WO2014003124A1 - Nouveau dérivé d'amide et sel correspondant - Google Patents

Nouveau dérivé d'amide et sel correspondant 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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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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Publication of WO2014003124A1 publication Critical patent/WO2014003124A1/fr

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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
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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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    • 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.

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Abstract

La présente invention concerne un composé représenté par la formule (1), ou un sel correspondant, qui produit un effet inhibiteur sur la production de collagène et est ainsi utile pour la prévention, le traitement ou analogue(s) d'affections associées à une surproduction de collagène, telles que la fibrose pulmonaire, la sclérodermie, la néphrosclérose et la cirrhose. Dans la formule (1) : R1 représente un groupe aryle ou analogue(s) qui peut être substitué par un ou plusieurs groupes choisis dans le groupe substituant (α); l'un des R2 ou R3 représente un groupe répondant à la formule -X1-R6 (dans la formule, X1 représente un atome d'oxygène, une liaison, ou analogue(s), et R6 représente un groupe aryle, ou analogue(s), qui peut être substitué; l'autre R2 ou R3 représente un atome d'hydrogène ou un atome d'halogène; Z1 et Z2 peuvent être identiques ou différents et représentent un atome d'azote ou le groupe répondant à la formule C-R7 (dans la formule, R7 représente un atome d'hydrogène ou un atome d'halogène); et Y représente -N=N-, -S(O)-O-, -C(O)-O-, -C(O)-S- ou -C(S)-O- (la liaison située à la gauche de chaque groupe étant une liaison se liant à NH).
PCT/JP2013/067668 2012-06-28 2013-06-27 Nouveau dérivé d'amide et sel correspondant WO2014003124A1 (fr)

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US9303034B2 (en) 2013-12-19 2016-04-05 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
JP2017512794A (ja) * 2014-03-26 2017-05-25 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＴｒｋＡキナーゼ阻害薬、その組成物および方法
WO2017147700A1 (fr) 2016-03-01 2017-09-08 Ontario Institute For Cancer Research (Oicr) Inhibiteurs de la liaison protéine wdr5-protéine
JP2019507179A (ja) * 2016-03-01 2019-03-14 プロペロン セラピューティックス インコーポレイテッド Ｗｄｒ５タンパク質−タンパク質結合の阻害剤
WO2024048478A1 (fr) * 2022-08-31 2024-03-07 学校法人東京理科大学 Traitement du cancer par utilisation combinée d'un régulateur des points de contrôle immunitaire et d'un composé de faible poids moléculaire présentant un effet anti-fibrotique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008003141A1 (fr) * 2006-07-05 2008-01-10 Fibrotech Therapeutics Pty Ltd Composés thérapeutiques
WO2009013915A1 (fr) * 2007-07-25 2009-01-29 Renascience Co., Ltd. Inhibiteur de l'inhibiteur de l'activateur du plasminogène de type 1
WO2010087430A1 (fr) * 2009-01-30 2010-08-05 富山化学工業株式会社 Dérivé de l'acide n-acyle anthranilique ou son sel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008003141A1 (fr) * 2006-07-05 2008-01-10 Fibrotech Therapeutics Pty Ltd Composés thérapeutiques
WO2009013915A1 (fr) * 2007-07-25 2009-01-29 Renascience Co., Ltd. Inhibiteur de l'inhibiteur de l'activateur du plasminogène de type 1
WO2010087430A1 (fr) * 2009-01-30 2010-08-05 富山化学工業株式会社 Dérivé de l'acide n-acyle anthranilique ou son sel

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US9303034B2 (en) 2013-12-19 2016-04-05 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9700559B2 (en) 2013-12-19 2017-07-11 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US11123348B2 (en) 2013-12-19 2021-09-21 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US10085989B2 (en) 2013-12-19 2018-10-02 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US10596175B2 (en) 2013-12-19 2020-03-24 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
JP2017512794A (ja) * 2014-03-26 2017-05-25 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＴｒｋＡキナーゼ阻害薬、その組成物および方法
JP2019507179A (ja) * 2016-03-01 2019-03-14 プロペロン セラピューティックス インコーポレイテッド Ｗｄｒ５タンパク質−タンパク質結合の阻害剤
CN109195965A (zh) * 2016-03-01 2019-01-11 普罗佩纶治疗公司 Wdr5蛋白质-蛋白质结合的抑制剂
JP2019512482A (ja) * 2016-03-01 2019-05-16 プロペロン セラピューティクス インコーポレイテッド Ｗｄｒ５タンパク質−タンパク質結合の阻害剤
EP3423437A4 (fr) * 2016-03-01 2019-07-24 Propellon Therapeutics Inc. Inhibiteurs de la liaison entre la protéine wdr5 et ses partenaires de liaison
EP3423451A4 (fr) * 2016-03-01 2019-09-04 Propellon Therapeutics Inc. Inhibiteurs de la liaison protéine wdr5-protéine
IL261472A (en) * 2016-03-01 2018-10-31 Propellon Therapeutics Inc Inhibitors of linking the wdr5 protein with other proteins
EA038109B1 (ru) * 2016-03-01 2021-07-07 Пропеллон Терапьютикс Инк. Ингибиторы связывания белка wdr5 с белками
WO2017147700A1 (fr) 2016-03-01 2017-09-08 Ontario Institute For Cancer Research (Oicr) Inhibiteurs de la liaison protéine wdr5-protéine
US11174250B2 (en) 2016-03-01 2021-11-16 Propellon Therapeutics Inc. Substituted carboxamides as inhibitors of WDR5 protein-protein binding
US11319299B2 (en) 2016-03-01 2022-05-03 Propellon Therapeutics Inc. Substituted carboxamides as inhibitors of WDR5 protein-protein binding
CN109195965B (zh) * 2016-03-01 2022-07-26 普罗佩纶治疗公司 Wdr5蛋白质-蛋白质结合的抑制剂
WO2024048478A1 (fr) * 2022-08-31 2024-03-07 学校法人東京理科大学 Traitement du cancer par utilisation combinée d'un régulateur des points de contrôle immunitaire et d'un composé de faible poids moléculaire présentant un effet anti-fibrotique

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