or a salt thereof according to any one of (1) to (23).
(26) A therapeutic agent for a disease involving excessive production of collagen containing the compound or salt thereof according to any one of (1) to (23).
(27) The compound or a salt thereof according to any one of (1) to (9), wherein the substituent group α is the substituent group α1.
Substituent group α1: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, C 1-6 alkoxy group which may be substituted, C 3-8 cycloalkyl group which may be substituted, heterocyclic group which may be substituted, cyclic amino group which may be substituted and general formula A group represented by: —NR 4 R 5 wherein R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
(28) The compound or a salt thereof according to (27), wherein X 2 is a bond.
(29) A pharmaceutical composition comprising the compound or salt thereof according to (27) or (28).
(30) A collagen production inhibitor containing the compound or salt thereof according to (27) or (28).
(31) A therapeutic agent for a disease involving the overproduction of collagen containing the compound or a salt thereof according to (27) or (28).
　本発明はまた下記を提供する。
（ａ）医薬として用いるための、上で定義した一般式［１］で表される化合物またはその塩。
（ｂ）コラーゲンの過剰産生が関連する疾患の予防または治療などの処置に用いるための、好ましくは線維症の予防または治療などの処置に用いるための、一般式［１］で表される化合物またはその塩。
（ｃ）一般式［１］で表される化合物またはその塩および薬理学的に許容される添加物を含む医薬組成物。
（ｄ）一般式［１］で表される化合物またはその塩の、コラーゲンの過剰産生が関連する疾患の予防または治療などの処置に用いるための方法であって、一般式［１］で表される化合物またはその塩の治療上有効量を対象（ヒトを含む哺乳動物）に投与する工程を含む方法。
（ｅ）医薬組成物の製造のための、（１）～（２３）のいずれか記載の化合物またはその塩の使用。
（ｆ）コラーゲン産生阻害剤の製造のための、（１）～（２３）のいずれか記載の化合物またはその塩の使用。
（ｇ）コラーゲンの過剰産生が関与する疾患の処置剤の製造のための、（１）～（２３）のいずれか記載の化合物またはその塩の使用。 The present invention also provides the following.
(A) A compound represented by the general formula [1] defined above or a salt thereof for use as a medicament.
(B) a compound represented by the general formula [1] for use in treatment such as prevention or treatment of a disease associated with overproduction of collagen, preferably for treatment such as prevention or treatment of fibrosis, or Its salt.
(C) A pharmaceutical composition comprising a compound represented by the general formula [1] or a salt thereof and a pharmacologically acceptable additive.
(D) A method of using a compound represented by the general formula [1] or a salt thereof for treatment such as prevention or treatment of a disease associated with overproduction of collagen, which is represented by the general formula [1]. Administering a therapeutically effective amount of a compound or salt thereof to a subject (mammal, including humans).
(E) Use of the compound according to any one of (1) to (23) or a salt thereof for the production of a pharmaceutical composition.
(F) Use of the compound or salt thereof according to any one of (1) to (23) for the production of a collagen production inhibitor.
(G) Use of the compound according to any one of (1) to (23) or a salt thereof for the manufacture of a therapeutic agent for a disease involving excessive production of collagen.
　本発明の新規なアミド誘導体またはその塩は、コラーゲン産生阻害作用を有し、安全性および動態に優れることから、たとえば、肺線維症、強皮症、腎硬化症および肝硬変などのコラーゲンの過剰産生が関与する疾患の予防または治療などの処置に有用である。さらに、本発明化合物は、優れた代謝安定性を有する。 Since the novel amide derivative of the present invention or a salt thereof has a collagen production inhibitory action and is excellent in safety and kinetics, for example, overproduction of collagen such as pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis It is useful for treatments such as prevention or treatment of diseases in which is involved. Furthermore, the compound of the present invention has excellent metabolic stability.
　以下、本発明化合物について詳述する。
　本明細書において、特にことわらない限り、各用語は、次の意味を有する。
　ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。
　Ｃ１－６アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ－ブチル、イソブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチルおよびヘキシル基などの直鎖状または分枝鎖状のＣ１－６アルキル基を意味する。
　Ｃ２－６アルケニル基とは、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、１，３－ブタジエニル、ペンテニルおよびヘキセニル基などの直鎖状または分枝鎖状のＣ２－６アルケニル基を意味する。
　Ｃ２－６アルキニル基とは、エチニル、２－プロピニルおよび２－ブチニル基などの直鎖状または分枝鎖状のＣ２－６アルキニル基を意味する。
　Ｃ３－８シクロアルキル基とは、シクロプロピル、シクロプロペニル、シクロブチル、シクロブテニル、シクロペンチル、シクロペンテニル、シクロヘキシルおよびシクロヘキセニル基などの分子内に不飽和結合を有していてもよいＣ３－８シクロアルキル基を意味する。 Hereinafter, the compound of the present invention will be described in detail.
In this specification, unless otherwise stated, each term has the following meaning.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C 1-6 alkyl group is a linear or branched C 1-6 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. An alkyl group is meant.
The C 2-6 alkenyl group is a linear or branched C 2-6 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups. means.
The C 2-6 alkynyl group means a linear or branched C 2-6 alkynyl group such as ethynyl, 2-propynyl and 2-butynyl groups.
The C 3-8 cycloalkyl group is a C 3-8 cyclo which may have an unsaturated bond in the molecule such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl groups. An alkyl group is meant.
　アリール基とは、フェニル、ナフチル、ジヒドロナフチルおよびテトラヒドロナフチル基などの部分的に飽和していてもよいアリール基を意味する。
　アルＣ１－６アルキル基とは、ベンジル、ジフェニルメチル、トリチル、フェネチルまたはナフチルメチル基などを意味する。 An aryl group means a partially saturated aryl group such as phenyl, naphthyl, dihydronaphthyl and tetrahydronaphthyl groups.
The ar C 1-6 alkyl group means a benzyl, diphenylmethyl, trityl, phenethyl or naphthylmethyl group or the like.
　Ｃ１－６アルキレン基とは、メチレン、エチレン、プロピレン、ブチレンおよびヘキシレン基などの直鎖状または分枝鎖状のＣ１－６アルキレン基を意味する。
　Ｃ２－６アルケニレン基とは、ビニレン、プロペニレン、１－ブテニレンおよび２－ブテニレン基などの直鎖状または分枝鎖状のＣ２－６アルケニレン基を意味する。
　Ｃ２－６アルキニレン基とは、エチニレン、プロピニレン、１－ブチニレンおよび２－ブチニレン基などの直鎖状または分枝鎖状のＣ２－６アルキニレン基を意味する。 The C 1-6 alkylene group means a linear or branched C 1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene groups.
The C 2-6 alkenylene group means a linear or branched C 2-6 alkenylene group such as vinylene, propenylene, 1-butenylene and 2-butenylene groups.
The C 2-6 alkynylene group means a linear or branched C 2-6 alkynylene group such as ethynylene, propynylene, 1-butynylene and 2-butynylene groups.
　Ｃ１－６アルコキシ基とは、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、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシおよびヘキシルオキシ基などの直鎖状または分枝鎖状のＣ１－６アルキルオキシ基を意味する。
　Ｃ１－６アルコキシＣ１－６アルキル基とは、メトキシメチルおよび１－エトキシエチル基などのＣ１－６アルキルオキシＣ１－６アルキル基を意味する。
　アルＣ１－６アルコキシＣ１－６アルキル基とは、ベンジルオキシメチルおよびフェネチルオキシメチル基などのアルＣ１－６アルキルオキシＣ１－６アルキル基を意味する。 The C 1-6 alkoxy group means a linear or branched C 1 -1 group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups. 6 means an alkyloxy group.
The C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyloxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
Al C 1-6 alkoxy C 1-6 alkyl group means an al C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl groups.
　Ｃ２－１２アルカノイル基とは、アセチル、プロピオニル、バレリル、イソバレリルおよびピバロイル基などの直鎖状または分枝鎖状のＣ２－１２アルカノイル基を意味する。
　アロイル基とは、ベンゾイルまたはナフトイル基などを意味する。
　複素環式カルボニル基とは、ニコチノイル、テノイル、ピロリジノカルボニルまたはフロイル基などを意味する。
　（α－置換）アミノアセチル基とは、アミノ酸（グリシン、アラニン、バリン、ロイシン、イソロイシン、セリン、トレオニン、システイン、メチオニン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、アルギニン、リジン、ヒスチジン、ヒドロキシリジン、フェニルアラニン、チロシン、トリプトファン、プロリンおよびヒドロキシプロリンなどのアミノ酸が挙げられる。）から誘導されるＮ末端が保護されていてもよい（α－置換）アミノアセチル基を意味する。
　アシル基とは、ホルミル基、スクシニル基、グルタリル基、マレオイル基、フタロイル基、Ｃ２－１２アルカノイル基、アロイル基、複素環式カルボニル基または（α－置換）アミノアセチル基を意味する。 The C 2-12 alkanoyl group means a linear or branched C 2-12 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
An aroyl group means a benzoyl or naphthoyl group.
The heterocyclic carbonyl group means nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.
The (α-substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, tryptophan, proline and hydroxyproline, etc.) means the N-terminus derived from (α-substituted) aminoacetyl group which may be protected.
Acyl group means formyl group, succinyl group, glutaryl group, maleoyl group, phthaloyl group, C 2-12 alkanoyl group, aroyl group, heterocyclic carbonyl group or (α-substituted) aminoacetyl group.
　Ｃ１－６アルコキシカルボニル基とは、メトキシカルボニル、エトキシカルボニル、イソプロポキシカルボニル、ｔｅｒｔ－ブトキシカルボニルおよび１，１－ジメチルプロポキシカルボニル基などの直鎖状または分枝鎖状のＣ１－６アルキルオキシカルボニル基を意味する。
　アルＣ１－６アルコキシカルボニル基とは、ベンジルオキシカルボニルまたはフェネチルオキシカルボニル基などを意味する。
　アリールオキシカルボニル基とは、フェニルオキシカルボニルまたはナフチルオキシカルボニル基などを意味する。 The C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 alkyloxy group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and 1,1-dimethylpropoxycarbonyl group. Means a carbonyl group.
The al C 1-6 alkoxycarbonyl group means a benzyloxycarbonyl or phenethyloxycarbonyl group.
An aryloxycarbonyl group means a phenyloxycarbonyl or naphthyloxycarbonyl group.
　アシルＣ１－６アルキル基とは、アセチルメチル、ベンゾイルメチルまたは１－ベンゾイルエチル基などを意味する。
　Ｃ２－６アルカノイルオキシ基とは、アセチルオキシおよびプロピオニルオキシ基などの直鎖状または分枝鎖状のＣ２－６アルカノイルオキシ基を意味する。
　アロイルオキシ基とは、ベンゾイルオキシまたはナフトイルオキシ基などを意味する。
　アシルオキシ基とは、Ｃ２－６アルカノイルオキシまたはアロイルオキシ基などを意味する。
　アシルオキシＣ１－６アルキル基とは、アセトキシメチル、プロピオニルオキシメチル、ピバロイルオキシメチル、ベンゾイルオキシメチルまたは１－（ベンゾイルオキシ）エチル基などを意味する。 An acyl C 1-6 alkyl group means an acetylmethyl, benzoylmethyl or 1-benzoylethyl group.
The C 2-6 alkanoyloxy group means a linear or branched C 2-6 alkanoyloxy group such as acetyloxy and propionyloxy groups.
An aroyloxy group means a benzoyloxy or naphthoyloxy group.
The acyloxy group means a C 2-6 alkanoyloxy or aroyloxy group.
The acyloxy C 1-6 alkyl group means an acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, benzoyloxymethyl or 1- (benzoyloxy) ethyl group.
　Ｃ１－６アルキルアミノ基とは、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、ｔｅｒｔ－ブチルアミノおよびペンチルアミノ基などのモノ（Ｃ１－６アルキル）アミノ基を意味する。
　ジＣ１－６アルキルアミノ基とは、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジブチルアミノ、（エチル）（メチル）アミノ、（メチル）（プロピル）アミノ、（ブチル）（メチル）アミノおよび（メチル）（ペンチル）アミノ基などのジ（Ｃ１－６アルキル）アミノ基を意味する。 The C 1-6 alkylamino group means a mono (C 1-6 alkyl) amino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino and pentylamino groups.
DiC 1-6 alkylamino group means dimethylamino, diethylamino, dipropylamino, dibutylamino, (ethyl) (methyl) amino, (methyl) (propyl) amino, (butyl) (methyl) amino and (methyl) It means a di (C 1-6 alkyl) amino group such as (pentyl) amino group.
　Ｃ１－６アルキルスルホニル基とは、メチルスルホニル、エチルスルホニルまたはプロピルスルホニル基などを意味する。
　アリールスルホニル基とは、ベンゼンスルホニル、ｐ－トルエンスルホニルまたはナフタレンスルホニル基などを意味する。
　Ｃ１－６アルキルスルホニルオキシ基とは、メチルスルホニルオキシまたはエチルスルホニルオキシ基などを意味する。
　アリールスルホニルオキシ基とは、ベンゼンスルホニルオキシまたはｐ－トルエンスルホニルオキシ基などを意味する。
　Ｃ１－６アルキルスルホニルアミノ基とは、メチルスルホニルアミノまたはエチルスルホニルアミノ基などを意味する。 The C 1-6 alkylsulfonyl group means a methylsulfonyl, ethylsulfonyl, propylsulfonyl group or the like.
The arylsulfonyl group means benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.
The C 1-6 alkylsulfonyloxy group means a methylsulfonyloxy or ethylsulfonyloxy group.
An arylsulfonyloxy group means a benzenesulfonyloxy or p-toluenesulfonyloxy group.
The C 1-6 alkylsulfonylamino group means a methylsulfonylamino or ethylsulfonylamino group.
　シリル基とは、トリメチルシリル、トリエチルシリルまたはトリブチルシリル基などを意味する。 A silyl group means a trimethylsilyl, triethylsilyl, or tributylsilyl group.
　含酸素複素環式基とは、２－テトラヒドロピラニルまたは２－テトラヒドロフラニル基などを意味する。
　含硫黄複素環式基とは、テトラヒドロチオピラニルなどを意味する。
　複素環式オキシカルボニル基とは、２－フルフリルオキシカルボニルまたは８－キノリルオキシカルボニル基などを意味する。
　含窒素複素環式アルキル基とは、フタルイミドメチルまたはスクシンイミドメチル基などを意味する。 The oxygen-containing heterocyclic group means a 2-tetrahydropyranyl or 2-tetrahydrofuranyl group.
The sulfur-containing heterocyclic group means tetrahydrothiopyranyl and the like.
The heterocyclic oxycarbonyl group means a 2-furfuryloxycarbonyl or 8-quinolyloxycarbonyl group.
The nitrogen-containing heterocyclic alkyl group means a phthalimidomethyl or succinimidomethyl group.
　単環の複素環式基とは、アゼチジニル、ピロリル、ピロリニル、ピロリジニル、ピペリジル、ピペラジニル、ホモピペラジニル、アゼパニル、ジアゼパニル、オクタヒドロアゾシニル、イミダゾリル、ピラゾリル、ピリジル、テトラヒドロピリジル、ピリダジニル、ピラジニル、ピリミジニル、テトラゾリル、イミダゾリニル、イミダゾリジニル、ピラゾリニルおよびピラゾリジニル基などの該環を形成する異項原子として窒素原子のみを含む単環の含窒素複素環式基；テトラヒドロフラニル、フラニルおよびピラニル基などの該環を形成する異項原子として酸素原子のみを含む単環の含酸素複素環式基；チエニル基などの該環を形成する異項原子として硫黄原子のみを含む単環の含硫黄複素環式基；オキサゾリル、オキサジアゾリル、イソオキサゾリル、モルホリニルおよびオキサゼパニル基などの該環を形成する異項原子として窒素原子および酸素原子のみを含む単環の含窒素・酸素複素環式基；チアゾリル、イソチアゾリル、チアジアゾリル、チオモルホリニル、１－オキシドチオモルホリニルおよび１，１－ジオキシドチオモルホリニル基などの該環を形成する異項原子として窒素原子および硫黄原子のみを含む単環の含窒素・硫黄複素環式基；またはチオキサニル基などの該環を形成する異項原子として酸素原子および硫黄原子のみを含む単環の含酸素・硫黄複素環式基などを意味する。 Monocyclic heterocyclic groups include azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperazinyl, azepanyl, diazepanyl, octahydroazosinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, A monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a hetero atom forming the ring, such as imidazolinyl, imidazolidinyl, pyrazolinyl and pyrazolidinyl groups; hetero rings forming the ring such as tetrahydrofuranyl, furanyl and pyranyl groups A monocyclic oxygen-containing heterocyclic group containing only an oxygen atom as an atom; a monocyclic sulfur-containing heterocyclic group containing only a sulfur atom as a hetero atom forming the ring, such as a thienyl group; oxazolyl, oxadiazolyl, i Monocyclic nitrogen-containing / oxygen heterocyclic groups containing only nitrogen and oxygen atoms as hetero atoms forming the ring, such as oxazolyl, morpholinyl and oxazepanyl groups; thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomol Monocyclic nitrogen-containing / sulfur heterocyclic groups containing only nitrogen and sulfur atoms as hetero atoms forming the ring, such as folinyl and 1,1-dioxidethiomorpholinyl groups; or thioxanyl groups, etc. It means a monocyclic oxygen-containing / sulfur heterocyclic group containing only oxygen and sulfur atoms as the hetero atoms forming the ring.
　二環式の複素環式基とは、インドリル、インドリニル、２－オキソインドリニル、イソインドリル、インドリジニル、ベンズイミダゾリル、ベンゾトリアゾリル、インダゾリル、キノリル、テトラヒドロキノリニル、テトラヒドロイソキノリニル、キノリジニル、イソキノリル、フタラジニル、ナフチリジニル、キノキサリニル、ジヒドロキノキサリニル、キナゾリニル、シンノリニル、キヌクリジニルおよび２，３－ジヒドロベンゾピロリル基などの該環を形成する異項原子として窒素原子のみを含む縮合環または架橋環で示される二環式の含窒素複素環式基；ベンゾフラニル、イソベンゾフラニル、クロメニル、クロマニル、イソクロマニル、ベンゾ－１，３－ジオキソリル、ベンゾ－１，４－ジオキサニルおよび２，３－ジヒドロベンゾフラニル基などの該環を形成する異項原子として酸素原子のみを含む縮合環または架橋環で示される二環式の含酸素複素環式基；ベンゾチエニルおよび２，３－ジヒドロベンゾチエニル基などの該環を形成する異項原子として硫黄原子のみを含む縮合環または架橋環で示される二環式の含硫黄複素環式基；ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾオキサジアゾリル、ベンゾモルホリニル、ジヒドロピラノピリジル、ジヒドロジオキシノピリジルおよびジヒドロピリドオキサジニル基などの該環を形成する異項原子として窒素原子および酸素原子のみを含む縮合環または架橋環で示される二環式の含窒素・酸素複素環式基；またはベンゾチアゾリルおよびベンゾチアジアゾリル基などの該環を形成する異項原子として窒素原子および硫黄原子を含む縮合環または架橋環で示される二環式の含窒素・硫黄複素環式基を意味する。 Bicyclic heterocyclic groups include indolyl, indolinyl, 2-oxoindolinyl, isoindolyl, indolizinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinolidinyl, Condensed or bridged rings containing only a nitrogen atom as a hetero atom forming the ring, such as isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, quinuclidinyl and 2,3-dihydrobenzopyrrolyl groups A bicyclic nitrogen-containing heterocyclic group represented by: benzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, benzo-1,3-dioxolyl, benzo-1,4-dioxanyl and 2,3-dihydrobenzene A bicyclic oxygen-containing heterocyclic group represented by a condensed or bridged ring containing only an oxygen atom as a hetero atom forming the ring, such as a zofuranyl group; a benzothienyl and a 2,3-dihydrobenzothienyl group, etc. A bicyclic sulfur-containing heterocyclic group represented by a condensed or bridged ring containing only a sulfur atom as a hetero atom forming the ring; benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzo Bicycles represented by fused or bridged rings containing only nitrogen and oxygen atoms as the hetero atoms forming the ring, such as morpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl and dihydropyridoxazinyl groups A nitrogen-containing / oxygen heterocyclic group of the formula; or a nitrogen atom as a hetero atom forming the ring such as benzothiazolyl and benzothiadiazolyl group And means bicyclic nitrogen-containing sulfur heterocyclic group represented by fused or bridged ring including the sulfur atom.
　複素環式基とは、単環の複素環式基；二環式の複素環式基；またはチアントレニル、キサンテニル、フェノキサチイニル、カルバゾリル、β－カルボリニル、フェナントリジニル、アクリジニル、ペリミジニル、フェナントロリニル、フェナジニル、フェノチアジニルおよびフェノキサジニルなどの三環式の複素環式基を意味する。 A heterocyclic group is a monocyclic heterocyclic group; a bicyclic heterocyclic group; or thiantenyl, xanthenyl, phenoxathinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenidinyl It means a tricyclic heterocyclic group such as nantrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl.
　環状アミノ基とは、アゼチジニル、ピロリジニル、ピペリジニル、ホモピペリジニル、イミダゾリジニル、ピペラジニル、ホモピペラジニル、モルホリニル、オキサゼパニル、チオモルホリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル、ベンゾモルホリニル、ジヒドロピリドオキサジニルおよびキヌクリジニルなどの該環を形成する異項原子として一つ以上の窒素原子を含み、さらに一つ以上の酸素原子または硫黄原子を含んでもよい４員、５員、６員もしくは７員環、縮合環または架橋環の環状アミノ基を意味する。 Cyclic amino groups are azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, imidazolidinyl, piperazinyl, homopiperazinyl, morpholinyl, oxazepanyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzomorpholinyl, dihydropyridoxazinyl and quinuclidinyl A four-membered, five-membered, six-membered or seven-membered ring, which contains one or more nitrogen atoms as a hetero atom forming the ring, and may further contain one or more oxygen atoms or sulfur atoms, a condensed ring or It means a cyclic amino group of a bridged ring.
　アミノ保護基としては、通常のアミノ基の保護基として使用し得るすべての基を含み、たとえば、Ｗ．グリーン（W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第696～926頁、2007年、ジョン・ウィリイ・アンド・サンズ社（John Wiley & Sons，INC.）に記載されている基が挙げられる。具体的には、アルＣ１－６アルキル基、Ｃ１－６アルコキシＣ１－６アルキル基、アシル基、Ｃ１－６アルコキシカルボニル基、アルＣ１－６アルコキシカルボニル基、アリールオキシカルボニル基、Ｃ１－６アルキルスルホニル基、アリールスルホニル基またはシリル基が挙げられる。 Amino protecting groups include all groups that can be used as protecting groups for ordinary amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group.
　イミノ保護基としては、通常のイミノ基の保護基として使用し得るすべての基を含み、たとえば、Ｗ．グリーン（W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第696～926頁、2007年、ジョン・ウィリイ・アンド・サンズ社（John Wiley & Sons,INC.）に記載されている基が挙げられる。具体的には、アルＣ１－６アルキル基、Ｃ１－６アルコキシＣ１－６アルキル基、アシル基、Ｃ１－６アルコキシカルボニル基、アルＣ１－６アルコキシカルボニル基、アリールオキシカルボニル基、Ｃ１－６アルキルスルホニル基、アリールスルホニル基またはシリル基が挙げられる。 The imino protecting group includes all groups that can be used as protecting groups for ordinary imino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group.
　Ｃ１－６アルキルアミノ保護基としては、イミノ保護基と同様の保護基が挙げられる。 C 1-6 alkylamino protecting groups include protecting groups similar to imino protecting groups.
　ヒドロキシル保護基としては、通常のヒドロキシル基の保護基として使用し得るすべての基を含み、たとえば、Ｗ．グリーン（W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第16～366頁、2007年、ジョン・ウィリイ・アンド・サンズ社（John Wiley & Sons，INC.）に記載されている基が挙げられる。具体的には、たとえば、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、アルＣ１－６アルキル基、Ｃ１－６アルコキシＣ１－６アルキル基、アルＣ１－６アルコキシＣ１－６アルキル基、アシル基、Ｃ１－６アルコキシカルボニル基、アルＣ１－６アルコキシカルボニル基、Ｃ１－６アルキルスルホニル基、アリールスルホニル基、シリル基、テトラヒドロフラニル基またはテトラヒドロピラニル基が挙げられる。 Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 16-366, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, a C 1-6 alkyl group, a C 2-6 alkenyl group, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an ar C 1-6 alkoxy C 1- 1 6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, al C 1-6 alkoxycarbonyl group, C 1-6 alkylsulfonyl group, arylsulfonyl group, silyl group, tetrahydrofuranyl group or tetrahydropyranyl group .
　カルボキシル保護基としては、通常のカルボキシル基の保護基として使用し得るすべての基を含み、たとえば、Ｗ．グリーン（W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第533～646頁、2007年、ジョン・ウィリイ・アンド・サンズ社（John Wiley & Sons，INC.）に記載されている基が挙げられる。具体的には、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、アリール基、アルＣ１－６アルキル基、Ｃ１－６アルコキシＣ１－６アルキル基、アルＣ１－６アルコキシＣ１－６アルキル基、アシルＣ１－６アルキル基、アシルオキシＣ１－６アルキル基またはシリル基が挙げられる。 The carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis 4th Edition, pp. 533-646, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, a C 1-6 alkyl group, a C 2-6 alkenyl group, an aryl group, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an ar C 1-6 alkoxy C 1 Examples include a -6 alkyl group, an acyl C 1-6 alkyl group, an acyloxy C 1-6 alkyl group, and a silyl group.
　酸性イミノ保護基とは、１Ｈ－テトラゾール－５－イル基、５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル基、５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル基、５－チオオキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル基などの酸性イミノ基の保護基を意味し、たとえば、Ｗ．グリーン（W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第872～894頁、2007年、ジョン・ウィリイ・アンド・サンズ社（John Wiley & Sons,INC.）に記載されている基が挙げられる。具体的には、たとえば、アシル基、Ｃ１－６アルコキシカルボニル基、アルＣ１－６アルキルオキシカルボニル基、アリールオキシカルボニル基、アルＣ１－６アルキル基、アシルＣ１－６アルキル基、Ｃ１－６アルコキシＣ１－６アルキル基、アリールスルホニル基およびシリル基などが挙げられる。 Acidic imino protecting groups are 1H-tetrazol-5-yl group, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl group, 5-oxo-4,5-dihydro Means a protecting group for acidic imino group such as -1,2,4-thiadiazol-3-yl group, 5-thiooxo-4,5-dihydro-1,2,4-oxadiazol-3-yl group, For example, W.W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 872-894, 2007, John Wiley & Sons, INC.). Specifically, for example, acyl group, C 1-6 alkoxycarbonyl group, al C 1-6 alkyloxycarbonyl group, aryloxycarbonyl group, al C 1-6 alkyl group, acyl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, arylsulfonyl group, silyl group and the like can be mentioned.
　脱離基としては、たとえば、ハロゲン原子、Ｃ１－６アルキルスルホニルオキシ基またはアリールスルホニルオキシ基などが挙げられる。 Examples of the leaving group include a halogen atom, a C 1-6 alkylsulfonyloxy group, an arylsulfonyloxy group, and the like.
　アルコール類としては、メタノール、エタノール、プロパノール、２－プロパノール、ブタノールまたは２－メチル－２－プロパノールが挙げられる。
　芳香族炭化水素類としては、ベンゼン、トルエンまたはキシレンが挙げられる。
　アミド類としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミドまたは１－メチル－２－ピロリドンが挙げられる。
　ハロゲン化炭化水素類としては、塩化メチレン、クロロホルムまたはジクロロエタンが挙げられる。
　エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、ジオキサン、テトラヒドロフラン、アニソール、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテルまたはジエチレングリコールジエチルエーテルが挙げられる。
　ケトン類としては、アセトン、２－ブタノンまたは４－メチル－２－ペンタノンが挙げられる。
　エステル類としては、酢酸メチル、酢酸エチル、酢酸プロピルまたは酢酸ブチルが挙げられる。
　脂肪族炭化水素類としては、ペンタン、ヘキサンまたはシクロヘキサンが挙げられる。 Alcohols include methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
Aromatic hydrocarbons include benzene, toluene or xylene.
Examples of amides include N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone.
Examples of halogenated hydrocarbons include methylene chloride, chloroform or dichloroethane.
Examples of ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.
Ketones include acetone, 2-butanone or 4-methyl-2-pentanone.
Esters include methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
Aliphatic hydrocarbons include pentane, hexane or cyclohexane.
　パラジウム触媒としては、パラジウム－炭素およびパラジウム黒などの金属パラジウム；塩化パラジウムなどの無機パラジウム塩；酢酸パラジウムなどの有機パラジウム塩；テトラキス（トリフェニルホスフィン）パラジウム（０）、ビス（トリフェニルホスフィン）パラジウム（II）ジクロリド、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、（Ｅ）－ジ（μ－アセタート）ビス（ｏ－（ジ－ｏ－トリルホスフィノ）ベンジル）ジパラジウム（II）、ビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリドおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）などの有機パラジウム錯体ならびにポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）およびポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）などのポリマー固定化有機パラジウム錯体が挙げられる。 Palladium catalysts include palladium-carbon and metal black such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium. (II) Dichloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride, (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II ), Organopalladium complexes such as bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride and tris (dibenzylideneacetone) dipalladium (0), and polymer supported bis (acetate) triphenylphos Examples include polymer-fixed organic palladium complexes such as fin palladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphine palladium (II).
　金属触媒としては、パラジウム－炭素およびパラジウム黒などの金属パラジウム；酸化パラジウムおよび水酸化パラジウムなどのパラジウム塩；ラネーニッケルなどのニッケル金属ならびに酸化白金などの白金塩が挙げられる。 Examples of the metal catalyst include palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metals such as Raney nickel and platinum salts such as platinum oxide.
　リガンドとしては、トリメチルホスフィンおよびトリ－ｔｅｒｔ－ブチルホスフィンなどのトリアルキルホスフィン類；トリシクロヘキシルホスフィンなどのトリシクロアルキルホスフィン類；トリフェニルホスフィンおよびトリトリルホスフィンなどのトリアリールホスフィン類；トリメチルホスファイト、トリエチルホスファイトおよびトリブチルホスファイトなどのトリアルキルホスファイト類；トリシクロヘキシルホスファイトなどのトリシクロアルキルホスファイト類；トリフェニルホスファイトなどのトリアリールホスファイト類；１，３－ビス（２，４，６－トリメチルフェニル）イミダゾリウムクロリドなどのイミダゾリウム塩；アセチルアセトンおよびオクタフルオロアセチルアセトンなどのジケトン類；トリメチルアミン、トリエチルアミン、トリプロピルアミンおよびトリイソプロピルアミンなどのアミン類；１，１’－ビス（ジフェニルホスフィノ）フェロセン、２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル、２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニル、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル、２－（ジ－ｔｅｒｔ－ブチルホスフィノ）－２’，４’，６’－トリイソプロピルビフェニル、２－ジシクロヘキシルホスフィノ－２’－（Ｎ，Ｎ－ジメチルアミノ）ビフェニル、４，５’－ビス（ジフェニルホスフィノ）－９，９’－ジメチルキサンテンならびに２－（ジ－ｔｅｒｔ－ブチルホスフィノ）ビフェニルが挙げられる。 Examples of the ligand include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trimethylphosphite, triethyl Trialkyl phosphites such as phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1,3-bis (2,4,6 Imidazolium salts such as trimethylphenyl) imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; , Amines such as triethylamine, tripropylamine and triisopropylamine; 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- Dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2- (di-tert-butylphosphino) -2 ′, 4 ′, 6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl, 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene and 2- (di -Tert-butylphosphino) biphenyl.
　コラーゲンの過剰産生が関与する疾患としては、たとえば、肺線維症、強皮症、腎硬化症および肝硬変が挙げられ、肺線維症が好ましい。 Examples of diseases involving excessive production of collagen include pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis, and pulmonary fibrosis is preferred.
　一般式［１］の化合物の塩としては、通常知られているアミノ基などの塩基性基またはフェノール性ヒドロキシル基もしくはカルボキシル基などの酸性基における塩が挙げられる。
　塩基性基における塩としては、たとえば、塩酸、臭化水素および硫酸などの鉱酸との塩；酒石酸、ギ酸、酢酸、クエン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩；ならびにメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩などが挙げられる。
　酸性基における塩としては、たとえば、ナトリウムおよびカリウムなどのアルカリ金属との塩；カルシウムおよびマグネシウムなどのアルカリ土類金属との塩；アンモニウム塩；ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、Ｎ－ベンジル－β－フェネチルアミンおよびＮ，Ｎ’－ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などを挙げることができる。
　さらに、上記、塩の中で一般式［１］の化合物の好ましい塩としては、薬理学的に許容される塩が挙げられる。 Examples of the salt of the compound represented by the general formula [1] include salts that are generally known in basic groups such as amino groups or acidic groups such as phenolic hydroxyl groups or carboxyl groups.
Salts in basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrogen bromide and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and Examples thereof include salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and N, N′-dibenzylethylenediamine Can be mentioned.
Furthermore, among the above salts, preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.
　他の置換基がいずれの場合においても、置換基群αのＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、複素環式基および環状アミノ基は、ハロゲン原子、シアノ基、ニトロ基、アシル基、アシルオキシ基、スルホ基、ホスホリル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、アセトアミド基、カルバモイル基、オキソ基、保護されていてもよいカルボキシル基、保護されていてもよいアミノ基、保護されていてもよいＣ１－６アルキルアミノ基、保護されていてもよいヒドロキシル基、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、ジＣ１－６アルキルアミノ基、環状アミノ基、アルＣ１－６アルキル基および置換基群βから選ばれる１つ以上の基で置換されていてもよい複素環式基から選ばれる１つ以上の基で置換されていてもよい。
　他の置換基がいずれの場合においても、置換基群α１のＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、Ｃ３－８シクロアルキル基、複素環式基および環状アミノ基は、ハロゲン原子、シアノ基、ニトロ基、アシル基、アシルオキシ基、スルホ基、ホスホリル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、アセトアミド基、カルバモイル基、オキソ基、保護されていてもよいカルボキシル基、保護されていてもよいアミノ基、保護されていてもよいＣ１－６アルキルアミノ基、保護されていてもよいヒドロキシル基、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、ジＣ１－６アルキルアミノ基、環状アミノ基、アルＣ１－６アルキル基および置換基群βから選ばれる１つ以上の基で置換されていてもよい複素環式基から選ばれる１つ以上の基で置換されていてもよい。 In any case of other substituents, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, heterocyclic group and cyclic group of substituent group α Amino group is halogen atom, cyano group, nitro group, acyl group, acyloxy group, sulfo group, phosphoryl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino group, acetamide group, carbamoyl group, oxo group , An optionally protected carboxyl group, an optionally protected amino group, an optionally protected C 1-6 alkylamino group, an optionally protected hydroxyl group, a C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, di C 1-6 alkylamino group, cyclic amino group, our aralkyl C 1-6 alkyl group Optionally substituted with one or more groups selected from finely substituent group β may be substituted with one or more groups also selected from heterocyclic radical.
In any case of the other substituents, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group of substituent group α1 Group, heterocyclic group and cyclic amino group are a halogen atom, cyano group, nitro group, acyl group, acyloxy group, sulfo group, phosphoryl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino group, An acetamido group, a carbamoyl group, an oxo group, an optionally protected carboxyl group, an optionally protected amino group, an optionally protected C 1-6 alkylamino group, an optionally protected hydroxyl group, C 1-6 alkyl groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 alkoxy group, di C 1-6 alkylamino group, cyclic amino , Optionally substituted with one or more groups selected from one or more good heterocyclic group optionally substituted by a group selected from aralkyl C 1-6 alkyl group and a substituent group beta.
　他の置換基がいずれの場合においても、Ｒ１の二環式の複素環式基は、ハロゲン原子、シアノ基、ニトロ基、アシル基、アシルオキシ基、スルホ基、ホスホリル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、アセトアミド基、カルバモイル基、オキソ基、保護されていてもよいカルボキシル基、保護されていてもよいアミノ基、保護されているＣ１－６アルキルアミノ基、保護されていてもよいヒドロキシル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルケニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルキニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルコキシ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアリール基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいジＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよい環状アミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアルＣ１－６アルキル基および置換基群βから選ばれる１つ以上の基で置換されていてもよい複素環式基から選ばれる１つ以上の基で置換されていてもよい。 In any case of other substituents, the bicyclic heterocyclic group of R 1 is a halogen atom, cyano group, nitro group, acyl group, acyloxy group, sulfo group, phosphoryl group, C 1-6 alkyl. Sulfonyl group, C 1-6 alkylsulfonylamino group, acetamide group, carbamoyl group, oxo group, optionally protected carboxyl group, optionally protected amino group, protected C 1-6 alkylamino group , protected also good hydroxyl group, substituted with one or more C 1-6 alkyl group optionally substituted with a group, one or more groups selected from substituent group β selected from substituent group β which may C 2-6 also be an alkenyl group, one or more good C 2-6 alkynyl group optionally substituted with a group selected from the substituent group beta, one or more groups selected from substituent group beta Optionally substituted C 1-6 alkoxy group, substituted with one or more aryl group which may be substituted with a group, one or more groups selected from substituent group β selected from substituent group β which may be C 1-6 alkyl amino group, one or more may be substituted with a group di-C 1-6 alkylamino group selected from substituent group beta, one or more selected from the substituent group beta One or more selected from the group consisting of a cyclic amino group optionally substituted by the above group, an ar C 1-6 alkyl group optionally substituted by one or more groups selected from substituent group β, and substituent group β It may be substituted with one or more groups selected from heterocyclic groups that may be substituted with the above group.
　他の置換基がいずれの場合においても、Ｒ２またはＲ３のＣ１－６アルキル基、Ｃ１－６アルコキシ基およびアリール基は、ハロゲン原子、シアノ基、ニトロ基、アシル基、アシルオキシ基、スルホ基、ホスホリル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、アセトアミド基、カルバモイル基、オキソ基、保護されていてもよいカルボキシル基、保護されていてもよいアミノ基、保護されているＣ１－６アルキルアミノ基、保護されていてもよいヒドロキシル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルケニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルキニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルコキシ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアリール基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいジＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよい環状アミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアルＣ１－６アルキル基および置換基群βから選ばれる１つ以上の基で置換されていてもよい複素環式基から選ばれる１つ以上の基で置換されていてもよい。 In any case of other substituents, the C 1-6 alkyl group, C 1-6 alkoxy group and aryl group of R 2 or R 3 are each a halogen atom, a cyano group, a nitro group, an acyl group, an acyloxy group, A sulfo group, a phosphoryl group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfonylamino group, an acetamide group, a carbamoyl group, an oxo group, an optionally protected carboxyl group, an optionally protected amino group, A protected C 1-6 alkylamino group, an optionally protected hydroxyl group, a C 1-6 alkyl group optionally substituted with one or more groups selected from substituent group β, substituent group one or more optionally substituted C 2-6 alkenyl group with a group selected from the beta, optionally substituted with one or more groups selected from substituent group beta C 2- 6 alkynyl group, C 1-6 alkoxy group optionally substituted with one or more groups selected from substituent group β, aryl optionally substituted with one or more groups selected from substituent group β A C 1-6 alkylamino group optionally substituted with one or more groups selected from the group, substituent group β, and a di-C optionally substituted with one or more groups selected from substituent group β A 1-6 alkylamino group, a cyclic amino group which may be substituted with one or more groups selected from substituent group β, and an alkyl which may be substituted with one or more groups selected from substituent group β It may be substituted with one or more groups selected from a heterocyclic group which may be substituted with one or more groups selected from a C 1-6 alkyl group and substituent group β.
　他の置換基がいずれの場合においても、Ｒ４またはＲ５のＣ１－６アルキル基は、ヒドロキシル基、保護されていてもよいカルボキシル基、保護されていてもよいアミノ基、保護されているＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルケニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルキニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルコキシ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアリール基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいジＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよい環状アミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアルＣ１－６アルキル基および置換基群βから選ばれる１つ以上の基で置換されていてもよい複素環式基から選ばれる１つ以上の基で置換されていてもよい。 In any case of other substituents, the C 1-6 alkyl group of R 4 or R 5 is a hydroxyl group, an optionally protected carboxyl group, an optionally protected amino group, or an protected group. C 1-6 alkylamino group, optionally substituted with one or more groups selected from substituent group β C 1-6 alkyl group, optionally substituted with one or more groups selected from substituent group β C 2-6 alkenyl group which may be substituted with one or more groups selected from substituent group β may be substituted with one or more groups selected from C 2-6 alkynyl group which may be substituted, or substituent group β A C 1-6 alkoxy group which may be substituted, an aryl group which may be substituted with one or more groups selected from substituent group β, and a substituent which is substituted with one or more groups selected from substituent group β It is a C 1-6 alkylamino group, substituent group One or more may be substituted with a group di-C 1-6 alkylamino group selected from one or more optionally substituted cyclic amino group with a group selected from the substituent group beta, substituent group Al C 1-6 alkyl group which may be substituted with one or more groups selected from β and a heterocyclic group which may be substituted with one or more groups selected from substituent group β It may be substituted with one or more groups.
　他の置換基がいずれの場合においても、Ｒ６のアリール基、複素環式基およびＣ３－８シクロアルキル基は、ハロゲン原子、シアノ基、ニトロ基、アシル基、アシルオキシ基、スルホ基、ホスホリル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、アセトアミド基、カルバモイル基、オキソ基、保護されていてもよいカルボキシル基、保護されていてもよいアミノ基、保護されているＣ１－６アルキルアミノ基、保護されていてもよいヒドロキシル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルケニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルキニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルコキシ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアリール基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいジＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよい環状アミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアルＣ１－６アルキル基および置換基群βから選ばれる１つ以上の基で置換されていてもよい複素環式基から選ばれる１つ以上の基で置換されていてもよい。 In any case of other substituents, the aryl group, heterocyclic group and C 3-8 cycloalkyl group of R 6 are each a halogen atom, a cyano group, a nitro group, an acyl group, an acyloxy group, a sulfo group, a phosphoryl group. Group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino group, acetamido group, carbamoyl group, oxo group, optionally protected carboxyl group, optionally protected amino group, protected C 1-6 alkylamino group, optionally protected hydroxyl group, C 1-6 alkyl group optionally substituted with one or more groups selected from substituent group β, selected from substituent group β one or more optionally substituted C 2-6 also be an alkenyl group with a group, one or more optionally substituted C 2-6 alkynyl group with a group selected from substituent group β One or more a C 1-6 alkoxy group optionally substituted with a group selected from the substituent group beta, one or more aryl group which may be substituted with a group selected from the substituent group beta, substituent C 1-6 alkylamino group optionally substituted with one or more groups selected from group β, diC 1-6 alkyl optionally substituted with one or more groups selected from substituent group β An amino group, a cyclic amino group optionally substituted with one or more groups selected from substituent group β, and an al C 1-6 optionally substituted with one or more groups selected from substituent group β It may be substituted with one or more groups selected from heterocyclic groups which may be substituted with one or more groups selected from an alkyl group and substituent group β.
　他の置換基がいずれの場合においても、Ｒ７のＣ１－６アルキル基およびＣ１－６アルコキシ基は、ヒドロキシル基、保護されていてもよいカルボキシル基、保護されていてもよいアミノ基、保護されているＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルケニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ２－６アルキニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルコキシ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアリール基、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいジＣ１－６アルキルアミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよい環状アミノ基、置換基群βから選ばれる１つ以上の基で置換されていてもよいアルＣ１－６アルキル基および置換基群βから選ばれる１つ以上の基で置換されていてもよい複素環式基から選ばれる１つ以上の基で置換されていてもよい。 In any case of other substituents, the C 1-6 alkyl group and the C 1-6 alkoxy group of R 7 are a hydroxyl group, an optionally protected carboxyl group, an optionally protected amino group, C 1-6 alkylamino group which is protected, C 1-6 alkyl group which may be substituted with one or more groups selected from substituent group β, one or more groups selected from substituent group β One or more selected from a C 2-6 alkynyl group optionally substituted with one or more groups selected from substituent group β and a C 2-6 alkenyl group optionally substituted with substituent group β A C 1-6 alkoxy group which may be substituted with the above group, an aryl group which may be substituted with one or more groups selected from the substituent group β, and one or more groups selected from the substituent group β in an optionally substituted C 1-6 alkylamine Amino group, one or more may be substituted with a group di-C 1-6 alkylamino group selected from substituent group beta, optionally substituted with one or more groups selected from substituent group beta A cyclic amino group, an al C 1-6 alkyl group which may be substituted with one or more groups selected from substituent group β, and an aryl group which may be substituted with one or more groups selected from substituent group β It may be substituted with one or more groups selected from heterocyclic groups.
　他の置換基がいずれの場合においても、Ｘ１のＣ１－６アルキレン基、Ｃ２－６アルケニレン基およびＣ２－６アルキニレン基は、ハロゲン原子、シアノ基、ヒドロキシル基およびＣ１－６アルコキシ基から選ばれる１つ以上の基で置換されていてもよい。 In any case of the other substituents, the C 1-6 alkylene group, C 2-6 alkenylene group and C 2-6 alkynylene group of X 1 are each a halogen atom, a cyano group, a hydroxyl group and a C 1-6 alkoxy group. It may be substituted with one or more groups selected from the group.
　他の置換基がいずれの場合においても、Ｘ２のＣ１－６アルキレン基、Ｃ２－６アルケニレン基およびＣ２－６アルキニレン基は、ハロゲン原子、置換基群βから選ばれる１つ以上の基で置換されていてもよいＣ１－６アルキル基、置換基群βから選ばれる１つ以上の基で置換されていてもよいフェニル基、置換基群βから選ばれる１つ以上の基で置換されていてもよい環状アミノ基および置換基群βから選ばれる１つ以上の基で置換されていてもよい複素環式基から選ばれる１つ以上の基で置換されていてもよい。 In any case of other substituents, the C 1-6 alkylene group, C 2-6 alkenylene group and C 2-6 alkynylene group of X 2 are one or more selected from a halogen atom and a substituent group β. A C 1-6 alkyl group optionally substituted with a group, a phenyl group optionally substituted with one or more groups selected from substituent group β, and one or more groups selected from substituent group β It may be substituted with one or more groups selected from an optionally substituted cyclic amino group and one or more heterocyclic groups optionally substituted with one or more groups selected from substituent group β.
　置換基群α：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基および一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基。
　置換基群α１：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよいＣ３－８シクロアルキル基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基および一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基。
　置換基群α２：ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、１つ以上のＣ１－６アルキル基で置換されていてもよい環状アミノ基および一般式－ＮＲ４ａＲ５ａ「式中、Ｒ４ａおよびＲ５ａは、同一または異なって、Ｃ１－６アルキル基を示す。」で表される基。 Substituent group α: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group and a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ”
Substituent group α1: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, C 1-6 alkoxy group which may be substituted, C 3-8 cycloalkyl group which may be substituted, heterocyclic group which may be substituted, cyclic amino group which may be substituted and general formula A group represented by: —NR 4 R 5 wherein R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
Substituent group α2: a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a cyclic amino group optionally substituted with one or more C 1-6 alkyl groups, and a general formula —NR 4a R 5a A group represented by the formula: wherein R 4a and R 5a are the same or different and each represents a C 1-6 alkyl group.
　置換基群β：ハロゲン原子、シアノ基、保護されていてもよいアミノ基、保護されていてもよいヒドロキシル基、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、Ｃ３－８シクロアルキル基、アリール基、複素環式基およびオキソ基。 Substituent group β: halogen atom, cyano group, amino group which may be protected, hydroxyl group which may be protected, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group An aryl group, a heterocyclic group and an oxo group.
　本発明の一般式［１］の化合物において、以下の化合物が好ましい。 In the compound of the general formula [1] of the present invention, the following compounds are preferable.
　Ｒ１が、置換基群αから選ばれる１つ以上の基で置換されていてもよいアリール基または置換基群αから選ばれる１つ以上の基で置換されていてもよい単環の複素環式基である化合物が好ましく、置換基群αから選ばれる１つ以上の基で置換されているアリール基または置換基群αから選ばれる１つ以上の基で置換されている単環の複素環式基である化合物がより好ましく、置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されているアリール基または置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されている単環の複素環式基である化合物がさらに好ましい。
　Ｒ１が、置換基群α１から選ばれる１つ以上の基で置換されていてもよいアリール基または置換基群α１から選ばれる１つ以上の基で置換されていてもよい単環の複素環式基である化合物が好ましく、置換基群α１から選ばれる１つ以上の基で置換されているアリール基または置換基群α１から選ばれる１つ以上の基で置換されている単環の複素環式基である化合物がより好ましく、置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されているアリール基または置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されている単環の複素環式基である化合物がさらに好ましい。
　置換基群αが、置換基群α２である化合物が好ましい。
　置換基群α１が、置換基群α２である化合物が好ましい。
　Ｒ１が、下記の一般式（Ｉ）～（ＶＩ）で表される基である化合物がよりさらに好ましく、下記の一般式（Ｉ）、（III）または（Ｖ）で表される基である化合物が最も好ましい。
Figure JPOXMLDOC01-appb-C000003
 「式中、Ｚ３は、窒素原子またはＣ－Ｈを；Ｒ４ａ、Ｒ４ｂ、Ｒ５ａおよびＲ５ｂは、同一または異なって、Ｃ１－６アルキル基を；Ｒ８ａ、Ｒ８ｂ、Ｒ８ｃ、Ｒ８ｄ、Ｒ９ａ、Ｒ９ｂ、Ｒ９ｃおよびＲ９ｄは、同一または異なって、水素原子またはＣ１－６アルキル基を；ｍ１およびｍ２は、０～３の整数を示す。」 R 1 is an aryl group which may be substituted with one or more groups selected from substituent group α or a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group α A compound which is a formula group is preferable, and an aryl group substituted with one or more groups selected from substituent group α or a monocyclic heterocyclic ring substituted with one or more groups selected from substituent group α A compound which is a formula group is more preferable, and may be a cyclic amino group which may be substituted or a general formula —NR 4 R 5 , wherein R 4 and R 5 have the same meaning as described above. An aryl group substituted with a group or an optionally substituted cyclic amino group or a general formula —NR 4 R 5 , wherein R 4 and R 5 have the same meanings as described above. Compounds that are monocyclic heterocyclic groups substituted by groups A further preferred.
R 1 is an aryl group which may be substituted with one or more groups selected from substituent group α1, or a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group α1 A compound which is a formula group is preferable, and an aryl group substituted with one or more groups selected from substituent group α1 or a monocyclic heterocyclic ring substituted with one or more groups selected from substituent group α1 A compound which is a formula group is more preferable, and may be a cyclic amino group which may be substituted or a general formula —NR 4 R 5 , wherein R 4 and R 5 have the same meaning as described above. An aryl group substituted with a group or an optionally substituted cyclic amino group or a general formula —NR 4 R 5 , wherein R 4 and R 5 have the same meanings as described above. A monocyclic heterocyclic group substituted by a group Compounds are more preferred.
A compound in which the substituent group α is the substituent group α2 is preferable.
A compound in which the substituent group α1 is the substituent group α2 is preferable.
More preferably, R 1 is a group represented by the following general formulas (I) to (VI), and is a group represented by the following general formula (I), (III) or (V) Compounds are most preferred.
Figure JPOXMLDOC01-appb-C000003
 “Wherein Z 3 represents a nitrogen atom or C—H; R 4a , R 4b , R 5a and R 5b are the same or different and represent a C 1-6 alkyl group; R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , R 9c and R 9d are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group; m1 and m2 represent an integer of 0 to 3 ”
　ｍ１およびｍ２が、１～３の整数である化合物が好ましく、１～２の整数である化合物がより好ましい。 A compound in which m1 and m2 are integers of 1 to 3 is preferable, and a compound in which integers of 1 to 2 are more preferable.
　Ｒ２が、一般式－Ｘ１－Ｒ６「式中、Ｘ１およびＲ６は、前記と同様な意味を有する。」で表される基である化合物が好ましく、一般式－Ｘ１－Ｒ６ａ「式中、Ｘ１およびＲ６ａは、前記と同様な意味を有する。」で表される基である化合物がより好ましく、一般式－Ｘ１ｄ－Ｒ６ａ「式中、Ｘ１ｄおよびＲ６ａは、前記と同様な意味を有する。」で表される基である化合物がさらに好ましい。Ｒ２が、一般式－Ｘ１ｄ－Ｒ６ｂ「式中、Ｒ６ｂは、アリール基を；Ｘ１ｄは、前記と同様な意味を有する。」で表される基である化合物がよりさらに好ましく、フェニル基である化合物が最も好ましい。 A compound in which R 2 is a group represented by the general formula —X 1 —R 6 , wherein X 1 and R 6 have the same meaning as described above is preferable, and the general formula —X 1 —R is preferable. 6a “wherein X 1 and R 6a have the same meaning as described above” is more preferable, and a compound represented by the general formula —X 1d —R 6a “wherein X 1d and R 6a Has the same meaning as described above. ”Is more preferable. R 2 is more preferably a compound represented by the general formula —X 1d —R 6b , wherein R 6b represents an aryl group; X 1d has the same meaning as described above. Most preferred are compounds that are phenyl groups.
　Ｒ３が、水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基または置換されていてもよいアリール基である化合物が好ましく、水素原子である化合物がより好ましい。 A compound in which R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or an optionally substituted aryl group is preferred, A compound that is a hydrogen atom is more preferable.
　Ｒ２が、一般式－Ｘ１－Ｒ６「式中、Ｘ１およびＲ６は、前記と同様な意味を有する。」で表される基、Ｒ３が、水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基または置換されていてもよいアリール基である化合物が好ましい。Ｒ２が、一般式－Ｘ１－Ｒ６ａ「式中、Ｘ１およびＲ６ａは、前記と同様な意味を有する。」で表される基、Ｒ３が、水素原子である化合物がより好ましい。Ｒ２が、一般式－Ｘ１ｄ－Ｒ６ａ「式中、Ｘ１ｄおよびＲ６ａは、前記と同様な意味を有する。」で表される基、Ｒ３が、水素原子である化合物がさらに好ましい。Ｒ２が、一般式－Ｘ１ｄ－Ｒ６ｂ「式中、Ｘ１ｄおよびＲ６ｂは、前記と同様な意味を有する。」で表される基、Ｒ３が、水素原子である化合物がよりさらに好ましい。Ｒ２が、フェニル基、Ｒ３が、水素原子である化合物が最も好ましい。 R 2 is a group represented by the general formula —X 1 —R 6 , wherein X 1 and R 6 have the same meaning as described above, and R 3 is a hydrogen atom, a halogen atom or a substituted group A compound which is an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or an optionally substituted aryl group is preferable. R 2 is more preferably a group represented by the general formula —X 1 —R 6a wherein “X 1 and R 6a have the same meaning as described above”, and R 3 is a hydrogen atom. . More preferably, R 2 is a group represented by the general formula —X 1d —R 6a , wherein X 1d and R 6a have the same meanings as described above, and R 3 is a hydrogen atom. . R 2 is a group represented by the general formula —X 1d —R 6b , wherein X 1d and R 6b have the same meaning as described above, and a compound in which R 3 is a hydrogen atom is more preferable. Most preferred is a compound wherein R 2 is a phenyl group and R 3 is a hydrogen atom.
　Ｚ１およびＺ２が、同一または異なって、一般式Ｃ－Ｒ７「式中、Ｒ７は、前記と同様な意味を有する。」で表される基である化合物が好ましく、Ｃ－Ｈで表される基である化合物がより好ましい。 A compound in which Z 1 and Z 2 are the same or different and each is a group represented by the general formula C—R 7 , wherein R 7 has the same meaning as described above, is preferable. The compound which is a group represented is more preferable.
　Ｙが、－Ｎ＝Ｎ－、－Ｃ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｓ－または－Ｃ（Ｓ）－Ｏ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）である化合物が好ましい。Ｙが、－Ｎ＝Ｎ－、－Ｃ（Ｏ）－Ｏ－または－Ｃ（Ｏ）－Ｓ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）である化合物がより好ましい。 Y is —N═N—, —C (O) —O—, —C (O) —S— or —C (S) —O— (where the bond on the left side of each group is bonded to NH) Is preferred). A compound in which Y is —N═N—, —C (O) —O— or —C (O) —S— (wherein the bond on the left side of each group is bonded to NH). Is more preferable.
　Ｘ２が、Ｃ１－６アルキレン基、Ｃ２－６アルケニレン基、Ｃ２－６アルキニレン基または結合手である化合物が好ましく、Ｘ２が、結合手である化合物がより好ましい。 A compound in which X 2 is a C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group or a bond is preferable, and a compound in which X 2 is a bond is more preferable.
　Ｒ１が、置換基群αから選ばれる１つ以上の基で置換されていてもよいアリール基または置換基群αから選ばれる１つ以上の基で置換されていてもよい単環の複素環式基、Ｘ２が、結合手である化合物が好ましく、Ｒ１が、置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基で置換されているアリール基または置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されている単環の複素環式基、Ｘ２が、結合手である化合物がより好ましい。
　Ｒ１が、置換基群α１から選ばれる１つ以上の基で置換されていてもよいアリール基または置換基群α１から選ばれる１つ以上の基で置換されていてもよい単環の複素環式基、Ｘ２が、結合手である化合物が好ましく、Ｒ１が、置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基で置換されているアリール基または置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されている単環の複素環式基、Ｘ２が、結合手である化合物がより好ましい。 R 1 is an aryl group which may be substituted with one or more groups selected from substituent group α or a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group α A compound in which the formula group, X 2 is a bond, is preferred, and R 1 is an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same or different Represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ”An aryl group substituted with a group represented by the formula: or an optionally substituted cyclic amino group or a general formula —NR 4 R 5 “In the formula, R 4 and R 5 have the same meanings as described above.” A monocyclic heterocyclic group substituted with a group represented by the formula: X 2 is a bond. preferable.
R 1 is an aryl group which may be substituted with one or more groups selected from substituent group α1, or a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group α1 A compound in which the formula group, X 2 is a bond, is preferred, and R 1 is an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same or different Represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ”An aryl group substituted with a group represented by the formula: or an optionally substituted cyclic amino group or a general formula —NR 4 R 5 “In the formula, R 4 and R 5 have the same meanings as described above.” A monocyclic heterocyclic group substituted with a group represented by the formula: X 2 is a bond. preferable.
　本発明の一般式［１］の化合物において、好ましい化合物としては、以下の化合物が挙げられる。
４－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド、３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド、３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（ピペリジン－１－イル）イソニコチンアミド、３－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド、４－（ジメチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド、３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド。 In the compound of the general formula [1] of the present invention, preferred compounds include the following compounds.
4- (Piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (piperidin-1-yl) -N- (4- (1H- Tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- (piperidine- 1-yl) isonicotinamide, 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4) -Oxadiazol-3-yl) biphenyl 3-yl) benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidine-1- Yl) benzamide, 4- (dimethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide, N -(4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide, 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) benzamide.
　一般式［１］中、下記の一般式[Ｔ]で表される基には、下記の式[ｔ１]～[ｔ６]で表される互変異性体が存在する。本発明は、これらの互変異性体も包含する。
Figure JPOXMLDOC01-appb-C000004
 In the general formula [1], the group represented by the following general formula [T] includes tautomers represented by the following formulas [t1] to [t6]. The present invention also includes these tautomers.
Figure JPOXMLDOC01-appb-C000004
　一般式［１］の化合物またはその塩において、異性体（たとえば、光学異性体および幾何異性体など）が存在する場合、本発明は、それらの異性体を包含し、また、溶媒和物、水和物および種々の形状の結晶を包含する。 In the compound of the general formula [1] or a salt thereof, when isomers (for example, optical isomers and geometric isomers, etc.) exist, the present invention includes those isomers, and also includes solvates, water Including hydrates and crystals of various shapes.
　次に、本発明化合物の製造法について説明する。
　本発明化合物は、自体公知の方法を組み合わせることにより製造されるが、たとえば、次に示す製造法にしたがって製造することができる。 Next, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.
［製造法１］
Figure JPOXMLDOC01-appb-C000005
 「式中、Ｒａは、水素原子またはＣ１－６アルキル基を；Ｒｂは、置換されていてもよいアルキレン基を；Ｌ１は、脱離基を；Ｒ１、Ｒ３、Ｒ６、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 1]
Figure JPOXMLDOC01-appb-C000005
 “In the formula, R a represents a hydrogen atom or a C 1-6 alkyl group; R b represents an optionally substituted alkylene group; L 1 represents a leaving group; R 1 , R 3 , R 6 , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
　一般式［３ａ］の化合物として、たとえば、ピリジン－３－ボロン酸、３－（メタンスルホンアミド）フェニルボロン酸、チオフェン－２－ボロン酸、ベンゾフラン－２－ボロン酸および３－メトキシフェニルボロン酸などが知られている。
　一般式［３ｂ］の化合物として、たとえば、３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フランなどが知られている。
　また、一般式［３ａ］および［３ｂ］の化合物は、たとえば、特開２００３－２０６２９０号公報およびザ・ジャーナル・オブ・オーガニック・ケミストリー（The Journal of Organic Chemistry）、1995年、第60巻、p.7508～7510などに記載された方法に準じ、対応するハロゲノ体から製造することができる。 Examples of the compound of the general formula [3a] include pyridine-3-boronic acid, 3- (methanesulfonamido) phenylboronic acid, thiophene-2-boronic acid, benzofuran-2-boronic acid, and 3-methoxyphenylboronic acid. It has been known.
As the compound of the general formula [3b], for example, 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furan and the like are known.
The compounds of the general formulas [3a] and [3b] are described in, for example, JP-A-2003-206290 and The Journal of Organic Chemistry, 1995, Vol. 60, p. According to the method described in .7508 to 7510, etc., it can be produced from the corresponding halogeno compound.
　一般式［１ａ］の化合物は、（１）塩基の存在下または不存在下、（２）パラジウム触媒の存在下、および（３）リガンドの存在下または不存在下、一般式［２］の化合物を一般式［３ａ］または［３ｂ］の化合物と反応させることにより製造することができる。
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、水、アルコール類、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ケトン類、アセトニトリル、エステル類およびジメチルスルホキシドなどが挙げられ、これらは混合して使用してもよい。 The compound of general formula [1a] is a compound of general formula [2] in the presence or absence of (1) a base, (2) in the presence of a palladium catalyst, and (3) in the presence or absence of a ligand. Can be produced by reacting with a compound of the general formula [3a] or [3b].
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, Examples include ketones, acetonitrile, esters, dimethyl sulfoxide, and the like, and these may be used as a mixture.
　この反応において所望により用いられる塩基としては、たとえば、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムおよびリン酸三カリウムなどの無機塩基ならびに１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、トリエチルアミンおよびＮ，Ｎ－ジイソプロピルエチルアミンなどの有機塩基が挙げられる。塩基の使用量は、一般式［２］の化合物に対して1～50倍モル、好ましくは、2～5倍モルであればよい。
　パラジウム触媒の使用量は、一般式［２］の化合物に対して、0.00001～1倍モル、好ましくは、0.001～0.1倍モルであればよい。
　リガンドの使用量は、一般式［２］の化合物に対して0.00001～1倍モル、好ましくは、0.001～0.1倍モルであればよい。
　一般式［３ａ］または［３ｂ］の化合物の使用量は、一般式［２］の化合物に対して、1～50倍モル、好ましくは、1～2倍モルであればよい。
　この反応は、好ましくは、不活性気体（たとえば、窒素、アルゴン）雰囲気下、40～170℃で、1分間～96時間実施すればよい。また、この反応は、加圧下、100～250℃、1分間～1時間実施してもよい。 Examples of the base optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and 1,8-diazabicyclo [5.4.0] -7- And organic bases such as undecene, triethylamine and N, N-diisopropylethylamine. The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [2].
The amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
The amount of the ligand used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
The amount of the compound of general formula [3a] or [3b] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [2].
This reaction is preferably carried out at 40 to 170 ° C. for 1 minute to 96 hours in an inert gas (eg, nitrogen, argon) atmosphere. This reaction may be carried out under pressure at 100 to 250 ° C. for 1 minute to 1 hour.
［製造法２］
Figure JPOXMLDOC01-appb-C000006
 「式中、Ｌ２は、脱離基を；Ｒ１、Ｒ２、Ｒ６、Ｒａ、Ｒｂ、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 2]
Figure JPOXMLDOC01-appb-C000006
 “Wherein L 2 represents a leaving group; R 1 , R 2 , R 6 , R a , R b , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
　一般式［１ｂ］の化合物は、製造法１に準じて、一般式［４］の化合物を一般式［３ａ］または［３ｂ］の化合物と反応させることにより製造することができる。 The compound of the general formula [1b] can be produced by reacting the compound of the general formula [4] with the compound of the general formula [3a] or [3b] according to the production method 1.
［製造法３］
Figure JPOXMLDOC01-appb-C000007
 「式中、Ｘ１ａは、酸素原子、硫黄原子または保護されていてもよいイミノ基を；Ｒ１、Ｒ３、Ｒ６、Ｌ１、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 3]
Figure JPOXMLDOC01-appb-C000007
 “Wherein X 1a represents an oxygen atom, a sulfur atom or an optionally protected imino group; R 1 , R 3 , R 6 , L 1 , X 2 , Y, Z 1 and Z 2 are as defined above. Have the same meaning. "
　一般式［５ａ］の化合物として、たとえば、アニリン、フェノールおよびチオフェノールなどが知られている。また、一般式［５ａ］の化合物は、たとえば、対応するハロゲノ化合物から、常法により製造することができる。 As the compound of the general formula [5a], for example, aniline, phenol, thiophenol and the like are known. Moreover, the compound of general formula [5a] can be manufactured by a conventional method from the corresponding halogeno compound, for example.
　一般式［１ｃ］の化合物は、製造法１に準じて、一般式［２］の化合物を一般式［５ａ］の化合物と反応させることにより製造することができる。 The compound of the general formula [1c] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [5a] according to the production method 1.
［製造法４］
Figure JPOXMLDOC01-appb-C000008
 「式中、Ｒ１、Ｒ２、Ｒ６、Ｌ２、Ｘ１ａ、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 4]
Figure JPOXMLDOC01-appb-C000008
 “Wherein R 1 , R 2 , R 6 , L 2 , X 1a , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
　一般式［１ｄ］の化合物は、製造法１に準じて、一般式［４］の化合物を一般式［５ａ］の化合物と反応させることにより製造することができる。 The compound of the general formula [1d] can be produced by reacting the compound of the general formula [4] with the compound of the general formula [5a] according to the production method 1.
［製造法５］
Figure JPOXMLDOC01-appb-C000009
 「式中、Ｘ１ｂは、置換されていてもよいアルケニレン基または置換されていてもよいアルキニレン基を；Ｘ１ｃは、置換されていてもよいアルキレン基を；Ｒ１、Ｒ３、Ｒ６、Ｌ１、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 5]
Figure JPOXMLDOC01-appb-C000009
 “ Wherein , X 1b represents an optionally substituted alkenylene group or an optionally substituted alkynylene group; X 1c represents an optionally substituted alkylene group; R 1 , R 3 , R 6 , L 1 , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
　一般式[５ｂ］の化合物として、たとえば、スチレン、アリルベンゼン、４－フェニル－１－ブテン、ビニルシクロヘキサンおよびアリルシクロヘキサンなどが知られている。また、一般式［５ｂ］の化合物は、たとえば、実験化学講座、第４版、第19巻、第298～361頁、1992年、丸善に記載の方法またはそれに準じた方法で製造することができる。 As the compound of the general formula [5b], for example, styrene, allylbenzene, 4-phenyl-1-butene, vinylcyclohexane and allylcyclohexane are known. Further, the compound of the general formula [5b] can be produced, for example, by the method described in Experimental Chemistry Course, 4th edition, volume 19, pages 298-361, 1992, Maruzen or a method analogous thereto. .
　（５－１Ａ）
　Ｘ１ｂが、置換されていてもよいアルケニレン基の場合、一般式［１ｅ］の化合物は、（１）塩基の存在下または不存在下、（２）相関移動触媒の存在下または不存在下、（３）リガンドの存在下または不存在下および（４）パラジウム触媒の存在下、一般式［２］の化合物を一般式［５ｂ］の化合物と反応させることにより製造することができる。
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、水、アルコール類、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ケトン類、アセトニトリル、エステル類およびジメチルスルホキシドなどが挙げられ、これらは混合して使用してもよい。
　この反応において所望により用いられる塩基としては、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムおよびリン酸三カリウムなどの無機塩基ならびに１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、トリエチルアミンおよびＮ，Ｎ－ジイソプロピルエチルアミンなどの有機塩基が挙げられる。塩基の使用量は、一般式［２］の化合物に対して1～50倍モル、好ましくは、2～5倍モルであればよい。
　この反応において所望により用いられる相間移動触媒としては、たとえば、テトラメチルアンモニウムクロリド、ベンジルトリメチルアンモニウムクロリド、ベンジルトリエチルアンモニウムクロリド、ベンジルトリブチルアンモニウムクロリド、テトラブチルアンモニウムブロミド、テトラブチルアンモニウムハイドロゲンサルフェートおよびトリオクチルメチルアンモニウムクロリドなどの４級アンモニウム塩；Ｎ－ラウリルピリジニウムクロリド、Ｎ－ラウリル－４－ピコリニウムクロリド、Ｎ－ラウリルピコリニウムクロリドならびにＮ－ベンジルピコリニウムクロリドなどが挙げられる。相間移動触媒の使用量は、一般式［２］の化合物に対して0.01～50倍モル、好ましくは、0.1～5倍モルであればよい。
　リガンドの使用量は、一般式［２］の化合物に対して0.00001～1倍モル、好ましくは、0.001～0.1倍モルであればよい。
　パラジウム触媒の使用量は、一般式［２］の化合物に対して、0.00001～1倍モル、好ましくは、0.001～0.1倍モルであればよい。
　一般式［５ｂ］の化合物の使用量は、一般式［２］の化合物に対して、1～50倍モル、好ましくは、1～2倍モルであればよい。
　この反応は、通常、不活性気体（たとえば、窒素、アルゴン）雰囲気下、40～170℃で、1分間～24時間実施すればよい。また、この反応は、加圧下、100～250℃、1分間～1時間実施してもよい。 (5-1A)
When X 1b is an optionally substituted alkenylene group, the compound of the general formula [1e] is (1) in the presence or absence of a base, (2) in the presence or absence of a phase transfer catalyst, (3) It can be produced by reacting a compound of general formula [2] with a compound of general formula [5b] in the presence or absence of a ligand and (4) in the presence of a palladium catalyst.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, Examples include ketones, acetonitrile, esters, dimethyl sulfoxide, and the like, and these may be used as a mixture.
Bases optionally used in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and 1,8-diazabicyclo [5.4.0] -7-undecene, And organic bases such as triethylamine and N, N-diisopropylethylamine. The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [2].
Phase transfer catalysts optionally used in this reaction include, for example, tetramethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate and trioctylmethylammonium. Quaternary ammonium salts such as chloride; N-laurylpyridinium chloride, N-lauryl-4-picolinium chloride, N-laurylpicolinium chloride, N-benzylpicolinium chloride, and the like. The amount of the phase transfer catalyst used may be 0.01 to 50 times mol, preferably 0.1 to 5 times mol, of the compound of the general formula [2].
The amount of the ligand used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
The amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
The amount of the compound of general formula [5b] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [2].
This reaction is usually carried out at 40 to 170 ° C. for 1 minute to 24 hours in an inert gas (eg, nitrogen, argon) atmosphere. This reaction may be carried out under pressure at 100 to 250 ° C. for 1 minute to 1 hour.
　（５－１Ｂ）
　Ｘ１ｂが、置換されていてもよいアルキニレン基の場合、一般式［１ｅ］の化合物は、（１）塩基の存在下または不存在下、（２）銅触媒存在下または不存在下および（３）パラジウム触媒の存在下、一般式［２］の化合物を一般式［５ｂ］の化合物と反応させることにより製造することができる。
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、水、アルコール類、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ケトン類、アセトニトリル、エステル類およびジメチルスルホキシドなどが挙げられ、これらは混合して使用してもよい。 (5-1B)
When X 1b is an optionally substituted alkynylene group, the compound of the general formula [1e] is (1) in the presence or absence of a base, (2) in the presence or absence of a copper catalyst, and (3 ) It can be produced by reacting the compound of the general formula [2] with the compound of the general formula [5b] in the presence of a palladium catalyst.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, Examples include ketones, acetonitrile, esters, dimethyl sulfoxide, and the like, and these may be used as a mixture.
　この反応において所望により用いられる塩基としては、たとえば、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムおよびリン酸三カリウムなどの無機塩基ならびに１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、トリエチルアミンおよびＮ，Ｎ－ジイソプロピルエチルアミンなどの有機塩基が挙げられる。塩基の使用量は、一般式［２］の化合物に対して1～50倍モル、好ましくは、2～5倍モルであればよい。
　この反応において所望により用いられる銅触媒としては、臭化銅およびヨウ化銅が挙げられる。銅触媒の使用量は、一般式［２］の化合物に対して0.01～50倍モル、好ましくは、0.1～5倍モルであればよい。
　パラジウム触媒の使用量は、一般式［２］の化合物に対して、0.00001～1倍モル、好ましくは、0.001～0.1倍モルであればよい。
　一般式［５ｂ］の化合物の使用量は、一般式［２］の化合物に対して、1～50倍モル、好ましくは、1～2倍モルであればよい。
　この反応は、通常、不活性気体（たとえば、窒素、アルゴン）雰囲気下、10～170℃で、1分間～24時間実施すればよい。また、この反応は、加圧下、100～250℃、1分間～1時間実施してもよい。 Examples of the base optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and 1,8-diazabicyclo [5.4.0] -7- And organic bases such as undecene, triethylamine and N, N-diisopropylethylamine. The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [2].
Copper catalysts optionally used in this reaction include copper bromide and copper iodide. The amount of the copper catalyst used may be 0.01 to 50 times mol, preferably 0.1 to 5 times mol, of the compound of the general formula [2].
The amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].
The amount of the compound of general formula [5b] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [2].
This reaction is usually carried out at 10 to 170 ° C. for 1 minute to 24 hours in an inert gas (eg, nitrogen, argon) atmosphere. This reaction may be carried out under pressure at 100 to 250 ° C. for 1 minute to 1 hour.
　（５－２）
　一般式［１ｆ］の化合物は、一般式［１ｅ］の化合物を還元することにより製造できる。
　還元反応としては、たとえば、金属触媒を用いる接触水素添加反応が挙げられる。
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、水、アルコール類、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、アセトニトリル、ケトン類、エステル類、酢酸およびピリジンなどが挙げられ、これらは混合して使用してもよい。
　金属触媒の使用量は、一般式［１ｅ］の化合物に対して0.001～1倍量（質量比）、好ましくは、0.01～0.5倍量（質量比）であればよい。
　水素源としては、たとえば、水素；ギ酸、ギ酸ナトリウム、ギ酸アンモニウムおよびギ酸トリエチルアンモニウムなどのギ酸塩；シクロヘキセンならびにシクロヘキサジエンなどが挙げられる。水素源の使用量は、一般式［１ｅ］の化合物に対して2～100倍モル、好ましくは、2～10倍モルであればよい。
　この反応は、0～200℃、好ましくは、0～100℃で1分間～24時間実施すればよい。 (5-2)
The compound of the general formula [1f] can be produced by reducing the compound of the general formula [1e].
Examples of the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, Acetonitrile, ketones, esters, acetic acid, pyridine and the like can be mentioned, and these may be used as a mixture.
The amount of the metal catalyst used may be 0.001 to 1 times (mass ratio), preferably 0.01 to 0.5 times (mass ratio) with respect to the compound of the general formula [1e].
Examples of the hydrogen source include hydrogen; formates such as formic acid, sodium formate, ammonium formate and triethylammonium formate; cyclohexene and cyclohexadiene. The amount of the hydrogen source to be used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [1e].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.
［製造法６］
Figure JPOXMLDOC01-appb-C000010
 「式中、Ｒ１、Ｒ３、Ｒ６、Ｌ２、Ｘ１ｂ、Ｘ１ｃ、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 6]
Figure JPOXMLDOC01-appb-C000010
 “Wherein R 1 , R 3 , R 6 , L 2 , X 1b , X 1c , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
　（６－１）
　一般式［１ｇ］の化合物は、前記（５－１Ａ）および（５－１Ｂ）に記載した方法に準じて、一般式［４］の化合物を一般式［５ｂ］の化合物と反応させることにより製造することができる。 (6-1)
The compound of the general formula [1g] is produced by reacting the compound of the general formula [4] with the compound of the general formula [5b] according to the method described in the above (5-1A) and (5-1B). can do.
　（６－２）
　一般式［１ｈ］の化合物は、前記（５－２）に記載した方法に準じて、一般式［１ｇ］の化合物を還元することにより製造できる。 (6-2)
The compound of the general formula [1h] can be produced by reducing the compound of the general formula [1g] according to the method described in the above (5-2).
［製造法７］
Figure JPOXMLDOC01-appb-C000011
 「式中、Ｒｃは、酸性イミノ保護基を；Ｒ１、Ｒ２、Ｒ３、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 7]
Figure JPOXMLDOC01-appb-C000011
 “Wherein R c is an acidic imino protecting group; R 1 , R 2 , R 3 , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
（７－１）
　一般式［７］の化合物は、一般式［６］の化合物をアシル化することにより製造することができる。具体的には、塩基の存在下または不存在下、酸ハロゲン化物を用いる方法が挙げられる。
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、アミド類、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、アセトニトリル、ケトン類、エステル類、スルホランおよびジメチルスルホキシドなどが挙げられ、これらは混合して使用してもよい。 (7-1)
The compound of the general formula [7] can be produced by acylating the compound of the general formula [6]. Specific examples include a method using an acid halide in the presence or absence of a base.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, amides, halogenated hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, ketones, Examples thereof include esters, sulfolane and dimethyl sulfoxide, and these may be used in combination.
　この反応に用いられる酸ハロゲン化物は、一般式［８］
Figure JPOXMLDOC01-appb-C000012
 「式中、Ｒ１およびＸ２は、前記と同様の意味を有する。」で表される化合物を塩化チオニルまたはオキサリルクロリドなどと反応させることにより製造することができる。
　酸ハロゲン化物の使用量は、一般式［６］の化合物に対して、1～50倍モル、好ましくは、１～5倍モルであればよい。 The acid halide used in this reaction is represented by the general formula [8].
Figure JPOXMLDOC01-appb-C000012
 It can be produced by reacting a compound represented by “wherein R 1 and X 2 have the same meaning as described above” with thionyl chloride or oxalyl chloride.
The amount of the acid halide used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [6].
　一般式［８］の化合物として、たとえば、３－（ジメチルアミノ）安息香酸、４－（ジメチルアミノ）安息香酸、３－（ジエチルアミノ）安息香酸、４－（ジエチルアミノ）安息香酸および２－クロロ－５－（ピペリジン－１－イル）安息香酸などが知られている。 Examples of the compound of the general formula [8] include 3- (dimethylamino) benzoic acid, 4- (dimethylamino) benzoic acid, 3- (diethylamino) benzoic acid, 4- (diethylamino) benzoic acid and 2-chloro-5. -(Piperidin-1-yl) benzoic acid and the like are known.
　この反応において所望により用いられる塩基としては、たとえば、水酸化ナトリウム、水酸化カリウムおよび水酸化リチウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウムおよび炭酸セシウムなどの無機塩基ならびに１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンおよびピリジンなどの有機塩基が挙げられる。塩基の使用量は、一般式［６］の化合物に対して1～50倍モル、好ましくは、1～5倍モルであればよい。
　この反応は、通常、－78～100℃、好ましくは、0～80℃で、10分間～24時間実施すればよい。 Examples of the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5. 4.0] -7-undecene, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, N, N-diisopropylethylamine and organic bases such as pyridine. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [6].
This reaction is usually carried out at −78 to 100 ° C., preferably 0 to 80 ° C., for 10 minutes to 24 hours.
（７－２）
　一般式［１］の化合物は、一般式［７］の化合物を脱保護することにより製造することができる。
　たとえば、Ｗ．グリーン（W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第872～894頁、2007年、ジョン・ウィリイ・アンド・サンズ社（John Wiley & Sons,INC.）に記載の方法などが挙げられる。
　具体的には、たとえば、酸または塩基を用いる加水分解反応、塩を用いた脱アルキル化反応、金属触媒を用いる接触水素添加反応を含む還元的脱アルキル化反応などが挙げられる。 (7-2)
The compound of general formula [1] can be produced by deprotecting the compound of general formula [7].
For example, W.W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 872-894, 2007, John Wiley & Sons, INC.).
Specific examples include a hydrolysis reaction using an acid or a base, a dealkylation reaction using a salt, a reductive dealkylation reaction including a catalytic hydrogenation reaction using a metal catalyst.
（Ｉ）
　酸を用いる加水分解反応において、使用される酸としては、たとえば、ギ酸、塩酸、硫酸、臭化水素酸、トリフルオロ酢酸、メタンスルホン酸、塩化アルミニウムおよびヨウ化トリメチルシリルなどが挙げられる。酸の使用量は、一般式［７］の化合物に対して1～100000倍モル、好ましくは、1～1000倍モルであればよい。
　塩基を用いる加水分解反応において、使用される塩基としては、たとえば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウムおよび炭酸ナトリウムなどの無機塩基；ナトリウムメトキシド、ナトリウムエトキシドおよびカリウムｔｅｒｔ－ブトキシドなどの有機塩基；ならびにフッ化テトラブチルアンモニウムなどが挙げられる。塩基の使用量は、一般式［７］の化合物に対して1～1000倍モル、好ましくは、1～50倍モルであればよい。
　塩を用いた脱アルキル化反応において、使用される塩としては、たとえば、ヨウ化リチウムおよび塩化ナトリウムなどが挙げられる。塩の使用量は、一般式［７］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。 (I)
In the hydrolysis reaction using an acid, examples of the acid used include formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, aluminum chloride, and trimethylsilyl iodide. The amount of the acid used may be 1 to 100000 times mol, preferably 1 to 1000 times mol, of the compound of the general formula [7].
In the hydrolysis reaction using a base, examples of the base used include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate; sodium methoxide, sodium ethoxide and potassium tert- And organic bases such as butoxide; and tetrabutylammonium fluoride. The amount of the base used may be 1 to 1000 times mol, preferably 1 to 50 times mol, of the compound of the general formula [7].
In the dealkylation reaction using a salt, examples of the salt used include lithium iodide and sodium chloride. The amount of the salt used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [7].
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、水、アルコール類、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、アセトニトリル、ケトン類およびエステル類などが挙げられ、これらは混合して使用してもよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, Acetonitrile, ketones, esters and the like can be mentioned, and these may be used in combination.
（ＩＩ）
　金属触媒を用いる接触水素添加反応において、使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、水、アルコール類、アミド類、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、アセトニトリル、ケトン類、エステル類、酢酸およびピリジンなどが挙げられ、これらは混合して使用してもよい。
　金属触媒の使用量は、一般式［７］の化合物に対して0.001～5倍量（質量比）、好ましくは、0.01～1倍量（質量比）であればよい。
　水素源としては、たとえば、水素；ギ酸；ギ酸ナトリウム、ギ酸アンモニウムおよびギ酸トリエチルアンモニウムなどのギ酸塩；シクロヘキセン；ならびにシクロヘキサジエンなどが挙げられる。水素源の使用量は、一般式［７］の化合物に対して2～100倍モル、好ましくは、2～10倍モルであればよい。
　この反応は、0～200℃、好ましくは、0～100℃で1分間～24時間実施すればよい。 (II)
In the catalytic hydrogenation reaction using a metal catalyst, the solvent used is not particularly limited as long as it does not adversely affect the reaction. For example, water, alcohols, amides, halogenated hydrocarbons, aromatics Examples thereof include hydrocarbons, ethers, acetonitrile, ketones, esters, acetic acid and pyridine, and these may be used as a mixture.
The amount of the metal catalyst used may be 0.001 to 5 times (mass ratio), preferably 0.01 to 1 times (mass ratio) with respect to the compound of the general formula [7].
Examples of the hydrogen source include hydrogen; formic acid; formate salts such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene; and cyclohexadiene. The amount of the hydrogen source to be used may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [7].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.
　なお、一般式［１］の化合物は、一般式［６］の化合物を前記（７－２）に記載した方法に準じて、脱保護した後に、前記（７－１）に記載した方法に準じて、一般式［８］の化合物またはその酸ハロゲン化物と反応させることによって製造することもできる。 The compound of the general formula [1] is obtained by deprotecting the compound of the general formula [6] according to the method described in the above (7-2) and then according to the method described in the above (7-1). It can also be produced by reacting with a compound of general formula [8] or an acid halide thereof.
［製造法８］
Figure JPOXMLDOC01-appb-C000013
 「式中、Ｙａは、－Ｎ＝Ｎ－を；Ｒ１、Ｒ２、Ｒ３、Ｘ２、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 8]
Figure JPOXMLDOC01-appb-C000013
 “In the formula, Y a represents —N═N—; R 1 , R 2 , R 3 , X 2 , Z 1 and Z 2 have the same meanings as described above.”
　一般式［１ｉ］の化合物は、たとえば、新編ヘテロ環化合物　応用編、第98～100頁、2004年、講談社に記載の方法またはそれに準じた方法で製造することができる。具体的には、一般式［９］の化合物を、塩の存在下または不存在下、アジドと反応させることにより製造することができる。 The compound of the general formula [1i] can be produced, for example, by the method described in Kodansha, or a method similar to that described in Kodansha, New Edition of Heterocyclic Compound Application, pages 98 to 100, 2004. Specifically, it can be produced by reacting the compound of the general formula [9] with an azide in the presence or absence of a salt.
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ジメチルスルホキシドおよび脂肪族炭化水素類などが挙げられ、これらは混合して使用してもよい。
　使用されるアジドとしては、たとえば、アジ化ナトリウムおよびトリメチルシリルアジドなどが挙げられる。アジドの使用量は、一般式［９］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　この反応において所望により用いられる塩としては、たとえば、塩化アンモニウムおよびトリエチルアミン塩酸塩などが挙げられる。塩の使用量は、一般式［９］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　この反応は、通常、－78～150℃、好ましくは、0～120℃で、10分間～24時間実施すればよい。また、この反応は、加圧下、60～200℃、1分間～1時間実施してもよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, dimethyl sulfoxide and aliphatic Hydrocarbons etc. are mentioned, and these may be used as a mixture.
Examples of the azide used include sodium azide and trimethylsilyl azide. The amount of azide used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of general formula [9].
Examples of salts used as desired in this reaction include ammonium chloride and triethylamine hydrochloride. The amount of the salt used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [9].
This reaction is usually carried out at −78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours. This reaction may be carried out under pressure at 60 to 200 ° C. for 1 minute to 1 hour.
［製造法９］
Figure JPOXMLDOC01-appb-C000014
 「式中、Ｙｂは、－Ｓ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｓ－または－Ｃ（Ｓ）－Ｏ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）を；Ｒ１、Ｒ２、Ｒ３、Ｘ２、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method 9]
Figure JPOXMLDOC01-appb-C000014
 “Wherein Y b represents —S (O) —O—, —C (O) —O—, —C (O) —S— or —C (S) —O— (wherein the left side of each group) And R 1 , R 2 , R 3 , X 2 , Z 1 and Z 2 have the same meaning as described above. ”
（９－１）
　一般式［１０］の化合物は、一般式［９］の化合物を、塩基の存在下または不存在下、ヒドロキシルアミンまたはその塩と反応させることにより製造することができる。 (9-1)
The compound of the general formula [10] can be produced by reacting the compound of the general formula [9] with hydroxylamine or a salt thereof in the presence or absence of a base.
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、水、アルコール類、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ジメチルスルホキシドおよび脂肪族炭化水素類などが挙げられ、これらは混合して使用してもよい。
　この反応において所望により用いられる塩基としては、たとえば、水酸化ナトリウム、水酸化カリウムおよび水酸化リチウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウムおよび炭酸セシウムなどの無機塩基ならびに１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンおよびピリジンなどの有機塩基が挙げられる。塩基の使用量は、一般式［９］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　ヒドロキシルアミンの塩としては、たとえば、塩酸塩および硫酸塩などが挙げられる。ヒドロキシルアミンまたはその塩の使用量は、一般式［９］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　この反応は、通常、－78～150℃、好ましくは、0～120℃で、10分間～24時間実施すればよい。また、この反応は、加圧下、40～150℃、1分間～1時間実施してもよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, water, alcohols, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, Examples include ketones, esters, dimethyl sulfoxide, and aliphatic hydrocarbons, and these may be used as a mixture.
Examples of the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5. 4.0] -7-undecene, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, N, N-diisopropylethylamine and organic bases such as pyridine. The amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [9].
Examples of the hydroxylamine salt include hydrochloride and sulfate. The amount of hydroxylamine or a salt thereof used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [9].
This reaction is usually carried out at −78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours. This reaction may be carried out under pressure at 40 to 150 ° C. for 1 minute to 1 hour.
（９－２Ａ）
　一般式［１］の化合物におけるＹ（一般式［１ｊ］の化合物におけるＹｂに相当）が－Ｃ（Ｏ）－Ｏ－である場合、一般式［１ｊ］の化合物は、一般式［１０］の化合物を、塩基の存在下または不存在下、活性カルボニル化合物と反応させることにより製造することができる。 (9-2A)
When Y in the compound of the general formula [1] (corresponding to Y b in the compound of the general formula [1j]) is —C (O) —O—, the compound of the general formula [1j] Can be prepared by reacting with an active carbonyl compound in the presence or absence of a base.
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ケトン類、アセトニトリル、エステル類、ジメチルスルホキシドおよび脂肪族炭化水素類などが挙げられ、これらは混合して使用してもよい。
　この反応において所望により用いられる塩基としては、たとえば、水酸化ナトリウム、水酸化カリウムおよび水酸化リチウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウムおよび炭酸セシウムなどの無機塩基ならびに１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンおよびピリジンなどの有機塩基が挙げられる。塩基の使用量は、一般式［１０］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　活性カルボニル化合物としては、たとえば、１，１’－カルボニルジイミダゾール、クロロ炭酸メチルおよびクロロ炭酸エチルなどが挙げられる。
　活性カルボニル化合物の使用量は、一般式［１０］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　この反応は、通常、－78～150℃、好ましくは、0～120℃で、10分間～24時間実施すればよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, ketones, acetonitrile, Examples thereof include esters, dimethyl sulfoxide and aliphatic hydrocarbons, and these may be used as a mixture.
Examples of the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5. 4.0] -7-undecene, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, N, N-diisopropylethylamine and organic bases such as pyridine. The amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [10].
Examples of the active carbonyl compound include 1,1′-carbonyldiimidazole, methyl chlorocarbonate and ethyl chlorocarbonate.
The amount of the active carbonyl compound used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [10].
This reaction is usually carried out at −78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.
（９－２Ｂ）
　一般式［１］の化合物におけるＹ（一般式［１ｊ］の化合物におけるＹｂに相当）が－Ｃ（Ｏ）－Ｓ－である場合、一般式［１ｊ］の化合物は、一般式［１０］の化合物を、１，１’－チオカルボニルジイミダゾールと反応させた後、三フッ化ホウ素ジエチルエーテル錯体と反応させることにより製造することができる。 (9-2B)
When Y in the compound of the general formula [1] (corresponding to Y b in the compound of the general formula [1j]) is —C (O) —S—, the compound of the general formula [1j] This compound can be produced by reacting with 1,1′-thiocarbonyldiimidazole and then reacting with boron trifluoride diethyl ether complex.
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ケトン類、アセトニトリル、エステル類、ジメチルスルホキシドおよび脂肪族炭化水素類などが挙げられ、これらは混合して使用してもよい。
　三フッ化ホウ素ジエチルエーテル錯体の使用量は、一般式［１０］の化合物に対して、1～100倍モル、好ましくは、3～10倍モルであればよい。
　この反応は、通常、－78～150℃、好ましくは、0～120℃で、10分間～24時間実施すればよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, ketones, acetonitrile, Examples thereof include esters, dimethyl sulfoxide and aliphatic hydrocarbons, and these may be used as a mixture.
The amount of boron trifluoride diethyl ether complex used may be 1 to 100 times mol, preferably 3 to 10 times mol, of the compound of general formula [10].
This reaction is usually carried out at −78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.
（９－２Ｃ）
　一般式［１］の化合物におけるＹ（一般式［１ｊ］の化合物におけるＹｂに相当）が－Ｃ（Ｓ）－Ｏ－である場合、一般式［１ｊ］の化合物は、一般式［１０］の化合物を、塩基の存在下、１，１’－チオカルボニルジイミダゾールと反応させることにより製造することができる。 (9-2C)
When Y in the compound of the general formula [1] (corresponding to Y b in the compound of the general formula [1j]) is —C (S) —O—, the compound of the general formula [1j] Can be produced by reacting the compound with 1,1′-thiocarbonyldiimidazole in the presence of a base.
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ケトン類、アセトニトリル、エステル類、ジメチルスルホキシドおよび脂肪族炭化水素類などがあげられ、これらは混合して使用してもよい。
　この反応において所望により用いられる塩基としては、たとえば、水酸化ナトリウム、水酸化カリウムおよび水酸化リチウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウムおよび炭酸セシウムなどの無機塩基ならびに１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンおよびピリジンなどの有機塩基が挙げられる。塩基の使用量は、一般式［１０］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　１，１’－チオカルボニルジイミダゾールの使用量は、一般式［１０］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　この反応は、通常、－78～150℃、好ましくは、0～120℃で、10分間～24時間実施すればよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, ketones, acetonitrile, Examples thereof include esters, dimethyl sulfoxide and aliphatic hydrocarbons, and these may be used as a mixture.
Examples of the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5. 4.0] -7-undecene, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, N, N-diisopropylethylamine and organic bases such as pyridine. The amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [10].
The amount of 1,1′-thiocarbonyldiimidazole used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of general formula [10].
This reaction is usually carried out at −78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.
（９－２Ｄ）
　一般式［１］の化合物におけるＹ（一般式［１ｊ］の化合物におけるＹｂに相当）が－Ｓ（Ｏ）－Ｏ－である場合、一般式［１ｊ］の化合物は、一般式［１０］の化合物を、塩基の存在下または不存在下、塩化チオニルと反応させることにより製造することができる。 (9-2D)
When Y in the compound of the general formula [1] (corresponding to Y b in the compound of the general formula [1j]) is —S (O) —O—, the compound of the general formula [1j] Can be prepared by reacting with thionyl chloride in the presence or absence of a base.
　この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、たとえば、芳香族炭化水素類、アミド類、ハロゲン化炭化水素類、エーテル類、ケトン類、アセトニトリル、エステル類、ジメチルスルホキシドおよび脂肪族炭化水素類などがあげられ、これらは混合して使用してもよい。
　この反応において所望により用いられる塩基としては、たとえば、水酸化ナトリウム、水酸化カリウムおよび水酸化リチウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウムおよび炭酸セシウムなどの無機塩基ならびに１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンおよびピリジンなどの有機塩基が挙げられる。塩基の使用量は、一般式［１０］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　塩化チオニルの使用量は、一般式［１０］の化合物に対して、1～100倍モル、好ましくは、1～10倍モルであればよい。
　この反応は、通常、－78～150℃、好ましくは、0～120℃で、10分間～24時間実施すればよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons, amides, halogenated hydrocarbons, ethers, ketones, acetonitrile, Examples thereof include esters, dimethyl sulfoxide and aliphatic hydrocarbons, and these may be used as a mixture.
Examples of the base optionally used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and 1,8-diazabicyclo [5. 4.0] -7-undecene, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, N, N-diisopropylethylamine and organic bases such as pyridine. The amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [10].
The amount of thionyl chloride to be used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of general formula [10].
This reaction is usually carried out at −78 to 150 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.
　次に、本発明化合物の製造原料の製造法について説明する。 Next, a method for producing a raw material for producing the compound of the present invention will be described.
［製造法Ａ］
Figure JPOXMLDOC01-appb-C000015
 「式中、Ｒ３、Ｒ６、Ｒａ、Ｒｂ、Ｒｃ、Ｌ１、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production method A]
Figure JPOXMLDOC01-appb-C000015
 “Wherein R 3 , R 6 , R a , R b , R c , L 1 , Y, Z 1 and Z 2 have the same meaning as described above.
　一般式［１２］の化合物として、たとえば、２－アミノ－４－クロロベンゾニトリルおよび３－アミノ－５－ブロモ－２－ピリジンカルボニトリルなどが知られている。 As compounds of general formula [12], for example, 2-amino-4-chlorobenzonitrile and 3-amino-5-bromo-2-pyridinecarbonitrile are known.
　（Ａ－１）
　一般式［１１］の化合物は、製造法８または９に準じて、一般式［１２］の化合物をアジド等と反応させることにより製造することができる。 (A-1)
The compound of the general formula [11] can be produced by reacting the compound of the general formula [12] with azide or the like according to production method 8 or 9.
　（Ａ－２）
　一般式［６ａ］の化合物は、製造法１に準じて、一般式［１１］の化合物を一般式［３ａ］または［３ｂ］の化合物と反応させることにより製造することができる。 (A-2)
The compound of the general formula [6a] can be produced by reacting the compound of the general formula [11] with the compound of the general formula [3a] or [3b] according to the production method 1.
［製造法Ｂ］
Figure JPOXMLDOC01-appb-C000016
 「式中、Ｒ１、Ｒ３、Ｒ６、Ｒａ、Ｒｂ、Ｌ１、Ｘ２、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production method B]
Figure JPOXMLDOC01-appb-C000016
 “Wherein R 1 , R 3 , R 6 , R a , R b , L 1 , X 2 , Z 1 and Z 2 have the same meaning as described above.
（Ｂ－１）
　一般式［１３］の化合物は、製造法１に準じて、一般式［１２］の化合物を一般式［３ａ］または［３ｂ］の化合物と反応させることにより製造することができる。 (B-1)
The compound of the general formula [13] can be produced by reacting the compound of the general formula [12] with the compound of the general formula [3a] or [3b] according to the production method 1.
（Ｂ－２）
　一般式［９ａ］の化合物は、前記（７－１）に記載した方法に準じて、一般式［１３］の化合物を一般式［８］の化合物またはその酸ハロゲン化物と反応させることにより製造することができる。 (B-2)
The compound of the general formula [9a] is produced by reacting the compound of the general formula [13] with the compound of the general formula [8] or an acid halide thereof according to the method described in (7-1) above. be able to.
［製造法Ｃ］
Figure JPOXMLDOC01-appb-C000017
 「式中、Ｒ２、Ｒ３、Ｒｃ、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method C]
Figure JPOXMLDOC01-appb-C000017
 “Wherein R 2 , R 3 , R c , Y, Z 1 and Z 2 have the same meaning as described above.”
　（Ｃ－１）
　一般式［１４］の化合物は、たとえば、製造法１に準じて、一般式［１２］の化合物を一般式［３ａ］または［３ｂ］の化合物と反応させることにより製造することができる。 (C-1)
The compound of the general formula [14] can be produced, for example, by reacting the compound of the general formula [12] with the compound of the general formula [3a] or [3b] according to the production method 1.
　（Ｃ－２）
　一般式［１５］の化合物は、製造法８または９に準じて、一般式［１４］の化合物をアジド等と反応させることにより製造することができる。 (C-2)
The compound of the general formula [15] can be produced by reacting the compound of the general formula [14] with azide or the like according to production method 8 or 9.
　（Ｃ－３）
　一般式［６ｂ］の化合物は、一般式［１５］の化合物の酸性イミノ基を保護することにより製造することができる。
　たとえば、Ｗ．グリーン（W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第872～894頁、2007年、ジョン・ウィリイ・アンド・サンズ社（John Wiley & Sons,INC.）に記載の方法などが挙げられる。 (C-3)
The compound of the general formula [6b] can be produced by protecting the acidic imino group of the compound of the general formula [15].
For example, W.W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 872-894, 2007, John Wiley & Sons, INC.).
［製造法Ｄ］
Figure JPOXMLDOC01-appb-C000018
 「式中、Ｒ１、Ｒ３、Ｌ１、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method D]
Figure JPOXMLDOC01-appb-C000018
 “Wherein R 1 , R 3 , L 1 , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
　（Ｄ－１）
　一般式［１６］の化合物は、前記（７－１）に記載した方法に準じて、一般式［１２］の化合物を一般式［８］の化合物またはその酸ハロゲン化物と反応させることにより製造することができる。 (D-1)
The compound of the general formula [16] is produced by reacting the compound of the general formula [12] with the compound of the general formula [8] or an acid halide thereof according to the method described in the above (7-1). be able to.
　（Ｄ－２）
　一般式［２ａ］の化合物は、製造法８または９に準じて、一般式［１６］の化合物をアジド等と反応させることにより製造することができる。 (D-2)
The compound of the general formula [2a] can be produced by reacting the compound of the general formula [16] with azide or the like according to production method 8 or 9.
［製造法Ｅ］
Figure JPOXMLDOC01-appb-C000019
 「式中、Ｒ１、Ｒ２、Ｌ２、Ｘ２、Ｙ、Ｚ１およびＺ２は、前記と同様の意味を有する。」 [Production Method E]
Figure JPOXMLDOC01-appb-C000019
 “Wherein R 1 , R 2 , L 2 , X 2 , Y, Z 1 and Z 2 have the same meaning as described above.
　（Ｅ－１）
　一般式［１７］の化合物として、たとえば、２－アミノ－５－クロロベンゾニトリル、２－アミノ－５－ブロモベンゾニトリルおよび２－アミノ－５－ブロモニコチノニトリルなどが知られている。
　一般式［１８］の化合物は、前記（７－１）に記載した方法に準じて、一般式［１７］の化合物を一般式［８］の化合物またはその酸ハロゲン化物と反応させることにより製造することができる。 (E-1)
As compounds of the general formula [17], for example, 2-amino-5-chlorobenzonitrile, 2-amino-5-bromobenzonitrile, 2-amino-5-bromonicotinonitrile and the like are known.
The compound of the general formula [18] is produced by reacting the compound of the general formula [17] with the compound of the general formula [8] or an acid halide thereof according to the method described in the above (7-1). be able to.
　（Ｅ－２）
　一般式［４ａ］の化合物は、製造法８または９に準じて、一般式［１８］の化合物をアジド等と反応させることにより製造することができる。 (E-2)
The compound of the general formula [4a] can be produced by reacting the compound of the general formula [18] with azide or the like according to the production method 8 or 9.
　上記した製造法で使用される化合物において、塩の形態を取り得る化合物は、塩として使用することもできる。それらの塩としては、たとえば、一般式［１］の化合物の塩と同様の塩が挙げられる。 In the compounds used in the above production method, a compound that can take the form of a salt can also be used as a salt. Examples of such salts include the same salts as the salts of the compound of the general formula [1].
　上記した製造法で使用される化合物において、異性体（たとえば、光学異性体、幾何異性体および互変異性体など）が存在する場合、これらの異性体も使用することができる。また、溶媒和物、水和物および種々の形状の結晶が存在する場合、これらの溶媒和物、水和物および種々の形状の結晶も使用することができる。また、上記した製造法で使用される化合物において、保護し得る置換基、たとえば、アミノ基、ヒドロキシル基またはカルボキシル基などを有している化合物は、予めこれらの基を通常の保護基で保護しておき、反応後、自体公知の方法でこれらの保護基を脱離することもできる。 In the compounds used in the above production method, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), these isomers can also be used. Also, when solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used. In addition, in the compounds used in the above-described production method, a compound having a substituent that can be protected, such as an amino group, a hydroxyl group, or a carboxyl group, is previously protected with a normal protecting group. In addition, after the reaction, these protecting groups can be removed by a method known per se.
　上記した製造法で得られる化合物またはそれらの塩は、たとえば、縮合、付加、酸化、還元、転位、置換、ハロゲン化、脱水または加水分解などの自体公知の反応に付すことによって、またはそれらの反応を適宜組み合わせることによって、他の化合物またはその塩に誘導することができる。 The compound obtained by the above-described production method or a salt thereof is subjected to a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or those reactions. Can be derived into other compounds or salts thereof by appropriately combining.
　本発明化合物を医薬として用いる場合、通常、薬理学的に許容される添加物を適宜混合してもよい。
　添加物としては、たとえば、賦形剤、崩壊剤、結合剤、滑沢剤、矯味剤、着色剤、着香剤、界面活性剤、コーティング剤および可塑剤が挙げられる。
　賦形剤としては、エリスリトール、マンニトール、キシリトールおよびソルビトールなどの糖アルコール類；白糖、粉糖、乳糖およびブドウ糖などの糖類；α－シクロデキストリン、β－シクロデキストリン、γ－シクロデキストリン、ヒドロキシプロピルβ－シクロデキストリンおよびスルホブチルエーテルβ－シクロデキストリンナトリウムなどのシクロデキストリン類；結晶セルロースおよび微結晶セルロースなどのセルロース類；ならびにトウモロコシデンプン、バレイショデンプンおよびアルファー化デンプンなどのでんぷん類などが挙げられる。
　崩壊剤としては、たとえば、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、クロスポピドン、低置換度ヒドロキシプロピルセルロースおよび部分α化デンプンが挙げられる。
　結合剤としては、たとえば、ヒドロキシプロピルセルロース、カルメロースナトリウムおよびメチルセルロースが挙げられる。
　滑沢剤としては、たとえば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、含水二酸化ケイ素、軽質無水ケイ酸およびショ糖脂肪酸エステルが挙げられる。
　矯味剤としては、たとえば、アスパルテーム、サッカリン、ステビア、ソーマチンおよびアセスルファムカリウムが挙げられる。
　着色剤としては、たとえば、二酸化チタン、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、食用赤色102号、食用黄色４号および食用黄色５号が挙げられる。
　着香剤としては、たとえば、オレンジ油、レモン油、ハッカ油およびパインオイルなどの精油；オレンジエッセンスおよびペパーミントエッセンスなどのエッセンス；チェリーフレーバー、バニラフレーバーおよびフルーツフレーバーなどのフレーバー；アップルミクロン、バナナミクロン、ピーチミクロン、ストロベリーミクロンおよびオレンジミクロンなどの粉末香料；バニリン；ならびにエチルバニリンが挙げられる。
　界面活性剤としては、たとえば、ラウリル硫酸ナトリウム、スルホコハク酸ジオクチルナトリウム、ポリソルベートおよびポリオキシエチレン硬化ヒマシ油が挙げられる。
　コーティング剤としては、たとえば、ヒドロキシプロピルメチルセルロース、アミノアルキルメタクリレートコポリマーＥ、アミノアルキルメタクリレートコポリマーＲＳ、エチルセルロース、酢酸フタル酸セルロース、ヒドロキシプロピルメチルセルロースフタレート、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤおよびメタクリル酸コポリマーＳが挙げられる。
　可塑剤としては、たとえば、クエン酸トリエチル、マクロゴール、トリアセチンおよびプロピレングリコールが挙げられる。
　これらの添加物は、いずれか一種または二種以上を組み合わせて用いてもよい。
　配合量は、特に限定されず、それぞれの目的に応じ、その効果が充分に発現されるよう適宜配合すればよい。
　これらは常法にしたがって、錠剤、カプセル剤、散剤、シロップ剤、顆粒剤、丸剤、懸濁剤、乳剤、液剤、粉体製剤、坐剤、点眼剤、点鼻剤、点耳剤、貼付剤、軟膏剤または注射剤などの形態で経口または非経口で投与することができる。また投与方法、投与量および投与回数は、患者の年齢、体重および症状に応じて適宜選択することができる。通常、成人に対しては、経口または非経口（たとえば、注射、点滴および直腸部位への投与など）投与により、１日、0.01～1000mg／kgを１回から数回に分割して投与すればよい。 When the compound of the present invention is used as a medicine, usually pharmacologically acceptable additives may be appropriately mixed.
Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a corrigent, a coloring agent, a flavoring agent, a surfactant, a coating agent, and a plasticizer.
Excipients include sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and glucose; α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl β- Cyclodextrins such as cyclodextrin and sulfobutyl ether β-cyclodextrin sodium; celluloses such as crystalline cellulose and microcrystalline cellulose; and starches such as corn starch, potato starch and pregelatinized starch.
Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, and partially pregelatinized starch.
Examples of the binder include hydroxypropylcellulose, carmellose sodium and methylcellulose.
Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, light anhydrous silicic acid, and sucrose fatty acid ester.
Examples of the corrigent include aspartame, saccharin, stevia, thaumatin and acesulfame potassium.
Examples of the colorant include titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, food red No. 102, food yellow No. 4, and food yellow No. 5.
Flavoring agents include, for example, essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, Powder fragrances such as peach micron, strawberry micron and orange micron; vanillin; and ethyl vanillin.
Examples of the surfactant include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate and polyoxyethylene hydrogenated castor oil.
Examples of the coating agent include hydroxypropyl methylcellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S. Can be mentioned.
Examples of the plasticizer include triethyl citrate, macrogol, triacetin, and propylene glycol.
These additives may be used alone or in combination of two or more.
The blending amount is not particularly limited, and may be blended appropriately so that the effect is sufficiently exhibited according to each purpose.
These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg daily may be divided into 1 to several doses. Good.
　次に、本発明の代表的化合物の有用性を以下の試験例で説明する。 Next, the usefulness of the representative compounds of the present invention will be explained by the following test examples.
試験例１　I型コラーゲンα1鎖mRNA発現阻害試験
　ヒト胎児肺線維芽細胞株WI-38細胞を10％牛胎児血清含有ダルベッコ改変イーグル培地に懸濁し、12ウェルプレートに7.0×104個播種し3日間培養した。細胞がサブコンフルエントの状態になった後に、0.4％牛胎児血清および50μg/mLアスコルビン酸を含有するダルベッコ改変イーグル培地に交換し、さらに24時間培養した。その後、試験化合物を添加し、1時間後にTGF-β1を終濃度1ng/mLになるように添加した。添加24時間後にRNA抽出キット（SV Total RNA Isolation System、Promega）を用い、細胞から総RNAを抽出し、さらに逆転写酵素（PrimeScript RT Master Mix (Perfect Real Time)、TaKaRa）を用いてcDNAを合成した。I型コラーゲンα1鎖mRNAの発現レベルは、リアルタイムPCR装置（StepOnePlus、Applied Biosystems）を用い、リアルタイムPCR用プレミックス試薬（SYBR Premix Ex Taq II（Perfect Real TimeまたはTli RNaseH Plus)、TaKaRa）を利用したリアルタイムPCR法により解析した。希釈したcDNAをテンプレートとして、I型コラーゲンα1鎖遺伝子あるいは内部標準としてGAPDH遺伝子に特異的なプライマーを用いてPCR反応を行い、その反応産物を測定した。PCR反応は、インキュベーション95℃10秒の後、変性95℃1秒、アニーリング／伸長60℃20秒を40サイクル行った。I型コラーゲンα1鎖mRNAの発現レベルはGAPDHで補正し、さらに試験化合物不存在下で得られる発現レベルを100％としたときの相対値で表した。
　結果を表１－１および表１－２に示す。 Test Example 1 Type I Collagen α1 Chain mRNA Expression Inhibition Test Human fetal lung fibroblast cell line WI-38 cells were suspended in Dulbecco's modified Eagle's medium containing 10% fetal calf serum, and seeded 7.0 × 10 4 in a 12-well plate. Cultured for days. After the cells became subconfluent, the cells were replaced with Dulbecco's modified Eagle's medium containing 0.4% fetal bovine serum and 50 μg / mL ascorbic acid, and further cultured for 24 hours. Thereafter, a test compound was added, and after 1 hour, TGF-β1 was added to a final concentration of 1 ng / mL. 24 hours after addition, total RNA was extracted from cells using an RNA extraction kit (SV Total RNA Isolation System, Promega), and cDNA was synthesized using reverse transcriptase (PrimeScript RT Master Mix (Perfect Real Time), TaKaRa). did. The expression level of type I collagen α1 chain mRNA was measured using a real-time PCR device (StepOnePlus, Applied Biosystems) and a real-time PCR premix reagent (SYBR Premix Ex Taq II (Perfect Real Time or Tli RNaseH Plus), TaKaRa). Analysis was performed by real-time PCR. A PCR reaction was performed using the diluted cDNA as a template and a primer specific for the type I collagen α1 chain gene or the GAPDH gene as an internal standard, and the reaction product was measured. The PCR reaction was carried out for 40 cycles of incubation at 95 ° C. for 10 seconds, denaturation at 95 ° C. for 1 second, and annealing / extension at 60 ° C. for 20 seconds. The expression level of type I collagen α1 chain mRNA was corrected by GAPDH, and expressed as a relative value when the expression level obtained in the absence of the test compound was taken as 100%.
The results are shown in Table 1-1 and Table 1-2.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
　本発明に用いられる化合物は、優れたコラーゲン産生阻害作用を示した。 The compound used in the present invention showed an excellent collagen production inhibitory action.
試験例２　ラットブレオマイシン誘発肺線維症
　7週齢の雄性SDラット（日本エスエルシー）を使用した。ブレオマイシン（日本化薬）を生理食塩液で溶解し、Microsprayer（Microsprayer model IA-IC、Penn-Century）を用いて、10mg/kgをラット気管内に投与して肺線維症を惹起した。試験化合物を水に溶解あるいは懸濁し、5mg/kg（塩の場合はフリー体換算）を惹起28日後から42日後まで1日2回経口投与した。対照群には、水を同様に投与した。惹起42日後に肺を採取し、ホモジネートを作製してヒドロキシプロリンの定量を行った。6N塩酸にて110℃16時間インキュベートし、遠心式濃縮器を用いて留去、乾固物を蒸留水に溶解して測定サンプルとした。測定サンプルにクロラミンT溶液を加え、室温20分間インキュベート後、過塩素酸溶液を加え、室温5分間インキュベート、さらにp-ジメチルアミノベンズアルデヒド溶液を加え、60℃20分間インキュベートした。反応を冷却停止し、マイクロプレートリーダーを用いて570nmの吸光度を測定した。測定サンプル中のヒドロキシプロリン量はヒドロキシプロリン標準溶液の吸光度から検量線を作成して算出した。
　抑制率は、以下の式で求めた。
式　抑制率（％）＝（1－試験化合物投与群の肺ヒドロキシプロリン量／対照群の肺ヒドロキシプロリン量）×100
　実施例２６のナトリウム塩、実施例４１のナトリウム塩および実施例６２のナトリウム塩の投与群の肺ヒドロキシプロリン量は、対照群に比べ20％以上低値であった。 Test Example 2 Rat Bleomycin-Induced Pulmonary Fibrosis Seven week old male SD rats (Japan SLC) were used. Bleomycin (Nippon Kayaku) was dissolved in physiological saline, and 10 mg / kg was administered into rat trachea using Microsprayer (Microsprayer model IA-IC, Penn-Century) to induce pulmonary fibrosis. The test compound was dissolved or suspended in water, and 5 mg / kg (in the form of free form in the case of a salt) was orally administered twice a day from 28 days to 42 days after induction. In the control group, water was similarly administered. Lungs were collected 42 days after induction, homogenates were prepared, and hydroxyproline was quantified. The mixture was incubated with 6N hydrochloric acid at 110 ° C. for 16 hours, distilled using a centrifugal concentrator, and the dried product was dissolved in distilled water to obtain a measurement sample. A chloramine T solution was added to the measurement sample, incubated at room temperature for 20 minutes, then a perchloric acid solution was added, incubated at room temperature for 5 minutes, further added with p-dimethylaminobenzaldehyde solution, and incubated at 60 ° C. for 20 minutes. The reaction was cooled and the absorbance at 570 nm was measured using a microplate reader. The amount of hydroxyproline in the measurement sample was calculated by creating a calibration curve from the absorbance of the hydroxyproline standard solution.
The suppression rate was calculated | required with the following formula | equation.
Formula Inhibition rate (%) = (1−Lung hydroxyproline amount in test compound administration group / Lung hydroxyproline amount in control group) × 100
The amount of pulmonary hydroxyproline in the group administered with the sodium salt of Example 26, the sodium salt of Example 41 and the sodium salt of Example 62 was 20% or more lower than that of the control group.
試験例３　反応性代謝物
　プールドヒト肝ミクロソーム（Celsis In Vitro Technologies社）を用いて、試験化合物を一定時間反応させ、放射能標識グルタチオンとのアダクト生成物量を算出し、反応性代謝物が生成する程度を評価した。
　1mgまたは2mgタンパク質/mLプールドヒト肝ミクロソーム、1.55mM NADP+（ニコチンアミドアデニンヌクレオチドリン酸 酸化型）、3.3mM G6P（グルコース-6-リン酸）、3.3mM MgCl2、0.4U/mL G6PDH（グルコース-6-リン酸デヒドロゲナーゼ）、100μMグルタチオンおよび40μMシアン化カリウムを含むリン酸カリウム緩衝液（pH7.4）0.12mLまたは0.15mLに、50μMまたは100μM化合物を加え、37℃で60分間または120分間反応させた。反応液を氷上に静置し、反応を停止し、固相抽出カラム（OASIS HLB、10mg；Waters社）に添加した。反応性代謝物と放射性標識グルタチオンとのアダクト生成物をカラムに保持させ、蒸留水で洗浄した後、メタノール/アセトニトリルで溶出した。溶出液中の放射能を液体シンチレーションカウンター（PerkinElmer社）で測定し、アダクト生成物量を計算した。
　実施例３、実施例１４、実施例１６、実施例２６、実施例３３、実施例３９、実施例４１、実施例４９、実施例５５、実施例６２、実施例６４、実施例７０、実施例７１、実施例８８、実施例９１、実施例９２、実施例９８、実施例１０２、実施例１０３、実施例１０８、実施例１１０、実施例１１２、実施例１１３、実施例１２２、実施例１２７、実施例１９２および実施例２２５の化合物は、グルタチオンとのアダクト生成量が10pmol以下であり、反応性代謝物を生成しにくかった。
　本発明の化合物は、優れた代謝安定性を示した。 Test Example 3 Reactive Metabolite Using pooled human liver microsomes (Celsis In Vitro Technologies), the test compound is reacted for a certain period of time, the amount of adduct product with radiolabeled glutathione is calculated, and the extent to which reactive metabolite is produced Evaluated.
1 mg or 2 mg protein / mL pooled human liver microsomes, 1.55 mM NADP + (nicotinamide adenine nucleotide phosphate oxidized form), 3.3 mM G6P (glucose-6-phosphate), 3.3 mM MgCl 2 , 0.4 U / mL G6PDH (glucose − 6-phosphate dehydrogenase), 100 μM glutathione and 40 μM potassium cyanide buffer solution (pH 7.4) 0.12 mL or 0.15 mL was added with 50 μM or 100 μM compound and reacted at 37 ° C. for 60 or 120 minutes. The reaction solution was allowed to stand on ice to stop the reaction, and added to a solid phase extraction column (OASIS HLB, 10 mg; Waters). The adduct product of the reactive metabolite and radiolabeled glutathione was retained on the column, washed with distilled water, and eluted with methanol / acetonitrile. The radioactivity in the eluate was measured with a liquid scintillation counter (PerkinElmer), and the amount of adduct product was calculated.
Example 3, Example 14, Example 16, Example 26, Example 33, Example 39, Example 41, Example 49, Example 55, Example 62, Example 64, Example 70, Example 71, Example 88, Example 91, Example 92, Example 98, Example 102, Example 103, Example 108, Example 110, Example 112, Example 113, Example 122, Example 127, In the compounds of Example 192 and Example 225, the amount of adduct produced with glutathione was 10 pmol or less, and it was difficult to produce a reactive metabolite.
The compounds of the present invention showed excellent metabolic stability.
　次に、本発明を参考例および実施例を挙げて説明するが、本発明はこれらに限定されるものではない。
　溶離液における混合比は、容量比である。例えば、「溶離液；97-60％ヘキサン／酢酸エチル」は、97％ヘキサン／3％酢酸エチルの溶離液を最終的に60％ヘキサン／40％酢酸エチルの溶離液へ変化させたことを意味する。特に記載のない場合、シリカゲルカラムクロマトグラフィーにおける担体は、富士シリシア化学株式会社、Ｐｕｒｉｆ－Ｐａｃｋ　ＳＩ（60μm）である。
　各実施例において各略号は、以下の意味を有する。
　Ｂｎ：ベンジル、Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル、Ｂｕ：ブチル、ｔＢｕ：ｔｅｒｔ－ブチル、Ｅｔ：エチル、ｉＰｒ：イソプロピル、Ｍｅ：メチル、Ｐｒ：プロピル、DMSO-d6：重ジメチルスルホキシド Next, the present invention will be described with reference examples and examples, but the present invention is not limited to these examples.
The mixing ratio in the eluent is a volume ratio. For example, “eluent: 97-60% hexane / ethyl acetate” means that the eluent of 97% hexane / 3% ethyl acetate was finally changed to the eluent of 60% hexane / 40% ethyl acetate. To do. Unless otherwise specified, the carrier in silica gel column chromatography is Fuji Silysia Chemical Ltd., Purif-Pack SI (60 μm).
In each example, each abbreviation has the following meaning.
Bn: benzyl, Boc: tert-butoxycarbonyl, Bu: butyl, t Bu: tert-butyl, Et: ethyl, i Pr: isopropyl, Me: methyl, Pr: propyl, DMSO-d 6: deuterated dimethyl sulfoxide
参考例１
Figure JPOXMLDOC01-appb-C000022
 　３－ニトロビフェニル－４－カルボン酸1.0gのテトラヒドロフラン10mL溶液に、Ｎ，Ｎ－ジメチルホルムアミド0.050mLおよびオキサリルクロリド0.54mLを順次加え、室温で1時間攪拌した。反応混合物にＮ，Ｎ－ジメチルホルムアミド0.050mLおよびオキサリルクロリド0.18mLを順次加え、室温で30分間攪拌した。反応混合物にＮ，Ｎ－ジメチルホルムアミド0.050mLを加え、室温で30分間攪拌した。減圧下で溶媒を留去し、テトラヒドロフラン10mLを加えた後、ベンジルアミン0.99mLのテトラヒドロフラン5.0mL溶液に加え、室温で2時間攪拌した。反応混合物に水および酢酸エチルを加えた。有機層を分取し、1.0mol/L塩酸、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体のＮ－ベンジル－３－ニトロビフェニル－４－カルボキサミド1.0gを得た。
1H-NMR(DMSO-d6)δ値：9.28(t,J=6.0Hz,1H),8.28(d,J=1.8Hz,1H),8.10(dd,J=8.0,1.8Hz,1H),7.84-7.78(m,2H),7.75(d,J=8.0Hz,1H),7.58-7.51(m,2H),7.51-7.45(m,1H),7.40-7.35(m,4H),7.32-7.24(m,1H),4.48(d,J=6.0Hz,2H). Reference example 1
Figure JPOXMLDOC01-appb-C000022
 To a solution of 1.0 g of 3-nitrobiphenyl-4-carboxylic acid in 10 mL of tetrahydrofuran were sequentially added 0.050 mL of N, N-dimethylformamide and 0.54 mL of oxalyl chloride, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 0.050 mL of N, N-dimethylformamide and 0.18 mL of oxalyl chloride were sequentially added, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 0.050 mL of N, N-dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, 10 mL of tetrahydrofuran was added, and then added to a 5.0 mL solution of benzylamine 0.99 mL in tetrahydrofuran, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 1.0 g of N-benzyl-3-nitrobiphenyl-4-carboxamide as a white solid.
1 H-NMR (DMSO-d 6 ) δ value: 9.28 (t, J = 6.0 Hz, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.10 (dd, J = 8.0, 1.8 Hz, 1H) , 7.84-7.78 (m, 2H), 7.75 (d, J = 8.0Hz, 1H), 7.58-7.51 (m, 2H), 7.51-7.45 (m, 1H), 7.40-7.35 (m, 4H), 7.32 -7.24 (m, 1H), 4.48 (d, J = 6.0Hz, 2H).
参考例２
Figure JPOXMLDOC01-appb-C000023
 　Ｎ－ベンジル－３－ニトロビフェニル－４－カルボキサミド1.4gのアセトニトリル30mL懸濁液に、アジ化ナトリウム0.53gを加え、窒素雰囲気下、同温度で30分間攪拌した。反応混合物に氷冷下、トリフルオロメタンスルホン酸無水物1.5mLを加え、同温度で30分間攪拌した。反応混合物に氷冷下、トリフルオロメタンスルホン酸無水物0.34mLを加え、同温度で30分間攪拌した。反応混合物にクロロホルム40mL、2mol/L水酸化ナトリウム水溶液30mLおよび水20mLを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にメタノールを加え、固形物をろ取し、白色固体の１－ベンジル－５－（３－ニトロビフェニル－４－イル）－１Ｈ－テトラゾール1.1gを得た。
1H-NMR(DMSO-d6)δ値：8.57(d,J=1.8Hz,1H),8.27(dd,J=8.1,1.8Hz,1H),7.92-7.87(m,2H),7.82(d,J=8.1Hz,1H),7.61-7.49(m,3H),7.33-7.26(m,3H),7.19-7.12(m,2H),5.64(s,2H). Reference example 2
Figure JPOXMLDOC01-appb-C000023
 To a suspension of 1.4 g of N-benzyl-3-nitrobiphenyl-4-carboxamide in 30 mL of acetonitrile was added 0.53 g of sodium azide, and the mixture was stirred at the same temperature for 30 minutes under a nitrogen atmosphere. To the reaction mixture, 1.5 mL of trifluoromethanesulfonic anhydride was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Under cooling with ice, 0.34 mL of trifluoromethanesulfonic anhydride was added to the reaction mixture, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 40 mL of chloroform, 30 mL of 2 mol / L aqueous sodium hydroxide solution and 20 mL of water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solid was collected by filtration to obtain 1.1 g of 1-benzyl-5- (3-nitrobiphenyl-4-yl) -1H-tetrazole as a white solid.
1 H-NMR (DMSO-d 6 ) δ value: 8.57 (d, J = 1.8 Hz, 1H), 8.27 (dd, J = 8.1, 1.8 Hz, 1H), 7.92-7.87 (m, 2H), 7.82 ( d, J = 8.1Hz, 1H), 7.61-7.49 (m, 3H), 7.33-7.26 (m, 3H), 7.19-7.12 (m, 2H), 5.64 (s, 2H).
参考例３
Figure JPOXMLDOC01-appb-C000024
 　１－ベンジル－５－（３－ニトロビフェニル－４－イル）－１Ｈ－テトラゾール0.89gのテトラヒドロフラン10mL、メタノール5.0mLおよび酢酸エチル5.0mL混液に、10％パラジウム－炭素0.090gを加え、水素雰囲気下、室温で3時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルおよびメタノールを加え、固形物をろ取し、白色固体の４－（１－ベンジル－１Ｈ－テトラゾール－５－イル）ビフェニル－３－アミン0.72gを得た。
1H-NMR(DMSO-d6)δ値：7.67-7.61(m,2H),7.52-7.44(m,2H),7.43-7.37(m,1H),7.36-7.28(m,3H),7.26(d,J=8.3Hz,1H),7.17(d,J=1.7Hz,1H),7.14-7.09(m,2H),6.94(dd,J=8.0,1.2Hz,1H),5.83(s,2H),5.68(s,2H). Reference example 3
Figure JPOXMLDOC01-appb-C000024
 To a mixture of 0.89 g of 1-benzyl-5- (3-nitrobiphenyl-4-yl) -1H-tetrazole in tetrahydrofuran (10 mL), methanol (5.0 mL) and ethyl acetate (5.0 mL) was added 10% palladium-carbon (0.090 g) under a hydrogen atmosphere. And stirred at room temperature for 3 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Diisopropyl ether and methanol were added to the obtained residue, and the solid was collected by filtration to obtain 0.72 g of 4- (1-benzyl-1H-tetrazol-5-yl) biphenyl-3-amine as a white solid.
1 H-NMR (DMSO-d 6 ) δ value: 7.67-7.61 (m, 2H), 7.52-7.44 (m, 2H), 7.43-7.37 (m, 1H), 7.36-7.28 (m, 3H), 7.26 (d, J = 8.3Hz, 1H), 7.17 (d, J = 1.7Hz, 1H), 7.14-7.09 (m, 2H), 6.94 (dd, J = 8.0,1.2Hz, 1H), 5.83 (s, 2H), 5.68 (s, 2H).
参考例４
Figure JPOXMLDOC01-appb-C000025
 　３－（ジメチルアミノ）安息香酸0.053gのテトラヒドロフラン2mL溶液に、Ｎ，Ｎ－ジメチルホルムアミド0.010mLおよびオキサリルクロリド0.034mLを順次加え、室温で40分間攪拌した。反応混合物にオキサリルクロリド0.034mLを加え、室温で20分間攪拌した。減圧下で溶媒を留去し、トルエンを加えた。減圧下で溶媒を留去し、テトラヒドロフラン2mLを加えた後、３－アミノビフェニル－４－カルボニトリル0.052gのピリジン0.037mLおよびテトラヒドロフラン1mL混液に加え、室温で3時間攪拌した。反応混合物に水を加え、飽和炭酸水素ナトリウム水溶液でpH8に調整後、減圧下で溶媒を留去した。得られた残留物に酢酸エチルおよび水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-60％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（４－シアノビフェニル－３－イル）－３－（ジメチルアミノ）ベンズアミド0.030gを得た。
1H-NMR(DMSO-d6)δ値：10.54(s,1H),7.96(d,J=8.0Hz,1H),7.92-7.88(m,1H),7.79-7.71(m,3H),7.57-7.50(m,2H),7.50-7.44(m,1H),7.36(dd,J=7.9,7.9Hz,1H),7.33-7.27(m,2H),7.01-6.95(m,1H),2.98(s,6H). Reference example 4
Figure JPOXMLDOC01-appb-C000025
 0.02 mL of N, N-dimethylformamide and 0.034 mL of oxalyl chloride were sequentially added to a solution of 0.053 g of 3- (dimethylamino) benzoic acid in 2 mL of tetrahydrofuran and stirred at room temperature for 40 minutes. 0.034 mL of oxalyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and toluene was added. The solvent was distilled off under reduced pressure, and 2 mL of tetrahydrofuran was added. Then, 0.052 g of 3-aminobiphenyl-4-carbonitrile was added to 0.037 mL of pyridine and 1 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, the pH was adjusted to 8 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the obtained residue. The organic layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-60% hexane / ethyl acetate], and white solid N- (4-cyanobiphenyl-3 0.030 g of -yl) -3- (dimethylamino) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.54 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.92-7.88 (m, 1H), 7.79-7.71 (m, 3H), 7.57-7.50 (m, 2H), 7.50-7.44 (m, 1H), 7.36 (dd, J = 7.9,7.9Hz, 1H), 7.33-7.27 (m, 2H), 7.01-6.95 (m, 1H), 2.98 (s, 6H).
参考例５～２１
　参考例４と同様にして、表２に示す化合物を得た。 Reference Examples 5-21
In the same manner as in Reference Example 4, the compounds shown in Table 2 were obtained.
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Ｎ－（４－シアノビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.50(s,1H),7.96(d,J=8.1Hz,1H),7.92(d,J=1.7Hz,1H),7.78-7.74(m,2H),7.73(dd,J=8.1,1.7Hz,1H),7.57-7.50(m,2H),7.50-7.44(m,1H),7.33(dd,J=7.9,7.9Hz,1H),7.27-7.19(m,2H),6.91(dd,J=8.3,2.4Hz,1H),3.41(q,J=7.0Hz,4H),1.12(t,J=7.0Hz,6H). N- (4-Cyanobiphenyl-3-yl) -3- (diethylamino) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.50 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.78-7.74 (m, 2H), 7.73 (dd, J = 8.1, 1.7Hz, 1H), 7.57-7.50 (m, 2H), 7.50-7.44 (m, 1H), 7.33 (dd, J = 7.9, 7.9Hz, 1H), 7.27 -7.19 (m, 2H), 6.91 (dd, J = 8.3,2.4Hz, 1H), 3.41 (q, J = 7.0Hz, 4H), 1.12 (t, J = 7.0Hz, 6H).
Ｎ－（４－シアノビフェニル－３－イル）－３－ニトロベンズアミド
1H-NMR(DMSO-d6)δ値：8.95-8.91(m,1H),8.54(d,J=7.8Hz,1H),8.38-8.31(m,2H),7.79-7.68(m,4H),7.54-7.47(m,2H),7.46-7.34(m,2H). N- (4-Cyanobiphenyl-3-yl) -3-nitrobenzamide
1 H-NMR (DMSO-d 6 ) δ value: 8.95-8.91 (m, 1H), 8.54 (d, J = 7.8 Hz, 1H), 8.38-8.31 (m, 2H), 7.79-7.68 (m, 4H ), 7.54-7.47 (m, 2H), 7.46-7.34 (m, 2H).
Ｎ－（４－シアノビフェニル－３－イル）－３－（ピロリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.52(s,1H),7.96(d,J=8.0Hz,1H),7.90(d,J=1.7Hz,1H),7.79-7.71(m,3H),7.57-7.50(m,2H),7.50-7.44(m,1H),7.34(dd,J=7.9,7.9Hz,1H),7.26-7.21(m,1H),7.16-7.12(m,1H),6.81-6.75(m,1H),3.32-3.27(m,4H),2.02-1.96(m,4H). N- (4-Cyanobiphenyl-3-yl) -3- (pyrrolidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.52 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.79-7.71 (m, 3H), 7.57-7.50 (m, 2H), 7.50-7.44 (m, 1H), 7.34 (dd, J = 7.9, 7.9Hz, 1H), 7.26-7.21 (m, 1H), 7.16-7.12 (m, 1H), 6.81-6.75 (m, 1H), 3.32-3.27 (m, 4H), 2.02-1.96 (m, 4H).
Ｎ－（４－シアノビフェニル－３－イル）－２－メチル－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.88(s,1H),7.99(s,1H),7.70-7.65(m,3H),7.52-7.41(m,4H),7.28-7.24(m,2H),7.17(dd,J=6.7,2.6Hz,1H),2.90-2.83(m,4H),2.48(s,3H),1.78-1.70(m,4H),1.64-1.56(m,2H). N- (4-Cyanobiphenyl-3-yl) -2-methyl-3- (piperidin-1-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.88 (s, 1H), 7.99 (s, 1H), 7.70-7.65 (m, 3H), 7.52-7.41 (m, 4H), 7.28-7.24 (m, 2H ), 7.17 (dd, J = 6.7, 2.6Hz, 1H), 2.90-2.83 (m, 4H), 2.48 (s, 3H), 1.78-1.70 (m, 4H), 1.64-1.56 (m, 2H).
２－クロロ－Ｎ－（４－シアノビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.90(s,1H),8.28(s,1H),7.71-7.65(m,3H),7.52-7.40(m,4H),7.36-7.31(m,2H),7.22-7.17(m,1H),3.04-2.97(m,4H),1.81-1.73(m,4H),1.65-1.57(m,2H). 2-Chloro-N- (4-cyanobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.90 (s, 1H), 8.28 (s, 1H), 7.71-7.65 (m, 3H), 7.52-7.40 (m, 4H), 7.36-7.31 (m, 2H) ), 7.22-7.17 (m, 1H), 3.04-2.97 (m, 4H), 1.81-1.73 (m, 4H), 1.65-1.57 (m, 2H).
Ｎ－（４－シアノビフェニル－３－イル）－２－メトキシ－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.80(s,1H),8.40-8.34(m,1H),7.96(d,J=8.0Hz,1H),7.77-7.71(m,2H),7.69-7.64(m,1H),7.58-7.51(m,2H),7.51-7.45(m,2H),7.25-7.17(m,2H),4.03(s,3H),3.07-2.99(m,4H),1.76-1.66(m,4H),1.60-1.52(m,2H). N- (4-Cyanobiphenyl-3-yl) -2-methoxy-3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.80 (s, 1H), 8.40-8.34 (m, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.77-7.71 (m, 2H), 7.69-7.64 (m, 1H), 7.58-7.51 (m, 2H), 7.51-7.45 (m, 2H), 7.25-7.17 (m, 2H), 4.03 (s, 3H), 3.07-2.99 (m, 4H ), 1.76-1.66 (m, 4H), 1.60-1.52 (m, 2H).
Ｎ－（４－シアノビフェニル－３－イル）－２－メチル－５－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.53(s,1H),7.95(d,J=8.1Hz,1H),7.92-7.88(m,1H),7.79-7.70(m,3H),7.58-7.51(m,2H),7.50-7.44(m,1H),7.18-7.11(m,2H),7.00(dd,J=8.3,2.4Hz,1H),3.19-3.12(m,4H),2.35(s,3H),1.68-1.59(m,4H),1.58-1.50(m,2H). N- (4-Cyanobiphenyl-3-yl) -2-methyl-5- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.53 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.92-7.88 (m, 1H), 7.79-7.70 (m, 3H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.18-7.11 (m, 2H), 7.00 (dd, J = 8.3, 2.4Hz, 1H), 3.19-3.12 (m, 4H), 2.35 (s, 3H), 1.68-1.59 (m, 4H), 1.58-1.50 (m, 2H).
２－クロロ－Ｎ－（４－シアノビフェニル－３－イル）－５－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.76(s,1H),7.99-7.91(m,2H),7.79-7.70(m,3H),7.59-7.51(m,2H),7.50-7.44(m,1H),7.34(d,J=8.8Hz,1H),7.17(d,J=2.9Hz,1H),7.08(dd,J=8.8,2.4Hz,1H),3.26-3.18(m,4H),1.67-1.51(m,6H). 2-Chloro-N- (4-cyanobiphenyl-3-yl) -5- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.76 (s, 1H), 7.99-7.91 (m, 2H), 7.79-7.70 (m, 3H), 7.59-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.34 (d, J = 8.8Hz, 1H), 7.17 (d, J = 2.9Hz, 1H), 7.08 (dd, J = 8.8,2.4Hz, 1H), 3.26-3.18 (m, 4H), 1.67-1.51 (m, 6H).
Ｎ－（４－シアノビフェニル－３－イル）－４－メチル－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.56(s,1H),7.98-7.94(m,1H),7.90-7.87(m,1H),7.79-7.72(m,3H),7.67-7.60(m,2H),7.57-7.50(m,2H),7.49-7.44(m,1H),7.35(d,J=7.8Hz,1H),2.90-2.83(m,4H),2.33(s,3H),1.73-1.65(m,4H),1.61-1.52(m,2H). N- (4-Cyanobiphenyl-3-yl) -4-methyl-3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.56 (s, 1H), 7.98-7.94 (m, 1H), 7.90-7.87 (m, 1H), 7.79-7.72 (m, 3H), 7.67-7.60 (m, 2H), 7.57-7.50 (m, 2H), 7.49-7.44 (m, 1H), 7.35 (d, J = 7.8Hz, 1H), 2.90-2.83 (m, 4H), 2.33 (s, 3H ), 1.73-1.65 (m, 4H), 1.61-1.52 (m, 2H).
Ｎ－（４－シアノビフェニル－３－イル）－４－メトキシ－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.94(d,J=1.5Hz,1H),8.42(s,1H),7.71-7.65(m,3H),7.60(d,J=2.2Hz,1H),7.57(dd,J=8.3,2.2Hz,1H),7.51-7.45(m,2H),7.45-7.40(m,2H),6.94(d,J=8.5Hz,1H),3.96(s,3H),3.09-3.02(m,4H),1.82-1.74(m,4H),1.64-1.57(m,2H). N- (4-Cyanobiphenyl-3-yl) -4-methoxy-3- (piperidin-1-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.94 (d, J = 1.5Hz, 1H), 8.42 (s, 1H), 7.71-7.65 (m, 3H), 7.60 (d, J = 2.2Hz, 1H) , 7.57 (dd, J = 8.3, 2.2Hz, 1H), 7.51-7.45 (m, 2H), 7.45-7.40 (m, 2H), 6.94 (d, J = 8.5Hz, 1H), 3.96 (s, 3H ), 3.09-3.02 (m, 4H), 1.82-1.74 (m, 4H), 1.64-1.57 (m, 2H).
Ｎ－（４－シアノビフェニル－３－イル）－６－（ピペリジン－１－イル）ピラジン－２－カルボキサミド
1H-NMR(CDCl3)δ値：10.59(s,1H),9.07(d,J=1.5Hz,1H),8.65(s,1H),8.39(s,1H),7.72-7.66(m,3H),7.52-7.46(m,2H),7.46-7.40(m,2H),3.80-3.71(m,4H),1.78-1.69(m,6H). N- (4-cyanobiphenyl-3-yl) -6- (piperidin-1-yl) pyrazine-2-carboxamide
1 H-NMR (CDCl 3 ) δ value: 10.59 (s, 1H), 9.07 (d, J = 1.5 Hz, 1H), 8.65 (s, 1H), 8.39 (s, 1H), 7.72-7.66 (m, 3H), 7.52-7.46 (m, 2H), 7.46-7.40 (m, 2H), 3.80-3.71 (m, 4H), 1.78-1.69 (m, 6H).
Ｎ－（４－シアノビフェニル－３－イル）－４－（ピペリジン－１－イル）ピリジン－２－カルボキサミド
1H-NMR(CDCl3)δ値：11.02(s,1H),9.00(d,J=1.7Hz,1H),8.28(d,J=6.1Hz,1H),7.72-7.65(m,4H),7.52-7.38(m,4H),6.77(dd,J=6.0,2.8Hz,1H),3.50-3.42(m,4H),1.73-1.63(m,6H). N- (4-Cyanobiphenyl-3-yl) -4- (piperidin-1-yl) pyridine-2-carboxamide
1 H-NMR (CDCl 3 ) δ value: 11.02 (s, 1H), 9.00 (d, J = 1.7Hz, 1H), 8.28 (d, J = 6.1Hz, 1H), 7.72-7.65 (m, 4H) , 7.52-7.38 (m, 4H), 6.77 (dd, J = 6.0, 2.8Hz, 1H), 3.50-3.42 (m, 4H), 1.73-1.63 (m, 6H).
Ｎ－（４－シアノビフェニル－３－イル）－２－（ピペリジン－１－イル）イソニコチンアミド
1H-NMR(CDCl3)δ値：8.90-8.85(m,1H),8.41(s,1H),8.33(d,J=5.1Hz,1H),7.72-7.63(m,3H),7.52-7.40(m,4H),7.16(s,1H),6.89(dd,J=5.1,1.0Hz,1H),3.68-3.60(m,4H),1.72-1.62(m,6H). N- (4-cyanobiphenyl-3-yl) -2- (piperidin-1-yl) isonicotinamide
1 H-NMR (CDCl 3 ) δ value: 8.90-8.85 (m, 1H), 8.41 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.72-7.63 (m, 3H), 7.52- 7.40 (m, 4H), 7.16 (s, 1H), 6.89 (dd, J = 5.1, 1.0Hz, 1H), 3.68-3.60 (m, 4H), 1.72-1.62 (m, 6H).
Ｎ－（４－シアノビフェニル－３－イル）－５－（ピペリジン－１－イル）ニコチンアミド
1H-NMR(CDCl3)δ値：8.86-8.82(m,1H),8.54(d,J=2.0Hz,1H),8.50(d,J=2.7Hz,1H),8.40(s,1H),7.73-7.64(m,4H),7.52-7.40(m,4H),3.35-3.29(m,4H),1.78-1.69(m,4H),1.69-1.61(m,2H). N- (4-Cyanobiphenyl-3-yl) -5- (piperidin-1-yl) nicotinamide
1 H-NMR (CDCl 3 ) δ value: 8.86-8.82 (m, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.7 Hz, 1H), 8.40 (s, 1H) , 7.73-7.64 (m, 4H), 7.52-7.40 (m, 4H), 3.35-3.29 (m, 4H), 1.78-1.69 (m, 4H), 1.69-1.61 (m, 2H).
Ｎ－（４－シアノビフェニル－３－イル）－６－（ピペリジン－１－イル）ピリジン－２－カルボキサミド
1H-NMR(CDCl3)δ値：10.92(s,1H),9.11(d,J=1.4Hz,1H),7.72-7.61(m,4H),7.53(d,J=7.3Hz,1H),7.51-7.37(m,4H),6.89(d,J=8.6Hz,1H),3.74-3.64(m,4H),1.74-1.66(m,6H). N- (4-Cyanobiphenyl-3-yl) -6- (piperidin-1-yl) pyridine-2-carboxamide
1 H-NMR (CDCl 3 ) δ value: 10.92 (s, 1H), 9.11 (d, J = 1.4 Hz, 1H), 7.72-7.61 (m, 4H), 7.53 (d, J = 7.3 Hz, 1H) 7.51-7.37 (m, 4H), 6.89 (d, J = 8.6Hz, 1H), 3.74-3.64 (m, 4H), 1.74-1.66 (m, 6H).
Ｎ－（４－シアノビフェニル－３－イル）－４－メチル－３，４－ジヒドロ－２Ｈ－１，４－ベンズオキサジン－６－カルボキサミド
1H-NMR(CDCl3)δ値：8.95(d,J=1.7Hz,1H),8.42(s,1H),7.70-7.64(m,3H),7.51-7.39(m,4H),7.31(d,J=2.1Hz,1H),7.22(dd,J=8.3,2.1Hz,1H),6.86(d,J=8.3Hz,1H),4.40-4.34(m,2H),3.35-3.30(m,2H),2.98(s,3H). N- (4-Cyanobiphenyl-3-yl) -4-methyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide
1 H-NMR (CDCl 3 ) δ value: 8.95 (d, J = 1.7 Hz, 1H), 8.42 (s, 1H), 7.70-7.64 (m, 3H), 7.51-7.39 (m, 4H), 7.31 ( d, J = 2.1Hz, 1H), 7.22 (dd, J = 8.3,2.1Hz, 1H), 6.86 (d, J = 8.3Hz, 1H), 4.40-4.34 (m, 2H), 3.35-3.30 (m , 2H), 2.98 (s, 3H).
Ｎ－（４－シアノビフェニル－３－イル）－４－（ピペリジン－１－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.96(d,J=1.5Hz,1H),8.37(s,1H),7.88-7.82(m,2H),7.70-7.63(m,3H),7.50-7.37(m,4H),6.97-6.91(m,2H),3.41-3.33(m,4H),1.74-1.63(m,6H). N- (4-Cyanobiphenyl-3-yl) -4- (piperidin-1-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.96 (d, J = 1.5 Hz, 1H), 8.37 (s, 1H), 7.88-7.82 (m, 2H), 7.70-7.63 (m, 3H), 7.50- 7.37 (m, 4H), 6.97-6.91 (m, 2H), 3.41-3.33 (m, 4H), 1.74-1.63 (m, 6H).
参考例２２
Figure JPOXMLDOC01-appb-C000027
 　３－アミノビフェニル－４－カルボニトリル10gの塩化メチレン80mLおよびピリジン5.0mL混液に、氷冷下３－ブロモベンゾイルクロリド7.1mLおよび塩化メチレン20mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、50％２－プロパノール水溶液を加え、固形物をろ取した。得られた固形物にテトラヒドロフランを加え、不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物に２－プロパノールを加え、固形物をろ取し、白色固体の３－ブロモ－Ｎ－（４－シアノビフェニル－３－イル）ベンズアミド18gを得た。
1H-NMR(DMSO-d6)δ値：10.83(s,1H),8.25-8.19(m,1H),8.05-8.00(m,1H),7.98(d,J=8.0Hz,1H),7.92-7.89(m,1H),7.89-7.84(m,1H),7.81-7.73(m,3H),7.60-7.51(m,3H),7.50-7.44(m,1H). Reference Example 22
Figure JPOXMLDOC01-appb-C000027
 To a mixture of 10 g of 3-aminobiphenyl-4-carbonitrile in 80 mL of methylene chloride and 5.0 mL of pyridine, 7.1 mL of 3-bromobenzoyl chloride and 20 mL of methylene chloride were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 50% 2-propanol aqueous solution was added, and the solid was collected by filtration. Tetrahydrofuran was added to the obtained solid, the insoluble material was filtered off, and the solvent was distilled off under reduced pressure. 2-Propanol was added to the obtained residue, and the solid was collected by filtration to obtain 18 g of 3-bromo-N- (4-cyanobiphenyl-3-yl) benzamide as a white solid.
1 H-NMR (DMSO-d 6 ) δ value: 10.83 (s, 1H), 8.25-8.19 (m, 1H), 8.05-8.00 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.92-7.89 (m, 1H), 7.89-7.84 (m, 1H), 7.81-7.73 (m, 3H), 7.60-7.51 (m, 3H), 7.50-7.44 (m, 1H).
参考例２３
Figure JPOXMLDOC01-appb-C000028
 　参考例２２と同様にして、以下の化合物を得た。
Ｎ－（３－シアノビフェニル－４－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.71(d,J=8.8Hz,1H),8.47-8.40(m,1H),7.99-7.94(m,2H),7.89(dd,J=8.8,2.2Hz,1H),7.85(d,J=2.2Hz,1H),7.66-7.60(m,1H),7.59-7.52(m,4H),7.51-7.45(m,2H),7.44-7.38(m,1H). Reference Example 23
Figure JPOXMLDOC01-appb-C000028
 In the same manner as in Reference Example 22, the following compound was obtained.
N- (3-Cyanobiphenyl-4-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.71 (d, J = 8.8 Hz, 1H), 8.47-8.40 (m, 1H), 7.99-7.94 (m, 2H), 7.89 (dd, J = 8.8, 2.2 Hz, 1H), 7.85 (d, J = 2.2Hz, 1H), 7.66-7.60 (m, 1H), 7.59-7.52 (m, 4H), 7.51-7.45 (m, 2H), 7.44-7.38 (m, 1H).
参考例２４
Figure JPOXMLDOC01-appb-C000029
 　参考例２２と同様にして、以下の化合物を得た。
Ｎ－（４－（１－ベンジル－１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－ブロモベンズアミド
1H-NMR(CDCl3)δ値：10.86(s,1H),9.01(d,J=1.7Hz,1H),8.22-8.18(m,1H),7.94-7.89(m,1H),7.73-7.68(m,3H),7.52-7.45(m,2H),7.45-7.39(m,6H),7.31-7.26(m,3H),5.72(s,2H). Reference Example 24
Figure JPOXMLDOC01-appb-C000029
 In the same manner as in Reference Example 22, the following compound was obtained.
N- (4- (1-Benzyl-1H-tetrazol-5-yl) biphenyl-3-yl) -3-bromobenzamide
1 H-NMR (CDCl 3 ) δ value: 10.86 (s, 1H), 9.01 (d, J = 1.7 Hz, 1H), 8.22-8.18 (m, 1H), 7.94-7.89 (m, 1H), 7.73 7.68 (m, 3H), 7.52-7.45 (m, 2H), 7.45-7.39 (m, 6H), 7.31-7.26 (m, 3H), 5.72 (s, 2H).
参考例２５
Figure JPOXMLDOC01-appb-C000030
 　３－（モルホリン－４－イル）安息香酸3.0gに、３－アミノビフェニル－４－カルボニトリル2.8g、アセトニトリル30mL、Ｎ，Ｎ－ジメチルホルムアミド0.050mLおよび塩化チオニル1.2mLを順次加え、2時間30分間加熱還流した。反応混合物を室温まで冷却した後、テトラヒドロフラン10mLおよび塩化チオニル0.6mLを加え、2時間加熱還流した。反応混合物に塩化チオニル0.6mLを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去し、クロロホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；85-65％ヘキサン／酢酸エチル］で精製し、微赤色固体のＮ－（４－シアノビフェニル－３－イル）－３－（モルホリン－４－イル）ベンズアミド0.8gを得た。
1H-NMR(DMSO-d6)δ値：10.60(s,1H),7.96(d,J=8.0Hz,1H),7.89(d,J=1.5Hz,1H),7.79-7.73(m,3H),7.58-7.50(m,3H),7.49-7.39(m,3H),7.25-7.20(m,1H),3.81-3.74(m,4H),3.25-3.17(m,4H). Reference Example 25
Figure JPOXMLDOC01-appb-C000030
 To 3.0 g of 3- (morpholin-4-yl) benzoic acid, 2.8 g of 3-aminobiphenyl-4-carbonitrile, 30 mL of acetonitrile, 0.050 mL of N, N-dimethylformamide and 1.2 mL of thionyl chloride were sequentially added for 2 hours 30 Heated to reflux for minutes. After the reaction mixture was cooled to room temperature, 10 mL of tetrahydrofuran and 0.6 mL of thionyl chloride were added, and the mixture was heated to reflux for 2 hours. To the reaction mixture, 0.6 mL of thionyl chloride was added and heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and chloroform and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 85-65% hexane / ethyl acetate] to give N- (4-cyanobiphenyl- 0.8 g of 3-yl) -3- (morpholin-4-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.60 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.79-7.73 (m, 3H), 7.58-7.50 (m, 3H), 7.49-7.39 (m, 3H), 7.25-7.20 (m, 1H), 3.81-3.74 (m, 4H), 3.25-3.17 (m, 4H).
参考例２６
Figure JPOXMLDOC01-appb-C000031
 　参考例２５と同様にして、以下の化合物を得た。
Ｎ－（４－シアノビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.57(s,1H),7.96(d,J=8.3Hz,1H),7.89(d,J=1.7Hz,1H),7.79-7.72(m,3H),7.57-7.50(m,3H),7.49-7.44(m,1H),7.41-7.35(m,2H),7.22-7.16(m,1H),3.28-3.20(m,4H),1.69-1.60(m,4H),1.60-1.52(m,2H). Reference Example 26
Figure JPOXMLDOC01-appb-C000031
 In the same manner as in Reference Example 25, the following compound was obtained.
N- (4-Cyanobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.57 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.79-7.72 (m, 3H), 7.57-7.50 (m, 3H), 7.49-7.44 (m, 1H), 7.41-7.35 (m, 2H), 7.22-7.16 (m, 1H), 3.28-3.20 (m, 4H), 1.69- 1.60 (m, 4H), 1.60-1.52 (m, 2H).
参考例２７
Figure JPOXMLDOC01-appb-C000032
 　３－（ピペリジン－１－イル）安息香酸0.13gの１－メチル－２－ピロリドン0.50mL溶液に、Ｎ，Ｎ－ジメチルホルムアミド0.010mL、アセトニトリル0.50mLおよび塩化チオニル0.051mLを順次加え、室温で1時間攪拌した。反応混合物に氷冷下、２－アミノ－４－（フラン－２－イル）ベンゾニトリル0.10gの１－メチル－２－ピロリドン0.10mL溶液およびアセトニトリル0.5mLを加え、室温で30分間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にメタノールを加え、固形物をろ取し、白色固体のＮ－（２－シアノ－５－（フラン－２－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド0.17gを得た。
1H-NMR(CDCl3)δ値：8.97(d,J=1.5Hz,1H),8.43(s,1H),7.62(d,J=8.2Hz,1H),7.58-7.51(m,2H),7.50(dd,J=8.2,1.5Hz,1H),7.38(dd,J=7.9,7.9Hz,1H),7.31-7.27(m,1H),7.15(dd,J=8.3,2.7Hz,1H),6.91(d,J=3.4Hz,1H),6.54(dd,J=3.4,1.7Hz,1H),3.31-3.24(m,4H),1.77-1.68(m,4H),1.66-1.58(m,2H). Reference Example 27
Figure JPOXMLDOC01-appb-C000032
 To a solution of 0.13 g of 3- (piperidin-1-yl) benzoic acid in 0.50 mL of 1-methyl-2-pyrrolidone, 0.010 mL of N, N-dimethylformamide, 0.50 mL of acetonitrile and 0.051 mL of thionyl chloride were sequentially added. Stir for hours. Under ice-cooling, a solution of 0.10 g of 2-amino-4- (furan-2-yl) benzonitrile in 0.10 mL of 1-methyl-2-pyrrolidone and 0.5 mL of acetonitrile were added, and the mixture was stirred at room temperature for 30 minutes. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, the solid was collected by filtration, and white solid N- (2-cyano-5- (furan-2-yl) phenyl) -3- (piperidin-1-yl) benzamide 0.17 g was obtained.
1 H-NMR (CDCl 3 ) δ value: 8.97 (d, J = 1.5 Hz, 1H), 8.43 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.58-7.51 (m, 2H) , 7.50 (dd, J = 8.2,1.5Hz, 1H), 7.38 (dd, J = 7.9,7.9Hz, 1H), 7.31-7.27 (m, 1H), 7.15 (dd, J = 8.3,2.7Hz, 1H ), 6.91 (d, J = 3.4Hz, 1H), 6.54 (dd, J = 3.4, 1.7Hz, 1H), 3.31-3.24 (m, 4H), 1.77-1.68 (m, 4H), 1.66-1.58 ( m, 2H).
参考例２８
Figure JPOXMLDOC01-appb-C000033
 　参考例２７と同様にして、以下の化合物を得た。
Ｎ－（４－シアノビフェニル－３－イル）－２－（ジエチルアミノ）イソニコチンアミド
1H-NMR(CDCl3)δ値：8.94-8.89(m,1H),8.43(s,1H),8.32(d,J=5.2Hz,1H),7.72-7.64(m,3H),7.52-7.40(m,4H),7.00-6.97(m,1H),6.87-6.81(m,1H),3.59(q,J=7.1Hz,4H),1.23(t,J=7.1Hz,6H). Reference Example 28
Figure JPOXMLDOC01-appb-C000033
 In the same manner as in Reference Example 27, the following compound was obtained.
N- (4-Cyanobiphenyl-3-yl) -2- (diethylamino) isonicotinamide
1 H-NMR (CDCl 3 ) δ value: 8.94-8.89 (m, 1H), 8.43 (s, 1H), 8.32 (d, J = 5.2Hz, 1H), 7.72-7.64 (m, 3H), 7.52- 7.40 (m, 4H), 7.00-6.97 (m, 1H), 6.87-6.81 (m, 1H), 3.59 (q, J = 7.1Hz, 4H), 1.23 (t, J = 7.1Hz, 6H).
参考例２９
Figure JPOXMLDOC01-appb-C000034
 　参考例２７と同様にして、以下の化合物を得た。
Ｎ－（３－シアノビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.70(d,J=8.8Hz,1H),8.44(s,1H),7.88(dd,J=8.8,2.2Hz,1H),7.83(d,J=2.0Hz,1H),7.60-7.54(m,2H),7.54-7.44(m,3H),7.44-7.35(m,2H),7.32-7.25(m,1H),7.15(dd,J=8.2,2.6Hz,1H),3.31-3.25(m,4H),1.77-1.69(m,4H),1.66-1.58(m,2H). Reference Example 29
Figure JPOXMLDOC01-appb-C000034
 In the same manner as in Reference Example 27, the following compound was obtained.
N- (3-Cyanobiphenyl-4-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.70 (d, J = 8.8 Hz, 1H), 8.44 (s, 1H), 7.88 (dd, J = 8.8, 2.2 Hz, 1H), 7.83 (d, J = 2.0Hz, 1H), 7.60-7.54 (m, 2H), 7.54-7.44 (m, 3H), 7.44-7.35 (m, 2H), 7.32-7.25 (m, 1H), 7.15 (dd, J = 8.2, 2.6Hz, 1H), 3.31-3.25 (m, 4H), 1.77-1.69 (m, 4H), 1.66-1.58 (m, 2H).
参考例３０
Figure JPOXMLDOC01-appb-C000035
 　３－ブロモ－Ｎ－（４－シアノビフェニル－３－イル）ベンズアミド0.15g、トリス（ジベンジリデンアセトン）ジパラジウム（０）37mg、ｒａｃ－２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル75mg、ナトリウムｔｅｒｔ－ブトキシド0.15g、４－メチルピペリジン0.14mLおよびトルエン4mL混液を、窒素雰囲気下、1時間30分間加熱還流した。反応混合物を室温まで冷却した後、10％クエン酸水溶液および酢酸エチルを加え、不溶物をろ去後、水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-50％ヘキサン／酢酸エチル］で精製し、淡黄色固体のＮ－（４－シアノビフェニル－３－イル）－３－（４－メチルピペリジン－１－イル）ベンズアミド0.065gを得た。
1H-NMR(CDCl3)δ値：8.96-8.92(m,1H),8.46(s,1H),7.71-7.66(m,3H),7.55-7.51(m,1H),7.51-7.40(m,4H),7.38(dd,J=7.9,7.9Hz,1H),7.31-7.27(m,1H),7.15(dd,J=8.2,2.3Hz,1H),3.82-3.74(m,2H),2.85-2.75(m,2H),1.81-1.72(m,2H),1.62-1.50(m,1H),1.41-1.29(m,2H),0.99(d,J=6.6Hz,3H). Reference Example 30
Figure JPOXMLDOC01-appb-C000035
 3-Bromo-N- (4-cyanobiphenyl-3-yl) benzamide 0.15 g, Tris (dibenzylideneacetone) dipalladium (0) 37 mg, rac-2,2′-bis (diphenylphosphino) -1,1 A mixture of 75 mg of '-binaphthyl, 0.15 g of sodium tert-butoxide, 0.14 mL of 4-methylpiperidine and 4 mL of toluene was heated to reflux for 1 hour 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 10% aqueous citric acid solution and ethyl acetate were added, insoluble materials were filtered off, and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-50% hexane / ethyl acetate], and a pale yellow solid N- (4-cyanobiphenyl- 0.065 g of 3-yl) -3- (4-methylpiperidin-1-yl) benzamide was obtained.
1 H-NMR (CDCl 3 ) δ value: 8.96-8.92 (m, 1H), 8.46 (s, 1H), 7.71-7.66 (m, 3H), 7.55-7.51 (m, 1H), 7.51-7.40 (m , 4H), 7.38 (dd, J = 7.9,7.9Hz, 1H), 7.31-7.27 (m, 1H), 7.15 (dd, J = 8.2,2.3Hz, 1H), 3.82-3.74 (m, 2H), 2.85-2.75 (m, 2H), 1.81-1.72 (m, 2H), 1.62-1.50 (m, 1H), 1.41-1.29 (m, 2H), 0.99 (d, J = 6.6Hz, 3H).
参考例３１
Figure JPOXMLDOC01-appb-C000036
 　参考例３０と同様にして、以下の化合物を得た。
Ｎ－（４－シアノビフェニル－３－イル）－３－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリン－４－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.95-8.92(m,1H),8.48(s,1H),7.71-7.66(m,3H),7.55-7.52(m,1H),7.51-7.42(m,4H),7.40(d,J=8.1Hz,1H),7.36-7.31(m,1H),7.13(dd,J=8.1,2.4Hz,1H),3.87-3.77(m,2H),3.61-3.54(m,2H),2.54-2.46(m,2H),1.28(d,J=6.4Hz,6H). Reference Example 31
Figure JPOXMLDOC01-appb-C000036
 In the same manner as in Reference Example 30, the following compound was obtained.
N- (4-cyanobiphenyl-3-yl) -3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.95-8.92 (m, 1H), 8.48 (s, 1H), 7.71-7.66 (m, 3H), 7.55-7.52 (m, 1H), 7.51-7.42 (m , 4H), 7.40 (d, J = 8.1Hz, 1H), 7.36-7.31 (m, 1H), 7.13 (dd, J = 8.1,2.4Hz, 1H), 3.87-3.77 (m, 2H), 3.61- 3.54 (m, 2H), 2.54-2.46 (m, 2H), 1.28 (d, J = 6.4Hz, 6H).
参考例３２
Figure JPOXMLDOC01-appb-C000037
 　Ｎ－（４－シアノビフェニル－３－イル）－３－ニトロベンズアミド2.5gのテトラヒドロフラン100mLおよびメタノール50mL混液に、10％パラジウム－炭素0.50gを加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、白色固体の３－アミノ－Ｎ－（４－シアノビフェニル－３－イル）ベンズアミド2.1gを得た。
1H-NMR(CDCl3)δ値：8.91(d,J=1.5Hz,1H),8.41(s,1H),7.71-7.65(m,3H),7.51-7.40(m,4H),7.34-7.26(m,3H),6.93-6.87(m,1H),3.94-3.86(m,2H). Reference Example 32
Figure JPOXMLDOC01-appb-C000037
 To a mixed solution of 2.5 g of N- (4-cyanobiphenyl-3-yl) -3-nitrobenzamide in 100 mL of tetrahydrofuran and 50 mL of methanol was added 0.50 g of 10% palladium-carbon, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2.1 g of white solid 3-amino-N- (4-cyanobiphenyl-3-yl) benzamide.
1 H-NMR (CDCl 3 ) δ value: 8.91 (d, J = 1.5 Hz, 1H), 8.41 (s, 1H), 7.71-7.65 (m, 3H), 7.51-7.40 (m, 4H), 7.34 7.26 (m, 3H), 6.93-6.87 (m, 1H), 3.94-3.86 (m, 2H).
参考例３３
Figure JPOXMLDOC01-appb-C000038
 　３－アミノ－Ｎ－（４－シアノビフェニル－３－イル）ベンズアミド1.5gのテトラヒドロフラン10mLおよびＮ，Ｎ－ジメチルホルムアミド20mL混液に、炭酸カリウム0.66gおよびヨウ化エチル0.74mLを加え、60℃で2時間攪拌した。反応混合物を室温まで冷却後、減圧下で溶媒を留去し、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；90-30％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（４－シアノビフェニル－３－イル）－３－（エチルアミノ）ベンズアミド0.51gを得た。
　得られたＮ－（４－シアノビフェニル－３－イル）－３－（エチルアミノ）ベンズアミド0.15gのＮ，Ｎ－ジメチルアセトアミド1mL溶液に、炭酸カリウム0.079gおよびヨウ化メチル0.036mLを加え、室温で6時間攪拌した。反応混合物に水および酢酸エチルを加えた。有機層を分取し、水で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；90-75％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（４－シアノビフェニル－３－イル）－３－（エチル（メチル）アミノ）ベンズアミド0.091gを得た。
1H-NMR(CDCl3)δ値：8.97(d,J=1.5Hz,1H),8.52-8.47(m,1H),7.71-7.65(m,3H),7.51-7.40(m,4H),7.35(dd,J=7.9,7.9Hz,1H),7.31-7.28(m,1H),7.18-7.14(m,1H),6.91(dd,J=8.5,2.7Hz,1H),3.49(q,J=7.1Hz,2H),3.00(s,3H),1.17(t,J=7.1Hz,3H). Reference Example 33
Figure JPOXMLDOC01-appb-C000038
 To a mixture of 1.5 g of 3-amino-N- (4-cyanobiphenyl-3-yl) benzamide in 10 mL of tetrahydrofuran and 20 mL of N, N-dimethylformamide, 0.66 g of potassium carbonate and 0.74 mL of ethyl iodide were added, Stir for hours. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-30% hexane / ethyl acetate], and white solid N- (4-cyanobiphenyl-3 0.51 g of -yl) -3- (ethylamino) benzamide was obtained.
To a solution of N- (4-cyanobiphenyl-3-yl) -3- (ethylamino) benzamide (0.15 g) in N, N-dimethylacetamide (1 mL) was added potassium carbonate (0.079 g) and methyl iodide (0.036 mL) at room temperature. For 6 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-75% hexane / ethyl acetate], and white solid N- (4-cyanobiphenyl-3 0.091 g of -yl) -3- (ethyl (methyl) amino) benzamide was obtained.
1 H-NMR (CDCl 3 ) δ value: 8.97 (d, J = 1.5 Hz, 1H), 8.52-8.47 (m, 1H), 7.71-7.65 (m, 3H), 7.51-7.40 (m, 4H), 7.35 (dd, J = 7.9,7.9Hz, 1H), 7.31-7.28 (m, 1H), 7.18-7.14 (m, 1H), 6.91 (dd, J = 8.5,2.7Hz, 1H), 3.49 (q, J = 7.1Hz, 2H), 3.00 (s, 3H), 1.17 (t, J = 7.1Hz, 3H).
参考例３４
Figure JPOXMLDOC01-appb-C000039
 　３－ブロモ－Ｎ－（４－シアノビフェニル－３－イル）ベンズアミド0.40gのエチレングリコールジメチルエーテル3.2mL懸濁液に、ｔｅｒｔ－ブチル＝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）－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシラート0.46g、炭酸ナトリウム0.32g、水0.8mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド15mgを加え、窒素雰囲気下、4時間加熱還流した。反応混合物を室温まで冷却後、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体のｔｅｒｔ－ブチル＝４－（３－（（（４－シアノビフェニル－３－イル）アミノ）カルボニル）フェニル）－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシラート0.43gを得た。
　得られたｔｅｒｔ－ブチル＝４－（３－（（（４－シアノビフェニル－３－イル）アミノ）カルボニル）フェニル）－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシラート0.42gのテトラヒドロフラン10mL溶液に、メタノール2.0mLおよび10％パラジウム－炭素0.050gを加え、水素雰囲気下、室温で4時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体のｔｅｒｔ－ブチル＝４－（３－（（（４－シアノビフェニル－３－イル）アミノ）カルボニル）フェニル）ピペリジン－１－カルボキシラート0.41gを得た。
1H-NMR(CDCl3)δ値：8.93-8.89(m,1H),8.43(s,1H),7.85-7.81(m,1H),7.79-7.74(m,1H),7.72-7.65(m,3H),7.53-7.41(m,6H),4.38-4.18(m,2H),2.91-2.71(m,3H),1.93-1.82(m,2H),1.75-1.61(m,2H),1.49(s,9H). Reference Example 34
Figure JPOXMLDOC01-appb-C000039
 To a suspension of 0.40 g of 3-bromo-N- (4-cyanobiphenyl-3-yl) benzamide in 3.2 mL of ethylene glycol dimethyl ether was added tert-butyl 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate 0.46 g, sodium carbonate 0.32 g, water 0.8 mL and bis (di-tert-butyl (4-dimethylaminophenyl) Phosphine) palladium (II) dichloride (15 mg) was added, and the mixture was heated to reflux for 4 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid matter was collected by filtration, and tert-butyl = 4- (3-(((4-cyanobiphenyl-3-yl) amino) carbonyl) phenyl) -3 as a white solid. , 6-Dihydropyridine-1 (2H) -carboxylate 0.43 g was obtained.
A solution of 0.42 g of the obtained tert-butyl = 4- (3-(((4-cyanobiphenyl-3-yl) amino) carbonyl) phenyl) -3,6-dihydropyridine-1 (2H) -carboxylate in 10 mL of tetrahydrofuran To the mixture, 2.0 mL of methanol and 0.050 g of 10% palladium-carbon were added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid matter was collected by filtration, and the white solid tert-butyl = 4- (3-(((4-cyanobiphenyl-3-yl) amino) carbonyl) phenyl) piperidine- 0.41 g of 1-carboxylate was obtained.
1 H-NMR (CDCl 3 ) δ value: 8.93-8.89 (m, 1H), 8.43 (s, 1H), 7.85-7.81 (m, 1H), 7.79-7.74 (m, 1H), 7.72-7.65 (m , 3H), 7.53-7.41 (m, 6H), 4.38-4.18 (m, 2H), 2.91-2.71 (m, 3H), 1.93-1.82 (m, 2H), 1.75-1.61 (m, 2H), 1.49 (s, 9H).
参考例３５
Figure JPOXMLDOC01-appb-C000040
 　参考例３４と同様にして、以下の化合物を得た。
ｔｅｒｔ－ブチル＝４－（３－（（（４－（１－ベンジル－１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）アミノ）カルボニル）フェニル）ピペリジン－１－カルボキシラート
1H-NMR(CDCl3)δ値：10.81(s,1H),9.06(d,J=1.7Hz,1H),7.91-7.88(m,1H),7.86-7.81(m,1H),7.74-7.69(m,2H),7.51-7.44(m,3H),7.44-7.27(m,9H),5.71(s,2H),4.39-4.18(m,2H),2.92-2.72(m,3H),1.93-1.84(m,2H),1.76-1.63(m,2H),1.50(s,9H). Reference Example 35
Figure JPOXMLDOC01-appb-C000040
 In the same manner as in Reference Example 34, the following compound was obtained.
tert-butyl = 4- (3-(((4- (1-benzyl-1H-tetrazol-5-yl) biphenyl-3-yl) amino) carbonyl) phenyl) piperidine-1-carboxylate
1 H-NMR (CDCl 3 ) δ value: 10.81 (s, 1H), 9.06 (d, J = 1.7 Hz, 1H), 7.91-7.88 (m, 1H), 7.86-7.81 (m, 1H), 7.74 7.69 (m, 2H), 7.51-7.44 (m, 3H), 7.44-7.27 (m, 9H), 5.71 (s, 2H), 4.39-4.18 (m, 2H), 2.92-2.72 (m, 3H), 1.93-1.84 (m, 2H), 1.76-1.63 (m, 2H), 1.50 (s, 9H).
参考例３６
Figure JPOXMLDOC01-appb-C000041
 　ｔｅｒｔ－ブチル＝４－（３－（（（４－シアノビフェニル－３－イル）アミノ）カルボニル）フェニル）ピペリジン－１－カルボキシラート0.25gのテトラヒドロフラン4.0mL溶液に、6.6mol/L塩化水素－酢酸エチル溶液4.0mLを加え、室温で6時間攪拌した。固形物をろ取し、白色固体のＮ－（４－シアノビフェニル－３－イル）－３－（ピペリジン－４－イル）ベンズアミド塩酸塩0.21gを得た。
　得られたＮ－（４－シアノビフェニル－３－イル）－３－（ピペリジン－４－イル）ベンズアミド塩酸塩0.15gのテトラヒドロフラン4.0mL懸濁液に、トリエチルアミン0.060mL、37％ホルムアルデヒド水溶液0.035mL、酢酸0.041mLおよびナトリウムトリアセトキシボロヒドリド0.19gを順次加え、室温で1時間攪拌した。反応混合物に水、酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；99-93％クロロホルム／メタノール］で精製し、白色固体のＮ－（４－シアノビフェニル－３－イル）－３－（１－メチルピペリジン－４－イル）ベンズアミド0.065gを得た。
1H-NMR(CDCl3)δ値：8.93-8.89(m,1H),8.43(s,1H),7.86-7.82(m,1H),7.79-7.73(m,1H),7.72-7.65(m,3H),7.52-7.40(m,6H),3.06-2.96(m,2H),2.65-2.54(m,1H),2.36-2.32(m,3H),2.14-2.03(m,2H),1.94-1.77(m,4H). Reference Example 36
Figure JPOXMLDOC01-appb-C000041
 tert-Butyl = 4- (3-((((4-cyanobiphenyl-3-yl) amino) carbonyl) phenyl) piperidine-1-carboxylate 0.25 g in tetrahydrofuran 4.0 mL solution, 6.6 mol / L hydrogen chloride-acetic acid The ethyl solution 4.0mL was added and it stirred at room temperature for 6 hours. The solid was collected by filtration to obtain 0.21 g of N- (4-cyanobiphenyl-3-yl) -3- (piperidin-4-yl) benzamide hydrochloride as a white solid.
To a suspension of the obtained N- (4-cyanobiphenyl-3-yl) -3- (piperidin-4-yl) benzamide hydrochloride 0.15 g in tetrahydrofuran 4.0 mL, triethylamine 0.060 mL, 37% formaldehyde aqueous solution 0.035 mL, Acetic acid 0.041 mL and sodium triacetoxyborohydride 0.19 g were sequentially added, and the mixture was stirred at room temperature for 1 hour. Water, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-93% chloroform / methanol], and white solid N- (4-cyanobiphenyl-3-yl) -3- (1-methylpiperidine- 0.065 g of 4-yl) benzamide was obtained.
1 H-NMR (CDCl 3 ) δ value: 8.93-8.89 (m, 1H), 8.43 (s, 1H), 7.86-7.82 (m, 1H), 7.79-7.73 (m, 1H), 7.72-7.65 (m , 3H), 7.52-7.40 (m, 6H), 3.06-2.96 (m, 2H), 2.65-2.54 (m, 1H), 2.36-2.32 (m, 3H), 2.14-2.03 (m, 2H), 1.94 -1.77 (m, 4H).
参考例３７
Figure JPOXMLDOC01-appb-C000042
 　参考例３６と同様にして、以下の化合物を得た。
Ｎ－（４－（１－ベンジル－１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（１－メチルピペリジン－４－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.04-8.00(m,1H),7.81-7.76(m,2H),7.75-7.67(m,3H),7.59-7.53(m,2H),7.53-7.45(m,3H),7.42-7.34(m,3H),7.34-7.25(m,3H),5.62(s,2H),3.56-3.43(m,2H),3.14-3.00(m,2H),2.96-2.86(m,1H),2.80(s,3H),2.09-2.00(m,2H),1.95-1.80(m,2H). Reference Example 37
Figure JPOXMLDOC01-appb-C000042
 In the same manner as in Reference Example 36, the following compound was obtained.
N- (4- (1-Benzyl-1H-tetrazol-5-yl) biphenyl-3-yl) -3- (1-methylpiperidin-4-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.04-8.00 (m, 1H), 7.81-7.76 (m, 2H), 7.75-7.67 (m, 3H), 7.59-7.53 (m, 2H), 7.53-7.45 (m, 3H), 7.42-7.34 (m, 3H), 7.34-7.25 (m, 3H), 5.62 (s, 2H), 3.56-3.43 (m, 2H), 3.14-3.00 ( m, 2H), 2.96-2.86 (m, 1H), 2.80 (s, 3H), 2.09-2.00 (m, 2H), 1.95-1.80 (m, 2H).
参考例３８
Figure JPOXMLDOC01-appb-C000043
 　３－アミノビフェニル－４－カルボニトリル3.0gのＮ，Ｎ－ジメチルホルムアミド30mL溶液に、トリエチルアミン塩酸塩8.5gおよびアジ化ナトリウム4.0gを順次加え、110℃で6時間30分間攪拌した。反応混合物を室温まで冷却した後、水およびクロロホルムを加え、1.0mol/L塩酸でpH4.0に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；75-50％ヘキサン／酢酸エチル］で精製し、淡黄色固体の４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－アミン3.4gを得た。
1H-NMR(DMSO-d6)δ値：7.82(d,J=8.2Hz,1H),7.69-7.63(m,2H),7.52-7.45(m,2H),7.43-7.37(m,1H),7.20(d,J=1.8Hz,1H),7.02(dd,J=8.2,1.8Hz,1H). Reference Example 38
Figure JPOXMLDOC01-appb-C000043
 To 30 mL of N, N-dimethylformamide in 3.0 g of 3-aminobiphenyl-4-carbonitrile, 8.5 g of triethylamine hydrochloride and 4.0 g of sodium azide were sequentially added, followed by stirring at 110 ° C. for 6 hours and 30 minutes. The reaction mixture was cooled to room temperature, water and chloroform were added, and the pH was adjusted to 4.0 with 1.0 mol / L hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 75-50% hexane / ethyl acetate] to give 4- (1H-tetrazole-5 as a pale yellow solid. -Yl) 3.4 g of biphenyl-3-amine were obtained.
1 H-NMR (DMSO-d 6 ) δ value: 7.82 (d, J = 8.2 Hz, 1H), 7.69-7.63 (m, 2H), 7.52-7.45 (m, 2H), 7.43-7.37 (m, 1H ), 7.20 (d, J = 1.8Hz, 1H), 7.02 (dd, J = 8.2, 1.8Hz, 1H).
参考例３９
Figure JPOXMLDOC01-appb-C000044
 　３－アミノビフェニル－４－カルボニトリル4.9gのテトラヒドロフラン20mL溶液に、（ジ－ｔｅｒｔ－ブチル）ジカルボナート12.4gおよび４－ジメチルアミノピリジン0.61gを加え、室温で4時間攪拌した。減圧下で溶媒を留去し、水を加え、固形物をろ取した。得られた固形物にメタノール50mLおよび炭酸カリウム10.4gを加え、室温で1時間30分間攪拌した。反応混合物にメタノール20mLおよびテトラヒドロフラン30mLを加え、室温で5時間攪拌した。反応混合物に炭酸カリウム3.5gを加え、室温で4時間攪拌した。減圧下で溶媒を留去し、水を加え、固形物をろ取した。得られた固形物を30％メタノール水溶液で洗浄し、淡黄色固体のｔｅｒｔ－ブチル＝（４－シアノビフェニル－３－イル）カルバマート7.1gを得た。
1H-NMR(CDCl3)δ値：8.55-8.51(m,1H),7.66-7.58(m,3H),7.49-7.38(m,3H),7.31(dd,J=8.1,1.7Hz,1H),7.12-7.04(m,1H),1.55(s,9H). Reference Example 39
Figure JPOXMLDOC01-appb-C000044
 To a solution of 4.9 g of 3-aminobiphenyl-4-carbonitrile in 20 mL of tetrahydrofuran were added 12.4 g of (di-tert-butyl) dicarbonate and 0.61 g of 4-dimethylaminopyridine, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, water was added, and the solid was collected by filtration. Methanol 50mL and potassium carbonate 10.4g were added to the obtained solid substance, and it stirred at room temperature for 1 hour and 30 minutes. 20 mL of methanol and 30 mL of tetrahydrofuran were added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, 3.5 g of potassium carbonate was added and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, water was added, and the solid was collected by filtration. The obtained solid was washed with a 30% aqueous methanol solution to obtain 7.1 g of tert-butyl = (4-cyanobiphenyl-3-yl) carbamate as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ value: 8.55-8.51 (m, 1H), 7.66-7.58 (m, 3H), 7.49-7.38 (m, 3H), 7.31 (dd, J = 8.1, 1.7 Hz, 1H ), 7.12-7.04 (m, 1H), 1.55 (s, 9H).
参考例４０
Figure JPOXMLDOC01-appb-C000045
 　ｔｅｒｔ－ブチル＝（４－シアノビフェニル－３－イル）カルバマート7.1gのテトラヒドロフラン50mL懸濁液に、50％ヒドロキシルアミン水溶液4.0mLを加え、60℃で2時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物にメタノールを加え、減圧下で溶媒を留去した。得られた残留物に１－メチル－２－ピロリドン10mL、テトラヒドロフラン40mL、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン5.4mLおよび１，１’－カルボニルジイミダゾール5.8gを順次加え、室温で1時間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール2.0gを加え、室温で2時間攪拌した。反応混合物を2mol/L塩酸でpH1.0に調整し、減圧下で溶媒を留去後、水を加え、固形物をろ取し、淡黄色固体のｔｅｒｔ－ブチル＝（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）カルバマート8.4gを得た。
　得られたｔｅｒｔ－ブチル＝（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）カルバマート8.4gに氷冷下、トリフルオロ酢酸40mLを加え、同温度で10分間攪拌後、室温で1時間攪拌した。減圧下で溶媒を留去し、10％メタノール水溶液を加え、2mol/L水酸化ナトリウム水溶液でpH4に調整後、固形物をろ取し、白色固体の３－（３－アミノビフェニル－４－イル）－１，２，４－オキサジアゾール－５（４Ｈ）－オン6.0gを得た。
1H-NMR(DMSO-d6)δ値：7.67-7.62(m,2H),7.56(d,J=8.3Hz,1H),7.51-7.45(m,2H),7.44-7.38(m,1H),7.16(d,J=1.7Hz,1H),6.98(dd,J=8.3,1.7Hz,1H). Reference Example 40
Figure JPOXMLDOC01-appb-C000045
 To 50 mL of a tetrahydrofuran suspension of 7.1 g of tert-butyl = (4-cyanobiphenyl-3-yl) carbamate was added 4.0 mL of a 50% aqueous hydroxylamine solution, and the mixture was stirred at 60 ° C. for 2 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solvent was distilled off under reduced pressure. To the obtained residue, 1 mL of 1-methyl-2-pyrrolidone, 40 mL of tetrahydrofuran, 5.4 mL of 1,8-diazabicyclo [5.4.0] -7-undecene and 5.8 g of 1,1′-carbonyldiimidazole were sequentially added. And stirred at room temperature for 1 hour. To the reaction mixture, 1,1′-carbonyldiimidazole (2.0 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 1.0 with 2 mol / L hydrochloric acid, the solvent was distilled off under reduced pressure, water was added, the solid was collected by filtration, and tert-butyl = (4- (5-oxo 8.4 g of -4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) carbamate was obtained.
To 8.4 g of the obtained tert-butyl = (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) carbamate, After adding 40 mL of fluoroacetic acid and stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 10% methanol aqueous solution was added, pH was adjusted to 4 with 2 mol / L sodium hydroxide aqueous solution, the solid was collected by filtration, and white solid 3- (3-aminobiphenyl-4-yl ) -1,2,4-oxadiazol-5 (4H) -one 6.0 g was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 7.67-7.62 (m, 2H), 7.56 (d, J = 8.3 Hz, 1H), 7.51-7.45 (m, 2H), 7.44-7.38 (m, 1H ), 7.16 (d, J = 1.7Hz, 1H), 6.98 (dd, J = 8.3, 1.7Hz, 1H).
参考例４１
Figure JPOXMLDOC01-appb-C000046
 　２－アミノ－４－クロロベンゾニトリル0.50gのエチレングリコールジメチルエーテル4.0mL溶液に、フラン－２－ボロン酸0.44g、炭酸ナトリウム0.84g、水1.0mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド10mgを加え、窒素雰囲気下、1時間加熱還流した。反応混合物を室温まで冷却後、フラン－２－ボロン酸0.19gおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド10mgを加え、窒素雰囲気下、30分間加熱還流した。反応混合物を室温まで冷却後、フラン－２－ボロン酸0.074gおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド10mgを加え、窒素雰囲気下、30分間加熱還流した。反応混合物を室温まで冷却後、水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；93-70％ヘキサン／酢酸エチル］で精製し、黄色固体の２－アミノ－４－（フラン－２－イル）ベンゾニトリル0.59gを得た。
1H-NMR(DMSO-d6)δ値：7.81(dd,J=1.8,0.7Hz,1H),7.42(d,J=8.2Hz,1H),7.12(d,J=1.5Hz,1H),6.99(dd,J=3.4,0.7Hz,1H),6.95(dd,J=8.2,1.5Hz,1H),6.62(dd,J=3.4,1.8Hz,1H),6.14(s,2H). Reference Example 41
Figure JPOXMLDOC01-appb-C000046
 To a 4.0 mL ethylene glycol dimethyl ether solution of 0.50 g 2-amino-4-chlorobenzonitrile, 0.44 g furan-2-boronic acid, 0.84 g sodium carbonate, 1.0 mL water and bis (di-tert-butyl (4-dimethylamino) Phenyl) phosphine) palladium (II) dichloride (10 mg) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 0.19 g of furan-2-boronic acid and 10 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride are added, and the mixture is heated to reflux for 30 minutes under a nitrogen atmosphere. did. After cooling the reaction mixture to room temperature, 0.074 g of furan-2-boronic acid and 10 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride are added, and the mixture is heated to reflux for 30 minutes under a nitrogen atmosphere. did. After cooling the reaction mixture to room temperature, water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 93-70% hexane / ethyl acetate] to give yellow solid 2-amino-4- (furan- 0.59 g of 2-yl) benzonitrile was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 7.81 (dd, J = 1.8, 0.7 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 1.5 Hz, 1H) 6.99 (dd, J = 3.4, 0.7Hz, 1H), 6.95 (dd, J = 8.2, 1.5Hz, 1H), 6.62 (dd, J = 3.4, 1.8Hz, 1H), 6.14 (s, 2H).
参考例４２
Figure JPOXMLDOC01-appb-C000047
 　３－ブロモベンゾニトリル0.50gにトルエン30mL、２－メチルピペリジン1.6mL、炭酸セシウム3.6g、トリス（ジベンジリデンアセトン）ジパラジウム（０）0.050g、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル0.13gおよび酢酸パラジウム（II）0.025gを加え、窒素雰囲気下、8時間加熱還流した。反応混合物を室温まで冷却後、不溶物をろ去し、水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-85％ヘキサン／酢酸エチル］で精製し、淡黄色油状物の３－（２－メチルピペリジン－１－イル）ベンゾニトリル0.25gを得た。
　得られた３－（２－メチルピペリジン－１－イル）ベンゾニトリル0.25gにエタノール1.3mLおよび水酸化ナトリウム0.50gの水2.6mL溶液を加え、4時間加熱還流した。反応混合物を室温まで冷却後、1mol/L塩酸でpH4.0に調整し、減圧下で溶媒を留去後、水および酢酸エチルを加えた。有機層を分取し、水層をクロロホルムで3回抽出した。得られた有機層と抽出液を併せ、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；98-90％クロロホルム／メタノール］で精製し、褐色固体の３－（２－メチルピペリジン－１－イル）安息香酸0.16gを得た。
1H-NMR(CDCl3)δ値：7.65-7.62(m,1H),7.54-7.50(m,1H),7.32(dd,J=7.9,7.9Hz,1H),7.15(dd,J=8.3,2.4Hz,1H),4.10-4.01(m,1H),3.36-3.29(m,1H),3.04-2.95(m,1H),1.93-1.83(m,1H),1.82-1.75(m,1H),1.70-1.56(m,4H),1.02(d,J=6.6Hz,3H). Reference Example 42
Figure JPOXMLDOC01-appb-C000047
 0.50 g of 3-bromobenzonitrile, 30 mL of toluene, 1.6 mL of 2-methylpiperidine, 3.6 g of cesium carbonate, 0.050 g of tris (dibenzylideneacetone) dipalladium (0), 2-dicyclohexylphosphino-2 ′, 4 ′, 6 '-Triisopropylbiphenyl (0.13 g) and palladium (II) acetate (0.025 g) were added, and the mixture was heated to reflux for 8 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-85% hexane / ethyl acetate] to give 3- (2-methylpiperidine as a pale yellow oily substance. -1-yl) benzonitrile (0.25 g) was obtained.
To 0.25 g of the obtained 3- (2-methylpiperidin-1-yl) benzonitrile, 1.3 mL of ethanol and a solution of 0.50 g of sodium hydroxide in 2.6 mL of water were added and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, adjusted to pH 4.0 with 1 mol / L hydrochloric acid, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with chloroform three times. The obtained organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 98-90% chloroform / methanol] to give 3- (2-methylpiperidine-1- I) 0.16 g of benzoic acid was obtained.
1 H-NMR (CDCl 3 ) δ value: 7.65-7.62 (m, 1H), 7.54-7.50 (m, 1H), 7.32 (dd, J = 7.9, 7.9 Hz, 1H), 7.15 (dd, J = 8.3 , 2.4Hz, 1H), 4.10-4.01 (m, 1H), 3.36-3.29 (m, 1H), 3.04-2.95 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.75 (m, 1H ), 1.70-1.56 (m, 4H), 1.02 (d, J = 6.6Hz, 3H).
参考例４３
Figure JPOXMLDOC01-appb-C000048
 　（２Ｒ，６Ｓ）－２，６－ジメチルピペリジン0.46mLのジオキサン3mL溶液に氷冷下、0.5mol/Lカリウムビス（トリメチルシリル）アミド－トルエン溶液6.6mLおよび３－ブロモベンゾニトリル0.30gのジオキサン3mL溶液を順次加え、窒素雰囲気下、100℃で1時間攪拌した。反応混合物を室温まで冷却した後、10％クエン酸水溶液でpH7に調整後、水および酢酸エチルを加えた。有機層を分取し、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-90％ヘキサン／酢酸エチル］で精製し、黄色油状物の３－（（２Ｒ，６Ｓ）－２，６－ジメチルピペリジン－１－イル）ベンゾニトリル0.14gを得た。
　得られた３－（（２Ｒ，６Ｓ）－２，６－ジメチルピペリジン－１－イル）ベンゾニトリル0.14gにエチレングリコール1mLを加え、130℃に加熱後、水酸化ナトリウム51mgを加え、3時間加熱還流した。反応混合物を室温まで冷却後、1mol/L塩酸でpH4に調整し、水およびクロロホルムを加えた。有機層を分取し、水層をクロロホルムで抽出した。得られた有機層と抽出液を併せ、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；98-70％クロロホルム／メタノール］で精製し、褐色固体の３－（（２Ｒ，６Ｓ）－２，６－ジメチルピペリジン－１－イル）安息香酸0.029gを得た。
1H-NMR(CDCl3)δ値：8.20(s,1H),8.03(d,J=7.6Hz,1H),7.74-7.64(m,1H),7.42(dd,J=7.8,7.8Hz,1H),3.37-3.25(m,2H),2.02-1.77(m,5H),1.69-1.55(m,1H),0.98(d,J=6.1Hz,6H). Reference Example 43
Figure JPOXMLDOC01-appb-C000048
 (2R, 6S) -2,6-Dimethylpiperidine 0.46 mL of dioxane 3 mL solution under ice-cooling, 0.5 mol / L potassium bis (trimethylsilyl) amide-toluene solution 6.6 mL and 3-bromobenzonitrile 0.30 g of dioxane 3 mL solution Were sequentially added and stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, adjusted to pH 7 with 10% aqueous citric acid solution, and water and ethyl acetate were added. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-90% hexane / ethyl acetate] to give yellow oil 3-((2R, 6S) -2,6-Dimethylpiperidin-1-yl) benzonitrile (0.14 g) was obtained.
To 0.14 g of the obtained 3-((2R, 6S) -2,6-dimethylpiperidin-1-yl) benzonitrile, add 1 mL of ethylene glycol, heat to 130 ° C., add 51 mg of sodium hydroxide, and heat for 3 hours. Refluxed. The reaction mixture was cooled to room temperature, adjusted to pH 4 with 1 mol / L hydrochloric acid, and water and chloroform were added. The organic layer was separated and the aqueous layer was extracted with chloroform. The obtained organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 98-70% chloroform / methanol] to give 3-((2R, 6S) -2,6-dimethylpiperidin-1-yl) benzoic acid as a brown solid. 0.029 g of acid was obtained.
1 H-NMR (CDCl 3 ) δ value: 8.20 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.74-7.64 (m, 1H), 7.42 (dd, J = 7.8, 7.8 Hz, 1H), 3.37-3.25 (m, 2H), 2.02-1.77 (m, 5H), 1.69-1.55 (m, 1H), 0.98 (d, J = 6.1Hz, 6H).
参考例４４
Figure JPOXMLDOC01-appb-C000049
 　ｔｅｒｔ－ブチル＝３－ブロモベンゾアート0.31gのトルエン8mL溶液に、１,４－オキサゼパン塩酸塩0.50g、炭酸セシウム2.4g、トリス（ジベンジリデンアセトン）ジパラジウム（０）0.022g、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル0.057gおよび酢酸パラジウム（II）0.011gを加え、窒素雰囲気下、90℃で7時間攪拌した。反応混合物を室温まで冷却後、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-75％ヘキサン／酢酸エチル］で精製し、ｔｅｒｔ－ブチル＝３－（１,４－オキサゼパン－４－イル）ベンゾアートを得た。
　得られたｔｅｒｔ－ブチル＝３－（１,４－オキサゼパン－４－イル）ベンゾアートにトリフルオロ酢酸5mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、水を加え、飽和炭酸水素ナトリウム水溶液でpH4に調整後、固形物をろ取し、淡褐色固体の３－（１,４－オキサゼパン－４－イル）安息香酸0.10gを得た。
1H-NMR(DMSO-d6)δ値：7.29-7.23(m,2H),7.20-7.16(m,1H),7.01-6.96(m,1H),3.74-3.70(m,2H),3.62-3.54(m,6H),1.93-1.85(m,2H). Reference Example 44
Figure JPOXMLDOC01-appb-C000049
 To a solution of 0.31 g of tert-butyl 3-bromobenzoate in 8 mL of toluene, 0.50 g of 1,4-oxazepane hydrochloride, 2.4 g of cesium carbonate, 0.022 g of tris (dibenzylideneacetone) dipalladium (0), 2-dicyclohexylphosphine Fino-2 ′, 4 ′, 6′-triisopropylbiphenyl (0.057 g) and palladium (II) acetate (0.011 g) were added, and the mixture was stirred at 90 ° C. for 7 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-75% hexane / ethyl acetate], and tert-butyl = 3- (1,4-oxazepane). -4-yl) benzoate was obtained.
To the obtained tert-butyl = 3- (1,4-oxazepan-4-yl) benzoate was added 5 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added, the pH was adjusted to 4 with a saturated aqueous sodium hydrogen carbonate solution, and the solid was collected by filtration to give 3- (1,4-oxazepan-4-yl) benzoic acid as a light brown solid. 0.10 g was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 7.29-7.23 (m, 2H), 7.20-7.16 (m, 1H), 7.01-6.96 (m, 1H), 3.74-3.70 (m, 2H), 3.62 -3.54 (m, 6H), 1.93-1.85 (m, 2H).
参考例４５
Figure JPOXMLDOC01-appb-C000050
 　メチル＝３－アミノ－５－メトキシベンゾアート0.40gにＮ，Ｎ－ジメチルアセトアミド1.5mL、炭酸カリウム0.92g、ヨウ化カリウム0.18gおよび１，５－ジブロモペンタン0.31mLを加え、100℃で2時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にメタノール2mLおよび2mol/L水酸化ナトリウム水溶液3.3mLを加え、70℃で1時間30分間攪拌した。反応混合物を室温まで冷却後、2mol/L塩酸でpH4に調整し、減圧下で溶媒を留去した。得られた残留物に水および酢酸エチルを加えた。有機層を分取し、水層を酢酸エチルで3回抽出した。得られた有機層と抽出液を併せ、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；99-93％クロロホルム／メタノール］で精製し、淡赤色油状物の３－メトキシ－５－（ピペリジン－１－イル）安息香酸0.47gを得た。
1H-NMR(CDCl3)δ値：7.34-7.31(m,1H),7.09-7.06(m,1H),6.68(dd,J=2.2,2.2Hz,1H),3.84(s,3H),3.24-3.18(m,4H),1.74-1.66(m,4H),1.64-1.56(m,2H). Reference Example 45
Figure JPOXMLDOC01-appb-C000050
 To 0.40 g of methyl 3-amino-5-methoxybenzoate, 1.5 mL of N, N-dimethylacetamide, 0.92 g of potassium carbonate, 0.18 g of potassium iodide and 0.31 mL of 1,5-dibromopentane are added, and then at 100 ° C. for 2 hours. Stir. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 2 mL of methanol and 3.3 mL of 2 mol / L sodium hydroxide aqueous solution were added and stirred at 70 ° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, adjusted to pH 4 with 2 mol / L hydrochloric acid, and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The obtained organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-93% chloroform / methanol] to give 3-methoxy-5- (piperidine as a pale red oily substance. -1-yl) benzoic acid 0.47 g was obtained.
1 H-NMR (CDCl 3 ) δ value: 7.34-7.31 (m, 1H), 7.09-7.06 (m, 1H), 6.68 (dd, J = 2.2, 2.2Hz, 1H), 3.84 (s, 3H), 3.24-3.18 (m, 4H), 1.74-1.66 (m, 4H), 1.64-1.56 (m, 2H).
参考例４６～４８
　参考例４５と同様にして、表３に示す化合物を得た。 Reference Examples 46-48
In the same manner as in Reference Example 45, the compounds shown in Table 3 were obtained.
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
２－クロロ－３－（ピペリジン－１－イル）安息香酸
1H-NMR(CDCl3)δ値：7.52(dd,J=7.6,1.7Hz,1H),7.30-7.27(m,1H),7.21(dd,J=8.0,1.7Hz,1H),3.01-2.95(m,4H),1.80-1.72(m,4H),1.65-1.55(m,2H). 2-Chloro-3- (piperidin-1-yl) benzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.52 (dd, J = 7.6, 1.7 Hz, 1H), 7.30-7.27 (m, 1H), 7.21 (dd, J = 8.0, 1.7 Hz, 1H), 3.01- 2.95 (m, 4H), 1.80-1.72 (m, 4H), 1.65-1.55 (m, 2H).
２－メトキシ－３－（ピペリジン－１－イル）安息香酸
1H-NMR(CDCl3)δ値：11.74-11.61(broad,1H),7.79(dd,J=7.3,2.2Hz,1H),7.23-7.15(m,2H),4.15(s,3H),3.06-2.99(m,4H),1.80-1.72(m,4H),1.65-1.57(m,2H). 2-Methoxy-3- (piperidin-1-yl) benzoic acid
1 H-NMR (CDCl 3 ) δ value: 11.74-11.61 (broad, 1H), 7.79 (dd, J = 7.3, 2.2 Hz, 1H), 7.23-7.15 (m, 2H), 4.15 (s, 3H), 3.06-2.99 (m, 4H), 1.80-1.72 (m, 4H), 1.65-1.57 (m, 2H).
２－メチル－５－（ピペリジン－１－イル）安息香酸
1H-NMR(CDCl3)δ値：7.63(d,J=2.7Hz,1H),7.14(d,J=8.5Hz,1H),7.06(dd,J=8.5,2.7Hz,1H),3.19-3.12(m,4H),2.54(s,3H),1.77-1.68(m,4H),1.62-1.54(m,2H). 2-Methyl-5- (piperidin-1-yl) benzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.63 (d, J = 2.7 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 8.5, 2.7 Hz, 1H), 3.19 -3.12 (m, 4H), 2.54 (s, 3H), 1.77-1.68 (m, 4H), 1.62-1.54 (m, 2H).
参考例４９
Figure JPOXMLDOC01-appb-C000052
 　メチル＝３－（プロピルアミノ）ベンゾアート0.20gのＮ，Ｎ－ジメチルアセトアミド1mL溶液に、炭酸カリウム0.14gおよびヨウ化エチル0.16mLを加え、100-110℃で3時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-80％ヘキサン／酢酸エチル］で精製し、無色油状物のメチル＝３－（エチル（プロピル）アミノ）ベンゾアート0.21gを得た。
　得られたメチル＝３－（エチル（プロピル）アミノ）ベンゾアート0.21gにメタノール3mLおよび2mol/L水酸化ナトリウム水溶液1.3mLを加え、50-60℃で1時間攪拌した。反応混合物を室温まで冷却後、2mol/L塩酸でpH3に調整し、水を加え、固形物をろ取し、淡黄色固体の３－（エチル（プロピル）アミノ）安息香酸0.10gを得た。
1H-NMR(CDCl3)δ値：7.39-7.32(m,2H),7.31-7.27(m,1H),6.90-6.85(m,1H),3.41(q,J=7.1Hz,2H),3.29-3.23(m,2H),1.68-1.58(m,2H),1.17(t,J=7.0Hz,3H),0.95(t,J=7.3Hz,3H). Reference Example 49
Figure JPOXMLDOC01-appb-C000052
 To a solution of 0.20 g of methyl 3- (propylamino) benzoate in 1 mL of N, N-dimethylacetamide was added 0.14 g of potassium carbonate and 0.16 mL of ethyl iodide, and the mixture was stirred at 100-110 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane / ethyl acetate] to give a colorless oily methyl 3- (ethyl (propyl) ) 0.21 g of amino) benzoate was obtained.
To 0.21 g of the methyl = 3- (ethyl (propyl) amino) benzoate obtained, 3 mL of methanol and 1.3 mL of 2 mol / L sodium hydroxide aqueous solution were added and stirred at 50-60 ° C. for 1 hour. The reaction mixture was cooled to room temperature, adjusted to pH 3 with 2 mol / L hydrochloric acid, water was added, and the solid was collected by filtration to obtain 0.10 g of 3- (ethyl (propyl) amino) benzoic acid as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ value: 7.39-7.32 (m, 2H), 7.31-7.27 (m, 1H), 6.90-6.85 (m, 1H), 3.41 (q, J = 7.1Hz, 2H), 3.29-3.23 (m, 2H), 1.68-1.58 (m, 2H), 1.17 (t, J = 7.0Hz, 3H), 0.95 (t, J = 7.3Hz, 3H).
参考例５０
Figure JPOXMLDOC01-appb-C000053
 　参考例４９と同様にして、以下の化合物を得た。
３－（メチル（プロピル）アミノ）安息香酸
1H-NMR(CDCl3)δ値：7.42-7.37(m,2H),7.32-7.28(m,1H),6.94-6.88(m,1H),3.36-3.29(m,2H),2.98(s,3H),1.67-1.56(m,2H),0.94(t,J=7.4Hz,3H). Reference Example 50
Figure JPOXMLDOC01-appb-C000053
 In the same manner as in Reference Example 49, the following compound was obtained.
3- (Methyl (propyl) amino) benzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.42-7.37 (m, 2H), 7.32-7.28 (m, 1H), 6.94-6.88 (m, 1H), 3.36-3.29 (m, 2H), 2.98 (s 3H), 1.67-1.56 (m, 2H), 0.94 (t, J = 7.4Hz, 3H).
参考例５１
Figure JPOXMLDOC01-appb-C000054
 　参考例４９と同様にして、以下の化合物を得た。
３－（イソプロピル（メチル）アミノ）安息香酸
1H-NMR(CDCl3)δ値：7.52-7.48(m,1H),7.43-7.38(m,1H),7.33-7.29(m,1H),7.00(dd,J=8.0,2.9Hz,1H),4.21-4.10(m,1H),2.78(s,3H),1.19(d,J=6.6Hz,6H). Reference Example 51
Figure JPOXMLDOC01-appb-C000054
 In the same manner as in Reference Example 49, the following compound was obtained.
3- (Isopropyl (methyl) amino) benzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.52-7.48 (m, 1H), 7.43-7.38 (m, 1H), 7.33-7.29 (m, 1H), 7.00 (dd, J = 8.0,2.9Hz, 1H ), 4.21-4.10 (m, 1H), 2.78 (s, 3H), 1.19 (d, J = 6.6Hz, 6H).
参考例５２
Figure JPOXMLDOC01-appb-C000055
 　Ｎ－（４－シアノビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド1.0gのテトラヒドロフラン5.0mLおよび50％ヒドロキシルアミン水溶液0.20mL混液を、50℃で1時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物に２－プロパノールを加え、固形物をろ取し、白色固体のＮ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド1.0gを得た。
1H-NMR(DMSO-d6)δ値：12.37(s,1H),10.19(s,1H),9.06(d,J=1.9Hz,1H),7.81(d,J=8.3Hz,1H),7.75-7.68(m,2H),7.56-7.45(m,4H),7.45-7.33(m,3H),7.24-7.16(m,1H),6.33(s,2H),3.27-3.20(m,4H),1.70-1.51(m,6H). Reference Example 52
Figure JPOXMLDOC01-appb-C000055
 A mixture of 1.0 g of N- (4-cyanobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide in 5.0 g of tetrahydrofuran and 0.20 mL of 50% aqueous hydroxylamine was stirred at 50 ° C. for 1 hour. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. 2-Propanol was added to the resulting residue, and the solid was collected by filtration to give 1.0 g of N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide as a white solid. Got.
1 H-NMR (DMSO-d 6 ) δ value: 12.37 (s, 1H), 10.19 (s, 1H), 9.06 (d, J = 1.9Hz, 1H), 7.81 (d, J = 8.3Hz, 1H) , 7.75-7.68 (m, 2H), 7.56-7.45 (m, 4H), 7.45-7.33 (m, 3H), 7.24-7.16 (m, 1H), 6.33 (s, 2H), 3.27-3.20 (m, 4H), 1.70-1.51 (m, 6H).
参考例５３
Figure JPOXMLDOC01-appb-C000056
 　参考例５２と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：12.31(s,1H),10.18(s,1H),9.08(d,J=1.5Hz,1H),7.80(d,J=8.1Hz,1H),7.75-7.68(m,2H),7.56-7.45(m,3H),7.45-7.38(m,1H),7.38-7.30(m,1H),7.27-7.22(m,1H),7.22-7.14(m,1H),6.91(dd,J=8.3,2.7Hz,1H),6.31(s,2H),3.40(q,J=6.9Hz,4H),1.12(t,J=6.9Hz,6H). Reference Example 53
Figure JPOXMLDOC01-appb-C000056
 In the same manner as in Reference Example 52, the following compound was obtained.
3- (Diethylamino) -N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 12.31 (s, 1H), 10.18 (s, 1H), 9.08 (d, J = 1.5Hz, 1H), 7.80 (d, J = 8.1Hz, 1H) , 7.75-7.68 (m, 2H), 7.56-7.45 (m, 3H), 7.45-7.38 (m, 1H), 7.38-7.30 (m, 1H), 7.27-7.22 (m, 1H), 7.22-7.14 ( m, 1H), 6.91 (dd, J = 8.3, 2.7Hz, 1H), 6.31 (s, 2H), 3.40 (q, J = 6.9Hz, 4H), 1.12 (t, J = 6.9Hz, 6H).
参考例５４
Figure JPOXMLDOC01-appb-C000057
 　３－（ジエチルアミノ）安息香酸6.98gのテトラヒドロフラン50mL溶液に、Ｎ，Ｎ－ジメチルホルムアミド0.10mLおよびオキサリルクロリド3.7mLを順次加え、室温で1時間攪拌した。減圧下で溶媒を留去し、１－メチル－２－ピロリドン10mL、アセトニトリル15mLおよび２－アミノ－４－クロロベンゾニトリル5.03gの１－メチル－２－ピロリドン8.0mL溶液を順次加え、室温で2時間攪拌した。反応混合物に水20mLを加え、2.0mol/L水酸化ナトリウム水溶液でpH6.0に調整後、固形物をろ取し、白色固体のＮ－（５－クロロ－２－シアノフェニル）－３－（ジエチルアミノ）ベンズアミド10.5gを得た。
1H-NMR(DMSO-d6)δ値：10.51(s,1H),7.93(d,J=8.4Hz,1H),7.76(d,J=2.0Hz,1H),7.52(dd,J=8.4,2.0Hz,1H),7.32(dd,J=7.9,7.9Hz,1H),7.22-7.13(m,2H),6.91(dd,J=8.4,2.6Hz,1H),3.40(q,J=7.0Hz,4H),1.12(t,J=7.0Hz,6H). Reference Example 54
Figure JPOXMLDOC01-appb-C000057
 To a solution of 6.98 g of 3- (diethylamino) benzoic acid in 50 mL of tetrahydrofuran were sequentially added 0.10 mL of N, N-dimethylformamide and 3.7 mL of oxalyl chloride, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 10 mL of 1-methyl-2-pyrrolidone, 15 mL of acetonitrile and 8.03 g of 1-methyl-2-pyrrolidone in 5.03 g of 2-amino-4-chlorobenzonitrile were added successively, Stir for hours. 20 mL of water was added to the reaction mixture, and the pH was adjusted to 6.0 with a 2.0 mol / L aqueous sodium hydroxide solution. The solid matter was collected by filtration, and white solid N- (5-chloro-2-cyanophenyl) -3- ( 10.5 g of diethylamino) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.51 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1 H), 7.32 (dd, J = 7.9, 7.9 Hz, 1 H), 7.22-7.13 (m, 2 H), 6.91 (dd, J = 8.4, 2.6 Hz, 1 H), 3.40 (q, J = 7.0Hz, 4H), 1.12 (t, J = 7.0Hz, 6H).
参考例５５
Figure JPOXMLDOC01-appb-C000058
 　参考例５４と同様にして、以下の化合物を得た。
Ｎ－（５－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.59(s,1H),7.93(d,J=8.5Hz,1H),7.73(d,J=2.1Hz,1H),7.53(dd,J=8.5,2.1Hz,1H),7.51-7.47(m,1H),7.41-7.31(m,2H),7.23-7.16(m,1H),3.27-3.20(m,4H),1.69-1.52(m,6H). Reference Example 55
Figure JPOXMLDOC01-appb-C000058
 In the same manner as in Reference Example 54, the following compound was obtained.
N- (5-Chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.59 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 8.5, 2.1Hz, 1H), 7.51-7.47 (m, 1H), 7.41-7.31 (m, 2H), 7.23-7.16 (m, 1H), 3.27-3.20 (m, 4H), 1.69-1.52 (m, 6H).
参考例５６
Figure JPOXMLDOC01-appb-C000059
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ジエチルアミノ）ベンズアミド0.25g、フェノール0.11g、リン酸三カリウム0.40g、酢酸パラジウム（II）12mgおよび２－（ジ－ｔｅｒｔ－ブチルホスフィノ）－２’，４’，６’－トリイソプロピルビフェニル32mgのトルエン2.0mL混液を、マイクロウェーブ照射下200℃で10分間攪拌した。反応混合物に酢酸パラジウム（II）12mgを加え、マイクロウェーブ照射下200℃で10分間攪拌した。不溶物をろ去し、得られたろ液をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、Ｎ－（２－シアノ－５－フェノキシフェニル）－３－（ジエチルアミノ）ベンズアミド0.16gを得た。
1H-NMR(DMSO-d6+D2O)δ値：7.85(d,J=8.5Hz,1H),7.54-7.48(m,2H),7.34-7.27(m,2H),7.22-7.09(m,5H),6.99(dd,J=8.6,2.4Hz,1H),6.90(dd,J=8.3,2.4Hz,1H),3.38(q,J=7.0Hz,4H),1.10(t,J=7.0Hz,6H). Reference Example 56
Figure JPOXMLDOC01-appb-C000059
 0.25 g of N- (5-chloro-2-cyanophenyl) -3- (diethylamino) benzamide, 0.11 g of phenol, 0.40 g of tripotassium phosphate, 12 mg of palladium (II) acetate and 2- (di-tert-butylphosphino ) A mixture of 2.0 mg of toluene and 32 mg of 2 ′, 4 ′, 6′-triisopropylbiphenyl was stirred at 200 ° C. for 10 minutes under microwave irradiation. To the reaction mixture was added 12 mg of palladium (II) acetate, and the mixture was stirred at 200 ° C. for 10 minutes under microwave irradiation. Insoluble matter was removed by filtration, and the obtained filtrate was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (2-cyano 0.16 g of -5-phenoxyphenyl) -3- (diethylamino) benzamide was obtained.
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 7.85 (d, J = 8.5 Hz, 1H), 7.54-7.48 (m, 2H), 7.34-7.27 (m, 2H), 7.22-7.09 (m, 5H), 6.99 (dd, J = 8.6,2.4Hz, 1H), 6.90 (dd, J = 8.3,2.4Hz, 1H), 3.38 (q, J = 7.0Hz, 4H), 1.10 (t, (J = 7.0Hz, 6H).
参考例５７
Figure JPOXMLDOC01-appb-C000060
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド0.51g、スチレン0.35mL、酢酸ナトリウム0.25g、テトラブチルアンモニウムブロミド0.97g、酢酸パラジウム（II）17mgおよび２－ジシクロヘキシルホスフィノ－２’－（Ｎ，Ｎ－ジメチルアミノ）ビフェニル89mgのジオキサン3.0mL混液を、マイクロウェーブ照射下200℃で10分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-75％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（２－シアノ－５－（（Ｅ）－２－フェニルビニル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド0.38gを得た。
1H-NMR(DMSO-d6)δ値：10.52(s,1H),7.87(d,J=8.3Hz,1H),7.81(s,1H),7.71-7.64(m,3H),7.57-7.30(m,8H),7.24-7.15(m,1H),3.29-3.20(m,4H),1.71-1.52(m,6H). Reference Example 57
Figure JPOXMLDOC01-appb-C000060
 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide 0.51 g, styrene 0.35 mL, sodium acetate 0.25 g, tetrabutylammonium bromide 0.97 g, palladium (II) acetate 17 mg and 2 A mixture of 89 mL of dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl and 3.0 mL of dioxane was stirred at 200 ° C. for 10 minutes under microwave irradiation. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-75% hexane / ethyl acetate] to give a white solid N- (2-cyano-5- 0.38 g of ((E) -2-phenylvinyl) phenyl) -3- (piperidin-1-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.52 (s, 1H), 7.87 (d, J = 8.3Hz, 1H), 7.81 (s, 1H), 7.71-7.64 (m, 3H), 7.57- 7.30 (m, 8H), 7.24-7.15 (m, 1H), 3.29-3.20 (m, 4H), 1.71-1.52 (m, 6H).
参考例５８
Figure JPOXMLDOC01-appb-C000061
 　Ｎ－（２－シアノ－５－（（Ｅ）－２－フェニルビニル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド0.18gのテトラヒドロフラン5.0mL、酢酸エチル2.0mLおよびメタノール1.0mL混液に、10％パラジウム－炭素36mgを加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、Ｎ－（２－シアノ－５－（２－フェニルエチル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド0.18gを得た。
1H-NMR(DMSO-d6)δ値：10.44(s,1H),7.76(d,J=7.8Hz,1H),7.53-7.47(m,2H),7.38-7.33(m,2H),7.31-7.23(m,5H),7.22-7.14(m,2H),3.26-3.20(m,4H),3.03-2.87(m,4H),1.69-1.52(m,6H). Reference Example 58
Figure JPOXMLDOC01-appb-C000061
 N- (2-cyano-5-((E) -2-phenylvinyl) phenyl) -3- (piperidin-1-yl) benzamide 0.18 g in tetrahydrofuran 5.0 mL, ethyl acetate 2.0 mL and methanol 1.0 mL 10% palladium-carbon 36 mg was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to obtain 0.18 g of N- (2-cyano-5- (2-phenylethyl) phenyl) -3- (piperidin-1-yl) benzamide.
1 H-NMR (DMSO-d 6 ) δ value: 10.44 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.53-7.47 (m, 2H), 7.38-7.33 (m, 2H), 7.31-7.23 (m, 5H), 7.22-7.14 (m, 2H), 3.26-3.20 (m, 4H), 3.03-2.87 (m, 4H), 1.69-1.52 (m, 6H).
参考例５９
Figure JPOXMLDOC01-appb-C000062
 　２－アミノ－５－ブロモ－４－クロロベンゾニトリル0.20gに、フェニルボロン酸0.13g、炭酸ナトリウム0.22g、ジオキサン1.6mL、水0.40mLおよびビス（トリフェニルホスフィン）パラジウム（II）ジクロリド5.0mgを加え、マイクロウェーブ照射下150℃で5分間攪拌した。反応混合物に水および酢酸エチルを加えた。有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-80％ヘキサン／酢酸エチル］で精製し、白色固体の４－アミノ－６－クロロビフェニル－３－カルボニトリル0.14gを得た。
1H-NMR(DMSO-d6)δ値：7.45(s,1H),7.44-7.33(m,5H),6.98(s,1H),6.42-6.38(broad,2H). Reference Example 59
Figure JPOXMLDOC01-appb-C000062
 To 0.20 g of 2-amino-5-bromo-4-chlorobenzonitrile, 0.13 g of phenylboronic acid, 0.22 g of sodium carbonate, 1.6 mL of dioxane, 0.40 mL of water and 5.0 mg of bis (triphenylphosphine) palladium (II) dichloride In addition, the mixture was stirred at 150 ° C. for 5 minutes under microwave irradiation. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane / ethyl acetate], and white solid 4-amino-6-chlorobiphenyl- 0.14 g of 3-carbonitrile was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 7.45 (s, 1H), 7.44-7.33 (m, 5H), 6.98 (s, 1H), 6.42-6.38 (broad, 2H).
参考例６０
Figure JPOXMLDOC01-appb-C000063
 　２－アミノ－４－クロロ－５－メチルベンゾニトリル0.20gに、フェニルボロン酸0.18g、炭酸カリウム0.40g、ジオキサン1.6mL、水0.40mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5.0mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物に水および酢酸エチルを加えた。有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；90-80％ヘキサン／酢酸エチル］で精製し、５－アミノ－２－メチルビフェニル－４－カルボニトリル0.24gを得た。
1H-NMR(CDCl3)δ値：7.46-7.34(m,3H),7.30-7.24(m,3H),6.63(s,1H),4.33-4.22(broad,2H),2.11(s,3H). Reference Example 60
Figure JPOXMLDOC01-appb-C000063
 0.20 g 2-amino-4-chloro-5-methylbenzonitrile, 0.18 g phenylboronic acid, 0.40 g potassium carbonate, 1.6 mL dioxane, 0.40 mL water and bis (di-tert-butyl (4-dimethylaminophenyl) Phosphine) palladium (II) dichloride (5.0 mg) was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-80% hexane / ethyl acetate] to give 5-amino-2-methylbiphenyl-4-carbohydrate. 0.24 g of nitrile was obtained.
1 H-NMR (CDCl 3 ) δ value: 7.46-7.34 (m, 3H), 7.30-7.24 (m, 3H), 6.63 (s, 1H), 4.33-4.22 (broad, 2H), 2.11 (s, 3H ).
参考例６１
Figure JPOXMLDOC01-appb-C000064
 　４－アミノ－６－クロロビフェニル－３－カルボニトリル0.10gに、トリメチルボロキシン0.12mL、炭酸セシウム0.29g、ジオキサン1.0mL、水0.10mLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）51mgを加え、マイクロウェーブ照射下150℃で15分間攪拌した。反応混合物に水およびクロロホルムを加えた。有機層を分取し、水で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、白色固体の４－アミノ－６－メチルビフェニル－３－カルボニトリル72mgを得た。
1H-NMR(DMSO-d6)δ値：7.43-7.36(m,2H),7.35-7.26(m,3H),7.18(s,1H),6.71(s,1H),6.04-5.99(broad,2H),2.14(s,3H). Reference Example 61
Figure JPOXMLDOC01-appb-C000064
 To 0.10 g of 4-amino-6-chlorobiphenyl-3-carbonitrile was added 0.12 mL of trimethylboroxine, 0.29 g of cesium carbonate, 1.0 mL of dioxane, 0.10 mL of water and 51 mg of tetrakis (triphenylphosphine) palladium (0), The mixture was stirred at 150 ° C. for 15 minutes under microwave irradiation. Water and chloroform were added to the reaction mixture. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate] to give 4-amino-6-methylbiphenyl- as a white solid. 72 mg of 3-carbonitrile was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 7.43-7.36 (m, 2H), 7.35-7.26 (m, 3H), 7.18 (s, 1H), 6.71 (s, 1H), 6.04-5.99 (broad , 2H), 2.14 (s, 3H).
参考例６２
Figure JPOXMLDOC01-appb-C000065
 　３－（ピペリジン－１－イル）安息香酸39mgのテトラヒドロフラン1.0mL溶液に、Ｎ，Ｎ－ジメチルホルムアミド0.010mLおよびオキサリルクロリド0.019mLを順次加え、室温で1時間攪拌した。反応混合物にオキサリルクロリド0.019mLを加え、室温で30分間攪拌した。減圧下で溶媒を留去し、１－メチル－２－ピロリドン0.10mL、アセトニトリル1.0mLおよび４－アミノ－６－クロロビフェニル－３－カルボニトリル36mgのアセトニトリル2.0mL溶液を順次加え、室温で2時間攪拌した。減圧下で溶媒を留去し、飽和炭酸水素ナトリウム水溶液および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（２－クロロ－５－シアノビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド34mgを得た。
1H-NMR(CDCl3)δ値：8.87(s,1H),8.42(s,1H),7.59(s,1H),7.52-7.35(m,7H),7.29-7.23(m,1H),7.16(dd,J=8.2,2.3Hz,1H),3.31-3.24(m,4H),1.77-1.67(m,4H),1.67-1.58(m,2H). Reference Example 62
Figure JPOXMLDOC01-appb-C000065
 To a solution of 39 mg of 3- (piperidin-1-yl) benzoic acid in 1.0 mL of tetrahydrofuran were sequentially added 0.010 mL of N, N-dimethylformamide and 0.019 mL of oxalyl chloride, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 0.019 mL of oxalyl chloride was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and 0.10 mL of 1-methyl-2-pyrrolidone, 1.0 mL of acetonitrile, and 2.0 mL of acetonitrile of 36 mg of 4-amino-6-chlorobiphenyl-3-carbonitrile were sequentially added, and the mixture was stirred at room temperature for 2 hours. Stir. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and white solid N- (2-chloro-5- 5 34 mg of cyanobiphenyl-4-yl) -3- (piperidin-1-yl) benzamide were obtained.
1 H-NMR (CDCl 3 ) δ value: 8.87 (s, 1H), 8.42 (s, 1H), 7.59 (s, 1H), 7.52-7.35 (m, 7H), 7.29-7.23 (m, 1H), 7.16 (dd, J = 8.2, 2.3Hz, 1H), 3.31-3.24 (m, 4H), 1.77-1.67 (m, 4H), 1.67-1.58 (m, 2H).
参考例６３
Figure JPOXMLDOC01-appb-C000066
 　参考例６２と同様にして、以下の化合物を得た。
Ｎ－（５－シアノ－２－メチルビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.55(s,1H),8.37(s,1H),7.53-7.34(m,6H),7.31-7.25(m,3H),7.17-7.12(m,1H),3.31-3.24(m,4H),2.37(s,3H),1.77-1.69(m,4H),1.66-1.58(m,2H). Reference Example 63
Figure JPOXMLDOC01-appb-C000066
 In the same manner as in Reference Example 62, the following compound was obtained.
N- (5-cyano-2-methylbiphenyl-4-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.55 (s, 1H), 8.37 (s, 1H), 7.53-7.34 (m, 6H), 7.31-7.25 (m, 3H), 7.17-7.12 (m, 1H ), 3.31-3.24 (m, 4H), 2.37 (s, 3H), 1.77-1.69 (m, 4H), 1.66-1.58 (m, 2H).
参考例６４
Figure JPOXMLDOC01-appb-C000067
 　参考例６２と同様にして、以下の化合物を得た。
Ｎ－（４－シアノ－６－メチルビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(CDCl3)δ値：8.49(s,1H),8.34(s,1H),7.52-7.32(m,8H),7.27-7.23(m,1H),7.13(dd,J=8.2,2.3Hz,1H),3.29-3.22(m,4H),2.27(s,3H),1.75-1.66(m,4H),1.66-1.57(m,2H). Reference Example 64
Figure JPOXMLDOC01-appb-C000067
 In the same manner as in Reference Example 62, the following compound was obtained.
N- (4-Cyano-6-methylbiphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.49 (s, 1H), 8.34 (s, 1H), 7.52-7.32 (m, 8H), 7.27-7.23 (m, 1H), 7.13 (dd, J = 8.2 , 2.3Hz, 1H), 3.29-3.22 (m, 4H), 2.27 (s, 3H), 1.75-1.66 (m, 4H), 1.66-1.57 (m, 2H).
参考例６５
Figure JPOXMLDOC01-appb-C000068
 　参考例６２と同様にして、以下の化合物を得た。
Ｎ－（３－シアノ－５－メチルビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.32(s,1H),8.06(d,J=2.0Hz,1H),8.01-7.98(m,1H),7.82-7.76(m,2H),7.55-7.47(m,3H),7.47-7.34(m,3H),7.22-7.15(m,1H),3.27-3.19(m,4H),2.33(s,3H),1.71-1.51(m,6H). Reference Example 65
Figure JPOXMLDOC01-appb-C000068
 In the same manner as in Reference Example 62, the following compound was obtained.
N- (3-cyano-5-methylbiphenyl-4-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.32 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.01-7.98 (m, 1H), 7.82-7.76 (m, 2H), 7.55-7.47 (m, 3H), 7.47-7.34 (m, 3H), 7.22-7.15 (m, 1H), 3.27-3.19 (m, 4H), 2.33 (s, 3H), 1.71-1.51 (m, 6H) ).
参考例６６、６７
　参考例４と同様にして、表４に示す化合物を得た。 Reference examples 66 and 67
In the same manner as in Reference Example 4, the compounds shown in Table 4 were obtained.
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Ｎ－（４－シアノビフェニル－３－イル）－３－（ジエチルアミノ）－２－メチルベンズアミド
1H-NMR(CDCl3)δ値：8.88(s,1H),8.01(s,1H),7.71-7.65(m,3H),7.52-7.40(m,4H),7.29-7.25(m,2H),7.25-7.20(m,1H),3.03(q,J=7.0Hz,4H),2.48(s,3H),1.01(t,J=7.0Hz,6H). N- (4-Cyanobiphenyl-3-yl) -3- (diethylamino) -2-methylbenzamide
1 H-NMR (CDCl 3 ) δ value: 8.88 (s, 1H), 8.01 (s, 1H), 7.71-7.65 (m, 3H), 7.52-7.40 (m, 4H), 7.29-7.25 (m, 2H ), 7.25-7.20 (m, 1H), 3.03 (q, J = 7.0Hz, 4H), 2.48 (s, 3H), 1.01 (t, J = 7.0Hz, 6H).
２－クロロ－Ｎ－（４－シアノビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド
1H-NMR(CDCl3)δ値：8.92-8.85(broad,1H),8.32-8.22(broad,1H),7.72-7.64(m,3H),7.54-7.40(m,4H),7.38-7.29(m,2H),7.27-7.21(m,1H),3.18(q,J=7.0Hz,4H),1.07(t,J=7.0Hz,6H). 2-Chloro-N- (4-cyanobiphenyl-3-yl) -3- (diethylamino) benzamide
1 H-NMR (CDCl 3 ) δ value: 8.92-8.85 (broad, 1H), 8.32-8.22 (broad, 1H), 7.72-7.64 (m, 3H), 7.54-7.40 (m, 4H), 7.38-7.29 (m, 2H), 7.27-7.21 (m, 1H), 3.18 (q, J = 7.0Hz, 4H), 1.07 (t, J = 7.0Hz, 6H).
参考例６８
Figure JPOXMLDOC01-appb-C000070
 　３－（アセトキシ）安息香酸1.1gのテトラヒドロフラン6.0mL溶液に、Ｎ，Ｎ－ジメチルホルムアミド0.020mLおよびオキサリルクロリド0.61mLを順次加え、室温で10分間攪拌した。減圧下で溶媒を留去し、トルエンを加え、減圧下で溶媒を留去した。得られた残留物にテトラヒドロフラン6mL、ピリジン0.68mLおよび３－アミノビフェニル－４－カルボニトリル1.1gのテトラヒドロフラン6mL溶液を順次加え、室温で2時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、減圧下で溶媒を留去後、水を加え、固形物をろ取した。得られた固形物を50％２－プロパノール水溶液で洗浄し、白色固体の３－（（（４－シアノビフェニル－３－イル）アミノ）カルボニル）フェニル＝アセタートを得た。
　得られた３－（（（４－シアノビフェニル－３－イル）アミノ）カルボニル）フェニル＝アセタートにテトラヒドロフラン30mL、メタノール10mLおよび2mol/L水酸化ナトリウム水溶液8.4mLを加え、室温で10分間攪拌した。反応混合物を濃塩酸でpH4に調整後、減圧下で溶媒を留去した。得られた残留物に水を加え、固形物をろ取した。得られた固形物を50％メタノール水溶液で洗浄し、淡黄色固体のＮ－（４－シアノビフェニル－３－イル）－３－ヒドロキシベンズアミド1.6gを得た。
1H-NMR(DMSO-d6)δ値：10.59(s,1H),9.90-9.76(broad,1H),7.95(d,J=8.1Hz,1H),7.88(d,J=1.7Hz,1H),7.78-7.71(m,3H),7.57-7.50(m,2H),7.50-7.43(m,2H),7.42-7.33(m,2H),7.06-7.00(m,1H). Reference Example 68
Figure JPOXMLDOC01-appb-C000070
 To a 6.0 mL tetrahydrofuran solution of 1.1 g of 3- (acetoxy) benzoic acid, 0.020 mL of N, N-dimethylformamide and 0.61 mL of oxalyl chloride were sequentially added and stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, toluene was added, and the solvent was distilled off under reduced pressure. To the obtained residue, tetrahydrofuran (6 mL), pyridine (0.68 mL) and 3-aminobiphenyl-4-carbonitrile (1.1 g) in tetrahydrofuran (6 mL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the solvent was evaporated under reduced pressure, water was added, and the solid was collected by filtration. The obtained solid was washed with 50% aqueous 2-propanol to obtain 3-(((4-cyanobiphenyl-3-yl) amino) carbonyl) phenyl acetate as a white solid.
To the obtained 3-(((4-cyanobiphenyl-3-yl) amino) carbonyl) phenyl acetate, 30 mL of tetrahydrofuran, 10 mL of methanol and 8.4 mL of 2 mol / L aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was adjusted to pH 4 with concentrated hydrochloric acid, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid was collected by filtration. The obtained solid was washed with 50% aqueous methanol solution to obtain 1.6 g of light yellow solid N- (4-cyanobiphenyl-3-yl) -3-hydroxybenzamide.
1 H-NMR (DMSO-d 6 ) δ value: 10.59 (s, 1H), 9.90-9.76 (broad, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.78-7.71 (m, 3H), 7.57-7.50 (m, 2H), 7.50-7.43 (m, 2H), 7.42-7.33 (m, 2H), 7.06-7.00 (m, 1H).
参考例６９
Figure JPOXMLDOC01-appb-C000071
 　参考例４５と同様にして、以下の化合物を得た。
（Ｅ）－３－（３－（ピペリジン－１－イル）フェニル）アクリル酸
1H-NMR(DMSO-d6)δ値：12.35-12.27(broad,1H),7.52(d,J=16.0Hz,1H),7.25-7.17(m,2H),7.07-7.00(m,1H),7.00-6.94(m,1H),6.49(d,J=16.0Hz,1H),3.22-3.14(m,4H),1.66-1.49(m,6H). Reference Example 69
Figure JPOXMLDOC01-appb-C000071
 In the same manner as in Reference Example 45, the following compound was obtained.
(E) -3- (3- (Piperidin-1-yl) phenyl) acrylic acid
1 H-NMR (DMSO-d 6 ) δ value: 12.35-12.27 (broad, 1H), 7.52 (d, J = 16.0 Hz, 1H), 7.25-7.17 (m, 2H), 7.07-7.00 (m, 1H ), 7.00-6.94 (m, 1H), 6.49 (d, J = 16.0Hz, 1H), 3.22-3.14 (m, 4H), 1.66-1.49 (m, 6H).
参考例７０
Figure JPOXMLDOC01-appb-C000072
 　メチル＝３－アミノ－４－メチルベンゾアート0.33gのＮ，Ｎ－ジメチルアセトアミド3.0mL溶液に、炭酸カリウム0.97gおよびヨウ化エチル0.72mLを加え、90-110℃で4時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-80％ヘキサン／酢酸エチル］で精製し、無色油状物のメチル＝３－（ジエチルアミノ）－４－メチルベンゾアートを得た。
　得られたメチル＝３－（ジエチルアミノ）－４－メチルベンゾアートにメタノール4.0mLおよび2mol/L水酸化ナトリウム水溶液3.0mLを加え、70℃で1時間攪拌した。反応混合物を室温まで冷却後、2mol/L塩酸でpH4に調整し、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去し、白色固体の３－（ジエチルアミノ）－４－メチル安息香酸0.30gを得た。
1H-NMR(CDCl3)δ値：7.80(d,J=1.5Hz,1H),7.72(dd,J=7.9,1.5Hz,1H),7.28(d,J=7.9Hz,1H),3.02(q,J=7.1Hz,4H),2.36(s,3H),0.99(t,J=7.1Hz,6H). Reference Example 70
Figure JPOXMLDOC01-appb-C000072
 To a solution of 0.33 g of methyl 3-amino-4-methylbenzoate in 3.0 mL of N, N-dimethylacetamide was added 0.97 g of potassium carbonate and 0.72 mL of ethyl iodide, and the mixture was stirred at 90-110 ° C. for 4 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-80% hexane / ethyl acetate] to give a colorless oily methyl 3- (diethylamino)- 4-Methylbenzoate was obtained.
To the obtained methyl = 3- (diethylamino) -4-methylbenzoate, 4.0 mL of methanol and 3.0 mL of a 2 mol / L aqueous sodium hydroxide solution were added, and the mixture was stirred at 70 ° C. for 1 hour. The reaction mixture was cooled to room temperature, adjusted to pH 4 with 2 mol / L hydrochloric acid, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.30 g of white solid 3- (diethylamino) -4-methylbenzoic acid.
1 H-NMR (CDCl 3 ) δ value: 7.80 (d, J = 1.5 Hz, 1H), 7.72 (dd, J = 7.9, 1.5 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 3.02 (q, J = 7.1Hz, 4H), 2.36 (s, 3H), 0.99 (t, J = 7.1Hz, 6H).
参考例７１、７２
　参考例７０と同様にして、表５に示す化合物を得た。 Reference examples 71 and 72
In the same manner as in Reference Example 70, the compounds shown in Table 5 were obtained.
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
２－クロロ－３－（ジエチルアミノ）安息香酸
1H-NMR(CDCl3)δ値：7.54(dd,J=6.6,2.7Hz,1H),7.29-7.23(m,2H),3.14(q,J=7.1Hz,4H),1.03(t,J=7.1Hz,6H). 2-Chloro-3- (diethylamino) benzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.54 (dd, J = 6.6, 2.7 Hz, 1H), 7.29-7.23 (m, 2H), 3.14 (q, J = 7.1 Hz, 4H), 1.03 (t, (J = 7.1Hz, 6H).
３－（ジエチルアミノ）－２－メチル安息香酸
1H-NMR(CDCl3)δ値：7.71(d,J=7.8Hz,1H),7.31-7.17(m,2H),3.00(q,J=7.1Hz,4H),2.58(s,3H),0.97(t,J=7.1Hz,6H). 3- (Diethylamino) -2-methylbenzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.71 (d, J = 7.8 Hz, 1H), 7.31-7.17 (m, 2H), 3.00 (q, J = 7.1 Hz, 4H), 2.58 (s, 3H) , 0.97 (t, J = 7.1Hz, 6H).
参考例７３
Figure JPOXMLDOC01-appb-C000074
 　参考例７０と同様にして、以下の化合物を得た。
５－（ジエチルアミノ）－２－メチル安息香酸
1H-NMR(CDCl3)δ値：7.52-7.32(m,1H),7.18-7.06(m,1H),6.96-6.70(m,1H),3.43-3.31(m,4H),2.54(s,3H),1.17(t,J=7.0Hz,6H). Reference Example 73
Figure JPOXMLDOC01-appb-C000074
 In the same manner as in Reference Example 70, the following compound was obtained.
5- (Diethylamino) -2-methylbenzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.52-7.32 (m, 1H), 7.18-7.06 (m, 1H), 6.96-6.70 (m, 1H), 3.43-3.31 (m, 4H), 2.54 (s , 3H), 1.17 (t, J = 7.0Hz, 6H).
参考例７４
Figure JPOXMLDOC01-appb-C000075
 　参考例７０と同様にして、以下の化合物を得た。
２－クロロ－５－（ジエチルアミノ）安息香酸
1H-NMR(CDCl3)δ値：7.25-7.19(m,2H),6.70(dd,J=9.0,3.2Hz,1H),3.34(q,J=7.1Hz,4H),1.15(t,J=7.1Hz,6H). Reference Example 74
Figure JPOXMLDOC01-appb-C000075
 In the same manner as in Reference Example 70, the following compound was obtained.
2-Chloro-5- (diethylamino) benzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.25-7.19 (m, 2H), 6.70 (dd, J = 9.0, 3.2 Hz, 1H), 3.34 (q, J = 7.1 Hz, 4H), 1.15 (t, (J = 7.1Hz, 6H).
参考例７５
Figure JPOXMLDOC01-appb-C000076
 参考例７０と同様にして、以下の化合物を得た。
３－クロロ－５－（ジエチルアミノ）安息香酸
1H-NMR(CDCl3)δ値：7.32-7.29(m,1H),7.27-7.24(m,1H),6.82-6.79(m,1H),3.38(q,J=7.1Hz,4H),1.18(t,J=7.1Hz,6H). Reference Example 75
Figure JPOXMLDOC01-appb-C000076
 In the same manner as in Reference Example 70, the following compound was obtained.
3-Chloro-5- (diethylamino) benzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.32-7.29 (m, 1H), 7.27-7.24 (m, 1H), 6.82-6.79 (m, 1H), 3.38 (q, J = 7.1 Hz, 4H), 1.18 (t, J = 7.1Hz, 6H).
参考例７６
Figure JPOXMLDOC01-appb-C000077
 　３－アミノ－５－メトキシ安息香酸0.50gのメタノール3.0mL懸濁液に、硫酸1.0mLを加え、70℃で4時間攪拌した。反応混合物を室温まで冷却した後、氷冷下、2mol/L水酸化ナトリウム水溶液でpH10に調整後、減圧下で溶媒を留去し、水および酢酸エチルを加えた。有機層を分取し、水層を酢酸エチルで抽出した。得られた有機層と抽出液を併せ、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去し、メチル＝３－アミノ－５－メトキシベンゾアートを得た。
　得られたメチル＝３－アミノ－５－メトキシベンゾアートのＮ，Ｎ－ジメチルアセトアミド2.0mL溶液に、炭酸カリウム1.0gおよびヨウ化エチル0.77mLを加え、70℃で3時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-80％ヘキサン／酢酸エチル］で精製し、無色油状物のメチル＝３－（ジエチルアミノ）－５－メトキシベンゾアートを得た。
　得られたメチル＝３－（ジエチルアミノ）－５－メトキシベンゾアートにメタノール4.0mLおよび2mol/L水酸化ナトリウム水溶液3.5mLを加え、60℃で2時間攪拌した。反応混合物を室温まで冷却後、2mol/L塩酸でpH4に調整し、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、不溶物をろ去後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去し、白色固体の３－（ジエチルアミノ）－５－メトキシ安息香酸0.38gを得た。
1H-NMR(CDCl3)δ値：7.11-7.05(m,1H),6.95-6.89(m,1H),6.45-6.40(m,1H),3.84(s,3H),3.42-3.33(m,4H),1.18(t,J=6.7Hz,6H). Reference Example 76
Figure JPOXMLDOC01-appb-C000077
 1.0 mL of sulfuric acid was added to a 3.0 mL methanol suspension of 0.50 g of 3-amino-5-methoxybenzoic acid, and the mixture was stirred at 70 ° C. for 4 hours. The reaction mixture was cooled to room temperature, adjusted to pH 10 with 2 mol / L aqueous sodium hydroxide under ice cooling, the solvent was evaporated under reduced pressure, and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The obtained organic layer and the extract were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain methyl 3-amino-5-methoxybenzoate.
To a 2.0 mL solution of methyl 3-amino-5-methoxybenzoate obtained in N, N-dimethylacetamide was added 1.0 g of potassium carbonate and 0.77 mL of ethyl iodide, and the mixture was stirred at 70 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-80% hexane / ethyl acetate] to give a colorless oily methyl 3- (diethylamino)- 5-Methoxybenzoate was obtained.
To the obtained methyl = 3- (diethylamino) -5-methoxybenzoate, 4.0 mL of methanol and 3.5 mL of 2 mol / L sodium hydroxide aqueous solution were added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, adjusted to pH 4 with 2 mol / L hydrochloric acid, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, the insoluble material was filtered off, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and white solid 3- (diethylamino) -5-methoxybenzoic acid 0.38 g Got.
1 H-NMR (CDCl 3 ) δ value: 7.11-7.05 (m, 1H), 6.95-6.89 (m, 1H), 6.45-6.40 (m, 1H), 3.84 (s, 3H), 3.42-3.33 (m , 4H), 1.18 (t, J = 6.7Hz, 6H).
参考例７７
Figure JPOXMLDOC01-appb-C000078
 　参考例７６と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－２－メトキシ安息香酸
1H-NMR(CDCl3)δ値：7.82-7.75(m,1H),7.25-7.14(m,2H),4.08(s,3H),3.25-3.16(m,4H),1.05(t,J=7.1Hz,6H). Reference Example 77
Figure JPOXMLDOC01-appb-C000078
 In the same manner as in Reference Example 76, the following compound was obtained.
3- (Diethylamino) -2-methoxybenzoic acid
1 H-NMR (CDCl 3 ) δ value: 7.82-7.75 (m, 1H), 7.25-7.14 (m, 2H), 4.08 (s, 3H), 3.25-3.16 (m, 4H), 1.05 (t, J = 7.1Hz, 6H).
参考例７８
Figure JPOXMLDOC01-appb-C000079
 　ｔｅｒｔ－ブチル＝３－ブロモ－５－ニトロベンゾアート0.74gにトリメチルボロキシン0.51mL、炭酸セシウム1.6g、ジオキサン30mL、水3.0mLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）0.28gを加え、窒素雰囲気下、7時間加熱還流した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-80％ヘキサン／酢酸エチル］で精製し、淡黄色固体のｔｅｒｔ－ブチル＝３－メチル－５－ニトロベンゾアート0.55gを得た。
1H-NMR(CDCl3)δ値：8.61-8.57(m,1H),8.21-8.17(m,1H),8.14-8.10(m,1H),2.54-2.50(m,3H),1.62(s,3H). Reference Example 78
Figure JPOXMLDOC01-appb-C000079
 Add 0.71 g of trimethylboroxine, 1.6 g of cesium carbonate, 30 mL of dioxane, 3.0 mL of water and 0.28 g of tetrakis (triphenylphosphine) palladium (0) to 0.74 g of tert-butyl = 3-bromo-5-nitrobenzoate, and add nitrogen. The mixture was heated to reflux for 7 hours under atmosphere. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-80% hexane / ethyl acetate], and tert-butyl 3-methyl- 0.55 g of 5-nitrobenzoate was obtained.
1 H-NMR (CDCl 3 ) δ value: 8.61-8.57 (m, 1H), 8.21-8.17 (m, 1H), 8.14-8.10 (m, 1H), 2.54-2.50 (m, 3H), 1.62 (s , 3H).
参考例７９
Figure JPOXMLDOC01-appb-C000080
 　ｔｅｒｔ－ブチル＝３－メチル－５－ニトロベンゾアート0.55gのメタノール10mL溶液に、10％パラジウム－炭素55mgを加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、無色油状物のｔｅｒｔ－ブチル＝３－アミノ－５－メチルベンゾアート0.47gを得た。
　得られたｔｅｒｔ－ブチル＝３－アミノ－５－メチルベンゾアート0.21gのＮ，Ｎ－ジメチルアセトアミド1.0mL溶液に、炭酸カリウム0.28g、ヨウ化カリウム50mgおよび１，５－ジブロモペンタン0.14mLを加え、100℃で3時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-80％ヘキサン／酢酸エチル］で精製し、無色油状物のｔｅｒｔ－ブチル＝３－メチル－５－（ピペリジン－１－イル）ベンゾアートを得た。
　得られたｔｅｒｔ－ブチル＝３－メチル－５－（ピペリジン－１－イル）ベンゾアートにトリフルオロ酢酸5.0mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、水を加え、2mol/L水酸化ナトリウム水溶液でpH4に調整後、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物に水を加え、飽和炭酸水素ナトリウム水溶液でpH5.5に調整後、固形物をろ取し、白色固体の３－メチル－５－（ピペリジン－１－イル）安息香酸50mgを得た。
1H-NMR(DMSO-d6)δ値：7.26-7.23(m,1H),7.16-7.13(m,1H),7.01-6.98(m,1H),3.18-3.12(m,4H),2.29(s,3H),1.65-1.57(m,4H),1.57-1.50(m,2H). Reference Example 79
Figure JPOXMLDOC01-appb-C000080
 To a solution of 0.55 g of tert-butyl = 3-methyl-5-nitrobenzoate in 10 mL of methanol was added 55 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.47 g of tert-butyl = 3-amino-5-methylbenzoate as a colorless oil.
0.28 g of potassium carbonate, 50 mg of potassium iodide and 0.14 mL of 1,5-dibromopentane were added to a solution of 0.21 g of tert-butyl 3-amino-5-methylbenzoate in 1.0 mL of N, N-dimethylacetamide. The mixture was stirred at 100 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-80% hexane / ethyl acetate] to give a colorless oily substance of tert-butyl = 3-methyl- 5- (Piperidin-1-yl) benzoate was obtained.
To the obtained tert-butyl = 3-methyl-5- (piperidin-1-yl) benzoate was added 5.0 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added, the pH was adjusted to 4 with a 2 mol / L aqueous sodium hydroxide solution, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the pH was adjusted to 5.5 with a saturated aqueous sodium hydrogen carbonate solution. The solid was collected by filtration, and 50 mg of white solid 3-methyl-5- (piperidin-1-yl) benzoic acid was added. Obtained.
1 H-NMR (DMSO-d 6 ) δ value: 7.26-7.23 (m, 1H), 7.16-7.13 (m, 1H), 7.01-6.98 (m, 1H), 3.18-3.12 (m, 4H), 2.29 (s, 3H), 1.65-1.57 (m, 4H), 1.57-1.50 (m, 2H).
参考例８０
Figure JPOXMLDOC01-appb-C000081
 　ｔｅｒｔ－ブチル＝３－メチル－５－ニトロベンゾアート0.50gのメタノール10mL溶液に、10％パラジウム－炭素35mgを加え、水素雰囲気下、室温で1時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、無色油状物のｔｅｒｔ－ブチル＝３－アミノ－５－メチルベンゾアートを得た。
　得られたｔｅｒｔ－ブチル＝３－アミノ－５－メチルベンゾアートのＮ，Ｎ－ジメチルアセトアミド3.0mL溶液に、炭酸カリウム0.58gおよびヨウ化エチル0.65mLを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；97-85％ヘキサン／酢酸エチル］で精製し、ｔｅｒｔ－ブチル＝３－（ジエチルアミノ）－５－メチルベンゾアートを得た。
　得られたｔｅｒｔ－ブチル＝３－（ジエチルアミノ）－５－メチルベンゾアートにトリフルオロ酢酸2.0mL溶液を加え、室温で1時間攪拌した。減圧下で溶媒を留去し、水を加え、飽和炭酸水素ナトリウム水溶液でpH4に調整後、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；75-0％ヘキサン／酢酸エチル］で精製し、淡黄色固体の３－（ジエチルアミノ）－５－メチル安息香酸0.19gを得た。
1H-NMR(CDCl3)δ値：7.45-7.38(m,2H),7.04-6.97(m,1H),3.44(q,J=7.1Hz,4H),2.40(s,3H),1.17(t,J=7.1Hz,6H). Reference Example 80
Figure JPOXMLDOC01-appb-C000081
 To a solution of 0.50 g of tert-butyl = 3-methyl-5-nitrobenzoate in 10 mL of methanol was added 35 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a colorless oily product of tert-butyl = 3-amino-5-methylbenzoate.
0.58 g of potassium carbonate and 0.65 mL of ethyl iodide were added to a 3.0 mL N, N-dimethylacetamide solution of the resulting tert-butyl = 3-amino-5-methylbenzoate, and the mixture was heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 97-85% hexane / ethyl acetate], and tert-butyl = 3- (diethylamino) -5- Methyl benzoate was obtained.
To the obtained tert-butyl = 3- (diethylamino) -5-methylbenzoate was added 2.0 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added, the pH was adjusted to 4 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 75-0% hexane / ethyl acetate] to give a pale yellow solid of 3- (diethylamino) -5- 0.19 g of methylbenzoic acid was obtained.
1 H-NMR (CDCl 3 ) δ value: 7.45-7.38 (m, 2H), 7.04-6.97 (m, 1H), 3.44 (q, J = 7.1 Hz, 4H), 2.40 (s, 3H), 1.17 ( t, J = 7.1Hz, 6H).
参考例８１
Figure JPOXMLDOC01-appb-C000082
 　参考例４１と同様にして、以下の化合物を得た。
３－アミノ－２’－フルオロビフェニル－４－カルボニトリル
1H-NMR(DMSO-d6)δ値：7.52-7.41(m,3H),7.37-7.26(m,2H),6.99-6.93(m,1H),6.79-6.71(m,1H),6.22-6.14(broad,2H). Reference Example 81
Figure JPOXMLDOC01-appb-C000082
 In the same manner as in Reference Example 41, the following compound was obtained.
3-Amino-2'-fluorobiphenyl-4-carbonitrile
1 H-NMR (DMSO-d 6 ) δ value: 7.52-7.41 (m, 3H), 7.37-7.26 (m, 2H), 6.99-6.93 (m, 1H), 6.79-6.71 (m, 1H), 6.22 -6.14 (broad, 2H).
参考例８２
Figure JPOXMLDOC01-appb-C000083
 　参考例２７と同様にして、以下の化合物を得た。
Ｎ－（４－シアノ－２’－フルオロビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.52(s,1H),7.98(d,J=8.0Hz,1H),7.83-7.79(m,1H),7.66-7.58(m,2H),7.56-7.48(m,1H),7.43-7.29(m,3H),7.25-7.16(m,2H),6.91(dd,J=8.3,2.2Hz,1H),3.41(q,J=7.0Hz,4H),1.12(t,J=7.0Hz,6H). Reference Example 82
Figure JPOXMLDOC01-appb-C000083
 In the same manner as in Reference Example 27, the following compound was obtained.
N- (4-Cyano-2'-fluorobiphenyl-3-yl) -3- (diethylamino) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.52 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.66-7.58 (m, 2H), 7.56-7.48 (m, 1H), 7.43-7.29 (m, 3H), 7.25-7.16 (m, 2H), 6.91 (dd, J = 8.3,2.2Hz, 1H), 3.41 (q, J = 7.0Hz, 4H), 1.12 (t, J = 7.0Hz, 6H).
参考例８３
Figure JPOXMLDOC01-appb-C000084
 　参考例６２と同様にして、以下の化合物を得た。
Ｎ－（４－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.55(s,1H),8.08(d,J=2.5Hz,1H),7.82(dd,J=8.7,2.5Hz,1H),7.60(d,J=8.7Hz,1H),7.51-7.47(m,1H),7.40-7.32(m,2H),7.21-7.16(m,1H),3.26-3.20(m,4H),1.68-1.60(m,4H),1.60-1.52(m,2H). Reference Example 83
Figure JPOXMLDOC01-appb-C000084
 In the same manner as in Reference Example 62, the following compound was obtained.
N- (4-Chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.55 (s, 1H), 8.08 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 8.7, 2.5 Hz, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.51-7.47 (m, 1H), 7.40-7.32 (m, 2H), 7.21-7.16 (m, 1H), 3.26-3.20 (m, 4H), 1.68-1.60 (m, 4H), 1.60-1.52 (m, 2H).
参考例８４
Figure JPOXMLDOC01-appb-C000085
 　参考例２７と同様にして、以下の化合物を得た。
（Ｅ）－Ｎ－（５－クロロ－２－シアノフェニル）－３－（３－（ジエチルアミノ）フェニル）アクリルアミド
1H-NMR(DMSO-d6)δ値：10.46-10.41(broad,1H),7.93(d,J=2.1Hz,1H),7.89(d,J=8.5Hz,1H),7.61(d,J=15.6Hz,1H),7.45(dd,J=8.5,2.1Hz,1H),7.22(dd,J=7.9,7.9Hz,1H),6.95-6.83(m,3H),6.73(dd,J=8.4,2.3Hz,1H),3.38(q,J=7.0Hz,4H),1.11(t,J=7.0Hz,6H). Reference Example 84
Figure JPOXMLDOC01-appb-C000085
 In the same manner as in Reference Example 27, the following compound was obtained.
(E) -N- (5-Chloro-2-cyanophenyl) -3- (3- (diethylamino) phenyl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 10.46-10.41 (broad, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 15.6Hz, 1H), 7.45 (dd, J = 8.5,2.1Hz, 1H), 7.22 (dd, J = 7.9,7.9Hz, 1H), 6.95-6.83 (m, 3H), 6.73 (dd, J = 8.4, 2.3Hz, 1H), 3.38 (q, J = 7.0Hz, 4H), 1.11 (t, J = 7.0Hz, 6H).
参考例８５
Figure JPOXMLDOC01-appb-C000086
 　参考例６２と同様にして、以下の化合物を得た。
Ｎ－（４－シアノビフェニル－３－イル）－５，６，７，８－テトラヒドロナフタレン－２－カルボキサミド
1H-NMR(CDCl3)δ値：8.92(d,J=1.7Hz,1H),8.46-8.38(broad,1H),7.71-7.62(m,5H),7.52-7.40(m,4H),7.21(d,J=7.8Hz,1H),2.93-2.80(m,4H),1.91-1.80(m,4H). Reference Example 85
Figure JPOXMLDOC01-appb-C000086
 In the same manner as in Reference Example 62, the following compound was obtained.
N- (4-Cyanobiphenyl-3-yl) -5,6,7,8-tetrahydronaphthalene-2-carboxamide
1 H-NMR (CDCl 3 ) δ value: 8.92 (d, J = 1.7 Hz, 1H), 8.46-8.38 (broad, 1H), 7.71-7.62 (m, 5H), 7.52-7.40 (m, 4H), 7.21 (d, J = 7.8Hz, 1H), 2.93-2.80 (m, 4H), 1.91-1.80 (m, 4H).
参考例８６、８７
　参考例８５と同様にして、表６に示す化合物を得た。 Reference examples 86 and 87
In the same manner as in Reference Example 85, the compounds shown in Table 6 were obtained.
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Ｎ－（４－シアノビフェニル－３－イル）－３－エトキシベンズアミド
1H-NMR(CDCl3)δ値：8.91(d,J=1.7Hz,1H),8.48-8.40(broad,1H),7.71-7.64(m,3H),7.52-7.40(m,7H),7.16-7.11(m,1H),4.13(q,J=7.0Hz,2H),1.46(t,J=7.0Hz,3H). N- (4-Cyanobiphenyl-3-yl) -3-ethoxybenzamide
1 H-NMR (CDCl 3 ) δ value: 8.91 (d, J = 1.7 Hz, 1H), 8.48-8.40 (broad, 1H), 7.71-7.64 (m, 3H), 7.52-7.40 (m, 7H), 7.16-7.11 (m, 1H), 4.13 (q, J = 7.0Hz, 2H), 1.46 (t, J = 7.0Hz, 3H).
Ｎ－（４－シアノビフェニル－３－イル）－３－シクロプロピルベンズアミド
1H-NMR(CDCl3)δ値：8.92(d,J=1.7Hz,1H),8.47-8.40(broad,1H),7.71-7.65(m,5H),7.52-7.39(m,5H),7.34-7.29(m,1H),2.05-1.96(m,1H),1.09-1.02(m,2H),0.82-0.77(m,2H). N- (4-Cyanobiphenyl-3-yl) -3-cyclopropylbenzamide
1 H-NMR (CDCl 3 ) δ value: 8.92 (d, J = 1.7 Hz, 1H), 8.47-8.40 (broad, 1H), 7.71-7.65 (m, 5H), 7.52-7.39 (m, 5H), 7.34-7.29 (m, 1H), 2.05-1.96 (m, 1H), 1.09-1.02 (m, 2H), 0.82-0.77 (m, 2H).
参考例８８
Figure JPOXMLDOC01-appb-C000088
 　参考例２７と同様にして、以下の化合物を得た。
（Ｅ）－３－（３－ブロモフェニル）－Ｎ－（４－シアノビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：10.47-10.42(broad,1H),8.08(d,J=1.7Hz,1H),7.96-7.89(m,2H),7.76-7.60(m,6H),7.57-7.40(m,4H),7.07(d,J=15.8Hz,1H). Reference Example 88
Figure JPOXMLDOC01-appb-C000088
 In the same manner as in Reference Example 27, the following compound was obtained.
(E) -3- (3-Bromophenyl) -N- (4-cyanobiphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 10.47-10.42 (broad, 1H), 8.08 (d, J = 1.7 Hz, 1H), 7.96-7.89 (m, 2H), 7.76-7.60 (m, 6H) ), 7.57-7.40 (m, 4H), 7.07 (d, J = 15.8Hz, 1H).
参考例８９、９０
　参考例８８と同様にして、表７に示す化合物を得た。 Reference examples 89 and 90
In the same manner as in Reference Example 88, the compounds shown in Table 7 were obtained.
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（３－ニトロフェニル）アクリルアミド
1H-NMR(DMSO-d6)δ値：10.65-10.40(broad,1H),8.55-8.50(m,1H),8.30-8.23(m,1H),8.16-8.08(m,2H),7.94(d,J=8.0Hz,1H),7.85-7.71(m,4H),7.68(dd,J=8.2,1.6Hz,1H),7.57-7.50(m,2H),7.50-7.44(m,1H),7.23(d,J=15.9Hz,1H). (E) -N- (4-cyanobiphenyl-3-yl) -3- (3-nitrophenyl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 10.65-10.40 (broad, 1H), 8.55-8.50 (m, 1H), 8.30-8.23 (m, 1H), 8.16-8.08 (m, 2H), 7.94 (d, J = 8.0Hz, 1H), 7.85-7.71 (m, 4H), 7.68 (dd, J = 8.2,1.6Hz, 1H), 7.57-7.50 (m, 2H), 7.50-7.44 (m, 1H ), 7.23 (d, J = 15.9Hz, 1H).
（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（４－ニトロフェニル）アクリルアミド
1H-NMR(DMSO-d6)δ値：10.62-10.58(broad,1H),8.34-8.29(m,2H),8.07(d,J=1.4Hz,1H),7.98-7.93(m,3H),7.79(d,J=15.9Hz,1H),7.76-7.72(m,2H),7.70(dd,J=8.2,1.8Hz,1H),7.57-7.50(m,2H),7.50-7.44(m,1H),7.20(d,J=15.9Hz,1H). (E) -N- (4-cyanobiphenyl-3-yl) -3- (4-nitrophenyl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 10.62-10.58 (broad, 1H), 8.34-8.29 (m, 2H), 8.07 (d, J = 1.4Hz, 1H), 7.98-7.93 (m, 3H) ), 7.79 (d, J = 15.9Hz, 1H), 7.76-7.72 (m, 2H), 7.70 (dd, J = 8.2, 1.8Hz, 1H), 7.57-7.50 (m, 2H), 7.50-7.44 ( m, 1H), 7.20 (d, J = 15.9Hz, 1H).
参考例９１
Figure JPOXMLDOC01-appb-C000090
 　（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（３－ニトロフェニル）アクリルアミド3.4gにテトラヒドロフラン340mL、２－プロパノール40mL、水20mL、塩化アンモニウム0.30gおよび鉄粉1.6gを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、鉄粉1.6gを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；80-40％ヘキサン／酢酸エチル］で精製し、淡黄色固体の（Ｅ）－３－（３－アミノフェニル）－Ｎ－（４－シアノビフェニル－３－イル）アクリルアミド2.1gを得た。
1H-NMR(DMSO-d6)δ値：10.46-10.42(broad,1H),8.05(d,J=1.8Hz,1H),7.93(d,J=8.2Hz,1H),7.76-7.71(m,2H),7.67(dd,J=8.2,1.8Hz,1H),7.57-7.44(m,4H),7.10(dd,J=7.7,7.7Hz,1H),6.88-6.77(m,3H),6.67-6.61(m,1H),5.29-5.24(broad,2H). Reference Example 91
Figure JPOXMLDOC01-appb-C000090
 (E) -N- (4-Cyanobiphenyl-3-yl) -3- (3-nitrophenyl) acrylamide 3.4 g, tetrahydrofuran 340 mL, 2-propanol 40 mL, water 20 mL, ammonium chloride 0.30 g and iron powder 1.6 g In addition, the mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 1.6 g of iron powder was added and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-40% hexane / ethyl acetate] to give (E) -3- (3 2.1 g of -aminophenyl) -N- (4-cyanobiphenyl-3-yl) acrylamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.46-10.42 (broad, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.76-7.71 ( m, 2H), 7.67 (dd, J = 8.2, 1.8Hz, 1H), 7.57-7.44 (m, 4H), 7.10 (dd, J = 7.7, 7.7Hz, 1H), 6.88-6.77 (m, 3H) , 6.67-6.61 (m, 1H), 5.29-5.24 (broad, 2H).
参考例９２
Figure JPOXMLDOC01-appb-C000091
 　参考例９１と同様にして、以下の化合物を得た。
（Ｅ）－３－（４－アミノフェニル）－Ｎ－（４－シアノビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：10.21-10.16(broad,1H),8.05(d,J=1.4Hz,1H),7.89(d,J=8.0Hz,1H),7.75-7.69(m,2H),7.63(dd,J=8.2,1.8Hz,1H),7.57-7.43(m,4H),7.37-7.31(m,2H),6.67-6.56(m,3H),5.81-5.66(broad,2H). Reference Example 92
Figure JPOXMLDOC01-appb-C000091
 In the same manner as in Reference Example 91, the following compound was obtained.
(E) -3- (4-Aminophenyl) -N- (4-cyanobiphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 10.21-10.16 (broad, 1H), 8.05 (d, J = 1.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.75-7.69 ( m, 2H), 7.63 (dd, J = 8.2,1.8Hz, 1H), 7.57-7.43 (m, 4H), 7.37-7.31 (m, 2H), 6.67-6.56 (m, 3H), 5.81-5.66 ( broad, 2H).
参考例９３
Figure JPOXMLDOC01-appb-C000092
 　（Ｅ）－３－（３－アミノフェニル）－Ｎ－（４－シアノビフェニル－３－イル）アクリルアミド1.0gのＮ，Ｎ－ジメチルアセトアミド10mL溶液に、炭酸カリウム0.58gおよびヨウ化エチル0.68mLを加え、100℃で2時間30分間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；80-60％ヘキサン／酢酸エチル］で精製し、黄色固体の（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（３－（ジエチルアミノ）フェニル）アクリルアミド0.76gを得た。
1H-NMR(DMSO-d6)δ値：10.45-10.39(broad,1H),8.03(d,J=1.4Hz,1H),7.93(d,J=8.3Hz,1H),7.76-7.71(m,2H),7.67(dd,J=8.1,1.7Hz,1H),7.61(d,J=15.6Hz,1H),7.57-7.50(m,2H),7.50-7.44(m,1H),7.23(dd,J=7.9,7.9Hz,1H),6.96-6.84(m,3H),6.76-6.70(m,1H),3.38(q,J=7.0Hz,4H),1.12(t,J=7.0Hz,6H). Reference Example 93
Figure JPOXMLDOC01-appb-C000092
 (E) -3- (3-Aminophenyl) -N- (4-cyanobiphenyl-3-yl) acrylamide (1.0 g) in N, N-dimethylacetamide (10 mL) solution was added potassium carbonate (0.58 g) and ethyl iodide (0.68 mL). In addition, the mixture was stirred at 100 ° C. for 2 hours and 30 minutes. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-60% hexane / ethyl acetate] to give (E) -N- (4- 0.76 g of cyanobiphenyl-3-yl) -3- (3- (diethylamino) phenyl) acrylamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.45-10.39 (broad, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.76-7.71 ( m, 2H), 7.67 (dd, J = 8.1,1.7Hz, 1H), 7.61 (d, J = 15.6Hz, 1H), 7.57-7.50 (m, 2H), 7.50-7.44 (m, 1H), 7.23 (dd, J = 7.9,7.9Hz, 1H), 6.96-6.84 (m, 3H), 6.76-6.70 (m, 1H), 3.38 (q, J = 7.0Hz, 4H), 1.12 (t, J = 7.0 Hz, 6H).
参考例９４
Figure JPOXMLDOC01-appb-C000093
 　参考例９３と同様にして、以下の化合物を得た。
（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（４－（ジエチルアミノ）フェニル）アクリルアミド
1H-NMR(DMSO-d6)δ値：10.23-10.18(broad,1H),8.06(d,J=1.6Hz,1H),7.90(d,J=8.1Hz,1H),7.75-7.69(m,2H),7.63(dd,J=8.1,1.6Hz,1H),7.56-7.50(m,3H),7.50-7.43(m,3H),6.74-6.64(m,3H),3.40(q,J=7.0Hz,4H),1.12(t,J=7.0Hz,6H). Reference Example 94
Figure JPOXMLDOC01-appb-C000093
 In the same manner as in Reference Example 93, the following compound was obtained.
(E) -N- (4-cyanobiphenyl-3-yl) -3- (4- (diethylamino) phenyl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 10.23-10.18 (broad, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.75-7.69 ( m, 2H), 7.63 (dd, J = 8.1, 1.6Hz, 1H), 7.56-7.50 (m, 3H), 7.50-7.43 (m, 3H), 6.74-6.64 (m, 3H), 3.40 (q, J = 7.0Hz, 4H), 1.12 (t, J = 7.0Hz, 6H).
参考例９５
Figure JPOXMLDOC01-appb-C000094
 　（Ｅ）－３－（４－アミノフェニル）－Ｎ－（４－シアノビフェニル－３－イル）アクリルアミド0.15gのＮ，Ｎ－ジメチルアセトアミド1.0mL溶液に、炭酸カリウム85mgおよび１，５－ジブロモペンタン0.072mLを加え、90℃で2時間攪拌した。反応混合物に１，５－ジブロモペンタン0.024mLを加え、100℃で1時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、橙色固体の（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（４－（ピペリジン－１－イル）フェニル）アクリルアミド98mgを得た。
1H-NMR(DMSO-d6)δ値：10.28-10.22(broad,1H),8.06(d,J=1.7Hz,1H),7.93-7.88(m,1H),7.75-7.69(m,2H),7.64(dd,J=8.3,1.7Hz,1H),7.58-7.44(m,6H),7.00-6.95(m,2H),6.75(d,J=15.6Hz,1H),3.33-3.26(m,4H),1.63-1.55(m,6H). Reference Example 95
Figure JPOXMLDOC01-appb-C000094
 (E) 3- (4-aminophenyl) -N- (4-cyanobiphenyl-3-yl) acrylamide 0.15 g in N, N-dimethylacetamide 1.0 mL solution was added potassium carbonate 85 mg and 1,5-dibromopentane. 0.072 mL was added and stirred at 90 ° C. for 2 hours. To the reaction mixture, 0.024 mL of 1,5-dibromopentane was added and stirred at 100 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give an orange solid (E) -N- (4-cyanobiphenyl-3-yl) -3- (4- (piperidin-1-yl) 98 mg of phenyl) acrylamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.28-10.22 (broad, 1H), 8.06 (d, J = 1.7 Hz, 1H), 7.93-7.88 (m, 1H), 7.75-7.69 (m, 2H ), 7.64 (dd, J = 8.3, 1.7Hz, 1H), 7.58-7.44 (m, 6H), 7.00-6.95 (m, 2H), 6.75 (d, J = 15.6Hz, 1H), 3.33-3.26 ( m, 4H), 1.63-1.55 (m, 6H).
参考例９６
Figure JPOXMLDOC01-appb-C000095
 　（Ｅ）－３－（３－アミノフェニル）－Ｎ－（４－シアノビフェニル－３－イル）アクリルアミド0.26gのＮ，Ｎ－ジメチルアセトアミド1.3mL溶液に、炭酸カリウム0.21gおよびヨウ化メチル0.084mLを加え、95℃で2時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-80％ヘキサン／酢酸エチル］で精製し、黄色固体の（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（３－（ジメチルアミノ）フェニル）アクリルアミド0.17gを得た。
1H-NMR(CDCl3)δ値：8.95-8.90(m,1H),7.83-7.76(m,2H),7.69-7.64(m,3H),7.51-7.39(m,4H),7.32-7.25(m,1H),6.99-6.93(m,1H),6.93-6.88(m,1H),6.80(dd,J=8.2,2.6Hz,1H),6.61(d,J=15.4Hz,1H),3.02(s,6H). Reference Example 96
Figure JPOXMLDOC01-appb-C000095
 (E) -3- (3-Aminophenyl) -N- (4-cyanobiphenyl-3-yl) acrylamide 0.26 g in a solution of N, N-dimethylacetamide 1.3 mL, potassium carbonate 0.21 g and methyl iodide 0.084 mL And stirred at 95 ° C. for 2 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane / ethyl acetate] to give (E) -N- (4- 0.17 g of cyanobiphenyl-3-yl) -3- (3- (dimethylamino) phenyl) acrylamide was obtained.
1 H-NMR (CDCl 3 ) δ value: 8.95-8.90 (m, 1H), 7.83-7.76 (m, 2H), 7.69-7.64 (m, 3H), 7.51-7.39 (m, 4H), 7.32-7.25 (m, 1H), 6.99-6.93 (m, 1H), 6.93-6.88 (m, 1H), 6.80 (dd, J = 8.2,2.6Hz, 1H), 6.61 (d, J = 15.4Hz, 1H), 3.02 (s, 6H).
参考例９７
Figure JPOXMLDOC01-appb-C000096
 　（Ｅ）－３－（３－アミノフェニル）－Ｎ－（４－シアノビフェニル－３－イル）アクリルアミド0.24gにＮ，Ｎ－ジメチルアセトアミド1.0mL、炭酸カリウム0.14g、ヨウ化カリウム70mgおよび１，４－ジブロモブタン0.099mLを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物に水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；90-70％ヘキサン／酢酸エチル］で精製し、黄色固体の（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（３－（ピロリジン－１－イル）フェニル）アクリルアミド88mgを得た。
1H-NMR(DMSO-d6)δ値：10.41(s,1H),8.07-8.02(m,1H),7.92(d,J=8.2Hz,1H),7.76-7.70(m,2H),7.67(dd,J=8.2,1.5Hz,1H),7.60(d,J=15.9Hz,1H),7.57-7.50(m,2H),7.50-7.44(m,1H),7.24(dd,J=7.8,7.8Hz,1H),6.99-6.86(m,2H),6.82-6.76(m,1H),6.65-6.58(m,1H),3.32-3.23(m,4H),2.02-1.93(m,4H). Reference Example 97
Figure JPOXMLDOC01-appb-C000096
 (E) -3- (3-Aminophenyl) -N- (4-cyanobiphenyl-3-yl) acrylamide 0.24 g, N, N-dimethylacetamide 1.0 mL, potassium carbonate 0.14 g, potassium iodide 70 mg and 1, 0.099 mL of 4-dibromobutane was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-70% hexane / ethyl acetate] to give (E) -N- (4- 88 mg of cyanobiphenyl-3-yl) -3- (3- (pyrrolidin-1-yl) phenyl) acrylamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.41 (s, 1H), 8.07-8.02 (m, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.67 (dd, J = 8.2,1.5Hz, 1H), 7.60 (d, J = 15.9Hz, 1H), 7.57-7.50 (m, 2H), 7.50-7.44 (m, 1H), 7.24 (dd, J = 7.8, 7.8Hz, 1H), 6.99-6.86 (m, 2H), 6.82-6.76 (m, 1H), 6.65-6.58 (m, 1H), 3.32-3.23 (m, 4H), 2.02-1.93 (m, 4H).
参考例９８
Figure JPOXMLDOC01-appb-C000097
 　（Ｅ）－３－（３－アミノフェニル）－Ｎ－（４－シアノビフェニル－３－イル）アクリルアミド0.11gにＮ，Ｎ－ジメチルアセトアミド2.0mL、炭酸カリウム63mg、ヨウ化カリウム32mgおよび１，５－ジブロモ－３－メチルペンタン95mgを加え、100℃で1時間攪拌した。反応混合物を室温まで冷却した後、１，５－ジブロモ－３－メチルペンタン40mgを加え、100℃で1時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-80％ヘキサン／酢酸エチル］で精製し、黄色固体の（Ｅ）－Ｎ－（４－シアノビフェニル－３－イル）－３－（３－（４－メチルピペリジン－１－イル）フェニル）アクリルアミド0.10gを得た。
1H-NMR(DMSO-d6)δ値：10.41-10.36(broad,1H),8.08-8.04(m,1H),7.92(d,J=8.1Hz,1H),7.76-7.70(m,2H),7.67(dd,J=8.1,1.8Hz,1H),7.62(d,J=15.9Hz,1H),7.57-7.50(m,2H),7.50-7.44(m,1H),7.27(dd,J=7.8,7.8Hz,1H),7.23-7.17(m,1H),7.07-6.93(m,3H),3.79-3.70(m,2H),2.76-2.65(m,2H),1.75-1.66(m,2H),1.31-1.15(m,2H),0.95(d,J=6.6Hz,3H),0.93-0.87(m,1H). Reference Example 98
Figure JPOXMLDOC01-appb-C000097
 (E) -3- (3-aminophenyl) -N- (4-cyanobiphenyl-3-yl) acrylamide 0.11 g, N, N-dimethylacetamide 2.0 mL, potassium carbonate 63 mg, potassium iodide 32 mg and 1,5 -95 mg of dibromo-3-methylpentane was added, and the mixture was stirred at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, 40 mg of 1,5-dibromo-3-methylpentane was added, and the mixture was stirred at 100 ° C. for 1 hr. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-80% hexane / ethyl acetate] to give (E) -N- (4- 0.10 g of cyanobiphenyl-3-yl) -3- (3- (4-methylpiperidin-1-yl) phenyl) acrylamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.41-10.36 (broad, 1H), 8.08-8.04 (m, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.76-7.70 (m, 2H) ), 7.67 (dd, J = 8.1, 1.8Hz, 1H), 7.62 (d, J = 15.9Hz, 1H), 7.57-7.50 (m, 2H), 7.50-7.44 (m, 1H), 7.27 (dd, J = 7.8, 7.8Hz, 1H), 7.23-7.17 (m, 1H), 7.07-6.93 (m, 3H), 3.79-3.70 (m, 2H), 2.76-2.65 (m, 2H), 1.75-1.66 ( m, 2H), 1.31-1.15 (m, 2H), 0.95 (d, J = 6.6Hz, 3H), 0.93-0.87 (m, 1H).
参考例９９
Figure JPOXMLDOC01-appb-C000098
 　参考例５６と同様にして、以下の化合物を得た。
Ｎ－（２－シアノ－５－フェノキシフェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.44(s,1H),7.85(d,J=8.8Hz,1H),7.53-7.42(m,3H),7.38-7.26(m,3H),7.22-7.14(m,3H),7.11(d,J=2.4Hz,1H),6.98(dd,J=8.7,2.6Hz,1H),3.24-3.18(m,4H),1.67-1.59(m,4H),1.59-1.50(m,2H). Reference Example 99
Figure JPOXMLDOC01-appb-C000098
 In the same manner as in Reference Example 56, the following compound was obtained.
N- (2-cyano-5-phenoxyphenyl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.44 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.53-7.42 (m, 3H), 7.38-7.26 (m, 3H), 7.22-7.14 (m, 3H), 7.11 (d, J = 2.4Hz, 1H), 6.98 (dd, J = 8.7, 2.6Hz, 1H), 3.24-3.18 (m, 4H), 1.67-1.59 (m, 4H), 1.59-1.50 (m, 2H).
参考例１００
Figure JPOXMLDOC01-appb-C000099
 　参考例６２と同様にして、以下の化合物を得た。
Ｎ－（３－シアノ－２－フルオロビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.73(s,1H),7.93(dd,J=8.8,8.8Hz,1H),7.65-7.60(m,2H),7.57-7.44(m,5H),7.42-7.35(m,2H),7.23-7.18(m,1H),3.27-3.20(m,4H),1.69-1.61(m,4H),1.61-1.53(m,2H). Reference Example 100
Figure JPOXMLDOC01-appb-C000099
 In the same manner as in Reference Example 62, the following compound was obtained.
N- (3-Cyano-2-fluorobiphenyl-4-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.73 (s, 1H), 7.93 (dd, J = 8.8, 8.8Hz, 1H), 7.65-7.60 (m, 2H), 7.57-7.44 (m, 5H ), 7.42-7.35 (m, 2H), 7.23-7.18 (m, 1H), 3.27-3.20 (m, 4H), 1.69-1.61 (m, 4H), 1.61-1.53 (m, 2H).
参考例１０１
Figure JPOXMLDOC01-appb-C000100
 　参考例２７と同様にして、以下の化合物を得た。
Ｎ－（４－シアノ－６－メトキシビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.39(s,1H),7.60(s,1H),7.55-7.49(m,3H),7.49-7.43(m,3H),7.43-7.37(m,1H),7.37-7.33(m,2H),7.20-7.13(m,1H),3.86(s,3H),3.25-3.19(m,4H),1.68-1.60(m,4H),1.60-1.52(m,2H). Reference Example 101
Figure JPOXMLDOC01-appb-C000100
 In the same manner as in Reference Example 27, the following compound was obtained.
N- (4-Cyano-6-methoxybiphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.39 (s, 1H), 7.60 (s, 1H), 7.55-7.49 (m, 3H), 7.49-7.43 (m, 3H), 7.43-7.37 (m , 1H), 7.37-7.33 (m, 2H), 7.20-7.13 (m, 1H), 3.86 (s, 3H), 3.25-3.19 (m, 4H), 1.68-1.60 (m, 4H), 1.60-1.52 (m, 2H).
参考例１０２
Figure JPOXMLDOC01-appb-C000101
 　参考例２７と同様にして、以下の化合物を得た。
Ｎ－（２－シアノ－５－フェニルピリジン－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.74(s,1H),8.97(d,J=2.2Hz,1H),8.36(d,J=2.2Hz,1H),7.88-7.82(m,2H),7.61-7.49(m,4H),7.42-7.37(m,2H),7.25-7.18(m,1H),3.28-3.21(m,4H),1.69-1.61(m,4H),1.61-1.53(m,2H). Reference Example 102
Figure JPOXMLDOC01-appb-C000101
 In the same manner as in Reference Example 27, the following compound was obtained.
N- (2-cyano-5-phenylpyridin-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.74 (s, 1H), 8.97 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H), 7.88-7.82 (m, 2H), 7.61-7.49 (m, 4H), 7.42-7.37 (m, 2H), 7.25-7.18 (m, 1H), 3.28-3.21 (m, 4H), 1.69-1.61 (m, 4H), 1.61- 1.53 (m, 2H).
参考例１０３
Figure JPOXMLDOC01-appb-C000102
 　参考例２７と同様にして、以下の化合物を得た。
Ｎ－（４－シアノ－６－フルオロビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.58-10.53(broad,1H),8.03(d,J=10.7Hz,1H),7.77-7.71(m,1H),7.65-7.60(m,2H),7.58-7.48(m,4H),7.39-7,34(m,2H),7.22-7.14(m,1H),3.26-3.20(m,4H),1.68-1.60(m,4H),1.60-1.52(m,2H). Reference Example 103
Figure JPOXMLDOC01-appb-C000102
 In the same manner as in Reference Example 27, the following compound was obtained.
N- (4-Cyano-6-fluorobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.58-10.53 (broad, 1H), 8.03 (d, J = 10.7Hz, 1H), 7.77-7.71 (m, 1H), 7.65-7.60 (m, 2H ), 7.58-7.48 (m, 4H), 7.39-7, 34 (m, 2H), 7.22-7.14 (m, 1H), 3.26-3.20 (m, 4H), 1.68-1.60 (m, 4H), 1.60 -1.52 (m, 2H).
参考例１０４
Figure JPOXMLDOC01-appb-C000103
 　参考例２７と同様にして、以下の化合物を得た。
Ｎ－（４－シアノ－５－フルオロビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.73(s,1H),7.83-7.75(m,4H),7.58-7.49(m,4H),7.42-7.35(m,2H),7.24-7.17(m,1H),3.28-3.21(m,4H),1.69-1.61(m,4H),1.61-1.53(m,2H). Reference Example 104
Figure JPOXMLDOC01-appb-C000103
 In the same manner as in Reference Example 27, the following compound was obtained.
N- (4-Cyano-5-fluorobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.73 (s, 1H), 7.83-7.75 (m, 4H), 7.58-7.49 (m, 4H), 7.42-7.35 (m, 2H), 7.24-7.17 (m, 1H), 3.28-3.21 (m, 4H), 1.69-1.61 (m, 4H), 1.61-1.53 (m, 2H).
参考例１０５
Figure JPOXMLDOC01-appb-C000104
 　参考例６０と同様にして、以下の化合物を得た。
４－アミノ－２－フルオロビフェニル－３－カルボニトリル
1H-NMR(DMSO-d6)δ値：7.52-7.40(m,5H),7.39-7.31(m,1H),6.70(d,J=8.8Hz,1H),6.59(s,2H). Reference Example 105
Figure JPOXMLDOC01-appb-C000104
 In the same manner as in Reference Example 60, the following compound was obtained.
4-Amino-2-fluorobiphenyl-3-carbonitrile
1 H-NMR (DMSO-d 6 ) δ value: 7.52-7.40 (m, 5H), 7.39-7.31 (m, 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.59 (s, 2H).
参考例１０６
Figure JPOXMLDOC01-appb-C000105
 　４－ブロモ－５－メトキシ－２－ニトロベンゾニトリル0.77gにエチレングリコールジメチルエーテル4.0mL、フェニルボロン酸0.44g、炭酸カリウム0.99g、水1.0mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド10mgを加え、マイクロウェーブ照射下110℃で10分間攪拌した。反応混合物に水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物のメタノール15mLおよびテトラヒドロフラン30mL混液に、10％パラジウム－炭素77mgを加え、水素雰囲気下、室温で3時間攪拌した。反応混合物に10％パラジウム－炭素0.15gを加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-50％ヘキサン／酢酸エチル］で精製し、褐色固体の５－アミノ－２－メトキシビフェニル－４－カルボニトリル0.43gを得た。
1H-NMR(DMSO-d6)δ値：7.44-7.40(m,4H),7.40-7.33(m,1H),7.09(s,1H),6.78(s,1H),5.67(s,2H),3.66(s,3H). Reference Example 106
Figure JPOXMLDOC01-appb-C000105
 4-Bromo-5-methoxy-2-nitrobenzonitrile (0.77 g), ethylene glycol dimethyl ether (4.0 mL), phenylboronic acid (0.44 g), potassium carbonate (0.99 g), water (1.0 mL) and bis (di-tert-butyl (4-dimethylaminophenyl) ) Phosphine) palladium (II) dichloride (10 mg) was added, and the mixture was stirred at 110 ° C. for 10 minutes under microwave irradiation. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To a mixture of 15 mL of the obtained residue and 30 mL of methanol, 77 mg of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. To the reaction mixture, 10% palladium-carbon (0.15 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-50% hexane / ethyl acetate] to give a brown solid of 5-amino-2-methoxybiphenyl- 0.43 g of 4-carbonitrile was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 7.44-7.40 (m, 4H), 7.40-7.33 (m, 1H), 7.09 (s, 1H), 6.78 (s, 1H), 5.67 (s, 2H ), 3.66 (s, 3H).
参考例１０７
Figure JPOXMLDOC01-appb-C000106
 　参考例１０６と同様にして、以下の化合物を得た。
３－アミノ－５－フェニルピリジン－２－カルボニトリル
1H-NMR(DMSO-d6)δ値：8.20(d,J=2.0Hz,1H),7.70-7.63(m,2H),7.56-7.45(m,3H),7.44(d,J=2.0Hz,1H),6.37(s,2H). Reference Example 107
Figure JPOXMLDOC01-appb-C000106
 In the same manner as in Reference Example 106, the following compound was obtained.
3-Amino-5-phenylpyridine-2-carbonitrile
1 H-NMR (DMSO-d 6 ) δ value: 8.20 (d, J = 2.0 Hz, 1H), 7.70-7.63 (m, 2H), 7.56-7.45 (m, 3H), 7.44 (d, J = 2.0 Hz, 1H), 6.37 (s, 2H).
参考例１０８
Figure JPOXMLDOC01-appb-C000107
 　参考例１０６と同様にして、以下の化合物を得た。
５－アミノ－２－フルオロビフェニル－４－カルボニトリル
1H-NMR(DMSO-d6)δ値：7.51-7.41(m,6H),6.89(d,J=6.8Hz,1H),6.02(s,2H). Reference Example 108
Figure JPOXMLDOC01-appb-C000107
 In the same manner as in Reference Example 106, the following compound was obtained.
5-Amino-2-fluorobiphenyl-4-carbonitrile
1 H-NMR (DMSO-d 6 ) δ value: 7.51-7.41 (m, 6H), 6.89 (d, J = 6.8 Hz, 1H), 6.02 (s, 2H).
参考例１０９
Figure JPOXMLDOC01-appb-C000108
 　参考例６０と同様にして、以下の化合物を得た。
３－アミノ－５－フルオロビフェニル－４－カルボニトリル
1H-NMR(DMSO-d6)δ値：7.64-7.59(m,2H),7.52-7.41(m,3H),6.91-6.87(m,1H),6.84-6.77(m,1H),6.55(s,2H). Reference Example 109
Figure JPOXMLDOC01-appb-C000108
 In the same manner as in Reference Example 60, the following compound was obtained.
3-Amino-5-fluorobiphenyl-4-carbonitrile
1 H-NMR (DMSO-d 6 ) δ value: 7.64-7.59 (m, 2H), 7.52-7.41 (m, 3H), 6.91-6.87 (m, 1H), 6.84-6.77 (m, 1H), 6.55 (s, 2H).
参考例１１０
Figure JPOXMLDOC01-appb-C000109
 　４－ブロモ－５－メトキシ－２－ニトロ安息香酸1.4gのテトラヒドロフラン15mL溶液に１－ヒドロキシベンゾトリアゾール0.76gおよびＮ－（３－（ジメチルアミノ）プロピル）－Ｎ’－エチルカルボジイミド塩酸塩1.1gを加え、室温で30分間攪拌した。反応混合物に25％アンモニア水溶液1.0mLを加え、室温で10分間攪拌した。反応混合物に水、酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水層を酢酸エチルで抽出後、有機層と抽出液を併せ、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；99-90％クロロホルム／メタノール］で精製し、４－ブロモ－５－メトキシ－２－ニトロベンズアミドを得た。
　得られた４－ブロモ－５－メトキシ－２－ニトロベンズアミドにジオキサン40mL、ピリジン5.0mLおよび無水トリフルオロ酢酸2.7mLを順次加え、室温で10分間攪拌した。氷水に反応混合物を加え、固形物をろ取し、白色固体の４－ブロモ－５－メトキシ－２－ニトロベンゾニトリル0.77gを得た。
1H-NMR(DMSO-d6)δ値：8.62(s,1H),7.89(s,1H),4.08(s,3H). Reference Example 110
Figure JPOXMLDOC01-appb-C000109
 To a solution of 1.4 g of 4-bromo-5-methoxy-2-nitrobenzoic acid in 15 mL of tetrahydrofuran was added 0.76 g of 1-hydroxybenzotriazole and 1.1 g of N- (3- (dimethylamino) propyl) -N′-ethylcarbodiimide hydrochloride. The mixture was further stirred at room temperature for 30 minutes. To the reaction mixture was added 1.0 mL of 25% aqueous ammonia solution, and the mixture was stirred at room temperature for 10 minutes. Water, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-90% chloroform / methanol] to give 4-bromo-5-methoxy-2-nitrobenzamide. Obtained.
To the obtained 4-bromo-5-methoxy-2-nitrobenzamide, 40 mL of dioxane, 5.0 mL of pyridine and 2.7 mL of trifluoroacetic anhydride were sequentially added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added to ice water, and the solid matter was collected by filtration to obtain 0.77 g of 4-bromo-5-methoxy-2-nitrobenzonitrile as a white solid.
1 H-NMR (DMSO-d 6 ) δ value: 8.62 (s, 1H), 7.89 (s, 1H), 4.08 (s, 3H).
参考例１１１
Figure JPOXMLDOC01-appb-C000110
 　参考例１１０と同様にして、以下の化合物を得た。
４－ブロモ－５－フルオロ－２－ニトロベンゾニトリル
1H-NMR(CDCl3)δ値：8.62(d,J=5.8Hz,1H),7.65(d,J=6.8Hz,1H). Reference Example 111
Figure JPOXMLDOC01-appb-C000110
 In the same manner as in Reference Example 110, the following compound was obtained.
4-Bromo-5-fluoro-2-nitrobenzonitrile
1 H-NMR (CDCl 3 ) δ value: 8.62 (d, J = 5.8 Hz, 1H), 7.65 (d, J = 6.8 Hz, 1H).
参考例１１２
Figure JPOXMLDOC01-appb-C000111
 　５－メトキシ－２－ニトロ安息香酸2.0gの硫酸10mL懸濁液に、氷冷下、１，３－ジブロモ－５，５－ジメチルヒダントイン1.5gを加え、同温度で30分間攪拌した。水100mLに反応混合物を加え、固形物をろ取し、褐色固体の４－ブロモ－５－メトキシ－２－ニトロ安息香酸1.4gを得た。
1H-NMR(CDCl3)δ値：8.25(s,1H),7.19(s,1H),4.05(s,3H). Reference Example 112
Figure JPOXMLDOC01-appb-C000111
 To a suspension of 2.0 g of 5-methoxy-2-nitrobenzoic acid in 10 mL of sulfuric acid, 1.5 g of 1,3-dibromo-5,5-dimethylhydantoin was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to 100 mL of water, and the solid was collected by filtration to obtain 1.4 g of 4-bromo-5-methoxy-2-nitrobenzoic acid as a brown solid.
1 H-NMR (CDCl 3 ) δ value: 8.25 (s, 1H), 7.19 (s, 1H), 4.05 (s, 3H).
参考例１１３
Figure JPOXMLDOC01-appb-C000112
 　参考例４５と同様にして、以下の化合物を得た。
３－（３－（ピペリジン－１－イル）フェニル）プロピオル酸
1H-NMR(CDCl3)δ値：7.29-7.18(m,2H),7.13-7.06(m,2H),3.24-3.16(m,4H),1.79-1.70(m,4H),1.65-1.55(m,2H). Reference Example 113
Figure JPOXMLDOC01-appb-C000112
 In the same manner as in Reference Example 45, the following compound was obtained.
3- (3- (Piperidin-1-yl) phenyl) propiolic acid
1 H-NMR (CDCl 3 ) δ value: 7.29-7.18 (m, 2H), 7.13-7.06 (m, 2H), 3.24-3.16 (m, 4H), 1.79-1.70 (m, 4H), 1.65-1.55 (m, 2H).
参考例１１４
Figure JPOXMLDOC01-appb-C000113
 　参考例７０と同様にして、以下の化合物を得た。
３－（３－（ジエチルアミノ）フェニル）プロピオル酸
1H-NMR(CDCl3)δ値：7.23-7.16(m,1H),6.92-6.86(m,2H),6.81-6.75(m,1H),3.35(q,J=7.1Hz,4H),1.16(t,J=7.1Hz,6H). Reference Example 114
Figure JPOXMLDOC01-appb-C000113
 In the same manner as in Reference Example 70, the following compound was obtained.
3- (3- (Diethylamino) phenyl) propiolic acid
1 H-NMR (CDCl 3 ) δ value: 7.23-7.16 (m, 1H), 6.92-6.86 (m, 2H), 6.81-6.75 (m, 1H), 3.35 (q, J = 7.1 Hz, 4H), 1.16 (t, J = 7.1Hz, 6H).
実施例１
Figure JPOXMLDOC01-appb-C000114
 　３－（２－メチルピペリジン－１－イル）安息香酸0.11gのテトラヒドロフラン3mL溶液に、Ｎ，Ｎ－ジメチルホルムアミド0.010mLおよびオキサリルクロリド0.053mLを順次加え、室温で10分間攪拌した。反応混合物にオキサリルクロリド0.030mLを加え、室温で20分間攪拌した。減圧下で溶媒を留去し、トルエンを加えた。減圧下で溶媒を留去し、テトラヒドロフラン6mLを加えた後、４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－アミン0.081gのピリジン0.055mLおよびテトラヒドロフラン1mL混液に加え、室温で3時間攪拌した。反応混合物に水を加え、飽和炭酸水素ナトリウム水溶液でpH4に調整後、減圧下で溶媒を留去した。得られた残留物にクロロホルムおよび水を加えた。有機層を分取し、水層をクロロホルムで抽出した。得られた有機層と抽出液を併せ、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；20-0％ヘキサン／酢酸エチル］で精製し、白色固体の３－（２－メチルピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド0.074gを得た。
1H-NMR(CD3OD)δ値：9.15(d,J=1.7Hz,1H),8.21(d,J=8.3Hz,1H),8.18-8.13(m,1H),8.10-8.03(m,1H),7.77-7.72(m,2H),7.67(dd,J=8.0,8.0Hz,1H),7.60-7.54(m,2H),7.52-7.46(m,2H),7.44-7.37(m,1H),4.13-4.03(m,1H),3.66-3.58(m,1H),3.50-3.41(m,1H),2.15-2.04(m,1H),1.98-1.84(m,3H),1.82-1.72(m,2H),1.13-1.09(m,3H). Example 1
Figure JPOXMLDOC01-appb-C000114
 To a solution of 0.11 g of 3- (2-methylpiperidin-1-yl) benzoic acid in 3 mL of tetrahydrofuran were sequentially added N, N-dimethylformamide 0.010 mL and oxalyl chloride 0.053 mL, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 0.030 mL of oxalyl chloride was added and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and toluene was added. Evaporate the solvent under reduced pressure, add 6 mL of tetrahydrofuran, add 0.081 g of 4- (1H-tetrazol-5-yl) biphenyl-3-amine to 0.055 mL of pyridine and 1 mL of tetrahydrofuran, and stir at room temperature for 3 hours. did. Water was added to the reaction mixture, the pH was adjusted to 4 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. Chloroform and water were added to the obtained residue. The organic layer was separated and the aqueous layer was extracted with chloroform. The obtained organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 20-0% hexane / ethyl acetate] to give 3- (2-methylpiperidin-1-yl) -N- (4- (1H 0.074 g of -tetrazol-5-yl) biphenyl-3-yl) benzamide was obtained.
1 H-NMR (CD 3 OD) δ value: 9.15 (d, J = 1.7 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.18-8.13 (m, 1H), 8.10-8.03 (m , 1H), 7.77-7.72 (m, 2H), 7.67 (dd, J = 8.0,8.0Hz, 1H), 7.60-7.54 (m, 2H), 7.52-7.46 (m, 2H), 7.44-7.37 (m , 1H), 4.13-4.03 (m, 1H), 3.66-3.58 (m, 1H), 3.50-3.41 (m, 1H), 2.15-2.04 (m, 1H), 1.98-1.84 (m, 3H), 1.82 -1.72 (m, 2H), 1.13-1.09 (m, 3H).
実施例２～１２
　実施例１と同様にして、表８に示す化合物を得た。 Examples 2-12
In the same manner as in Example 1, the compounds shown in Table 8 were obtained.
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000115
３－（（２Ｒ，６Ｓ）－２，６－ジメチルピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：9.10-9.06(m,1H),8.44-8.34(m,3H),8.00-7.86(m,2H),7.79-7.73(m,2H),7.63(dd,J=8.2,1.8Hz,1H),7.60-7.54(m,2H),7.50-7.43(m,1H),3.98-3.84(m,2H),2.18-2.05(m,2H),1.94-1.73(m,4H),1.02(d,J=6.4Hz,6H). 3-((2R, 6S) -2,6-dimethylpiperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 9.10-9.06 (m, 1H), 8.44-8.34 (m, 3H), 8.00-7.86 (m, 2H), 7.79-7.73 (m, 2H), 7.63 (dd, J = 8.2, 1.8Hz, 1H), 7.60-7.54 (m, 2H), 7.50-7.43 (m, 1H), 3.98-3.84 (m, 2H), 2.18-2.05 (m, 2H), 1.94-1.73 (m, 4H), 1.02 (d, J = 6.4Hz, 6H).
４－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：9.06-9.01(m,1H),8.12(d,J=8.0Hz,1H),8.00-7.93(m,2H),7.80-7.73(m,2H),7.66-7.61(m,1H),7.59-7.53(m,2H),7.50-7.44(m,1H),7.11-7.05(m,2H),3.43-3.34(m,4H),1.65-1.57(m,6H). 4- (Piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 9.06-9.01 (m, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.00-7.93 (m, 2H), 7.80-7.73 (m, 2H), 7.66-7.61 (m, 1H), 7.59-7.53 (m, 2H), 7.50-7.44 (m, 1H), 7.11-7.05 (m, 2H), 3.43-3.34 (m, 4H) 1.65-1.57 (m, 6H).
３－（フラン－３－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.80(s,1H),9.02(d,J=1.7Hz,1H),8.42-8.38(m,1H),8.38-8.34(m,1H),8.14(d,J=8.3Hz,1H),8.00-7.90(m,2H),7.88-7.83(m,1H),7.82-7.76(m,2H),7.73(dd,J=8.3,1.7Hz,1H),7.65(dd,J=7.8,7.8Hz,1H),7.60-7.53(m,2H),7.51-7.44(m,1H),7.17-7.12(m,1H). 3- (Furan-3-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.80 (s, 1H), 9.02 (d, J = 1.7 Hz, 1H), 8.42-8.38 (m, 1H), 8.38-8.34 (m, 1H), 8.14 (d, J = 8.3Hz, 1H), 8.00-7.90 (m, 2H), 7.88-7.83 (m, 1H), 7.82-7.76 (m, 2H), 7.73 (dd, J = 8.3,1.7Hz, 1H), 7.65 (dd, J = 7.8, 7.8Hz, 1H), 7.60-7.53 (m, 2H), 7.51-7.44 (m, 1H), 7.17-7.12 (m, 1H).
３－（１，３－オキサゾール－５－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.73(s,1H),8.92(d,J=1.7Hz,1H),8.56(s,1H),8.50-8.45(m,1H),8.13(d,J=8.3Hz,1H),8.10-8.05(m,1H),8.05-7.99(m,1H),7.88(s,1H),7.82-7.71(m,4H),7.60-7.53(m,2H),7.51-7.44(m,1H). 3- (1,3-Oxazol-5-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.73 (s, 1H), 8.92 (d, J = 1.7 Hz, 1H), 8.56 (s, 1H), 8.50-8.45 (m, 1H), 8.13 ( d, J = 8.3Hz, 1H), 8.10-8.05 (m, 1H), 8.05-7.99 (m, 1H), 7.88 (s, 1H), 7.82-7.71 (m, 4H), 7.60-7.53 (m, 2H), 7.51-7.44 (m, 1H).
５－（フラン－３－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ニコチンアミド
1H-NMR(DMSO-d6)δ値：11.67(s,1H),9.16(d,J=2.2Hz,1H),9.10(d,J=2.0Hz,1H),8.84(d,J=1.7Hz,1H),8.68-8.62(m,1H),8.48(s,1H),8.13(d,J=8.3Hz,1H),7.93-7.87(m,1H),7.83-7.73(m,3H),7.60-7.52(m,2H),7.51-7.44(m,1H),7.23-7.18(m,1H). 5- (Furan-3-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) nicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 11.67 (s, 1H), 9.16 (d, J = 2.2 Hz, 1H), 9.10 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 1.7Hz, 1H), 8.68-8.62 (m, 1H), 8.48 (s, 1H), 8.13 (d, J = 8.3Hz, 1H), 7.93-7.87 (m, 1H), 7.83-7.73 (m, 3H ), 7.60-7.52 (m, 2H), 7.51-7.44 (m, 1H), 7.23-7.18 (m, 1H).
５－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ニコチンアミド
1H-NMR(DMSO-d6)δ値：11.76(s,1H),8.89(d,J=1.7Hz,1H),8.59(d,J=1.7Hz,1H),8.56(d,J=2.9Hz,1H),8.13(d,J=8.2Hz,1H),7.96-7.92(m,1H),7.80-7.75(m,2H),7.72(dd,J=8.2,1.7Hz,1H),7.59-7.52(m,2H),7.50-7.43(m,1H),3.41-3.34(m,4H),1.72-1.56(m,6H). 5- (Piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) nicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 11.76 (s, 1H), 8.89 (d, J = 1.7 Hz, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.56 (d, J = 2.9Hz, 1H), 8.13 (d, J = 8.2Hz, 1H), 7.96-7.92 (m, 1H), 7.80-7.75 (m, 2H), 7.72 (dd, J = 8.2,1.7Hz, 1H), 7.59-7.52 (m, 2H), 7.50-7.43 (m, 1H), 3.41-3.34 (m, 4H), 1.72-1.56 (m, 6H).
３－（１Ｈ－ピロール－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.72(s,1H),8.96-8.90(m,1H),8.30-8.25(m,1H),8.13(d,J=8.1Hz,1H),7.96-7.86(m,2H),7.83-7.76(m,2H),7.76-7.67(m,2H),7.61-7.51(m,4H),7.51-7.44(m,1H),6.39-6.32(m,2H). 3- (1H-pyrrol-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.72 (s, 1H), 8.96-8.90 (m, 1H), 8.30-8.25 (m, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.96-7.86 (m, 2H), 7.83-7.76 (m, 2H), 7.76-7.67 (m, 2H), 7.61-7.51 (m, 4H), 7.51-7.44 (m, 1H), 6.39-6.32 (m , 2H).
４－クロロ－３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.79(s,1H),8.97(d,J=2.0Hz,1H),8.13(d,J=8.0Hz,1H),7.89(d,J=2.0Hz,1H),7.80-7.75(m,2H),7.74-7.67(m,2H),7.65(d,J=8.3Hz,1H),7.58-7.52(m,2H),7.50-7.44(m,1H),3.12-3.02(m,4H),1.77-1.67(m,4H),1.64-1.54(m,2H). 4-Chloro-3- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.79 (s, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 2.0Hz, 1H), 7.80-7.75 (m, 2H), 7.74-7.67 (m, 2H), 7.65 (d, J = 8.3Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.44 (m , 1H), 3.12-3.02 (m, 4H), 1.77-1.67 (m, 4H), 1.64-1.54 (m, 2H).
３－メトキシ－５－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.82(s,1H),9.07(d,J=1.8Hz,1H),8.14(d,J=8.1Hz,1H),7.80-7.75(m,2H),7.70(dd,J=8.1,1.8Hz,1H),7.59-7.52(m,2H),7.50-7.44(m,1H),7.34-7.30(m,1H),7.08-7.04(m,1H),6.74-6.69(m,1H),3.85(s,3H),3.34-3.28(m,4H),1.69-1.62(m,4H),1.62-1.55(m,2H). 3-Methoxy-5- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.82 (s, 1H), 9.07 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.80-7.75 (m, 2H), 7.70 (dd, J = 8.1, 1.8Hz, 1H), 7.59-7.52 (m, 2H), 7.50-7.44 (m, 1H), 7.34-7.30 (m, 1H), 7.08-7.04 (m, 1H), 6.74-6.69 (m, 1H), 3.85 (s, 3H), 3.34-3.28 (m, 4H), 1.69-1.62 (m, 4H), 1.62-1.55 (m, 2H).
３－ニトロ－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.63(s,1H),8.90-8.84(m,1H),8.70(d,J=1.7Hz,1H),8.53-8.45(m,2H),8.11(d,J=8.0Hz,1H),7.94(dd,J=7.9,7.9Hz,1H),7.82-7.74(m,3H),7.59-7.52(m,2H),7.51-7.43(m,1H). 3-Nitro-N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.63 (s, 1H), 8.90-8.84 (m, 1H), 8.70 (d, J = 1.7 Hz, 1H), 8.53-8.45 (m, 2H), 8.11 (d, J = 8.0Hz, 1H), 7.94 (dd, J = 7.9,7.9Hz, 1H), 7.82-7.74 (m, 3H), 7.59-7.52 (m, 2H), 7.51-7.43 (m, 1H).
３－（エチル（メチル）アミノ）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：9.04-8.98(m,1H),8.14(d,J=8.5Hz,1H),7.82-7.74(m,2H),7.71-7.64(m,1H),7.61-7.54(m,2H),7.52-7.40(m,3H),7.39-7.34(m,1H),7.07-7.01(m,1H),3.57-3.47(m,2H),3.00(s,3H),1.11(t,J=6.8Hz,3H). 3- (Ethyl (methyl) amino) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 9.04-8.98 (m, 1H), 8.14 (d, J = 8.5Hz, 1H), 7.82-7.74 (m, 2H), 7.71-7.64 (m, 1H), 7.61-7.54 (m, 2H), 7.52-7.40 (m, 3H), 7.39-7.34 (m, 1H), 7.07-7.01 (m, 1H), 3.57-3.47 (m, 2H) , 3.00 (s, 3H), 1.11 (t, J = 6.8Hz, 3H).
実施例１３
Figure JPOXMLDOC01-appb-C000116
 　３－（ジプロピルアミノ）安息香酸0.086gのテトラヒドロフラン2mL溶液に、Ｎ，Ｎ－ジメチルホルムアミド0.010mLおよびオキサリルクロリド0.039mLを順次加え、室温で20分間攪拌した。反応混合物にオキサリルクロリド0.039mLを加え、室温で20分間攪拌した。減圧下で溶媒を留去し、トルエンを加えた。減圧下で溶媒を留去し、テトラヒドロフラン2mLを加えた後、３－（３－アミノビフェニル－４－イル）－１，２，４－オキサジアゾール－５（４Ｈ）－オン0.076gのピリジン0.044mLおよびテトラヒドロフラン1mL混液に加え、室温で2時間攪拌した。反応混合物に水を加え、飽和炭酸水素ナトリウム水溶液でpH4に調整後、減圧下で溶媒を留去した。得られた残留物に酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；70-0％ヘキサン／酢酸エチル］で精製し、淡黄色固体の３－（ジプロピルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド0.048gを得た。
1H-NMR(DMSO-d6+D2O)δ値：8.76-8.71(m,1H),7.85-7.80(m,1H),7.79-7.73(m,2H),7.70-7.65(m,1H),7.59-7.52(m,2H),7.51-7.45(m,1H),7.38-7.30(m,1H),7.21-7.11(m,2H),6.94-6.86(m,1H),3.31(t,J=7.4Hz,4H),1.63-1.51(m,4H),0.91(t,J=7.3Hz,6H). Example 13
Figure JPOXMLDOC01-appb-C000116
 To a solution of 0.086 g of 3- (dipropylamino) benzoic acid in 2 mL of tetrahydrofuran were sequentially added 0.010 mL of N, N-dimethylformamide and 0.039 mL of oxalyl chloride, and the mixture was stirred at room temperature for 20 minutes. 0.039 mL of oxalyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and toluene was added. The solvent was distilled off under reduced pressure, 2 mL of tetrahydrofuran was added, and 3- (3-aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one 0.076 g of pyridine 0.044 g The mixture was added to a mixed solution of mL and 1 mL of tetrahydrofuran, and stirred at room temperature for 2 hours. Water was added to the reaction mixture, the pH was adjusted to 4 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the obtained residue. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-0% hexane / ethyl acetate] to give 3- (dipropylamino)- 0.048 g of N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.76-8.71 (m, 1H), 7.85-7.80 (m, 1H), 7.79-7.73 (m, 2H), 7.70-7.65 (m, 1H), 7.59-7.52 (m, 2H), 7.51-7.45 (m, 1H), 7.38-7.30 (m, 1H), 7.21-7.11 (m, 2H), 6.94-6.86 (m, 1H), 3.31 ( t, J = 7.4Hz, 4H), 1.63-1.51 (m, 4H), 0.91 (t, J = 7.3Hz, 6H).
実施例１４～１７
　実施例１３と同様にして、表９に示す化合物を得た。 Examples 14-17
In the same manner as in Example 13, the compounds shown in Table 9 were obtained.
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000117
（Ｅ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－フェニルアクリルアミド
1H-NMR(DMSO-d6)δ値：12.96-12.76(broad,1H),10.12(s,1H),8.43(d,J=1.7Hz,1H),7.76-7.71(m,3H),7.71-7.60(m,4H),7.57-7.51(m,2H),7.50-7.41(m,4H),6.91(d,J=15.9Hz,1H). (E) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3-phenylacrylamide
1 H-NMR (DMSO-d 6 ) δ value: 12.96-12.76 (broad, 1H), 10.12 (s, 1H), 8.43 (d, J = 1.7 Hz, 1H), 7.76-7.71 (m, 3H), 7.71-7.60 (m, 4H), 7.57-7.51 (m, 2H), 7.50-7.41 (m, 4H), 6.91 (d, J = 15.9Hz, 1H).
３－（メチル（プロピル）アミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.74-8.70(m,1H),7.83(d,J=8.3Hz,1H),7.79-7.74(m,2H),7.70-7.64(m,1H),7.59-7.53(m,2H),7.51-7.44(m,1H),7.39-7.33(m,1H),7.27-7.23(m,1H),7.22-7.17(m,1H),6.98-6.92(m,1H),3.37(t,J=7.2Hz,2H),2.98(s,3H),1.61-1.51(m,2H),0.90(t,J=7.1Hz,3H). 3- (Methyl (propyl) amino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.74-8.70 (m, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.79-7.74 (m, 2H), 7.70-7.64 (m, 1H), 7.59-7.53 (m, 2H), 7.51-7.44 (m, 1H), 7.39-7.33 (m, 1H), 7.27-7.23 (m, 1H), 7.22-7.17 (m, 1H) , 6.98-6.92 (m, 1H), 3.37 (t, J = 7.2Hz, 2H), 2.98 (s, 3H), 1.61-1.51 (m, 2H), 0.90 (t, J = 7.1Hz, 3H).
３－（イソプロピル（メチル）アミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.56(s,1H),8.73(d,J=1.7Hz,1H),7.83(d,J=8.0Hz,1H),7.79-7.74(m,2H),7.68(dd,J=8.0,1.7Hz,1H),7.58-7.52(m,2H),7.50-7.44(m,1H),7.39-7.33(m,2H),7.24-7.19(m,1H),7.03(dd,J=8.3,2.4Hz,1H),4.27-4.16(m,1H),2.77(s,3H),1.16(d,J=6.6Hz,6H). 3- (Isopropyl (methyl) amino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.56 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79-7.74 (m, 2H), 7.68 (dd, J = 8.0, 1.7Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.44 (m, 1H), 7.39-7.33 (m, 2H), 7.24-7.19 (m, 1H), 7.03 (dd, J = 8.3, 2.4Hz, 1H), 4.27-4.16 (m, 1H), 2.77 (s, 3H), 1.16 (d, J = 6.6Hz, 6H).
３－（エチル（プロピル）アミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.73-8.70(m,1H),7.83(d,J=8.3Hz,1H),7.79-7.74(m,2H),7.67(dd,J=8.3,1.7Hz,1H),7.60-7.53(m,2H),7.51-7.45(m,1H),7.35(dd,J=7.9,7.9Hz,1H),7.22-7.19(m,1H),7.16(d,J=7.8Hz,1H),6.91(dd,J=8.8,2.4Hz,1H),3.47-3.39(m,2H),3.34-3.26(m,2H),1.64-1.53(m,2H),1.13(t,J=7.0Hz,3H),0.92(t,J=7.3Hz,3H). 3- (Ethyl (propyl) amino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.73-8.70 (m, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.79-7.74 (m, 2H), 7.67 (dd , J = 8.3,1.7Hz, 1H), 7.60-7.53 (m, 2H), 7.51-7.45 (m, 1H), 7.35 (dd, J = 7.9,7.9Hz, 1H), 7.22-7.19 (m, 1H ), 7.16 (d, J = 7.8Hz, 1H), 6.91 (dd, J = 8.8, 2.4Hz, 1H), 3.47-3.39 (m, 2H), 3.34-3.26 (m, 2H), 1.64-1.53 ( m, 2H), 1.13 (t, J = 7.0Hz, 3H), 0.92 (t, J = 7.3Hz, 3H).
実施例１８
Figure JPOXMLDOC01-appb-C000118
 　３－（３－アミノビフェニル－４－イル）－１，２，４－オキサジアゾール－５（４Ｈ）－オン0.050gのテトラヒドロフラン1mLおよびピリジン0.021mL混液に、ベンゾイルクロリド0.025mLを加え、室温で3時間攪拌した。反応混合物にベンゾイルクロリド0.025mLを加え、室温で2時間攪拌した。反応混合物に水を加え、減圧下で溶媒を留去後、固形物をろ取した。得られた固形物を、50％メタノール水溶液およびメタノールで洗浄し、白色固体のＮ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド0.062gを得た。
1H-NMR(DMSO-d6)δ値：13.13-12.82(broad,1H),10.53(s,1H),8.54(d,J=1.8Hz,1H),8.02-7.96(m,2H),7.81(d,J=8.3Hz,1H),7.79-7.74(m,2H),7.70(dd,J=8.3,1.8Hz,1H),7.68-7.62(m,1H),7.62-7.51(m,4H),7.50-7.43(m,1H). Example 18
Figure JPOXMLDOC01-appb-C000118
 To a mixed solution of 0.050 g of 3- (3-aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one in tetrahydrofuran and 0.021 mL of pyridine was added 0.025 mL of benzoyl chloride at room temperature. Stir for 3 hours. To the reaction mixture was added 0.025 mL of benzoyl chloride, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the solid was collected by filtration. The obtained solid was washed with 50% aqueous methanol and methanol, and white solid N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) benzamide 0.062g was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.13-12.82 (broad, 1H), 10.53 (s, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.02-7.96 (m, 2H), 7.81 (d, J = 8.3Hz, 1H), 7.79-7.74 (m, 2H), 7.70 (dd, J = 8.3,1.8Hz, 1H), 7.68-7.62 (m, 1H), 7.62-7.51 (m, 4H), 7.50-7.43 (m, 1H).
実施例１９～２４
　実施例１８と同様にして、表１０に示す化合物を得た。 Examples 19-24
In the same manner as in Example 18, the compounds shown in Table 10 were obtained.
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
２－クロロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：12.98-12.76(broad,1H),10.51(s,1H),8.34-8.27(m,1H),7.80-7.68(m,5H),7.62-7.44(m,6H). 2-Chloro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 12.98-12.76 (broad, 1H), 10.51 (s, 1H), 8.34-8.27 (m, 1H), 7.80-7.68 (m, 5H), 7.62-7.44 (m, 6H).
３－クロロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.04-12.80(broad,1H),10.59(s,1H),8.37-8.33(m,1H),8.04-8.00(m,1H),7.96-7.90(m,1H),7.80(d,J=8.0Hz,1H),7.78-7.70(m,4H),7.63(dd,J=7.9,7.9Hz,1H),7.57-7.51(m,2H),7.49-7.43(m,1H). 3-Chloro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.04-12.80 (broad, 1H), 10.59 (s, 1H), 8.37-8.33 (m, 1H), 8.04-8.00 (m, 1H), 7.96-7.90 (m, 1H), 7.80 (d, J = 8.0Hz, 1H), 7.78-7.70 (m, 4H), 7.63 (dd, J = 7.9,7.9Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.43 (m, 1H).
４－クロロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.08-12.82(broad,1H),10.56(s,1H),8.44-8.40(m,1H),8.03-7.97(m,2H),7.80(d,J=8.1Hz,1H),7.78-7.74(m,2H),7.72(dd,J=8.1,1.5Hz,1H),7.70-7.66(m,2H),7.58-7.51(m,2H),7.49-7.43(m,1H). 4-Chloro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.08-12.82 (broad, 1H), 10.56 (s, 1H), 8.44-8.40 (m, 1H), 8.03-7.97 (m, 2H), 7.80 (d , J = 8.1Hz, 1H), 7.78-7.74 (m, 2H), 7.72 (dd, J = 8.1,1.5Hz, 1H), 7.70-7.66 (m, 2H), 7.58-7.51 (m, 2H), 7.49-7.43 (m, 1H).
２－メトキシ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.16-12.90(broad,1H),11.11(s,1H),8.94-8.90(m,1H),8.00(dd,J=7.8,1.7Hz,1H),7.82-7.72(m,3H),7.66(dd,J=8.2,1.8Hz,1H),7.63-7.58(m,1H),7.58-7.51(m,2H),7.50-7.43(m,1H),7.26(d,J=8.3Hz,1H),7.14(dd,J=7.4,7.4Hz,1H),4.00(s,3H). 2-Methoxy-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.16-12.90 (broad, 1H), 11.11 (s, 1H), 8.94–8.90 (m, 1H), 8.00 (dd, J = 7.8, 1.7 Hz, 1H ), 7.82-7.72 (m, 3H), 7.66 (dd, J = 8.2,1.8Hz, 1H), 7.63-7.58 (m, 1H), 7.58-7.51 (m, 2H), 7.50-7.43 (m, 1H ), 7.26 (d, J = 8.3Hz, 1H), 7.14 (dd, J = 7.4, 7.4Hz, 1H), 4.00 (s, 3H).
３－メトキシ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.54(s,1H),8.56(d,J=1.7Hz,1H),7.81(d,J=8.3Hz,1H),7.79-7.73(m,2H),7.70(dd,J=8.3,1.7Hz,1H),7.59-7.44(m,6H),7.25-7.19(m,1H),3.86(s,3H). 3-Methoxy-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.54 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.79-7.73 (m, 2H), 7.70 (dd, J = 8.3, 1.7Hz, 1H), 7.59-7.44 (m, 6H), 7.25-7.19 (m, 1H), 3.86 (s, 3H).
４－メトキシ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.42(s,1H),8.58(d,J=1.4Hz,1H),8.00-7.94(m,2H),7.84-7.73(m,3H),7.71-7.64(m,1H),7.58-7.51(m,2H),7.49-7.43(m,1H),7.16-7.10(m,2H),3.86(s,3H). 4-Methoxy-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.42 (s, 1H), 8.58 (d, J = 1.4 Hz, 1H), 8.00-7.94 (m, 2H), 7.84-7.73 (m, 3H), 7.71-7.64 (m, 1H), 7.58-7.51 (m, 2H), 7.49-7.43 (m, 1H), 7.16-7.10 (m, 2H), 3.86 (s, 3H).
実施例２５
Figure JPOXMLDOC01-appb-C000120
 　実施例１８と同様にして、以下の化合物を得た。
３－メトキシ－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.71(s,1H),9.00(d,J=1.8Hz,1H),8.13(d,J=8.3Hz,1H),7.83-7.75(m,2H),7.71(dd,J=8.3,1.8Hz,1H),7.70-7.63(m,2H),7.60-7.52(m,3H),7.51-7.42(m,1H),7.29-7.20(m,1H),3.90(s,3H). Example 25
Figure JPOXMLDOC01-appb-C000120
 In the same manner as in Example 18, the following compounds were obtained.
3-Methoxy-N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.71 (s, 1H), 9.00 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.83-7.75 (m, 2H), 7.71 (dd, J = 8.3, 1.8Hz, 1H), 7.70-7.63 (m, 2H), 7.60-7.52 (m, 3H), 7.51-7.42 (m, 1H), 7.29-7.20 (m, 1H), 3.90 (s, 3H).
実施例２６
Figure JPOXMLDOC01-appb-C000121
 　３－（ピペリジン－１－イル）安息香酸0.11g、４－（１－ベンジル－１Ｈ－テトラゾール－５－イル）ビフェニル－３－アミン0.15g、アセトニトリル2.0mLおよびＮ，Ｎ－ジメチルホルムアミド0.010mLの混液に、60℃で塩化チオニル0.045mLを加え、同温度で1時間30分間攪拌した。反応混合物に60℃で塩化チオニル0.010mLを加え、同温度で1時間攪拌した。反応混合物を室温まで冷却後、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-75％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（４－（１－ベンジル－１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.11gを得た。
　得られたＮ－（４－（１－ベンジル－１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.11gのテトラヒドロフラン12mLおよびメタノール4.0mL混液に、10％パラジウム－炭素0.10gを加え、水素雰囲気下、室温で3時間攪拌した。反応混合物に10％パラジウム－炭素0.10gを加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；99-92％クロロホルム／メタノール］で精製し、淡黄色固体の３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド0.038gを得た。
1H-NMR(DMSO-d6)δ値：11.78(s,1H),9.05(d,J=2.0Hz,1H),8.13(d,J=8.0Hz,1H),7.81-7.75(m,2H),7.72-7.66(m,2H),7.59-7.52(m,2H),7.50-7.38(m,3H),7.27-7.20(m,1H),3.38-3.25(m,4H),1.73-1.63(m,4H),1.63-1.54(m,2H). Example 26
Figure JPOXMLDOC01-appb-C000121
 3- (piperidin-1-yl) benzoic acid 0.11 g, 4- (1-benzyl-1H-tetrazol-5-yl) biphenyl-3-amine 0.15 g, acetonitrile 2.0 mL and N, N-dimethylformamide 0.010 mL To the mixture, 0.045 mL of thionyl chloride was added at 60 ° C., and the mixture was stirred at the same temperature for 1 hour 30 minutes. To the reaction mixture, 0.010 mL of thionyl chloride was added at 60 ° C., and the mixture was stirred at the same temperature for 1 hour. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-75% hexane / ethyl acetate] to obtain N- (4- (1-benzyl) as a white solid. 0.11 g of -1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide was obtained.
To a mixed solution of 0.11 g of the obtained N- (4- (1-benzyl-1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide in 12 mL of tetrahydrofuran and 4.0 mL of methanol, 10% palladium-carbon (0.10 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. To the reaction mixture, 10% palladium-carbon (0.10 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-92% chloroform / methanol], and 3- (piperidin-1-yl) -N- (4- (1H-tetrazole- 0.038 g of 5-yl) biphenyl-3-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 11.78 (s, 1H), 9.05 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.81-7.75 (m, 2H), 7.72-7.66 (m, 2H), 7.59-7.52 (m, 2H), 7.50-7.38 (m, 3H), 7.27-7.20 (m, 1H), 3.38-3.25 (m, 4H), 1.73- 1.63 (m, 4H), 1.63-1.54 (m, 2H).
実施例２７
Figure JPOXMLDOC01-appb-C000122
 　Ｎ－（４－シアノビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド0.10gの１－メチル－２－ピロリドン0.30mL溶液に、トリエチルアミン塩酸塩0.075gおよびアジ化ナトリウム0.035gを順次加え、120℃で1時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加え、10％クエン酸水溶液でpH5.0に調整した。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；100-92％クロロホルム／メタノール］で精製し、淡黄色固体の３－（ジエチルアミノ）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド0.060gを得た。
1H-NMR(DMSO-d6)δ値：11.81(s,1H),9.13(d,J=1.8Hz,1H),8.14(d,J=8.2Hz,1H),7.82-7.75(m,2H),7.69(dd,J=8.2,1.8Hz,1H),7.60-7.52(m,2H),7.51-7.44(m,1H),7.43-7.35(m,2H),7.30(d,J=7.6Hz,1H),6.95(dd,J=8.3,2.2Hz,1H),3.47(q,J=7.0Hz,4H),1.16(t,J=7.0Hz,6H). Example 27
Figure JPOXMLDOC01-appb-C000122
 To a solution of 0.10 g of N- (4-cyanobiphenyl-3-yl) -3- (diethylamino) benzamide in 0.30 mL of 1-methyl-2-pyrrolidone, 0.075 g of triethylamine hydrochloride and 0.035 g of sodium azide were sequentially added. Stir at 1 ° C. for 1 hour. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the pH was adjusted to 5.0 with 10% aqueous citric acid solution. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform / methanol] to give 3- (diethylamino) -N- (4- (1H-tetrazol-5-yl) as a pale yellow solid. Biphenyl-3-yl) benzamide 0.060 g was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 11.81 (s, 1H), 9.13 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.82-7.75 (m, 2H), 7.69 (dd, J = 8.2, 1.8Hz, 1H), 7.60-7.52 (m, 2H), 7.51-7.44 (m, 1H), 7.43-7.35 (m, 2H), 7.30 (d, J = 7.6Hz, 1H), 6.95 (dd, J = 8.3, 2.2Hz, 1H), 3.47 (q, J = 7.0Hz, 4H), 1.16 (t, J = 7.0Hz, 6H).
実施例２８～３９
　実施例２７と同様にして、表１１に示す化合物を得た。 Examples 28-39
In the same manner as in Example 27, the compounds shown in Table 11 were obtained.
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.68(s,1H),8.98(d,J=1.9Hz,1H),8.15-8.08(m,3H),7.81-7.75(m,2H),7.71(dd,J=8.2,1.9Hz,1H),7.69-7.61(m,3H),7.59-7.52(m,2H),7.50-7.44(m,1H). N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.68 (s, 1H), 8.98 (d, J = 1.9 Hz, 1H), 8.15-8.08 (m, 3H), 7.81-7.75 (m, 2H), 7.71 (dd, J = 8.2, 1.9Hz, 1H), 7.69-7.61 (m, 3H), 7.59-7.52 (m, 2H), 7.50-7.44 (m, 1H).
３－ブロモ－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.50(s,1H),8.78(d,J=1.9Hz,1H),8.25-8.20(m,1H),8.09(d,J=8.2Hz,1H),8.08-8.02(m,1H),7.90-7.83(m,1H),7.80-7.74(m,2H),7.73(dd,J=8.2,1.9Hz,1H),7.63-7.51(m,3H),7.49-7.42(m,1H). 3-Bromo-N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.50 (s, 1H), 8.78 (d, J = 1.9 Hz, 1H), 8.25-8.20 (m, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.08-8.02 (m, 1H), 7.90-7.83 (m, 1H), 7.80-7.74 (m, 2H), 7.73 (dd, J = 8.2, 1.9Hz, 1H), 7.63-7.51 (m, 3H), 7.49-7.42 (m, 1H).
４－メトキシ－３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.87(s,1H),9.10(d,J=1.7Hz,1H),8.14(d,J=8.3Hz,1H),7.82-7.71(m,4H),7.67(dd,J=8.3,1.7Hz,1H),7.60-7.51(m,2H),7.50-7.42(m,1H),7.17(d,J=8.5Hz,1H),3.91(s,3H),3.12-3.00(m,4H),1.75-1.64(m,4H),1.63-1.51(m,2H). 4-Methoxy-3- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.87 (s, 1H), 9.10 (d, J = 1.7 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.82-7.71 (m, 4H), 7.67 (dd, J = 8.3, 1.7Hz, 1H), 7.60-7.51 (m, 2H), 7.50-7.42 (m, 1H), 7.17 (d, J = 8.5Hz, 1H), 3.91 (s , 3H), 3.12-3.00 (m, 4H), 1.75-1.64 (m, 4H), 1.63-1.51 (m, 2H).
３－（ピロリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：9.11-9.08(m,1H),8.13(d,J=8.3Hz,1H),7.80-7.75(m,2H),7.68(dd,J=8.3,1.9Hz,1H),7.59-7.53(m,2H),7.51-7.45(m,1H),7.39(dd,J=7.8,7.8Hz,1H),7.32-7.25(m,2H),6.84-6.77(m,1H),3.38-3.32(m,4H),2.05-1.98(m,4H). 3- (Pyrrolidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 9.11-9.08 (m, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.80-7.75 (m, 2H), 7.68 (dd , J = 8.3,1.9Hz, 1H), 7.59-7.53 (m, 2H), 7.51-7.45 (m, 1H), 7.39 (dd, J = 7.8,7.8Hz, 1H), 7.32-7.25 (m, 2H ), 6.84-6.77 (m, 1H), 3.38-3.32 (m, 4H), 2.05-1.98 (m, 4H).
４－メチル－３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.85(s,1H),9.11-9.05(m,1H),8.14(d,J=8.1Hz,1H),7.85-7.74(m,3H),7.74-7.64(m,2H),7.60-7.51(m,2H),7.51-7.43(m,1H),7.40(d,J=8.1Hz,1H),2.99-2.88(m,4H),2.35(s,3H),1.78-1.66(m,4H),1.64-1.52(m,2H). 4-Methyl-3- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.85 (s, 1H), 9.11-9.05 (m, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.85-7.74 (m, 3H), 7.74-7.64 (m, 2H), 7.60-7.51 (m, 2H), 7.51-7.43 (m, 1H), 7.40 (d, J = 8.1Hz, 1H), 2.99-2.88 (m, 4H), 2.35 ( s, 3H), 1.78-1.66 (m, 4H), 1.64-1.52 (m, 2H).
２－クロロ－５－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.25(s,1H),8.82-8.77(m,1H),8.07(d,J=7.9Hz,1H),7.80-7.74(m,2H),7.72(dd,J=7.9,1.6Hz,1H),7.60-7.52(m,2H),7.51-7.43(m,1H),7.38-7.31(m,2H),7.09(dd,J=9.1,2.8Hz,1H),3.28-3.22(m,4H),1.67-1.53(m,6H). 2-Chloro-5- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.25 (s, 1H), 8.82-8.77 (m, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.80-7.74 (m, 2H), 7.72 (dd, J = 7.9,1.6Hz, 1H), 7.60-7.52 (m, 2H), 7.51-7.43 (m, 1H), 7.38-7.31 (m, 2H), 7.09 (dd, J = 9.1,2.8 Hz, 1H), 3.28-3.22 (m, 4H), 1.67-1.53 (m, 6H).
２－メトキシ－３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.45(s,1H),8.96-8.90(m,1H),8.05(d,J=8.3Hz,1H),7.82-7.73(m,2H),7.72-7.65(m,1H),7.60-7.52(m,2H),7.52-7.42(m,1H),7.42-7.32(m,1H),7.23-7.14(m,2H),3.86(s,3H),3.10-2.98(m,4H),1.78-1.65(m,4H),1.62-1.50(m,2H). 2-Methoxy-3- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.45 (s, 1H), 8.96-8.90 (m, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.82-7.73 (m, 2H), 7.72-7.65 (m, 1H), 7.60-7.52 (m, 2H), 7.52-7.42 (m, 1H), 7.42-7.32 (m, 1H), 7.23-7.14 (m, 2H), 3.86 (s, 3H ), 3.10-2.98 (m, 4H), 1.78-1.65 (m, 4H), 1.62-1.50 (m, 2H).
２－メチル－５－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.32(s,1H),8.94-8.87(m,1H),8.08(d,J=8.0Hz,1H),7.82-7.72(m,2H),7.72-7.64(m,1H),7.60-7.51(m,2H),7.51-7.41(m,1H),7.39-7.31(m,1H),7.18(d,J=8.3Hz,1H),7.09-7.01(m,1H),3.26-3.16(m,4H),2.35(s,3H),1.71-1.60(m,4H),1.60-1.49(m,2H). 2-Methyl-5- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.32 (s, 1H), 8.94–8.87 (m, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.82–7.72 (m, 2H), 7.72-7.64 (m, 1H), 7.60-7.51 (m, 2H), 7.51-7.41 (m, 1H), 7.39-7.31 (m, 1H), 7.18 (d, J = 8.3Hz, 1H), 7.09- 7.01 (m, 1H), 3.26-3.16 (m, 4H), 2.35 (s, 3H), 1.71-1.60 (m, 4H), 1.60-1.49 (m, 2H).
３－（４－メチルピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.78(s,1H),9.06(d,J=1.2Hz,1H),8.13(d,J=8.3Hz,1H),7.81-7.74(m,2H),7.72-7.66(m,2H),7.59-7.52(m,2H),7.50-7.39(m,3H),7.28-7.20(m,1H),3.90-3.80(m,2H),2.86-2.75(m,2H),1.80-1.69(m,2H),1.64-1.51(m,1H),1.34-1.21(m,2H),0.96(d,J=6.6Hz,3H). 3- (4-Methylpiperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.78 (s, 1H), 9.06 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.81-7.74 (m, 2H), 7.72-7.66 (m, 2H), 7.59-7.52 (m, 2H), 7.50-7.39 (m, 3H), 7.28-7.20 (m, 1H), 3.90-3.80 (m, 2H), 2.86- 2.75 (m, 2H), 1.80-1.69 (m, 2H), 1.64-1.51 (m, 1H), 1.34-1.21 (m, 2H), 0.96 (d, J = 6.6Hz, 3H).
３－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリン－４－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.80(s,1H),9.09(d,J=1.7Hz,1H),8.15-8.10(m,1H),7.80-7.74(m,2H),7.73-7.67(m,2H),7.58-7.52(m,2H),7.52-7.42(m,3H),7.28-7.22(m,1H),3.82-3.70(m,4H),2.44-2.32(m,2H),1.25-1.18(m,6H). 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.80 (s, 1H), 9.09 (d, J = 1.7 Hz, 1H), 8.15-8.10 (m, 1H), 7.80-7.74 (m, 2H), 7.73-7.67 (m, 2H), 7.58-7.52 (m, 2H), 7.52-7.42 (m, 3H), 7.28-7.22 (m, 1H), 3.82-3.70 (m, 4H), 2.44-2.32 (m , 2H), 1.25-1.18 (m, 6H).
２－（ジエチルアミノ）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：11.88(s,1H),8.99(d,J=1.9Hz,1H),8.29(d,J=5.1Hz,1H),8.15(d,J=8.2Hz,1H),7.81-7.75(m,2H),7.73(dd,J=8.2,1.9Hz,1H),7.59-7.51(m,2H),7.50-7.43(m,1H),7.25(s,1H),7.08(dd,J=5.4,1.2Hz,1H),3.62(q,J=7.0Hz,4H),1.19(t,J=7.0Hz,6H). 2- (Diethylamino) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) isonicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 11.88 (s, 1H), 8.99 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 5.1 Hz, 1H), 8.15 (d, J = 8.2Hz, 1H), 7.81-7.75 (m, 2H), 7.73 (dd, J = 8.2,1.9Hz, 1H), 7.59-7.51 (m, 2H), 7.50-7.43 (m, 1H), 7.25 (s , 1H), 7.08 (dd, J = 5.4, 1.2Hz, 1H), 3.62 (q, J = 7.0Hz, 4H), 1.19 (t, J = 7.0Hz, 6H).
２－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：11.78(s,1H),8.91(d,J=1.8Hz,1H),8.32(d,J=5.4Hz,1H),8.14(d,J=8.2Hz,1H),7.80-7.75(m,2H),7.73(dd,J=8.2,1.8Hz,1H),7.59-7.52(m,2H),7.50-7.42(m,2H),7.13(dd,J=5.1,1.2Hz,1H),3.70-3.62(m,4H),1.71-1.54(m,6H). 2- (Piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) isonicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 11.78 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.32 (d, J = 5.4 Hz, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.80-7.75 (m, 2H), 7.73 (dd, J = 8.2,1.8Hz, 1H), 7.59-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.13 (dd , J = 5.1, 1.2Hz, 1H), 3.70-3.62 (m, 4H), 1.71-1.54 (m, 6H).
実施例４０
Figure JPOXMLDOC01-appb-C000124
 　Ｎ－（４－（１－ベンジル－１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（１－メチルピペリジン－４－イル）ベンズアミド0.045gのメタノール20mLおよび酢酸エチル10mL混液に、10％パラジウム－炭素0.045gを加え、水素雰囲気下、40℃で4時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、固形物をろ取した。得られた固形物に6.6mol/L塩化水素－酢酸エチル溶液1.0mLを加え、室温で30分間攪拌した。減圧下で溶媒を留去し、クロロホルムを加え、固形物をろ取し、白色固体の３－（１－メチルピペリジン－４－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド塩酸塩0.020gを得た。
1H-NMR(DMSO-d6+D2O)δ値：8.93-8.86(m,1H),8.18-8.10(m,1H),8.02-7.95(m,2H),7.81-7.73(m,2H),7.73-7.66(m,1H),7.65-7.54(m,4H),7.52-7.45(m,1H),3.61-3.52(m,2H),3.20-3.08(m,2H),3.07-2.96(m,1H),2.87-2.80(m,3H),2.20-2.10(m,2H),2.03-1.88(m,2H). Example 40
Figure JPOXMLDOC01-appb-C000124
 N- (4- (1-benzyl-1H-tetrazol-5-yl) biphenyl-3-yl) -3- (1-methylpiperidin-4-yl) benzamide (0.045 g) in a mixture of methanol (20 mL) and ethyl acetate (10 mL) 0.045 g of 10% palladium-carbon was added, and the mixture was stirred at 40 ° C. for 4 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid was collected by filtration. To the obtained solid was added 1.0 mL of a 6.6 mol / L hydrogen chloride-ethyl acetate solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, chloroform was added, the solid was collected by filtration, and white solid 3- (1-methylpiperidin-4-yl) -N- (4- (1H-tetrazol-5-yl) Biphenyl-3-yl) benzamide hydrochloride 0.020 g was obtained.
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.93-8.86 (m, 1H), 8.18-8.10 (m, 1H), 8.02-7.95 (m, 2H), 7.81-7.73 (m, 2H), 7.73-7.66 (m, 1H), 7.65-7.54 (m, 4H), 7.52-7.45 (m, 1H), 3.61-3.52 (m, 2H), 3.20-3.08 (m, 2H), 3.07- 2.96 (m, 1H), 2.87-2.80 (m, 3H), 2.20-2.10 (m, 2H), 2.03-1.88 (m, 2H).
実施例４１
Figure JPOXMLDOC01-appb-C000125
 　Ｎ－（４－シアノビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド0.10gのテトラヒドロフラン2mL溶液に、50％ヒドロキシルアミン水溶液0.14mLを加え、60℃で30分攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物にメタノールを加え、固形物をろ取し、淡黄色固体の３－（ジエチルアミノ）－Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）ベンズアミドを得た。
　得られた３－（ジエチルアミノ）－Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）ベンズアミドのテトラヒドロフラン2mL溶液に、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.061mLおよび１，１’－カルボニルジイミダゾール0.066gを順次加え、室温で2時間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.066gを加え、室温で30分間攪拌した。反応混合物にクロロホルムおよび水を加え、10％クエン酸水溶液でpH4.0に調整した。有機層を分取し、水層をクロロホルムで抽出した。得られた有機層と抽出液を併せ、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、淡黄色固体の３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド0.092gを得た。
1H-NMR(DMSO-d6)δ値：10.56(s,1H),8.79(d,J=1.8Hz,1H),7.83(d,J=8.2Hz,1H),7.79-7.74(m,2H),7.67(dd,J=8.2,1.8Hz,1H),7.58-7.51(m,2H),7.50-7.44(m,1H),7.34(dd,J=7.9,7.9Hz,1H),7.25-7.22(m,1H),7.16(d,J=7.6Hz,1H),6.91(dd,J=8.3,2.4Hz,1H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). Example 41
Figure JPOXMLDOC01-appb-C000125
 To a solution of 0.10 g of N- (4-cyanobiphenyl-3-yl) -3- (diethylamino) benzamide in 2 mL of tetrahydrofuran was added 0.14 mL of a 50% aqueous hydroxylamine solution, and the mixture was stirred at 60 ° C. for 30 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solid was collected by filtration to obtain 3- (diethylamino) -N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide as a pale yellow solid.
To a solution of the obtained 3- (diethylamino) -N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide in 2 mL of tetrahydrofuran was added 0.061 mL of 1,8-diazabicyclo [5.4.0] -7-undecene and 0.06 g of 1,1′-carbonyldiimidazole was sequentially added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, 0.066 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 30 minutes. Chloroform and water were added to the reaction mixture, and the pH was adjusted to 4.0 with a 10% aqueous citric acid solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The obtained organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-) was obtained as a pale yellow solid. 0.092 g of oxadiazol-3-yl) biphenyl-3-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.56 (s, 1H), 8.79 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.79-7.74 (m, 2H), 7.67 (dd, J = 8.2, 1.8Hz, 1H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.34 (dd, J = 7.9, 7.9Hz, 1H), 7.25 -7.22 (m, 1H), 7.16 (d, J = 7.6Hz, 1H), 6.91 (dd, J = 8.3,2.4Hz, 1H), 3.42 (q, J = 7.0Hz, 4H), 1.14 (t, (J = 7.0Hz, 6H).
実施例４２～５８
　実施例４１と同様にして、表１２に示す化合物を得た。 Examples 42-58
In the same manner as in Example 41, the compounds shown in Table 12 were obtained.
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
３－（モルホリン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.13-12.86(broad,1H),10.52(s,1H),8.61(d,J=1.8Hz,1H),7.81(d,J=8.3Hz,1H),7.79-7.73(m,2H),7.69(dd,J=8.3,1.8Hz,1H),7.58-7.50(m,3H),7.50-7.37(m,3H),7.26-7.19(m,1H),3.82-3.74(m,4H),3.25-3.18(m,4H). 3- (Morpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.13-12.86 (broad, 1H), 10.52 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.79-7.73 (m, 2H), 7.69 (dd, J = 8.3, 1.8Hz, 1H), 7.58-7.50 (m, 3H), 7.50-7.37 (m, 3H), 7.26-7.19 (m, 1H), 3.82-3.74 (m, 4H), 3.25-3.18 (m, 4H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピロリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.67-8.64(m,1H),7.83(d,J=8.3Hz,1H),7.79-7.73(m,2H),7.70-7.64(m,1H),7.60-7.53(m,2H),7.51-7.46(m,1H),7.40-7.34(m,1H),7.21-7.16(m,1H),7.13-7.10(m,1H),6.83-6.78(m,1H),3.33-3.27(m,4H),2.03-1.97(m,4H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (pyrrolidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.67-8.64 (m, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.79-7.73 (m, 2H), 7.70-7.64 (m, 1H), 7.60-7.53 (m, 2H), 7.51-7.46 (m, 1H), 7.40-7.34 (m, 1H), 7.21-7.16 (m, 1H), 7.13-7.10 (m, 1H) , 6.83-6.78 (m, 1H), 3.33-3.27 (m, 4H), 2.03-1.97 (m, 4H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－４－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.69(d,J=1.8Hz,1H),7.87-7.80(m,3H),7.78-7.73(m,2H),7.62(dd,J=8.2,1.8Hz,1H),7.58-7.52(m,2H),7.50-7.44(m,1H),7.07-7.01(m,2H),3.40-3.32(m,4H),1.63-1.57(m,6H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -4- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.69 (d, J = 1.8 Hz, 1H), 7.87-7.80 (m, 3H), 7.78-7.73 (m, 2H), 7.62 (dd , J = 8.2, 1.8Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.44 (m, 1H), 7.07-7.01 (m, 2H), 3.40-3.32 (m, 4H), 1.63-1.57 (m, 6H).
２－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.05-12.66(broad,1H),10.29(s,1H),8.45-8.36(m,1H),7.78-7.71(m,3H),7.68(dd,J=8.3,1.5Hz,1H),7.58-7.51(m,2H),7.50-7.42(m,1H),7.32-7.23(m,2H),7.18(dd,J=7.3,1.4Hz,1H),2.85-2.76(m,4H),2.33(s,3H),1.72-1.62(m,4H),1.60-1.50(m,2H). 2-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.05-12.66 (broad, 1H), 10.29 (s, 1H), 8.45-8.36 (m, 1H), 7.78-7.71 (m, 3H), 7.68 (dd , J = 8.3,1.5Hz, 1H), 7.58-7.51 (m, 2H), 7.50-7.42 (m, 1H), 7.32-7.23 (m, 2H), 7.18 (dd, J = 7.3,1.4Hz, 1H ), 2.85-2.76 (m, 4H), 2.33 (s, 3H), 1.72-1.62 (m, 4H), 1.60-1.50 (m, 2H).
２－クロロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.00-12.72(broad,1H),10.47(s,1H),8.38-8.31(m,1H),7.80-7.67(m,4H),7.60-7.51(m,2H),7.51-7.38(m,2H),7.31-7.24(m,2H),3.00-2.90(m,4H),1.72-1.63(m,4H),1.60-1.51(m,2H). 2-Chloro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.72 (broad, 1H), 10.47 (s, 1H), 8.38-8.31 (m, 1H), 7.80-7.67 (m, 4H), 7.60-7.51 (m, 2H), 7.51-7.38 (m, 2H), 7.31-7.24 (m, 2H), 3.00-2.90 (m, 4H), 1.72-1.63 (m, 4H), 1.60-1.51 (m, 2H) .
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－６－（ピペリジン－１－イル）ピラジン－２－カルボキサミド
1H-NMR(DMSO-d6)δ値：11.84(s,1H),9.23(d,J=1.7Hz,1H),8.60(s,1H),8.46(s,1H),7.87(d,J=8.3Hz,1H),7.80-7.73(m,2H),7.67(dd,J=8.3,1.7Hz,1H),7.60-7.52(m,2H),7.52-7.43(m,1H),3.87-3.72(m,4H),1.75-1.55(m,6H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -6- (piperidin-1-yl) pyrazin-2- Carboxamide
1 H-NMR (DMSO-d 6 ) δ value: 11.84 (s, 1H), 9.23 (d, J = 1.7 Hz, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 7.87 (d, J = 8.3Hz, 1H), 7.80-7.73 (m, 2H), 7.67 (dd, J = 8.3,1.7Hz, 1H), 7.60-7.52 (m, 2H), 7.52-7.43 (m, 1H), 3.87 -3.72 (m, 4H), 1.75-1.55 (m, 6H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－４－（ピペリジン－１－イル）ピリジン－２－カルボキサミド
1H-NMR(DMSO-d6)δ値：12.02-11.80(broad,1H),9.09-9.04(m,1H),8.27(dd,J=6.1,1.5Hz,1H),7.85(dd,J=8.3,1.5Hz,1H),7.80-7.72(m,2H),7.70-7.63(m,1H),7.61-7.50(m,3H),7.50-7.43(m,1H),7.09-7.02(m,1H),3.52-3.44(m,4H),1.68-1.53(m,6H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -4- (piperidin-1-yl) pyridin-2- Carboxamide
1 H-NMR (DMSO-d 6 ) δ value: 12.02-11.80 (broad, 1H), 9.09-9.04 (m, 1H), 8.27 (dd, J = 6.1, 1.5 Hz, 1H), 7.85 (dd, J = 8.3,1.5Hz, 1H), 7.80-7.72 (m, 2H), 7.70-7.63 (m, 1H), 7.61-7.50 (m, 3H), 7.50-7.43 (m, 1H), 7.09-7.02 (m , 1H), 3.52-3.44 (m, 4H), 1.68-1.53 (m, 6H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（ピペリジン－１－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：13.13-12.85(broad,1H),10.62(s,1H),8.52-8.44(m,1H),8.28(d,J=5.1Hz,1H),7.82(d,J=8.1Hz,1H),7.80-7.69(m,3H),7.59-7.50(m,2H),7.50-7.42(m,1H),7.28(s,1H),7.01(d,J=5.1Hz,1H),3.66-3.57(m,4H),1.69-1.61(m,2H),1.61-1.51(m,4H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- (piperidin-1-yl) isonicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 13.13-12.85 (broad, 1H), 10.62 (s, 1H), 8.52-8.44 (m, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 8.1Hz, 1H), 7.80-7.69 (m, 3H), 7.59-7.50 (m, 2H), 7.50-7.42 (m, 1H), 7.28 (s, 1H), 7.01 (d, J = 5.1Hz, 1H), 3.66-3.57 (m, 4H), 1.69-1.61 (m, 2H), 1.61-1.51 (m, 4H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－５－（ピペリジン－１－イル）ニコチンアミド
1H-NMR(DMSO-d6)δ値：10.63(s,1H),8.51(d,J=2.7Hz,1H),8.50-8.43(m,2H),7.82(d,J=8.3Hz,1H),7.80-7.68(m,4H),7.59-7.50(m,2H),7.50-7.42(m,1H),3.40-3.26(m,4H),1.71-1.55(m,6H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -5- (piperidin-1-yl) nicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 10.63 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.50-8.43 (m, 2H), 7.82 (d, J = 8.3 Hz, 1H), 7.80-7.68 (m, 4H), 7.59-7.50 (m, 2H), 7.50-7.42 (m, 1H), 3.40-3.26 (m, 4H), 1.71-1.55 (m, 6H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－６－（ピペリジン－１－イル）ピリジン－２－カルボキサミド
1H-NMR(DMSO-d6)δ値：13.24-13.06(broad,1H),11.87(s,1H),9.25(d,J=1.7Hz,1H),7.86(d,J=8.3Hz,1H),7.80-7.70(m,3H),7.66(dd,J=8.3,1.7Hz,1H),7.59-7.52(m,2H),7.51-7.44(m,1H),7.42(d,J=7.3Hz,1H),7.12(d,J=8.8Hz,1H),3.76-3.68(m,4H),1.71-1.57(m,6H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -6- (piperidin-1-yl) pyridin-2- Carboxamide
1 H-NMR (DMSO-d 6 ) δ value: 13.24-13.06 (broad, 1H), 11.87 (s, 1H), 9.25 (d, J = 1.7 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.80-7.70 (m, 3H), 7.66 (dd, J = 8.3, 1.7Hz, 1H), 7.59-7.52 (m, 2H), 7.51-7.44 (m, 1H), 7.42 (d, J = 7.3Hz, 1H), 7.12 (d, J = 8.8Hz, 1H), 3.76-3.68 (m, 4H), 1.71-1.57 (m, 6H).
３－（ジメチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.21-12.86(broad,1H),10.53(s,1H),8.75-8.71(m,1H),7.82(d,J=8.0Hz,1H),7.79-7.73(m,2H),7.71-7.65(m,1H),7.58-7.51(m,2H),7.50-7.44(m,1H),7.37(dd,J=7.8,7.8Hz,1H),7.33-7.28(m,1H),7.28-7.22(m,1H),6.98(dd,J=8.3,2.4Hz,1H),2.99(s,6H). 3- (Dimethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.21-12.86 (broad, 1H), 10.53 (s, 1H), 8.75-8.71 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.79-7.73 (m, 2H), 7.71-7.65 (m, 1H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.37 (dd, J = 7.8,7.8Hz, 1H), 7.33-7.28 (m, 1H), 7.28-7.22 (m, 1H), 6.98 (dd, J = 8.3, 2.4Hz, 1H), 2.99 (s, 6H).
３－（エチル（メチル）アミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.54(s,1H),8.75(d,J=1.7Hz,1H),7.83(d,J=8.3Hz,1H),7.79-7.74(m,2H),7.68(dd,J=8.3,1.7Hz,1H),7.58-7.52(m,2H),7.50-7.44(m,1H),7.36(dd,J=8.1,8.1Hz,1H),7.30-7.26(m,1H),7.21(d,J=7.6Hz,1H),6.96(dd,J=8.3,2.4Hz,1H),3.48(q,J=7.0Hz,2H),2.95(s,3H),1.08(t,J=7.0Hz,3H). 3- (Ethyl (methyl) amino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.54 (s, 1H), 8.75 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.79-7.74 (m, 2H), 7.68 (dd, J = 8.3, 1.7Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.44 (m, 1H), 7.36 (dd, J = 8.1, 8.1Hz, 1H), 7.30 -7.26 (m, 1H), 7.21 (d, J = 7.6Hz, 1H), 6.96 (dd, J = 8.3,2.4Hz, 1H), 3.48 (q, J = 7.0Hz, 2H), 2.95 (s, 3H), 1.08 (t, J = 7.0Hz, 3H).
４－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３，４－ジヒドロ－２Ｈ－１，４－ベンズオキサジン－６－カルボキサミド
1H-NMR(DMSO-d6+D2O)δ値：8.74-8.71(m,1H),7.83(d,J=8.1Hz,1H),7.78-7.73(m,2H),7.65(dd,J=8.1,1.7Hz,1H),7.58-7.52(m,2H),7.50-7.44(m,1H),7.31(d,J=2.0Hz,1H),7.27(dd,J=8.3,2.0Hz,1H),6.84(d,J=8.3Hz,1H),4.35-4.28(m,2H),3.34-3.27(m,2H),2.94(s,3H). 4-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3,4-dihydro-2H-1 , 4-Benzoxazine-6-carboxamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.74-8.71 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.78-7.73 (m, 2H), 7.65 (dd , J = 8.1,1.7Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.44 (m, 1H), 7.31 (d, J = 2.0Hz, 1H), 7.27 (dd, J = 8.3,2.0 Hz, 1H), 6.84 (d, J = 8.3Hz, 1H), 4.35-4.28 (m, 2H), 3.34-3.27 (m, 2H), 2.94 (s, 3H).
３－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.16-12.92(broad,1H),10.55(s,1H),8.69(d,J=1.9Hz,1H),7.82(d,J=8.2Hz,1H),7.79-7.73(m,2H),7.69(dd,J=8.2,1.9Hz,1H),7.58-7.51(m,3H),7.50-7.35(m,3H),7.25-7.20(m,1H),3.79-3.66(m,4H),2.40-2.29(m,2H),1.20(d,J=6.3Hz,6H). 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) ) Biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.16-12.92 (broad, 1H), 10.55 (s, 1H), 8.69 (d, J = 1.9 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.79-7.73 (m, 2H), 7.69 (dd, J = 8.2, 1.9Hz, 1H), 7.58-7.51 (m, 3H), 7.50-7.35 (m, 3H), 7.25-7.20 (m, 1H), 3.79-3.66 (m, 4H), 2.40-2.29 (m, 2H), 1.20 (d, J = 6.3Hz, 6H).
２－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：13.30-12.80(broad,1H),10.62(s,1H),8.60(d,J=1.2Hz,1H),8.25(d,J=5.1Hz,1H),7.83(d,J=8.3Hz,1H),7.80-7.74(m,2H),7.72(dd,J=8.2,1.8Hz,1H),7.59-7.51(m,2H),7.51-7.43(m,1H),7.06(s,1H),6.99-6.93(m,1H),3.57(q,J=7.0Hz,4H),1.16(t,J=7.0Hz,6H). 2- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) isonicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.80 (broad, 1H), 10.62 (s, 1H), 8.60 (d, J = 1.2 Hz, 1H), 8.25 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 8.3Hz, 1H), 7.80-7.74 (m, 2H), 7.72 (dd, J = 8.2,1.8Hz, 1H), 7.59-7.51 (m, 2H), 7.51-7.43 (m, 1H), 7.06 (s, 1H), 6.99-6.93 (m, 1H), 3.57 (q, J = 7.0Hz, 4H), 1.16 (t, J = 7.0Hz, 6H).
３－ニトロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.08-12.80(broad,1H),10.79(s,1H),8.84-8.80(m,1H),8.49(ddd,J=8.3,2.4,1.0Hz,1H),8.43-8.36(m,1H),8.30-8.25(m,1H),7.90(dd,J=8.1,8.1Hz,1H),7.84-7.73(m,4H),7.58-7.51(m,2H),7.50-7.43(m,1H). 3-Nitro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.08-12.80 (broad, 1H), 10.79 (s, 1H), 8.84-8.80 (m, 1H), 8.49 (ddd, J = 8.3, 2.4, 1.0 Hz , 1H), 8.43-8.36 (m, 1H), 8.30-8.25 (m, 1H), 7.90 (dd, J = 8.1,8.1Hz, 1H), 7.84-7.73 (m, 4H), 7.58-7.51 (m , 2H), 7.50-7.43 (m, 1H).
３－（１－メチルピペリジン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.16(s,1H),9.54-9.21(broad,1H),9.18(d,J=1.8Hz,1H),8.42(s,1H),8.07(d,J=8.3Hz,1H),7.99-7.91(m,1H),7.75-7.69(m,2H),7.57-7.49(m,4H),7.47(dd,J=8.3,1.8Hz,1H),7.45-7.39(m,1H),3.66-3.50(m,2H),3.20-3.05(m,2H),3.03-2.92(m,1H),2.90(s,3H),2.22-2.06(m,4H). 3- (1-Methylpiperidin-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.16 (s, 1H), 9.54-9.21 (broad, 1H), 9.18 (d, J = 1.8 Hz, 1H), 8.42 (s, 1H), 8.07 ( d, J = 8.3Hz, 1H), 7.99-7.91 (m, 1H), 7.75-7.69 (m, 2H), 7.57-7.49 (m, 4H), 7.47 (dd, J = 8.3,1.8Hz, 1H) , 7.45-7.39 (m, 1H), 3.66-3.50 (m, 2H), 3.20-3.05 (m, 2H), 3.03-2.92 (m, 1H), 2.90 (s, 3H), 2.22-2.06 (m, 4H).
実施例５９
Figure JPOXMLDOC01-appb-C000127
 　実施例４１と同様にして、以下の化合物を得た。
Ｎ－（３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.13-12.90(broad,1H),10.53(s,1H),8.36(d,J=8.8Hz,1H),8.06(d,J=2.2Hz,1H),8.03-7.96(m,3H),7.83-7.77(m,2H),7.68-7.57(m,3H),7.56-7.49(m,2H),7.45-7.39(m,1H). Example 59
Figure JPOXMLDOC01-appb-C000127
 In the same manner as in Example 41, the following compound was obtained.
N- (3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.13-12.90 (broad, 1H), 10.53 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 8.03-7.96 (m, 3H), 7.83-7.77 (m, 2H), 7.68-7.57 (m, 3H), 7.56-7.49 (m, 2H), 7.45-7.39 (m, 1H).
実施例６０
Figure JPOXMLDOC01-appb-C000128
 　実施例４１と同様にして、以下の化合物を得た。
Ｎ－（３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.18-12.93(broad,1H),10.50(s,1H),8.45(d,J=8.6Hz,1H),8.07(d,J=2.2Hz,1H),7.99(dd,J=8.7,2.1Hz,1H),7.83-7.76(m,2H),7.56-7.48(m,3H),7.46-7.29(m,3H),7.24-7.16(m,1H),3.30-3.22(m,4H),1.71-1.62(m,4H),1.62-1.53(m,2H). Example 60
Figure JPOXMLDOC01-appb-C000128
 In the same manner as in Example 41, the following compound was obtained.
N- (3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.18-12.93 (broad, 1H), 10.50 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.99 (dd, J = 8.7, 2.1Hz, 1H), 7.83-7.76 (m, 2H), 7.56-7.48 (m, 3H), 7.46-7.29 (m, 3H), 7.24-7.16 (m, 1H), 3.30-3.22 (m, 4H), 1.71-1.62 (m, 4H), 1.62-1.53 (m, 2H).
実施例６１
Figure JPOXMLDOC01-appb-C000129
 　実施例４１と同様にして、以下の化合物を得た。
Ｎ－（５－（フラン－２－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.14-12.84(broad,1H),10.54(s,1H),8.72-8.68(m,1H),7.90-7.86(m,1H),7.77(d,J=8.3Hz,1H),7.69(dd,J=8.4,1.6Hz,1H),7.55-7.49(m,1H),7.42-7.30(m,2H),7.23-7.17(m,1H),7.17(d,J=3.4Hz,1H),6.69(dd,J=3.3,1.6Hz,1H),3.29-3.22(m,4H),1.71-1.62(m,4H),1.62-1.54(m,2H). Example 61
Figure JPOXMLDOC01-appb-C000129
 In the same manner as in Example 41, the following compound was obtained.
N- (5- (furan-2-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidine-1- Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.14-12.84 (broad, 1H), 10.54 (s, 1H), 8.72-8.68 (m, 1H), 7.90-7.86 (m, 1H), 7.77 (d , J = 8.3Hz, 1H), 7.69 (dd, J = 8.4,1.6Hz, 1H), 7.55-7.49 (m, 1H), 7.42-7.30 (m, 2H), 7.23-7.17 (m, 1H), 7.17 (d, J = 3.4Hz, 1H), 6.69 (dd, J = 3.3,1.6Hz, 1H), 3.29-3.22 (m, 4H), 1.71-1.62 (m, 4H), 1.62-1.54 (m, 2H).
実施例６２
Figure JPOXMLDOC01-appb-C000130
 　Ｎ－（４－シアノビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.10gのＮ，Ｎ－ジメチルホルムアミド0.50mL溶液に、50％ヒドロキシルアミン水溶液0.087mLを加え、60℃で2時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体のＮ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.11gを得た。
　得られたＮ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.080gのテトラヒドロフラン2mLおよびピリジン0.020mL混液に、氷冷下２－エチルヘキシルクロロホルマート0.045mLを加え、室温で1時間攪拌した。反応混合物に酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にキシレン2.0mLを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；80-30％ヘキサン／酢酸エチル］で精製し、黄色固体のＮ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.038gを得た。
1H-NMR(DMSO-d6)δ値：13.20-12.80(broad,1H),10.58(s,1H),8.66(d,J=1.7Hz,1H),7.82(d,J=8.2Hz,1H),7.79-7.73(m,2H),7.68(dd,J=8.2,1.7Hz,1H),7.58-7.50(m,3H),7.50-7.43(m,1H),7.42-7.30(m,2H),7.22-7.16(m,1H),3.29-3.22(m,4H),1.70-1.62(m,4H),1.62-1.53(m,2H). Example 62
Figure JPOXMLDOC01-appb-C000130
 To a solution of N- (4-cyanobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide (0.10 g) in N, N-dimethylformamide (0.50 mL) was added 50% hydroxylamine aqueous solution (0.087 mL) at 60 ° C. Stir for 2 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give 0.11 g of N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide as a white solid. Obtained.
The obtained N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide (0.080 g) in a mixture of 2 mL of tetrahydrofuran and 0.020 mL of pyridine was mixed with 2-ethylhexyl chloroformate under ice cooling. 0.045 mL was added and stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 2.0 mL of xylene was added and heated to reflux for 3 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 80-30% hexane / ethyl acetate] to give N- (4- (5-oxo-4,5-dihydro-1,2, 0.038 g of 4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.80 (broad, 1H), 10.58 (s, 1H), 8.66 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.79-7.73 (m, 2H), 7.68 (dd, J = 8.2, 1.7Hz, 1H), 7.58-7.50 (m, 3H), 7.50-7.43 (m, 1H), 7.42-7.30 (m, 2H), 7.22-7.16 (m, 1H), 3.29-3.22 (m, 4H), 1.70-1.62 (m, 4H), 1.62-1.53 (m, 2H).
実施例６３
Figure JPOXMLDOC01-appb-C000131
 　４－（ジエチルアミノ）安息香酸0.10gのアセトニトリル1mL、１－メチル－２－ピロリドン0.10mLおよびＮ，Ｎ－ジメチルホルムアミド0.010mL混液に、室温で塩化チオニル0.044mLを加え、同温度で10分間攪拌した。反応混合物に水冷下、３－（３－アミノビフェニル－４－イル）－１，２，４－オキサジアゾール－５（４Ｈ）－オン0.10gの１－メチル－２－ピロリドン0.30mL溶液を加え、室温で2時間攪拌した。反応混合物に水を加え、飽和炭酸水素ナトリウム水溶液でpH4に調整後、酢酸エチルおよび水を加え、固形物をろ取し、白色固体の４－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド0.090gを得た。
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.33(s,1H),8.78(d,J=1.9Hz,1H),7.84-7.78(m,3H),7.78-7.72(m,2H),7.62(dd,J=8.2,1.9Hz,1H),7.57-7.51(m,2H),7.49-7.43(m,1H),6.80-6.75(m,2H),3.43(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). Example 63
Figure JPOXMLDOC01-appb-C000131
 To a mixture of 4- (diethylamino) benzoic acid (0.10 g) with acetonitrile (1 mL), 1-methyl-2-pyrrolidone (0.10 mL) and N, N-dimethylformamide (0.010 mL) was added thionyl chloride (0.044 mL) at room temperature, and the mixture was stirred at the same temperature for 10 minutes. . To the reaction mixture was added a solution of 0.10 g of 3- (3-aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one in 0.30 mL of 1-methyl-2-pyrrolidone under water cooling. And stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the pH was adjusted to 4 with a saturated aqueous sodium hydrogen carbonate solution. Ethyl acetate and water were added, and the solid was collected by filtration to give 4- (diethylamino) -N- (4- (5-oxo 0.090 g of -4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.33 (s, 1H), 8.78 (d, J = 1.9 Hz, 1H), 7.84-7.78 (m, 3H), 7.78-7.72 (m, 2H), 7.62 (dd, J = 8.2,1.9Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.43 (m, 1H), 6.80-6.75 (m, 2H), 3.43 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
実施例６４～６６
　実施例６３と同様にして、表１３に示す化合物を得た。 Examples 64-66
In the same manner as in Example 63, the compounds shown in Table 13 were obtained.
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000132
４－（ジメチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.17-12.86(broad,1H),10.35(s,1H),8.77(d,J=1.7Hz,1H),7.87-7.82(m,2H),7.80(d,J=8.3Hz,1H),7.78-7.73(m,2H),7.63(dd,J=8.3,1.7Hz,1H),7.57-7.51(m,2H),7.49-7.43(m,1H),6.85-6.79(m,2H),3.03(s,6H). 4- (Dimethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.17-12.86 (broad, 1H), 10.35 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 7.87-7.82 (m, 2H), 7.80 (d, J = 8.3Hz, 1H), 7.78-7.73 (m, 2H), 7.63 (dd, J = 8.3,1.7Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.43 (m, 1H), 6.85-6.79 (m, 2H), 3.03 (s, 6H).
３－（アゼパン－１－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.52(s,1H),8.77(d,J=1.7Hz,1H),7.83(d,J=8.3Hz,1H),7.79-7.74(m,2H),7.68(dd,J=8.3,1.7Hz,1H),7.58-7.52(m,2H),7.50-7.44(m,1H),7.33(dd,J=8.1,8.1Hz,1H),7.28-7.24(m,1H),7.15(d,J=7.6Hz,1H),6.93(dd,J=8.3,2.4Hz,1H),3.57-3.50(m,4H),1.82-1.73(m,4H),1.53-1.45(m,4H). 3- (Azepan-1-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.52 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.79-7.74 (m, 2H), 7.68 (dd, J = 8.3, 1.7Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.44 (m, 1H), 7.33 (dd, J = 8.1, 8.1Hz, 1H), 7.28 -7.24 (m, 1H), 7.15 (d, J = 7.6Hz, 1H), 6.93 (dd, J = 8.3,2.4Hz, 1H), 3.57-3.50 (m, 4H), 1.82-1.73 (m, 4H ), 1.53-1.45 (m, 4H).
３－（１，４－オキサゼパン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.52(s,1H),8.75(d,J=1.2Hz,1H),7.83(d,J=8.1Hz,1H),7.79-7.74(m,2H),7.71-7.65(m,1H),7.58-7.51(m,2H),7.50-7.43(m,1H),7.35(dd,J=7.9,7.9Hz,1H),7.33-7.29(m,1H),7.20(d,J=7.6Hz,1H),7.01(dd,J=8.6,2.4Hz,1H),3.80-3.74(m,2H),3.70-3.62(m,4H),3.62-3.56(m,2H),1.98-1.90(m,2H). 3- (1,4-Oxazepan-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.52 (s, 1H), 8.75 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.79-7.74 (m, 2H), 7.71-7.65 (m, 1H), 7.58-7.51 (m, 2H), 7.50-7.43 (m, 1H), 7.35 (dd, J = 7.9, 7.9Hz, 1H), 7.33-7.29 (m, 1H), 7.20 (d, J = 7.6Hz, 1H), 7.01 (dd, J = 8.6, 2.4Hz, 1H), 3.80-3.74 (m, 2H), 3.70-3.62 (m, 4H), 3.62-3.56 (m, 2H), 1.98-1.90 (m, 2H).
実施例６７
Figure JPOXMLDOC01-appb-C000133
 　３－ニトロ－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド0.39gのテトラヒドロフラン30mLおよびメタノール5.0mL混液に、10％パラジウム－炭素0.078gを加え、水素雰囲気下、室温で2時間攪拌した。反応混合物に10％パラジウム－炭素0.078gを加え、水素雰囲気下、室温で5時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；99-95％クロロホルム／メタノール］で精製し、淡黄色固体の３－アミノ－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド0.23gを得た。
　得られた３－アミノ－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド0.15gのテトラヒドロフラン5.0mL溶液に、酢酸0.094mL、37％ホルムアルデヒド水溶液0.080mLおよびナトリウムトリアセトキシボロヒドリド0.43gを順次加え、室温で24時間攪拌した。反応混合物に水およびクロロホルムを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；99-95％クロロホルム／メタノール］で精製し、淡黄色固体の３－（ジメチルアミノ）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド0.050gを得た。
1H-NMR(DMSO-d6)δ値：11.83(s,1H),9.11(d,J=1.8Hz,1H),8.14(d,J=8.3Hz,1H),7.81-7.75(m,2H),7.70(dd,J=8.3,1.8Hz,1H),7.59-7.52(m,2H),7.50-7.34(m,4H),7.04-6.97(m,1H),3.04(s,6H). Example 67
Figure JPOXMLDOC01-appb-C000133
 To a mixture of 3-nitro-N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide (0.39 g) in tetrahydrofuran (30 mL) and methanol (5.0 mL) was added 10% palladium-carbon (0.078 g) under a hydrogen atmosphere. And stirred at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (0.078 g) was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-95% chloroform / methanol] to give a pale yellow solid of 3-amino-N- (4- 0.23 g of (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide was obtained.
The resulting 3-amino-N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide (0.15 g) in tetrahydrofuran (5.0 mL) was added to acetic acid (0.094 mL), 37% formaldehyde aqueous solution (0.080 mL) and sodium trioxide. Acetoxyborohydride (0.43 g) was sequentially added, and the mixture was stirred at room temperature for 24 hours. Water and chloroform were added to the reaction mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-95% chloroform / methanol] to give 3- (dimethylamino) -N- (4- (1H-tetrazol-5-yl) as a pale yellow solid. 0.050 g) Biphenyl-3-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 11.83 (s, 1H), 9.11 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.81-7.75 (m, 2H), 7.70 (dd, J = 8.3, 1.8Hz, 1H), 7.59-7.52 (m, 2H), 7.50-7.34 (m, 4H), 7.04-6.97 (m, 1H), 3.04 (s, 6H) .
実施例６８
Figure JPOXMLDOC01-appb-C000134
 　Ｎ－（４－シアノビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.50gのテトラヒドロフラン2.5mLおよび50％ヒドロキシルアミン水溶液0.10mL混液を、50℃で1時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物に２－プロパノールを加え、固形物をろ取し、Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドを得た。
　得られたＮ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドのテトラヒドロフラン5.0mLおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.23mL混液に、１，１’－チオカルボニルジイミダゾール0.28gを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、クロロホルムおよび10％クエン酸水溶液を加えた。有機層を分取し、無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；100-91％クロロホルム／メタノール］で精製し、微黄色固体の３－（ピペリジン－１－イル）－Ｎ－（４－（５－チオオキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド0.33gを得た。
1H-NMR(DMSO-d6)δ値：11.70-11.30(broad,1H),8.73(s,1H),7.98(d,J=8.3Hz,1H),7.83-7.35(m,10H),3.50-3.32(m,4H),1.84-1.52(m,6H). Example 68
Figure JPOXMLDOC01-appb-C000134
 A mixture of 0.50 g of N- (4-cyanobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide in 2.5 mL of tetrahydrofuran and 0.10 mL of 50% aqueous hydroxylamine was stirred at 50 ° C. for 1 hour. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. 2-Propanol was added to the obtained residue, and the solid was collected by filtration to obtain N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide.
The resulting N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide in 5.0 mL of tetrahydrofuran and 1,8-diazabicyclo [5.4.0] -7-undecene To 0.23 mL mixed solution, 0.21 g of 1,1′-thiocarbonyldiimidazole was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and chloroform and a 10% aqueous citric acid solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-91% chloroform / methanol] to give 3- (piperidin-1-yl) -N- (4- (5-thiooxo-) as a pale yellow solid. 0.35 g of 4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 11.70-11.30 (broad, 1H), 8.73 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.83-7.35 (m, 10H), 3.50-3.32 (m, 4H), 1.84-1.52 (m, 6H).
実施例６９
Figure JPOXMLDOC01-appb-C000135
 　実施例６８と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－Ｎ－（４－（５－チオオキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：8.77(s,1H),7.98(d,J=8.3Hz,1H),7.80-6.85(m,10H),3.65-3.30(m,4H),1.12(t,J=6.8Hz,6H). Example 69
Figure JPOXMLDOC01-appb-C000135
 In the same manner as in Example 68, the following compound was obtained.
3- (Diethylamino) -N- (4- (5-thiooxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 8.77 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.80-6.85 (m, 10H), 3.65-3.30 (m, 4H), 1.12 (t, J = 6.8Hz, 6H).
実施例７０
Figure JPOXMLDOC01-appb-C000136
 　Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.31gのテトラヒドロフラン3.1mL溶液に、１，１’－チオカルボニルジイミダゾール0.16gを加え、室温で30分間攪拌した。反応混合物にクロロホルムおよび水を加え、固形物をろ取した。有機層を分取し、無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去した。得られた残留物と固形物を併せ、テトラヒドロフラン6.0mLおよび三フッ化ホウ素ジエチルエーテル錯体0.47mLを順次加え、室温で1時間30分間攪拌した。反応混合物に水および酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液でpH4.0に調整後、固形物をろ取し、白色固体のＮ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.12gを得た。
1H-NMR(DMSO-d6)δ値：13.60-13.30(broad,1H),11.66(s,1H),8.93(d,J=2.0Hz,1H),7.92(d,J=8.3Hz,1H),7.78-7.73(m,2H),7.60(dd,J=8.3,2.0Hz,1H),7.57-7.51(m,2H),7.49-7.42(m,2H),7.39(dd,J=7.8,7.8Hz,1H),7.35-7.30(m,1H),7.20(dd,J=8.1,1.7Hz,1H),3.28-3.21(m,4H),1.71-1.53(m,6H). Example 70
Figure JPOXMLDOC01-appb-C000136
 To a solution of 0.31 g of N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide in 3.1 mL of tetrahydrofuran was added 0.16 g of 1,1′-thiocarbonyldiimidazole, For 30 minutes. Chloroform and water were added to the reaction mixture, and the solid was collected by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue and solid were combined, tetrahydrofuran (6.0 mL) and boron trifluoride diethyl ether complex (0.47 mL) were sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water and ethyl acetate are added to the reaction mixture, and the pH is adjusted to 4.0 with a saturated aqueous sodium hydrogen carbonate solution. The solid matter is collected by filtration, and a white solid N- (4- (5-oxo-4,5-dihydro-1) , 2,4-thiadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.60-13.30 (broad, 1H), 11.66 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.78-7.73 (m, 2H), 7.60 (dd, J = 8.3, 2.0Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.42 (m, 2H), 7.39 (dd, J = 7.8, 7.8Hz, 1H), 7.35-7.30 (m, 1H), 7.20 (dd, J = 8.1, 1.7Hz, 1H), 3.28-3.21 (m, 4H), 1.71-1.53 (m, 6H).
実施例７１
Figure JPOXMLDOC01-appb-C000137
 　実施例７０と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.75-13.42(broad,1H),11.66(s,1H),8.97(d,J=1.8Hz,1H),7.93(d,J=8.3Hz,1H),7.79-7.73(m,2H),7.60(dd,J=8.3,1.8Hz,1H),7.57-7.51(m,2H),7.49-7.43(m,1H),7.34(dd,J=7.9,7.9Hz,1H),7.21-7.16(m,1H),7.16-7.10(m,1H),6.91(dd,J=8.3,2.4Hz,1H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). Example 71
Figure JPOXMLDOC01-appb-C000137
 In the same manner as in Example 70, the following compound was obtained.
3- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.75-13.42 (broad, 1H), 11.66 (s, 1H), 8.97 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.79-7.73 (m, 2H), 7.60 (dd, J = 8.3, 1.8Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.43 (m, 1H), 7.34 (dd, J = 7.9,7.9Hz, 1H), 7.21-7.16 (m, 1H), 7.16-7.10 (m, 1H), 6.91 (dd, J = 8.3,2.4Hz, 1H), 3.42 (q, J = 7.0Hz, 4H ), 1.14 (t, J = 7.0Hz, 6H).
実施例７２
Figure JPOXMLDOC01-appb-C000138
 　Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド0.50gのテトラヒドロフラン10mL、１－メチル－２－ピロリドン5.0mL、アセトニトリル5.0mLおよびピリジン0.29mL混液に、氷冷下塩化チオニル0.097mLを加え、同温度で30分間攪拌した。反応混合物に塩化チオニル0.097mLを加え、室温で20分間攪拌した。反応混合物にピリジン0.29mLおよび塩化チオニル0.097mLを加え、室温で30分間攪拌した。減圧下で溶媒を留去し、水およびクロロホルムを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム］で精製後、シリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、Ｐｕｒｉｆ－Ｐａｃｋ　ＤＩＯＬ（60μm）、溶離液；クロロホルム］で再精製し、白色固体のＮ－（４－（２－オキシド－３Ｈ－１，２，３，５－オキサチアジアゾール－４－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド23mgを得た。
1H-NMR(DMSO-d6)δ値：11.05-10.80(broad,1H),8.75(d,J=1.8Hz,1H),7.92(d,J=8.2Hz,1H),7.82-7.72(m,2H),7.69(dd,J=8.2,1.8Hz,1H),7.63-7.30(m,6H),7.30-7.15(m,1H),3.35-3.20(m,4H),1.75-1.50(m,6H). Example 72
Figure JPOXMLDOC01-appb-C000138
 N- (4- (hydroxyamidino) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide 0.50 g in tetrahydrofuran 10 mL, 1-methyl-2-pyrrolidone 5.0 mL, acetonitrile 5.0 mL and pyridine 0.29 mL Under ice cooling, 0.097 mL of thionyl chloride was added, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 0.097 mL of thionyl chloride, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture were added 0.29 mL of pyridine and 0.097 mL of thionyl chloride, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and water and chloroform were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform] and then re-purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., Purif-Pack DIOL (60 μm), eluent: chloroform] 23 mg of solid N- (4- (2-oxide-3H-1,2,3,5-oxathiadiazol-4-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide was obtained. .
1 H-NMR (DMSO-d 6 ) δ value: 11.05-10.80 (broad, 1H), 8.75 (d, J = 1.8 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.82-7.72 ( m, 2H), 7.69 (dd, J = 8.2, 1.8Hz, 1H), 7.63-7.30 (m, 6H), 7.30-7.15 (m, 1H), 3.35-3.20 (m, 4H), 1.75-1.50 ( m, 6H).
実施例７３
Figure JPOXMLDOC01-appb-C000139
 　実施例７２と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－Ｎ－（４－（２－オキシド－３Ｈ－１，２，３，５－オキサチアジアゾール－４－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.01-10.82(broad,1H),8.87(s,1H),7.92(d,J=8.3Hz,1H),7.84-7.74(m,2H),7.69(dd,J=8.3,1.7Hz,1H),7.62-7.51(m,2H),7.51-7.43(m,1H),7.43-7.12(m,3H),7.05-6.85(m,1H),3.44(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). Example 73
Figure JPOXMLDOC01-appb-C000139
 In the same manner as in Example 72, the following compound was obtained.
3- (Diethylamino) -N- (4- (2-oxide-3H-1,2,3,5-oxathiadiazol-4-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.01-10.82 (broad, 1H), 8.87 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.84-7.74 (m, 2H), 7.69 (dd, J = 8.3,1.7Hz, 1H), 7.62-7.51 (m, 2H), 7.51-7.43 (m, 1H), 7.43-7.12 (m, 3H), 7.05-6.85 (m, 1H), 3.44 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
実施例７４
Figure JPOXMLDOC01-appb-C000140
 　Ｎ－（２－シアノ－５－フェノキシフェニル）－３－（ジエチルアミノ）ベンズアミド90mgのテトラヒドロフラン2.0mL溶液に、50％ヒドロキシルアミン水溶液0.075mLを加え、55℃で1時間攪拌した。反応混合物に50％ヒドロキシルアミン水溶液0.075mLを加え、55℃で1時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去し、３－（ジエチルアミノ）－Ｎ－（２－（ヒドロキシアミジノ）－５－フェノキシフェニル）ベンズアミドを得た。
　得られた３－（ジエチルアミノ）－Ｎ－（２－（ヒドロキシアミジノ）－５－フェノキシフェニル）ベンズアミドに、テトラヒドロフラン2.0mL、１，１’－カルボニルジイミダゾール0.13gおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.11mLを順次加え、室温で1時間攪拌した。減圧下で溶媒を留去し、酢酸エチルおよび水を加え、10％クエン酸水溶液でpH5.5に調整した。有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；99-92％クロロホルム／メタノール］で精製し、白色固体の３－（ジエチルアミノ）－Ｎ－（２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－５－フェノキシフェニル）ベンズアミド49mgを得た。
1H-NMR(DMSO-d6)δ値：13.14-12.86(broad,1H),10.55(s,1H),8.19(d,J=2.5Hz,1H),7.74(d,J=8.7Hz,1H),7.53-7.46(m,2H),7.34-7.24(m,2H),7.20-7.13(m,3H),7.11-7.06(m,1H),6.95(dd,J=8.7,2.5Hz,1H),6.89(dd,J=8.3,2.2Hz,1H),3.40(q,J=7.0Hz,4H),1.12(t,J=7.0Hz,6H). Example 74
Figure JPOXMLDOC01-appb-C000140
 To a 2.0 mL tetrahydrofuran solution of 90 mg of N- (2-cyano-5-phenoxyphenyl) -3- (diethylamino) benzamide was added 0.075 mL of a 50% aqueous hydroxylamine solution, and the mixture was stirred at 55 ° C. for 1 hour. To the reaction mixture, 0.075 mL of 50% aqueous hydroxylamine solution was added, and the mixture was stirred at 55 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure to obtain 3- (diethylamino) -N- (2- (hydroxyamidino) -5-phenoxyphenyl) benzamide.
To the obtained 3- (diethylamino) -N- (2- (hydroxyamidino) -5-phenoxyphenyl) benzamide, 2.0 mL of tetrahydrofuran, 0.13 g of 1,1′-carbonyldiimidazole and 1,8-diazabicyclo [5. 4.0] -7-undecene (0.11 mL) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 5.5 with a 10% aqueous citric acid solution. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-92% chloroform / methanol] to give 3- (diethylamino) -N- (2- (5-oxo-4,5-dihydro) as a white solid. 49 mg of -1,2,4-oxadiazol-3-yl) -5-phenoxyphenyl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.14-12.86 (broad, 1H), 10.55 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.53-7.46 (m, 2H), 7.34-7.24 (m, 2H), 7.20-7.13 (m, 3H), 7.11-7.06 (m, 1H), 6.95 (dd, J = 8.7, 2.5Hz, 1H), 6.89 (dd, J = 8.3, 2.2Hz, 1H), 3.40 (q, J = 7.0Hz, 4H), 1.12 (t, J = 7.0Hz, 6H).
実施例７５
Figure JPOXMLDOC01-appb-C000141
 　実施例２７と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－Ｎ－（５－フェノキシ－２－（１Ｈ－テトラゾール－５－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.91(s,1H),8.48(d,J=2.6Hz,1H),8.05(d,J=8.8Hz,1H),7.52-7.46(m,2H),7.39-7.31(m,2H),7.31-7.16(m,4H),6.99(dd,J=8.8,2.6Hz,1H),6.93(dd,J=8.4,2.1Hz,1H),3.45(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). Example 75
Figure JPOXMLDOC01-appb-C000141
 In the same manner as in Example 27, the following compound was obtained.
3- (Diethylamino) -N- (5-phenoxy-2- (1H-tetrazol-5-yl) phenyl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.91 (s, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.52-7.46 (m, 2H), 7.39-7.31 (m, 2H), 7.31-7.16 (m, 4H), 6.99 (dd, J = 8.8, 2.6Hz, 1H), 6.93 (dd, J = 8.4, 2.1Hz, 1H), 3.45 (q, J = 7.0Hz, 4H), 1.14 (t, J = 7.0Hz, 6H).
実施例７６
Figure JPOXMLDOC01-appb-C000142
 　実施例７４と同様にして、以下の化合物を得た。
Ｎ－（２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－５－（（Ｅ）－２－フェニルビニル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.80(broad,1H),10.46(s,1H),8.50(s,1H),7.76-7.60(m,4H),7.54-7.28(m,8H),7.24-7.15(m,1H),3.30-3.20(m,4H),1.70-1.52(m,6H). Example 76
Figure JPOXMLDOC01-appb-C000142
 In the same manner as in Example 74, the following compound was obtained.
N- (2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -5-((E) -2-phenylvinyl) phenyl) -3- (piperidine -1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.80 (broad, 1H), 10.46 (s, 1H), 8.50 (s, 1H), 7.76-7.60 (m, 4H), 7.54-7.28 (m , 8H), 7.24-7.15 (m, 1H), 3.30-3.20 (m, 4H), 1.70-1.52 (m, 6H).
実施例７７
Figure JPOXMLDOC01-appb-C000143
 　実施例７４と同様にして、以下の化合物を得た。
Ｎ－（２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－５－（２－フェニルエチル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.00-12.74(broad,1H),10.50-10.40(broad,1H),8.24-8.20(m,1H),7.62(d,J=8.1Hz,1H),7.51-7.47(m,1H),7.40-7.33(m,1H),7.33-7.24(m,5H),7.24-7.15(m,3H),3.28-3.20(m,4H),3.02-2.90(m,4H),1.70-1.52(m,6H). Example 77
Figure JPOXMLDOC01-appb-C000143
 In the same manner as in Example 74, the following compound was obtained.
N- (2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -5- (2-phenylethyl) phenyl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.74 (broad, 1H), 10.50-10.40 (broad, 1H), 8.24-8.20 (m, 1H), 7.62 (d, J = 8.1 Hz, 1H ), 7.51-7.47 (m, 1H), 7.40-7.33 (m, 1H), 7.33-7.24 (m, 5H), 7.24-7.15 (m, 3H), 3.28-3.20 (m, 4H), 3.02-2.90 (m, 4H), 1.70-1.52 (m, 6H).
実施例７８
Figure JPOXMLDOC01-appb-C000144
 　Ｎ－（５－シアノ－２－メチルビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド60mgにテトラヒドロフラン0.50mL、１－メチル－２－ピロリドン0.10mL、ヒドロキシルアミン塩酸塩23mgおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLを加え、マイクロウェーブ照射下90℃で4分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で1時間攪拌した。反応混合物に水を加え10分間攪拌後、酢酸エチルおよび10％クエン酸水溶液を加え、固形物をろ取し、白色固体のＮ－（２－メチル－５－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド34mgを得た。
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.70-10.53(broad,1H),8.34(s,1H),7.64(s,1H),7.54-7.46(m,3H),7.46-7.30(m,5H),7.22-7.15(m,1H),3.29-3.20(m,4H),2.35(s,3H),1.70-1.53(m,6H). Example 78
Figure JPOXMLDOC01-appb-C000144
 To 60 mg of N- (5-cyano-2-methylbiphenyl-4-yl) -3- (piperidin-1-yl) benzamide, 0.50 mL of tetrahydrofuran, 0.10 mL of 1-methyl-2-pyrrolidone, 23 mg of hydroxylamine hydrochloride and 1 , 8-diazabicyclo [5.4.0] -7-undecene (0.10 mL) was added, and the mixture was stirred at 90 ° C. for 4 minutes under microwave irradiation. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethyl acetate and 10% aqueous citric acid solution were added, and the solid was collected by filtration to give N- (2-methyl-5- (5-oxo-4,5- 34 mg of dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl) benzamide were obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.70-10.53 (broad, 1H), 8.34 (s, 1H), 7.64 (s, 1H), 7.54-7.46 (m , 3H), 7.46-7.30 (m, 5H), 7.22-7.15 (m, 1H), 3.29-3.20 (m, 4H), 2.35 (s, 3H), 1.70-1.53 (m, 6H).
実施例７９
Figure JPOXMLDOC01-appb-C000145
 　実施例７８と同様にして、以下の化合物を得た。
Ｎ－（２－クロロ－５－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.72-10.58(broad,1H),8.64(s,1H),7.83(s,1H),7.56-7.44(m,6H),7.43-7.36(m,1H),7.35-7.29(m,1H),7.25-7.16(m,1H),3.30-3.22(m,4H),1.70-1.53(m,6H). Example 79
Figure JPOXMLDOC01-appb-C000145
 In the same manner as in Example 78, the following compound was obtained.
N- (2-chloro-5- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.72-10.58 (broad, 1H), 8.64 (s, 1H), 7.83 (s, 1H), 7.56-7.44 (m, 6H), 7.43-7.36 (m , 1H), 7.35-7.29 (m, 1H), 7.25-7.16 (m, 1H), 3.30-3.22 (m, 4H), 1.70-1.53 (m, 6H).
実施例８０
Figure JPOXMLDOC01-appb-C000146
 　実施例７８と同様にして、以下の化合物を得た。
Ｎ－（６－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.07-12.80(broad,1H),10.38(s,1H),8.15(s,1H),7.68(s,1H),7.55-7.40(m,6H),7.39-7.32(m,1H),7.32-7.26(m,1H),7.21-7.14(m,1H),3.28-3.20(m,4H),2.28(s,3H),1.70-1.52(m,6H). Example 80
Figure JPOXMLDOC01-appb-C000146
 In the same manner as in Example 78, the following compound was obtained.
N- (6-Methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.07-12.80 (broad, 1H), 10.38 (s, 1H), 8.15 (s, 1H), 7.68 (s, 1H), 7.55-7.40 (m, 6H) ), 7.39-7.32 (m, 1H), 7.32-7.26 (m, 1H), 7.21-7.14 (m, 1H), 3.28-3.20 (m, 4H), 2.28 (s, 3H), 1.70-1.52 (m , 6H).
実施例８１
Figure JPOXMLDOC01-appb-C000147
 　実施例７８と同様にして、以下の化合物を得た。
Ｎ－（３－メチル－５－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：12.78-12.70(broad,1H),9.94(s,1H),7.92-7.76(m,4H),7.57-7.40(m,4H),7.37-7.29(m,2H),7.19-7.10(m,1H),3.26-3.18(m,4H),2.35(s,3H),1.70-1.52(m,6H). Example 81
Figure JPOXMLDOC01-appb-C000147
 In the same manner as in Example 78, the following compound was obtained.
N- (3-Methyl-5- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 12.78-12.70 (broad, 1H), 9.94 (s, 1H), 7.92-7.76 (m, 4H), 7.57-7.40 (m, 4H), 7.37-7.29 (m, 2H), 7.19-7.10 (m, 1H), 3.26-3.18 (m, 4H), 2.35 (s, 3H), 1.70-1.52 (m, 6H).
実施例８２～８４
　実施例１８と同様にして、表１４に示す化合物を得た。 Examples 82-84
In the same manner as in Example 18, the compounds shown in Table 14 were obtained.
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000148
２－フルオロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.07-12.83(broad,1H),10.50(d,J=3.2Hz,1H),8.50(s,1H),7.89-7.83(m,1H),7.79(d,J=8.3Hz,1H),7.78-7.74(m,2H),7.72(dd,J=8.2,1.8Hz,1H),7.69-7.61(m,1H),7.58-7.51(m,2H),7.50-7.37(m,3H). 2-Fluoro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.07-12.83 (broad, 1H), 10.50 (d, J = 3.2 Hz, 1H), 8.50 (s, 1H), 7.89-7.83 (m, 1H), 7.79 (d, J = 8.3Hz, 1H), 7.78-7.74 (m, 2H), 7.72 (dd, J = 8.2,1.8Hz, 1H), 7.69-7.61 (m, 1H), 7.58-7.51 (m, 2H), 7.50-7.37 (m, 3H).
４－フルオロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.08-12.83(broad,1H),10.49(s,1H),8.45(d,J=1.7Hz,1H),8.09-8.02(m,2H),7.80(d,J=8.3Hz,1H),7.78-7.73(m,2H),7.71(dd,J=8.3,1.7Hz,1H),7.57-7.51(m,2H),7.49-7.41(m,3H). 4-Fluoro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.08-12.83 (broad, 1H), 10.49 (s, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.09-8.02 (m, 2H), 7.80 (d, J = 8.3Hz, 1H), 7.78-7.73 (m, 2H), 7.71 (dd, J = 8.3,1.7Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.41 (m, 3H).
４－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.88(broad,1H),10.47(s,1H),8.58(d,J=1.7Hz,1H),7.92-7.86(m,2H),7.81(d,J=8.3Hz,1H),7.78-7.73(m,2H),7.69(dd,J=8.3,1.7Hz,1H),7.58-7.51(m,2H),7.50-7.43(m,1H),7.42-7.37(m,2H),2.41(s,3H). 4-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.88 (broad, 1H), 10.47 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 7.92-7.86 (m, 2H), 7.81 (d, J = 8.3Hz, 1H), 7.78-7.73 (m, 2H), 7.69 (dd, J = 8.3,1.7Hz, 1H), 7.58-7.51 (m, 2H), 7.50-7.43 (m, 1H), 7.42-7.37 (m, 2H), 2.41 (s, 3H).
実施例８５～１０２
　実施例６３と同様にして、表１５に示す化合物を得た。 Examples 85-102
In the same manner as in Example 63, the compounds shown in Table 15 were obtained.
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000149
３－フルオロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.09-12.80(broad,1H),10.53(s,1H),8.40(d,J=1.7Hz,1H),7.85-7.75(m,5H),7.73(dd,J=8.3,1.7Hz,1H),7.69-7.62(m,1H),7.58-7.44(m,4H). 3-Fluoro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.09-12.80 (broad, 1H), 10.53 (s, 1H), 8.40 (d, J = 1.7 Hz, 1H), 7.85-7.75 (m, 5H), 7.73 (dd, J = 8.3, 1.7Hz, 1H), 7.69-7.62 (m, 1H), 7.58-7.44 (m, 4H).
２－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.03-12.75(broad,1H),10.33(s,1H),8.40-8.36(m,1H),7.79-7.73(m,3H),7.70(dd,J=8.3,1.5Hz,1H),7.63(d,J=7.3Hz,1H),7.58-7.52(m,2H),7.50-7.40(m,2H),7.38-7.31(m,2H),2.43(s,3H). 2-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.03-12.75 (broad, 1H), 10.33 (s, 1H), 8.40-8.36 (m, 1H), 7.79-7.73 (m, 3H), 7.70 (dd , J = 8.3,1.5Hz, 1H), 7.63 (d, J = 7.3Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.40 (m, 2H), 7.38-7.31 (m, 2H), 2.43 (s, 3H).
３－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.09-12.83(broad,1H),10.50(s,1H),8.52(d,J=1.7Hz,1H),7.83-7.73(m,5H),7.70(dd,J=8.1,1.7Hz,1H),7.58-7.51(m,2H),7.50-7.44(m,3H),2.42(s,3H). 3-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.09-12.83 (broad, 1H), 10.50 (s, 1H), 8.52 (d, J = 1.7 Hz, 1H), 7.83-7.73 (m, 5H), 7.70 (dd, J = 8.1, 1.7Hz, 1H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 3H), 2.42 (s, 3H).
３－（ジエチルアミノ）－５－メトキシ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.77-8.72(m,1H),7.83(d,J=8.3Hz,1H),7.78-7.74(m,2H),7.67(dd,J=8.3,2.0Hz,1H),7.59-7.53(m,2H),7.51-7.45(m,1H),6.90-6.86(m,1H),6.79-6.75(m,1H),6.40-6.36(m,1H),3.81(s,3H),3.40(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -5-methoxy-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.77-8.72 (m, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.78-7.74 (m, 2H), 7.67 (dd , J = 8.3, 2.0 Hz, 1H), 7.59-7.53 (m, 2H), 7.51-7.45 (m, 1H), 6.90-6.86 (m, 1H), 6.79-6.75 (m, 1H), 6.40-6.36 (m, 1H), 3.81 (s, 3H), 3.40 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－４－メトキシ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.69-8.62(m,1H),7.95-7.82(m,3H),7.79-7.74(m,2H),7.71-7.66(m,1H),7.59-7.52(m,2H),7.51-7.45(m,1H),7.38-7.26(m,1H),3.96(s,3H),3.48-3.35(m,4H),1.01(t,J=6.9Hz,6H). 3- (Diethylamino) -4-methoxy-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.69-8.62 (m, 1H), 7.95-7.82 (m, 3H), 7.79-7.74 (m, 2H), 7.71-7.66 (m, 1H), 7.59-7.52 (m, 2H), 7.51-7.45 (m, 1H), 7.38-7.26 (m, 1H), 3.96 (s, 3H), 3.48-3.35 (m, 4H), 1.01 (t, (J = 6.9Hz, 6H).
５－（ジエチルアミノ）－２－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.60-8.52(m,1H),7.79(d,J=8.2Hz,1H),7.77-7.73(m,2H),7.67(dd,J=8.2,1.8Hz,1H),7.59-7.53(m,2H),7.51-7.45(m,1H),7.12(d,J=8.6Hz,1H),7.02-6.95(m,1H),6.82-6.73(m,1H),3.38(q,J=7.0Hz,4H),2.30(s,3H),1.11(t,J=7.0Hz,6H). 5- (Diethylamino) -2-methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.60-8.52 (m, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.67 (dd , J = 8.2,1.8Hz, 1H), 7.59-7.53 (m, 2H), 7.51-7.45 (m, 1H), 7.12 (d, J = 8.6Hz, 1H), 7.02-6.95 (m, 1H), 6.82-6.73 (m, 1H), 3.38 (q, J = 7.0Hz, 4H), 2.30 (s, 3H), 1.11 (t, J = 7.0Hz, 6H).
２－クロロ－５－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.45-8.37(m,1H),7.81-7.68(m,4H),7.60-7.52(m,2H),7.51-7.45(m,1H),7.28(d,J=9.0Hz,1H),6.97(d,J=2.7Hz,1H),6.78(dd,J=9.0,2.7Hz,1H),3.38(q,J=6.9Hz,4H),1.12(t,J=6.9Hz,6H). 2-Chloro-5- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.45-8.37 (m, 1H), 7.81-7.68 (m, 4H), 7.60-7.52 (m, 2H), 7.51-7.45 (m, 1H), 7.28 (d, J = 9.0Hz, 1H), 6.97 (d, J = 2.7Hz, 1H), 6.78 (dd, J = 9.0,2.7Hz, 1H), 3.38 (q, J = 6.9Hz, 4H), 1.12 (t, J = 6.9Hz, 6H).
４－クロロ－３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.86(broad,1H),10.55(s,1H),8.62(d,J=1.7Hz,1H),7.83(d,J=8.3Hz,1H),7.79-7.74(m,3H),7.71(dd,J=8.3,1.7Hz,1H),7.65-7.59(m,2H),7.58-7.51(m,2H),7.50-7.44(m,1H),3.18(q,J=7.0Hz,4H),1.03(t,J=7.0Hz,6H). 4-Chloro-3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.86 (broad, 1H), 10.55 (s, 1H), 8.62 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.79-7.74 (m, 3H), 7.71 (dd, J = 8.3, 1.7Hz, 1H), 7.65-7.59 (m, 2H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 1H), 3.18 (q, J = 7.0Hz, 4H), 1.03 (t, J = 7.0Hz, 6H).
２－（モルホリン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：13.10-12.80(broad,1H),10.64-10.54(broad,1H),8.42(d,J=1.7Hz,1H),8.34(d,J=5.1Hz,1H),7.81(d,J=8.0Hz,1H),7.79-7.71(m,3H),7.58-7.50(m,2H),7.50-7.43(m,1H),7.30(s,1H),7.13(dd,J=5.1,1.0Hz,1H),3.77-3.70(m,4H),3.58-3.50(m,4H). 2- (Morpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) isonicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.80 (broad, 1H), 10.64-10.54 (broad, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.34 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.79-7.71 (m, 3H), 7.58-7.50 (m, 2H), 7.50-7.43 (m, 1H), 7.30 (s, 1H) , 7.13 (dd, J = 5.1, 1.0Hz, 1H), 3.77-3.70 (m, 4H), 3.58-3.50 (m, 4H).
２－（２－メチルピペリジン－１－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：13.20-12.80(broad,1H),10.59(s,1H),8.49(d,J=1.7Hz,1H),8.28(d,J=5.1Hz,1H),7.82(d,J=8.1Hz,1H),7.79-7.70(m,3H),7.58-7.50(m,2H),7.50-7.43(m,1H),7.23(s,1H),7.00(dd,J=5.1,1.2Hz,1H),4.78-4.66(m,1H),4.26-4.16(m,1H),3.00-2.89(m,1H),1.80-1.54(m,5H),1.52-1.36(m,1H),1.14(d,J=6.8Hz,3H). 2- (2-Methylpiperidin-1-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) iso Nicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.80 (broad, 1H), 10.59 (s, 1H), 8.49 (d, J = 1.7 Hz, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 8.1Hz, 1H), 7.79-7.70 (m, 3H), 7.58-7.50 (m, 2H), 7.50-7.43 (m, 1H), 7.23 (s, 1H), 7.00 (dd, J = 5.1,1.2Hz, 1H), 4.78-4.66 (m, 1H), 4.26-4.16 (m, 1H), 3.00-2.89 (m, 1H), 1.80-1.54 (m, 5H), 1.52 -1.36 (m, 1H), 1.14 (d, J = 6.8Hz, 3H).
２－（アゼパン－１－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：10.70-10.60(broad,1H),8.58(d,J=1.5Hz,1H),8.25(d,J=5.1Hz,1H),7.83(d,J=8.3Hz,1H),7.79-7.74(m,2H),7.72(dd,J=8.3,1.5Hz,1H),7.58-7.51(m,2H),7.50-7.43(m,1H),7.09(s,1H),6.97(dd,J=5.3,1.1Hz,1H),3.72-3.65(m,4H),1.82-1.70(m,4H),1.54-1.46(m,4H). 2- (Azepan-1-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) isonicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 10.70-10.60 (broad, 1H), 8.58 (d, J = 1.5 Hz, 1H), 8.25 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 8.3Hz, 1H), 7.79-7.74 (m, 2H), 7.72 (dd, J = 8.3,1.5Hz, 1H), 7.58-7.51 (m, 2H), 7.50-7.43 (m, 1H), 7.09 (s, 1H), 6.97 (dd, J = 5.3, 1.1Hz, 1H), 3.72-3.65 (m, 4H), 1.82-1.70 (m, 4H), 1.54-1.46 (m, 4H).
２－（３－メチルピペリジン－１－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：13.20-12.70(broad,1H),10.60(s,1H),8.50(d,J=1.7Hz,1H),8.27(d,J=5.1Hz,1H),7.82(d,J=8.3Hz,1H),7.79-7.70(m,3H),7.58-7.51(m,2H),7.50-7.43(m,1H),7.29(s,1H),7.01(dd,J=5.3,1.1Hz,1H),4.38-4.20(m,2H),2.93-2.79(m,1H),2.56(dd,J=12.9,10.7Hz,1H),1.87-1.40(m,4H),1.25-1.11(m,1H),0.94(d,J=6.6Hz,3H). 2- (3-Methylpiperidin-1-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) iso Nicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.70 (broad, 1H), 10.60 (s, 1H), 8.50 (d, J = 1.7 Hz, 1H), 8.27 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 8.3Hz, 1H), 7.79-7.70 (m, 3H), 7.58-7.51 (m, 2H), 7.50-7.43 (m, 1H), 7.29 (s, 1H), 7.01 (dd, J = 5.3,1.1Hz, 1H), 4.38-4.20 (m, 2H), 2.93-2.79 (m, 1H), 2.56 (dd, J = 12.9,10.7Hz, 1H), 1.87-1.40 (m , 4H), 1.25-1.11 (m, 1H), 0.94 (d, J = 6.6Hz, 3H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（１Ｈ－ピラゾール－１－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：13.04-12.84(broad,1H),10.85(s,1H),8.74-8.68(m,2H),8.48-8.45(m,1H),8.28(d,J=1.7Hz,1H),7.93-7.91(m,1H),7.84-7.75(m,5H),7.58-7.51(m,2H),7.50-7.43(m,1H),6.65(dd,J=2.4,1.7Hz,1H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- (1H-pyrazol-1-yl) isonicotine Amide
1 H-NMR (DMSO-d 6 ) δ value: 13.04-12.84 (broad, 1H), 10.85 (s, 1H), 8.74-8.68 (m, 2H), 8.48-8.45 (m, 1H), 8.28 (d , J = 1.7Hz, 1H), 7.93-7.91 (m, 1H), 7.84-7.75 (m, 5H), 7.58-7.51 (m, 2H), 7.50-7.43 (m, 1H), 6.65 (dd, J = 2.4,1.7Hz, 1H).
３－（ジエチルアミノ）－５－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.74-8.68(m,1H),7.82(d,J=8.3Hz,1H),7.78-7.73(m,2H),7.69-7.63(m,1H),7.59-7.52(m,2H),7.51-7.45(m,1H),7.08-6.99(m,2H),6.78-6.73(m,1H),3.41(q,J=6.9Hz,4H),2.33(s,3H),1.13(t,J=6.9Hz,6H). 3- (Diethylamino) -5-methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.74-8.68 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78-7.73 (m, 2H), 7.69-7.63 (m, 1H), 7.59-7.52 (m, 2H), 7.51-7.45 (m, 1H), 7.08-6.99 (m, 2H), 6.78-6.73 (m, 1H), 3.41 (q, J = 6.9Hz , 4H), 2.33 (s, 3H), 1.13 (t, J = 6.9Hz, 6H).
３－クロロ－５－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.56-8.53(m,1H),7.84-7.79(m,1H),7.78-7.73(m,2H),7.72-7.67(m,1H),7.59-7.53(m,2H),7.51-7.45(m,1H),7.16-7.09(m,2H),6.85(d,J=1.7Hz,1H),3.42(q,J=6.8Hz,4H),1.14(t,J=6.8Hz,6H). 3-chloro-5- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.56-8.53 (m, 1H), 7.84-7.79 (m, 1H), 7.78-7.73 (m, 2H), 7.72-7.67 (m, 1H), 7.59-7.53 (m, 2H), 7.51-7.45 (m, 1H), 7.16-7.09 (m, 2H), 6.85 (d, J = 1.7Hz, 1H), 3.42 (q, J = 6.8Hz , 4H), 1.14 (t, J = 6.8Hz, 6H).
２－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－５－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.32(s,1H),8.50-8.43(m,1H),7.79-7.73(m,3H),7.68(dd,J=8.2,1.3Hz,1H),7.58-7.52(m,2H),7.50-7.44(m,1H),7.25(d,J=2.4Hz,1H),7.14(d,J=8.4Hz,1H),7.00(dd,J=8.4,2.4Hz,1H),3.21-3.15(m,4H),2.32(s,3H),1.68-1.60(m,4H),1.60-1.51(m,2H). 2-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -5- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.32 (s, 1H), 8.50-8.43 (m, 1H), 7.79-7.73 (m, 3H), 7.68 (dd, J = 8.2, 1.3Hz, 1H ), 7.58-7.52 (m, 2H), 7.50-7.44 (m, 1H), 7.25 (d, J = 2.4Hz, 1H), 7.14 (d, J = 8.4Hz, 1H), 7.00 (dd, J = 8.4, 2.4Hz, 1H), 3.21-3.15 (m, 4H), 2.32 (s, 3H), 1.68-1.60 (m, 4H), 1.60-1.51 (m, 2H).
４－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.53(s,1H),8.68(d,J=1.7Hz,1H),7.82(d,J=8.2Hz,1H),7.79-7.74(m,2H),7.68(dd,J=8.2,1.7Hz,1H),7.64(d,J=1.7Hz,1H),7.59-7.51(m,3H),7.49-7.44(m,1H),7.36(d,J=8.0Hz,1H),2.91-2.85(m,4H),2.33(s,3H),1.74-1.65(m,4H),1.61-1.53(m,2H). 4-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.53 (s, 1H), 8.68 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.79-7.74 (m, 2H), 7.68 (dd, J = 8.2, 1.7Hz, 1H), 7.64 (d, J = 1.7Hz, 1H), 7.59-7.51 (m, 3H), 7.49-7.44 (m, 1H), 7.36 (d , J = 8.0Hz, 1H), 2.91-2.85 (m, 4H), 2.33 (s, 3H), 1.74-1.65 (m, 4H), 1.61-1.53 (m, 2H).
（Ｅ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（３－（ピペリジン－１－イル）フェニル）アクリルアミド
1H-NMR(DMSO-d6)δ値：12.91-12.76(broad,1H),10.08(s,1H),8.42(d,J=1.8Hz,1H),7.76-7.70(m,3H),7.64(dd,J=8.2,1.8Hz,1H),7.61-7.50(m,3H),7.49-7.43(m,1H),7.27(dd,J=7.9,7.9Hz,1H),7.22-7.18(m,1H),7.05(d,J=8.0Hz,1H),7.00(dd,J=8.4,2.1Hz,1H),6.86(d,J=15.9Hz,1H),3.23-3.17(m,4H),1.67-1.60(m,4H),1.59-1.52(m,2H). (E) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (3- (piperidine-1 -Yl) phenyl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 12.91-12.76 (broad, 1H), 10.08 (s, 1H), 8.42 (d, J = 1.8 Hz, 1H), 7.76-7.70 (m, 3H), 7.64 (dd, J = 8.2,1.8Hz, 1H), 7.61-7.50 (m, 3H), 7.49-7.43 (m, 1H), 7.27 (dd, J = 7.9,7.9Hz, 1H), 7.22-7.18 ( m, 1H), 7.05 (d, J = 8.0Hz, 1H), 7.00 (dd, J = 8.4,2.1Hz, 1H), 6.86 (d, J = 15.9Hz, 1H), 3.23-3.17 (m, 4H ), 1.67-1.60 (m, 4H), 1.59-1.52 (m, 2H).
実施例１０３
Figure JPOXMLDOC01-appb-C000150
 　３－（ジエチルアミノ）－４－メチル安息香酸0.14gのアセトニトリル2.0mL、１－メチル－２－ピロリドン0.10mLおよびＮ，Ｎ－ジメチルホルムアミド0.010mL混液に、塩化チオニル0.063mLを加え、室温で30分間攪拌した。反応混合物に塩化チオニル0.031mLを加え、室温で30分間攪拌した。反応混合物に３－（３－アミノビフェニル－４－イル）－１，２，４－オキサジアゾール－５（４Ｈ）－オン0.12gの１－メチル－２－ピロリドン0.30mL溶液を加え、室温で3時間攪拌した。反応混合物に水を加え、飽和炭酸水素ナトリウム水溶液でpH4に調整後、酢酸エチルを加え、固形物をろ取した。得られた固形物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；70-30％ヘキサン／酢酸エチル］で精製し、白色固体の３－（ジエチルアミノ）－４－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド61mgを得た。
1H-NMR(DMSO-d6)δ値：10.60(s,1H),8.77(d,J=1.8Hz,1H),7.84(d,J=8.3Hz,1H),7.79-7.71(m,3H),7.68(dd,J=8.3,1.8Hz,1H),7.64-7.58(m,1H),7.58-7.51(m,2H),7.50-7.44(m,1H),7.40(d,J=8.1Hz,1H),3.12-3.01(m,4H),2.33(s,3H),0.98(t,J=7.1Hz,6H). Example 103
Figure JPOXMLDOC01-appb-C000150
 Add 0.063 mL of thionyl chloride to a mixture of 2.0 mL of acetonitrile, 0.14 g of 3- (diethylamino) -4-methylbenzoic acid, 0.10 mL of 1-methyl-2-pyrrolidone, and 0.010 mL of N, N-dimethylformamide, and then at room temperature for 30 minutes Stir. 0.031 mL of thionyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 0.12 g of 3- (3-aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one in 0.30 mL of 1-methyl-2-pyrrolidone at room temperature. Stir for 3 hours. Water was added to the reaction mixture, the pH was adjusted to 4 with a saturated aqueous sodium hydrogen carbonate solution, ethyl acetate was added, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-30% hexane / ethyl acetate], and white solid 3- (diethylamino) -4-methyl 61 mg of —N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.60 (s, 1H), 8.77 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.79-7.71 (m, 3H), 7.68 (dd, J = 8.3, 1.8Hz, 1H), 7.64-7.58 (m, 1H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.40 (d, J = 8.1Hz, 1H), 3.12-3.01 (m, 4H), 2.33 (s, 3H), 0.98 (t, J = 7.1Hz, 6H).
実施例１０４、１０５
　実施例１０３と同様にして、表１６に示す化合物を得た。 Examples 104 and 105
In the same manner as in Example 103, the compounds shown in Table 16 were obtained.
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000151
３－（ジエチルアミノ）－２－メトキシ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.09-12.83(broad,1H),10.79(s,1H),8.70-8.63(m,1H),7.80-7.72(m,3H),7.67(dd,J=8.2,1.8Hz,1H),7.58-7.51(m,2H),7.49-7.44(m,1H),7.43-7.36(m,1H),7.24-7.14(m,2H),3.83(s,3H),3.26-3.15(m,4H),1.01(t,J=7.0Hz,6H). 3- (Diethylamino) -2-methoxy-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.09-12.83 (broad, 1H), 10.79 (s, 1H), 8.70-8.63 (m, 1H), 7.80-7.72 (m, 3H), 7.67 (dd , J = 8.2,1.8Hz, 1H), 7.58-7.51 (m, 2H), 7.49-7.44 (m, 1H), 7.43-7.36 (m, 1H), 7.24-7.14 (m, 2H), 3.83 (s , 3H), 3.26-3.15 (m, 4H), 1.01 (t, J = 7.0 Hz, 6H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（ピロリジン－１－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：10.76(s,1H),8.58(d,J=1.6Hz,1H),8.25(d,J=5.4Hz,1H),7.83(d,J=8.2Hz,1H),7.79-7.73(m,2H),7.71(dd,J=8.2,1.6Hz,1H),7.58-7.51(m,2H),7.50-7.43(m,1H),7.03-6.96(m,2H),3.51-3.43(m,4H),2.03-1.95(m,4H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- (pyrrolidin-1-yl) isonicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 10.76 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 5.4 Hz, 1H), 7.83 (d, J = 8.2Hz, 1H), 7.79-7.73 (m, 2H), 7.71 (dd, J = 8.2, 1.6Hz, 1H), 7.58-7.51 (m, 2H), 7.50-7.43 (m, 1H), 7.03-6.96 (m, 2H), 3.51-3.43 (m, 4H), 2.03-1.95 (m, 4H).
実施例１０６
Figure JPOXMLDOC01-appb-C000152
 　４－クロロ－３－（ピペリジン－１－イル）安息香酸0.12gのアセトニトリル2.0mLおよびＮ，Ｎ－ジメチルホルムアミド0.010mL混液に、オキサリルクロリド0.051mLを加え、室温で30分間攪拌した。反応混合物にオキサリルクロリド0.051mLを加え、室温で30分間攪拌した。減圧下で溶媒を留去し、アセトニトリル2.0mLおよび３－（３－アミノビフェニル－４－イル）－１，２，４－オキサジアゾール－５（４Ｈ）－オン0.10gの１－メチル－２－ピロリドン0.30mL溶液を順次加え、室温で5時間攪拌した。反応混合物に水を加え、飽和炭酸水素ナトリウム水溶液でpH4に調整後、酢酸エチルを加え、固形物をろ取した。得られた固形物をメタノールで洗浄し、白色固体の４－クロロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド79mgを得た。
1H-NMR(DMSO-d6)δ値：10.62-10.54(broad,1H),8.53(d,J=1.7Hz,1H),7.82(d,J=8.3Hz,1H),7.78-7.74(m,2H),7.74-7.69(m,2H),7.64-7.58(m,2H),7.57-7.51(m,2H),7.49-7.44(m,1H),3.05-2.98(m,4H),1.74-1.66(m,4H),1.62-1.54(m,2H). Example 106
Figure JPOXMLDOC01-appb-C000152
 To a mixed solution of 0.12 g of 4-chloro-3- (piperidin-1-yl) benzoic acid in 2.0 mL of acetonitrile and 0.010 mL of N, N-dimethylformamide was added 0.051 mL of oxalyl chloride, and the mixture was stirred at room temperature for 30 minutes. 0.051 mL of oxalyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and 2.0 mL of acetonitrile and 0.10 g of 1-methyl-2 of 3- (3-aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one -Pyrrolidone 0.30mL solution was added sequentially and stirred at room temperature for 5 hours. Water was added to the reaction mixture, the pH was adjusted to 4 with a saturated aqueous sodium hydrogen carbonate solution, ethyl acetate was added, and the solid was collected by filtration. The obtained solid was washed with methanol, and white solid 4-chloro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl- 79 mg of 3-yl) -3- (piperidin-1-yl) benzamide were obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.62-10.54 (broad, 1H), 8.53 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78-7.74 ( m, 2H), 7.74-7.69 (m, 2H), 7.64-7.58 (m, 2H), 7.57-7.51 (m, 2H), 7.49-7.44 (m, 1H), 3.05-2.98 (m, 4H), 1.74-1.66 (m, 4H), 1.62-1.54 (m, 2H).
実施例１０７～１１７
　実施例１０６と同様にして、表１７に示す化合物を得た。 Examples 107-117
In the same manner as in Example 106, the compounds shown in Table 17 were obtained.
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000153
３－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－５－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.52(s,1H),8.62(d,J=1.8Hz,1H),7.81(d,J=8.3Hz,1H),7.78-7.73(m,2H),7.68(dd,J=8.3,1.8Hz,1H),7.57-7.51(m,2H),7.49-7.43(m,1H),7.35-7.30(m,1H),7.18-7.15(m,1H),7.04-7.00(m,1H),3.27-3.21(m,4H),2.34(s,3H),1.68-1.61(m,4H),1.61-1.53(m,2H). 3-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -5- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.52 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.78-7.73 (m, 2H), 7.68 (dd, J = 8.3, 1.8Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.43 (m, 1H), 7.35-7.30 (m, 1H), 7.18-7.15 (m, 1H), 7.04-7.00 (m, 1H), 3.27-3.21 (m, 4H), 2.34 (s, 3H), 1.68-1.61 (m, 4H), 1.61-1.53 (m, 2H).
３－クロロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－４－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.43(s,1H),8.42(d,J=1.7Hz,1H),8.00(d,J=2.2Hz,1H),7.88(dd,J=8.3,2.2Hz,1H),7.82-7.72(m,3H),7.69(dd,J=8.3,1.7Hz,1H),7.57-7.51(m,2H),7.49-7.43(m,1H),7.28(d,J=8.3Hz,1H),3.09-3.01(m,4H),1.73-1.64(m,4H),1.62-1.53(m,2H). 3-chloro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -4- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.43 (s, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.88 (dd, J = 8.3,2.2Hz, 1H), 7.82-7.72 (m, 3H), 7.69 (dd, J = 8.3,1.7Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.43 (m, 1H), 7.28 (d, J = 8.3Hz, 1H), 3.09-3.01 (m, 4H), 1.73-1.64 (m, 4H), 1.62-1.53 (m, 2H).
２－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－４－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.52-8.46(m,1H),7.80-7.72(m,3H),7.64(dd,J=8.2,1.8Hz,1H),7.59-7.52(m,3H),7.51-7.44(m,1H),6.87-6.81(m,2H),3.34-3.25(m,4H),2.42(s,3H),1.64-1.55(m,6H). 2-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -4- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.52-8.46 (m, 1H), 7.80-7.72 (m, 3H), 7.64 (dd, J = 8.2, 1.8Hz, 1H), 7.59 -7.52 (m, 3H), 7.51-7.44 (m, 1H), 6.87-6.81 (m, 2H), 3.34-3.25 (m, 4H), 2.42 (s, 3H), 1.64-1.55 (m, 6H) .
３－クロロ－４－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.38(d,J=1.7Hz,1H),7.99(d,J=2.2Hz,1H),7.85(dd,J=8.6,2.2Hz,1H),7.81-7.72(m,3H),7.68(dd,J=8.0,1.7Hz,1H),7.59-7.52(m,2H),7.51-7.45(m,1H),7.29(d,J=8.5Hz,1H),3.23(q,J=7.0Hz,4H),1.04(t,J=7.0Hz,6H). 3-Chloro-4- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.38 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.85 (dd, J = 8.6, 2.2 Hz, 1H), 7.81-7.72 (m, 3H), 7.68 (dd, J = 8.0, 1.7Hz, 1H), 7.59-7.52 (m, 2H), 7.51-7.45 (m, 1H), 7.29 (d, J = 8.5Hz, 1H), 3.23 (q, J = 7.0Hz, 4H), 1.04 (t, J = 7.0Hz, 6H).
２－クロロ－４－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.50-8.43(m,1H),7.80-7.72(m,3H),7.69-7.64(m,1H),7.61-7.53(m,3H),7.51-7.45(m,1H),6.75-6.68(m,2H),3.45-3.36(m,4H),1.16-1.09(m,6H). 2-Chloro-4- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.50-8.43 (m, 1H), 7.80-7.72 (m, 3H), 7.69-7.64 (m, 1H), 7.61-7.53 (m, 3H), 7.51-7.45 (m, 1H), 6.75-6.68 (m, 2H), 3.45-3.36 (m, 4H), 1.16-1.09 (m, 6H).
４－（ジエチルアミノ）－２－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.56-8.51(m,1H),7.79-7.71(m,3H),7.62(dd,J=8.1,1.5Hz,1H),7.59-7.52(m,3H),7.50-7.44(m,1H),6.61-6.53(m,2H),3.44-3.34(m,4H),2.43(s,3H),1.15-1.08(m,6H). 4- (Diethylamino) -2-methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.56-8.51 (m, 1H), 7.79-7.71 (m, 3H), 7.62 (dd, J = 8.1, 1.5 Hz, 1H), 7.59 -7.52 (m, 3H), 7.50-7.44 (m, 1H), 6.61-6.53 (m, 2H), 3.44-3.34 (m, 4H), 2.43 (s, 3H), 1.15-1.08 (m, 6H) .
４－（ジエチルアミノ）－３－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.43-8.39(m,1H),7.93-7.87(m,2H),7.82-7.78(m,1H),7.78-7.73(m,2H),7.72-7.68(m,1H),7.59-7.52(m,3H),7.51-7.45(m,1H),3.43-3.31(m,4H),2.42(s,3H),1.01(t,J=7.1Hz,6H). 4- (Diethylamino) -3-methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.43-8.39 (m, 1H), 7.93-7.87 (m, 2H), 7.82-7.78 (m, 1H), 7.78-7.73 (m, 2H), 7.72-7.68 (m, 1H), 7.59-7.52 (m, 3H), 7.51-7.45 (m, 1H), 3.43-3.31 (m, 4H), 2.42 (s, 3H), 1.01 (t, (J = 7.1Hz, 6H).
３－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－４－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.44(s,1H),8.60(d,J=2.0Hz,1H),7.83-7.72(m,5H),7.66(dd,J=8.3,2.0Hz,1H),7.57-7.51(m,2H),7.49-7.43(m,1H),7.13(d,J=8.1Hz,1H),2.93-2.84(m,4H),2.32(s,3H),1.72-1.63(m,4H),1.61-1.53(m,2H). 3-Methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -4- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.44 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 7.83-7.72 (m, 5H), 7.66 (dd, J = 8.3, 2.0 Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.43 (m, 1H), 7.13 (d, J = 8.1Hz, 1H), 2.93-2.84 (m, 4H), 2.32 (s, 3H) , 1.72-1.63 (m, 4H), 1.61-1.53 (m, 2H).
２－クロロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－４－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.46-8.41(m,1H),7.80-7.71(m,3H),7.69-7.65(m,1H),7.61-7.52(m,3H),7.50-7.45(m,1H),7.00-6.95(m,2H),3.36-3.30(m,4H),1.63-1.53(m,6H). 2-Chloro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -4- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.46-8.41 (m, 1H), 7.80-7.71 (m, 3H), 7.69-7.65 (m, 1H), 7.61-7.52 (m, 3H), 7.50-7.45 (m, 1H), 7.00-6.95 (m, 2H), 3.36-3.30 (m, 4H), 1.63-1.53 (m, 6H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（チオモルホリン－４－イル）イソニコチンアミド
1H-NMR(DMSO-d6)δ値：13.15-12.80(broad,1H),10.56(s,1H),8.45(d,J=1.7Hz,1H),8.31(d,J=5.1Hz,1H),7.81(d,J=8.0Hz,1H),7.79-7.71(m,3H),7.58-7.50(m,2H),7.50-7.43(m,1H),7.30(s,1H),7.05(dd,J=5.1Hz,1.2Hz,1H),4.04-3.96(m,4H),2.69-2.60(m,4H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- (thiomorpholin-4-yl) isonicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 13.15-12.80 (broad, 1H), 10.56 (s, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.79-7.71 (m, 3H), 7.58-7.50 (m, 2H), 7.50-7.43 (m, 1H), 7.30 (s, 1H), 7.05 (dd, J = 5.1Hz, 1.2Hz, 1H), 4.04-3.96 (m, 4H), 2.69-2.60 (m, 4H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－５－（１Ｈ－ピロール－１－イル）ニコチンアミド
1H-NMR(DMSO-d6)δ値：13.10-12.80(broad,1H),10.70(s,1H),9.15(d,J=2.7Hz,1H),8.97(d,J=1.7Hz,1H),8.48(dd,J=2.4,2.0Hz,1H),8.35(d,J=1.7Hz,1H),7.83(d,J=8.3Hz,1H),7.80-7.74(m,3H),7.60-7.52(m,4H),7.50-7.44(m,1H),6.41-6.38(m,2H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -5- (1H-pyrrol-1-yl) nicotinamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.80 (broad, 1H), 10.70 (s, 1H), 9.15 (d, J = 2.7 Hz, 1H), 8.97 (d, J = 1.7 Hz, 1H), 8.48 (dd, J = 2.4, 2.0Hz, 1H), 8.35 (d, J = 1.7Hz, 1H), 7.83 (d, J = 8.3Hz, 1H), 7.80-7.74 (m, 3H), 7.60-7.52 (m, 4H), 7.50-7.44 (m, 1H), 6.41-6.38 (m, 2H).
実施例１１８
Figure JPOXMLDOC01-appb-C000154
 　実施例１０３と同様にして、以下の化合物を得た。
３－（エチル（プロピル）アミノ）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：9.11-9.07(m,1H),8.15(d,J=8.3Hz,1H),7.81-7.76(m,2H),7.71-7.66(m,1H),7.59-7.54(m,2H),7.51-7.45(m,1H),7.42-7.36(m,2H),7.32-7.27(m,1H),6.95(dd,J=8.2,1.8Hz,1H),3.52-3.45(m,2H),3.38-3.31(m,2H),1.66-1.55(m,2H),1.15(t,J=6.9Hz,3H),0.91(t,J=7.3Hz,3H). Example 118
Figure JPOXMLDOC01-appb-C000154
 In the same manner as in Example 103, the following compound was obtained.
3- (Ethyl (propyl) amino) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 9.11-9.07 (m, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.81-7.76 (m, 2H), 7.71-7.66 (m, 1H), 7.59-7.54 (m, 2H), 7.51-7.45 (m, 1H), 7.42-7.36 (m, 2H), 7.32-7.27 (m, 1H), 6.95 (dd, J = 8.2, 1.8Hz, 1H), 3.52-3.45 (m, 2H), 3.38-3.31 (m, 2H), 1.66-1.55 (m, 2H), 1.15 (t, J = 6.9Hz, 3H), 0.91 (t, J = 7.3Hz, 3H).
実施例１１９
Figure JPOXMLDOC01-appb-C000155
 　実施例１０３と同様にして、以下の化合物を得た。
３－（ジプロピルアミノ）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：9.10-9.05(m,1H),8.16-8.11(m,1H),7.80-7.76(m,2H),7.71-7.66(m,1H),7.60-7.54(m,2H),7.51-7.45(m,1H),7.38(dd,J=7.9,7.9Hz,1H),7.35-7.32(m,1H),7.27(d,J=7.8Hz,1H),6.93(dd,J=8.4,2.3Hz,1H),3.40-3.32(m,4H),1.65-1.54(m,4H),0.90(t,J=7.2Hz,6H). Example 119
Figure JPOXMLDOC01-appb-C000155
 In the same manner as in Example 103, the following compound was obtained.
3- (Dipropylamino) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 9.10-9.05 (m, 1H), 8.16-8.11 (m, 1H), 7.80-7.76 (m, 2H), 7.71-7.66 (m, 1H), 7.60-7.54 (m, 2H), 7.51-7.45 (m, 1H), 7.38 (dd, J = 7.9, 7.9Hz, 1H), 7.35-7.32 (m, 1H), 7.27 (d, J = 7.8Hz, 1H), 6.93 (dd, J = 8.4, 2.3Hz, 1H), 3.40-3.32 (m, 4H), 1.65-1.54 (m, 4H), 0.90 (t, J = 7.2Hz, 6H).
実施例１２０
Figure JPOXMLDOC01-appb-C000156
 　２－クロロ－Ｎ－（４－シアノビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド22mgのテトラヒドロフラン1.0mL溶液に、50％ヒドロキシルアミン水溶液0.014mLを加え、50-60℃で1時間30分間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物にメタノールを加え、減圧下で溶媒を留去し、２－クロロ－３－（ジエチルアミノ）－Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）ベンズアミドを得た。
　得られた２－クロロ－３－（ジエチルアミノ）－Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）ベンズアミドのテトラヒドロフラン1.0mL溶液に、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.024mLおよび１，１’－カルボニルジイミダゾール26mgを順次加え、室温で30分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール26mgを加え、室温で30分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール26mgを加え、室温で1時間攪拌した。反応混合物に水を加え、10％クエン酸水溶液でpH4に調整後、クロロホルムを加えた。有機層を分取し、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；75-25％ヘキサン／酢酸エチル］で精製し、白色固体の２－クロロ－３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド7mgを得た。
1H-NMR(DMSO-d6)δ値：12.95-12.73(broad,1H),10.46(s,1H),8.30-8.24(m,1H),7.78-7.68(m,4H),7.58-7.51(m,2H),7.50-7.38(m,2H),7.35-7.26(m,2H),3.12(q,J=7.0Hz,4H),0.99(t,J=7.0Hz,6H). Example 120
Figure JPOXMLDOC01-appb-C000156
 To a 1.0 mL tetrahydrofuran solution of 22 mg 2-chloro-N- (4-cyanobiphenyl-3-yl) -3- (diethylamino) benzamide was added 0.014 mL of a 50% aqueous hydroxylamine solution, and the mixture was at 50-60 ° C. for 1 hour 30 minutes. Stir. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solvent was distilled off under reduced pressure to obtain 2-chloro-3- (diethylamino) -N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide.
To a 1.0 mL tetrahydrofuran solution of the obtained 2-chloro-3- (diethylamino) -N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide was added 1,8-diazabicyclo [5.4.0] -7. -Undecene 0.024 mL and 1,1'-carbonyldiimidazole 26 mg were sequentially added, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, 26 mg of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 30 minutes. To the reaction mixture was added 26 mg of 1,1′-carbonyldiimidazole, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, pH was adjusted to 4 with a 10% aqueous citric acid solution, and chloroform was added. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 75-25% hexane / ethyl acetate] to give 2-chloro-3- (diethylamino) as a white solid. 7 mg of —N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 12.95-12.73 (broad, 1H), 10.46 (s, 1H), 8.30-8.24 (m, 1H), 7.78-7.68 (m, 4H), 7.58-7.51 (m, 2H), 7.50-7.38 (m, 2H), 7.35-7.26 (m, 2H), 3.12 (q, J = 7.0Hz, 4H), 0.99 (t, J = 7.0Hz, 6H).
実施例１２１
Figure JPOXMLDOC01-appb-C000157
 　実施例１２０と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－２－メチル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.35(s,1H),8.40-8.33(m,1H),7.80-7.66(m,4H),7.58-7.51(m,2H),7.50-7.42(m,1H),7.35-7.22(m,3H),3.05-2.94(m,4H),2.34(s,3H),0.95(t,J=6.8Hz,6H). Example 121
Figure JPOXMLDOC01-appb-C000157
 In the same manner as in Example 120, the following compound was obtained.
3- (Diethylamino) -2-methyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.35 (s, 1H), 8.40-8.33 (m, 1H), 7.80-7.66 (m, 4H), 7.58-7.51 (m, 2H), 7.50-7.42 (m, 1H), 7.35-7.22 (m, 3H), 3.05-2.94 (m, 4H), 2.34 (s, 3H), 0.95 (t, J = 6.8Hz, 6H).
実施例１２２
Figure JPOXMLDOC01-appb-C000158
 　３－ブロモ－Ｎ－（４－シアノビフェニル－３－イル）ベンズアミド0.97gのテトラヒドロフラン10mL懸濁液に、50％ヒドロキシルアミン水溶液0.51mLを加え、60℃で1時間30分間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物にメタノールを加え、固形物をろ取し、白色固体の３－ブロモ－Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）ベンズアミドを得た。
　得られた３－ブロモ－Ｎ－（４－（ヒドロキシアミジノ）ビフェニル－３－イル）ベンズアミドにテトラヒドロフラン10mL、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.97mLおよび１，１’－カルボニルジイミダゾール1.1gを順次加え、室温で1時間攪拌した。反応混合物に水を加え、10％クエン酸水溶液でpH4.0に調整後、酢酸エチルを加え、固形物をろ取した。得られた固形物を、水および酢酸エチルで順次洗浄し、白色固体の３－ブロモ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド0.93gを得た。
1H-NMR(DMSO-d6)δ値：13.02-12.80(broad,1H),10.56(s,1H),8.33(d,J=1.7Hz,1H),8.16(dd,J=1.8,1.8Hz,1H),7.99-7.93(m,1H),7.88-7.83(m,1H),7.82-7.70(m,4H),7.59-7.50(m,3H),7.49-7.43(m,1H). Example 122
Figure JPOXMLDOC01-appb-C000158
 To a suspension of 0.97 g of 3-bromo-N- (4-cyanobiphenyl-3-yl) benzamide in 10 mL of tetrahydrofuran was added 0.51 mL of a 50% aqueous hydroxylamine solution, and the mixture was stirred at 60 ° C. for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solid matter was collected by filtration to give 3-bromo-N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide as a white solid.
To the obtained 3-bromo-N- (4- (hydroxyamidino) biphenyl-3-yl) benzamide, 10 mL of tetrahydrofuran, 0.97 mL of 1,8-diazabicyclo [5.4.0] -7-undecene and 1,1 ′ -1.1 g of carbonyldiimidazole was sequentially added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, pH was adjusted to 4.0 with a 10% aqueous citric acid solution, ethyl acetate was added, and the solid was collected by filtration. The obtained solid was washed successively with water and ethyl acetate, and white solid 3-bromo-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 0.93 g of -yl) biphenyl-3-yl) benzamide were obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.02-12.80 (broad, 1H), 10.56 (s, 1H), 8.33 (d, J = 1.7 Hz, 1H), 8.16 (dd, J = 1.8, 1.8 Hz, 1H), 7.99-7.93 (m, 1H), 7.88-7.83 (m, 1H), 7.82-7.70 (m, 4H), 7.59-7.50 (m, 3H), 7.49-7.43 (m, 1H).
実施例１２３
Figure JPOXMLDOC01-appb-C000159
 　実施例１２２と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－Ｎ－（２’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.80(broad,1H),10.52(s,1H),8.68-8.64(m,1H),7.83(d,J=8.0Hz,1H),7.66-7.60(m,1H),7.57-7.48(m,2H),7.43-7.30(m,3H),7.25-7.20(m,1H),7.18-7.12(m,1H),6.91(dd,J=8.3,2.2Hz,1H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). Example 123
Figure JPOXMLDOC01-appb-C000159
 In the same manner as in Example 122, the following compound was obtained.
3- (Diethylamino) -N- (2′-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.80 (broad, 1H), 10.52 (s, 1H), 8.68-8.64 (m, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.66-7.60 (m, 1H), 7.57-7.48 (m, 2H), 7.43-7.30 (m, 3H), 7.25-7.20 (m, 1H), 7.18-7.12 (m, 1H), 6.91 (dd, J = 8.3,2.2Hz, 1H), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
実施例１２４
Figure JPOXMLDOC01-appb-C000160
 　２－クロロ－Ｎ－（４－シアノビフェニル－３－イル）－５－（ピペリジン－１－イル）ベンズアミド0.10gの１－メチル－２－ピロリドン0.10mLおよびテトラヒドロフラン0.50mL混液に、ヒドロキシルアミン塩酸塩23mgおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLを加え、マイクロウェーブ照射下90℃で4分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で30分間攪拌した。反応混合物に水0.50mL、10％クエン酸水溶液2.5mLおよび酢酸エチル0.50mLを加え、固形物をろ取した。得られた固形物を、水および酢酸エチルで順次洗浄し、白色固体の２－クロロ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－５－（ピペリジン－１－イル）ベンズアミド82mgを得た。
1H-NMR(DMSO-d6)δ値：13.10-12.70(broad,1H),10.42(s,1H),8.37(s,1H),7.80-7.67(m,4H),7.59-7.51(m,2H),7.50-7.43(m,1H),7.32(d,J=9.0Hz,1H),7.27(d,J=2.7Hz,1H),7.06(dd,J=8.9,3.1Hz,1H),3.27-3.20(m,4H),1.68-1.52(m,6H). Example 124
Figure JPOXMLDOC01-appb-C000160
 To a mixture of 2-chloro-N- (4-cyanobiphenyl-3-yl) -5- (piperidin-1-yl) benzamide (0.10 g) with 1-methyl-2-pyrrolidone (0.10 mL) and tetrahydrofuran (0.50 mL), hydroxylamine hydrochloride 23 mg and 1,8-diazabicyclo [5.4.0] -7-undecene (0.10 mL) were added, and the mixture was stirred at 90 ° C. for 4 minutes under microwave irradiation. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 30 minutes. To the reaction mixture, 0.50 mL of water, 2.5 mL of 10% aqueous citric acid solution and 0.50 mL of ethyl acetate were added, and the solid was collected by filtration. The obtained solid was washed successively with water and ethyl acetate, and white solid 2-chloro-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 82 mg of -yl) biphenyl-3-yl) -5- (piperidin-1-yl) benzamide were obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.70 (broad, 1H), 10.42 (s, 1H), 8.37 (s, 1H), 7.80-7.67 (m, 4H), 7.59-7.51 (m , 2H), 7.50-7.43 (m, 1H), 7.32 (d, J = 9.0Hz, 1H), 7.27 (d, J = 2.7Hz, 1H), 7.06 (dd, J = 8.9,3.1Hz, 1H) 3.27-3.20 (m, 4H), 1.68-1.52 (m, 6H).
実施例１２５
Figure JPOXMLDOC01-appb-C000161
 　Ｎ－（４－シアノビフェニル－３－イル）－３－ヒドロキシベンズアミド0.31g、１－（２－ヒドロキシエチル）ピペリジン0.65gおよびトリフェニルホスフィン1.3gのテトラヒドロフラン10mL懸濁液に、ジイソプロピル＝アゾジカルボキシラート1.0gを加え、室温で30分間攪拌した。減圧下で溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；クロロホルム：メタノール＝１００：１］で精製し、白色固体のＮ－（４－シアノビフェニル－３－イル）－３－（２－（ピペリジン－１－イル）エトキシ）ベンズアミド48mgを得た。
　得られたＮ－（４－シアノビフェニル－３－イル）－３－（２－（ピペリジン－１－イル）エトキシ）ベンズアミド48mgのテトラヒドロフラン0.50mLおよび１－メチル－２－ピロリドン0.10mL混液に、ヒドロキシルアミン塩酸塩23mgおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLを加え、85-90℃で10分間攪拌した。反応混合物にヒドロキシルアミン塩酸塩23mgを加え、85-90℃で30分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で1時間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で1時間攪拌した。反応混合物に2.0mol/L水酸化ナトリウム水溶液0.30mLを加え、室温で10分間攪拌後、酢酸エチルを加え、10％クエン酸水溶液でpH4.0に調整した。減圧下で溶媒を留去し、水を加え、固形物をろ取した。得られた固形物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；99-90％クロロホルム／メタノール］で精製し、白色固体のＮ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（２－（ピペリジン－１－イル）エトキシ）ベンズアミド10mgを得た。
1H-NMR(DMSO-d6+D2O)δ値：9.12(d,J=1.7Hz,1H),8.06(d,J=8.1Hz,1H),7.85-7.80(m,1H),7.77-7.69(m,3H),7.60-7.41(m,5H),7.27(dd,J=8.0,2.0Hz,1H),4.60-4.50(m,2H),3.62-2.84(m,6H),1.90-1.36(m,6H). Example 125
Figure JPOXMLDOC01-appb-C000161
 To a suspension of 0.31 g of N- (4-cyanobiphenyl-3-yl) -3-hydroxybenzamide, 0.65 g of 1- (2-hydroxyethyl) piperidine and 1.3 g of triphenylphosphine in 10 mL of tetrahydrofuran was added diisopropyl azodicarboxyl. 1.0 g of Lat was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform: methanol = 100: 1], and white solid N 48 mg of-(4-cyanobiphenyl-3-yl) -3- (2- (piperidin-1-yl) ethoxy) benzamide was obtained.
To a mixture of 48 mg of the obtained N- (4-cyanobiphenyl-3-yl) -3- (2- (piperidin-1-yl) ethoxy) benzamide in 0.50 mL of tetrahydrofuran and 0.10 mL of 1-methyl-2-pyrrolidone, hydroxyl group was added. 23 mg of amine hydrochloride and 0.10 mL of 1,8-diazabicyclo [5.4.0] -7-undecene were added and stirred at 85-90 ° C. for 10 minutes. To the reaction mixture, 23 mg of hydroxylamine hydrochloride was added and stirred at 85-90 ° C. for 30 minutes. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. To the reaction mixture was added 2.0 mol / L aqueous sodium hydroxide solution (0.30 mL), and the mixture was stirred at room temperature for 10 minutes. Ethyl acetate was added, and the pH was adjusted to 4.0 with a 10% aqueous citric acid solution. The solvent was distilled off under reduced pressure, water was added, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-90% chloroform / methanol], and white solid N- (4- (5-oxo- 10 mg of 4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (2- (piperidin-1-yl) ethoxy) benzamide was obtained.
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 9.12 (d, J = 1.7 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.85-7.80 (m, 1H), 7.77-7.69 (m, 3H), 7.60-7.41 (m, 5H), 7.27 (dd, J = 8.0,2.0Hz, 1H), 4.60-4.50 (m, 2H), 3.62-2.84 (m, 6H), 1.90-1.36 (m, 6H).
実施例１２６
Figure JPOXMLDOC01-appb-C000162
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド0.10gにフラン－３－ボロン酸50mg、酢酸カリウム88mg、ブタノール1mL、水0.3mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド10mgを加え、窒素雰囲気下、2時間加熱還流した。反応混合物を室温まで冷却後、水および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、Ｎ－（２－シアノ－５－（フラン－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド93mgを得た。
　得られたＮ－（２－シアノ－５－（フラン－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド47mgのテトラヒドロフラン2.0mL溶液に、50％ヒドロキシルアミン水溶液0.033mLを加え、50-60℃で2時間攪拌した。反応混合物を室温まで冷却後、減圧下で溶媒を留去し、メタノールを加え、減圧下で溶媒を留去した。得られた残留物にテトラヒドロフラン2mL、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.028mLおよび１，１’－カルボニルジイミダゾール31mgを順次加え、室温で1時間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール31mgを加え、室温で1時間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール31mgを加え、室温で3時間攪拌した。反応混合物に水を加え、10％クエン酸水溶液でpH4.0に調整後、減圧下で溶媒を留去した。得られた残留物に水および酢酸エチルを加え、固形物をろ取した。得られた固形物を酢酸エチルおよび50％メタノール水溶液で順次洗浄し、白色固体のＮ－（５－（フラン－３－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド32mgを得た。
1H-NMR(DMSO-d6)δ値：13.04-12.84(broad,1H),10.49-10.42(broad,1H),8.49-8.45(m,1H),8.34(s,1H),7.84-7.81(m,1H),7.73(d,J=8.3Hz,1H),7.64(dd,J=8.2,1.1Hz,1H),7.53-7.50(m,1H),7.38(dd,J=7.7,7.7Hz,1H),7.35-7.30(m,1H),7.21-7.16(m,1H),7.04-7.00(m,1H),3.28-3.22(m,4H),1.69-1.61(m,4H),1.61-1.54(m,2H). Example 126
Figure JPOXMLDOC01-appb-C000162
 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide (0.10 g), furan-3-boronic acid (50 mg), potassium acetate (88 mg), butanol (1 mL), water (0.3 mL) and bis (di-tert -Butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (10 mg) was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid was collected by filtration to obtain 93 mg of N- (2-cyano-5- (furan-3-yl) phenyl) -3- (piperidin-1-yl) benzamide. .
To a 2.0 mL tetrahydrofuran solution of 47 mg of the obtained N- (2-cyano-5- (furan-3-yl) phenyl) -3- (piperidin-1-yl) benzamide was added 0.033 mL of a 50% aqueous hydroxylamine solution, The mixture was stirred at 50-60 ° C for 2 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure, methanol was added, and the solvent was distilled off under reduced pressure. To the obtained residue, tetrahydrofuran (2 mL), 1,8-diazabicyclo [5.4.0] -7-undecene (0.028 mL) and 1,1′-carbonyldiimidazole (31 mg) were sequentially added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 31 mg of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. To the reaction mixture, 31 mg of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, the pH was adjusted to 4.0 with a 10% aqueous citric acid solution, and the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the solid was collected by filtration. The obtained solid was washed successively with ethyl acetate and 50% aqueous methanol, and white solid N- (5- (furan-3-yl) -2- (5-oxo-4,5-dihydro-1,2, , 4-oxadiazol-3-yl) phenyl) -3- (piperidin-1-yl) benzamide 32 mg was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.04-12.84 (broad, 1H), 10.49-10.42 (broad, 1H), 8.49-8.45 (m, 1H), 8.34 (s, 1H), 7.84-7.81 (m, 1H), 7.73 (d, J = 8.3Hz, 1H), 7.64 (dd, J = 8.2,1.1Hz, 1H), 7.53-7.50 (m, 1H), 7.38 (dd, J = 7.7,7.7 Hz, 1H), 7.35-7.30 (m, 1H), 7.21-7.16 (m, 1H), 7.04-7.00 (m, 1H), 3.28-3.22 (m, 4H), 1.69-1.61 (m, 4H), 1.61-1.54 (m, 2H).
実施例１２７
Figure JPOXMLDOC01-appb-C000163
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド0.10gに３－フルオロフェニルボロン酸50mg、炭酸カリウム0.10g、ジオキサン0.80mL、水0.20mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で5分間攪拌した。反応混合物にビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド3mgを加え、マイクロウェーブ照射下150℃で5分間攪拌した。反応混合物の有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；90-70％ヘキサン／酢酸エチル］で精製し、Ｎ－（４－シアノ－３’－フルオロビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドを得た。
　得られたＮ－（４－シアノ－３’－フルオロビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドのテトラヒドロフラン2.0mLおよび１－メチル－２－ピロリドン0.10mL混液に、ヒドロキシルアミン塩酸塩23mgおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLを加え、マイクロウェーブ照射下90℃で4分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で1時間攪拌した。反応混合物に水2.0mL、酢酸エチル0.5mLおよび10％クエン酸水溶液2.5mLを加え、減圧下で溶媒を留去した。得られた残留物に水および酢酸エチルを加え、固形物をろ取した。得られた固形物を水および酢酸エチルで順次洗浄し、淡黄色固体のＮ－（３’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド33mgを得た。
1H-NMR(DMSO-d6)δ値：13.10-12.90(broad,1H),10.58-10.48(broad,1H),8.64(d,J=1.8Hz,1H),7.82(d,J=8.2Hz,1H),7.73(dd,J=8.2,1.8Hz,1H),7.64-7.55(m,3H),7.55-7.49(m,1H),7.42-7.26(m,3H),7.23-7.16(m,1H),3.29-3.22(m,4H),1.70-1.53(m,6H). Example 127
Figure JPOXMLDOC01-appb-C000163
 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide (0.10 g), 3-fluorophenylboronic acid (50 mg), potassium carbonate (0.10 g), dioxane (0.80 mL), water (0.20 mL) and bis (di -Tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 5 minutes under microwave irradiation. To the reaction mixture, 3 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride was added and stirred at 150 ° C. for 5 minutes under microwave irradiation. The organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-70% hexane / ethyl acetate], and N- (4-cyano-3′-fluorobiphenyl -3-yl) -3- (piperidin-1-yl) benzamide was obtained.
To the resulting mixture of N- (4-cyano-3'-fluorobiphenyl-3-yl) -3- (piperidin-1-yl) benzamide in tetrahydrofuran (2.0 mL) and 1-methyl-2-pyrrolidone (0.10 mL), hydroxylamine was added. 23 mg of hydrochloride and 0.10 mL of 1,8-diazabicyclo [5.4.0] -7-undecene were added, and the mixture was stirred at 90 ° C. for 4 minutes under microwave irradiation. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. To the reaction mixture were added 2.0 mL of water, 0.5 mL of ethyl acetate and 2.5 mL of 10% aqueous citric acid solution, and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the solid was collected by filtration. The obtained solid was sequentially washed with water and ethyl acetate, and N- (3′-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole- 33 mg of 3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide were obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.90 (broad, 1H), 10.58-10.48 (broad, 1H), 8.64 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.73 (dd, J = 8.2,1.8Hz, 1H), 7.64-7.55 (m, 3H), 7.55-7.49 (m, 1H), 7.42-7.26 (m, 3H), 7.23-7.16 ( m, 1H), 3.29-3.22 (m, 4H), 1.70-1.53 (m, 6H).
実施例１２８～１４７
　実施例１２７と同様にして、表１８に示す化合物を得た。 Examples 128-147
In the same manner as in Example 127, compounds shown in Table 18 were obtained.
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Ｎ－（２’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.57-10.50(broad,1H),8.54-8.50(m,1H),7.82(d,J=8.3Hz,1H),7.66-7.59(m,1H),7.58-7.47(m,3H),7.43-7.34(m,3H),7.34-7.29(m,1H),7.19(dd,J=8.2,1.6Hz,1H),3.29-3.20(m,4H),1.70-1.52(m,6H). N- (2′-Fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.57-10.50 (broad, 1H), 8.54-8.50 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.66-7.59 (m, 1H ), 7.58-7.47 (m, 3H), 7.43-7.34 (m, 3H), 7.34-7.29 (m, 1H), 7.19 (dd, J = 8.2, 1.6Hz, 1H), 3.29-3.20 (m, 4H ), 1.70-1.52 (m, 6H).
Ｎ－（４’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.57-10.49(broad,1H),8.62(d,J=1.7Hz,1H),7.84-7.77(m,3H),7.67(dd,J=8.2,1.8Hz,1H),7.54-7.49(m,1H),7.42-7.30(m,4H),7.19(dd,J=8.2,1.6Hz,1H),3.29-3.20(m,4H),1.70-1.53(m,6H). N- (4′-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.57-10.49 (broad, 1H), 8.62 (d, J = 1.7 Hz, 1H), 7.84-7.77 (m, 3H), 7.67 (dd, J = 8.2 , 1.8Hz, 1H), 7.54-7.49 (m, 1H), 7.42-7.30 (m, 4H), 7.19 (dd, J = 8.2,1.6Hz, 1H), 3.29-3.20 (m, 4H), 1.70- 1.53 (m, 6H).
Ｎ－（４’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.50(s,1H),8.61(d,J=1.8Hz,1H),7.78(d,J=8.3Hz,1H),7.74-7.68(m,2H),7.64(dd,J=8.3,1.8Hz,1H),7.54-7.49(m,1H),7.42-7.30(m,2H),7.23-7.15(m,1H),7.13-7.06(m,2H),3.83(s,3H),3.29-3.21(m,4H),1.70-1.53(m,6H). N- (4′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.50 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.74-7.68 (m, 2H), 7.64 (dd, J = 8.3, 1.8Hz, 1H), 7.54-7.49 (m, 1H), 7.42-7.30 (m, 2H), 7.23-7.15 (m, 1H), 7.13-7.06 (m, 2H), 3.83 (s, 3H), 3.29-3.21 (m, 4H), 1.70-1.53 (m, 6H).
Ｎ－（２’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.80(m,1H),10.47(s,1H),8.41(d,J=1.7Hz,1H),7.74(d,J=8.0Hz,1H),7.52-7.28(m,6H),7.21-7.15(m,2H),7.12-7.05(m,1H),3.81(s,3H),3.28-3.20(m,4H),1.70-1.52(m,6H). N- (2′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.80 (m, 1H), 10.47 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.52-7.28 (m, 6H), 7.21-7.15 (m, 2H), 7.12-7.05 (m, 1H), 3.81 (s, 3H), 3.28-3.20 (m, 4H), 1.70-1.52 ( m, 6H).
Ｎ－（５－（シクロヘキセン－１－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.40-8.35(m,1H),7.70-7.65(m,1H),7.51-7.47(m,1H),7.42-7.35(m,2H),7.34-7.28(m,1H),7.22-7.16(m,1H),6.40-6.34(m,1H),3.28-3.21(m,4H),2.43-2.33(m,2H),2.27-2.18(m,2H),1.80-1.71(m,2H),1.69-1.54(m,8H). N- (5- (cyclohexen-1-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidine-1- Il) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.40-8.35 (m, 1H), 7.70-7.65 (m, 1H), 7.51-7.47 (m, 1H), 7.42-7.35 (m, 2H), 7.34-7.28 (m, 1H), 7.22-7.16 (m, 1H), 6.40-6.34 (m, 1H), 3.28-3.21 (m, 4H), 2.43-2.33 (m, 2H), 2.27- 2.18 (m, 2H), 1.80-1.71 (m, 2H), 1.69-1.54 (m, 8H).
Ｎ－（５－（２－ナフチル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.62-10.53(broad,1H),8.79(d,J=1.2Hz,1H),8.37-8.32(m,1H),8.12-8.04(m,2H),8.02-7.97(m,1H),7.92(dd,J=8.7,1.8Hz,1H),7.90-7.82(m,2H),7.63-7.52(m,3H),7.43-7.32(m,2H),7.24-7.17(m,1H),3.30-3.23(m,4H),1.70-1.54(m,6H). N- (5- (2-naphthyl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.62-10.53 (broad, 1H), 8.79 (d, J = 1.2 Hz, 1H), 8.37-8.32 (m, 1H), 8.12-8.04 (m, 2H ), 8.02-7.97 (m, 1H), 7.92 (dd, J = 8.7,1.8Hz, 1H), 7.90-7.82 (m, 2H), 7.63-7.52 (m, 3H), 7.43-7.32 (m, 2H ), 7.24-7.17 (m, 1H), 3.30-3.23 (m, 4H), 1.70-1.54 (m, 6H).
Ｎ－（５－（ベンゾチオフェン－３－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.70-10.60(broad,1H),8.64(d,J=1.7Hz,1H),8.15-8.11(m,1H),8.08-8.04(m,2H),7.88(d,J=8.1Hz,1H),7.62(dd,J=8.1,1.7Hz,1H),7.56-7.45(m,3H),7.42-7.31(m,2H),7.23-7.16(m,1H),3.29-3.20(m,4H),1.70-1.53(m,6H). N- (5- (benzothiophen-3-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidine-1 -Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.70-10.60 (broad, 1H), 8.64 (d, J = 1.7 Hz, 1H), 8.15-8.11 (m, 1H), 8.08-8.04 (m, 2H) ), 7.88 (d, J = 8.1Hz, 1H), 7.62 (dd, J = 8.1,1.7Hz, 1H), 7.56-7.45 (m, 3H), 7.42-7.31 (m, 2H), 7.23-7.16 ( m, 1H), 3.29-3.20 (m, 4H), 1.70-1.53 (m, 6H).
Ｎ－（５－（ベンゾフラン－２－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.73-10.60(broad,1H),8.91(d,J=1.5Hz,1H),7.92(dd,J=8.3,1.7Hz,1H),7.85(d,J=8.3Hz,1H),7.76-7.68(m,2H),7.65(s,1H),7.57-7.52(m,1H),7.44-7.28(m,4H),7.24-7.17(m,1H),3.30-3.22(m,4H),1.70-1.53(m,6H). N- (5- (benzofuran-2-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidine-1- Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.73-10.60 (broad, 1H), 8.91 (d, J = 1.5 Hz, 1H), 7.92 (dd, J = 8.3, 1.7 Hz, 1H), 7.85 ( d, J = 8.3Hz, 1H), 7.76-7.68 (m, 2H), 7.65 (s, 1H), 7.57-7.52 (m, 1H), 7.44-7.28 (m, 4H), 7.24-7.17 (m, 1H), 3.30-3.22 (m, 4H), 1.70-1.53 (m, 6H).
Ｎ－（２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－５－（キノリン－６－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.66-10.53(broad,1H),8.96(dd,J=4.3,1.8Hz,1H),8.81(d,J=1.5Hz,1H),8.52(dd,J=8.4,1.6Hz,1H),8.44-8.41(m,1H),8.19-8.16(m,2H),7.91-7.83(m,2H),7.62(dd,J=8.3,4.4Hz,1H),7.56-7.52(m,1H),7.43-7.33(m,2H),7.24-7.17(m,1H),3.30-3.22(m,4H),1.70-1.54(m,6H). N- (2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -5- (quinolin-6-yl) phenyl) -3- (piperidine-1- Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.66-10.53 (broad, 1H), 8.96 (dd, J = 4.3, 1.8 Hz, 1H), 8.81 (d, J = 1.5 Hz, 1H), 8.52 ( dd, J = 8.4,1.6Hz, 1H), 8.44-8.41 (m, 1H), 8.19-8.16 (m, 2H), 7.91-7.83 (m, 2H), 7.62 (dd, J = 8.3,4.4Hz, 1H), 7.56-7.52 (m, 1H), 7.43-7.33 (m, 2H), 7.24-7.17 (m, 1H), 3.30-3.22 (m, 4H), 1.70-1.54 (m, 6H).
Ｎ－（４’－イソプロポキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.55-10.45(broad,1H),8.62(d,J=1.7Hz,1H),7.77(d,J=8.3Hz,1H),7.72-7.66(m,2H),7.63(dd,J=8.3,1.7Hz,1H),7.54-7.49(m,1H),7.42-7.30(m,2H),7.22-7.16(m,1H),7.09-7.04(m,2H),4.75-4.65(m,1H),3.30-3.20(m,4H),1.70-1.53(m,6H),1.31(d,J=6.1Hz,6H). N- (4′-isopropoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidine-1- Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.55-10.45 (broad, 1H), 8.62 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.72-7.66 ( m, 2H), 7.63 (dd, J = 8.3,1.7Hz, 1H), 7.54-7.49 (m, 1H), 7.42-7.30 (m, 2H), 7.22-7.16 (m, 1H), 7.09-7.04 ( m, 2H), 4.75-4.65 (m, 1H), 3.30-3.20 (m, 4H), 1.70-1.53 (m, 6H), 1.31 (d, J = 6.1Hz, 6H).
Ｎ－（５－（１Ｈ－インドール－５－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.15-12.80(broad,1H),11.26(s,1H),10.50(s,1H),8.71(d,J=2.0Hz,1H),7.97-7.94(m,1H),7.79(d,J=8.3Hz,1H),7.69(dd,J=8.3,2.0Hz,1H),7.56-7.47(m,3H),7.45-7.32(m,3H),7.23-7.16(m,1H),6.58-6.53(m,1H),3.30-3.22(m,4H),1.70-1.53(m,6H). N- (5- (1H-Indol-5-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidine- 1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.15-12.80 (broad, 1H), 11.26 (s, 1H), 10.50 (s, 1H), 8.71 (d, J = 2.0Hz, 1H), 7.97- 7.94 (m, 1H), 7.79 (d, J = 8.3Hz, 1H), 7.69 (dd, J = 8.3,2.0Hz, 1H), 7.56-7.47 (m, 3H), 7.45-7.32 (m, 3H) 7.23-7.16 (m, 1H), 6.58-6.53 (m, 1H), 3.30-3.22 (m, 4H), 1.70-1.53 (m, 6H).
Ｎ－（２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－５－（チオフェン－２－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.80(broad,1H),10.54(s,1H),8.66(d,J=1.5Hz,1H),7.79-7.67(m,4H),7.55-7.49(m,1H),7.43-7.30(m,2H),7.27-7.16(m,2H),3.30-3.21(m,4H),1.72-1.52(m,6H). N- (2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -5- (thiophen-2-yl) phenyl) -3- (piperidine-1- Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.80 (broad, 1H), 10.54 (s, 1H), 8.66 (d, J = 1.5 Hz, 1H), 7.79-7.67 (m, 4H), 7.55-7.49 (m, 1H), 7.43-7.30 (m, 2H), 7.27-7.16 (m, 2H), 3.30-3.21 (m, 4H), 1.72-1.52 (m, 6H).
Ｎ－（２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－５－（チオフェン－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.80(broad,1H),10.48(s,1H),8.62(d,J=1.2Hz,1H),8.06(dd,J=2.9,1.2Hz,1H),7.79-7.70(m,3H),7.62(dd,J=5.1,1.2Hz,1H),7.54-7.50(m,1H),7.41-7.30(m,2H),7.22-7.16(m,1H),3.29-3.21(m,4H),1.70-1.53(m,6H). N- (2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -5- (thiophen-3-yl) phenyl) -3- (piperidine-1- Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.80 (broad, 1H), 10.48 (s, 1H), 8.62 (d, J = 1.2 Hz, 1H), 8.06 (dd, J = 2.9, 1.2 Hz, 1H), 7.79-7.70 (m, 3H), 7.62 (dd, J = 5.1, 1.2Hz, 1H), 7.54-7.50 (m, 1H), 7.41-7.30 (m, 2H), 7.22-7.16 ( m, 1H), 3.29-3.21 (m, 4H), 1.70-1.53 (m, 6H).
Ｎ－（２’－フルオロ－４’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.51(s,1H),8.51-8.48(m,1H),7.80(d,J=8.3Hz,1H),7.55-7.47(m,3H),7.41-7.28(m,2H),7.25-7.15(m,3H),3.30-3.20(m,4H),2.39(s,3H),1.70-1.52(m,6H). N- (2′-Fluoro-4′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- ( Piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.51 (s, 1H), 8.51-8.48 (m, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.55-7.47 (m, 3H), 7.41-7.28 (m, 2H), 7.25-7.15 (m, 3H), 3.30-3.20 (m, 4H), 2.39 (s, 3H), 1.70-1.52 (m, 6H).
Ｎ－（３’－（シクロプロピルメトキシ）－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.58-10.49(broad,1H),8.64-8.60(m,1H),7.80(d,J=8.0Hz,1H),7.72-7.66(m,1H),7.54-7.50(m,1H),7.47-7.23(m,5H),7.23-7.16(m,1H),7.05-6.99(m,1H),3.95-3.89(m,2H),3.29-3.22(m,4H),1.70-1.53(m,6H),1.32-1.20(m,1H),0.63-0.56(m,2H),0.39-0.32(m,2H). N- (3 ′-(cyclopropylmethoxy) -4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidine -1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.58-10.49 (broad, 1H), 8.64-8.60 (m, 1H), 7.80 (d, J = 8.0Hz, 1H ), 7.72-7.66 (m, 1H), 7.54-7.50 (m, 1H), 7.47-7.23 (m, 5H), 7.23-7.16 (m, 1H), 7.05-6.99 (m, 1H), 3.95-3.89 (m, 2H), 3.29-3.22 (m, 4H), 1.70-1.53 (m, 6H), 1.32-1.20 (m, 1H), 0.63-0.56 (m, 2H), 0.39-0.32 (m, 2H) .
Ｎ－（４’－（シクロプロピルメトキシ）－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.13-12.83(broad,1H),10.54-10.47(broad,1H),8.61(d,J=1.7Hz,1H),7.77(d,J=8.3Hz,1H),7.72-7.66(m,2H),7.63(dd,J=8.3,1.7Hz,1H),7.54-7.50(m,1H),7.41-7.30(m,2H),7.22-7.16(m,1H),7.11-7.04(m,2H),3.92-3.85(m,2H),3.29-3.21(m,4H),1.70-1.52(m,6H),1.31-1.18(m,1H),0.63-0.55(m,2H),0.39-0.31(m,2H). N- (4 ′-(cyclopropylmethoxy) -4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidine -1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.13-12.83 (broad, 1H), 10.54-10.47 (broad, 1H), 8.61 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.72-7.66 (m, 2H), 7.63 (dd, J = 8.3, 1.7Hz, 1H), 7.54-7.50 (m, 1H), 7.41-7.30 (m, 2H), 7.22-7.16 ( m, 1H), 7.11-7.04 (m, 2H), 3.92-3.85 (m, 2H), 3.29-3.21 (m, 4H), 1.70-1.52 (m, 6H), 1.31-1.18 (m, 1H), 0.63-0.55 (m, 2H), 0.39-0.31 (m, 2H).
Ｎ－（５－（３－メチルピリジン－４－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.68-10.58(m,1H),8.59(s,1H),8.56-8.50(m,1H),8.36(s,1H),7.84(d,J=8.0Hz,1H),7.53-7.27(m,5H),7.23-7.14(m,1H),3.29-3.18(m,4H),2.33(s,3H),1.70-1.50(m,6H). N- (5- (3-Methylpyridin-4-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidine -1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.68-10.58 (m, 1H), 8.59 (s, 1H), 8.56-8.50 (m, 1H), 8.36 (s, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.53-7.27 (m, 5H), 7.23-7.14 (m, 1H), 3.29-3.18 (m, 4H), 2.33 (s, 3H), 1.70-1.50 (m, 6H).
Ｎ－（２’－フルオロ－４’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.80(broad,1H),10.50(s,1H),8.50-8.46(m,1H),7.79(d,J=8.3Hz,1H),7.59-7.48(m,3H),7.42-7.35(m,1H),7.35-7.29(m,1H),7.19(dd,J=8.0,1.7Hz,1H),7.02(dd,J=13.2,2.4Hz,1H),6.96(dd,J=8.5,2.4Hz,1H),3.84(s,3H),3.29-3.20(m,4H),1.70-1.53(m,6H). N- (2′-Fluoro-4′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- ( Piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.80 (broad, 1H), 10.50 (s, 1H), 8.50-8.46 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.59-7.48 (m, 3H), 7.42-7.35 (m, 1H), 7.35-7.29 (m, 1H), 7.19 (dd, J = 8.0,1.7Hz, 1H), 7.02 (dd, J = 13.2,2.4 Hz, 1H), 6.96 (dd, J = 8.5, 2.4Hz, 1H), 3.84 (s, 3H), 3.29-3.20 (m, 4H), 1.70-1.53 (m, 6H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－３’－（トリフルオロメチル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.60-10.52(broad,1H),8.66(d,J=1.7Hz,1H),8.11-8.03(m,2H),7.88-7.75(m,4H),7.54-7.50(m,1H),7.42-7.30(m,2H),7.23-7.16(m,1H),3.29-3.21(m,4H),1.70-1.53(m,6H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -3 '-(trifluoromethyl) biphenyl-3-yl) -3- (piperidine -1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.60-10.52 (broad, 1H), 8.66 (d, J = 1.7Hz, 1H), 8.11-8.03 (m, 2H), 7.88-7.75 (m, 4H ), 7.54-7.50 (m, 1H), 7.42-7.30 (m, 2H), 7.23-7.16 (m, 1H), 3.29-3.21 (m, 4H), 1.70-1.53 (m, 6H).
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－４’－（トリフルオロメチル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.56(s,1H),8.69(d,J=1.8Hz,1H),8.01-7.96(m,2H),7.93-7.88(m,2H),7.86(d,J=8.3Hz,1H),7.76(dd,J=8.3,1.8Hz,1H),7.54-7.50(m,1H),7.42-7.31(m,2H),7.23-7.17(m,1H),3.29-3.22(m,4H),1.70-1.53(m,6H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -4 '-(trifluoromethyl) biphenyl-3-yl) -3- (piperidine -1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.56 (s, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.01-7.96 (m, 2H), 7.93-7.88 (m, 2H), 7.86 (d, J = 8.3Hz, 1H), 7.76 (dd, J = 8.3,1.8Hz, 1H), 7.54-7.50 (m, 1H), 7.42-7.31 (m, 2H), 7.23-7.17 (m, 1H), 3.29-3.22 (m, 4H), 1.70-1.53 (m, 6H).
実施例１４８
Figure JPOXMLDOC01-appb-C000165
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド0.10gに２－メチルフェニルボロン酸53mg、炭酸カリウム0.10g、ジオキサン0.80mL、水0.20mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物に２－メチルフェニルボロン酸20mgおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物の有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、Ｎ－（４－シアノ－２’－メチルビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドを得た。
　得られたＮ－（４－シアノ－２’－メチルビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドのテトラヒドロフラン0.50mL溶液に、ヒドロキシルアミン塩酸塩23mgおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLを加え、マイクロウェーブ照射下90℃で4分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で1時間攪拌した。反応混合物に水2.0mL、酢酸エチル0.5mLおよび10％クエン酸水溶液2.5mLを加えた。有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；75-20％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（２’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド20mgを得た。
1H-NMR(DMSO-d6+D2O)δ値：8.28-8.22(m,1H),7.79(d,J=8.0Hz,1H),7.51-7.48(m,1H),7.43-7.26(m,7H),7.24-7.18(m,1H),3.29-3.21(m,4H),2.31(s,3H),1.69-1.61(m,4H),1.61-1.53(m,2H). Example 148
Figure JPOXMLDOC01-appb-C000165
 To 0.10 g of N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide, 53 mg of 2-methylphenylboronic acid, 0.10 g of potassium carbonate, 0.80 mL of dioxane, 0.20 mL of water and bis (di -Tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. To the reaction mixture, 20 mg of 2-methylphenylboronic acid and 5 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride were added and stirred at 150 ° C. for 10 minutes under microwave irradiation. The organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (4-cyano-2′-methylbiphenyl). -3-yl) -3- (piperidin-1-yl) benzamide was obtained.
To a solution of N- (4-cyano-2′-methylbiphenyl-3-yl) -3- (piperidin-1-yl) benzamide in 0.50 mL of tetrahydrofuran was added 23 mg of hydroxylamine hydrochloride and 1,8-diazabicyclo [ 5.4.0] -7-undecene (0.10 mL) was added, and the mixture was stirred at 90 ° C. for 4 minutes under microwave irradiation. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. To the reaction mixture were added 2.0 mL of water, 0.5 mL of ethyl acetate, and 2.5 mL of 10% aqueous citric acid solution. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 75-20% hexane / ethyl acetate], and white solid N- (2′-methyl-4 20 mg of-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.28-8.22 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.51-7.48 (m, 1H), 7.43-7.26 (m, 7H), 7.24-7.18 (m, 1H), 3.29-3.21 (m, 4H), 2.31 (s, 3H), 1.69-1.61 (m, 4H), 1.61-1.53 (m, 2H).
実施例１４９～１５７
　実施例１４８と同様にして、表１９に示す化合物を得た。 Examples 149-157
In the same manner as in Example 148, the compounds shown in Table 19 were obtained.
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Ｎ－（３’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.61-8.55(m,1H),7.83-7.78(m,1H),7.69-7.64(m,1H),7.58-7.50(m,3H),7.46-7.37(m,2H),7.34(d,J=7.6Hz,1H),7.29(d,J=7.6Hz,1H),7.21(dd,J=8.0,1.7Hz,1H),3.29-3.23(m,4H),2.41(s,3H),1.70-1.62(m,4H),1.62-1.54(m,2H). N- (3′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.61-8.55 (m, 1H), 7.83-7.78 (m, 1H), 7.69-7.64 (m, 1H), 7.58-7.50 (m, 3H), 7.46-7.37 (m, 2H), 7.34 (d, J = 7.6Hz, 1H), 7.29 (d, J = 7.6Hz, 1H), 7.21 (dd, J = 8.0, 1.7Hz, 1H), 3.29-3.23 (m, 4H), 2.41 (s, 3H), 1.70-1.62 (m, 4H), 1.62-1.54 (m, 2H).
Ｎ－（５－（１－ナフチル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.25-12.84(broad,1H),10.57(s,1H),8.45(d,J=1.7Hz,1H),8.09-8.01(m,2H),7.92-7.86(m,2H),7.68-7.46(m,6H),7.41-7.34(m,1H),7.34-7.28(m,1H),7.19(dd,J=8.0,1.4Hz,1H),3.28-3.20(m,4H),1.70-1.52(m,6H). N- (5- (1-naphthyl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.25-12.84 (broad, 1H), 10.57 (s, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.09-8.01 (m, 2H), 7.92-7.86 (m, 2H), 7.68-7.46 (m, 6H), 7.41-7.34 (m, 1H), 7.34-7.28 (m, 1H), 7.19 (dd, J = 8.0,1.4Hz, 1H), 3.28-3.20 (m, 4H), 1.70-1.52 (m, 6H).
Ｎ－（４’－（ｔｅｒｔ－ブチル）－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.80(broad,1H),10.51(s,1H),8.63(d,J=1.7Hz,1H),7.79(d,J=8.3Hz,1H),7.72-7.63(m,3H),7.59-7.49(m,3H),7.42-7.30(m,2H),7.19(dd,J=8.1,1.5Hz,1H),3.29-3.21(m,4H),1.70-1.52(m,6H),1.33(s,9H). N- (4 ′-(tert-butyl) -4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidine -1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.80 (broad, 1H), 10.51 (s, 1H), 8.63 (d, J = 1.7 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.72-7.63 (m, 3H), 7.59-7.49 (m, 3H), 7.42-7.30 (m, 2H), 7.19 (dd, J = 8.1, 1.5Hz, 1H), 3.29-3.21 (m, 4H), 1.70-1.52 (m, 6H), 1.33 (s, 9H).
Ｎ－（２’－クロロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.57-10.50(broad,1H),8.39(d,J=1.5Hz,1H),7.81(d,J=8.1Hz,1H),7.66-7.60(m,1H),7.52-7.46(m,4H),7.43(dd,J=8.1,1.7Hz,1H),7.41-7.34(m,1H),7.33-7.28(m,1H),7.19(dd,J=8.0,1.7Hz,1H),3.28-3.21(m,4H),1.70-1.52(m,6H). N- (2′-chloro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.57-10.50 (broad, 1H), 8.39 (d, J = 1.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.66-7.60 ( m, 1H), 7.52-7.46 (m, 4H), 7.43 (dd, J = 8.1,1.7Hz, 1H), 7.41-7.34 (m, 1H), 7.33-7.28 (m, 1H), 7.19 (dd, J = 8.0, 1.7Hz, 1H), 3.28-3.21 (m, 4H), 1.70-1.52 (m, 6H).
Ｎ－（３’－ニトロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.69-8.63(m,1H),8.53-8.50(m,1H),8.35-8.30(m,1H),8.23(d,J=8.0Hz,1H),7.90-7.78(m,3H),7.56-7.50(m,1H),7.41(dd,J=7.8,7.8Hz,1H),7.35(d,J=7.8Hz,1H),7.22(dd,J=8.0,1.7Hz,1H),3.30-3.22(m,4H),1.70-1.62(m,4H),1.62-1.54(m,2H). N- (3′-nitro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.69-8.63 (m, 1H), 8.53-8.50 (m, 1H), 8.35-8.30 (m, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.90-7.78 (m, 3H), 7.56-7.50 (m, 1H), 7.41 (dd, J = 7.8,7.8Hz, 1H), 7.35 (d, J = 7.8Hz, 1H), 7.22 (dd, J = 8.0, 1.7Hz, 1H), 3.30-3.22 (m, 4H), 1.70-1.62 (m, 4H), 1.62-1.54 (m, 2H).
Ｎ－（４’－ニトロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.72-8.66(m,1H),8.42-8.36(m,2H),8.07-8.01(m,2H),7.89(d,J=8.3Hz,1H),7.78(dd,J=8.3,1.7Hz,1H),7.54-7.50(m,1H),7.44-7.38(m,1H),7.37-7.32(m,1H),7.25-7.18(m,1H),3.29-3.23(m,4H),1.70-1.62(m,4H),1.62-1.54(m,2H). N- (4′-nitro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.72-8.66 (m, 1H), 8.42-8.36 (m, 2H), 8.07-8.01 (m, 2H), 7.89 (d, J = 8.3Hz, 1H), 7.78 (dd, J = 8.3,1.7Hz, 1H), 7.54-7.50 (m, 1H), 7.44-7.38 (m, 1H), 7.37-7.32 (m, 1H), 7.25-7.18 (m, 1H), 3.29-3.23 (m, 4H), 1.70-1.62 (m, 4H), 1.62-1.54 (m, 2H).
Ｎ－（３’，４’－ジメトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.85(broad,1H),10.53-10.45(broad,1H),8.57(d,J=1.8Hz,1H),7.77(d,J=8.1Hz,1H),7.68(dd,J=8.1,1.8Hz,1H),7.54-7.50(m,1H),7.42-7.28(m,4H),7.22-7.15(m,1H),7.14-7.08(m,1H),3.87(s,3H),3.82(s,3H),3.29-3.21(m,4H),1.70-1.52(m,6H). N- (3 ′, 4′-dimethoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidine- 1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.85 (broad, 1H), 10.53-10.45 (broad, 1H), 8.57 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 8.1, 1.8Hz, 1H), 7.54-7.50 (m, 1H), 7.42-7.28 (m, 4H), 7.22-7.15 (m, 1H), 7.14-7.08 ( m, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.29-3.21 (m, 4H), 1.70-1.52 (m, 6H).
Ｎ－（５－（ベンゾ［１，３］ジオキソール－５－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.80(broad,1H),10.64-10.47(broad,1H),8.58(d,J=1.7Hz,1H),7.77(d,J=8.3Hz,1H),7.62(dd,J=8.3,1.7Hz,1H),7.54-7.49(m,1H),7.41-7.30(m,3H),7.26(dd,J=8.2,1.8Hz,1H),7.22-7.16(m,1H),7.07(d,J=8.0Hz,1H),6.11(s,2H),3.29-3.21(m,4H),1.70-1.53(m,6H). N- (5- (Benzo [1,3] dioxol-5-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3 -(Piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.80 (broad, 1H), 10.64-10.47 (broad, 1H), 8.58 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3, 1.7Hz, 1H), 7.54-7.49 (m, 1H), 7.41-7.30 (m, 3H), 7.26 (dd, J = 8.2, 1.8Hz, 1H) , 7.22-7.16 (m, 1H), 7.07 (d, J = 8.0Hz, 1H), 6.11 (s, 2H), 3.29-3.21 (m, 4H), 1.70-1.53 (m, 6H).
Ｎ－（４’－ヒドロキシ－３’，５’－ジメチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.80(broad,1H),10.50-10.43(broad,1H),8.59(s,1H),8.56(d,J=1.8Hz,1H),7.74(d,J=8.4Hz,1H),7.59(dd,J=8.4,1.8Hz,1H),7.54-7.49(m,1H),7.41-7.30(m,4H),7.22-7.15(m,1H),3.29-3.21(m,4H),2.26(s,6H),1.70-1.53(m,6H). N- (4′-hydroxy-3 ′, 5′-dimethyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl)- 3- (Piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.80 (broad, 1H), 10.50-10.43 (broad, 1H), 8.59 (s, 1H), 8.56 (d, J = 1.8Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 7.59 (dd, J = 8.4,1.8Hz, 1H), 7.54-7.49 (m, 1H), 7.41-7.30 (m, 4H), 7.22-7.15 (m, 1H), 3.29-3.21 (m, 4H), 2.26 (s, 6H), 1.70-1.53 (m, 6H).
実施例１５８
Figure JPOXMLDOC01-appb-C000167
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド0.10gに４－メチルフェニルボロン酸49mg、炭酸カリウム0.10g、ジオキサン0.80mL、水0.20mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で5分間攪拌した。反応混合物の有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、Ｎ－（４－シアノ－４’－メチルビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドを得た。
　得られたＮ－（４－シアノ－４’－メチルビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドのテトラヒドロフラン2.0mLおよび１－メチル－２－ピロリドン0.10mL混液に、ヒドロキシルアミン塩酸塩23mgおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLを加え、マイクロウェーブ照射下90℃で4分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で1時間攪拌した。反応混合物に水2.0mL、酢酸エチル0.5mLおよび10％クエン酸水溶液2.5mLを加え、減圧下で溶媒を留去した。得られた残留物に水および酢酸エチルを加え、固形物をろ取した。得られた固形物に酢酸エチル10mLおよび2.8mol/L塩化水素－酢酸エチル溶液1.0mLを加え、固形物をろ取し、白色固体のＮ－（４’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド塩酸塩49mgを得た。
1H-NMR(DMSO-d6+D2O)δ値：8.36-8.31(m,1H),8.05-8.00(m,1H),7.90-7.84(m,1H),7.79(d,J=8.3Hz,1H),7.76-7.64(m,5H),7.40-7.34(m,2H),3.55-3.48(m,4H),2.38(s,3H),1.92-1.81(m,4H),1.71-1.62(m,2H). Example 158
Figure JPOXMLDOC01-appb-C000167
 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide (0.10 g), 4-methylphenylboronic acid (49 mg), potassium carbonate (0.10 g), dioxane (0.80 mL), water (0.20 mL) and bis (di -Tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 5 minutes under microwave irradiation. The organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (4-cyano-4′-methylbiphenyl). -3-yl) -3- (piperidin-1-yl) benzamide was obtained.
To the resulting mixture of N- (4-cyano-4'-methylbiphenyl-3-yl) -3- (piperidin-1-yl) benzamide in tetrahydrofuran (2.0 mL) and 1-methyl-2-pyrrolidone (0.10 mL), hydroxylamine was added. 23 mg of hydrochloride and 0.10 mL of 1,8-diazabicyclo [5.4.0] -7-undecene were added and stirred at 90 ° C. for 4 minutes under microwave irradiation. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. To the reaction mixture were added 2.0 mL of water, 0.5 mL of ethyl acetate and 2.5 mL of 10% aqueous citric acid solution, and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the solid was collected by filtration. To the obtained solid were added 10 mL of ethyl acetate and 1.0 mL of a 2.8 mol / L hydrogen chloride-ethyl acetate solution, and the solid was collected by filtration to give N- (4′-methyl-4- (5-oxo-) as a white solid. 49 mg of 4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide hydrochloride was obtained.
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.36-8.31 (m, 1H), 8.05-8.00 (m, 1H), 7.90-7.84 (m, 1H), 7.79 (d, J = 8.3Hz, 1H), 7.76-7.64 (m, 5H), 7.40-7.34 (m, 2H), 3.55-3.48 (m, 4H), 2.38 (s, 3H), 1.92-1.81 (m, 4H), 1.71 -1.62 (m, 2H).
実施例１５９
Figure JPOXMLDOC01-appb-C000168
 　実施例１５８と同様にして、以下の化合物を得た。
Ｎ－（３’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド塩酸塩
1H-NMR(DMSO-d6+D2O)δ値：8.41(d,J=1.7Hz,1H),7.88-7.83(m,1H),7.81(d,J=8.3Hz,1H),7.76-7.67(m,2H),7.63-7.52(m,2H),7.48(dd,J=8.1,8.1Hz,1H),7.36-7.30(m,1H),7.29-7.25(m,1H),7.05(dd,J=8.3,1.9Hz,1H),3.85(s,3H),3.47-3.39(m,4H),1.84-1.74(m,4H),1.68-1.59(m,2H). Example 159
Figure JPOXMLDOC01-appb-C000168
 In the same manner as in Example 158, the following compound was obtained.
N- (3′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl ) Benzamide hydrochloride
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.41 (d, J = 1.7 Hz, 1H), 7.88-7.83 (m, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.76-7.67 (m, 2H), 7.63-7.52 (m, 2H), 7.48 (dd, J = 8.1,8.1Hz, 1H), 7.36-7.30 (m, 1H), 7.29-7.25 (m, 1H), 7.05 (dd, J = 8.3, 1.9Hz, 1H), 3.85 (s, 3H), 3.47-3.39 (m, 4H), 1.84-1.74 (m, 4H), 1.68-1.59 (m, 2H).
実施例１６０
Figure JPOXMLDOC01-appb-C000169
 　実施例１２７と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－Ｎ－（２’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.41-8.37(m,1H),7.81(d,J=7.8Hz,1H),7.40-7.27(m,6H),7.23-7.19(m,1H),7.17-7.12(m,1H),6.95-6.89(m,1H),3.42(q,J=7.0Hz,4H),2.31(s,3H),1.13(t,J=7.0Hz,6H). Example 160
Figure JPOXMLDOC01-appb-C000169
 In the same manner as in Example 127, the following compound was obtained.
3- (Diethylamino) -N- (2′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.41-8.37 (m, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.40-7.27 (m, 6H), 7.23-7.19 (m, 1H), 7.17-7.12 (m, 1H), 6.95-6.89 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 2.31 (s, 3H), 1.13 (t, J = 7.0 Hz, 6H).
実施例１６１～１７９
　実施例１６０と同様にして、表２０に示す化合物を得た。 Examples 161-179
In the same manner as in Example 160, the compounds shown in Table 20 were obtained.
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
３－（ジエチルアミノ）－Ｎ－（３’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.56-10.49(broad,1H),8.76(d,J=1.7Hz,1H),7.82(d,J=8.3Hz,1H),7.66(dd,J=8.3,1.7Hz,1H),7.59-7.53(m,2H),7.43(dd,J=7.7,7.7Hz,1H),7.34(d,J=8.1,8.1Hz,1H),7.30-7.25(m,1H),7.25-7.21(m,1H),7.18-7.13(m,1H),6.94-6.88(m,1H),3.42(q,J=7.0Hz,4H),2.42(s,3H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (3′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.56-10.49 (broad, 1H), 8.76 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.66 (dd, J = 8.3,1.7Hz, 1H), 7.59-7.53 (m, 2H), 7.43 (dd, J = 7.7,7.7Hz, 1H), 7.34 (d, J = 8.1,8.1Hz, 1H), 7.30-7.25 (m, 1H), 7.25-7.21 (m, 1H), 7.18-7.13 (m, 1H), 6.94-6.88 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 2.42 (s, 3H ), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（５－（１－メチル－１Ｈ－インドール－５－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.60-10.50(broad,1H),8.86(d,J=1.8Hz,1H),7.98-7.94(m,1H),7.81(d,J=8.3Hz,1H),7.69(dd,J=8.3,1.8Hz,1H),7.61-7.54(m,2H),7.41(d,J=3.2Hz,1H),7.34(dd,J=7.9,7.9Hz,1H),7.27-7.23(m,1H),7.20-7.14(m,1H),6.91(dd,J=8.4,2.3Hz,1H),6.56(d,J=2.7Hz,1H),3.84(s,3H),3.43(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (5- (1-methyl-1H-indol-5-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3- Yl) phenyl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.60-10.50 (broad, 1H), 8.86 (d, J = 1.8 Hz, 1H), 7.98-7.94 (m, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.69 (dd, J = 8.3, 1.8Hz, 1H), 7.61-7.54 (m, 2H), 7.41 (d, J = 3.2Hz, 1H), 7.34 (dd, J = 7.9, 7.9Hz , 1H), 7.27-7.23 (m, 1H), 7.20-7.14 (m, 1H), 6.91 (dd, J = 8.4,2.3Hz, 1H), 6.56 (d, J = 2.7Hz, 1H), 3.84 ( s, 3H), 3.43 (q, J = 7.0Hz, 4H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４’－（モルホリン－４－イル）－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.80(broad,1H),10.50(s,1H),8.77(d,J=1.7Hz,1H),7.77(d,J=8.3Hz,1H),7.70-7.64(m,2H),7.62(dd,J=8.3,1.7Hz,1H),7.33(dd,J=8.0,8.0Hz,1H),7.26-7.20(m,1H),7.20-7.12(m,1H),7.12-7.05(m,2H),6.90(dd,J=8.4,2.3Hz,1H),3.80-3.72(m,4H),3.42(q,J=7.0Hz,4H),3.23-3.17(m,4H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (4 ′-(morpholin-4-yl) -4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3 -Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.80 (broad, 1H), 10.50 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.70-7.64 (m, 2H), 7.62 (dd, J = 8.3, 1.7Hz, 1H), 7.33 (dd, J = 8.0, 8.0Hz, 1H), 7.26-7.20 (m, 1H), 7.20 -7.12 (m, 1H), 7.12-7.05 (m, 2H), 6.90 (dd, J = 8.4,2.3Hz, 1H), 3.80-3.72 (m, 4H), 3.42 (q, J = 7.0Hz, 4H ), 3.23-3.17 (m, 4H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４’－（ジメチルアミノ）－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.53-10.45(broad,1H),8.75(d,J=1.7Hz,1H),7.75(d,J=8.3Hz,1H),7.67-7.61(m,2H),7.59(dd,J=8.3,1.7Hz,1H),7.33(dd,J=7.9,7.9Hz,1H),7.26-7.21(m,1H),7.19-7.13(m,1H),6.90(dd,J=8.4,2.1Hz,1H),6.88-6.81(m,2H),3.42(q,J=7.0Hz,4H),2.98(s,6H),1.14(t,J=7.0Hz,6H). 3- (diethylamino) -N- (4 ′-(dimethylamino) -4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.53-10.45 (broad, 1H), 8.75 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.67-7.61 ( m, 2H), 7.59 (dd, J = 8.3,1.7Hz, 1H), 7.33 (dd, J = 7.9,7.9Hz, 1H), 7.26-7.21 (m, 1H), 7.19-7.13 (m, 1H) , 6.90 (dd, J = 8.4,2.1Hz, 1H), 6.88-6.81 (m, 2H), 3.42 (q, J = 7.0Hz, 4H), 2.98 (s, 6H), 1.14 (t, J = 7.0 Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－２’－（トリフルオロメチル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.60-10.50(broad,1H),8.48-8.43(m,1H),7.90(d,J=7.6Hz,1H),7.83-7.75(m,2H),7.73-7.66(m,1H),7.49(d,J=7.6Hz,1H),7.36-7.27(m,2H),7.22-7.16(m,1H),7.16-7.07(m,1H),6.94-6.84(m,1H),3.46-3.36(m,4H),1.12(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -2 '-(trifluoromethyl) biphenyl-3-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.60-10.50 (broad, 1H), 8.48-8.43 (m, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.83-7.75 (m, 2H ), 7.73-7.66 (m, 1H), 7.49 (d, J = 7.6Hz, 1H), 7.36-7.27 (m, 2H), 7.22-7.16 (m, 1H), 7.16-7.07 (m, 1H), 6.94-6.84 (m, 1H), 3.46-3.36 (m, 4H), 1.12 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（５－（５－メチルフラン－２－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.90(broad,1H),10.52-10.46(m,1H),8.75(d,J=1.6Hz,1H),7.74(d,J=8.3Hz,1H),7.62(dd,J=8.3,1.6Hz,1H),7.33(dd,J=8.0,8.0Hz,1H),7.26-7.20(m,1H),7.18-7.12(m,1H),7.05(d,J=3.2Hz,1H),6.94-6.87(m,1H),6.32-6.28(m,1H),3.42(q,J=7.0Hz,4H),2.40(s,3H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (5- (5-methylfuran-2-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.90 (broad, 1H), 10.52-10.46 (m, 1H), 8.75 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3,1.6Hz, 1H), 7.33 (dd, J = 8.0,8.0Hz, 1H), 7.26-7.20 (m, 1H), 7.18-7.12 (m, 1H) , 7.05 (d, J = 3.2Hz, 1H), 6.94-6.87 (m, 1H), 6.32-6.28 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 2.40 (s, 3H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（３’，４’－ジフルオロ－５’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.52-10.47(broad,1H),8.68(d,J=1.7Hz,1H),7.82(d,J=8.3Hz,1H),7.73(dd,J=8.3,1.7Hz,1H),7.43-7.30(m,3H),7.26-7.19(m,1H),7.19-7.12(m,1H),6.95-6.87(m,1H),4.01(s,3H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (3 ′, 4′-difluoro-5′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl -3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.52-10.47 (broad, 1H), 8.68 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 8.3,1.7Hz, 1H), 7.43-7.30 (m, 3H), 7.26-7.19 (m, 1H), 7.19-7.12 (m, 1H), 6.95-6.87 (m, 1H), 4.01 (s, 3H), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（５－（２，６－ジメトキシピリジン－３－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.54-10.45(broad,1H),8.60(d,J=1.6Hz,1H),7.82(d,J=8.0Hz,1H),7.75(d,J=8.3Hz,1H),7.52(dd,J=8.3,1.6Hz,1H),7.32(dd,J=8.0,8.0Hz,1H),7.23-7.18(m,1H),7.18-7.10(m,1H),6.90(dd,J=8.0,2.2Hz,1H),6.58-6.52(m,1H),3.95(s,3H),3.94(s,3H),3.42(q,J=6.9Hz,4H),1.13(t,J=6.9Hz,6H). 3- (Diethylamino) -N- (5- (2,6-dimethoxypyridin-3-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) ) Phenyl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.54-10.45 (broad, 1H), 8.60 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.3Hz, 1H), 7.52 (dd, J = 8.3,1.6Hz, 1H), 7.32 (dd, J = 8.0,8.0Hz, 1H), 7.23-7.18 (m, 1H), 7.18-7.10 (m , 1H), 6.90 (dd, J = 8.0,2.2Hz, 1H), 6.58-6.52 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.42 (q, J = 6.9Hz, 4H), 1.13 (t, J = 6.9Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（５－（１－メチル－１Ｈ－ピロール－２－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.80(broad,1H),10.54-10.47(broad,1H),8.57(d,J=1.8Hz,1H),7.75(d,J=8.1Hz,1H),7.44(dd,J=8.1,1.8Hz,1H),7.33(dd,J=7.9,7.9Hz,1H),7.24-7.19(m,1H),7.17-7.12(m,1H),6.96(dd,J=2.1,2.1Hz,1H),6.90(dd,J=8.3,2.2Hz,1H),6.39(dd,J=3.7,1.7Hz,1H),6.14(dd,J=3.7,2.7Hz,1H),3.78(s,3H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (5- (1-methyl-1H-pyrrol-2-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3- Yl) phenyl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.80 (broad, 1H), 10.54-10.47 (broad, 1H), 8.57 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 8.1,1.8Hz, 1H), 7.33 (dd, J = 7.9,7.9Hz, 1H), 7.24-7.19 (m, 1H), 7.17-7.12 (m, 1H) , 6.96 (dd, J = 2.1,2.1Hz, 1H), 6.90 (dd, J = 8.3,2.2Hz, 1H), 6.39 (dd, J = 3.7,1.7Hz, 1H), 6.14 (dd, J = 3.7 , 2.7Hz, 1H), 3.78 (s, 3H), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（３’，５’－ジメトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.52-10.46(broad,1H),8.70(d,J=2.0Hz,1H),7.80(d,J=8.3Hz,1H),7.68(dd,J=8.3,2.0Hz,1H),7.33(dd,J=7.9,7.9Hz,1H),7.25-7.20(m,1H),7.20-7.12(m,1H),6.94-6.88(m,1H),6.86(d,J=2.2Hz,2H),6.61(dd,J=2.2,2.2Hz,1H),3.84(s,6H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (diethylamino) -N- (3 ′, 5′-dimethoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.52-10.46 (broad, 1H), 8.70 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.68 (dd, J = 8.3, 2.0Hz, 1H), 7.33 (dd, J = 7.9, 7.9Hz, 1H), 7.25-7.20 (m, 1H), 7.20-7.12 (m, 1H) , 6.94-6.88 (m, 1H), 6.86 (d, J = 2.2Hz, 2H), 6.61 (dd, J = 2.2,2.2Hz, 1H), 3.84 (s, 6H), 3.42 (q, J = 7.0 Hz, 4H), 1.13 (t, J = 7.0 Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４’－エトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.85(broad,1H),10.49(s,1H),8.76(d,J=1.8Hz,1H),7.78(d,J=8.3Hz,1H),7.73-7.67(m,2H),7.63(dd,J=8.3,1.8Hz,1H),7.34(dd,J=7.9,7.9Hz,1H),7.26-7.21(m,1H),7.19-7.13(m,1H),7.11-7.05(m,2H),6.91(dd,J=8.3,2.2Hz,1H),4.10(q,J=6.9Hz,2H),3.42(q,J=7.0Hz,4H),1.36(t,J=6.9Hz,3H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (4′-ethoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.85 (broad, 1H), 10.49 (s, 1H), 8.76 (d, J = 1.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.73-7.67 (m, 2H), 7.63 (dd, J = 8.3,1.8Hz, 1H), 7.34 (dd, J = 7.9,7.9Hz, 1H), 7.26-7.21 (m, 1H), 7.19 -7.13 (m, 1H), 7.11-7.05 (m, 2H), 6.91 (dd, J = 8.3,2.2Hz, 1H), 4.10 (q, J = 6.9Hz, 2H), 3.42 (q, J = 7.0 Hz, 4H), 1.36 (t, J = 6.9Hz, 3H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－４’－プロポキシビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.78-10.65(broad,1H),8.79(d,J=1.8Hz,1H),7.81(d,J=8.3Hz,1H),7.73-7.67(m,2H),7.60(dd,J=8.3,1.8Hz,1H),7.33(dd,J=7.9,7.9Hz,1H),7.26-7.22(m,1H),7.19-7.14(m,1H),7.11-7.05(m,2H),6.90(dd,J=8.4,2.3Hz,1H),4.00(t,J=6.6Hz,2H),3.42(q,J=6.9Hz,4H),1.82-1.71(m,2H),1.14(t,J=6.9Hz,6H),1.01(t,J=7.4Hz,3H). 3- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -4'-propoxybiphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.78-10.65 (broad, 1H), 8.79 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.73-7.67 ( m, 2H), 7.60 (dd, J = 8.3,1.8Hz, 1H), 7.33 (dd, J = 7.9,7.9Hz, 1H), 7.26-7.22 (m, 1H), 7.19-7.14 (m, 1H) 7.11-7.05 (m, 2H), 6.90 (dd, J = 8.4,2.3Hz, 1H), 4.00 (t, J = 6.6Hz, 2H), 3.42 (q, J = 6.9Hz, 4H), 1.82- 1.71 (m, 2H), 1.14 (t, J = 6.9Hz, 6H), 1.01 (t, J = 7.4Hz, 3H).
３－（ジエチルアミノ）－Ｎ－（３’，４’－ジメチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.66(s,1H),8.78(d,J=1.7Hz,1H),7.81(d,J=8.3Hz,1H),7.62(dd,J=8.3,1.7Hz,1H),7.56-7.52(m,1H),7.51-7.45(m,1H),7.37-7.26(m,2H),7.26-7.21(m,1H),7.20-7.14(m,1H),6.90(dd,J=8.4,2.3Hz,1H),3.42(q,J=7.0Hz,4H),2.33(s,3H),2.29(s,3H),1.14(t,J=7.0Hz,6H). 3- (diethylamino) -N- (3 ′, 4′-dimethyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.66 (s, 1H), 8.78 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3, 1.7Hz, 1H), 7.56-7.52 (m, 1H), 7.51-7.45 (m, 1H), 7.37-7.26 (m, 2H), 7.26-7.21 (m, 1H), 7.20-7.14 (m, 1H), 6.90 (dd, J = 8.4, 2.3Hz, 1H), 3.42 (q, J = 7.0Hz, 4H), 2.33 (s, 3H), 2.29 (s, 3H), 1.14 (t, J = 7.0 Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（５－（イソキノリン－４－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.92-10.77(broad,1H),9.44-9.41(m,1H),8.67(d,J=1.7Hz,1H),8.54(s,1H),8.31-8.26(m,1H),7.99-7.93(m,2H),7.90-7.83(m,1H),7.83-7.76(m,1H),7.54(dd,J=8.0,1.7Hz,1H),7.32(dd,J=7.9,7.9Hz,1H),7.24-7.20(m,1H),7.18-7.12(m,1H),6.90(dd,J=8.5,2.4Hz,1H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (5- (isoquinolin-4-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.92-10.77 (broad, 1H), 9.44-9.41 (m, 1H), 8.67 (d, J = 1.7 Hz, 1H), 8.54 (s, 1H), 8.31-8.26 (m, 1H), 7.99-7.93 (m, 2H), 7.90-7.83 (m, 1H), 7.83-7.76 (m, 1H), 7.54 (dd, J = 8.0,1.7Hz, 1H), 7.32 (dd, J = 7.9,7.9Hz, 1H), 7.24-7.20 (m, 1H), 7.18-7.12 (m, 1H), 6.90 (dd, J = 8.5,2.4Hz, 1H), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（２’，３’－ジメチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.50(s,1H),8.41-8.36(m,1H),7.79(d,J=8.3Hz,1H),7.36-7.16(m,5H),7.16-7.06(m,2H),6.94-6.86(m,1H),3.41(q,J=6.9Hz,4H),2.33(s,3H),2.17(s,3H),1.13(t,J=6.9Hz,6H). 3- (diethylamino) -N- (2 ′, 3′-dimethyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.50 (s, 1H), 8.41-8.36 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.36-7.16 (m, 5H), 7.16-7.06 (m, 2H), 6.94-6.86 (m, 1H), 3.41 (q, J = 6.9Hz, 4H), 2.33 (s, 3H), 2.17 (s, 3H), 1.13 (t, J = 6.9Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（２’，６’－ジメチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.90(broad,1H),10.51(s,1H),8.22(d,J=1.7Hz,1H),7.82(d,J=8.0Hz,1H),7.32(dd,J=8.1,8.1Hz,1H),7.25-7.09(m,6H),6.89(dd,J=8.4,2.3Hz,1H),3.41(q,J=7.0Hz,4H),2.04(s,6H),1.12(t,J=7.0Hz,6H). 3- (diethylamino) -N- (2 ′, 6′-dimethyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.90 (broad, 1H), 10.51 (s, 1H), 8.22 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 8.1,8.1Hz, 1H), 7.25-7.09 (m, 6H), 6.89 (dd, J = 8.4,2.3Hz, 1H), 3.41 (q, J = 7.0Hz, 4H ), 2.04 (s, 6H), 1.12 (t, J = 7.0Hz, 6H).
Ｎ－（５－シクロプロピル－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ジエチルアミノ）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.72(broad,1H),10.37(s,1H),8.18(d,J=1.7Hz,1H),7.60(d,J=8.3Hz,1H),7.32(dd,J=7.9,7.9Hz,1H),7.22-7.17(m,1H),7.15-7.09(m,1H),7.05(dd,J=8.3,1.7Hz,1H),6.89(dd,J=8.2,2.3Hz,1H),3.41(q,J=7.0Hz,4H),2.08-1.97(m,1H),1.13(t,J=7.0Hz,6H),1.11-1.04(m,2H),0.82-0.75(m,2H). N- (5-cyclopropyl-2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (diethylamino) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.72 (broad, 1H), 10.37 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 7.9,7.9Hz, 1H), 7.22-7.17 (m, 1H), 7.15-7.09 (m, 1H), 7.05 (dd, J = 8.3,1.7Hz, 1H), 6.89 (dd, J = 8.2,2.3Hz, 1H), 3.41 (q, J = 7.0Hz, 4H), 2.08-1.97 (m, 1H), 1.13 (t, J = 7.0Hz, 6H), 1.11-1.04 ( m, 2H), 0.82-0.75 (m, 2H).
３－（ジエチルアミノ）－Ｎ－（４’－フルオロ－２’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.86(broad,1H),10.54-10.46(broad,1H),8.43-8.37(m,1H),7.79(d,J=8.0Hz,1H),7.37-7.28(m,3H),7.26-7.10(m,4H),6.94-6.86(m,1H),3.41(q,J=7.0Hz,4H),2.31(s,3H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (4′-fluoro-2′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3- Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.86 (broad, 1H), 10.54-10.46 (broad, 1H), 8.43-8.37 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H ), 7.37-7.28 (m, 3H), 7.26-7.10 (m, 4H), 6.94-6.86 (m, 1H), 3.41 (q, J = 7.0Hz, 4H), 2.31 (s, 3H), 1.13 ( t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（５－（２，３－ジヒドロベンゾ［１，４］ジオキシン－６－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.13-12.90(broad,1H),10.48(s,1H),8.72(d,J=1.8Hz,1H),7.77(d,J=8.3Hz,1H),7.61(dd,J=8.3,1.8Hz),7.33(dd,J=7.9,7.9Hz,1H),7.28-7.21(m,3H),7.18-7.12(m,1H),7.04-6.99(m,1H),6.94-6.87(m,1H),4.31(s,4H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (5- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxa Diazol-3-yl) phenyl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.13-12.90 (broad, 1H), 10.48 (s, 1H), 8.72 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.3, 1.8Hz), 7.33 (dd, J = 7.9, 7.9Hz, 1H), 7.28-7.21 (m, 3H), 7.18-7.12 (m, 1H), 7.04-6.99 (m, 1H), 6.94-6.87 (m, 1H), 4.31 (s, 4H), 3.42 (q, J = 7.0Hz, 4H), 1.14 (t, J = 7.0Hz, 6H).
実施例１８０
Figure JPOXMLDOC01-appb-C000171
 　実施例１４８と同様にして、以下の化合物を得た。
３－（ジエチルアミノ）－Ｎ－（４’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.73-8.69(m,1H),7.83-7.78(m,1H),7.69-7.62(m,3H),7.40-7.32(m,3H),7.25-7.21(m,1H),7.20-7.13(m,1H),6.96-6.89(m,1H),3.42(q,J=6.8Hz,4H),2.38(s,3H),1.14(t,J=6.8Hz,6H). Example 180
Figure JPOXMLDOC01-appb-C000171
 In the same manner as in Example 148, the following compound was obtained.
3- (Diethylamino) -N- (4′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.73-8.69 (m, 1H), 7.83-7.78 (m, 1H), 7.69-7.62 (m, 3H), 7.40-7.32 (m, 3H), 7.25-7.21 (m, 1H), 7.20-7.13 (m, 1H), 6.96-6.89 (m, 1H), 3.42 (q, J = 6.8Hz, 4H), 2.38 (s, 3H), 1.14 (t, J = 6.8Hz, 6H).
実施例１８１～２０２
　実施例１８０と同様にして、表２１に示す化合物を得た。 Examples 181 to 202
In the same manner as in Example 180, the compounds shown in Table 21 were obtained.
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
３－（ジエチルアミノ）－Ｎ－（２’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.51-8.47(m,1H),7.75(d,J=8.3Hz,1H),7.49-7.41(m,2H),7.40-7.31(m,2H),7.23-7.07(m,4H),6.95-6.88(m,1H),3.81(s,3H),3.41(q,J=6.9Hz,4H),1.13(t,J=6.9Hz,6H). 3- (Diethylamino) -N- (2′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.51-8.47 (m, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.49-7.41 (m, 2H), 7.40-7.31 (m, 2H), 7.23-7.07 (m, 4H), 6.95-6.88 (m, 1H), 3.81 (s, 3H), 3.41 (q, J = 6.9Hz, 4H), 1.13 (t, J = 6.9 Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（３’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.70-8.66(m,1H),7.82(d,J=8.1Hz,1H),7.68(dd,J=8.1,1.6Hz,1H),7.48(dd,J=7.9,7.9Hz,1H),7.39-7.30(m,2H),7.28-7.21(m,2H),7.19-7.14(m,1H),7.05(dd,J=8.3,2.4Hz,1H),6.97-6.90(m,1H),3.86(s,3H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (3′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.70-8.66 (m, 1H), 7.82 (d, J = 8.1Hz, 1H), 7.68 (dd, J = 8.1, 1.6Hz, 1H ), 7.48 (dd, J = 7.9, 7.9Hz, 1H), 7.39-7.30 (m, 2H), 7.28-7.21 (m, 2H), 7.19-7.14 (m, 1H), 7.05 (dd, J = 8.3 , 2.4Hz, 1H), 6.97-6.90 (m, 1H), 3.86 (s, 3H), 3.42 (q, J = 7.0Hz, 4H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.68-8.63(m,1H),7.79(d,J=8.0Hz,1H),7.75-7.69(m,2H),7.65-7.60(m,1H),7.40-7.33(m,1H),7.25-7.21(m,1H),7.20-7.15(m,1H),7.14-7.09(m,2H),6.97-6.91(m,1H),3.83(s,3H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (4′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.68-8.63 (m, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.75-7.69 (m, 2H), 7.65-7.60 (m, 1H), 7.40-7.33 (m, 1H), 7.25-7.21 (m, 1H), 7.20-7.15 (m, 1H), 7.14-7.09 (m, 2H), 6.97-6.91 (m, 1H) , 3.83 (s, 3H), 3.42 (q, J = 7.0Hz, 4H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－２’－（トリフルオロメトキシ）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.56-10.48(broad,1H),8.58(d,J=1.5Hz,1H),7.83(d,J=8.1Hz,1H),7.67-7.52(m,4H),7.46(dd,J=8.1,1.5Hz,1H),7.37-7.29(m,1H),7.26-7.18(m,1H),7.18-7.10(m,1H),6.96-6.86(m,1H),3.42(q,J=6.9Hz,4H),1.13(t,J=6.9Hz,6H). 3- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -2 '-(trifluoromethoxy) biphenyl-3-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.56-10.48 (broad, 1H), 8.58 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.67-7.52 ( m, 4H), 7.46 (dd, J = 8.1,1.5Hz, 1H), 7.37-7.29 (m, 1H), 7.26-7.18 (m, 1H), 7.18-7.10 (m, 1H), 6.96-6.86 ( m, 1H), 3.42 (q, J = 6.9Hz, 4H), 1.13 (t, J = 6.9Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－３’－（トリフルオロメトキシ）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.53(s,1H),8.77(d,J=1.7Hz,1H),7.87-7.80(m,2H),7.76-7.72(m,2H),7.69(dd,J=7.9,7.9Hz,1H),7.51-7.45(m,1H),7.34(dd,J=7.9,7.9Hz,1H),7.26-7.20(m,1H),7.20-7.12(m,1H),6.95-6.87(m,1H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -3 '-(trifluoromethoxy) biphenyl-3-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.53 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 7.87-7.80 (m, 2H), 7.76-7.72 (m, 2H), 7.69 (dd, J = 7.9,7.9Hz, 1H), 7.51-7.45 (m, 1H), 7.34 (dd, J = 7.9,7.9Hz, 1H), 7.26-7.20 (m, 1H), 7.20-7.12 ( m, 1H), 6.95-6.87 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－４’－（トリフルオロメトキシ）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.57-8.53(m,1H),7.92-7.86(m,2H),7.84(d,J=8.3Hz,1H),7.73(dd,J=8.3,2.0Hz,1H),7.70-7.50(m,5H),7.46-7.30(m,1H),3.54(q,J=7.1Hz,4H),1.10(t,J=7.1Hz,6H). 3- (Diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -4 '-(trifluoromethoxy) biphenyl-3-yl Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.57-8.53 (m, 1H), 7.92-7.86 (m, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.73 (dd , J = 8.3,2.0Hz, 1H), 7.70-7.50 (m, 5H), 7.46-7.30 (m, 1H), 3.54 (q, J = 7.1Hz, 4H), 1.10 (t, J = 7.1Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（２’，３’－ジフルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.80(broad,1H),10.53(s,1H),8.67(s,1H),7.85(d,J=8.0Hz,1H),7.61-7.50(m,2H),7.49-7.42(m,1H),7.42-7.29(m,2H),7.25-7.19(m,1H),7.18-7.11(m,1H),6.96-6.86(m,1H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (diethylamino) -N- (2 ′, 3′-difluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.80 (broad, 1H), 10.53 (s, 1H), 8.67 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.61 7.50 (m, 2H), 7.49-7.42 (m, 1H), 7.42-7.29 (m, 2H), 7.25-7.19 (m, 1H), 7.18-7.11 (m, 1H), 6.96-6.86 (m, 1H ), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（２’，４’－ジフルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.57-10.50(broad,1H),8.65-8.61(m,1H),7.83(d,J=8.0Hz,1H),7.73-7.65(m,1H),7.55-7.49(m,1H),7.49-7.42(m,1H),7.36-7.24(m,2H),7.24-7.19(m,1H),7.17-7.11(m,1H),6.94-6.86(m,1H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (diethylamino) -N- (2 ′, 4′-difluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.57-10.50 (broad, 1H), 8.65-8.61 (m, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.73-7.65 (m, 1H ), 7.55-7.49 (m, 1H), 7.49-7.42 (m, 1H), 7.36-7.24 (m, 2H), 7.24-7.19 (m, 1H), 7.17-7.11 (m, 1H), 6.94-6.86 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（２’，５’－ジフルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.65-8.59(m,1H),7.88-7.83(m,1H),7.60-7.54(m,1H),7.54-7.51(m,2H),7.39-7.32(m,2H),7.24-7.20(m,1H),7.16(d,J=7.6Hz,1H),6.97-6.90(m,1H),3.47-3.38(m,4H),1.17-1.11(m,6H). 3- (diethylamino) -N- (2 ′, 5′-difluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.65-8.59 (m, 1H), 7.88-7.83 (m, 1H), 7.60-7.54 (m, 1H), 7.54-7.51 (m, 2H), 7.39-7.32 (m, 2H), 7.24-7.20 (m, 1H), 7.16 (d, J = 7.6Hz, 1H), 6.97-6.90 (m, 1H), 3.47-3.38 (m, 4H) 1.17-1.11 (m, 6H).
３－（ジエチルアミノ）－Ｎ－（３’，５’－ジフルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.70-8.64(m,1H),7.86-7.80(m,1H),7.75-7.68(m,1H),7.53-7.42(m,2H),7.39-7.27(m,2H),7.25-7.20(m,1H),7.19-7.14(m,1H),6.97-6.90(m,1H),3.46-3.36(m,4H),1.14(t,J=6.8Hz,6H). 3- (diethylamino) -N- (3 ′, 5′-difluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.70-8.64 (m, 1H), 7.86-7.80 (m, 1H), 7.75-7.68 (m, 1H), 7.53-7.42 (m, 2H), 7.39-7.27 (m, 2H), 7.25-7.20 (m, 1H), 7.19-7.14 (m, 1H), 6.97-6.90 (m, 1H), 3.46-3.36 (m, 4H), 1.14 ( t, J = 6.8Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（３’，４’－ジフルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.70-8.65(m,1H),7.88-7.79(m,2H),7.70-7.65(m,1H),7.65-7.55(m,2H),7.38-7.32(m,1H),7.25-7.20(m,1H),7.19-7.13(m,1H),6.96-6.90(m,1H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (diethylamino) -N- (3 ′, 4′-difluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.70-8.65 (m, 1H), 7.88-7.79 (m, 2H), 7.70-7.65 (m, 1H), 7.65-7.55 (m, 2H), 7.38-7.32 (m, 1H), 7.25-7.20 (m, 1H), 7.19-7.13 (m, 1H), 6.96-6.90 (m, 1H), 3.42 (q, J = 7.0Hz, 4H) , 1.13 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（３’－エトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.17-12.90(broad,1H),10.50(s,1H),8.75(d,J=1.7Hz,1H),7.81(d,J=8.2Hz,1H),7.68(dd,J=8.2,1.7Hz,1H),7.44(dd,J=7.9,7.9Hz,1H),7.37-7.28(m,2H),7.28-7.20(m,2H),7.20-7.12(m,1H),7.06-6.99(m,1H),6.95-6.86(m,1H),4.13(q,J=6.9Hz,2H),3.42(q,J=7.0Hz,4H),1.37(t,J=6.9Hz,3H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (3′-ethoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.17-12.90 (broad, 1H), 10.50 (s, 1H), 8.75 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.68 (dd, J = 8.2, 1.7Hz, 1H), 7.44 (dd, J = 7.9, 7.9Hz, 1H), 7.37-7.28 (m, 2H), 7.28-7.20 (m, 2H), 7.20 -7.12 (m, 1H), 7.06-6.99 (m, 1H), 6.95-6.86 (m, 1H), 4.13 (q, J = 6.9Hz, 2H), 3.42 (q, J = 7.0Hz, 4H), 1.37 (t, J = 6.9Hz, 3H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（２’－エトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.90(broad,1H),10.44(s,1H),8.63(d,J=1.7Hz,1H),7.75(d,J=8.3Hz,1H),7.50(dd,J=8.3,1.7Hz,1H),7.43-7.37(m,2H),7.35-7.29(m,1H),7.23-7.19(m,1H),7.18-7.11(m,2H),7.11-7.04(m,1H),6.90(dd,J=8.3,1.9Hz,1H),4.10(q,J=7.0Hz,2H),3.42(q,J=7.0Hz,4H),1.30(t,J=7.0Hz,3H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (2′-ethoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.90 (broad, 1H), 10.44 (s, 1H), 8.63 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.3, 1.7Hz, 1H), 7.43-7.37 (m, 2H), 7.35-7.29 (m, 1H), 7.23-7.19 (m, 1H), 7.18-7.11 (m, 2H), 7.11-7.04 (m, 1H), 6.90 (dd, J = 8.3, 1.9Hz, 1H), 4.10 (q, J = 7.0Hz, 2H), 3.42 (q, J = 7.0Hz, 4H), 1.30 (t, J = 7.0Hz, 3H), 1.13 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（３’，４’，５’－トリフルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.53-10.48(broad,1H),8.72(d,J=1.7Hz,1H),7.86-7.70(m,4H),7.34(dd,J=8.1,8.1Hz,1H),7.25-7.20(m,1H),7.19-7.12(m,1H),6.95-6.87(m,1H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (3 ′, 4 ′, 5′-trifluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl- 3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.53-10.48 (broad, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.86-7.70 (m, 4H), 7.34 (dd, J = 8.1 , 8.1Hz, 1H), 7.25-7.20 (m, 1H), 7.19-7.12 (m, 1H), 6.95-6.87 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, (J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（５－（３－メチルピリジン－４－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.68-10.58(broad,1H),8.59(s,1H),8.53(d,J=5.1Hz,1H),8.49(d,J=1.7Hz,1H),7.85(d,J=8.2Hz,1H),7.43(dd,J=8.2,1.7Hz,1H),7.37-7.29(m,2H),7.23-7.18(m,1H),7.16-7.10(m,1H),6.90(dd,J=8.4,2.3Hz,1H),3.41(q,J=7.0Hz,4H),2.33(s,3H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (5- (3-methylpyridin-4-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.68-10.58 (broad, 1H), 8.59 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 8.2Hz, 1H), 7.43 (dd, J = 8.2, 1.7Hz, 1H), 7.37-7.29 (m, 2H), 7.23-7.18 (m, 1H), 7.16-7.10 (m, 1H), 6.90 (dd, J = 8.4,2.3Hz, 1H), 3.41 (q, J = 7.0Hz, 4H), 2.33 (s, 3H), 1.13 (t, J = 7.0Hz, 6H) .
３－（ジエチルアミノ）－Ｎ－（５－（２－メトキシピリジン－３－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.51-10.55(broad,1H),8.60(d,J=1.8Hz,1H),8.26(dd,J=5.0,1.8Hz,1H),7.85(dd,J=7.5,1.8Hz,1H),7.78(d,J=8.1Hz,1H),7.55(dd,J=8.1,1.8Hz,1H),7.33(dd,J=7.9,7.9Hz,1H),7.24-7.19(m,1H),7.19-7.11(m,2H),6.94-6.86(m,1H),3.92(s,3H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (5- (2-methoxypyridin-3-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.51-10.55 (broad, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.26 (dd, J = 5.0 , 1.8Hz, 1H), 7.85 (dd, J = 7.5,1.8Hz, 1H), 7.78 (d, J = 8.1Hz, 1H), 7.55 (dd, J = 8.1,1.8Hz, 1H), 7.33 (dd , J = 7.9,7.9Hz, 1H), 7.24-7.19 (m, 1H), 7.19-7.11 (m, 2H), 6.94-6.86 (m, 1H), 3.92 (s, 3H), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H).
Ｎ－（４’－ブトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.15-12.90(m,1H),10.52-10.46(broad,1H),8.75(d,J=1.8Hz,1H),7.79(d,J=8.3Hz,1H),7.74-7.65(m,2H),7.63(dd,J=8.3,1.8Hz,1H),7.37-7.30(m,1H),7.26-7.20(m,1H),7.20-7.13(m,1H),7.13-7.04(m,2H),6.95-6.86(m,1H),4.04(t,J=6.5Hz,2H),3.47-3.37(m,4H),1.79-1.68(m,2H),1.53-1.40(m,2H),1.14(t,J=7.0Hz,6H),0.95(t,J=7.3Hz,3H). N- (4′-butoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (diethylamino) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.15-12.90 (m, 1H), 10.52-10.46 (broad, 1H), 8.75 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.74-7.65 (m, 2H), 7.63 (dd, J = 8.3,1.8Hz, 1H), 7.37-7.30 (m, 1H), 7.26-7.20 (m, 1H), 7.20-7.13 ( m, 1H), 7.13-7.04 (m, 2H), 6.95-6.86 (m, 1H), 4.04 (t, J = 6.5Hz, 2H), 3.47-3.37 (m, 4H), 1.79-1.68 (m, 2H), 1.53-1.40 (m, 2H), 1.14 (t, J = 7.0Hz, 6H), 0.95 (t, J = 7.3Hz, 3H).
３－（ジエチルアミノ）－Ｎ－（５－（１Ｈ－インドール－４－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),11.38(s,1H),10.54-10.48(broad,1H),8.84(d,J=1.7Hz,1H),7.85(d,J=8.3Hz,1H),7.65(dd,J=8.3,1.7Hz,1H),7.53-7.47(m,2H),7.37-7.30(m,1H),7.27-7.21(m,3H),7.19-7.14(m,1H),6.96-6.86(m,1H),6.80-6.76(m,1H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (5- (1H-indol-4-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 11.38 (s, 1H), 10.54-10.48 (broad, 1H), 8.84 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 8.3Hz, 1H), 7.65 (dd, J = 8.3,1.7Hz, 1H), 7.53-7.47 (m, 2H), 7.37-7.30 (m, 1H), 7.27-7.21 (m, 3H), 7.19-7.14 (m, 1H), 6.96-6.86 (m, 1H), 6.80-6.76 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 1.14 (t, J = 7.0Hz , 6H).
Ｎ－（３’－クロロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.22-12.86(broad,1H),10.57-10.50(broad,1H),8.77(d,J=1.7Hz,1H),7.86-7.79(m,2H),7.77-7.70(m,2H),7.61-7.51(m,2H),7.34(dd,J=7.9,7.9Hz,1H),7.26-7.20(m,1H),7.19-7.13(m,1H),6.91(dd,J=8.5,2.2Hz,1H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). N- (3′-chloro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (diethylamino) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.22-12.86 (broad, 1H), 10.57-10.50 (broad, 1H), 8.77 (d, J = 1.7Hz, 1H), 7.86-7.79 (m, 2H) ), 7.77-7.70 (m, 2H), 7.61-7.51 (m, 2H), 7.34 (dd, J = 7.9, 7.9Hz, 1H), 7.26-7.20 (m, 1H), 7.19-7.13 (m, 1H ), 6.91 (dd, J = 8.5, 2.2 Hz, 1 H), 3.42 (q, J = 7.0 Hz, 4 H), 1.14 (t, J = 7.0 Hz, 6 H).
Ｎ－（４’－クロロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.62-10.50(broad,1H),8.81-8.76(m,1H),7.89-7.77(m,3H),7.71-7.65(m,1H),7.63-7.58(m,2H),7.37-7.30(m,1H),7.26-7.21(m,1H),7.19-7.12(m,1H),6.95-6.87(m,1H),3.47-3.37(m,4H),1.17-1.10(m,6H). N- (4′-chloro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (diethylamino) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.62-10.50 (broad, 1H), 8.81-8.76 (m, 1H), 7.89-7.77 (m, 3H), 7.71-7.65 (m, 1H), 7.63 -7.58 (m, 2H), 7.37-7.30 (m, 1H), 7.26-7.21 (m, 1H), 7.19-7.12 (m, 1H), 6.95-6.87 (m, 1H), 3.47-3.37 (m, 4H), 1.17-1.10 (m, 6H).
３－（ジエチルアミノ）－Ｎ－（３’－フルオロ－４’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.22-12.84(broad,1H),10.50(s,1H),8.77(d,J=1.7Hz,1H),7.81(d,J=8.2Hz,1H),7.69(dd,J=8.2,1.7Hz,1H),7.59-7.50(m,2H),7.45(dd,J=7.9Hz,7.9Hz,1H),7.34(dd,J=7.9,7.9Hz,1H),7.26-7.21(m,1H),7.19-7.13(m,1H),6.95-6.87(m,1H),3.42(q,J=7.0Hz,4H),2.34-2.28(m,3H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (3′-fluoro-4′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3- Il) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.22-12.84 (broad, 1H), 10.50 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.69 (dd, J = 8.2, 1.7Hz, 1H), 7.59-7.50 (m, 2H), 7.45 (dd, J = 7.9Hz, 7.9Hz, 1H), 7.34 (dd, J = 7.9, 7.9 Hz, 1H), 7.26-7.21 (m, 1H), 7.19-7.13 (m, 1H), 6.95-6.87 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 2.34-2.28 (m, 3H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（２’，３’－ジメトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.16-12.88(broad,1H),10.47(s,1H),8.56(d,J=1.7Hz,1H),7.78(d,J=8.2Hz,1H),7.45(dd,J=8.2,1.7Hz,1H),7.32(dd,J=7.9,7.9Hz,1H),7.24-7.11(m,4H),6.99(dd,J=7.4,1.8Hz,1H),6.93-6.87(m,1H),3.87(s,3H),3.63(s,3H),3.42(q,J=7.0Hz,4H),1.13(t,J=7.0Hz,6H). 3- (diethylamino) -N- (2 ′, 3′-dimethoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.16-12.88 (broad, 1H), 10.47 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.45 (dd, J = 8.2,1.7Hz, 1H), 7.32 (dd, J = 7.9,7.9Hz, 1H), 7.24-7.11 (m, 4H), 6.99 (dd, J = 7.4,1.8Hz , 1H), 6.93-6.87 (m, 1H), 3.87 (s, 3H), 3.63 (s, 3H), 3.42 (q, J = 7.0Hz, 4H), 1.13 (t, J = 7.0Hz, 6H) .
実施例２０３
Figure JPOXMLDOC01-appb-C000173
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ジエチルアミノ）ベンズアミド98mgに３－フルオロフェニルボロン酸54mg、炭酸カリウム0.10g、ジオキサン0.50mL、水0.10mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物の有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、Ｎ－（４－シアノ－３’－フルオロビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミドを得た。
　得られたＮ－（４－シアノ－３’－フルオロビフェニル－３－イル）－３－（ジエチルアミノ）ベンズアミドにテトラヒドロフラン2.0mLおよび50％ヒドロキシルアミン水溶液0.10mLを加え、60℃で1時間30分間攪拌した。減圧下で溶媒を留去後、メタノールを加え、固形物をろ取した。得られた固形物にテトラヒドロフラン2.0mL、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.12mLおよび１，１’－カルボニルジイミダゾール0.13gを順次加え、室温で30分間攪拌した。反応混合物に水および酢酸エチルを加え、10％クエン酸水溶液でpH4.0に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、固形物をろ取し、淡黄色固体の３－（ジエチルアミノ）－Ｎ－（３’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド78mgを得た。
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.52(s,1H),8.78(d,J=1.7Hz,1H),7.84(d,J=8.3Hz,1H),7.72(dd,J=8.3,1.7Hz,1H),7.65-7.55(m,3H),7.38-7.27(m,2H),7.26-7.21(m,1H),7.20-7.13(m,1H),6.95-6.87(m,1H),3.42(q,J=7.1Hz,4H),1.17-1.11(m,6H). Example 203
Figure JPOXMLDOC01-appb-C000173
 N- (5-chloro-2-cyanophenyl) -3- (diethylamino) benzamide 98 mg, 3-fluorophenylboronic acid 54 mg, potassium carbonate 0.10 g, dioxane 0.50 mL, water 0.10 mL and bis (di-tert-butyl ( 4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. The organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (4-cyano-3′-fluorobiphenyl -3-yl) -3- (diethylamino) benzamide was obtained.
To the obtained N- (4-cyano-3′-fluorobiphenyl-3-yl) -3- (diethylamino) benzamide, 2.0 mL of tetrahydrofuran and 0.10 mL of 50% hydroxylamine aqueous solution were added, and the mixture was stirred at 60 ° C. for 1 hour and 30 minutes. did. After the solvent was distilled off under reduced pressure, methanol was added and the solid was collected by filtration. To the obtained solid, 2.0 mL of tetrahydrofuran, 0.12 mL of 1,8-diazabicyclo [5.4.0] -7-undecene and 0.13 g of 1,1′-carbonyldiimidazole were sequentially added, followed by stirring at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the pH was adjusted to 4.0 with a 10% aqueous citric acid solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, the solid was collected by filtration, and 3- (diethylamino) -N- (3′-fluoro-4- (5-oxo-4,5-dihydro-1) was obtained as a pale yellow solid. 78 mg of 2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide were obtained.
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.52 (s, 1H), 8.78 (d, J = 1.7 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.72 (dd, J = 8.3, 1.7Hz, 1H), 7.65-7.55 (m, 3H), 7.38-7.27 (m, 2H), 7.26-7.21 (m, 1H), 7.20-7.13 (m, 1H), 6.95-6.87 (m, 1H), 3.42 (q, J = 7.1 Hz, 4H), 1.17-1.11 (m, 6H).
実施例２０４、２０５
　実施例２０３と同様にして、表２２に示す化合物を得た。 Examples 204 and 205
In the same manner as in Example 203, the compounds shown in Table 22 were obtained.
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
３－（ジエチルアミノ）－Ｎ－（４’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.80(broad,1H),10.56-10.47(broad,1H),8.81-8.74(m,1H),7.87-7.78(m,3H),7.70-7.64(m,1H),7.43-7.30(m,3H),7.28-7.21(m,1H),7.20-7.13(m,1H),6.97-6.88(m,1H),3.42(q,J=7.0Hz,4H),1.14(t,J=7.0Hz,6H). 3- (Diethylamino) -N- (4′-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.80 (broad, 1H), 10.56-10.47 (broad, 1H), 8.81-8.74 (m, 1H), 7.87-7.78 (m, 3H), 7.70 -7.64 (m, 1H), 7.43-7.30 (m, 3H), 7.28-7.21 (m, 1H), 7.20-7.13 (m, 1H), 6.97-6.88 (m, 1H), 3.42 (q, J = 7.0Hz, 4H), 1.14 (t, J = 7.0Hz, 6H).
３－（ジエチルアミノ）－Ｎ－（５－（１Ｈ－インドール－６－イル）－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.90(broad,1H),11.29(s,1H),10.68-10.56(broad,1H),8.90(d,J=1.7Hz,1H),7.85-7.77(m,2H),7.72-7.65(m,2H),7.46(dd,J=2.8,2.8Hz,1H),7.43(dd,J=8.4,1.6Hz,1H),7.37-7.31(m,1H),7.27-7.24(m,1H),7.20-7.16(m,1H),6.94-6.88(m,1H),6.52-6.47(m,1H),3.47-3.38(m,4H),1.17-1.11(m,6H). 3- (Diethylamino) -N- (5- (1H-indol-6-yl) -2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.90 (broad, 1H), 11.29 (s, 1H), 10.68-10.56 (broad, 1H), 8.90 (d, J = 1.7Hz, 1H), 7.85-7.77 (m, 2H), 7.72-7.65 (m, 2H), 7.46 (dd, J = 2.8,2.8Hz, 1H), 7.43 (dd, J = 8.4,1.6Hz, 1H), 7.37-7.31 ( m, 1H), 7.27-7.24 (m, 1H), 7.20-7.16 (m, 1H), 6.94-6.88 (m, 1H), 6.52-6.47 (m, 1H), 3.47-3.38 (m, 4H), 1.17-1.11 (m, 6H).
実施例２０６
Figure JPOXMLDOC01-appb-C000175
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド0.20gに１－シクロヘキセンボロン酸98mg、炭酸カリウム0.20g、ジオキサン1.60mL、水0.40mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド10mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物に１－シクロヘキセンボロン酸38mgおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物の有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、Ｎ－（２－シアノ－５－（シクロヘキセン－１－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミドを得た。
　得られたＮ－（２－シアノ－５－（シクロヘキセン－１－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミドのテトラヒドロフラン15mLおよびメタノール5.0mL混液に、10％パラジウム－炭素18mgを加え、水素雰囲気下、室温で1時間攪拌した。反応混合物に10％パラジウム－炭素18mgを加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、Ｎ－（２－シアノ－５－シクロヘキシルフェニル）－３－（ピペリジン－１－イル）ベンズアミドを得た。
　得られたＮ－（２－シアノ－５－シクロヘキシルフェニル）－３－（ピペリジン－１－イル）ベンズアミドにテトラヒドロフラン0.50mL、ヒドロキシルアミン塩酸塩23mgおよび１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLを加え、マイクロウェーブ照射下90℃で4分間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で1時間攪拌した。反応混合物に１，１’－カルボニルジイミダゾール0.13gを加え、室温で1時間攪拌した。反応混合物に水2.0mL、酢酸エチル0.5mLおよび10％クエン酸水溶液2.5mLを加えた。有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；15-0％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（５－シクロヘキシル－２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド17mgを得た。
1H-NMR(DMSO-d6)δ値：10.41-10.35(broad,1H),8.21-8.16(m,1H),7.63(d,J=8.3Hz,1H),7.51-7.46(m,1H),7.37(dd,J=7.9,7.9Hz,1H),7.32-7.27(m,1H),7.25-7.20(m,1H),7.20-7.15(m,1H),3.28-3.21(m,4H),2.65-2.56(m,1H),1.88-1.77(m,4H),1.76-1.69(m,1H),1.68-1.53(m,6H),1.50-1.33(m,4H),1.32-1.20(m,1H). Example 206
Figure JPOXMLDOC01-appb-C000175
 N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide (0.20 g), 1-cyclohexeneboronic acid (98 mg), potassium carbonate (0.20 g), dioxane (1.60 mL), water (0.40 mL) and bis (di- 10 mg of tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. To the reaction mixture, 1-cyclohexeneboronic acid (38 mg) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) were added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. The organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (2-cyano-5- (cyclohexene- 1-yl) phenyl) -3- (piperidin-1-yl) benzamide was obtained.
To the obtained N- (2-cyano-5- (cyclohexen-1-yl) phenyl) -3- (piperidin-1-yl) benzamide in 15 mL of tetrahydrofuran and 5.0 mL of methanol was added 18 mg of 10% palladium-carbon. The mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. To the reaction mixture, 10% palladium-carbon (18 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to give N- (2-cyano-5-cyclohexylphenyl) -3- (piperidin-1-yl) benzamide.
To the obtained N- (2-cyano-5-cyclohexylphenyl) -3- (piperidin-1-yl) benzamide, 0.50 mL of tetrahydrofuran, 23 mg of hydroxylamine hydrochloride and 1,8-diazabicyclo [5.4.0]- 0.10 mL of 7-undecene was added and stirred at 90 ° C. for 4 minutes under microwave irradiation. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. To the reaction mixture, 0.13 g of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 1 hour. To the reaction mixture were added 2.0 mL of water, 0.5 mL of ethyl acetate, and 2.5 mL of 10% aqueous citric acid solution. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 15-0% hexane / ethyl acetate], and white solid N- (5-cyclohexyl-2- 17 mg of (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl) -3- (piperidin-1-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 10.41-10.35 (broad, 1H), 8.21-8.16 (m, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.51-7.46 (m, 1H ), 7.37 (dd, J = 7.9, 7.9Hz, 1H), 7.32-7.27 (m, 1H), 7.25-7.20 (m, 1H), 7.20-7.15 (m, 1H), 3.28-3.21 (m, 4H ), 2.65-2.56 (m, 1H), 1.88-1.77 (m, 4H), 1.76-1.69 (m, 1H), 1.68-1.53 (m, 6H), 1.50-1.33 (m, 4H), 1.32-1.20 (m, 1H).
実施例２０７
Figure JPOXMLDOC01-appb-C000176
 　実施例１２７と同様にして、以下の化合物を得た。
Ｎ－（２’－フルオロ－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.80(broad,1H),10.57-10.50(broad,1H),8.41(d,J=8.5Hz,1H),7.95-7.92(m,1H),7.89-7.83(m,1H),7.68-7.61(m,1H),7.53-7.44(m,2H),7.42-7.30(m,4H),7.24-7.16(m,1H),3.29-3.22(m,4H),1.70-1.62(m,4H),1.62-1.53(m,2H). Example 207
Figure JPOXMLDOC01-appb-C000176
 In the same manner as in Example 127, the following compound was obtained.
N- (2'-Fluoro-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.80 (broad, 1H), 10.57-10.50 (broad, 1H), 8.41 (d, J = 8.5Hz, 1H), 7.95-7.92 (m, 1H) ), 7.89-7.83 (m, 1H), 7.68-7.61 (m, 1H), 7.53-7.44 (m, 2H), 7.42-7.30 (m, 4H), 7.24-7.16 (m, 1H), 3.29-3.22 (m, 4H), 1.70-1.62 (m, 4H), 1.62-1.53 (m, 2H).
実施例２０８～２１５
　実施例２０７と同様にして、表２３に示す化合物を得た。 Examples 208-215
In the same manner as in Example 207, the compounds shown in Table 23 were obtained.
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Ｎ－（３’－フルオロ－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.90(broad,1H),10.62-10.53(broad,1H),8.49(d,J=8.5Hz,1H),8.11(d,J=2.2Hz,1H),8.04(dd,J=8.8,2.2Hz,1H),7.70-7.63(m,2H),7.61-7.52(m,1H),7.52-7.48(m,1H),7.42-7.35(m,1H),7.35-7.29(m,1H),7.29-7.16(m,2H),3.29-3.22(m,4H),1.71-1.62(m,4H),1.62-1.54(m,2H). N- (3′-fluoro-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.90 (broad, 1H), 10.62-10.53 (broad, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 8.8, 2.2Hz, 1H), 7.70-7.63 (m, 2H), 7.61-7.52 (m, 1H), 7.52-7.48 (m, 1H), 7.42-7.35 ( m, 1H), 7.35-7.29 (m, 1H), 7.29-7.16 (m, 2H), 3.29-3.22 (m, 4H), 1.71-1.62 (m, 4H), 1.62-1.54 (m, 2H).
Ｎ－（４’－フルオロ－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.25-12.90(broad,1H),10.57-10.48(broad,1H),8.45(d,J=8.8Hz,1H),8.05(d,J=2.2Hz,1H),7.97(dd,J=8.5,2.2Hz,1H),7.87-7.80(m,2H),7.51-7.48(m,1H),7.41-7.29(m,4H),7.22-7.17(m,1H),3.29-3.21(m,4H),1.70-1.62(m,4H),1.62-1.53(m,2H). N- (4′-Fluoro-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.25-12.90 (broad, 1H), 10.57-10.48 (broad, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.5, 2.2Hz, 1H), 7.87-7.80 (m, 2H), 7.51-7.48 (m, 1H), 7.41-7.29 (m, 4H), 7.22-7.17 ( m, 1H), 3.29-3.21 (m, 4H), 1.70-1.62 (m, 4H), 1.62-1.53 (m, 2H).
Ｎ－（２’－メチル－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.70(broad,1H),10.52-10.47(broad,1H),8.39(d,J=8.6Hz,1H),7.72(d,J=1.9Hz,1H),7.66(dd,J=8.5,2.2Hz,1H),7.52-7.49(m,1H),7.42-7.26(m,6H),7.23-7.17(m,1H),3.29-3.22(m,4H),2.30(s,3H),1.70-1.62(m,4H),1.62-1.54(m,2H). N- (2′-Methyl-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.70 (broad, 1H), 10.52-10.47 (broad, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.66 (dd, J = 8.5,2.2Hz, 1H), 7.52-7.49 (m, 1H), 7.42-7.26 (m, 6H), 7.23-7.17 (m, 1H), 3.29-3.22 ( m, 4H), 2.30 (s, 3H), 1.70-1.62 (m, 4H), 1.62-1.54 (m, 2H).
Ｎ－（３’－メチル－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.90(broad,1H),10.56(s,1H),8.45(d,J=8.8Hz,1H),8.05(d,J=2.2Hz,1H),7.97(dd,J=8.7,2.1Hz,1H),7.63-7.53(m,2H),7.52-7.48(m,1H),7.43-7.35(m,2H),7.35-7.26(m,1H),7.25-7.16(m,2H),3.29-3.22(m,4H),2.41(s,3H),1.70-1.62(m,4H),1.62-1.53(m,2H). N- (3′-methyl-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.90 (broad, 1H), 10.56 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.7, 2.1Hz, 1H), 7.63-7.53 (m, 2H), 7.52-7.48 (m, 1H), 7.43-7.35 (m, 2H), 7.35-7.26 (m, 1H), 7.25-7.16 (m, 2H), 3.29-3.22 (m, 4H), 2.41 (s, 3H), 1.70-1.62 (m, 4H), 1.62-1.53 (m, 2H).
Ｎ－（４’－メチル－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.90(broad,1H),10.56(s,1H),8.44(d,J=8.8Hz,1H),8.05(d,J=2.0Hz,1H),7.95(dd,J=8.6,2.1Hz,1H),7.72-7.65(m,2H),7.52-7.48(m,1H),7.41-7.29(m,4H),7.22-7.16(m,1H),3.29-3.21(m,4H),2.37(s,3H),1.70-1.62(m,4H),1.62-1.52(m,2H). N- (4′-Methyl-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.90 (broad, 1H), 10.56 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 8.6, 2.1Hz, 1H), 7.72-7.65 (m, 2H), 7.52-7.48 (m, 1H), 7.41-7.29 (m, 4H), 7.22-7.16 (m, 1H), 3.29-3.21 (m, 4H), 2.37 (s, 3H), 1.70-1.62 (m, 4H), 1.62-1.52 (m, 2H).
Ｎ－（２’－メトキシ－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.10-12.80(broad,1H),10.53-10.43(broad,1H),8.31(d,J=8.8Hz,1H),7.84(d,J=2.0Hz,1H),7.78(dd,J=8.5,2.0Hz,1H),7.52-7.48(m,1H),7.43-7.29(m,4H),7.22-7.13(m,2H),7.11-7.05(m,1H),3.81(s,3H),3.29-3.21(m,4H),1.70-1.62(m,4H),1.62-1.53(m,2H). N- (2′-methoxy-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.10-12.80 (broad, 1H), 10.53-10.43 (broad, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.5, 2.0Hz, 1H), 7.52-7.48 (m, 1H), 7.43-7.29 (m, 4H), 7.22-7.13 (m, 2H), 7.11-7.05 ( m, 1H), 3.81 (s, 3H), 3.29-3.21 (m, 4H), 1.70-1.62 (m, 4H), 1.62-1.53 (m, 2H).
Ｎ－（３’－メトキシ－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.25-12.90(broad,1H),10.56-10.48(broad,1H),8.45(d,J=8.3Hz,1H),8.09-8.05(m,1H),8.03-7.97(m,1H),7.53-7.48(m,1H),7.47-7.30(m,5H),7.23-7.16(m,1H),7.03-6.96(m,1H),3.86(s,3H),3.30-3.22(m,4H),1.71-1.62(m,4H),1.62-1.54(m,2H). N- (3′-methoxy-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.25-12.90 (broad, 1H), 10.56-10.48 (broad, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.09-8.05 (m, 1H ), 8.03-7.97 (m, 1H), 7.53-7.48 (m, 1H), 7.47-7.30 (m, 5H), 7.23-7.16 (m, 1H), 7.03-6.96 (m, 1H), 3.86 (s) 3H), 3.30-3.22 (m, 4H), 1.71-1.62 (m, 4H), 1.62-1.54 (m, 2H).
Ｎ－（４’－メトキシ－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.90(broad,1H),10.53-10.46(broad,1H),8.40(d,J=8.8Hz,1H),8.01(d,J=2.0Hz,1H),7.93(dd,J=8.8,2.2Hz,1H),7.76-7.70(m,2H),7.51-7.48(m,1H),7.41-7.29(m,2H),7.21-7.16(m,1H),7.11-7.05(m,2H),3.82(s,3H),3.29-3.22(m,4H),1.70-1.62(m,4H),1.62-1.53(m,2H). N- (4′-methoxy-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.90 (broad, 1H), 10.53-10.46 (broad, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 8.8,2.2Hz, 1H), 7.76-7.70 (m, 2H), 7.51-7.48 (m, 1H), 7.41-7.29 (m, 2H), 7.21-7.16 ( m, 1H), 7.11-7.05 (m, 2H), 3.82 (s, 3H), 3.29-3.22 (m, 4H), 1.70-1.62 (m, 4H), 1.62-1.53 (m, 2H).
実施例２１６
Figure JPOXMLDOC01-appb-C000178
 　Ｎ－（５－クロロ－２－シアノフェニル）－３－（ピペリジン－１－イル）ベンズアミド0.10gに２－メチルフェニルボロン酸53mg、炭酸カリウム0.10g、ジオキサン0.80mL、水0.20mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物の有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、Ｎ－（４－シアノ－２’－メチルビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドを得た。
　得られたＮ－（４－シアノ－２’－メチルビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドに１－メチル－２－ピロリドン0.30mL、トリエチルアミン塩酸塩0.21gおよびアジ化ナトリウム98mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物に酢酸エチル2.0mLおよび10％クエン酸水溶液2.0mLを加え、有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；70-50％ヘキサン／酢酸エチル］で精製し、白色固体のＮ－（２’－メチル－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド83mgを得た。
1H-NMR(DMSO-d6)δ値：11.76(s,1H),8.70(d,J=1.7Hz,1H),8.10(d,J=8.0Hz,1H),7.68-7.62(m,1H),7.46-7.28(m,7H),7.26-7.20(m,1H),3.34-3.26(m,4H),2.33(s,3H),1.72-1.63(m,4H),1.63-1.53(m,2H). Example 216
Figure JPOXMLDOC01-appb-C000178
 To 0.10 g of N- (5-chloro-2-cyanophenyl) -3- (piperidin-1-yl) benzamide, 53 mg of 2-methylphenylboronic acid, 0.10 g of potassium carbonate, 0.80 mL of dioxane, 0.20 mL of water and bis (di -Tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (5 mg) was added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. The organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and N- (4-cyano-2′-methylbiphenyl). -3-yl) -3- (piperidin-1-yl) benzamide was obtained.
To the obtained N- (4-cyano-2′-methylbiphenyl-3-yl) -3- (piperidin-1-yl) benzamide, 0.30 mL of 1-methyl-2-pyrrolidone, 0.21 g of triethylamine hydrochloride and azide Sodium 98mg was added and it stirred at 150 degreeC under microwave irradiation for 10 minutes. To the reaction mixture, 2.0 mL of ethyl acetate and 2.0 mL of 10% aqueous citric acid solution were added, and the organic layer was subjected to silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-50% hexane / ethyl acetate]. Purification gave 83 mg of N- (2′-methyl-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide as a white solid.
1 H-NMR (DMSO-d 6 ) δ value: 11.76 (s, 1H), 8.70 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.68-7.62 (m, 1H), 7.46-7.28 (m, 7H), 7.26-7.20 (m, 1H), 3.34-3.26 (m, 4H), 2.33 (s, 3H), 1.72-1.63 (m, 4H), 1.63-1.53 ( m, 2H).
実施例２１７～２２４
　実施例２１６と同様にして、表２４に示す化合物を得た。 Examples 217-224
In the same manner as in Example 216, the compounds shown in Table 24 were obtained.
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Ｎ－（２’－フルオロ－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.81-11.75(broad,1H),8.96-8.90(m,1H),8.14(d,J=8.0Hz,1H),7.69-7.66(m,1H),7.64(dd,J=8.0,1.7Hz,1H),7.59-7.48(m,2H),7.47-7.35(m,4H),7.27-7.20(m,1H),3.34-3.27(m,4H),1.71-1.63(m,4H),1.63-1.54(m,2H). N- (2′-Fluoro-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.81-11.75 (broad, 1H), 8.96-8.90 (m, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.69-7.66 (m, 1H ), 7.64 (dd, J = 8.0, 1.7Hz, 1H), 7.59-7.48 (m, 2H), 7.47-7.35 (m, 4H), 7.27-7.20 (m, 1H), 3.34-3.27 (m, 4H ), 1.71-1.63 (m, 4H), 1.63-1.54 (m, 2H).
Ｎ－（３’－フルオロ－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.78(s,1H),9.05(d,J=1.8Hz,1H),8.14(d,J=8.3Hz,1H),7.74(dd,J=8.3,1.8Hz,1H),7.70-7.66(m,1H),7.65-7.56(m,3H),7.49-7.40(m,2H),7.34-7.27(m,1H),7.27-7.21(m,1H),3.34-3.27(m,4H),1.72-1.63(m,4H),1.63-1.54(m,2H). N- (3′-fluoro-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.78 (s, 1H), 9.05 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.74 (dd, J = 8.3,1.8Hz, 1H), 7.70-7.66 (m, 1H), 7.65-7.56 (m, 3H), 7.49-7.40 (m, 2H), 7.34-7.27 (m, 1H), 7.27-7.21 (m, 1H), 3.34-3.27 (m, 4H), 1.72-1.63 (m, 4H), 1.63-1.54 (m, 2H).
Ｎ－（４’－フルオロ－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.88(s,1H),9.04(d,J=2.0Hz,1H),8.14(d,J=8.3Hz,1H),7.85-7.78(m,2H),7.70-7.64(m,2H),7.49-7.34(m,4H),7.26-7.19(m,1H),3.34-3.26(m,4H),1.71-1.63(m,4H),1.63-1.54(m,2H). N- (4′-fluoro-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.88 (s, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.85-7.78 (m, 2H), 7.70-7.64 (m, 2H), 7.49-7.34 (m, 4H), 7.26-7.19 (m, 1H), 3.34-3.26 (m, 4H), 1.71-1.63 (m, 4H), 1.63- 1.54 (m, 2H).
Ｎ－（３’－メチル－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.77(s,1H),9.03(d,J=2.0Hz,1H),8.12(d,J=8.3Hz,1H),7.71-7.65(m,2H),7.60-7.53(m,2H),7.49-7.39(m,3H),7.31-7.21(m,2H),3.35-3.28(m,4H),2.43(s,3H),1.72-1.63(m,4H),1.63-1.54(m,2H). N- (3′-methyl-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.77 (s, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.71-7.65 (m, 2H), 7.60-7.53 (m, 2H), 7.49-7.39 (m, 3H), 7.31-7.21 (m, 2H), 3.35-3.28 (m, 4H), 2.43 (s, 3H), 1.72-1.63 ( m, 4H), 1.63-1.54 (m, 2H).
Ｎ－（４’－メチル－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.81-11.76(broad,1H),9.04(d,J=1.7Hz,1H),8.11(d,J=8.3Hz,1H),7.71-7.65(m,4H),7.49-7.39(m,2H),7.39-7.33(m,2H),7.26-7.20(m,1H),3.35-3.28(m,4H),2.39(s,3H),1.72-1.63(m,4H),1.63-1.55(m,2H). N- (4′-methyl-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.81-11.76 (broad, 1H), 9.04 (d, J = 1.7 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.71-7.65 ( m, 4H), 7.49-7.39 (m, 2H), 7.39-7.33 (m, 2H), 7.26-7.20 (m, 1H), 3.35-3.28 (m, 4H), 2.39 (s, 3H), 1.72- 1.63 (m, 4H), 1.63-1.55 (m, 2H).
Ｎ－（２’－メトキシ－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.70(s,1H),8.83(d,J=1.5Hz,1H),8.05(d,J=8.1Hz,1H),7.69-7.63(m,1H),7.48(dd,J=8.1,1.5Hz,1H),7.46-7.37(m,4H),7.26-7.16(m,2H),7.13-7.07(m,1H),3.82(s,3H),3.34-3.27(m,4H),1.72-1.63(m,4H),1.63-1.54(m,2H). N- (2′-methoxy-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.70 (s, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.69-7.63 (m, 1H), 7.48 (dd, J = 8.1,1.5Hz, 1H), 7.46-7.37 (m, 4H), 7.26-7.16 (m, 2H), 7.13-7.07 (m, 1H), 3.82 (s, 3H) 3.34-3.27 (m, 4H), 1.72-1.63 (m, 4H), 1.63-1.54 (m, 2H).
Ｎ－（３’－メトキシ－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.79-11.75(broad,1H),9.03(d,J=1.7Hz,1H),8.12(d,J=8.0Hz,1H),7.73-7.65(m,2H),7.50-7.39(m,3H),7.36-7.31(m,1H),7.30-7.27(m,1H),7.26-7.21(m,1H),7.04(dd,J=7.9,2.1Hz,1H),3.86(s,3H),3.35-3.28(m,4H),1.72-1.63(m,4H),1.63-1.55(m,2H). N- (3′-methoxy-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.79-11.75 (broad, 1H), 9.03 (d, J = 1.7 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.73-7.65 ( m, 2H), 7.50-7.39 (m, 3H), 7.36-7.31 (m, 1H), 7.30-7.27 (m, 1H), 7.26-7.21 (m, 1H), 7.04 (dd, J = 7.9,2.1 Hz, 1H), 3.86 (s, 3H), 3.35-3.28 (m, 4H), 1.72-1.63 (m, 4H), 1.63-1.55 (m, 2H).
Ｎ－（４’－メトキシ－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.83-11.78(broad,1H),9.02(d,J=1.8Hz,1H),8.10(d,J=8.3Hz,1H),7.76-7.70(m,2H),7.70-7.67(m,1H),7.65(dd,J=8.3,1.8Hz,1H),7.49-7.39(m,2H),7.25-7.21(m,1H),7.14-7.08(m,2H),3.84(s,3H),3.35-3.27(m,4H),1.72-1.63(m,4H),1.63-1.55(m,2H). N- (4′-methoxy-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.83-11.78 (broad, 1H), 9.02 (d, J = 1.8 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.76-7.70 ( m, 2H), 7.70-7.67 (m, 1H), 7.65 (dd, J = 8.3,1.8Hz, 1H), 7.49-7.39 (m, 2H), 7.25-7.21 (m, 1H), 7.14-7.08 ( m, 2H), 3.84 (s, 3H), 3.35-3.27 (m, 4H), 1.72-1.63 (m, 4H), 1.63-1.55 (m, 2H).
実施例２２５～２２７
　実施例１０３と同様にして、表２５に示す化合物を得た。 Examples 225 to 227
In the same manner as in Example 103, the compounds shown in Table 25 were obtained.
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6+D2O)δ値：8.35-8.30(m,1H),7.77-7.71(m,3H),7.68-7.62(m,1H),7.60-7.52(m,3H),7.50-7.43(m,1H),7.28-7.21(m,1H),6.94-6.87(m,2H),6.84-6.72(m,2H),3.38(q,J=6.9Hz,4H),1.11(t,J=6.9Hz,6H). (E) -3- (3- (Diethylamino) phenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl ) Acrylamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.35-8.30 (m, 1H), 7.77-7.71 (m, 3H), 7.68-7.62 (m, 1H), 7.60-7.52 (m, 3H), 7.50-7.43 (m, 1H), 7.28-7.21 (m, 1H), 6.94-6.87 (m, 2H), 6.84-6.72 (m, 2H), 3.38 (q, J = 6.9Hz, 4H) , 1.11 (t, J = 6.9Hz, 6H).
（Ｅ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（２－（ピペリジン－１－イル）フェニル）アクリルアミド
1H-NMR(DMSO-d6)δ値：13.00-12.76(broad,1H),10.10(s,1H),8.56-8.52(m,1H),7.93(d,J=15.9Hz,1H),7.77-7.71(m,3H),7.67-7.61(m,2H),7.57-7.51(m,2H),7.50-7.43(m,1H),7.41-7.34(m,1H),7.15-7.06(m,2H),6.85(d,J=15.9Hz,1H),2.89-2.82(m,4H),1.74-1.66(m,4H),1.60-1.50(m,2H). (E) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (2- (piperidine-1 -Yl) phenyl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.76 (broad, 1H), 10.10 (s, 1H), 8.56-8.52 (m, 1H), 7.93 (d, J = 15.9 Hz, 1H), 7.77-7.71 (m, 3H), 7.67-7.61 (m, 2H), 7.57-7.51 (m, 2H), 7.50-7.43 (m, 1H), 7.41-7.34 (m, 1H), 7.15-7.06 (m , 2H), 6.85 (d, J = 15.9Hz, 1H), 2.89-2.82 (m, 4H), 1.74-1.66 (m, 4H), 1.60-1.50 (m, 2H).
（Ｅ）－３－（２－（ジエチルアミノ）フェニル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：12.95-12.80(broad,1H),10.15-10.09(broad,1H),8.55-8.50(m,1H),8.01(d,J=15.7Hz,1H),7.77-7.71(m,3H),7.69-7.61(m,2H),7.57-7.50(m,2H),7.49-7.43(m,1H),7.41-7.35(m,1H),7.20(d,J=8.0Hz,1H),7.15-7.07(m,1H),6.80(d,J=15.7Hz,1H),3.04(q,J=7.0Hz,4H),0.96(t,J=7.0Hz,6H). (E) -3- (2- (Diethylamino) phenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl ) Acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 12.95-12.80 (broad, 1H), 10.15-10.09 (broad, 1H), 8.55-8.50 (m, 1H), 8.01 (d, J = 15.7Hz, 1H ), 7.77-7.71 (m, 3H), 7.69-7.61 (m, 2H), 7.57-7.50 (m, 2H), 7.49-7.43 (m, 1H), 7.41-7.35 (m, 1H), 7.20 (d , J = 8.0Hz, 1H), 7.15-7.07 (m, 1H), 6.80 (d, J = 15.7Hz, 1H), 3.04 (q, J = 7.0Hz, 4H), 0.96 (t, J = 7.0Hz , 6H).
実施例２２８～２３０
　実施例１２４と同様にして、表２６に示す化合物を得た。 Examples 228-230
In the same manner as in Example 124, the compounds shown in Table 26 were obtained.
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－５，６，７，８－テトラヒドロナフタレン－２－カルボキサミド
1H-NMR(DMSO-d6)δ値：13.30-12.80(broad,1H),10.63-10.53(broad,1H),8.61-8.56(m,1H),7.81(d,J=8.3Hz,1H),7.78-7.72(m,2H),7.72-7.63(m,3H),7.58-7.50(m,2H),7.50-7.42(m,1H),7.25(d,J=7.8Hz,1H),2.85-2.76(m,4H),1.82-1.73(m,4H). N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -5,6,7,8-tetrahydronaphthalene-2- Carboxamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.80 (broad, 1H), 10.63-10.53 (broad, 1H), 8.61-8.56 (m, 1H), 7.81 (d, J = 8.3 Hz, 1H ), 7.78-7.72 (m, 2H), 7.72-7.63 (m, 3H), 7.58-7.50 (m, 2H), 7.50-7.42 (m, 1H), 7.25 (d, J = 7.8Hz, 1H), 2.85-2.76 (m, 4H), 1.82-1.73 (m, 4H).
３－エトキシ－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.85(broad,1H),10.50(s,1H),8.55(d,J=1.6Hz,1H),7.81(d,J=8.2Hz,1H),7.78-7.73(m,2H),7.70(dd,J=8.2,1.6Hz,1H),7.58-7.44(m,6H),7.23-7.16(m,1H),4.13(q,J=6.9Hz,2H),1.38(t,J=6.9Hz,3H). 3-Ethoxy-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.85 (broad, 1H), 10.50 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.78-7.73 (m, 2H), 7.70 (dd, J = 8.2,1.6Hz, 1H), 7.58-7.44 (m, 6H), 7.23-7.16 (m, 1H), 4.13 (q, J = 6.9Hz, 2H), 1.38 (t, J = 6.9Hz, 3H).
３－シクロプロピル－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.30-12.80(broad,1H),10.72-10.60(broad,1H),8.63-8.59(m,1H),7.83(d,J=8.1Hz,1H),7.79-7.71(m,3H),7.71-7.64(m,2H),7.58-7.51(m,2H),7.49-7.42(m,2H),7.41-7.35(m,1H),2.08-1.98(m,1H),1.08-0.99(m,2H),0.82-0.76(m,2H). 3-Cyclopropyl-N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.30-12.80 (broad, 1H), 10.72-10.60 (broad, 1H), 8.63-8.59 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H ), 7.79-7.71 (m, 3H), 7.71-7.64 (m, 2H), 7.58-7.51 (m, 2H), 7.49-7.42 (m, 2H), 7.41-7.35 (m, 1H), 2.08-1.98 (m, 1H), 1.08-0.99 (m, 2H), 0.82-0.76 (m, 2H).
実施例２３１～２３７
　実施例１２０と同様にして、表２７に示す化合物を得た。 Examples 231 to 237
In the same manner as in Example 120, the compounds shown in Table 27 were obtained.
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
（Ｅ）－３－（３－（ジメチルアミノ）フェニル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：13.00-12.70(broad,1H),10.07(s,1H),8.40(d,J=1.8Hz,1H),7.76-7.70(m,3H),7.64(dd,J=8.2,1.8Hz,1H),7.61-7.50(m,3H),7.49-7.43(m,1H),7.29-7.23(m,1H),6.99-6.94(m,2H),6.85(d,J=15.6Hz,1H),6.82-6.77(m,1H),2.95(s,6H). (E) -3- (3- (Dimethylamino) phenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3- Yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.70 (broad, 1H), 10.07 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 7.76-7.70 (m, 3H), 7.64 (dd, J = 8.2,1.8Hz, 1H), 7.61-7.50 (m, 3H), 7.49-7.43 (m, 1H), 7.29-7.23 (m, 1H), 6.99-6.94 (m, 2H), 6.85 (d, J = 15.6Hz, 1H), 6.82-6.77 (m, 1H), 2.95 (s, 6H).
（Ｅ）－３－（３－ブロモフェニル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：13.00-12.75(broad,1H),10.21-10.11(broad,1H),8.48-8.44(m,1H),7.94-7.91(m,1H),7.78-7.57(m,7H),7.57-7.50(m,2H),7.49-7.39(m,2H),6.98(d,J=15.6Hz,1H). (E) -3- (3-Bromophenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.75 (broad, 1H), 10.21-10.11 (broad, 1H), 8.48-8.44 (m, 1H), 7.94-7.91 (m, 1H), 7.78 -7.57 (m, 7H), 7.57-7.50 (m, 2H), 7.49-7.39 (m, 2H), 6.98 (d, J = 15.6Hz, 1H).
（Ｅ）－３－（４－ニトロフェニル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：13.00-12.75(broad,1H),10.38-10.30(broad,1H),8.46-8.42(m,1H),8.33-8.28(m,2H),7.99-7.93(m,2H),7.79-7.71(m,4H),7.67(dd,J=8.3,1.7Hz,1H),7.57-7.51(m,2H),7.49-7.43(m,1H),7.11(d,J=15.9Hz,1H). (E) -3- (4-Nitrophenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.75 (broad, 1H), 10.38-10.30 (broad, 1H), 8.46-8.42 (m, 1H), 8.33-8.28 (m, 2H), 7.99 -7.93 (m, 2H), 7.79-7.71 (m, 4H), 7.67 (dd, J = 8.3,1.7Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.43 (m, 1H), 7.11 (d, J = 15.9Hz, 1H).
（Ｅ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（４－（ピペリジン－１－イル）フェニル）アクリルアミド
1H-NMR(DMSO-d6+D2O)δ値：8.45-8.41(m,1H),7.77-7.70(m,3H),7.64-7.59(m,1H),7.58-7.43(m,6H),7.00-6.94(m,2H),6.61(d,J=15.6Hz,1H),3.33-3.25(m,4H),1.64-1.54(m,6H). (E) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (4- (piperidine-1 -Yl) phenyl) acrylamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.45-8.41 (m, 1H), 7.77-7.70 (m, 3H), 7.64-7.59 (m, 1H), 7.58-7.43 (m, 6H), 7.00-6.94 (m, 2H), 6.61 (d, J = 15.6Hz, 1H), 3.33-3.25 (m, 4H), 1.64-1.54 (m, 6H).
（Ｅ）－３－（４－（ジエチルアミノ）フェニル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：13.00-12.70(broad,1H),9.91(s,1H),8.51(d,J=1.8Hz,1H),7.75-7.69(m,3H),7.60(dd,J=8.2,1.8Hz,1H),7.57-7.42(m,6H),6.73-6.67(m,2H),6.55(d,J=15.4Hz,1H),3.40(q,J=7.0Hz,4H),1.12(t,J=7.0Hz,6H). (E) -3- (4- (Diethylamino) phenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl ) Acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.70 (broad, 1H), 9.91 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 7.75-7.69 (m, 3H), 7.60 (dd, J = 8.2,1.8Hz, 1H), 7.57-7.42 (m, 6H), 6.73-6.67 (m, 2H), 6.55 (d, J = 15.4Hz, 1H), 3.40 (q, J = 7.0Hz, 4H), 1.12 (t, J = 7.0Hz, 6H).
（Ｅ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（３－（ピロリジン－１－イル）フェニル）アクリルアミド
1H-NMR(DMSO-d6)δ値：12.94-12.70(broad,1H),10.10-10.04(broad,1H),8.43-8.38(m,1H),7.76-7.70(m,3H),7.64(dd,J=8.1,1.7Hz,1H),7.60-7.50(m,3H),7.49-7.43(m,1H),7.23(dd,J=7.8,7.8Hz,1H),6.93-6.76(m,3H),6.61(dd,J=8.2,2.3Hz,1H),3.30-3.24(m,4H),2.01-1.94(m,4H). (E) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (3- (pyrrolidine-1 -Yl) phenyl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 12.94-12.70 (broad, 1H), 10.10-10.04 (broad, 1H), 8.43-8.38 (m, 1H), 7.76-7.70 (m, 3H), 7.64 (dd, J = 8.1,1.7Hz, 1H), 7.60-7.50 (m, 3H), 7.49-7.43 (m, 1H), 7.23 (dd, J = 7.8,7.8Hz, 1H), 6.93-6.76 (m , 3H), 6.61 (dd, J = 8.2, 2.3Hz, 1H), 3.30-3.24 (m, 4H), 2.01-1.94 (m, 4H).
（Ｅ）－３－（３－（４－メチルピペリジン－１－イル）フェニル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：13.00-12.70(broad,1H),10.10-10.02(broad,1H),8.44-8.39(m,1H),7.77-7.69(m,3H),7.67-7.61(m,1H),7.61-7.49(m,3H),7.49-7.41(m,1H),7.30-7.23(m,1H),7.22-7.18(m,1H),7.08-6.96(m,2H),6.86(d,J=15.9Hz,1H),3.80-3.68(m,2H),2.77-2.63(m,2H),1.78-1.64(m,2H),1.61-1.45(m,1H),1.32-1.16(m,2H),0.95(d,J=6.6Hz,3H). (E) -3- (3- (4-Methylpiperidin-1-yl) phenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3- Yl) biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.70 (broad, 1H), 10.10-10.02 (broad, 1H), 8.44-8.39 (m, 1H), 7.77-7.69 (m, 3H), 7.67 -7.61 (m, 1H), 7.61-7.49 (m, 3H), 7.49-7.41 (m, 1H), 7.30-7.23 (m, 1H), 7.22-7.18 (m, 1H), 7.08-6.96 (m, 2H), 6.86 (d, J = 15.9Hz, 1H), 3.80-3.68 (m, 2H), 2.77-2.63 (m, 2H), 1.78-1.64 (m, 2H), 1.61-1.45 (m, 1H) , 1.32-1.16 (m, 2H), 0.95 (d, J = 6.6Hz, 3H).
実施例２３８
Figure JPOXMLDOC01-appb-C000183
 　Ｎ－（２－シアノ－５－フェノキシフェニル）－３－（ピペリジン－１－イル）ベンズアミド0.050g、トリエチルアミン塩酸塩0.084gおよびアジ化ナトリウム0.040gの１－メチル－２－ピロリドン0.50mL懸濁液を、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物にトリエチルアミン塩酸塩0.084gおよびアジ化ナトリウム0.040gを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物に酢酸エチル2.0mLおよび10％クエン酸水溶液2.5mLを加え、有機層を分取した。得られた有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；80-50％ヘキサン／酢酸エチル］で精製し、淡黄色固体のＮ－（５－フェノキシ－２－（１Ｈ－テトラゾール－５－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド0.046gを得た。
1H-NMR(DMSO-d6)δ値：11.94-11.88(broad,1H),8.42(d,J=2.4Hz,1H),8.05(d,J=8.5Hz,1H),7.64-7.58(m,1H),7.53-7.45(m,2H),7.43-7.37(m,2H),7.30-7.16(m,4H),6.99(dd,J=8.6,2.6Hz,1H),3.33-3.25(m,4H),1.71-1.62(m,4H),1.62-1.54(m,2H). Example 238
Figure JPOXMLDOC01-appb-C000183
 A suspension of 0.050 g of N- (2-cyano-5-phenoxyphenyl) -3- (piperidin-1-yl) benzamide, 0.084 g of triethylamine hydrochloride and 0.040 g of sodium azide in 0.50 mL of 1-methyl-2-pyrrolidone Was stirred at 150 ° C. for 10 minutes under microwave irradiation. To the reaction mixture, 0.084 g of triethylamine hydrochloride and 0.040 g of sodium azide were added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. To the reaction mixture, 2.0 mL of ethyl acetate and 2.5 mL of 10% aqueous citric acid solution were added, and the organic layer was separated. The obtained organic layer was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-50% hexane / ethyl acetate] to obtain N- (5-phenoxy-2) as a pale yellow solid. 0.046 g of-(1H-tetrazol-5-yl) phenyl) -3- (piperidin-1-yl) benzamide was obtained.
1 H-NMR (DMSO-d 6 ) δ value: 11.94-11.88 (broad, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.64-7.58 ( m, 1H), 7.53-7.45 (m, 2H), 7.43-7.37 (m, 2H), 7.30-7.16 (m, 4H), 6.99 (dd, J = 8.6,2.6Hz, 1H), 3.33-3.25 ( m, 4H), 1.71-1.62 (m, 4H), 1.62-1.54 (m, 2H).
実施例２３９
Figure JPOXMLDOC01-appb-C000184
 　実施例２３８と同様にして、以下の化合物を得た。
Ｎ－（６－メチル－４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.56(s,1H),8.53(s,1H),8.01(s,1H),7.83-7.70(m,1H),7.59-7.30(m,8H),3.40-3.32(m,4H),2.32(s,3H),1.78-1.68(m,4H),1.65-1.56(m,2H). Example 239
Figure JPOXMLDOC01-appb-C000184
 In the same manner as in Example 238, the following compound was obtained.
N- (6-Methyl-4- (1H-tetrazol-5-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.56 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 7.83-7.70 (m, 1H), 7.59-7.30 (m, 8H) ), 3.40-3.32 (m, 4H), 2.32 (s, 3H), 1.78-1.68 (m, 4H), 1.65-1.56 (m, 2H).
実施例２４０
Figure JPOXMLDOC01-appb-C000185
 　実施例２３８と同様にして、以下の化合物を得た。
Ｎ－（５－（（Ｅ）－２－フェニルビニル）－２－（１Ｈ－テトラゾール－５－イル）フェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.76-11.69(broad,1H),8.92-8.88(m,1H),8.05(d,J=8.3Hz,1H),7.73-7.67(m,3H),7.67-7.62(m,1H),7.48-7.37(m,6H),7.37-7.30(m,1H),7.26-7.21(m,1H),3.35-3.28(m,4H),1.72-1.63(m,4H),1.63-1.55(m,2H). Example 240
Figure JPOXMLDOC01-appb-C000185
 In the same manner as in Example 238, the following compound was obtained.
N- (5-((E) -2-Phenylvinyl) -2- (1H-tetrazol-5-yl) phenyl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.76-11.69 (broad, 1H), 8.92-8.88 (m, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.73-7.67 (m, 3H ), 7.67-7.62 (m, 1H), 7.48-7.37 (m, 6H), 7.37-7.30 (m, 1H), 7.26-7.21 (m, 1H), 3.35-3.28 (m, 4H), 1.72-1.63 (m, 4H), 1.63-1.55 (m, 2H).
実施例２４１
Figure JPOXMLDOC01-appb-C000186
 　実施例２３８と同様にして、以下の化合物を得た。
Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）－５，６，７，８－テトラヒドロナフタレン－２－カルボキサミド
1H-NMR(DMSO-d6)δ値：11.66(s,1H),9.02-8.96(m,1H),8.12(d,J=8.3Hz,1H),7.84-7.74(m,4H),7.72-7.66(m,1H),7.59-7.52(m,2H),7.50-7.43(m,1H),7.30(d,J=7.8Hz,1H),2.88-2.77(m,4H),1.84-1.74(m,4H). Example 241
Figure JPOXMLDOC01-appb-C000186
 In the same manner as in Example 238, the following compound was obtained.
N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) -5,6,7,8-tetrahydronaphthalene-2-carboxamide
1 H-NMR (DMSO-d 6 ) δ value: 11.66 (s, 1H), 9.02-8.96 (m, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.84-7.74 (m, 4H), 7.72-7.66 (m, 1H), 7.59-7.52 (m, 2H), 7.50-7.43 (m, 1H), 7.30 (d, J = 7.8Hz, 1H), 2.88-2.77 (m, 4H), 1.84- 1.74 (m, 4H).
実施例２４２～２４５
　実施例２４１と同様にして、表２８に示す化合物を得た。 Examples 242 to 245
In the same manner as in Example 241, compounds shown in Table 28 were obtained.
Figure JPOXMLDOC01-appb-T000187
  
Figure JPOXMLDOC01-appb-T000187
  
３－エトキシ－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.74-11.69(broad,1H),9.02-8.97(m,1H),8.13(d,J=8.0Hz,1H),7.81-7.75(m,2H),7.74-7.63(m,3H),7.59-7.44(m,4H),7.25-7.20(m,1H),4.18(q,J=6.9Hz,2H),1.40(t,J=6.9Hz,3H). 3-Ethoxy-N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.74-11.69 (broad, 1H), 9.02-8.97 (m, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.81-7.75 (m, 2H) ), 7.74-7.63 (m, 3H), 7.59-7.44 (m, 4H), 7.25-7.20 (m, 1H), 4.18 (q, J = 6.9Hz, 2H), 1.40 (t, J = 6.9Hz, 3H).
３－シクロプロピル－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：11.75-11.68(broad,1H),9.03-8.98(m,1H),8.13(d,J=8.1Hz,1H),7.87-7.81(m,1H),7.81-7.75(m,3H),7.74-7.68(m,1H),7.60-7.40(m,5H),2.11-2.01(m,1H),1.10-1.02(m,2H),0.88-0.81(m,2H). 3-Cyclopropyl-N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 11.75-11.68 (broad, 1H), 9.03-8.98 (m, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.87-7.81 (m, 1H ), 7.81-7.75 (m, 3H), 7.74-7.68 (m, 1H), 7.60-7.40 (m, 5H), 2.11-2.01 (m, 1H), 1.10-1.02 (m, 2H), 0.88-0.81 (m, 2H).
６－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ピリジン－２－カルボキサミド
1H-NMR(DMSO-d6)δ値：12.75-12.69(broad,1H),9.34-9.30(m,1H),8.11(d,J=8.2Hz,1H),7.82-7.71(m,3H),7.69(dd,J=8.2,1.8Hz,1H),7.59-7.53(m,2H),7.50-7.41(m,2H),7.12(d,J=8.5Hz,1H),3.89-3.80(m,4H),1.71-1.62(m,6H). 6- (Piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) pyridine-2-carboxamide
1 H-NMR (DMSO-d 6 ) δ value: 12.75-12.69 (broad, 1H), 9.34-9.30 (m, 1H), 8.11 (d, J = 8.2Hz, 1H), 7.82-7.71 (m, 3H ), 7.69 (dd, J = 8.2, 1.8Hz, 1H), 7.59-7.53 (m, 2H), 7.50-7.41 (m, 2H), 7.12 (d, J = 8.5Hz, 1H), 3.89-3.80 ( m, 4H), 1.71-1.62 (m, 6H).
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：10.90-10.83(broad,1H),8.72-8.68(m,1H),8.02(d,J=8.2Hz,1H),7.78-7.72(m,2H),7.67(dd,J=8.2,1.8Hz,1H),7.63-7.51(m,3H),7.49-7.43(m,1H),7.28-7.20(m,1H),6.99-6.91(m,2H),6.83(d,J=15.6Hz,1H),6.79-6.73(m,1H),3.45-3.35(m,4H),1.11(t,J=7.1Hz,6H). (E) -3- (3- (Diethylamino) phenyl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 10.90-10.83 (broad, 1H), 8.72-8.68 (m, 1H), 8.02 (d, J = 8.2Hz, 1H), 7.78-7.72 (m, 2H ), 7.67 (dd, J = 8.2, 1.8Hz, 1H), 7.63-7.51 (m, 3H), 7.49-7.43 (m, 1H), 7.28-7.20 (m, 1H), 6.99-6.91 (m, 2H) ), 6.83 (d, J = 15.6Hz, 1H), 6.79-6.73 (m, 1H), 3.45-3.35 (m, 4H), 1.11 (t, J = 7.1Hz, 6H).
実施例２４６
Figure JPOXMLDOC01-appb-C000188
 　実施例２３８と同様にして、以下の化合物を得た。
Ｎ－（５－フェニル－２－（１Ｈ－テトラゾール－５－イル）ピリジン－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：9.40-9.35(m,1H),8.86-8.82(m,1H),7.86-7.80(m,2H),7.71-7.66(m,1H),7.64-7.57(m,2H),7.57-7.51(m,1H),7.49-7.42(m,2H),7.29-7.22(m,1H),3.35-3.28(m,4H),1.71-1.63(m,4H),1.63-1.55(m,2H). Example 246
Figure JPOXMLDOC01-appb-C000188
 In the same manner as in Example 238, the following compound was obtained.
N- (5-phenyl-2- (1H-tetrazol-5-yl) pyridin-3-yl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 9.40-9.35 (m, 1H), 8.86-8.82 (m, 1H), 7.86-7.80 (m, 2H), 7.71-7.66 (m, 1H), 7.64-7.57 (m, 2H), 7.57-7.51 (m, 1H), 7.49-7.42 (m, 2H), 7.29-7.22 (m, 1H), 3.35-3.28 (m, 4H), 1.71- 1.63 (m, 4H), 1.63-1.55 (m, 2H).
実施例２４７
Figure JPOXMLDOC01-appb-C000189
 　（Ｅ）－Ｎ－（５－クロロ－２－シアノフェニル）－３－（３－（ジエチルアミノ）フェニル）アクリルアミド0.11gに２－フルオロフェニルボロン酸84mg、炭酸カリウム0.10g、ジオキサン0.80mL、水0.20mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物の有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、（Ｅ）－Ｎ－（４－シアノ－２’－フルオロビフェニル－３－イル）－３－（３－（ジエチルアミノ）フェニル）アクリルアミドを得た。
　得られた（Ｅ）－Ｎ－（４－シアノ－２’－フルオロビフェニル－３－イル）－３－（３－（ジエチルアミノ）フェニル）アクリルアミドに50％ヒドロキシルアミン水溶液0.050mLおよびテトラヒドロフラン1.0mLを加え、60-70℃で30分間攪拌した。減圧下で溶媒を留去し、テトラヒドロフラン2.0mL、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLおよび１，１’－カルボニルジイミダゾール0.13gを順次加え、室温で1時間攪拌した。反応混合物に水1.0mL、酢酸エチル2.0mLおよび10％クエン酸水溶液2.5mLを加えた。有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；80-50％ヘキサン／酢酸エチル］で精製し、黄色固体の（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（２’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド70mgを得た。
1H-NMR(DMSO-d6)δ値：12.98-12.70(broad,1H),10.11(s,1H),8.29-8.24(m,1H),7.74(d,J=8.3Hz,1H),7.64-7.58(m,1H),7.58-7.46(m,3H),7.43-7.33(m,2H),7.22(dd,J=7.8,7.8Hz,1H),6.93-6.85(m,2H),6.80(d,J=15.6Hz,1H),6.76-6.68(m,1H),3.42-3.33(m,4H),1.11(t,J=7.0Hz,6H). Example 247
Figure JPOXMLDOC01-appb-C000189
 (E) -N- (5-chloro-2-cyanophenyl) -3- (3- (diethylamino) phenyl) acrylamide 0.11 g, 2-fluorophenylboronic acid 84 mg, potassium carbonate 0.10 g, dioxane 0.80 mL, water 0.20 mL and 5 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride were added and stirred at 150 ° C. for 10 minutes under microwave irradiation. The organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and (E) -N- (4-cyano-2 '-Fluorobiphenyl-3-yl) -3- (3- (diethylamino) phenyl) acrylamide was obtained.
To the obtained (E) -N- (4-cyano-2′-fluorobiphenyl-3-yl) -3- (3- (diethylamino) phenyl) acrylamide, 0.050 mL of a 50% hydroxylamine aqueous solution and 1.0 mL of tetrahydrofuran were added. And stirred at 60-70 ° C. for 30 minutes. The solvent was distilled off under reduced pressure, and 2.0 mL of tetrahydrofuran, 0.10 mL of 1,8-diazabicyclo [5.4.0] -7-undecene, and 0.13 g of 1,1′-carbonyldiimidazole were sequentially added for 1 hour at room temperature. Stir. To the reaction mixture, 1.0 mL of water, 2.0 mL of ethyl acetate and 2.5 mL of 10% aqueous citric acid solution were added. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-50% hexane / ethyl acetate] to give (E) -3- (3- 70 mg of (diethylamino) phenyl) -N- (2′-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) acrylamide Obtained.
1 H-NMR (DMSO-d 6 ) δ value: 12.98-12.70 (broad, 1H), 10.11 (s, 1H), 8.29-8.24 (m, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.64-7.58 (m, 1H), 7.58-7.46 (m, 3H), 7.43-7.33 (m, 2H), 7.22 (dd, J = 7.8,7.8Hz, 1H), 6.93-6.85 (m, 2H), 6.80 (d, J = 15.6Hz, 1H), 6.76-6.68 (m, 1H), 3.42-3.33 (m, 4H), 1.11 (t, J = 7.0Hz, 6H).
実施例２４８～２５３
　実施例２４７と同様にして、表２９に示す化合物を得た。 Examples 248-253
In the same manner as in Example 247, the compounds shown in Table 29 were obtained.
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（３’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6+D2O)δ値：8.35-8.29(m,1H),7.79-7.68(m,2H),7.66-7.44(m,7H),7.36-7.24(m,2H),6.91(d,J=15.4Hz,1H),3.59-3.48(m,4H),1.07(t,J=7.1Hz,6H). (E) -3- (3- (Diethylamino) phenyl) -N- (3′-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.35-8.29 (m, 1H), 7.79-7.68 (m, 2H), 7.66-7.44 (m, 7H), 7.36-7.24 (m, 2H), 6.91 (d, J = 15.4Hz, 1H), 3.59-3.48 (m, 4H), 1.07 (t, J = 7.1Hz, 6H).
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（４’－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：12.92-12.74(broad,1H),10.14-10.06(broad,1H),8.38-8.33(m,1H),7.82-7.75(m,2H),7.72(d,J=8.3Hz,1H),7.63(dd,J=8.1,1.5Hz,1H),7.57(d,J=15.8Hz,1H),7.41-7.33(m,2H),7.22(dd,J=7.8,7.8Hz,1H),6.93-6.85(m,2H),6.81(d,J=15.8Hz,1H),6.76-6.69(m,1H),3.42-3.33(m,4H),1.11(t,J=7.0Hz,6H). (E) -3- (3- (Diethylamino) phenyl) -N- (4′-fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 12.92-12.74 (broad, 1H), 10.14-10.06 (broad, 1H), 8.38-8.33 (m, 1H), 7.82-7.75 (m, 2H), 7.72 (d, J = 8.3Hz, 1H), 7.63 (dd, J = 8.1,1.5Hz, 1H), 7.57 (d, J = 15.8Hz, 1H), 7.41-7.33 (m, 2H), 7.22 (dd, J = 7.8,7.8Hz, 1H), 6.93-6.85 (m, 2H), 6.81 (d, J = 15.8Hz, 1H), 6.76-6.69 (m, 1H), 3.42-3.33 (m, 4H), 1.11 (t, J = 7.0Hz, 6H).
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（３’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：12.90-12.70(broad,1H),10.11-10.04(broad,1H),8.36(d,J=1.7Hz,1H),7.72(d,J=8.2Hz,1H),7.63(dd,J=8.2,1.7Hz,1H),7.60-7.49(m,3H),7.45-7.38(m,1H),7.30-7.18(m,2H),6.93-6.85(m,2H),6.81(d,J=15.6Hz,1H),6.76-6.70(m,1H),3.42-3.33(m,4H),2.41(s,3H),1.11(t,J=7.0Hz,6H). (E) -3- (3- (Diethylamino) phenyl) -N- (3′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 12.90-12.70 (broad, 1H), 10.11-10.04 (broad, 1H), 8.36 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.2, 1.7Hz, 1H), 7.60-7.49 (m, 3H), 7.45-7.38 (m, 1H), 7.30-7.18 (m, 2H), 6.93-6.85 ( m, 2H), 6.81 (d, J = 15.6Hz, 1H), 6.76-6.70 (m, 1H), 3.42-3.33 (m, 4H), 2.41 (s, 3H), 1.11 (t, J = 7.0Hz , 6H).
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（４’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：13.00-12.65(broad,1H),10.15-10.08(broad,1H),8.36(d,J=1.4Hz,1H),7.74-7.69(m,1H),7.65-7.54(m,4H),7.37-7.30(m,2H),7.25-7.19(m,1H),6.93-6.84(m,2H),6.80(d,J=15.9Hz,1H),6.75-6.70(m,1H),3.42-3.34(m,4H),2.37(s,3H),1.14-1.08(m,6H). (E) -3- (3- (Diethylamino) phenyl) -N- (4′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 13.00-12.65 (broad, 1H), 10.15-10.08 (broad, 1H), 8.36 (d, J = 1.4 Hz, 1H), 7.74-7.69 (m, 1H ), 7.65-7.54 (m, 4H), 7.37-7.30 (m, 2H), 7.25-7.19 (m, 1H), 6.93-6.84 (m, 2H), 6.80 (d, J = 15.9Hz, 1H), 6.75-6.70 (m, 1H), 3.42-3.34 (m, 4H), 2.37 (s, 3H), 1.14-1.08 (m, 6H).
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（２’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：12.87-12.67(broad,1H),10.07-10.00(broad,1H),8.18-8.14(m,1H),7.66(d,J=8.1Hz,1H),7.54(d,J=15.6Hz,1H),7.46-7.38(m,2H),7.36(dd,J=7.6,1.4Hz,1H),7.25-7.14(m,2H),7.11-7.05(m,1H),6.92-6.84(m,2H),6.79(d,J=15.6Hz,1H),6.75-6.69(m,1H),3.80(s,3H),3.42-3.33(m,4H),1.10(t,J=6.9Hz,6H). (E) -3- (3- (Diethylamino) phenyl) -N- (2′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 12.87-12.67 (broad, 1H), 10.07-10.00 (broad, 1H), 8.18-8.14 (m, 1H), 7.66 (d, J = 8.1 Hz, 1H ), 7.54 (d, J = 15.6Hz, 1H), 7.46-7.38 (m, 2H), 7.36 (dd, J = 7.6,1.4Hz, 1H), 7.25-7.14 (m, 2H), 7.11-7.05 ( m, 1H), 6.92-6.84 (m, 2H), 6.79 (d, J = 15.6Hz, 1H), 6.75-6.69 (m, 1H), 3.80 (s, 3H), 3.42-3.33 (m, 4H) , 1.10 (t, J = 6.9Hz, 6H).
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（３’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド
1H-NMR(DMSO-d6)δ値：12.93-12.72(broad,1H),10.13-10.06(broad,1H),8.38-8.33(m,1H),7.72(d,J=8.2Hz,1H),7.65(dd,J=8.2,1.8Hz,1H),7.57(d,J=15.9Hz,1H),7.48-7.41(m,1H),7.31-7.19(m,3H),7.06-7.00(m,1H),6.93-6.85(m,2H),6.84-6.70(m,2H),3.85(s,3H),3.42-3.34(m,4H),1.11(t,J=7.0Hz,6H). (E) -3- (3- (Diethylamino) phenyl) -N- (3′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) acrylamide
1 H-NMR (DMSO-d 6 ) δ value: 12.93-12.72 (broad, 1H), 10.13-10.06 (broad, 1H), 8.38-8.33 (m, 1H), 7.72 (d, J = 8.2Hz, 1H ), 7.65 (dd, J = 8.2, 1.8Hz, 1H), 7.57 (d, J = 15.9Hz, 1H), 7.48-7.41 (m, 1H), 7.31-7.19 (m, 3H), 7.06-7.00 ( m, 1H), 6.93-6.85 (m, 2H), 6.84-6.70 (m, 2H), 3.85 (s, 3H), 3.42-3.34 (m, 4H), 1.11 (t, J = 7.0Hz, 6H) .
実施例２５４
Figure JPOXMLDOC01-appb-C000191
 　（Ｅ）－Ｎ－（５－クロロ－２－シアノフェニル）－３－（３－（ジエチルアミノ）フェニル）アクリルアミド0.11gに２－メチルフェニルボロン酸82mg、炭酸カリウム0.10g、ジオキサン0.80mL、水0.20mLおよびビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）パラジウム（II）ジクロリド5mgを加え、マイクロウェーブ照射下150℃で10分間攪拌した。反応混合物の有機層をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；95-70％ヘキサン／酢酸エチル］で精製し、（Ｅ）－Ｎ－（４－シアノ－２’－メチルビフェニル－３－イル）－３－（３－（ジエチルアミノ）フェニル）アクリルアミドを得た。
　得られた（Ｅ）－Ｎ－（４－シアノ－２’－メチルビフェニル－３－イル）－３－（３－（ジエチルアミノ）フェニル）アクリルアミドに50％ヒドロキシルアミン水溶液0.050mLおよびテトラヒドロフラン1.0mLを加え、60-70℃で30分間攪拌した。減圧下で溶媒を留去し、テトラヒドロフラン2.0mL、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン0.10mLおよび１，１’－カルボニルジイミダゾール0.13gを順次加え、室温で1時間攪拌した。反応混合物に水0.5mL、酢酸エチル2.0mLおよび10％クエン酸水溶液2.5mLを加えた。有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；80-50％ヘキサン／酢酸エチル］で精製し、（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（２’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミドを得た。
　得られた（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（２’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミドに酢酸エチル10mLおよび4.0mol/L塩化水素－酢酸エチル溶液1.0mLを加え、固形物をろ取し、白色固体の（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（２’－メチル－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド塩酸塩38mgを得た。
1H-NMR(DMSO-d6+D2O)δ値：7.99-7.95(m,1H),7.76-7.58(m,5H),7.52-7.46(m,1H),7.40-7.26(m,5H),6.94(d,J=15.6Hz,1H),3.59(q,J=7.1Hz,4H),2.30(s,3H),1.06(t,J=7.1Hz,6H). Example 254
Figure JPOXMLDOC01-appb-C000191
 (E) -N- (5-chloro-2-cyanophenyl) -3- (3- (diethylamino) phenyl) acrylamide 0.11 g, 2-methylphenylboronic acid 82 mg, potassium carbonate 0.10 g, dioxane 0.80 mL, water 0.20 mL and 5 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride were added and stirred at 150 ° C. for 10 minutes under microwave irradiation. The organic layer of the reaction mixture was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane / ethyl acetate], and (E) -N- (4-cyano-2 '-Methylbiphenyl-3-yl) -3- (3- (diethylamino) phenyl) acrylamide was obtained.
To the obtained (E) -N- (4-cyano-2'-methylbiphenyl-3-yl) -3- (3- (diethylamino) phenyl) acrylamide, 0.050 mL of a 50% hydroxylamine aqueous solution and 1.0 mL of tetrahydrofuran were added. And stirred at 60-70 ° C. for 30 minutes. The solvent was distilled off under reduced pressure, and 2.0 mL of tetrahydrofuran, 0.10 mL of 1,8-diazabicyclo [5.4.0] -7-undecene, and 0.13 g of 1,1′-carbonyldiimidazole were sequentially added for 1 hour at room temperature. Stir. To the reaction mixture, 0.5 mL of water, 2.0 mL of ethyl acetate and 2.5 mL of 10% aqueous citric acid solution were added. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-50% hexane / ethyl acetate], and (E) -3- (3- (diethylamino) Phenyl) -N- (2′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) acrylamide was obtained.
The obtained (E) -3- (3- (diethylamino) phenyl) -N- (2′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3) To -yl) biphenyl-3-yl) acrylamide was added 10 mL of ethyl acetate and 1.0 mL of 4.0 mol / L hydrogen chloride-ethyl acetate solution, and the solid was collected by filtration to give a white solid of (E) -3- (3- (3- ( Diethylamino) phenyl) -N- (2′-methyl-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) acrylamide hydrochloride 38 mg Got.
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 7.99-7.95 (m, 1H), 7.76-7.58 (m, 5H), 7.52-7.46 (m, 1H), 7.40-7.26 (m, 5H), 6.94 (d, J = 15.6Hz, 1H), 3.59 (q, J = 7.1Hz, 4H), 2.30 (s, 3H), 1.06 (t, J = 7.1Hz, 6H).
実施例２５５
Figure JPOXMLDOC01-appb-C000192
 　実施例２５４と同様にして、以下の化合物を得た。
（Ｅ）－３－（３－（ジエチルアミノ）フェニル）－Ｎ－（４’－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）アクリルアミド塩酸塩
1H-NMR(DMSO-d6+D2O)δ値：8.17-8.13(m,1H),7.78-7.60(m,8H),7.52-7.45(m,1H),7.15-7.09(m,2H),6.94(d,J=15.8Hz,1H),3.83(s,3H),3.60(q,J=7.0Hz,4H),1.07(t,J=7.0Hz,6H). Example 255
Figure JPOXMLDOC01-appb-C000192
 In the same manner as in Example 254, the following compound was obtained.
(E) -3- (3- (Diethylamino) phenyl) -N- (4′-methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-3-yl) acrylamide hydrochloride
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.17-8.13 (m, 1H), 7.78-7.60 (m, 8H), 7.52-7.45 (m, 1H), 7.15-7.09 (m, 2H), 6.94 (d, J = 15.8Hz, 1H), 3.83 (s, 3H), 3.60 (q, J = 7.0Hz, 4H), 1.07 (t, J = 7.0Hz, 6H).
実施例２５６
Figure JPOXMLDOC01-appb-C000193
 　実施例１２２と同様にして、以下の化合物を得た。
Ｎ－（２－フルオロ－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－４－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：12.94-12.65(broad,1H),10.53-10.37(broad,1H),7.87-7.78(m,2H),7.63-7.57(m,2H),7.57-7.50(m,2H),7.49-7.43(m,1H),7.42-7.39(m,1H),7.38-7.32(m,1H),7.28-7.23(m,1H),7.20-7.15(m,1H),3.27-3.18(m,4H),1.70-1.61(m,4H),1.61-1.52(m,2H). Example 256
Figure JPOXMLDOC01-appb-C000193
 In the same manner as in Example 122, the following compound was obtained.
N- (2-Fluoro-3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 12.94-12.65 (broad, 1H), 10.53-10.37 (broad, 1H), 7.87-7.78 (m, 2H), 7.63-7.57 (m, 2H), 7.57 -7.50 (m, 2H), 7.49-7.43 (m, 1H), 7.42-7.39 (m, 1H), 7.38-7.32 (m, 1H), 7.28-7.23 (m, 1H), 7.20-7.15 (m, 1H), 3.27-3.18 (m, 4H), 1.70-1.61 (m, 4H), 1.61-1.52 (m, 2H).
実施例２５７
Figure JPOXMLDOC01-appb-C000194
 　実施例１２２と同様にして、以下の化合物を得た。
Ｎ－（６－メトキシ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：10.35-10.26(broad,1H),8.16(s,1H),7.58-7.53(m,2H),7.50-7.32(m,6H),7.32-7.26(m,1H),7.19-7.13(m,1H),3.85(s,3H),3.27-3.20(m,4H),1.68-1.61(m,4H),1.60-1.53(m,2H). Example 257
Figure JPOXMLDOC01-appb-C000194
 In the same manner as in Example 122, the following compound was obtained.
N- (6-Methoxy-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 10.35-10.26 (broad, 1H), 8.16 (s, 1H), 7.58-7.53 (m, 2H), 7.50-7.32 (m, 6H), 7.32-7.26 (m, 1H), 7.19-7.13 (m, 1H), 3.85 (s, 3H), 3.27-3.20 (m, 4H), 1.68-1.61 (m, 4H), 1.60-1.53 (m, 2H).
実施例２５８
Figure JPOXMLDOC01-appb-C000195
 　実施例１２２と同様にして、以下の化合物を得た。
Ｎ－（２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－５－フェニルピリジン－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.41-13.29(broad,1H),10.55-10.44(broad,1H),9.16(d,J=1.9Hz,1H),8.87(d,J=2.0Hz,1H),7.87-7.82(m,2H),7.62-7.56(m,2H),7.56-7.50(m,2H),7.45-7.39(m,1H),7.37-7.32(m,1H),7.26-7.20(m,1H),3.30-3.24(m,4H),1.69-1.62(m,4H),1.62-1.54(m,2H). Example 258
Figure JPOXMLDOC01-appb-C000195
 In the same manner as in Example 122, the following compound was obtained.
N- (2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -5-phenylpyridin-3-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.41-13.29 (broad, 1H), 10.55-10.44 (broad, 1H), 9.16 (d, J = 1.9 Hz, 1H), 8.87 (d, J = 2.0 Hz, 1H), 7.87-7.82 (m, 2H), 7.62-7.56 (m, 2H), 7.56-7.50 (m, 2H), 7.45-7.39 (m, 1H), 7.37-7.32 (m, 1H), 7.26-7.20 (m, 1H), 3.30-3.24 (m, 4H), 1.69-1.62 (m, 4H), 1.62-1.54 (m, 2H).
実施例２５９
Figure JPOXMLDOC01-appb-C000196
 　実施例１２２と同様にして、以下の化合物を得た。
Ｎ－（６－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6+D2O)δ値：8.40-8.34(m,1H),7.71(d,J=11.0Hz,1H),7.67-7.61(m,2H),7.61-7.54(m,2H),7.54-7.48(m,2H),7.40(dd,J=7.8,7.8Hz,1H),7.36-7.31(m,1H),7.25-7.19(m,1H),3.29-3.22(m,4H),1.69-1.62(m,4H),1.62-1.54(m,2H). Example 259
Figure JPOXMLDOC01-appb-C000196
 In the same manner as in Example 122, the following compound was obtained.
N- (6-Fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.40-8.34 (m, 1H), 7.71 (d, J = 11.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.61-7.54 (m, 2H), 7.54-7.48 (m, 2H), 7.40 (dd, J = 7.8,7.8Hz, 1H), 7.36-7.31 (m, 1H), 7.25-7.19 (m, 1H), 3.29-3.22 (m, 4H), 1.69-1.62 (m, 4H), 1.62-1.54 (m, 2H).
実施例２６０
Figure JPOXMLDOC01-appb-C000197
 　実施例１２２と同様にして、以下の化合物を得た。
Ｎ－（５－フルオロ－４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：12.90-12.70(broad,1H),10.55-10.43(broad,1H),8.10(s,1H),7.82-7.76(m,2H),7.66(d,J=11.2Hz,1H),7.58-7.52(m,2H),7.52-7.46(m,1H),7.45-7.40(m,1H),7.36(dd,J=7.9,7.9Hz,1H),7.26(d,J=7.6Hz,1H),7.21-7.14(m,1H),3.27-3.20(m,4H),1.69-1.61(m,4H),1.61-1.53(m,2H). Example 260
Figure JPOXMLDOC01-appb-C000197
 In the same manner as in Example 122, the following compound was obtained.
N- (5-Fluoro-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) Benzamide
1 H-NMR (DMSO-d 6 ) δ value: 12.90-12.70 (broad, 1H), 10.55-10.43 (broad, 1H), 8.10 (s, 1H), 7.82-7.76 (m, 2H), 7.66 (d , J = 11.2Hz, 1H), 7.58-7.52 (m, 2H), 7.52-7.46 (m, 1H), 7.45-7.40 (m, 1H), 7.36 (dd, J = 7.9,7.9Hz, 1H), 7.26 (d, J = 7.6Hz, 1H), 7.21-7.14 (m, 1H), 3.27-3.20 (m, 4H), 1.69-1.61 (m, 4H), 1.61-1.53 (m, 2H).
実施例２６１
Figure JPOXMLDOC01-appb-C000198
 　実施例１２０と同様にして、以下の化合物を得た。
Ｎ－（２－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）－５－フェノキシフェニル）－３－（ピペリジン－１－イル）ベンズアミド
1H-NMR(DMSO-d6)δ値：13.20-12.70(broad,1H),10.58-10.51(broad,1H),8.06(d,J=2.4Hz,1H),7.73(d,J=8.8Hz,1H),7.53-7.41(m,3H),7.39-7.32(m,1H),7.31-7.23(m,2H),7.21-7.14(m,3H),6.95(dd,J=8.5,2.4Hz,1H),3.27-3.20(m,4H),1.68-1.60(m,4H),1.60-1.52(m,2H). Example 261
Figure JPOXMLDOC01-appb-C000198
 In the same manner as in Example 120, the following compound was obtained.
N- (2- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -5-phenoxyphenyl) -3- (piperidin-1-yl) benzamide
1 H-NMR (DMSO-d 6 ) δ value: 13.20-12.70 (broad, 1H), 10.58-10.51 (broad, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.53-7.41 (m, 3H), 7.39-7.32 (m, 1H), 7.31-7.23 (m, 2H), 7.21-7.14 (m, 3H), 6.95 (dd, J = 8.5, 2.4 Hz, 1H), 3.27-3.20 (m, 4H), 1.68-1.60 (m, 4H), 1.60-1.52 (m, 2H).
実施例２６２
Figure JPOXMLDOC01-appb-C000199
 　３－（３－（ピペリジン－１－イル）フェニル）プロピオル酸0.055gの塩化メチレン3mL溶液にＮ，Ｎ－ジイソプロピルエチルアミン0.10mL、ヘキサフルオロリン酸ブロモトリス（ピロリジノ）ホスホニウム0.14gおよび３－（３－アミノビフェニル－４－イル）－１，２，４－オキサジアゾール－５（４Ｈ）－オン0.062gを順次加え、室温で4時間攪拌した。減圧下で溶媒を留去し、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［関東化学株式会社、シリカゲル６０（球状）、溶離液；80-40％ヘキサン／酢酸エチル］で精製し、淡黄色固体のＮ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（３－（ピペリジン－１－イル）フェニル）プロピオルアミド0.019gを得た。
1H-NMR(DMSO-d6)δ値：10.76-10.67(broad,1H),8.18-8.12(m,1H),7.78-7.68(m,4H),7.57-7.49(m,2H),7.49-7.43(m,1H),7.34-7.25(m,1H),7.16-7.08(m,2H),7.04-6.95(m,1H),3.25-3.15(m,4H),1.66-1.51(m,6H). Example 262
Figure JPOXMLDOC01-appb-C000199
 To a solution of 0.055 g of 3- (3- (piperidin-1-yl) phenyl) propiolic acid in 3 mL of methylene chloride, 0.10 mL of N, N-diisopropylethylamine, 0.14 g of bromotris (pyrrolidino) phosphonium hexafluorophosphate and 3- (3- Aminobiphenyl-4-yl) -1,2,4-oxadiazol-5 (4H) -one (0.062 g) was sequentially added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-40% hexane / ethyl acetate] to give a pale yellow solid N- (4- (5- 0.019 g of oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (3- (piperidin-1-yl) phenyl) propiolamido is obtained. It was.
1 H-NMR (DMSO-d 6 ) δ value: 10.76-10.67 (broad, 1H), 8.18-8.12 (m, 1H), 7.78-7.68 (m, 4H), 7.57-7.49 (m, 2H), 7.49 -7.43 (m, 1H), 7.34-7.25 (m, 1H), 7.16-7.08 (m, 2H), 7.04-6.95 (m, 1H), 3.25-3.15 (m, 4H), 1.66-1.51 (m, 6H).
実施例２６３
Figure JPOXMLDOC01-appb-C000200
 　実施例２６２と同様にして、以下の化合物を得た。
３－（３－（ジエチルアミノ）フェニル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）プロピオルアミド
1H-NMR(DMSO-d6+D2O)δ値：8.13-8.08(m,1H),7.78-7.69(m,4H),7.58-7.51(m,2H),7.50-7.44(m,1H),7.31-7.23(m,1H),6.88-6.80(m,3H),3.40-3.31(m,4H),1.13-1.07(m,6H). Example 263
Figure JPOXMLDOC01-appb-C000200
 In the same manner as in Example 262, the following compound was obtained.
3- (3- (Diethylamino) phenyl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) propioramide
1 H-NMR (DMSO-d 6 + D 2 O) δ value: 8.13-8.08 (m, 1H), 7.78-7.69 (m, 4H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.31-7.23 (m, 1H), 6.88-6.80 (m, 3H), 3.40-3.31 (m, 4H), 1.13-1.07 (m, 6H).
　本発明の新規なアミド誘導体またはその塩は、コラーゲン産生阻害作用を有し、安全性および動態に優れることから、たとえば、肺線維症、強皮症、腎硬化症および肝硬変などのコラーゲンの過剰産生が関与する疾患の予防または治療などの処置に有用である。さらに、本発明化合物は、優れた代謝安定性を有する。 Since the novel amide derivative of the present invention or a salt thereof has a collagen production inhibitory action and is excellent in safety and kinetics, for example, overproduction of collagen such as pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis It is useful for treatments such as prevention or treatment of diseases in which is involved. Furthermore, the compound of the present invention has excellent metabolic stability.

Claims (26)

  1. 一般式[１]
    Figure JPOXMLDOC01-appb-C000001
     「式中、
    Ｒ１は、置換基群αから選ばれる１つ以上の基で置換されていてもよいアリール基、置換基群αから選ばれる１つ以上の基で置換されていてもよい単環の複素環式基または置換されていてもよい二環式の複素環式基を；
    Ｒ２およびＲ３の一方は、一般式－Ｘ１－Ｒ６「式中、Ｘ１は、酸素原子、硫黄原子、保護されていてもよいイミノ基、置換されていてもよいＣ１－６アルキレン基、置換されていてもよいＣ２－６アルケニレン基、置換されていてもよいＣ２－６アルキニレン基または結合手を；Ｒ６は、置換されていてもよいアリール基、置換されていてもよい複素環式基または置換されていてもよいＣ３－８シクロアルキル基を示す。」で表される基を；
    Ｒ２およびＲ３の他方は、水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよいアリール基または一般式－Ｘ１－Ｒ６「式中、Ｘ１およびＲ６は、前記と同様な意味を有する。」で表される基を；
    Ｘ２は、置換されていてもよいＣ１－６アルキレン基、置換されていてもよいＣ２－６アルケニレン基、置換されていてもよいＣ２－６アルキニレン基または結合手を；
    Ｚ１およびＺ２は、同一または異なって、窒素原子または一般式Ｃ－Ｒ７「式中、Ｒ７は、水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基または置換されていてもよいＣ１－６アルコキシ基を示す。」で表される基を；
    Ｙは、－Ｎ＝Ｎ－、－Ｓ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｓ－または－Ｃ（Ｓ）－Ｏ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）を示す。
    但し、Ｒ３が一般式－Ｘ１－Ｒ６「式中、Ｘ１およびＲ６は前記と同様な意味を有する。」で表される基であるとき、Ｙは、－Ｓ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｓ－または－Ｃ（Ｓ）－Ｏ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）であり、かつ、Ｘ２は結合手である。」で表される化合物またはその塩。
    置換基群α：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基または一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基     General formula [1]
    Figure JPOXMLDOC01-appb-C000001
     "In the formula,
    R 1 represents an aryl group which may be substituted with one or more groups selected from substituent group α, and a monocyclic heterocyclic ring which may be substituted with one or more groups selected from substituent group α A formula group or an optionally substituted bicyclic heterocyclic group;
    One of R 2 and R 3 has the general formula —X 1 —R 6 wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 An alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6 is an optionally substituted aryl group, A heterocyclic group or an optionally substituted C 3-8 cycloalkyl group ”.
    The other of R 2 and R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an optionally substituted aryl group, or A group represented by the general formula -X 1 -R 6 , wherein X 1 and R 6 have the same meaning as described above;
    X 2 represents an optionally substituted C 1-6 alkylene group, an optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond;
    Z 1 and Z 2 may be the same or different and each represents a nitrogen atom or a general formula C—R 7 wherein R 7 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or a substituted A C 1-6 alkoxy group which may optionally be represented by the formula:
    Y represents —N═N—, —S (O) —O—, —C (O) —O—, —C (O) —S— or —C (S) —O— (in each group It is assumed that the bond on the left side is bonded to NH.)
    However, when R 3 is a group represented by the general formula —X 1 —R 6 , wherein X 1 and R 6 have the same meanings as described above, Y represents —S (O) — O—, —C (O) —O—, —C (O) —S— or —C (S) —O— (provided that the bond on the left side of each group is bonded to NH) And X 2 is a bond. Or a salt thereof.
    Substituent group α: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ”
  2. Ｙが－Ｎ＝Ｎ－、－Ｃ（Ｏ）－Ｏ－、－Ｃ（Ｏ）－Ｓ－または－Ｃ（Ｓ）－Ｏ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）である請求項１に記載の化合物またはその塩。 Y is —N═N—, —C (O) —O—, —C (O) —S— or —C (S) —O— (where the bond on the left side of each group binds to NH) The compound according to claim 1 or a salt thereof.
  3. Ｒ２が一般式－Ｘ１－Ｒ６「式中、Ｘ１は、酸素原子、硫黄原子、保護されていてもよいイミノ基、置換されていてもよいＣ１－６アルキレン基、置換されていてもよいＣ２－６アルケニレン基、置換されていてもよいＣ２－６アルキニレン基または結合手を；Ｒ６は、置換されていてもよいアリール基、置換されていてもよい複素環式基または置換されていてもよいＣ３－８シクロアルキル基を示す。」で表される基、Ｒ３が水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基または置換されていてもよいアリール基である請求項１または２に記載の化合物またはその塩。 R 2 is represented by the general formula —X 1 —R 6 wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 alkylene group, a substituted An optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6 is an optionally substituted aryl group, an optionally substituted heterocyclic group Or a C 3-8 cycloalkyl group which may be substituted. ”, A group represented by R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or a substituted group. The compound or a salt thereof according to claim 1 or 2, which is an optionally substituted C 1-6 alkoxy group or an optionally substituted aryl group.
  4. Ｒ１が置換基群αから選ばれる１つ以上の基で置換されていてもよいアリール基または置換基群αから選ばれる１つ以上の基で置換されていてもよい単環の複素環式基である請求項１～３のいずれか一項に記載の化合物またはその塩。
    置換基群α：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基または一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基     R 1 is an aryl group which may be substituted with one or more groups selected from substituent group α or a monocyclic heterocyclic group which may be substituted with one or more groups selected from substituent group α The compound or a salt thereof according to any one of claims 1 to 3, which is a group.
    Substituent group α: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ”
  5. Ｙが－Ｎ＝Ｎ－、－Ｃ（Ｏ）－Ｏ－または－Ｃ（Ｏ）－Ｓ－（但し、各基の左側の結合手が、ＮＨに結合するものとする。）である請求項１～４のいずれか一項に記載の化合物またはその塩。 Y is —N═N—, —C (O) —O— or —C (O) —S— (where the bond on the left side of each group is bonded to NH). 5. The compound according to any one of 1 to 4 or a salt thereof.
  6. Ｚ１およびＺ２が、同一または異なって、一般式Ｃ－Ｒ７「式中、Ｒ７は、水素原子、ハロゲン原子、置換されていてもよいＣ１－６アルキル基または置換されていてもよいＣ１－６アルコキシ基を示す。」で表される基である請求項１～５のいずれか一項に記載の化合物またはその塩。 Z 1 and Z 2 may be the same or different and have the general formula C—R 7 , wherein R 7 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted The compound or a salt thereof according to any one of claims 1 to 5, wherein the compound is a group represented by the formula: a good C 1-6 alkoxy group.
  7. Ｒ２が一般式－Ｘ１－Ｒ６ａ「式中、Ｘ１は、酸素原子、硫黄原子、保護されていてもよいイミノ基、置換されていてもよいＣ１－６アルキレン基、置換されていてもよいＣ２－６アルケニレン基、置換されていてもよいＣ２－６アルキニレン基または結合手を；Ｒ６ａは、置換されていてもよいアリール基を示す。」で表される基、Ｒ３が水素原子である請求項１～６のいずれか一項に記載の化合物またはその塩。 R 2 has the general formula —X 1 —R 6a “wherein X 1 is an oxygen atom, a sulfur atom, an optionally protected imino group, an optionally substituted C 1-6 alkylene group, a substituted An optionally substituted C 2-6 alkenylene group, an optionally substituted C 2-6 alkynylene group or a bond; R 6a represents an optionally substituted aryl group; a group represented by R The compound or a salt thereof according to any one of claims 1 to 6, wherein 3 is a hydrogen atom.
  8. Ｒ２が一般式－Ｘ１ｄ－Ｒ６ａ「式中、Ｘ１ｄは、結合手を；Ｒ６ａは、置換されていてもよいアリール基を示す。」で表される基、Ｒ３が水素原子である請求項１～７のいずれか一項に記載の化合物またはその塩。 R 2 is a group represented by the general formula —X 1d —R 6a wherein X 1d represents a bond; R 6a represents an optionally substituted aryl group, and R 3 represents a hydrogen atom. The compound or a salt thereof according to any one of claims 1 to 7, wherein
  9. Ｘ２がＣ１－６アルキレン基、Ｃ２－６アルケニレン基、Ｃ２－６アルキニレン基または結合手である請求項１～８のいずれか一項に記載の化合物またはその塩。 The compound or a salt thereof according to any one of claims 1 to 8, wherein X 2 is a C 1-6 alkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group or a bond.
  10. Ｒ１が置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基で置換されているアリール基または置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されている単環の複素環式基である請求項１～９のいずれか一項に記載の化合物またはその塩。 R 1 is an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same or different and are a hydrogen atom or an optionally substituted C 1-6 alkyl An aryl group substituted with a group represented by the formula: or an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same as defined above The compound or a salt thereof according to any one of claims 1 to 9, which is a monocyclic heterocyclic group substituted with a group represented by:
  11. Ｘ２が結合手である請求項１～１０のいずれか一項に記載の化合物またはその塩。 The compound or a salt thereof according to any one of claims 1 to 10, wherein X 2 is a bond.
  12. Ｒ１が置換基群αから選ばれる１つ以上の基で置換されていてもよいアリール基または置換基群αから選ばれる１つ以上の基で置換されていてもよい単環の複素環式基、Ｘ２が結合手である請求項１～９のいずれか一項に記載の化合物またはその塩。
    置換基群α：ハロゲン原子、ニトロ基、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ２－６アルケニル基、置換されていてもよいＣ２－６アルキニル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよい複素環式基、置換されていてもよい環状アミノ基または一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基     R 1 is an aryl group which may be substituted with one or more groups selected from substituent group α or a monocyclic heterocyclic group which may be substituted with one or more groups selected from substituent group α The compound or a salt thereof according to any one of claims 1 to 9, wherein the group X 2 is a bond.
    Substituent group α: a halogen atom, a nitro group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted heterocyclic group, an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 Are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group. ”
  13. Ｒ１が置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。」で表される基で置換されているアリール基または置換されていてもよい環状アミノ基もしくは一般式－ＮＲ４Ｒ５「式中、Ｒ４およびＲ５は、前記と同様な意味を有する。」で表される基で置換されている単環の複素環式基、Ｘ２が結合手である請求項１～１２のいずれか一項に記載の化合物またはその塩。 R 1 is an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same or different and are a hydrogen atom or an optionally substituted C 1-6 alkyl An aryl group substituted with a group represented by the formula: or an optionally substituted cyclic amino group or a general formula —NR 4 R 5 wherein R 4 and R 5 are the same as defined above The compound or a salt thereof according to any one of claims 1 to 12, wherein X 2 is a monocyclic heterocyclic group substituted with a group represented by:
  14. 化合物が４－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド、３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミド、３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（ピペリジン－１－イル）イソニコチンアミド、３－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミド、４－（ジメチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミド、Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドおよび３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドから選ばれる化合物である請求項１に記載の化合物またはその塩。 The compound is 4- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (piperidin-1-yl) -N- (4- ( 1H-tetrazol-5-yl) biphenyl-3-yl) benzamide, 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3- Yl) biphenyl-3-yl) benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- ( Piperidin-1-yl) isonicotinamide, 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2) , 4-Oxadiazol-3-yl) bi Enyl-3-yl) benzamide, N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidine- 1-yl) benzamide, 4- (dimethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide and 3- ( 2. The compound according to claim 1, which is a compound selected from diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) benzamide. Compound or Salt.
  15. ４－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。 4- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide or a salt thereof.
  16. ３－（ピペリジン－１－イル）－Ｎ－（４－（１Ｈ－テトラゾール－５－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。 3- (piperidin-1-yl) -N- (4- (1H-tetrazol-5-yl) biphenyl-3-yl) benzamide or a salt thereof.
  17. ３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide or a salt thereof.
  18. Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－２－（ピペリジン－１－イル）イソニコチンアミドまたはその塩。 N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -2- (piperidin-1-yl) isonicotinamide or Its salt.
  19. ３－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリン－４－イル）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。 3-((2R, 6S) -2,6-dimethylmorpholin-4-yl) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) ) Biphenyl-3-yl) benzamide or a salt thereof.
  20. Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドまたはその塩。 N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide or a salt thereof .
  21. ４－（ジメチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。 4- (Dimethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-3-yl) benzamide or a salt thereof.
  22. Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）－３－（ピペリジン－１－イル）ベンズアミドまたはその塩。 N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) -3- (piperidin-1-yl) benzamide or a salt thereof.
  23. ３－（ジエチルアミノ）－Ｎ－（４－（５－オキソ－４，５－ジヒドロ－１，２，４－チアジアゾール－３－イル）ビフェニル－３－イル）ベンズアミドまたはその塩。 3- (diethylamino) -N- (4- (5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl) biphenyl-3-yl) benzamide or a salt thereof.
  24. 請求項１～２３のいずれか一項に記載の化合物またはその塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 23 or a salt thereof.
  25. 請求項１～２３のいずれか一項に記載の化合物またはその塩を含有するコラーゲン産生阻害剤。 A collagen production inhibitor comprising the compound according to any one of claims 1 to 23 or a salt thereof.
  26. 請求項１～２３のいずれか一項に記載の化合物またはその塩を含有するコラーゲンの過剰産生が関与する疾患の処置剤。 An agent for treating a disease involving excessive production of collagen, comprising the compound or salt thereof according to any one of claims 1 to 23.
PCT/JP2013/067668 2012-06-28 2013-06-27 Novel amide derivative and salt thereof WO2014003124A1 (en)

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US9186361B2 (en) 2013-03-15 2015-11-17 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9233961B2 (en) 2013-03-15 2016-01-12 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9296754B2 (en) 2013-03-15 2016-03-29 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
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CN109195965B (en) * 2016-03-01 2022-07-26 普罗佩纶治疗公司 Inhibitors of WDR5 protein-protein binding
WO2024048478A1 (en) * 2022-08-31 2024-03-07 学校法人東京理科大学 Cancer treatment by combined use of immune checkpoint regulator and low-molecular-weight compound having anti-fibrotic effect

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