WO2006046552A1 - Novel nitrogenous heterocyclic compounds and salts thereof - Google Patents

Novel nitrogenous heterocyclic compounds and salts thereof Download PDF

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Publication number
WO2006046552A1
WO2006046552A1 PCT/JP2005/019586 JP2005019586W WO2006046552A1 WO 2006046552 A1 WO2006046552 A1 WO 2006046552A1 JP 2005019586 W JP2005019586 W JP 2005019586W WO 2006046552 A1 WO2006046552 A1 WO 2006046552A1
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group
optionally substituted
general formula
atom
alkyl
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PCT/JP2005/019586
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French (fr)
Japanese (ja)
Inventor
Taro Kiyoto
Yasuhiro Tsutsui
Tadashi Tanaka
Sumie Shimada
Nobuhiko Nomura
Toshiya Noguchi
Fumihito Ushiyama
Yasunobu Ushiki
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Toyama Chemical Co., Ltd.
Taisho Pharmaceutical Co., Ltd.
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Priority to JP2006543165A priority Critical patent/JP5314244B2/en
Publication of WO2006046552A1 publication Critical patent/WO2006046552A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel nitrogen-containing heterocyclic compound or a salt thereof having strong antibacterial activity against gram positive bacteria, gram negative bacteria and resistant bacteria, and an antibacterial agent containing them.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE viterrator-resistant enterococci
  • PRSP penicillin-resistant pneumococci
  • Patent Document 1 discloses a quinolone compound effective for MRSA. Further, compounds having an action mechanism different from that of existing drugs are described in WO04 Z002490 (Patent Document 2), WO04Z002992 (Patent Document 3) and WO04Z089947 (Patent Document 4). Things are known.
  • Patent Literature l WO99Z07682
  • Patent Document 2 WO04Z002490
  • Patent Document 3 Publication of WO04Z002992
  • Patent Document 4 WO04Z089947
  • R 1 represents a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkoxy or acyloxy group
  • R 2 , R 3 , R 4 and R 5 are A hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, cycloalkyl, amino or rubamoyl group
  • Z 1 and Z 2 represents a nitrogen atom or CR 7 wherein R 7 is a hydrogen atom, a halogen atom, a cyan group, an optionally protected carboxy group or an optionally substituted alkyl, alkenyl, alkoxy, An amino group or a rubamoyl group ”, and at least one of Z 1 and Z 2 represents a nitrogen atom
  • X 1 represents an oxygen atom, a sulfur atom, Fier group, sulfol group, NR 8a
  • X 2 represents a carbonyl group, NR 8b , wherein R 8b Represents a hydrogen atom or an optionally substituted alkyl or aryl group, or a bond;
  • X 3 represents a C alkylene group or a bond.
  • the Gote; R 6 has the general formula
  • R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group
  • R lla , R llb and R lle are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino-substituted lower alkyl, alkoxy or rubamoyl group
  • R 1 2 is the general formula
  • R 14 represents a hydrogen atom, an optionally protected carboxyl group or an optionally substituted cycloalkyl, cycloalkyl, aralkyl, aryl or heterocyclic group;
  • X 4 represents oxygen An atom, a sulfur atom, a carbonyl group or a bond;
  • X 5 is an optionally substituted alkylene group or a bond;
  • X 6 is an optionally substituted alkylene, alkylene or alkylene group.
  • X 7 represents an optionally substituted alkylene group or a bond; and
  • R 13 represents a hydrogen atom, an amino group protecting group or a substituted group; Means an alkyl or aryl group which may be "Means.
  • the present invention has been completed by finding that the nitrogen-containing heterocyclic compound represented by the above formula or a salt thereof has strong antibacterial activity and high safety.
  • the compound of the general formula [1] or a salt thereof is useful as an excellent antibacterial agent because it has strong antibacterial activity and high safety.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom
  • an alkyl group means, for example, methyl, ethyl, propyl, isopropyl, butyl, sec— Linear or branched C such as butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl
  • An alkyl group; a lower alkyl group is, for example, methyl, ethyl, propyl, isopropyl
  • a linear or branched C alkyl group such as butyl, sec butyl, isobutyl, tert butyl, pentyl and isopentyl;
  • Linear or branched C alkenyl such as nyl, aryl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3 butaenyl, pentenyl, 1,3 pentagenyl, hexenyl, heptenol and octenyl
  • An alkynyl group for example
  • linear or branched C such as ethynyl, 2-propyl and 2-butynyl
  • a cycloalkyl group is, for example, a C cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a cycloalkenyl group is, for example,
  • An alkylene group is, for example, a C-alkylene group such as methylene, ethylene, propylene, butylene, and hexylene; an ananolenylene group is, for example, vinylene, pro
  • C keywords such as penylene, butenylene, hexenylene, heptenylene and octenylene
  • alkylene group is, for example, a C alkynylene group such as ethylene, propynylene, petitylene, hexynylene, heptylene and octylene.
  • reel group examples include phenyl, naphthyl, 3,4-dihydronaphthyl, fluorine and phenanthryl; examples of the aralkyl group include benzyl, diphenylmethyl, trityl, phenethyl and naphthyl. Al C alkyl groups such as methyl
  • An alkoxy group is, for example, a linear or branched C alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec butoxy, tert butoxy, pentyloxy and isopentoxy;
  • Xoxy groups include, for example, alkoxy groups such as benzyloxy, diphenylmethyloxy, trityloxy, phenethyloxy and naphthylmethyloxy;
  • a alkoxyalkyl group is, for example, a C alkyloxy C alkyl group such as methoxymethyl and 1 ethoxyethyl; an aralkyloxyalkyl group is, for example,
  • Alkyl alkoxy such as benzyloxymethyl and phenethyloxymethyl C alkyl group
  • the acyl group is, for example, a linear or branched C alkanoyl group such as formyl group, acetyl, propiol and isovaleryl, or an al Cyl group such as benzyl carboyl.
  • Cyclic hydrocarbon carbo such as alkyl carbo groups, benzoyl and naphthoyl
  • -Heterocyclic groups nicotinol, tenol, pyrrolidinocarbol and furoyl, etc., heterocyclic carbol groups, succinyl groups, glutaryl groups, maleoyl groups, phthaloyl groups and amino acids (as amino acids, for example glycine , Alanine, noline, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, wasparagine, glutamine, anoleginine, lysine, histidine, hydroxylysine, phenenolealanine, tyrosine, tryptophan, proline and hydroxyproline, etc.
  • amino acids for example glycine , Alanine, noline, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, wasparagine, glutamine, anolegi
  • a linear or branched aaminoalkanoyl group which may be protected at the N-terminus derived from the above; an alkyloxycarbonyl group is, for example, methoxycarbo- , Ethoxycarbonyl, Linear or branched C alkyloxycarbons such as 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tert butoxycarbonyl, and tert pentyloxycarbon
  • An arylcarbonyl group is, for example, a group such as a phenylcarbol
  • the acyloxy group includes, for example, linear or branched C alkanoyloxy groups such as acetyloxy and propio-oxy and benzoyloxy.
  • Aroyloxy group for example, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methoxybenzoylmethyl and 1-benzoylethyl;
  • a group such as acetoxymethyl, propio-loxymethyl and bivalyloxymethyl
  • an alkylthioalkyl group is a C alkylthioC alkyl group such as methylthiomethyl, ethylthiomethyl and propylthiomethyl;
  • the thio group is, for example, a group such as phenolthio; the alkanesulfonyl group is, for example, Substituted with a halogen atom such as methanesulfonyl, trichloromethanesulfonyl, trifluoromethanesulfonyl, ethanesulfol, and propanesulfol.
  • a halogen atom such as methanesulfonyl, trichloromethanesulfonyl, trifluoromethanesulfonyl, ethanesulfol, and propanesulfol.
  • Xyl groups are for example groups such as benzenesulfo-oxyl and toluenesulfo-loxy; arylthioalkyl groups are for example phenylsulfurmethyl and 2- (p-trophenylsulfuryl) An aryl group such as p-toluenesulfo-ruethyl; an arylsulfur group such as benzenesulfiel; and an alkylamino group.
  • a mono- or di-C alkylamino group such as methylamino-containing ethylamino, propylamino-containing isopropylamino-containing butylamino-containing dimethylamino, jetylamino-containing diisopropylamino or dibutylamino;
  • the cycloalkylidene group is, for example, a group such as cyclopentylidene and cyclohexylidene; the alkylidene group is, for example, a group such as benzylidene and naphthylmethylene; and the dialkylaminoalkylidene group is, for example, N, N dimethyl A group such as aminomethylene and N, N-deethylaminomethylene; a dialalkylphosphoryl group, for example, a group such as dibenzylphosphoryl; a diallyl phosphoryl group, for example, a group such as diphenylphosphoryl;
  • oxygen-containing heterocyclic groups include groups such as 2-tetrahydrobiranyl and 2-tetrahydrofuranyl; examples of oxygen-containing heterocyclic alkyl groups include, for example, 5 methyl 2-oxo 2H—1, 3 dioxol 4-ylmethyl, etc.
  • a sulfur-containing heterocyclic group is, for example, tetra A group such as drothiopyranyl; a heterocyclic oxycarbonyl group, for example, a group such as 2 furfuryloxycarbonyl, 8 quinolyloxycarbonyl; a nitrogen-containing heterocyclic alkyl group, for example, phthalimidomethyl and A group such as succinimidomethyl; a nitrogen-containing heterocyclic alkylidene group, for example, a group such as 3-hydroxy-4-pyridylmethylene; a substituted silyl group, for example, a group such as trimethylsilyl, triethylsilyl, and tributylsilyl; an alkylsilylalkyl group, for example, a group such as 2- (trimethylsilyl) ethyl;
  • Monocyclic heterocyclic groups include, for example, furyl, furfuryl, chael, 2 tulle, pyrrolyl, 1 pyrrolyl, 2 pyrrolyl, imidazolyl, pyrazolyl, 3 pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl , Oxaziazolyl, thiadiazolyl, furazal, pyrrolidyl, imidazolidyl, pyridyl, pyrimidyl, pyridazil, 1-piperidyl, 2 piperidyl, 3 piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperadil Groups such as 2-morpholinyl and 2-thiomorpholinyl;
  • Bicyclic heterocyclic groups include, for example, benzofuryl, isobenzofural, benzochel, benzo [b] thiophene-2-yl, indolyl, indole-2-yl, isoindolyl, Indolyl, benzimidazolyl, 1H— 1,2,3 Benzotriazole 5—yl, benzoxa xazolinole, benzoisoxa xazolinole, benzothiazolinole, 1,2,3 Benzoxa xadiazole 5 1, 2, 3 Benzothiadiazole 5 yl, 1H-indazolyl, prill, chromel, quinolyl, quinoline 2-yl, quinoline 3-yl, quinoline 6- , Isoquinolyl, phthaladyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chroman 6-y
  • the heterocyclic group includes, for example, a monocyclic heterocyclic group; a bicyclic heterocyclic group; and thianthenyl, xanthenyl, phenoxathiinyl, carbazolyl, 13 carbolinyl, phenanthridinyl, and atalidinyl. , Perimidinyl, phenanthracinyl, phenazinyl, phenothiazyl, and phenoxazinyl.
  • the protecting group of the amino group includes all groups that can be used as ordinary amino protecting groups.
  • W. Green et al. Protective 'Groups' In 'Organic' Synthesis (Protective Groups in Organic Synthesis) 3rd edition, 494-653, 1999, John Wiley & Sons, INC.
  • an acyl group an alkyl carboxy group, an aralkyl carboxy group, an aralkyl carboxy group, an aralkyl group, an alkoxyalkyl group, an aralkyloxyalkyl group, an allylthio group.
  • Examples thereof include an alkyl group and a substituted silyl group.
  • the hydroxyl-protecting group includes all groups that can be used as ordinary hydroxyl-protecting groups.
  • W. Green et al. Protective 'Groups' In 'Organic' Synthesis ( Protective Groups in Organic Synthesis) 3rd edition, pages 17-245, 1999, John Wiley & Sons JNC.
  • an acyl group an alkyloxycarbon group, an aralkyloxycarbonyl group, a heterocyclic oxycarbon group, an alkyl group, an alkenyl group, an aralkyl group, an oxygen-containing heterocyclic group And sulfur-containing heterocyclic groups, alkoxyalkyl groups, aralkyloxyalkyl groups, alkanesulfonyl groups, arylsulfonyl groups and substituted silyl groups.
  • the carboxyl protecting group includes all groups that can be used as ordinary carboxyl protecting groups.
  • W. Green et al. Protective 'Groups' In 'Organic' Synthesis (Protective Groups in Organic Synthesis) 3rd edition, Pp. 369-453, 1999, John Wiley & Sons, INC.
  • Examples of the leaving group include a halogen atom, an alkanesulfoxy group, an arylsulfonyl group, an acyloxy group, and the like.
  • substituted! May be alkyl, lower alkyl, alkyl, alkyl, cycloalkyl, cycloalkenyl, alkoxy, acyl, acyloxy, alkylene, alkylene, alkylene, aryl, Substituents for the substituents of aralkyl, heterocyclic, monocyclic heterocyclic and bicyclic heterocyclic groups include halogen atom; cyano group; nitro group; protected!
  • substituents include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a nitro group, a hydroxyl group, a carboxyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a jetylamino group, and a powerful rubamoyl group.
  • Methanesulfol group chloromethanesulfol group, ethanesulfol group, propanesulfol group, benzenesulfonyl group, toluenesulfol group, methyl group, fluoromethyl group, difluoromethyl group, triflate Fluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, hydroxymethyl group, carboxymethyl group, ethyl group, fluorethyl group, difluoroethyl group, trifluoroethyl group, chloroethyl group, dichloroethyl group, trifluoroethyl group, Hydroxyethyl group, carboxyethyl group, propyl group, fluoropropyl group, difluoropropyl group, trifluoropropyl group, chloropropyl group, dichloropropyl group, trichloropropyl group,
  • Substituents of carbamoyl and amino groups may be protected, may be protected, hydroxyl groups; protected !, may, amino groups; alkylamino groups; Alkanesulfonyl group substituted by halogen atom; aryl hydrocarbon group; alkyl group; alkenyl group; alkyl group; alkoxy group; alkoxy carbo ol group; acyl group; Substituted with an atom, an acyl group; an aryl group; a halogen atom, protected, hydroxyl group and protected, substituted with one or more groups selected from carboxyl groups An aryl group; an alkyl group substituted with a halogen atom; and one or more groups selected from a heterocyclic basic force.
  • substituents include hydroxyl group, amino group, methylamino group, ethylamino group, dimethylamino group, jetylamino group, methanesulfol group, chloromethanesulfol group, ethanesulfol group, propanesulfol group, and benzene.
  • substituents for the optionally substituted hydroxyl and mercapto groups include alkyl Alkyl group; cycloalkyl group; acyl group; aryl group; alkyl group; and halogen atom, optionally protected hydroxyl group and protected!
  • substituents for the optionally substituted hydroxyl and mercapto groups include alkyl Alkyl group; cycloalkyl group; acyl group; aryl group; alkyl group; and halogen atom, optionally protected hydroxyl group and protected!
  • alkyl, alkenyl, alkynyl and aryl bases substituted with one or more groups selected from carboxyl group power may be mentioned.
  • substituents include a methyl group, a carboxylmethyl group, an ethyl group, a fluorethyl group, a difluoroethyl group, a trifluoroethyl group, a chloroethyl group, a dichloroethyl group, a trichloroethyl group, a hydroxyethyl group, a carboxy group, and the like.
  • Examples of the salt of the compound represented by the general formula [1] include a known basic group such as an amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group.
  • Examples of the salt in the basic group include 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, citrate, trichloroacetic acid and trifluoroacetic acid; And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • mineral acids such as hydrochloric acid, hydrogen bromide and sulfuric acid
  • salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citrate, trichloroacetic acid and trifluoroacetic acid
  • salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, me
  • Salts in acidic groups include, for example, 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-dimethylaniline, N-methylbiperidine, N-methylmorpholine, jetylamine, dicycl Mention may be made of oral hexylamine, pro-in, dibenzylamine, N-benzyl-1- ⁇ -phenethylamine, and salts with nitrogen-containing organic bases such as dibenzylethylenediamine.
  • preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.
  • preferable compounds include the following compounds.
  • a compound in which R 1 is a halogen atom, a cyano group or an optionally substituted alkyl, alkoxy or acyloxy group is preferably a cyano group or a substituted, may be! / ⁇ alkyl or alkoxy group
  • Even more preferred are compounds in which the compound is an alkoxy group, which is more preferably an alkoxy group, which may be more preferably substituted.
  • R 2 , R 3 , R 4 and R 5 forces may be the same or different and each may be a hydrogen atom, halogen atom, cyano group, protected, carboxyl group or substituted, alkyl, alkke
  • the same or different hydrogen atom, halogen atom, optionally protected carboxyl group or substituted or alkyl or alkenyl group which is preferably the same or different for the compounds which are -l, alkoxy, amino or rubamoyl groups More preferably, the same or different hydrogen atom, protected, may be a carboxyl group or substituted !, and an alkyl or alkenyl group which may be further preferred is more preferable R 2, R 3, one of R 4 and R 5 is an optionally substituted alkyl or Aruke - group, the compound is externally powered hydrogen atom is more preferred more instrument R 2, R Particularly preferred are compounds in which one of 3 , R 4 and R 5 is an alkyl or alkenyl group substituted with a carboxyl
  • Z 1 is a nitrogen atom
  • Z 2 is CR 7 “wherein R 7 has the same meaning as described above”
  • R 6 is
  • R 3 is a hydrogen atom
  • R 4 is an optionally protected carboxyl group, protected or may be carboxyl R, alkyl, alkenyl, or cycloalkyl groups substituted with a group or a compound substituted with a strong rubermoyl group and being an alkyl or alkenyl group are more preferred
  • R 3 is a hydrogen atom
  • R 4 is protected !, but a compound that is substituted with a carboxyl group and is an alkenyl group is more preferred R 2 , R 3 and R 5 forces Hydrogen atom, R 4 , Be protected is substituted in good carboxyl group !, Ru compounds and even more preferably an
  • Z 1 and Z 2 are nitrogen atom, and the other is CR 7 wherein R 7 has the same meaning as described above.
  • Z 1 is preferably a nitrogen atom.
  • Z 2 is CR 7 , wherein R 7 has the same meaning as above. More preferred is a compound in which Z 1 is a nitrogen atom and Z 2 is CH. .
  • X 1 is an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, NR 8a "wherein R 8a has the same meaning as described above” or CR 9a R 1C> a "wherein R 9a and R 1C> a are the same or different and each represents a hydrogen atom or a substituted group, which may be a hydroxyl, an amino or a mercapto group. ”NR 8a wherein R 8a is , Or CR 9a R 1C> a wherein R 9a and R 1C> a have the same meaning as described above. CH, NH Or more preferably a compound that is CHOH.
  • a compound in which X 2 is a carbonyl group or a bond is preferred! /.
  • a compound in which X 3 is CH or a bond is preferred.
  • X 1 — X 2 — X 3 is NHCO, CH 2 CH
  • R 6 is
  • R ⁇ is a general formula
  • R 14a represents an optionally substituted aralkyl, monocyclic heterocyclic or bicyclic heterocyclic group
  • X 6a represents an alkylene group
  • X 4 and X 5 represent the above and that having a meaning similar to a group represented by ";. continuous 11, R lla, R llb, R lle and R 13 have the same meaning. ”Is preferred
  • R 12b is a general formula
  • R 14b is an optionally substituted monocyclic heterocyclic or bicyclic heterocyclic group
  • X 4a represents an oxygen atom, a sulfur atom or a bond
  • m represents an integer of 1-4.
  • R 13a represents a hydrogen atom or a substituted or unsubstituted alkyl or aryl group; 1 , R 11a , R llb and R llc have the same meanings as described above. Is more preferred,
  • the compound is “wherein has the same meaning as described above.”
  • R 12b has the same meaning as described above.
  • at least one of R 3 and R 4 is a halogen atom, an optionally protected carboxyl group, or an optionally substituted rubamoyl, alkyl, alkenyl, or cycloalkyl group;
  • Z 1 is nitrogen atom;
  • Z 2 is ".
  • R 7 is that having a said the same meaning" CR 7 cases, R 6 is,
  • R 3 is a hydrogen atom; R 4 is substituted with an optionally protected carboxyl group R 6 is an alkenyl group
  • R 12e is a general formula
  • R 14e represents an optionally substituted aryl, monocyclic heterocyclic or bicyclic bicyclic group
  • X 6b represents an optionally substituted alkylene, alkene, or An alkylene group
  • X 4a has the same meaning as described above
  • R 11 and R 13a have the same meaning as described above. Is more preferable.
  • R 1 is an alkoxy group
  • R 2 and R 5 are hydrogen atoms
  • R 6 is
  • R 6 , R 12a , R 12b and R 12c are the same as R 6 , R 12a , R 12b and R 12c.
  • R 12a , R 12b and R 12e a compound having an m force of 1, 2 or 3 is preferred, and a compound of 1 or 2 is more preferred.
  • R 14b is an optionally substituted aryl, monocyclic heterocyclic or bicyclic heterocyclic group is preferably substituted.
  • representative compounds include, for example, compounds described in Tables 1, 2 and 3 below.
  • the compound of the present invention is produced by a combination of methods known per se.
  • the compound of the present invention can be produced by the following production method.
  • R 2a , R 3a , R 4a and R 5a are the same or different and each represents a hydrogen atom, a halogen atom, a cyan group, a protected carboxyl group, or an optionally substituted protected amino group.
  • X la is an oxygen atom, sulfur atom or NR 8a , wherein R 8a is the same as defined above Z la and Z 2a are a nitrogen atom or CR 7a wherein R 7a is a hydrogen atom, a halogen atom, a cyano group, a protected carboxyl group or an optionally substituted group.
  • Protected, amino or substituted may mean alkyl, alkenyl, alkoxy, or rubamoyl groups, and at least one of z la and z 2a is a nitrogen atom.
  • R 6 and X 3 Has the same meaning as described above.
  • the compound of the general formula [la] can be produced by reacting the compound of the general formula [2] with a reactive derivative of the compound of the general formula [3] in the presence or absence of a base. This reaction can be carried out by the method described in WO03Z010138, WO03Z087098 and Izumiya et al., Peptide synthesis basics and experiments, pp. 89-142, 1985, Maruzen et al.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone.
  • Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Dioxane, Tetrahydrofuran, Carsol, Ethylene glycol dimethyl ether, Diethylene glycol dimethyl ether and Diethylene glycol
  • ethers such as cetyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone and esters such as ethyl acetate. These may be used as a mixture. .
  • Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminoviridine and triethylamine; sodium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate.
  • organic bases such as pyridine, dimethylaminoviridine and triethylamine
  • sodium hydroxide sodium hydroxide
  • sodium bicarbonate sodium bicarbonate
  • potassium carbonate sodium carbonate
  • Examples include inorganic bases.
  • reactive derivatives used in this reaction include acid chloride and acid promide.
  • Acid halides such as: p-trophyl esters, N hydroxysuccinimide esters and N hydroxyphthalimide esters; active esters such as ethyl ester carbonates, mixed acid anhydrides with monoalkyl ester carbonates such as isobutyl acid and
  • Examples thereof include mixed acid anhydrides with organic acids such as bivalic acid. These reactive derivatives may be used without isolation.
  • a reactive reagent may be generated in the system using a coupling reagent.
  • the amount of the base used as desired, the reactivity derivative of the compound of the general formula [3], and the coupling reagent is 1 to 50 times mol, preferably the compound of the general formula [2] It should be 1 to 5 times the mole!
  • This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
  • Y 3 represents a protecting group for an amino group; 1 , R 11a , R llb , R llc , R 12 , R 13 have the same meanings as described above.
  • R 2a , R 3a , R 4a , R 5a , X la , Z la and Z 2a have the same meaning as described above.
  • the compound of the general formula [lb] can be produced by reacting the compound of the general formula [2] with a carbonyl compound in the presence or absence of a base and then reacting with the compound of the general formula [4]. it can.
  • the compound of general formula [lb] can be reacted with the compound of general formula [2] after reacting the compound of general formula [4] with a carbonyl compound in the presence or absence of a base.
  • This reaction may be carried out by the method described in WO02 / 50061, WO02Z56882 or the like or a method analogous thereto.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone.
  • Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Dioxane, Tetrahydrofuran, Carsol, Ethylene glycol dimethyl ether, Diethylene glycol dimethyl ether and Diethylene glycol
  • ethers such as cetyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone and esters such as ethyl acetate. These may be used as a mixture. .
  • Examples of the carbonyl compound used in this reaction include 1,1'-carbodiimidazole, carbonyl chloride [phosgene] and bis (trichloromethyl) carbonate [triphosgene].
  • Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminoviridine and triethylamine; sodium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate. Inorganic bases I can get lost.
  • organic bases such as pyridine, dimethylaminoviridine and triethylamine
  • sodium hydroxide sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate.
  • Inorganic bases I can get lost.
  • the use amount of the base, the compound of the general formula [4] and the carbocyclic compound used as desired is 1 to 50 times mol, preferably 1 to 5 times that of the compound of the general formula [2]. It should be double mole.
  • This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
  • the compound of the general formula [lc] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [6] in the presence of a reducing agent.
  • This reaction is described in WO02Z50061, WO02Z56882 and Jerry March, Advanced Organic Chemistry 4th edition, pages 898-900, 1992, John Willie. You can do it by the method described in 'And' Sons, Inc. (John Wiley & Sons, INC.) Or a similar method!
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as form and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • dioxane, tetrahydrofuran, azole ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol
  • ethers such as monomethyl ether
  • sulfoxides such as dimethyl sulfoxide
  • esters such as ethyl acetate and water. These may be used as a mixture.
  • Examples of the reducing agent used in this reaction include lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride complex compounds such as borane, sodium and sodium. Examples include amalgam.
  • electrolytic reduction using copper or platinum as a cathode catalytic reduction using Raney nickel, platinum oxide or palladium black and reduction using “zinc acid” can be used.
  • the amount of the compound of the general formula [6] and the reducing agent used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [5].
  • This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 120 hours.
  • the compound of the general formula [lc] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [7] 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 influence the reaction.
  • methanol, ethanol, 2-propanol and 2-methyl-2-propano Alcohols such as alcohol; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; dioxane, tetrahydrofuran, alcohol, ethylene glycol dimethyl ether,
  • ethers such as polyethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate and water, and these may be used as a mixture.
  • Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminoviridine and triethylamine; sodium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate.
  • organic bases such as pyridine, dimethylaminoviridine and triethylamine
  • sodium hydroxide sodium hydroxide
  • sodium bicarbonate sodium bicarbonate
  • potassium carbonate sodium carbonate
  • Examples include inorganic bases.
  • the amount of the base and the compound of the general formula [7] used as desired may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [5]. Yes.
  • This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
  • R 2a , R 3a , R 4a , R 5a , R 6a , Z la and Z 2a have the same meaning as described above.
  • the compound of the general formula [Id] can be produced by reacting the compound of the general formula [8] with the compound of the general formula [4] in the presence of a reducing agent.
  • This reaction may be carried out according to production method 3-1.
  • R is an optionally substituted cycloalkyl, cycloalkyl, alkyl, aryl, or heterocyclic group;
  • R 15 is CR 2a , R 3a , R 4a
  • the compound of the general formula [le] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [9]. This reaction is the same as or similar to the method described in Bioorganic. Med. Chem. Lett., Vol. 13, pages 241-245, 2003. You can do this by
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as form and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • dioxane, tetrahydrofuran, azole ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Ethers such as monomethyl ether
  • sulfoxides such as dimethyl sulfoxide
  • ketones such as acetone and 2-butanone
  • esters such as ethyl acetate
  • water Water
  • the amount of the compound of the general formula [9] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [5]!
  • This reaction may be carried out at 30 to 150 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
  • R ⁇ R 2a , R 3a , R 4a , R 5a , R 14d , Q ⁇ X 1 , X 2 , X 3 , Z la and Z 2a have the same meaning as described above.
  • the compound of the general formula [If] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [10] in the presence or absence of a solvent. This reaction may be carried out by the method described in the Chemical Society of Japan, New Experimental Science Course 14, Synthesis and Reaction of Organic Compounds III, pp. 1628-1644, 1978, Maruzen, etc. !
  • Solvents used in this reaction are not particularly limited as long as they do not adversely influence the reaction.
  • halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • aromatics such as benzene, toluene and xylene.
  • Hydrocarbons such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol jetyl ether
  • sulfoxides such as dimethyl sulfoxide
  • ketones such as acetone and 2-butanone and ethyl acetate
  • the amount of the compound of the general formula [10] used is 1 to 50 times mol, preferably 1 to 5 times mol of the compound of the general formula [5]!
  • This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
  • T 1 is an oxygen atom, a sulfur atom or NR 8a ” wherein R 8a has the same meaning as described above; RR 2a , R 3a , R 4a , R 5a , R 6a , Z la and Z 2a have the same meaning as described above. "
  • the compound of the general formula [lg] or [lh] can be produced by reacting the compound of the general formula [11] with a compound of the general formula [4]. This reaction is carried out according to the method described in the journal 'Ob' Oga. Chem., Vol. 56, pages 5939 to 5942, 1991, or the like. Just do it.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • N, N dimethylformamide Amides such as N, N dimethylacetamide and 1-methyl-2-pyrrolidone
  • Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • Aromatic hydrocarbons such as benzene--, toluene and xylene
  • Dioxane Tetrahydrofuran, ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ether glycol such as ethylene glycol monomethyl ether
  • sulfoxides such as dimethyl sulfoxide
  • Ketones such as emissions and 2-butanone
  • esters and water such as acetic Echiru the like, Choi and used these were mixed.
  • the amount of the compound of the general formula [4] used may be 1 to 50 times mol, preferably 1 to 5 times mol of the compound of the general formula [11]!
  • This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
  • the compound of the general formula [li] is a solvent It can be produced by reacting the compound of general formula [28] with the compound of general formula [4] in the presence or absence of. This reaction may be carried out by the method described in W02 004Z058144 or the like, or a method according thereto. Solvents used in this reaction may be those which do not adversely affect the reaction.
  • methanol, ethanol , Alcohols such as 2-propanol and 2-methyl-2-propanol; amides such as N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone; methylene chloride, black mouth form and di Halogenated hydrocarbons such as chloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, azole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol Ethers such as methyl ether; sulfoxides such as di-methyl sulfoxide; ketones such as acetone and 2-butanone; and esters and water, such as acetic Echiru the like, Choi and used these were mixed.
  • amides such as N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidon
  • the amount of the compound of the general formula [4] to be used is 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [28]!
  • This reaction may be carried out at 30 to 150 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
  • the compound of the general formula [lj] can be produced by reacting the compound of the general formula [5] with a compound of the general formula [29] in the presence or absence of a solvent. This reaction may be carried out by a method described in WOO 3Z010138 or the like or a method analogous thereto.
  • Solvents used in this reaction are not particularly limited as long as they do not adversely influence the reaction.
  • halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • aromatics such as benzene, toluene and xylene.
  • Hydrocarbons such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol jetyl ether
  • sulfoxides such as dimethyl sulfoxide
  • ketones such as acetone and 2-butanone and ethyl acetate
  • the amount of the compound of the general formula [29] used is 1 to 50 times mol, preferably 1 to 5 times mol of the compound of the general formula [5]!
  • This reaction may be carried out at 30 to 200 ° C., preferably 0 to 150 ° C. for 30 minutes to 48 hours.
  • U 1 represents a halogen atom, an alkanesulfoxy group or an arylsulfol.
  • R 2a , R 3a , R 4a , R 5a , R 6 , X 3 , Z la and Z 2a have the same meaning as described above.
  • the compound of the general formula [lk] is produced by reacting the compound of the general formula [15] with the compound of the general formula [30] in the presence of a base and a catalyst and in the presence or absence of phosphine. can do.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • amides such as N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone
  • Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as ether
  • sulfoxides such as dimethyl sulfoxide
  • ketones such as acetone and 2-butanone
  • esters such as ethyl acetate; and the like.
  • Examples of the base used in this reaction include organic bases such as sodium tert-butoxide, pyridine, dimethylaminopyridine, and triethylamine; sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate And inorganic bases such as sodium carbonate and cesium carbonate.
  • Examples of the catalyst used in this reaction include tetrakis (triphenylphosphine) palladium, palladium acetate (11), sodium chloride palladium (II), and tris (dibenzylideneacetone) dipalladium (0). Can be mentioned.
  • Examples of the phosphine optionally used in this reaction include triphenylphosphine, tritert-butylbutylphosphine, diphenyl (orthotolyl) phosphine, tri (tolyl) phosphine and 2,2,1bis (diphenylphosphino). ) 1, 1, 1 and 1 binaphthyl.
  • the used amount of the base and the compound of the general formula [30] may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [15].
  • the amount of catalyst used is 0.001 to 10 times mol, preferably 0.01 to 2 times mol, of the compound of the general formula [15].
  • the amount of phosphine used as desired may be 0.001 to 40 times mol, preferably 0.01 to 8 times mol, of the compound of general formula [15].
  • This reaction may be carried out at 30 to 150 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours. Yes.
  • U 2 represents a halogen atom, an alkanesulfo-oxy group or an aryl sulfo-oxy group
  • R 16 represents a protecting group for a carboxyl group
  • RR 2a , R 3a , R 5a , R 6 , X 1 , X 2 , X 3 , Z la and Z 2a have the same meaning as described above.
  • a compound of general formula [lm] can be reacted with a compound of general formula [11] in the presence of a catalyst, in the presence or absence of a base, or in the presence or absence of phosphine. It can be manufactured from Sasako. This reaction may be performed, for example, by the method described in, for example, Organic Synthesis Opened by Transition Metals, pp. 19-22, 1997, Maruzen et al.
  • Examples of the compound of the general formula [14] include methyl acrylate, ethyl acrylate, tert-butyl acrylate.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone
  • Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane
  • Aromatic hydrocarbons such as benzene, toluene, and xylene
  • Dioxane Tetrahydrofuran, ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, and ethers such as ethylene glycol monomethyl ether
  • sulfoxy such as dimethyl sulfoxide
  • Ketones such as acetone and 2-butanone
  • esters such as ethyl acetate
  • -tolyls such as
  • Examples of the catalyst used in this reaction include bis (triphenylphosphine) paradichloride ( ⁇ ), tetrakis (triphenylphosphine) palladium, palladium acetate (11), salty palladium (II), bis ( And tri-tert-butylphosphine) palladium (0) and tris (dibenzylideneacetone) dipalladium (0).
  • the phosphine optionally used in this reaction includes, for example, triphenylphosphine, tritertbutylbutylphosphine, diphenyl (orthotolyl) phosphine, tri (tolyl) phosphine and 2,2,1bis (diphenylphosphino). ) 1, 1, 1 binaphthyl.
  • bases optionally used in this reaction include organic bases such as pyridine, dimethylaminoviridine, triethylamine, N, N dimethylbenzylamine, sodium acetate and potassium acetate;
  • examples thereof include inorganic bases such as potassium hydroxide, sodium hydrogen carbonate, potassium carbonate and sodium carbonate.
  • the amount of the compound of the general formula [14] used may be 1 to 10 times mol, preferably 1 to 5 times mol of the compound of the general formula [11]!
  • the amount of the catalyst used may be 0.001 to 10 times mol, preferably 0.01 to 2 times mol for the compound of the general formula [11].
  • the amount of phosphine used as desired may be 0.001 to 40 times mol, preferably 0.01 to 8 times mol, of the compound of general formula [11].
  • the amount of the base used may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [11].
  • This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
  • an isomer for example, an optical isomer, If present, such as geometric isomers and tautomers, these isomers can also be used, and solvates, hydrates and various forms of crystals can also be used.
  • Examples of the compound represented by the general formula [2] include 8 amino-2-methylquinoline and 8 amino-2-methoxyquinoline [Janano Reb American American Chemicanor Society (j.Am.Chem.So) 68, pp. 1553-1556, 1946 and Australian 'Journal' of Chemistry (Aus. J. Org. Chem.), Verse 56, pp. 39-44, 2003] It has been. Further, the compound of the general formula [2] is produced by combining methods known per se, and can be produced, for example, by the production method shown below.
  • the compound of the general formula [2a] can be produced by reacting the compound of the general formula [12] with sodium amide. This reaction is described, for example, in the method described in Journal 'Ob' Organic 'Chemistry (J. Org. Chem.), Vol. 11, pages 239-246, 1946, etc. Or if you follow a similar method.
  • solvent used in this reaction examples include those that do not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; Aromatic amines and liquid ammonia may be mentioned, and these may be used as a mixture.
  • the amount of sodium amide to be used is 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [12]!
  • This reaction may be carried out at 100 to 150 ° C. for 30 minutes to 48 hours.
  • the compound of the general formula [13] can be produced by nitration of the compound of the general formula [12].
  • the compound of the general formula [2a] can be produced by reducing the compound of the general formula [13].
  • Reduction of the compound of general formula [13] can be performed, for example, by Jerry March, Advanced 'Organic' Advanced Organic Chemistry, 4th edition, pp. 1026-1121, 1992, John 'Willy.
  • the method described in “And” Sands (John Wiley & Sons, INC.) Or the like may be used.
  • R 4b is R 2a , R 3a , R 16 , Z la and Z 2a have the same meaning as described above.
  • Examples of the compound of the general formula [2b] include, for example, 8 amino-2-methylquinoline and 8 amino-2-methoxyquinoline [Journal of American Chemical Society (j. Am. Chem.So), 68, 1553-1556, 1946 and Australian 'Journal' of Chemistry (Aus. J. Chem., 56, 39-44, 2003) are known. .
  • the compound of the general formula [2c] can be produced by halogenating the compound of the general formula [2b]. This reaction is described, for example, by Jerry March, Advanced Organic Chemistry 4th Edition, pp. 531-534, 1992, John Wiley & And Sons (John Wiley). & Sons, INC.), Etc., or a method similar to that.
  • the compound of the general formula [2d] can be reacted with the compound of the general formula [14] in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of phosphine. Can be manufactured. This reaction may be carried out according to production method 11.
  • the compound of the general formula [2e] can be produced by reducing the compound of the general formula [2d]. it can. This reaction is described, for example, by Jerry March, Advanced Organic Chemistry 4th edition, pp. 771-780, 1992, John Y'Willy 'And'Sands (John (Wiley & Sons, INC.)
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Aromatic hydrocarbons such as: dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethers such as ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; acetone and 2-butanone Ketones: Esters such as ethyl acetate and water, etc., and these may be used as a mixture.
  • Examples of the reducing agent used in this reaction include hydrogenated complex compounds such as sodium cyanoborohydride and sodium borohydride, and borane.
  • the reducing agent may be used in an amount of 0.5 to 10 times that of the compound of the general formula [2d].
  • reduction using a metal such as zinc under acidic conditions; electrolytic reduction using copper or platinum as a cathode; catalytic reduction using Raney nickel, platinum oxide, noradium carbon or palladium black as a catalyst can also be used.
  • the amount of the catalyst used may be 0.001 to 5 times mol of the compound of the general formula [2d].
  • This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
  • R 2a , R 3a , R 4a , R 5a , Z la and Z 2a have the same meaning as described above.
  • the compound of the general formula [2f] can be produced by diazotizing the compound of the general formula [2b], reacting with the thio compound A, and then hydrolyzing.
  • water is usually used as a solvent used in this reaction.
  • Examples of the sulfur compound A used in this reaction include thiourea and potassium xanthate.
  • the amount of io compound A used should be 1 to 20 moles compared to the compound of general formula [2b]!
  • This reaction may be carried out at 30 to 200 ° C., preferably 0 to 150 ° C. for 30 minutes to 48 hours.
  • the compound of the general formula [2f] can be produced by reacting the compound of the general formula [15] with the thio compound B and then deprotecting as necessary.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as form and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • Ethers such as oxane, tetrahydrofuran, ether, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether
  • sulfoxides such as dimethyl sulfoxide
  • ketones such as acetone and 2-butanone
  • thio compound B used in this reaction examples include inorganic thio compounds such as sodium sulfate and organic thio compounds such as methane thiol and 1,1-dimethylethane thiol.
  • the amount of iodo compound B used should be 1 to 20 moles compared to the compound of general formula [15]!
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
  • R 17 is R 2a , R 3a , R 4a , R 5a , Z la and Z 2a have the same meaning as described above.
  • the compound of the general formula [2g] can be produced by diazotizing the compound of the general formula [2b] and then treating with an acid.
  • water is usually used as a solvent used in this reaction.
  • Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid and nitric acid.
  • the acid may be used in an amount of 1 to 100 moles compared to the compound of the general formula [2b].
  • This reaction may be carried out at 30 to 200 ° C., preferably 0 to 150 ° C. for 30 minutes to 48 hours.
  • the compound of the general formula [2g] can be produced by reacting the compound of the general formula [15] with the compound of the general formula [16] and then deprotecting it.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as form and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • dioxane, tetrahydrofuran, azole ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Ethers such as monomethyl ether
  • sulfoxides such as dimethyl sulfoxide
  • ketones such as acetone and 2-butanone
  • esters such as ethyl acetate
  • water Water
  • Examples of the compound of the general formula [16] used in this reaction include metal alkoxides such as sodium methoxide and sodium ethoxide.
  • the amount of the compound of the general formula [16] used may be 1 to 20 times the mole of the compound of the general formula [15]!
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
  • R 17 Removal of the group represented by R 17 is described, for example, by W. Green et al., Protective Groups in Organic Synthesis, 3rd edition, pages 246-292, 1999. The method described in John Wiley & Sons, INC. May be used.
  • the compound of the general formula [3] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below. [Production method E]
  • Examples of the compound of the general formula [6] include 2,3 (methylenedioxy) benzaldehyde, 1,4 monobenzodioxane-6 carbaldehyde and (2,3 dihydro [1,4] dioxin monoyl).
  • WO02Z50061 publication] is known!
  • the compound of the general formula [3a] can be produced by reacting the compound of the general formula [17] with the compound of the general formula [6] in the presence of a reducing agent.
  • This reaction may be carried out according to production method 3-1.
  • the compound of the general formula [3a] can be produced by reacting the compound of the general formula [17] with the compound of the general formula [7].
  • This reaction may be carried out according to production method 3-2.
  • the compound of the general formula [4] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.
  • Y e is a protecting group for an amino group
  • Examples of the compound of the general formula [6] include 2,3- (methylenedioxy) benzaldehyde, 1,4-monobenzodioxane-6-carbaldehyde and (2,3-dihydro [1,4] dioxin-6-yl).
  • Acetaldehyde [WO02Z50061] is known!
  • the compound of the general formula [4a] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [6] and then deprotecting it.
  • reaction of the compound of general formula [18] and the compound of general formula [6] may be carried out according to production method 3-1.
  • the compound of the general formula [4a] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [7] and then deprotecting it.
  • reaction of the compound of general formula [18] and the compound of general formula [7] may be carried out according to production method 3-2.
  • the compound of the general formula [5] is produced by a combination of methods known per se.
  • the compound can be produced by the following production method.
  • Y d is a protecting group for the amino group
  • z 2a has the same meaning as described above.
  • the compound of the general formula [5a] can be produced by reacting the compound of the general formula [2] with a reactive derivative of the compound of the general formula [19] and then deprotecting it.
  • reaction of the compound of the general formula [2] and the reactive derivative of the compound of the general formula [19] may be carried out according to production method 1.
  • Y e represents a protecting group for an amino group
  • R 1 R 2a , R 3a , R 4a , R 5a , Q 2 , X la , Z la and Z 2a have the same meaning as described above.
  • Examples of the compound represented by the general formula [20] include 1 tert butoxycarborubiperazine and 4 ((tertbutoxycarboro) amino) piperidine.
  • the compound of general formula [5b] must be deprotected after reacting the compound of general formula [2] with a carbonyl compound in the presence or absence of a base, followed by reaction with the compound of general formula [20]. Can be manufactured. In addition, the compound of the general formula [5b] is reacted with the compound of the general formula [2] after reacting the compound of the general formula [20] with a carbonyl compound in the presence or absence of a base. It can be manufactured by deprotection.
  • reaction of the compound of the general formula [2] and the compound of the general formula [20] may be performed according to the production method 2.
  • Removal of the protecting group of the Amino group represented by Y 6 is, for example, W. Green (W.Green) et flop Rotekutibu 'Gunorepusu' in 'Organic' Synthesis (Protective groups in Organi c synthesis) , third edition, 494-653, 1999, John Wiley & Sons, INC ..
  • the compound of the general formula [5c] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [21] in the presence or absence of a base and then deprotecting the compound.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as form and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • dioxane, tetrahydrofuran, azole ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Ethers
  • monomethyl ether sulfoxides such as dimethyl sulfoxide
  • ketones such as acetone and 2-butanone
  • esters such as ethyl acetate
  • water Water
  • Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminoviridine and triethylamine; sodium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate.
  • organic bases such as pyridine, dimethylaminoviridine and triethylamine
  • sodium hydroxide sodium hydroxide
  • sodium bicarbonate sodium bicarbonate
  • potassium carbonate sodium carbonate
  • Examples include inorganic bases.
  • the compound and the base used in the general formula [21] may be used in an amount of 1 to 20 moles compared to the compound of the general formula [2].
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
  • Removal of the protecting group of the Amino group represented by Y 6 is, for example, W. Green (W.Green) et flop Rotekutibu 'Gunorepusu' in 'Organic' Synthesis (Protective groups in Organi c synthesis), 3rd edition, pp. 494-653, 1999, John Wiley & Sons, INC. may be used.
  • RR 2a , R 3a , R 4a , R 5a , Q 2 , T ⁇ Y e , Z la and Z 2a have the same meaning as described above.
  • the compound of the general formula [5d] can be produced by reacting the compound of the general formula [11] with the compound of the general formula [20], followed by deprotection.
  • reaction of the compound of the general formula [11] and the compound of the general formula [20] may be performed according to the production method 7.
  • Removal of the protecting group of the Amino group represented by Y 6 is, for example, W. Green (W.Green) et flop Rotekutibu 'Gunorepusu' in 'Organic' Synthesis (Protective groups in Organi c synthesis) , third edition, 494-653, 1999, John Wiley & Sons, INC ..
  • R 18 and R 19 are halogen atoms; n is 2— R 2a , R 3a , R 4a , R 5a , Q ⁇ Y d , z la and z 2a have the same meaning as described above. "
  • the compound of the general formula [5e] can be produced by reacting the compound of the general formula [8] with the Wittig reagent produced by the compound power of the general formula [22], followed by reduction and deprotection. it can.
  • the Witztig reaction can be described, for example, by Jerry March, Advanced Organic Chemistry, 4th edition, pages 956-963, 1992, John 'Willie' and'Sands. The method described in the company (John Wiley & SonsJNC.) Or the like may be used.
  • the Wittig reagent produced from the compound of the general formula [22] can be produced, for example, by reacting the compound of the general formula [22] with triphenylphosphine.
  • catalytic reduction using a catalyst may be used.
  • the catalyst used in this reaction include Raney nickel, platinum oxide, noradium carbon, and paraffin.
  • Jim Black This reaction is described, for example, by Jerry March, Advanced Organic Chemistry, 4th edition, pp. 771-780, 1992, John Wiley & Sons (John Wiley & Sons, INC.) Etc. or a method based thereon.
  • the compound of the general formula [5e] is prepared by reacting the compound of the general formula [24] with the Wittig reagent produced by the compound power of the general formula [23], followed by reduction and deprotection. It is out.
  • the compound of the general formula [23] can be produced, for example, by using a carbon chain extension reaction.
  • Compounds of general formula [24] include, for example, 1 benzylpiperidine 4 carbaldehyde, l- (tert-butoxycarbol) piperidine-4 carbaldehyde, 1-acetylbiperidine 4 carbaldehyde and 1-trifluoro Loacetylbiperidine 4 strength rubaldehyde is known.
  • This reaction may be performed according to the production method K1.
  • the compound of the general formula [8] can be produced by oxidizing the compound of the general formula [25].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane
  • aromatics such as benzene, toluene and xylene.
  • Hydrocarbons sulfoxides such as dimethyl sulfoxide
  • acids such as acetic acid; water and the like.
  • oxidizing agent used in this reaction examples include chromium trioxide, manganese dioxide, salt-chromyl, and diacid-selenium.
  • the oxidant may be used in an amount of 0.5 to 10 times that of the compound of the general formula [25].
  • This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
  • the compound of the general formula [9] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.
  • the compound of the general formula [27] can be produced by reacting the compound of the general formula [26] with ammonia.
  • Solvents used in this reaction are not particularly limited as long as they do not adversely influence the reaction.
  • halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • aromatics such as benzene, toluene and xylene.
  • Hydrocarbons such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol dimethyl ether
  • ketones such as acetone and 2-butanone
  • esters such as ethyl acetate
  • the amount of ammonia used may be equimolar or more with respect to the compound of the general formula [26].
  • This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
  • the compound of the general formula [9] can be produced by reacting the compound of the general formula [27] with an alkyl agent. This reaction may be performed, for example, by a method described in DE10Z061541 or a similar method.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as form and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • dioxane, tetrahydrofuran, azole ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Ethers such as monomethyl ether; dimethyl sulfoxide, etc.
  • Sulfoxides ketones such as acetone and 2-butanone
  • esters such as ethyl acetate and water, and the like.
  • alkylating agent used in this reaction examples include alkyl halides such as methyl iodide and yowiethyl.
  • the alkylating agent may be used in an amount of 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [27]!
  • This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
  • the compound of the general formula [11a] can be produced by reacting the compound of the general formula [8] with sulfur ylide.
  • Solvents used in this reaction are not particularly limited as long as they do not adversely influence the reaction.
  • halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • aromatics such as benzene, toluene and xylene.
  • Hydrocarbons ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether
  • sulfoxides such as dimethyl sulfoxide and water. You may mix and use.
  • sulfur ylide used in this reaction examples include sulfur ylides used in ordinary oxosilane synthesis. For example, dimethylsulfo-methyl methacrylate, dimethyloxosulfo-methyl methacrylate, dimethylamino (methyl) oxosulfo-methyl ester. And dimethylamino (phenyl) oxosulfoium methylide.
  • the amount of sulfur ylide used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [8].
  • This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
  • the compound of the general formula [l ib] can be produced by reacting the compound of the general formula [11a] with potassium isocyanate.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • Halogenated hydrocarbons such as form and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • dioxane, tetrahydrofuran, azole ethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol
  • ethers such as monomethyl ether
  • sulfoxides such as dimethyl sulfoxide, and water. These may be used as a mixture.
  • the amount of potassium isocyanate used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [11a].
  • This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
  • the compound of the general formula [28] can be produced by reacting the compound of the general formula [15] with a bulure metal compound in the presence of a catalyst, in the presence or absence of a base.
  • vinyl metal compound used in this reaction examples include organic tin compounds such as (triptyl) (bulu) tin and organoboron compounds such as bulboronic acid pinacol ester.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol
  • N, N dimethylformamide Amides such as N, N dimethylacetamide and 1-methyl-2-pyrrolidone
  • Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • Aromatic hydrocarbons such as benzene, toluene and xylene
  • sulfoxides such as dimethyl sulfoxide
  • Ketone such as acetone and 2-butanone
  • esters such as acetic Echiru; Asetonitoriru etc. - tolyl ethers and water, and the like, may be used which are
  • Examples of the catalyst used in this reaction include bis (triphenylphosphine) paradichloride dichloride (11), tetrakis (triphenylphosphine) palladium, palladium acetate (11), and sodium chloride palladium (II).
  • Bases optionally used in this reaction include, for example, pyridine, dimethylaminopyridine, triethylamine, N, N dimethylbenzylamine, sodium acetate and acetic acid.
  • Organic bases such as potassium; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate.
  • the amount of vinyl metal compound used should be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of general formula [15]!
  • the amount of the catalyst used may be 0.001 to 10 times mol, preferably 0.01 to 2 times mol, of the compound of the general formula [15].
  • the amount of the base used as required may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [15]!
  • This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
  • U 3 represents a halogen atom, an alkanesulfooxy group and an arylsulfooxy group; R 14d has the same meaning as described above.”
  • the compound of the general formula [29] can be synthesized in the presence of a catalyst in the presence or absence of a base.
  • the compound of [31] can be produced by reacting with a bur metal compound. This reaction may be performed according to production method O.
  • the compound of the general formula [30] can be produced by reacting a reactive derivative of the compound of the general formula [3] with ammonia in the presence or absence of a base. This reaction is
  • the production method 1 may be performed.
  • the compound of the general formula [5f] can be produced by reacting the compound of the general formula [11c] with the compound of the general formula [20]. This reaction may be performed according to production method 7.
  • the compound of general formula [5g] should be deprotected after reacting the compound of general formula [5f] with the compound of general formula [14] in the presence of a catalyst and a base, in the presence or absence of phosphine. Can be manufactured. This reaction may be carried out according to production method 11.
  • R 9, R 9a , R 10 , R 10 ⁇ R 11 R lla , R llb and R llc groups may be halogen atoms, protected, hydroxyl and carboxyl groups, substituted! Alkanesulfo- Alkyl group, protected or substituted by carboxyl group, alkyl group and optionally substituted alkyl, alkyl, alkyl, alkoxy and aryl groups, etc.
  • Preferred substituents include halogen atoms; protected, hydroxyl and carboxyl groups; substituted with nitrogen atoms! /, May! /, Alkanesulfonyl groups; protected! , May!
  • alkyl group substituted with a carboxyl group; and a halogen atom, protected or a hydroxyl group or protected, may be substituted with a carboxyl group
  • alkyl, alkyl, alkyl, alkoxy and aryl groups are mentioned. More preferred substituents are halogen atom; hydroxyl group; carboxyl group; substituted with halogen atom, methanesulfol group; and halogen atom, hydroxyl group and force ruxyl group force one or more selected And methyl, ethyl, propyl, vinyl, allyl, ethynyl, methoxy, ethoxy and phenyl groups which may be substituted with these groups.
  • R 13 and R 13a may be substituted !, or may be substituted with one or more groups selected from forces such as alkyl, alkaryl, alkyl, alkoxy and aryl groups.
  • Preferred substituents include halogen atoms, optionally protected hydroxyl groups or optionally protected alkyl groups, alkyl, alkyl, alkyl, alkoxy and aryl groups which may be substituted.
  • More preferred substituents include methyl, ethyl, propyl, vinyl, aryl, ethynyl, methoxy and phenyl groups which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group and a carboxyl group. It is done.
  • R ", R 14a , R 14b , R 14c and R 14d are halogen atom, nitro group, cyano group, oxo group, protected, hydroxy, amino and carboxyl groups and substituted!
  • the alkyl group may be substituted with one or more groups which may be optionally selected, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, aryl, heterocyclic, amino and rubamoyl groups.
  • substituents are halogen atom; nitro group; cyano group; oxo group; hydroxyl group; amino group; carboxyl group; and halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, and phenyl group.
  • phenylsulfurmethyl group May be substituted with one or more groups selected from a phenylsulfurmethyl group, and may be methyl, ethyl, propyl, vinyl, allyl, ethynyl, methoxy, ethoxy, methylthio, ethylthio, acetyl, propionyl, phenyl , Furyl, chenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, amino and force rubamoyl groups.
  • groups selected from a phenylsulfurmethyl group may be methyl, ethyl, propyl, vinyl, allyl, ethynyl, methoxy, ethoxy, methylthio, ethylthio, acetyl, propionyl, phenyl , Furyl, chenyl, thiazolyl, oxazolyl, pyri
  • X 5 , X 6 , X 6a , X 6b and X 7 are each a halogen atom, a protected, optionally substituted hydroxy, amino and carboxyl group, and an optionally substituted alkyl, alkenyl, It may be substituted with one or more groups selected by force, such as alkynyl, alkoxy, aryl, amino and force rubamoyl groups.
  • Preferred substituents include halogen atoms; optionally protected hydroxyl, amino and carboxyl groups; and halogen atoms, protected
  • V may be a hydroxyl group or protected !, may! /, Alkyl, alkaryl, alkyl, alkoxy, and aryl groups optionally substituted with a carboxyl group. More preferable substituents include a halogen atom; a hydroxyl group; an amino group; a carboxy group; and methyl, ethyl, propyl, which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group, and a carboxyl group. Examples include bur, aryl, ethyl, methoxy, ethoxy and phenol groups.
  • formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed.
  • excipients such as excipients, carriers and diluents usually used for formulation
  • these are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powders, suppositories, eye drops, nasal drops, ear drops according to conventional methods. It can be administered orally or parenterally in the form of a patch, 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 Zkg may be administered in several divided doses once a day.
  • MIC Antibacterial activity
  • Staphylococcus aureus (S. aureus FDA209) was used as the cells.
  • Cells cultured overnight at 35 ° C on a Mueller-Hinton agar (MHA) plate were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculum solution was inoculated into a cation-adjusted Mueller-Hinton broth (CAMHB) containing a test substance and cultured overnight at 35 ° C. The lowest microbial growth was not observed macroscopically, and the drug concentration was MIC. The results are shown in Table 4.
  • Test Example 2 Sensitivity Test 2 Using methicillin-resistant Staphylococcus aureus (S. aureus F3095) as the microbial cell, antimicrobial activity (MIC) was measured in the same manner as in Test Example 1. The results are shown in Table 5.
  • test substance solution 51.2 ⁇ g / mL
  • Vero cells suspended in E'MEM containing 100 ⁇ L / well of test substance solution and 10% FBS combine 3 X 10 3 cells / 100 ⁇ L / well in a 5% CO incubator at 37 ° C, Cultured for 3 days. Lmg / mL after incubation
  • test substance Dissolve the test substance in dimethyl sulfoxide, dilute it with Eagles 'Minimum'Essential'medium(E'MEM) supplemented with 10% Fatal Bovine Serum (FBS), and Prepared. Vero cells suspended in E'MEM containing 100 L / well of test substance solution and 10% FBS 3 X 10 3 cells / 100 ⁇ L / well are combined in a 5% CO incubator at 37 ° C, 3 Cultured for days. After incubation, lmg / mL2, 3-bis
  • the absorbance at 450 nm was measured using a microplate reader, and the concentration of the test substance showing a 50% inhibition rate from the value of the test substance-treated well and the value of the test substance non-added lowell ( CC, / zg / mL).
  • the compound of Example 8 was selected as the test substance.
  • test substance was dissolved in 22.5% 2 hydroxypropyl ⁇ -cyclodextrin (HP-CD) to a final concentration of 10 mg / mL.
  • HP-CD 2 hydroxypropyl ⁇ -cyclodextrin
  • the test substance solution was administered subcutaneously (100 mg / kg) once 1 hour after infection.
  • the control group received 22.5% HP-j8-CD. Mice were observed daily and the number of surviving animals 3 days after infection was recorded. The results are shown in Table 8.
  • the compounds of Examples 50 and 126 were selected as test substances.
  • S. aureus Smith cultured overnight in C was suspended to a final concentration of 10 9 CFU / mL.
  • This suspension was diluted 10-fold with a l / 15 mol / L phosphate buffer (pH 7) containing 5.6% mucin to prepare an inoculum.
  • a l / 15 mol / L phosphate buffer (pH 7) containing 5.6% mucin to prepare an inoculum.
  • mice ICR line, 4 weeks old, male, 5 mice / group
  • 0.4 mL of the inoculum was inoculated intraperitoneally (4 ⁇ 10 7 CFU / mouse).
  • test substance was dissolved in O.lmol / L sodium hydroxide aqueous solution and adjusted to a concentration of 1 mg / mL.
  • the test substance solution was administered subcutaneously once 1 hour after infection.
  • the control group was administered 22.5% HP- ⁇ -CD. Mice were observed daily and the number of surviving animals 3 days after infection was recorded. The results are shown in Table 9.
  • the compound of Example 1 was selected as the test substance.
  • the presence or absence of gene mutagenesis was examined by preincubation using non-stiff teeth, almonella typhimunum TA98 and Salmonella typhimunum TA100).
  • a test substance was dissolved or suspended in water, and a dilution series was prepared using a glass test tube so as to obtain a predetermined test substance concentration.
  • phosphate buffer was added, and in the case of metabolic activation, rat liver-derived S9mix was added.
  • glass test tubes were preincubated in a warm bath at 37 ° C for 20 minutes.
  • Example 1 The compound of Example 1 was negative.
  • Test Example 8 Bone marrow micronucleus test using mice The compound of Example 1 was selected as the test substance.
  • mice ICR system, 8 weeks old, male, 5 / group
  • mice were repeatedly subcutaneously administered with 100 mg / kg of the test substance for 2 days.
  • physiological saline was administered subcutaneously.
  • the mice were euthanized by cervical dislocation and bilateral femurs were collected.
  • the bone marrow of the femur was washed with calf serum, and a bone marrow smear was prepared.
  • micronucleus sample is observed under a microscope (600 times magnification), and the number of micronucleated red blood cells per 1000 polychromatic erythrocytes (the number of polychromatic erythrocytes having micronuclei) is calculated (micronucleus appearance frequency). I put it out. Subsequently, a statistically significant test of the frequency of micronucleus appearance between the negative control group and the test substance-administered group was performed by a conditional binomial test using the Kastenbaum and Bowman number table. Positive cases were observed where there was a significant increase in the frequency of micronucleus appearance compared to the negative control group.
  • Example 1 The compound of Example 1 was negative.
  • the mixing ratio in the eluent is a volume ratio.
  • the carrier in silica gel column chromatography is Fuji Silica Chemical Co., Ltd., B. W. Silica Gel, BW-127ZH; the carrier in reverse phase silica gel column chromatography is Seki YMC, ODS-AM120-S50.
  • tert butyl 4 (2- (2, 3 dihydrobenz [b] [1, 4] dioxin 6 yl) ethyl) piperazine 1 carboxylate 4.5 g of methylene chloride solution in 13 mL of trifluoroacetic acid 13 mL was added and stirred for 2 hours. Evaporate the solvent under reduced pressure, add 1.6 mL / L salt / hydrogen chloride / ethyl acetate 30 mL, evaporate the solvent under reduced pressure, and remove 1- (2- (2,3 dihydrobenzene) as a pale orange solid. Zo [b] [1,4] dioxin 6yl) ethyl) piperazine hydrochloride 3.2g was obtained.
  • the organic layer was separated, washed successively with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained oil was dissolved in ethyl acetate, and water and 6.0 mol / L hydrochloric acid were added to adjust to pHl.O.
  • the aqueous layer was separated, and the organic layer was extracted with 1.Omol / L hydrochloric acid.
  • the aqueous layer and the extract were combined and washed with acetyl acetate.
  • Ethyl 1— (2— (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl)
  • Piperidine mono 4-carboxylate 1.0 g in ethanol 10 mL solution at room temperature 12.5 mL of / L sodium hydroxide aqueous solution was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and water and ethyl acetate were added. The aqueous layer was separated and the organic layer was extracted with water. The aqueous layer and the extract were combined and washed with ethyl acetate.
  • the reaction mixture was added to a mixture of 20 mL of ethyl acetate and 20 mL of water.
  • the organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate.
  • the organic layer and the extract were combined, washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • An oily tertbutyl 4- (2-methoxyquinoline-1-ylcarbamoyl) piperidine-1-carboxylate was obtained.
  • tert-Butyl 4— ((7-methoxyisoquinoline 1-yl) rubamoyl) piperidine 1 carboxylate
  • 150 mL of methylene chloride in 1.5 mL of trifluoroacetic acid at room temperature was added at room temperature and stirred at the same temperature for 1 hour.
  • the solvent was distilled off under reduced pressure.
  • 30 mL of black mouth form and 30 mL of saturated aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was separated. After 30 mL of black mouth form was added to the aqueous layer, 20% aqueous sodium hydroxide solution was added to adjust the pH to 0.0.
  • tert-Butyl 4— (2 Hydroxy-1- (7-methoxyisoquinoline-1-yl) ethyl) Piperazinecarboxylate 0.33 g of methylene chloride in 6 mL
  • the solvent was distilled off under reduced pressure.
  • the obtained residue was charged with 20 mL of black mouth form and 10 mL of water, and adjusted to pH 12.5 with 20% aqueous sodium hydroxide solution.
  • the organic layer was separated, and the aqueous layer was extracted twice with 10 mL of black mouth form.
  • Ethyl 1, 2 Dihydro-2-oxoquinoline-3
  • Ethyl 2 Black-mouthed quinoline-3 carboxylate
  • 0.2 mL of fuming nitric acid was added at 5 ° C, and the mixture was stirred at room temperature for 3 hours.
  • the reaction mixture was poured into ice water and 20 mL of ethyl acetate was collected. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate.
  • Ethyl 2 Chloro-8 Nitroquinoline-3 Carboxylate 0.49 g of methanol in a 5 mL suspension of methanol was charged with 0.40 g of 28% sodium methoxide / methanol and stirred for 1 hour under heating to reflux. To the reaction mixture were added 0.5 mL of 6 mol / L hydrochloric acid, 20 mL of ethyl acetate, 20 mL of water, and 5 mL of a saturated aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate.
  • Methyl 2-methoxy 8 -troquinoline 3 carboxylate 0.22 g of acetic acid (4 mL) was suspended in 10 mL of palladium-carbon (50 mg) at room temperature and stirred for 1 hour in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to 8.0. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • 1,4 Monobenzodioxane-6 Carbaldehyde 0.20 g of dichloroethane in 5 mL solution was added 0.27 g of 4 ((tert-butoxycarbol) amino) piperidine and 77 ⁇ L of acetic acid at room temperature and stirred at the same temperature for 20 minutes . Then, 0.39 g of sodium triacetoxyborohydride was added at the same temperature and stirred for 2 hours and 10 minutes. Further, 49 mg of 4-((tert-butoxycarbonyl) amino) piperidine was added and stirred for 55 minutes, and then 0.13 g of sodium triacetoxyborohydride was added and stirred for 50 minutes. Add 10 mL of water and 10 mL of black mouth form to the reaction mixture.
  • tert butyl 3 (methylamino) propyl strength rubamate 0.14 g of N, N dimethylformamide in 2 mL solution, 7-methoxy-1- (oxylan-2-yl) isoquinoline 0.10 g of N, N dimethylformamide in lmL and perchlorine 53 mg of lithium acid was added, and the mixture was stirred at 80 ° C for 1 hour and 50 minutes. The reaction mixture was cooled to room temperature, 5 mL of water and 5 mL of ethyl acetate were added, 6.0 mol / L hydrochloric acid was added, and the pH was adjusted to 4.0.
  • tert-Butyl 3— ((2 Hydroxy-2- (7-methoxyisoquinoline-1-yl) ethyl) (methyl) amino) propyl-powered rubamate
  • methylene chloride 0.13 g
  • 1 mL of rifluoroacetic acid 1 mL
  • the solvent was distilled off under reduced pressure, and 10 mL of chloroform, 10 mL of water and 20% aqueous sodium hydroxide solution were added to the resulting residue to adjust the pH to 11.5.
  • the organic layer was separated, and the aqueous layer was extracted with black mouth form.
  • tert Butyl 1 (2 (thiophene-2-ylthio) ethyl) piperidine 1- 4il Forced rubamate llOmg in methylene chloride (2 mL) was added with trifluoroacetic acid (1 mL) under ice-cooling, stirred at room temperature for 40 minutes, and reduced in pressure. The solvent was distilled off under. To the obtained residue, 10 mL of chloroform, 10 mL of water and 20% aqueous sodium hydroxide solution were added to adjust to pHll.O. The organic layer was separated and the aqueous layer was extracted with black mouth form.
  • the reaction mixture was cooled to room temperature, and 10 mL of water and 10 mL of ethyl acetate were added, 6.0 mol / L hydrochloric acid was added, and the pH was adjusted to 3.5.
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate.
  • the organic layer and the extract were combined, washed with water, and 20% aqueous sodium hydroxide solution was added to adjust to ⁇ . ⁇ .
  • the organic layer was separated, washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the organic layer of the filtrate was separated, and the aqueous layer was extracted twice with 20 mL of ethyl acetate.
  • the organic layer and the extract were combined, washed successively with 25% aqueous ammonia and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
  • Reference example 47 tert-Butyl 4— ((2-Chronoquinoquinone 8-yloxy) methyl) piperidine 1—carboxylate 80 mg of toluene and 3 mL of methanol were added, and 28% sodium methoxide / methanol 62 mg was added. And then heated to reflux for 1 hour. Further, 124 mg of 28% sodium methoxide / methanol and 2 mL of toluene were added and heated under reflux for 2 hours. Furthermore, 28% sodium methoxide / methanol 124 mg and toluene 2 mL were added, and the mixture was heated to reflux for 3 hours.
  • tert-Butyl 4-((2-methoxyquinoline-l-8yloxy) methyl) piperidine 1 carboxylate
  • 60 mL of methylene chloride was added to 1 mL of trifluoroacetic acid and stirred at room temperature for 1 hour.
  • the solvent was distilled off under reduced pressure, and 30 mL of ethyl acetate and 10 mL of water were added to the resulting residue, and 20% aqueous sodium hydroxide solution was added to adjust the pH to 12.0.
  • the organic layer was separated, and the aqueous layer was extracted with lOmL of ethyl acetate.
  • Methyl 2 Chloroquinoline-4 carboxylate To a solution of 1.3 g of concentrated sulfuric acid in 6.0 mL of concentrated sulfuric acid was added dropwise 0.27 mL of fuming nitric acid under ice cooling, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C for 1 hour. The reaction mixture was poured into ice water and 50 mL of ethyl acetate was collected. The organic layer was separated, and the aqueous layer was extracted with 30 mL of ethyl acetate.
  • Methyl 2 Chloro-8 ditroquinoline-4 carboxylate 0.22 g of methanol was added to 0.20 g of a suspension of methanol, and 0.22 g of 28% sodium methoxide / methanol was added, and the mixture was heated to reflux for 1 hour. To the reaction mixture, 30 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate.
  • Methyl 2-methoxy 8 ditroquinoline 4-carboxylate 1
  • 10 mg of palladium-carbon 20 mg at room temperature was added 10 mg of palladium-carbon 20 mg at room temperature, and the mixture was stirred under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure.
  • 20 mL of ethyl acetate and 10 mL of water were added, and the mixture was adjusted to pH 9.0 with a saturated aqueous solution of sodium bicarbonate under ice cooling. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate.
  • 2-methoxy 8-methylquinoline 20 0.6 g of carbon tetrachloride in 500 mL was added with 20.6 g of N-bromosuccinimide and 3.64 g of benzoyl peroxide (75%) at room temperature, and heated to reflux for 1 hour. The reaction mixture was allowed to cool, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 300 mL of chloroform and 300 mL of a 10% aqueous sodium carbonate solution. The organic layer was separated, washed with 300 mL of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 30.1 g of 8 bromomethyl-2-methoxyquinoline as a pale yellow solid.
  • tert-Butyl 4— (2 Hydroxy-2- (2-methoxyquinoline-8-yl) ethyl) Piperazinecarboxylate 3 mL of trifluoroacetic acid is added dropwise to 9 mL of 0.49 g of chloroform under ice-cooling. And stirred for 40 minutes at room temperature. After concentration of the reaction mixture under reduced pressure, 20 mL of black mouth form and 10 mL of water were added, and the pH was adjusted to 11-12 with a 20% aqueous sodium hydroxide solution (pH test paper). The organic layer was separated, and the aqueous layer was extracted with 20 mL of black mouth form.
  • Butyl 8 benzyloxy 2-methoxyquinoline-5 carboxylate
  • Butyl 8 Hydroxy 2-methoxyquinoline 5 Carboxylate 0.16 g Methylene chloride in 5 mL solution 2,6-Lutidine O.lOmL and 4-Dimethylaminopyridine 7 mg were added and cooled to 2 ° C, then anhydrous Trifluoromethanesulfonic acid 0.1 ImL was added dropwise and stirred for 1 hour. did. To the reaction mixture was added 10 mL of a saturated aqueous solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 5 mL of methylene chloride. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

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Abstract

[PROBLEMS] To provide compounds which have potent antibacterial activity and are useful in prevention and treatment as excellent antibacterial agents. [MEANS FOR SOLVING PROBLEMS] Compounds represented by the general formula [1] or salts thereof, which have potent antibacterial activity and high safety and are therefore useful as excellent antibacterial agents: [1] wherein R1 is optionally substituted alkyl, alkoxy, acyloxy, or the like; R2, R3, R4 and R5 are each independently hydrogen, optionally substituted alkyl or alkenyl, or the like; Z1 and Z2 are each nitrogen, CH, or the like; X1 is oxygen, NH, CH2, or the like; X2 is carbonyl, NH, a free valency, or the like; X3 is C1-4 alkylene or a free valency; and R6 is substituted cyclic amino or the like.

Description

明 細 書  Specification
新規な含窒素複素環化合物およびその塩  Novel nitrogen-containing heterocyclic compounds and salts thereof
技術分野  Technical field
[0001] 本発明は、グラム陽性菌、グラム陰性菌および耐性菌に対して強い抗菌活性を有 する新規な含窒素複素環化合物またはその塩ならびにそれらを含有する抗菌剤に 関する。  The present invention relates to a novel nitrogen-containing heterocyclic compound or a salt thereof having strong antibacterial activity against gram positive bacteria, gram negative bacteria and resistant bacteria, and an antibacterial agent containing them.
背景技術  Background art
[0002] 医療現場にお 、て、感染症の治療のために種々の抗生物質や合成抗菌剤が使用 されてきた。し力しながら、近年、メチシリン耐性黄色ブドウ球菌（MRSA)、バンコマ イシン耐性腸球菌 (VRE)およびペニシリン耐性肺炎球菌（PRSP)などの耐性菌が 出現している。そのような耐性菌に感染した患者の治療が重要な課題となっている。 カロえて、複数の薬剤に対して耐性を獲得した多剤耐性菌が出現している。多剤耐性 菌による感染症は、難治性の疾病として、世界的に大きな問題となっている。  In the medical field, various antibiotics and synthetic antibacterial agents have been used for the treatment of infectious diseases. In recent years, however, resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), bancomycin-resistant enterococci (VRE), and penicillin-resistant pneumococci (PRSP) have emerged. Treatment of patients infected with such resistant bacteria is an important issue. Multi-drug resistant bacteria that have acquired resistance to multiple drugs have emerged. Infectious diseases caused by multidrug-resistant bacteria are a major problem worldwide as an intractable disease.
これらの耐性菌に有効な抗生物質の登場が強く望まれており、たとえば、 W099/ 07682号公報 (特許文献 1)には、 MRSAに有効とするキノロン系化合物が開示され ている。また、既存の薬剤とは異なる作用メカニズムを有する化合物として、 WO04 Z002490号公報（特許文献 2)、 WO04Z002992号公報（特許文献 3)および W O04Z089947号公報 (特許文献 4)に記載されたィ匕合物が知られて 、る。  The emergence of antibiotics effective against these resistant bacteria is strongly desired. For example, W099 / 07682 (Patent Document 1) discloses a quinolone compound effective for MRSA. Further, compounds having an action mechanism different from that of existing drugs are described in WO04 Z002490 (Patent Document 2), WO04Z002992 (Patent Document 3) and WO04Z089947 (Patent Document 4). Things are known.
[0003] 特許文献 l :WO99Z07682号公報  [0003] Patent Literature l: WO99Z07682
特許文献 2： WO04Z002490号公報  Patent Document 2: WO04Z002490
特許文献 3： WO04Z002992号公報  Patent Document 3: Publication of WO04Z002992
特許文献 4:WO04Z089947号公報  Patent Document 4: WO04Z089947
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0004] グラム陽性菌、グラム陰性菌および耐性菌に対して強い抗菌活性を有し、高い安 全性を有する薬剤の開発が望まれて!/、る。 [0004] Development of a drug having strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and resistant bacteria and high safety is desired!
課題を解決するための手段 このような状況下において、本発明者らは、鋭意検討を行った結果、一般式 [1] [化 1] Means for solving the problem Under such circumstances, the present inventors have conducted extensive studies and found that the general formula [1] [Chemical Formula 1]
Figure imgf000004_0001
Figure imgf000004_0001
「式中、 R1は、ハロゲン原子、シァノ基、保護されていてもよいカルボキシル基または 置換されていてもよいアルキル、アルコキシもしくはァシルォキシ基を; R2、 R3、 R4お よび R5は、同一または異なって水素原子、ハロゲン原子、シァノ基、保護されていて もよいカルボキシル基または置換されていてもよいアルキル、ァルケ-ル、アルコキシ 、シクロアルキル、ァミノもしくは力ルバモイル基を; Z1および Z2は、窒素原子または C R7「式中、 R7は、水素原子、ハロゲン原子、シァノ基、保護されていてもよいカルボキ シル基または置換されていてもよいアルキル、ァルケ-ル、アルコキシ、ァミノもしくは 力ルバモイル基を意味する。」であり、かつ、 Z1および Z2の少なくとも一方が窒素原子 を; X1は、酸素原子、硫黄原子、スルフィエル基、スルホ-ル基、 NR8a「式中、 R8aは、 水素原子または置換されて 、てもよ 、アルキルもしくはァリール基を意味する。」また は CR9R1C>「式中、 R9および R1C>は、同一または異なって水素原子または置換されて いてもよいアルキル、ヒドロキシル、ァミノもしくはメルカプト基を意味する。」を ;x2は、 カルボニル基、 NR8b「式中、 R8bは、水素原子または置換されていてもよいアルキル もしくはァリール基を意味する。」または結合手を; X3は、 C アルキレン基または結 "Wherein R 1 represents a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkoxy or acyloxy group; R 2 , R 3 , R 4 and R 5 are A hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, cycloalkyl, amino or rubamoyl group; Z 1 and Z 2 represents a nitrogen atom or CR 7 wherein R 7 is a hydrogen atom, a halogen atom, a cyan group, an optionally protected carboxy group or an optionally substituted alkyl, alkenyl, alkoxy, An amino group or a rubamoyl group ”, and at least one of Z 1 and Z 2 represents a nitrogen atom; X 1 represents an oxygen atom, a sulfur atom, Fier group, sulfol group, NR 8a [wherein R 8a represents a hydrogen atom or a substituted or optionally alkyl or aryl group] or CR 9 R 1C> “wherein R 9 and R 1C> are the same or different and represent a hydrogen atom or an optionally substituted alkyl, hydroxyl, amino or mercapto group. ”; X 2 represents a carbonyl group, NR 8b , wherein R 8b Represents a hydrogen atom or an optionally substituted alkyl or aryl group, or a bond; X 3 represents a C alkylene group or a bond.
1-4  1-4
合手を; R6は、一般式 The Gote; R 6 has the general formula
[化 2] [Chemical 2]
3 R11 、
Figure imgf000004_0002
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を; Rlla、 Rllbおよび Rlleは、同一または異なって水素原 子、ハロゲン原子、保護されていてもよいヒドロキシルもしくはカルボキシル基または 置換されていてもよいアミ入低級アルキル、アルコキシもしくは力ルバモイル基を; R1 2は、一般式 3 R 11 ,
Figure imgf000004_0002
"Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group; R lla , R llb and R lle are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino-substituted lower alkyl, alkoxy or rubamoyl group; R 1 2 is the general formula
[化 3]
Figure imgf000005_0001
[Chemical 3]
Figure imgf000005_0001
「式中、 R14は、水素原子、保護されていてもよいカルボキシル基または置換されてい てもよぃシクロアルキル、シクロアルケ-ル、アルアルキル、ァリールもしくは複素環式 基を; X4は、酸素原子、硫黄原子、カルボニル基または結合手を; X5は、置換されて いてもよいアルキレン基または結合手を; X6は、置換されていてもよいアルキレン、ァ ルケ-レンもしくはアルキ-レン基またはスルホ -ル基を; X7は、置換されていてもよ いアルキレン基または結合手を意味する。」で表される基を; R13は、水素原子、ァミノ 基の保護基または置換されていてもよいアルキルもしくはァリール基を意味する。」を 意味する。」で表される含窒素複素環化合物またはその塩が、強い抗菌活性と高い 安全性を有することを見出し、本発明を完成した。 "Wherein R 14 represents a hydrogen atom, an optionally protected carboxyl group or an optionally substituted cycloalkyl, cycloalkyl, aralkyl, aryl or heterocyclic group; X 4 represents oxygen An atom, a sulfur atom, a carbonyl group or a bond; X 5 is an optionally substituted alkylene group or a bond; X 6 is an optionally substituted alkylene, alkylene or alkylene group. X 7 represents an optionally substituted alkylene group or a bond; and R 13 represents a hydrogen atom, an amino group protecting group or a substituted group; Means an alkyl or aryl group which may be "Means. The present invention has been completed by finding that the nitrogen-containing heterocyclic compound represented by the above formula or a salt thereof has strong antibacterial activity and high safety.
発明の効果  The invention's effect
[0006] 一般式 [1]の化合物またはその塩は、強い抗菌活性と高い安全性を有することから 、優れた抗菌剤として有用である。  [0006] The compound of the general formula [1] or a salt thereof is useful as an excellent antibacterial agent because it has strong antibacterial activity and high safety.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0007] 以下、本発明化合物について詳述する。  Hereinafter, the compound of the present invention will be described in detail.
本明細書において、特にことわらない限り、ハロゲン原子とは、フッ素原子、塩素原 子、臭素原子およびヨウ素原子を;アルキル基とは、たとえば、メチル、ェチル、プロピ ル、イソプロピル、ブチル、 sec—ブチル、イソブチル、 tert—ブチル、ペンチル、イソ ペンチル、へキシル、ヘプチルおよびォクチルなどの直鎖状または分枝鎖状の C アルキル基を;低級アルキル基とは、たとえば、メチル、ェチル、プロピル、イソプロピIn this specification, unless otherwise specified, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkyl group means, for example, methyl, ethyl, propyl, isopropyl, butyl, sec— Linear or branched C such as butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl An alkyl group; a lower alkyl group is, for example, methyl, ethyl, propyl, isopropyl
2 2
ル、ブチル、 sec ブチル、イソブチル、 tert ブチル、ペンチルおよびイソペンチル などの直鎖状または分枝鎖状の C アルキル基を；ァルケ-ル基とは、たとえば、ビ A linear or branched C alkyl group such as butyl, sec butyl, isobutyl, tert butyl, pentyl and isopentyl;
1-6  1-6
ニル、ァリル、プロぺニル、イソプロぺニル、ブテニル、イソブテニル、 1, 3 ブタジェ ニル、ペンテニル、 1, 3 ペンタジェニル、へキセニル、ヘプテニノレおよびォクテ二 ルなどの直鎖状または分枝鎖状の C アルケニル基を;アルキニル基とは、たとえ Linear or branched C alkenyl such as nyl, aryl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3 butaenyl, pentenyl, 1,3 pentagenyl, hexenyl, heptenol and octenyl An alkynyl group, for example
2-12  2-12
ば、ェチニル、 2—プロピ-ルおよび 2—ブチニルなどの直鎖状または分枝鎖状の C For example, linear or branched C such as ethynyl, 2-propyl and 2-butynyl
2 アルキ-ル基を；  2 alkyl groups;
- 12  -12
シクロアルキル基とは、たとえば、シクロプロピル、シクロブチル、シクロペンチルおよ びシクロへキシルなどの C シクロアルキル基を；シクロアルケ-ル基とは、たとえば A cycloalkyl group is, for example, a C cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a cycloalkenyl group is, for example,
3-8  3-8
、シクロプロぺニノレ、シクロブテニノレ、シクロペンテ二ノレおよびシクロへキセニノレなどの , Cyclopropeninole, cyclobuteninole, cyclopenteninole and cyclohexeninole
C シクロアルケ-ル基ならびにォクタヒドロナフチルなどの二環式のシクロアルケ-C Cycloalkenyl groups and bicyclic cycloalkenyls such as octahydronaphthyl
3-8 3-8
ル基を；アルキレン基とは、たとえば、メチレン、エチレン、プロピレン、ブチレンおよび へキシレンなどの C ァノレキレン基を；ァノレケニレン基とは、たとえば、ビニレン、プロ An alkylene group is, for example, a C-alkylene group such as methylene, ethylene, propylene, butylene, and hexylene; an ananolenylene group is, for example, vinylene, pro
1-6  1-6
ぺニレン、ブテニレン、へキセニレン、ヘプテニレンおよびォクテ二レンなどの C ァ C keywords such as penylene, butenylene, hexenylene, heptenylene and octenylene
2-12 ルケ-レン基を；アルキ-レン基とは、たとえば、ェチ-レン、プロピニレン、プチ-レ ン、へキシニレン、へプチ二レンおよびォクチ二レンなどの C ァノレキニレン基を；ァ  2-12 a alkylene group; an alkylene group is, for example, a C alkynylene group such as ethylene, propynylene, petitylene, hexynylene, heptylene and octylene.
2-12  2-12
リール基とは、たとえば、フエ-ル、ナフチル、 3, 4ージヒドロナフチル、フルォレ -ル およびフエナントレ-ルなどの基を；アルアルキル基とは、たとえば、ベンジル、ジフヱ ニルメチル、トリチル、フエネチルおよびナフチルメチルなどのアル C アルキル基を Examples of the reel group include phenyl, naphthyl, 3,4-dihydronaphthyl, fluorine and phenanthryl; examples of the aralkyl group include benzyl, diphenylmethyl, trityl, phenethyl and naphthyl. Al C alkyl groups such as methyl
1 -6  1 -6
；アルコキシ基とは、たとえば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキ シ、イソブトキシ、 sec ブトキシ、 tert ブトキシ、ペンチルォキシおよびイソペンチ ルォキシなどの直鎖状または分枝鎖状の C アルキルォキシ基を；アルアルキルォ  An alkoxy group is, for example, a linear or branched C alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec butoxy, tert butoxy, pentyloxy and isopentoxy;
1-6  1-6
キシ基とは、たとえば、ベンジルォキシ、ジフエ-ルメチルォキシ、トリチルォキシ、フ エネチルォキシおよびナフチルメチルォキシなどのアル C アルキルォキシ基を；ァ Xoxy groups include, for example, alkoxy groups such as benzyloxy, diphenylmethyloxy, trityloxy, phenethyloxy and naphthylmethyloxy;
1-6  1-6
ルコキシアルキル基とは、たとえば、メトキシメチルおよび 1 エトキシェチルなどの C アルキルォキシ C アルキル基を；アルアルキルォキシアルキル基とは、たとえばA alkoxyalkyl group is, for example, a C alkyloxy C alkyl group such as methoxymethyl and 1 ethoxyethyl; an aralkyloxyalkyl group is, for example,
-6 1-6 -6 1-6
、ベンジルォキシメチルおよびフエネチルォキシメチルなどのアル C アルキルォキ シ c アルキル基を； , Alkyl alkoxy such as benzyloxymethyl and phenethyloxymethyl C alkyl group;
1-6  1-6
[0009] ァシル基とは、たとえば、ホルミル基、ァセチル、プロピオ-ルおよびイソバレリルなど の直鎖状または分枝鎖状の C アルカノィル基、ベンジルカルボ-ルなどのアル C  [0009] The acyl group is, for example, a linear or branched C alkanoyl group such as formyl group, acetyl, propiol and isovaleryl, or an al Cyl group such as benzyl carboyl.
2- 12  2- 12
アルキルカルボ-ル基、ベンゾィルおよびナフトイルなどの環式炭化水素カルボ Cyclic hydrocarbon carbo such as alkyl carbo groups, benzoyl and naphthoyl
1 -6 1 -6
-ル基、ニコチノィル、テノィル、ピロリジノカルボ-ルおよびフロイルなどの複素環式 カルボ-ル基、スクシ-ル基、グルタリル基、マレオイル基、フタロイル基ならびにアミ ノ酸 (アミノ酸としては、たとえば、グリシン、ァラニン、ノ リン、ロイシン、イソロイシン、 セリン、トレオニン、システィン、メチォニン、ァスパラギン酸、グルタミン酸、ァスパラギ ン、グルタミン、ァノレギニン、リジン、ヒスチジン、ヒドロキシリジン、フエニノレアラニン、 チロシン、トリプトファン、プロリンおよびヒドロキシプロリンなどが挙げられる。）から誘 導される N末端が保護されていてもよい直鎖状または分枝鎖状の aーァミノアルカノ ィル基を；アルキルォキシカルボ-ル基とは、たとえば、メトキシカルボ-ル、エトキシ カルボニル、 1, 1ージメチルプロポキシカルボニル、イソプロポキシカルボニル、 2— ェチルへキシルォキシカルボニル、 tert ブトキシカルボニルおよび tert ペンチル ォキシカルボ-ルなどの直鎖状または分枝鎖状の C アルキルォキシカルボ-ル  -Heterocyclic groups, nicotinol, tenol, pyrrolidinocarbol and furoyl, etc., heterocyclic carbol groups, succinyl groups, glutaryl groups, maleoyl groups, phthaloyl groups and amino acids (as amino acids, for example glycine , Alanine, noline, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, wasparagine, glutamine, anoleginine, lysine, histidine, hydroxylysine, phenenolealanine, tyrosine, tryptophan, proline and hydroxyproline, etc. A linear or branched aaminoalkanoyl group which may be protected at the N-terminus derived from the above; an alkyloxycarbonyl group is, for example, methoxycarbo- , Ethoxycarbonyl, Linear or branched C alkyloxycarbons such as 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tert butoxycarbonyl, and tert pentyloxycarbon
1 -12  1 -12
基を；アルアルキルォキシカルボ-ル基とは、たとえば、ベンジルォキシカルボ-ル およびフエネチルォキシカルボ-ル基などのアル C アルキルォキシカルボ-ル基  A group; an aralkyloxycarboxyl group, for example, an aralkyloxycarbon group such as a benzyloxycarbol and a phenoxycarboxyl group;
1 -6  1 -6
を；ァリールォキシカルボ-ル基とは、たとえば、フエ-ルォキシカルボ-ルなどの基 を；  An arylcarbonyl group is, for example, a group such as a phenylcarbol;
[0010] ァシルォキシ基とは、たとえば、ァセチルォキシおよびプロピオ-ルォキシなどの直 鎖状または分枝鎖状の C アルカノィルォキシ基ならびにベンゾィルォキシなどの  [0010] The acyloxy group includes, for example, linear or branched C alkanoyloxy groups such as acetyloxy and propio-oxy and benzoyloxy.
2-6  2-6
ァロイルォキシ基を;ァシルアルキル基とは、たとえば、ァセチルメチル、ベンゾィルメ チル、 p 二トロべンゾィルメチル、 p ブロモベンゾィルメチル、 p—メトキシベンゾィ ルメチルおよび 1 ベンゾィルェチルなどの基を；ァシルォキシアルキル基とは、たと えば、ァセトキシメチル、プロピオ-ルォキシメチルおよびビバロイルォキシメチルな どの基を；アルキルチオアルキル基とは、たとえば、メチルチオメチル、ェチルチオメ チルおよびプロピルチオメチルなどの C アルキルチオ C アルキル基を；ァリール  Aroyloxy group; for example, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methoxybenzoylmethyl and 1-benzoylethyl; For example, a group such as acetoxymethyl, propio-loxymethyl and bivalyloxymethyl; an alkylthioalkyl group is a C alkylthioC alkyl group such as methylthiomethyl, ethylthiomethyl and propylthiomethyl;
1 -6 1-6  1 -6 1-6
チォ基とは、たとえば、フエ-ルチオなどの基を；アルカンスルホ-ル基とは、たとえば 、メタンスルホニル、トリクロロメタンスルホニル、トリフルォロメタンスルホニル、ェタン スルホ-ルおよびプロパンスルホ-ルなどのハロゲン原子で置換されて 、てもよ ヽ c アルカンスルホ -ル基を；ァリールスルホ-ル基とは、たとえば、ベンゼンスルホ-The thio group is, for example, a group such as phenolthio; the alkanesulfonyl group is, for example, Substituted with a halogen atom such as methanesulfonyl, trichloromethanesulfonyl, trifluoromethanesulfonyl, ethanesulfol, and propanesulfol. For example, benzenesulfo-
- 6 -6
ル、トルエンスルホ-ルおよびナフタレンスルホ-ルなどの基を；アルカンスルホ-ル ォキシ基とは、たとえば、メタンスルホ -ルォキシ、トリクロロメタンスルホ -ルォキシ、ト リフルォロメタンスルホ-ルォキシおよびエタンスルホ-ルォキシなどのハロゲン原子 で置換されて 、てもよ 、c アルカンスルホ -ルォキシ基を；ァリールスルホ -ルォ A group such as methanesulfoloxy, trichloromethanesulfuroxy, trifluoromethanesulfuroxy and ethanesulfoloxyl. Substituted with a halogen atom, the c-alkanesulfo-loxy group;
1 -6  1 -6
キシ基とは、たとえば、ベンゼンスルホ-ルォキシおよびトルエンスルホ -ルォキシな どの基を；ァリールチオアルキル基とは、たとえば、フエ-ルスルファ-ルメチルおよ び 2— (p -トロフエ-ルスルファ -ル）ェチルなどの基を；ァリールスルホ-ルアル キル基とは、たとえば、 p トルエンスルホ-ルェチルなどの基を；ァリールスルフィ- ル基とは、たとえば、ベンゼンスルフィエルなどの基を；アルキルアミノ基とは、メチル アミ入ェチルァミノ、プロピルアミ入イソプロピルアミ入ブチルアミ入ジメチルァミノ 、ジェチルアミ入ジイソプロピルァミノおよびジブチルァミノなどのモノーまたはジー C アルキルアミノ基を； Xyl groups are for example groups such as benzenesulfo-oxyl and toluenesulfo-loxy; arylthioalkyl groups are for example phenylsulfurmethyl and 2- (p-trophenylsulfuryl) An aryl group such as p-toluenesulfo-ruethyl; an arylsulfur group such as benzenesulfiel; and an alkylamino group. A mono- or di-C alkylamino group such as methylamino-containing ethylamino, propylamino-containing isopropylamino-containing butylamino-containing dimethylamino, jetylamino-containing diisopropylamino or dibutylamino;
1 -6  1 -6
シクロアルキリデン基とは、たとえば、シクロペンチリデンおよびシクロへキシリデンな どの基を；アルアルキリデン基とは、たとえば、ベンジリデンおよびナフチルメチレンな どの基を；ジアルキルアミノアルキリデン基とは、たとえば、 N, N ジメチルアミノメチ レンおよび N, N ジェチルアミノメチレンなどの基を；ジアルアルキルホスホリル基と は、たとえば、ジベンジルホスホリルなど基を；ジァリールホスホリル基とは、たとえば、 ジフエニルホスホリルなどの基を;含酸素複素環式基とは、たとえば、 2—テトラヒドロ ビラニルおよび 2—テトラヒドロフラニルなどの基を;含酸素複素環式アルキル基とは、 たとえば、 5 メチル 2 ォキソ 2H— 1 , 3 ジォキソール 4ーィルメチルなどの 基を;含硫黄複素環式基とは、たとえば、テトラヒドロチォピラニルなどの基を;複素環 ォキシカルボ-ル基とは、たとえば、 2 フルフリルォキシカルボ-ル、 8 キノリルォ キシカルボニルなどの基を;含窒素複素環式アルキル基とは、たとえば、フタルイミド メチルおよびスクシンイミドメチルなどの基を;含窒素複素環式アルキリデン基とは、 たとえば、 3—ヒドロキシー4 ピリジルメチレンなどの基を;置換シリル基とは、たとえ ば、トリメチルシリル、トリェチルシリルおよびトリブチルシリルなどの基を；アルキルシリ ルアルキル基とは、たとえば、 2- (トリメチルシリル)ェチルなどの基を； The cycloalkylidene group is, for example, a group such as cyclopentylidene and cyclohexylidene; the alkylidene group is, for example, a group such as benzylidene and naphthylmethylene; and the dialkylaminoalkylidene group is, for example, N, N dimethyl A group such as aminomethylene and N, N-deethylaminomethylene; a dialalkylphosphoryl group, for example, a group such as dibenzylphosphoryl; a diallyl phosphoryl group, for example, a group such as diphenylphosphoryl; Examples of oxygen-containing heterocyclic groups include groups such as 2-tetrahydrobiranyl and 2-tetrahydrofuranyl; examples of oxygen-containing heterocyclic alkyl groups include, for example, 5 methyl 2-oxo 2H—1, 3 dioxol 4-ylmethyl, etc. A sulfur-containing heterocyclic group is, for example, tetra A group such as drothiopyranyl; a heterocyclic oxycarbonyl group, for example, a group such as 2 furfuryloxycarbonyl, 8 quinolyloxycarbonyl; a nitrogen-containing heterocyclic alkyl group, for example, phthalimidomethyl and A group such as succinimidomethyl; a nitrogen-containing heterocyclic alkylidene group, for example, a group such as 3-hydroxy-4-pyridylmethylene; a substituted silyl group, for example For example, a group such as trimethylsilyl, triethylsilyl, and tributylsilyl; an alkylsilylalkyl group, for example, a group such as 2- (trimethylsilyl) ethyl;
[0012] 単環の複素環式基とは、たとえば、フリル、フルフリル、チェ-ル、 2 テュル、ピロリ ル、 1 ピロリル、 2 ピロリル、イミダゾリル、ピラゾリル、 3 ピラゾリル、チアゾリル、ィ ソチアゾリル、ォキサゾリル、イソォキサゾリル、ォキサジァゾリル、チアジアゾリル、フ ラザ-ル、ピロリジ -ル、イミダゾリジ -ル、ピリジル、ピリミジ -ル、ピリダジ -ル、 1 - ピペリジル、 2 ピペリジル、 3 ピペリジル、 4ーピペリジル、 1—ピペラジニル、 2— ピぺラジュル、 2—モルホリニルおよび 2—チオモルホリニルなどの基を； [0012] Monocyclic heterocyclic groups include, for example, furyl, furfuryl, chael, 2 tulle, pyrrolyl, 1 pyrrolyl, 2 pyrrolyl, imidazolyl, pyrazolyl, 3 pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl , Oxaziazolyl, thiadiazolyl, furazal, pyrrolidyl, imidazolidyl, pyridyl, pyrimidyl, pyridazil, 1-piperidyl, 2 piperidyl, 3 piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperadil Groups such as 2-morpholinyl and 2-thiomorpholinyl;
[0013] 二環式の複素環式基とは、たとえば、ベンゾフラ -ル、イソベンゾフラ -ル、ベンゾチ ェ -ル、ベンゾ [b]チォフェンー2—ィル、インドリル、インドールー 2—ィル、イソイン ドリル、インドリ-ル、ベンズイミダゾリル、 1H— 1,2,3 べンゾトリァゾールー 5—ィル 、ベンゾ才キサゾリノレ、ベンゾイソ才キサゾリノレ、ベンゾチアゾリノレ、 1,2, 3 べンゾ才 キサジァゾールー 5 ィル、 1, 2, 3 べンゾチアジアゾールー 5 ィル、 1H—イン ダゾリル、プリ-ル、クロメ-ル、キノリル、キノリン一 2—ィル、キノリン一 3—ィル、キノ リン 6—ィル、イソキノリル、フタラジュル、ナフチリジニル、キノキサリニル、キナゾリ ニル、シンノリニル、クロマン 6—ィル、クロマニル、イソクロマニル、キヌクリジニル、 1,3 ベンゾジォキサニノレ、 1,4 ベンゾジォキサニノレ、ベンゾモルホリニル、ベンゾ モルホロ-ル、キノキサリン 6 ィル、 2, 3 ジヒドロ [1, 4]ジォキシノ [2, 3— c]ピ リジン一 7—ィノレ、 3, 4 ジヒドロ一 2H ピリド [3, 2— b] [l, 4]ォキサジン一 6—ィ ノレ、 3, 4ージヒドロー 2H ピリド [3, 2— b] [l, 4]チアジン 6—ィノレ、 3, 4 ジヒド ロー 2H べンゾチアジンー6 ィル、 2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6 —ィル、 3, 4 ジヒドロ一 2H ベンゾ [1, 4]ォキサジン一 7—ィル、 3, 4 ジヒドロ —2H べンゾ [b] [l, 5]ジォキセピンー7 ィル、 2, 3 ジヒドロべンゾ [b]フラン 5 ィル、 3, 4ージヒドロイソキノリン 2 (1H) ィル、 1, 2 ジヒドロキノリンー3—ィ ル、 4H べンゾ [1, 4]ォキサジン 6 ィル、 4H べンゾ [1, 4]チアジン 6—ィ ル、 4H ピリド [3, 2— b] [l, 4]チアジン— 6—ィル、イミダゾ [1, 2— a]ピリジン— 2 ィル、チエノ [3, 2—b]チォフェンー2 ィル、チエノ [2, 3—b]チォフェンー2—ィ ル、 2H チォクロメン 3—ィルおよびべンゾ [1, 3]ジォキソールー 5—ィルなどの 基を； [0013] Bicyclic heterocyclic groups include, for example, benzofuryl, isobenzofural, benzochel, benzo [b] thiophene-2-yl, indolyl, indole-2-yl, isoindolyl, Indolyl, benzimidazolyl, 1H— 1,2,3 Benzotriazole 5—yl, benzoxa xazolinole, benzoisoxa xazolinole, benzothiazolinole, 1,2,3 Benzoxa xadiazole 5 1, 2, 3 Benzothiadiazole 5 yl, 1H-indazolyl, prill, chromel, quinolyl, quinoline 2-yl, quinoline 3-yl, quinoline 6- , Isoquinolyl, phthaladyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chroman 6-yl, chromanyl, isochromanyl, quinuclidinyl, 1,3 benzodioxaninole, 1,4 Nzodioxaninole, benzomorpholinyl, benzomorpholine, quinoxaline 6 yl, 2, 3 dihydro [1, 4] dixino [2, 3—c] pyridine 1-7-inore, 3, 4 dihydro 1 2H pyrido [3, 2— b] [l, 4] oxazine 1 6—inole, 3, 4-dihydro-2H pyrido [3, 2— b] [l, 4] thiazine 6—inole, 3, 4 dihydr 2H benzothiazine-6 yl, 2, 3 dihydrobenzo [b] [l, 4] dioxin-6 —yl, 3, 4 dihydro-1 2H benzo [1, 4] oxazine 1-7-yl, 3, 4 Dihydro —2H benzo [b] [l, 5] dioxepin-7 yl, 2, 3 dihydrobenzo [b] furan 5 yl, 3, 4-dihydroisoquinoline 2 (1H) yl, 1, 2 Dihydroquinoline-3-yl, 4H benzo [1, 4] oxazine 6 yl, 4H benzo [1, 4] thiazine 6-yl, 4H pyrido [3, 2-b] [l, 4 ] Thiazine-6-yl, imidazo [1, 2- a] pyri 2-yl, thieno [3,2-b] thiophene-2-yl, thieno [2,3-b] thiophene-2-yl, 2H-thiochromene 3-yl and benzo [1,3] dioxole-5 — Such as A group;
[0014] 複素環式基とは、たとえば、単環の複素環式基;二環式の複素環式基;ならびにチア ントレニル、キサンテニル、フエノキサチイニル、カルバゾリル、 13 カルボリニル、フ ェナントリジニル、アタリジニル、ペリミジニル、フエナント口リニル、フエナジニル、フエ ノチアジ-ルおよびフエノキサジニルなどの三環式の複素環式基を意味する。  [0014] The heterocyclic group includes, for example, a monocyclic heterocyclic group; a bicyclic heterocyclic group; and thianthenyl, xanthenyl, phenoxathiinyl, carbazolyl, 13 carbolinyl, phenanthridinyl, and atalidinyl. , Perimidinyl, phenanthracinyl, phenazinyl, phenothiazyl, and phenoxazinyl.
[0015] ァミノ基の保護基としては、通常のァミノ保護基として使用しうるすベての基を含み、 たとえば、 W.グリーン (W.Green)ら、プロテクティブ'グループス'イン'オーガニック' シンセシス（Protective Groups in Organic Synthesis)第 3版、第 494〜653頁、 1999年 、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)に記載されている基が挙 げられる。具体的には、たとえば、ァシル基、アルキルォキシカルボ-ル基、アルアル キルォキシカルボ-ル基、ァリールォキシカルボ-ル基、アルアルキル基、アルコキ シアルキル基、アルアルキルォキシアルキル基、ァリールチオ基、アルカンスルホ- ル基、ァリールスルホ-ル基、ジアルキルアミノアルキリデン基、アルアルキリデン基、 含窒素複素環式アルキリデン基、シクロアルキリデン基、ジァリールホスホリル基、ジ アルアルキルホスホリル基、含酸素複素環式アルキル基および置換シリル基などが 挙げられる。  [0015] The protecting group of the amino group includes all groups that can be used as ordinary amino protecting groups. For example, W. Green et al., Protective 'Groups' In 'Organic' Synthesis (Protective Groups in Organic Synthesis) 3rd edition, 494-653, 1999, John Wiley & Sons, INC. Specifically, for example, an acyl group, an alkyl carboxy group, an aralkyl carboxy group, an aralkyl carboxy group, an aralkyl group, an alkoxyalkyl group, an aralkyloxyalkyl group, an allylthio group. , Alkane sulfonyl group, aryl sulfonyl group, dialkylamino alkylidene group, alkylidene group, nitrogen-containing heterocyclic alkylidene group, cycloalkylidene group, dialyl phosphoryl group, dialkyl phosphoryl group, oxygen-containing heterocyclic group Examples thereof include an alkyl group and a substituted silyl group.
[0016] ヒドロキシル基の保護基としては、通常のヒドロキシル保護基として使用し得るすべ ての基を含み、たとえば、 W.グリーン (W.Green)ら、プロテクティブ'グループス 'イン 'オーガニック 'シンセシス（Protective Groups in Organic Synthesis)第 3版、第 17〜2 45頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & SonsJNC.)に記載され ている基が挙げられる。具体的には、たとえば、ァシル基、アルキルォキシカルボ- ル基、アルアルキルォキシカルボ-ル基、複素環ォキシカルボ-ル基、アルキル基、 アルケニル基、アルアルキル基、含酸素複素環式基、含硫黄複素環式基、アルコキ シアルキル基、アルアルキルォキシアルキル基、アルカンスルホ-ル基、ァリールス ルホニル基および置換シリル基などが挙げられる。  [0016] The hydroxyl-protecting group includes all groups that can be used as ordinary hydroxyl-protecting groups. For example, W. Green et al., Protective 'Groups' In 'Organic' Synthesis ( Protective Groups in Organic Synthesis) 3rd edition, pages 17-245, 1999, John Wiley & Sons JNC. Specifically, for example, an acyl group, an alkyloxycarbon group, an aralkyloxycarbonyl group, a heterocyclic oxycarbon group, an alkyl group, an alkenyl group, an aralkyl group, an oxygen-containing heterocyclic group And sulfur-containing heterocyclic groups, alkoxyalkyl groups, aralkyloxyalkyl groups, alkanesulfonyl groups, arylsulfonyl groups and substituted silyl groups.
[0017] カルボキシル基の保護基としては、通常のカルボキシル基の保護基として使用し得 るすべての基を含み、たとえば、 W.グリーン (W.Green)ら、プロテクティブ'グループ ス'イン'オーガニック 'シンセシス（Protective Groups in Organic Synthesis)第 3版、 第 369〜453頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.) に記載されている基が挙げられる。具体的には、たとえば、アルキル基、ァリール基、 アルアルキル基、ァシルアルキル基、ァリールチオアルキル基、ァリールスルホ-ル アルキル基、含酸素複素環式基、アルキルシリルアルキル基、ァシルォキシアルキル 基、含窒素複素環式アルキル基、シクロアルキル基、アルコキシアルキル基、アルア ルキルォキシアルキル基、アルキルチオアルキル基、ァルケ-ル基ならびに置換シリ ル基などが挙げられる。 [0017] The carboxyl protecting group includes all groups that can be used as ordinary carboxyl protecting groups. For example, W. Green et al., Protective 'Groups' In 'Organic' Synthesis (Protective Groups in Organic Synthesis) 3rd edition, Pp. 369-453, 1999, John Wiley & Sons, INC. Specifically, for example, an alkyl group, aryl group, aralkyl group, acyl alkyl group, aryl thioalkyl group, aryl aryl alkyl group, oxygen-containing heterocyclic group, alkylsilylalkyl group, acyloxyalkyl group And nitrogen-containing heterocyclic alkyl group, cycloalkyl group, alkoxyalkyl group, alkyloxyalkyl group, alkylthioalkyl group, alkenyl group and substituted silyl group.
[0018] 脱離基としては、たとえば、ハロゲン原子、アルカンスルホ-ルォキシ基、ァリールス ルホニルォキシ基およびァシルォキシ基などが挙げられる。  [0018] Examples of the leaving group include a halogen atom, an alkanesulfoxy group, an arylsulfonyl group, an acyloxy group, and the like.
[0019] 置換されて!、てもよ 、アルキル、低級アルキル、ァルケ-ル、アルキ -ル、シクロア ルキル、シクロアルケ-ル、アルコキシ、ァシル、ァシルォキシ、アルキレン、ァルケ- レン、アルキ-レン、ァリール、アルアルキル、複素環式、単環の複素環式および二 環式の複素環式基の置換基の置換基としては、ハロゲン原子；シァノ基；ニトロ基；保 護されて!、てもよ 、ヒドロキシル基；保護されて 、てもよ 、カルボキシル基；保護され て 、てもよ 、ァミノ基；アルキルアミノ基；力ルバモイル基；アルカンスルホ -ル基；ハロ ゲン原子で置換されて 、るアルカンスルホ -ル基；ァリールスルホ -ル基；アルキル 基；ァルケ-ル基；アルキ-ル基；アルコキシ基；アルアルキルォキシ基；アルコキシ力 ルボニル基；シクロアルキル基；ァシル基；ァリール基；アルアルキル基;メルカプト基； アルキルチオ基；複素環式基；ォキソ基；ならびにハロゲン原子、保護されて 、てもよ ぃヒドロキシル基、保護されていてもよいカルボキシル基、低級アルキル基、ァリール 基およびァリールスルフィエル基力 選ばれる 1つ以上の基で置換されているアルキ ル、ァルケ-ル、アルキ -ル、アルコキシ、ァシル、ァリール、複素環式、ァミノおよび 力ルバモイル基カゝら選ばれる一種以上の基が挙げられる。  [0019] substituted! May be alkyl, lower alkyl, alkyl, alkyl, cycloalkyl, cycloalkenyl, alkoxy, acyl, acyloxy, alkylene, alkylene, alkylene, aryl, Substituents for the substituents of aralkyl, heterocyclic, monocyclic heterocyclic and bicyclic heterocyclic groups include halogen atom; cyano group; nitro group; protected! Hydroxyl group; protected or carboxyl group; protected or may amino group; alkylamino group; strong rubamoyl group; alkanesulfonyl group; alkanesulfo substituted with a halogen atom -Alkyl group; alkyl group; alkyl group; alkoxy group; aralkyloxy group; alkoxy group carbonyl group; cycloalkyl group; Group; aryl group; aralkyl group; mercapto group; alkylthio group; heterocyclic group; oxo group; and halogen atom, protected, hydroxyl group, optionally protected carboxyl group, lower alkyl group , Aryl groups and aryl sulfier groups selected from alkyl, alkyl, alkyl, alkoxy, acyl, aryl, heterocyclic, amino, and rubamoyl groups substituted with one or more selected groups 1 type or more groups selected from these.
具体的な置換基としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子、シァノ基 、ニトロ基、ヒドロキシル基、カルボキシル基、アミノ基、メチルァミノ基、ェチルァミノ基 、ジメチルァミノ基、ジェチルァミノ基、力ルバモイル基、メタンスルホ-ル基、クロロメ タンスルホ-ル基、エタンスルホ-ル基、プロパンスルホ-ル基、ベンゼンスルホニル 基、トルエンスルホ-ル基、メチル基、フルォロメチル基、ジフルォロメチル基、トリフ ルォロメチル基、クロロメチル基、ジクロロメチル基、トリクロロメチル基、ヒドロキシメチ ル基、カルボキシメチル基、ェチル基、フルォロェチル基、ジフルォロェチル基、トリ フルォロェチル基、クロ口ェチル基、ジクロロェチル基、トリクロ口ェチル基、ヒドロキシ ェチル基、カルボキシェチル基、プロピル基、フルォロプロピル基、ジフルォロプロピ ル基、トリフルォロプロピル基、クロ口プロピル基、ジクロロプロピル基、トリクロ口プロピ ル基、ヒドロキシプロピル基、カルボキシプロピル基、ビニル基、ァリル基、ェチニル基 、フエ-ルェチュル基、プロピ-ル基、メトキシ基、フルォロメトキシ基、ジフルォロメト キシ基、トリフルォロメトキシ基、クロロメトキシ基、ジクロロメトキシ基、トリクロロメトキシ 基、エトキシ基、クロ口エトキシ基、ジクロロエトキシ基、トリクロ口エトキシ基、ベンジル ォキシ基、カルボキシメトキシ基、メトキシカルボ-ル基、エトキシカルボ-ル基、シク 口プロピル基、シクロブチル基、シクロペンチル基、シクロへキシル基、ホルミル基、ァ セチル基、クロロアセチル基、ジクロロアセチル基、プロピオ-ル基、ベンゾィル基、 フルォロベンゾィル基、ジフルォロベンゾィル基、クロ口べンゾィル基、ジクロロべンゾ ィル基、フヱ-ル基、フルオロフヱ-ル基、ジフルオロフヱ-ル基、トリフルオロフェ- ル基、クロ口フエ-ル基、ジクロロフエ-ル基、トリクロ口フエ-ル基、クロ口フルオロフェ -ル基、ヒドロキシフエ-ル基、（フルォロ）ヒドロキシフエ-ル基、（クロ口）ヒドロキシフ ェニル基、カルボキシフエ-ル基、（カルボキシ）フルオロフェ-ル基、（カルボキシ）ク ロロフエ-ル基、ベンジル基、フエネチル基、メルカプト基、メチルチオ基、ェチルチ ォ基、フリル基、チェニル基、ピロリル基、ァゼチジュル基、ピロリジニル基、ピベリジ ル基、ヒドロキシピロリジ-ル基、カルボキシピロリジ -ル基、ヒドロキシピペリジル基、 カルボキシピペリジル基、ピペラジニル基、イミダゾリル基、ピラゾリル基、ピリジル基、 テトラヒドロピリジル基、ピリミジ -ル基、モルホリニル基、チオモルホリニル基、キノリル 基、キノリジニル基、テトラヒドロキノリニル基、テトラヒドロイソキノリニル基、キヌクリジ ニル基、チアゾリル基、テトラゾリル基、チアジアゾリル基、ピロリニル基、イミダゾリニ ル基、イミダゾリジニル基、ビラゾリニル基、ビラゾリジニル基、プリニル基、インダゾリ ル基、ベンゼンスルフィエルメチル基およびォキソ基が挙げられる。 Specific examples of the substituent include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a nitro group, a hydroxyl group, a carboxyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a jetylamino group, and a powerful rubamoyl group. , Methanesulfol group, chloromethanesulfol group, ethanesulfol group, propanesulfol group, benzenesulfonyl group, toluenesulfol group, methyl group, fluoromethyl group, difluoromethyl group, triflate Fluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, hydroxymethyl group, carboxymethyl group, ethyl group, fluorethyl group, difluoroethyl group, trifluoroethyl group, chloroethyl group, dichloroethyl group, trifluoroethyl group, Hydroxyethyl group, carboxyethyl group, propyl group, fluoropropyl group, difluoropropyl group, trifluoropropyl group, chloropropyl group, dichloropropyl group, trichloropropyl group, hydroxypropyl group, carboxypropyl group, vinyl group , Aryl group, ethynyl group, phenolic group, propyl group, methoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, chloromethoxy group, dichloromethoxy group, trichloromethoxy group, etho Xyl, chloroethoxy, dichloroethoxy, trichloroethoxy, benzyloxy, carboxymethoxy, methoxycarboxyl, ethoxycarboxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohex Xyl, formyl, acetyl, chloroacetyl, dichloroacetyl, propiool, benzoyl, fluorobenzoyl, difluorobenzoyl, black benzoyl, dichlorobenzoyl Azol group, file group, fluoro file group, difluoro file group, trifluoro file group, black port file group, dichloro file group, tri black port file group, black port Fluorophenyl, hydroxyphenyl, (fluoro) hydroxyphenyl, (black) hydroxyphenyl, carboxyphenyl, (Ruboxy) fluorophenyl group, (carboxy) chlorophenol group, benzyl group, phenethyl group, mercapto group, methylthio group, ethylthio group, furyl group, chenyl group, pyrrolyl group, azetidyl group, pyrrolidinyl group, piperidyl group , Hydroxypyrrolidyl group, carboxypyrrolidyl group, hydroxypiperidyl group, carboxypiperidyl group, piperazinyl group, imidazolyl group, pyrazolyl group, pyridyl group, tetrahydropyridyl group, pyrimidyl group, morpholinyl group, thiomorpholinyl group, Quinolyl group, quinolidinyl group, tetrahydroquinolinyl group, tetrahydroisoquinolinyl group, quinuclidinyl group, thiazolyl group, tetrazolyl group, thiadiazolyl group, pyrrolinyl group, imidazolinyl group, imidazolidinyl group, virazolinyl group, villanyl group Lysinyl group, purinyl group, Indazori group, include a benzene sulfide el methyl and Okiso group.
置換されて!ヽてもよ ヽカルバモイルおよびァミノ基の置換基としては、保護されて ヽ てもよ 、ヒドロキシル基；保護されて!、てもよ 、ァミノ基；アルキルアミノ基；アルカンス ルホ -ル基；ハロゲン原子で置換されて 、るアルカンスルホ -ル基；ァリールスルホ- ル基；アルキル基；ァルケ-ル基；アルキ-ル基；アルコキシ基；アルコキシカルボ- ル基；ァシル基；ハロゲン原子で置換されて 、るァシル基；ァリール基；ハロゲン原子 、保護されて 、てもよ 、ヒドロキシル基および保護されて 、てもよ 、カルボキシル基か ら選ばれる 1つ以上の基で置換されて 、るァリール基；アルアルキル基；ハロゲン原 子で置換されて 、るアルアルキル基；ならびに複素環式基力 選ばれる一種以上の 基が挙げられる。 Substituents of carbamoyl and amino groups may be protected, may be protected, hydroxyl groups; protected !, may, amino groups; alkylamino groups; Alkanesulfonyl group substituted by halogen atom; aryl hydrocarbon group; alkyl group; alkenyl group; alkyl group; alkoxy group; alkoxy carbo ol group; acyl group; Substituted with an atom, an acyl group; an aryl group; a halogen atom, protected, hydroxyl group and protected, substituted with one or more groups selected from carboxyl groups An aryl group; an alkyl group substituted with a halogen atom; and one or more groups selected from a heterocyclic basic force.
具体的な置換基としては、ヒドロキシル基、アミノ基、メチルァミノ基、ェチルァミノ基 、ジメチルァミノ基、ジェチルァミノ基、メタンスルホ-ル基、クロロメタンスルホ -ル基 、エタンスルホ-ル基、プロパンスルホ-ル基、ベンゼンスルホ-ル基、トルエンスル ホニル基、メチル基、ェチル基、プロピル基、ブチル基、ペンチル基、へキシル基、ァ リル基、プロピ-ル基、メトキシ基、エトキシ基、メトキシカルボ-ル基、エトキシカルボ ニル基、プロポキシカルボ-ル基、 tert—ブトキシカルボ-ル基、ホルミル基、ァセチ ル基、プロピオ-ル基、ブチリル基、ベンゾィル基、フルォロベンゾィル基、ジフルォ 口ベンゾィル基、クロ口ベンゾィル基、ジクロロベンゾィル基、フエ-ル基、フルオロフ ェ-ル基、ジフルオロフヱ-ル基、トリフルオロフヱ-ル基、クロロフヱ-ル基、ジクロロ フエ-ル基、トリクロ口フエ-ル基、クロ口フルオロフヱ-ル基、ヒドロキシフヱ-ル基、（ フルォロ）ヒドロキシフエ-ル基、（クロ口）ヒドロキシフエ-ル基、カルボキシフエ-ル基 、（カルボキシ）フルオロフェ-ル基、（カルボキシ）クロ口フエ-ル基、ベンジル基、フ ルォ口べンジル基、ジフルォ口べンジル基、クロ口べンジル基、ジクロロべンジル基、 クロ口フルォ口べンジル基、フエネチル基、フリル基、チェ-ル基、ピロリル基、ァゼチ ジニル基、ピロリジ -ル基、ピペリジル基、ピペラジニル基、イミダゾリル基、ピラゾリル 基、ピリジル基、テトラヒドロピリジル基、ピリミジ -ル基、モルホリニル基、チオモルホリ -ル基、キノリル基、キノリジ-ル基、テトラヒドロキノリニル基、テトラヒドロイソキノリニ ル基、キヌタリジニル基、チアゾリル基、テトラゾリル基、チアジアゾリル基、ピロリニル 基、イミダゾリニル基、イミダゾリジニル基、ビラゾリニル基、ビラゾリジニル基、プリニル 基およびインダゾリル基が挙げられる。  Specific examples of the substituent include hydroxyl group, amino group, methylamino group, ethylamino group, dimethylamino group, jetylamino group, methanesulfol group, chloromethanesulfol group, ethanesulfol group, propanesulfol group, and benzene. Sulfol group, toluene sulfonyl group, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, aryl group, propyl group, methoxy group, ethoxy group, methoxycarbon group, Ethoxycarbonyl group, propoxycarbonyl group, tert-butoxycarbol group, formyl group, acetyl group, propiol group, butyryl group, benzoyl group, fluorobenzoyl group, difluorine benzoyl group, Closed benzoyl group, dichlorobenzoyl group, phenyl group, fluorophenyl group, difluorophenyl group, trifluoro Phyl group, Chlorophenol group, Dichlorophenol group, Trichlorophle group, Chlorofluoro group, Hydroxyl group, (Fluoro) Hydroxyphenol group, (Chloro) Hydroxy group Phenyl group, Carboxyphenol group, (Carboxy) fluorophenol group, (Carboxy) chlorophenol group, Benzyl group, Fluorobenzyl group, Difluorobenzene group, Chronobenzene group , Dichlorobenzil group, chlorofluorobenzene group, phenethyl group, furyl group, chael group, pyrrolyl group, azetidinyl group, pyrrolidyl group, piperidyl group, piperazinyl group, imidazolyl group, pyrazolyl group, pyridyl group Group, tetrahydropyridyl group, pyrimidyl group, morpholinyl group, thiomorpholyl group, quinolyl group, quinolidyl group, tetrahydroquinolinyl group, tetra Examples include hydroisoquinolinyl group, quinutalidinyl group, thiazolyl group, tetrazolyl group, thiadiazolyl group, pyrrolinyl group, imidazolinyl group, imidazolidinyl group, virazolinyl group, virazolidinyl group, purinyl group and indazolyl group.
置換されていてもよいヒドロキシルおよびメルカプト基の置換基としては、アルキル 基；ァルケ-ル基；アルキ-ル基；シクロアルキル基；ァシル基；ァリール基；アルアル キル基;ならびにハロゲン原子、保護されていてもよいヒドロキシル基および保護され て！、てもよ 、カルボキシル基力 選ばれる 1つ以上の基で置換されて 、るアルキル、 ァルケ-ル、アルキニルおよびァリール基力 選ばれる一種以上の基が挙げられる。 具体的な置換基としては、メチル基、カルボキシルメチル基、ェチル基、フルォロェ チル基、ジフルォロェチル基、トリフルォロェチル基、クロ口ェチル基、ジクロロェチル 基、トリクロ口ェチル基、ヒドロキシェチル基、カルボキシェチル基、プロピル基、フル ォロプロピル基、ジフルォロプロピル基、トリフルォロプロピル基、クロ口プロピル基、 ジクロロプロピル基、トリクロ口プロピル基、ヒドロキシプロピル基、カルボキシプロピル 基、ァリル基、プロピ-ル基、シクロプロピル基、シクロブチル基、シクロペンチル基、 シクロへキシル基、ァセチル基、プロピオ-ル基、ベンゾィル基、フエ-ル基、フルォ 口フエ-ル基、ジフルオロフヱ-ル基、トリフルオロフヱ-ル基、クロロフヱ-ル基、ジク ロロフエ-ル基、トリクロ口フエ-ル基、クロ口フルオロフェ-ル基、ヒドロキシフエ-ル 基、（フルォロ）ヒドロキシフエ-ル基、（クロ口）ヒドロキシフエ-ル基、カルボキシフエ- ル基、（カルボキシ）フルオロフェ-ル基、（カルボキシ）クロ口フエ-ル基、ベンジル基 およびフエネチル基が挙げられる。 Examples of the substituent for the optionally substituted hydroxyl and mercapto groups include alkyl Alkyl group; cycloalkyl group; acyl group; aryl group; alkyl group; and halogen atom, optionally protected hydroxyl group and protected! However, one or more groups selected from alkyl, alkenyl, alkynyl and aryl bases substituted with one or more groups selected from carboxyl group power may be mentioned. Specific examples of the substituent include a methyl group, a carboxylmethyl group, an ethyl group, a fluorethyl group, a difluoroethyl group, a trifluoroethyl group, a chloroethyl group, a dichloroethyl group, a trichloroethyl group, a hydroxyethyl group, a carboxy group, and the like. Ethyl, propyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, trichloropropyl, hydroxypropyl, carboxypropyl, aryl, propylene Group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, acetyl group, propiol group, benzoyl group, phenol group, fluorine-containing group, difluoro-phenol group, trifluoro-phenol group , Chlorophenol group, dichlorophenol group, triclonal mouth , Black-open fluorophore group, hydroxy-phenol group, (fluoro) hydroxy-phenyl group, (black-open) hydroxy-phenyl group, carboxy-phenol group, (carboxy) fluoro-phenol group, (carboxy) Examples thereof include a black mouth phenol group, a benzyl group and a phenethyl group.
一般式 [1]の化合物の塩としては、通常、知られているアミノ基などの塩基性基また はフエノール性ヒドロキシル基もしくはカルボキシル基などの酸性基における塩を挙 げることができる。  Examples of the salt of the compound represented by the general formula [1] include a known basic group such as an amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group.
塩基性基における塩としては、たとえば、塩酸、臭化水素および硫酸などの鉱酸と の塩;酒石酸、ギ酸、酢酸、クェン酸、トリクロ口酢酸およびトリフルォロ酢酸などの有 機カルボン酸との塩；ならびにメタンスルホン酸、ベンゼンスルホン酸、 p—トルエンス ルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩 などが挙げられる。  Examples of the salt in the basic group include 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, citrate, trichloroacetic acid and trifluoroacetic acid; And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
酸性基における塩としては、たとえば、ナトリウムおよびカリウムなどのアルカリ金属 との塩;カルシウムおよびマグネシウムなどのアルカリ土類金属との塩；アンモ-ゥム 塩；ならびにトリメチルァミン、トリェチルァミン、トリブチルァミン、ピリジン、 N, N—ジ メチルァニリン、 N—メチルビペリジン、 N—メチルモルホリン、ジェチルァミン、ジシク 口へキシルァミン、プロ力イン、ジベンジルァミン、 N—ベンジル一 β—フエネチルアミ ンぉよび Ν, Ν，ージベンジルエチレンジァミンなどの含窒素有機塩基との塩などを挙 げることができる。 Salts in acidic groups include, for example, 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-dimethylaniline, N-methylbiperidine, N-methylmorpholine, jetylamine, dicycl Mention may be made of oral hexylamine, pro-in, dibenzylamine, N-benzyl-1-β-phenethylamine, and salts with nitrogen-containing organic bases such as dibenzylethylenediamine.
さらに、上記、塩の中で一般式 [1]の化合物の好ましい塩としては、薬理学的に許 容される塩が挙げられる。  Furthermore, among the above salts, preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.
[0023] 本発明化合物において、好ましい化合物としては、以下の化合物が挙げられる。 [0023] Among the compounds of the present invention, preferable compounds include the following compounds.
R1が、ハロゲン原子、シァノ基または置換されていてもよいアルキル、アルコキシも しくはァシルォキシ基である化合物が好ましぐシァノ基または置換されて 、てもよ!/ヽ アルキルもしくはアルコキシ基である化合物がより好ましぐ置換されていてもよいァ ルコキシ基である化合物がさらに好ましぐアルコキシ基である化合物がよりさらに好 ましい。 A compound in which R 1 is a halogen atom, a cyano group or an optionally substituted alkyl, alkoxy or acyloxy group is preferably a cyano group or a substituted, may be! / ヽ alkyl or alkoxy group Even more preferred are compounds in which the compound is an alkoxy group, which is more preferably an alkoxy group, which may be more preferably substituted.
[0024] R2、 R3、 R4および R5力 同一または異なって水素原子、ハロゲン原子、シァノ基、 保護されて 、てもよ 、カルボキシル基または置換されて 、てもよ 、アルキル、ァルケ -ル、アルコキシ、ァミノもしくは力ルバモイル基である化合物が好ましぐ同一または 異なって水素原子、ハロゲン原子、保護されていてもよいカルボキシル基または置換 されて 、てもよ 、アルキルもしくはァルケ-ル基である化合物がより好ましく、同一ま たは異なって水素原子、保護されて 、てもよ 、カルボキシル基または置換されて!、て もよいアルキルもしくはァルケ-ル基である化合物がさらに好ましぐ R2、 R3、 R4およ び R5の一つが、置換されていてもよいアルキルもしくはァルケ-ル基、他力 水素原 子である化合物がよりさらに好ましぐ R2、 R3、 R4および R5の一つが、カルボキシル基 で置換されたアルキルまたはァルケ-ル基、他力 水素原子である化合物が特に好 ましい。 [0024] R 2 , R 3 , R 4 and R 5 forces may be the same or different and each may be a hydrogen atom, halogen atom, cyano group, protected, carboxyl group or substituted, alkyl, alkke The same or different hydrogen atom, halogen atom, optionally protected carboxyl group or substituted or alkyl or alkenyl group, which is preferably the same or different for the compounds which are -l, alkoxy, amino or rubamoyl groups More preferably, the same or different hydrogen atom, protected, may be a carboxyl group or substituted !, and an alkyl or alkenyl group which may be further preferred is more preferable R 2, R 3, one of R 4 and R 5 is an optionally substituted alkyl or Aruke - group, the compound is externally powered hydrogen atom is more preferred more instrument R 2, R Particularly preferred are compounds in which one of 3 , R 4 and R 5 is an alkyl or alkenyl group substituted with a carboxyl group, or another hydrogen atom.
ただし、 Z1が、窒素原子、 Z2が、 CR7「式中、 R7は、前記と同様な意味を有する。」、 R6が、 However, Z 1 is a nitrogen atom, Z 2 is CR 7 “wherein R 7 has the same meaning as described above”, R 6 is
[化 4]
Figure imgf000015_0001
「式中、 1、 R12および R13は、前記と同様な意味を有する。」の場合、 R3または の 少なくとも一方が、ハロゲン原子、保護されていてもよいカルボキシル基または置換さ れていてもよい力ルバモイル、アルキル、ァルケ-ルもしくはシクロアルキル基である 化合物が好ましぐ R3が、水素原子、 R4が、保護されていてもよいカルボキシル基、 保護されて 、てもよ 、カルボキシル基で置換されて 、るアルキル、ァルケ-ルもしく はシクロアルキル基または置換されて 、てもよ 、力ルバモイル基で置換されて 、るァ ルキルもしくはアルケニル基である化合物がより好ましぐ R3が、水素原子、 R4が、保 護されて!、てもよ 、カルボキシル基で置換されて 、るアルケニル基である化合物がさ らに好ましぐ R2、 R3および R5力 水素原子、 R4が、保護されていてもよいカルボキシ ル基で置換されて!、るアルケニル基である化合物がよりさらに好まし!/、。 [Chemical 4]
Figure imgf000015_0001
In the case of “in the formula, 1 , R 12 and R 13 have the same meaning as described above,” at least one of R 3 or is a halogen atom, an optionally protected carboxyl group or a substituted group. Preferred compounds are rubamoyl, alkyl, alkyl or cycloalkyl groups R 3 is a hydrogen atom, R 4 is an optionally protected carboxyl group, protected or may be carboxyl R, alkyl, alkenyl, or cycloalkyl groups substituted with a group or a compound substituted with a strong rubermoyl group and being an alkyl or alkenyl group are more preferred R 3 is a hydrogen atom, R 4 is protected !, but a compound that is substituted with a carboxyl group and is an alkenyl group is more preferred R 2 , R 3 and R 5 forces Hydrogen atom, R 4 , Be protected is substituted in good carboxyl group !, Ru compounds and even more preferably an alkenyl group! /,.
[0025] Z1および Z2のいずれか一方力 窒素原子、他方が CR7「式中、 R7は、前記と同様な 意味を有する。」である化合物が好ましぐ Z1が、窒素原子、 Z2が、 CR7「式中、 R7は、 前記と同様な意味を有する。」である化合物がより好ましぐ Z1が、窒素原子、 Z2が、 CHである化合物がさらに好ましい。 [0025] One of the forces of Z 1 and Z 2 is a nitrogen atom, and the other is CR 7 wherein R 7 has the same meaning as described above. Z 1 is preferably a nitrogen atom. Z 2 is CR 7 , wherein R 7 has the same meaning as above. More preferred is a compound in which Z 1 is a nitrogen atom and Z 2 is CH. .
[0026] X1が、酸素原子、硫黄原子、スルフィニル基、スルホニル基、 NR8a「式中、 R8aは、 前記と同様な意味を有する。」または CR9aR1C>a「式中、 R9aおよび R1C>aは、同一または 異なって水素原子または置換されて 、てもよ 、ヒドロキシル、ァミノもしくはメルカプト 基を意味する。」である化合物が好ましぐ NR8a「式中、 R8aは、前記と同様な意味を 有する。」または CR9aR1C>a「式中、 R9aおよび R1C>aは、前記と同様な意味を有する。」で ある化合物がより好ましぐ CH、 NHまたは CHOHである化合物がさらに好ましい。 [0026] X 1 is an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, NR 8a "wherein R 8a has the same meaning as described above" or CR 9a R 1C> a "wherein R 9a and R 1C> a are the same or different and each represents a hydrogen atom or a substituted group, which may be a hydroxyl, an amino or a mercapto group. ”NR 8a wherein R 8a is , Or CR 9a R 1C> a wherein R 9a and R 1C> a have the same meaning as described above. CH, NH Or more preferably a compound that is CHOH.
2  2
X2が、カルボニル基または結合手である化合物が好まし!/、。 A compound in which X 2 is a carbonyl group or a bond is preferred! /.
X3が、 CHまたは結合手である化合物が好ましい。 A compound in which X 3 is CH or a bond is preferred.
2  2
さらに、 X1、 X2、 X3の組み合わせにおいて、 X1— X2— X3が、 NHCO、 CH CHま Furthermore, in the combination of X 1 , X 2 , and X 3 , X 1 — X 2 — X 3 is NHCO, CH 2 CH
2 2 たは CHOHCHである化合物が好ましい。  Compounds that are 2 2 or CHOHCH are preferred.
2  2
[0027] R6が、 [0027] R 6 is
[化 5]
Figure imgf000017_0001
または [Chemical 5]
Figure imgf000017_0001
Or
「式中、 R ^は、一般式 "In the formula, R ^ is a general formula
[化 6] [Chemical 6]
NH .0  NH .0
N— X5— R N一 R N — X 5 — RN I R
H または H  H or H
「式中、 R14aは、置換されていてもよいアルアルキル、単環の複素環式または二環式 の複素環式基を; X6aは、アルキレン基を; X4および X5は、前記と同様な意味を有す る。」で表される基を;尺11、 Rlla、 Rllb、 Rlleおよび R13は、前記と同様な意味を有する 。」である化合物が好ましぐ Wherein R 14a represents an optionally substituted aralkyl, monocyclic heterocyclic or bicyclic heterocyclic group; X 6a represents an alkylene group; and X 4 and X 5 represent the above and that having a meaning similar to a group represented by ";. continuous 11, R lla, R llb, R lle and R 13 have the same meaning. ”Is preferred
[化 7]  [Chemical 7]
Figure imgf000017_0002
または
Figure imgf000017_0002
Or
「式中、 R12bは、一般式 "Wherein R 12b is a general formula
[化 8]
Figure imgf000017_0003
[Chemical 8]
Figure imgf000017_0003
「式中、 R14bは、置換されていてもよい単環の複素環式または二環式の複素環式基 を; X4aは、酸素原子、硫黄原子または結合手を; mは、 1—4の整数を意味する。」で 表される基を; R13aは、水素原子または置換されて 、てもよ 、アルキルもしくはァリー ル基を; 1、 Rlla、 Rllbおよび Rllcは、前記と同様な意味を有する。」である化合物が より好ましく、 Wherein R 14b is an optionally substituted monocyclic heterocyclic or bicyclic heterocyclic group X 4a represents an oxygen atom, a sulfur atom or a bond; m represents an integer of 1-4. R 13a represents a hydrogen atom or a substituted or unsubstituted alkyl or aryl group; 1 , R 11a , R llb and R llc have the same meanings as described above. Is more preferred,
[化 9]
Figure imgf000018_0001
または [Chemical 9]
Figure imgf000018_0001
Or
「式中、 R12bは、前記と同様な意味を有する。」である化合物がさらに好ましぐ More preferred are compounds wherein “wherein R 12b has the same meaning as described above.”
[化 10][Chemical 10]
Figure imgf000018_0002
または
Figure imgf000018_0002
Or
「式中、 は、前記と同様な意味を有する。」である化合物がよりさらに好ましく、 More preferably, the compound is “wherein has the same meaning as described above.”
[化 11][Chemical 11]
Figure imgf000018_0003
Figure imgf000018_0003
「式中、 R"bは、前記と同様な意味を有する。」である化合物が特に好ましい。 “Wherein R” b has the same meaning as described above. Are particularly preferred.
ただし、 Z2が、 CR7「式中、 R7は、前記と同様な意味を有する。」の場合、 R6が、 [化 12]
Figure imgf000018_0004
However, when Z 2 is CR 7 “wherein R 7 has the same meaning as described above,” R 6 is
Figure imgf000018_0004
「式中、 1、 Rlla、 Rllb、 Rlle、 R12aおよび R13は、前記と同様な意味を有する。」であ る化合物が好ましぐ
Figure imgf000019_0001
A compound in which 1 , R lla , R llb , R lle , R 12a and R 13 have the same meaning as described above is preferred.
Figure imgf000019_0001
'および Rldaは、前記と同様な意味を有する。」であ 'And R lda have the same meaning as above. "
Figure imgf000019_0002
Figure imgf000019_0002
「式中、 は、前記と同様な意味を有する。」である化合物がさらに好ましぐ  Even more preferred are compounds wherein “has the same meaning as described above.”
[化 14] [Chemical 14]
— N N-R — N N-R
N ^ f  N ^ f
「式中、 R12bは、前記と同様な意味を有する。」である化合物がよりさらに好ましい。 なお、 R3または R4の少なくとも一方が、ハロゲン原子、保護されていてもよいカルボ キシル基または置換されていてもよい力ルバモイル、アルキル、ァルケ-ルもしくはシ クロアルキル基; Z1が、窒素原子; Z2が、 CR7「式中、 R7は、前記と同様な意味を有す る。」の場合、 R6が、
Figure imgf000019_0003
More preferred are compounds wherein “wherein R 12b has the same meaning as described above”. Note that at least one of R 3 and R 4 is a halogen atom, an optionally protected carboxyl group, or an optionally substituted rubamoyl, alkyl, alkenyl, or cycloalkyl group; Z 1 is nitrogen atom; Z 2 is ". wherein, R 7 is that having a said the same meaning" CR 7 cases, R 6 is,
Figure imgf000019_0003
「式中、 R , R"および R"は、前記と同様な意味を有する。」である化合物が好ましく 、 R3が、水素原子; R4が、保護されていてもよいカルボキシル基で置換されているァ ルケニル基の場合、 R6が、 A compound in which “wherein R 1, R ″ and R ″ have the same meaning as described above” is preferred, R 3 is a hydrogen atom; R 4 is substituted with an optionally protected carboxyl group R 6 is an alkenyl group
Figure imgf000019_0004
「式中、 R12eは、一般式
Figure imgf000019_0004
"In the formula, R 12e is a general formula
[化 15] [Chemical 15]
- X6b- X4a _ R1 4c 4ο -X 6b- X 4a _ R 1 4c 4ο
Figure imgf000020_0001
Figure imgf000020_0001
、 H または H , H or H
「式中、 R14eは、置換されていてもよいァリール、単環の複素環式または二環式の複 素環式基を; X6bは、置換されていてもよいアルキレン、ァルケ-レンまたはアルキ- レン基を; X4aは、前記と同様な意味を有する。」で表される基を; R11および R13aは、前 記と同様な意味を有する。」である化合物がより好ましい。さらに、 R1が、アルコキシ基 ； R2および R5が、水素原子の場合、 R6が、
Figure imgf000020_0002
"Wherein R 14e represents an optionally substituted aryl, monocyclic heterocyclic or bicyclic bicyclic group; X 6b represents an optionally substituted alkylene, alkene, or An alkylene group; X 4a has the same meaning as described above; and R 11 and R 13a have the same meaning as described above. Is more preferable. Furthermore, when R 1 is an alkoxy group; R 2 and R 5 are hydrogen atoms, R 6 is
Figure imgf000020_0002
「式中、 X6eは、置換されていてもよいアルキレン基を; R11および R1 は、前記と同様 な意味を有する。」である化合物が好ましい。 A compound in which X 6e represents an optionally substituted alkylene group; R 11 and R 1 have the same meaning as described above is preferable.
上記、 R6において、 R12a、 R12bおよび R12cが、 In the above R 6 , R 12a , R 12b and R 12c are
[化 16]
Figure imgf000020_0003
[Chemical 16]
Figure imgf000020_0003
「式中、 R14bおよび mは、前記と同様な意味を有する。」である化合物が好ましぐ - ( CH ) — R14b「式中、 R14bおよび mは、前記と同様の意味を有する。」である化合物Preferred are compounds wherein “wherein R 14b and m have the same meanings as described above.” — (CH) — R 14b “wherein R 14b and m have the same meanings as described above. Is a compound
2 m 2 m
力 り好ましい。 It is preferable.
上記、 R12a、 R12bおよび R12eにおいて、 m力 1、 2または 3である化合物が好ましぐ 1または 2である化合物がより好ま 、。 In the above R 12a , R 12b and R 12e , a compound having an m force of 1, 2 or 3 is preferred, and a compound of 1 or 2 is more preferred.
上記、 R12a、 R12bおよび R12cにおいて、 R14bが、置換されていてもよいァリール、単 環の複素環式または二環式の複素環式基である化合物が好ましぐ置換されていて もよい 2, 3—ジヒドロべンゾ [b] [l, 4]ジォキシンー6—ィル、 2, 3—ジヒドロ [1, 4]ジ ォキシノ [2, 3— c]ピリジン一 7—ィル、 3—フルオロー 4—メチルフエ-ル、 4— (トリフ ルォロメチル）フエニル、ベンゾフラン一 5—ィル、 1, 2, 3 ベンゾチアジアゾール一 5—ィルまたは 5 （チォフェンー2 ィル） イソォキサゾールー 3—ィルである化合 物がより好ましぐ 2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルである化合物 力 Sさらに好ましい。 In the above R 12a , R 12b and R 12c , a compound in which R 14b is an optionally substituted aryl, monocyclic heterocyclic or bicyclic heterocyclic group is preferably substituted. 2,3-dihydrobenzo [b] [l, 4] dioxin-6-yl, 2,3-dihydro [1, 4] dioxino [2,3-c] pyridine-7-yl, 3-Fluoro-4-methylphenol, 4- Compounds that are (fluoromethyl) phenyl, benzofuran 5-yl, 1, 2, 3 benzothiadiazole 5-yl or 5 (thiophene-2-yl) isoxazole-3-yl are more preferred 2 , 3 Dihydrobenzo [b] [l, 4] Dioxin 6-yl Compound Power S More preferred.
[0030] 本発明化合物中、代表的化合物としては、たとえば、以下の表 1、 2および 3に記載 される化合物が挙げられる。  [0030] Among the compounds of the present invention, representative compounds include, for example, compounds described in Tables 1, 2 and 3 below.
[0031] [表 1] [0031] [Table 1]
Figure imgf000021_0001
Figure imgf000021_0001
Z1 Z2 R1 R2 R3 R4 Z 1 Z 2 R 1 R 2 R 3 R 4
N CH OCH3 H H H N CH OCH 3 HHH
Figure imgf000021_0002
Figure imgf000021_0002
N CH CN H H H
Figure imgf000021_0003
N CH CN HHH
Figure imgf000021_0003
[0032] [表 2]
Figure imgf000022_0001
[0032] [Table 2]
Figure imgf000022_0001
z1 Z2 R1 - X1 - X2 - X3 - R6 z1 Z2 R1 -X'-X2-X3-R6 z 1 Z 2 R 1 -X 1 -X 2 -X 3 -R 6 z 1 Z 2 R 1 -X'-X 2 -X 3 -R 6
Figure imgf000022_0002
Figure imgf000022_0002
H0H0
N CH OCH3 N CH OCH3 N CH OCH 3 N CH OCH3
义  义
Figure imgf000022_0003
3]
Figure imgf000022_0003
3]
Figure imgf000023_0001
Figure imgf000023_0001
[0034] 次に、本発明化合物の製造法について説明する。 [0034] Next, a method for producing the compound of the present invention will be described.
本発明化合物は、自体公知の方法を組み合わせることにより製造されるが、たとえ ば、次に示す製造法により製造することができる。  The compound of the present invention is produced by a combination of methods known per se. For example, the compound of the present invention can be produced by the following production method.
[0035] [製造法 1] [0035] [Production method 1]
Figure imgf000023_0002
Figure imgf000023_0002
[2] [1a] 「式中、 R2a、 R3a、 R4aおよび R5aは、同一または異なって水素原子、ハロゲン原子、シ ァノ基、保護されているカルボキシル基、置換されていてもよい保護されているァミノ 基または置換されていてもよいアルキル、ァルケ-ル、アルコキシ、シクロアルキルも しくは力ルバモイル基を; Xlaは、酸素原子、硫黄原子または NR8a「式中、 R8aは、前 記と同様の意味を有する。」を; Zlaおよび Z2aは、窒素原子または CR7a「式中、 R7aは、 水素原子、ハロゲン原子、シァノ基、保護されているカルボキシル基、置換されてい てもよ 、保護されて 、るァミノ基または置換されて 、てもよ 、アルキル、ァルケ-ル、 アルコキシもしくは力ルバモイル基を意味する。」であり、かつ、 zlaおよび z2aの少なく とも一方が窒素原子を; 、 R6および X3は、前記と同様の意味を有する。」 [2] [1a] “In the formula, R 2a , R 3a , R 4a and R 5a are the same or different and each represents a hydrogen atom, a halogen atom, a cyan group, a protected carboxyl group, or an optionally substituted protected amino group. A group or an optionally substituted alkyl, alkenyl, alkoxy, cycloalkyl or rubamoyl group; X la is an oxygen atom, sulfur atom or NR 8a , wherein R 8a is the same as defined above Z la and Z 2a are a nitrogen atom or CR 7a wherein R 7a is a hydrogen atom, a halogen atom, a cyano group, a protected carboxyl group or an optionally substituted group. , Protected, amino or substituted, may mean alkyl, alkenyl, alkoxy, or rubamoyl groups, and at least one of z la and z 2a is a nitrogen atom. ;, R 6 and X 3 Has the same meaning as described above. "
一般式 [la]の化合物は、塩基の存在下または不存在下、一般式 [2]の化合物を 一般式 [3]の化合物の反応性誘導体と反応させることにより製造することができる。 この反応は、 WO03Z010138号公報、 WO03Z087098号公報および泉屋ら、 ペプチド合成の基礎と実験、第 89〜142頁、 1985年、丸善などに記載された方法また はそれに準じた方法で行えばょ 、。  The compound of the general formula [la] can be produced by reacting the compound of the general formula [2] with a reactive derivative of the compound of the general formula [3] in the presence or absence of a base. This reaction can be carried out by the method described in WO03Z010138, WO03Z087098 and Izumiya et al., Peptide synthesis basics and experiments, pp. 89-142, 1985, Maruzen et al.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、 N, N—ジメチルホルムアミド、 N, N—ジメチルァセトアミドおよび 1—メチ ルー 2—ピロリドンなどのアミド類;塩化メチレン、クロ口ホルムおよびジクロロェタンな どのハロゲンィ匕炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水 素類；ジォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテ ル、ジエチレングリコールジメチルエーテルおよびジエチレングリコールジェチルェ 一テルなどのエーテル類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよ び 2—ブタノンなどのケトン類ならびに酢酸ェチルなどのエステル類などが挙げられ、 これらは混合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone. Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Dioxane, Tetrahydrofuran, Carsol, Ethylene glycol dimethyl ether, Diethylene glycol dimethyl ether and Diethylene glycol Examples include ethers such as cetyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone and esters such as ethyl acetate. These may be used as a mixture. .
この反応において所望により使用される塩基としては、たとえば、ピリジン、ジメチル アミノビリジンおよびトリェチルァミンなどの有機塩基;水酸ィ匕ナトリウム、水酸ィ匕カリウ ム、炭酸水素ナトリウム、炭酸カリウムおよび炭酸ナトリウムなどの無機塩基などが挙 げられる。  Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminoviridine and triethylamine; sodium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate. Examples include inorganic bases.
この反応に使用される反応性誘導体としては、たとえば、酸クロリドおよび酸プロミド などの酸ハロゲン化物； p -トロフエ-ルエステル、 N ヒドロキシスクシンイミドエス テルおよび N ヒドロキシフタルイミドエステルなどの活性エステル；クロ口炭酸ェチル 、クロ口 [酸イソブチルなどの炭酸モノアルキルエステルとの混合酸無水物ならびに Examples of reactive derivatives used in this reaction include acid chloride and acid promide. Acid halides such as: p-trophyl esters, N hydroxysuccinimide esters and N hydroxyphthalimide esters; active esters such as ethyl ester carbonates, mixed acid anhydrides with monoalkyl ester carbonates such as isobutyl acid and
2  2
ビバリン酸などの有機酸との混合酸無水物などが挙げられる。これらの反応性誘導 体は、単離せずに使用してもよい。 Examples thereof include mixed acid anhydrides with organic acids such as bivalic acid. These reactive derivatives may be used without isolation.
カップリング試薬を用いて、系内で反応性誘導体を生成させてもよい。カップリング 試薬としては、たとえば、 N, N'—ジシクロへキシルカルボジイミドおよび N ェチル N，一（3—ジメチルァミノプロピル）カルボジイミドなどのカルボジイミド類；カルボ- ルジイミダゾールなどのカルボ-ル類；ジフヱ-ルホスホリルアジドなどの酸アジド類； ジェチルホスホリルシア-ドなどの酸シアニド類； 2—エトキシ 1 エトキシカルボ- ル一 1, 2 ジヒドロキノリン； O ベンゾトリアゾール 1—ィル一 1, 1, 3, 3—テトラメ チルゥ口-ゥム =へキサフルォロホスフェートならびに O— (7—ァザべンゾトリァゾー ルー 1—ィル） 1, 1, 3, 3—テトラメチルゥ口-ゥム = [キサフルォロホスフェートな どが挙げられる。  A reactive reagent may be generated in the system using a coupling reagent. Coupling reagents include, for example, carbodiimides such as N, N′-dicyclohexylcarbodiimide and Nethyl N, mono (3-dimethylaminopropyl) carbodiimide; carbodiimides such as carbodiimidazole; Acid azides such as ruphosphoryl azide; Acid cyanides such as jetyl phosphoryl cyanide; 2-Ethoxy 1 ethoxycarbonyl 1,2 Dihydroquinoline; O Benzotriazole 1-yl 1, 1, 3, 3—Tetramethylthiol-um = hexafluorophosphate and O— (7-azabenzotriazol 1-yl) 1, 1, 3, 3—Tetramethylthiol-um = [xafluoro Examples include phosphates.
この反応において、所望により使用される塩基、一般式 [3]の化合物の反応性誘導 体およびカップリング試薬の使用量は、一般式 [2]の化合物に対して 1〜50倍モル、 好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of the base used as desired, the reactivity derivative of the compound of the general formula [3], and the coupling reagent is 1 to 50 times mol, preferably the compound of the general formula [2] It should be 1 to 5 times the mole!
この反応は、 30〜150°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
[製造法 2] [Production method 2]
Figure imgf000025_0001
Figure imgf000025_0001
b]  b]
「式中、 R°aは、
Figure imgf000026_0001
`` Where R ° a is
Figure imgf000026_0001
「式中、 Y3は、ァミノ基の保護基を; 1、 Rlla、 Rllb、 Rllc、 R12、 R13は、前記と同様の 意味を有する。
Figure imgf000026_0002
R2a、 R3a、 R4a、 R5a、 Xla、 Zlaおよび Z2aは、前記と同様の意味 を有する。」 “Wherein Y 3 represents a protecting group for an amino group; 1 , R 11a , R llb , R llc , R 12 , R 13 have the same meanings as described above.
Figure imgf000026_0002
R 2a , R 3a , R 4a , R 5a , X la , Z la and Z 2a have the same meaning as described above. "
一般式 [lb]の化合物は、塩基の存在下または不存在下、一般式 [2]の化合物を カルボニル化合物と反応させた後、一般式 [4]の化合物と反応させることにより製造 することができる。また、一般式 [lb]の化合物は、塩基の存在下または不存在下、一 般式 [4]の化合物をカルボニル化合物と反応させた後、一般式 [2]の化合物と反応 させること〖こより製造することができる。この反応は、 WO02/50061号公報および WO02Z56882号公報などに記載された方法またはそれに準じた方法で行えばよ い。  The compound of the general formula [lb] can be produced by reacting the compound of the general formula [2] with a carbonyl compound in the presence or absence of a base and then reacting with the compound of the general formula [4]. it can. In addition, the compound of general formula [lb] can be reacted with the compound of general formula [2] after reacting the compound of general formula [4] with a carbonyl compound in the presence or absence of a base. Can be manufactured. This reaction may be carried out by the method described in WO02 / 50061, WO02Z56882 or the like or a method analogous thereto.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、 N, N—ジメチルホルムアミド、 N, N—ジメチルァセトアミドおよび 1—メチ ルー 2—ピロリドンなどのアミド類;塩化メチレン、クロ口ホルムおよびジクロロェタンな どのハロゲンィ匕炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水 素類；ジォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテ ル、ジエチレングリコールジメチルエーテルおよびジエチレングリコールジェチルェ 一テルなどのエーテル類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよ び 2—ブタノンなどのケトン類ならびに酢酸ェチルなどのエステル類などが挙げられ、 これらは混合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone. Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Dioxane, Tetrahydrofuran, Carsol, Ethylene glycol dimethyl ether, Diethylene glycol dimethyl ether and Diethylene glycol Examples include ethers such as cetyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone and esters such as ethyl acetate. These may be used as a mixture. .
この反応に使用されるカルボ二ルイ匕合物としては、たとえば、 1, 1 '—カルボ-ルジ イミダゾール、塩化カルボ-ル [ホスゲン]およびビス（トリクロロメチル)カーボナート [ トリホスゲン]などが挙げられる。  Examples of the carbonyl compound used in this reaction include 1,1'-carbodiimidazole, carbonyl chloride [phosgene] and bis (trichloromethyl) carbonate [triphosgene].
この反応において所望により使用される塩基としては、たとえば、ピリジン、ジメチル アミノビリジンおよびトリェチルァミンなどの有機塩基;水酸ィ匕ナトリウム、水酸ィ匕カリウ ム、炭酸水素ナトリウム、炭酸カリウムおよび炭酸ナトリウムなどの無機塩基などが挙 げられる。 Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminoviridine and triethylamine; sodium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate. Inorganic bases I can get lost.
この反応において、所望により使用される塩基、一般式 [4]の化合物およびカルボ 二ルイヒ合物の使用量は、一般式 [2]の化合物に対して 1〜50倍モル、好ましくは 1〜 5倍モルであればよレ、。  In this reaction, the use amount of the base, the compound of the general formula [4] and the carbocyclic compound used as desired is 1 to 50 times mol, preferably 1 to 5 times that of the compound of the general formula [2]. It should be double mole.
この反応は、 30〜150°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
[製造法 3]  [Production method 3]
Figure imgf000027_0001
Figure imgf000027_0001
「式中、 1、 Rlla、 Rllb、 Rlle、 R13は、前記と同様の意味を有する。」を; L1は、脱離 基を;
Figure imgf000027_0002
Zla、 Z2aおよび mは、前記と同様 の意味を有する。」 " Wherein , 1 , R lla , R llb , R lle , R 13 have the same meaning as described above."; L 1 represents a leaving group;
Figure imgf000027_0002
Z la , Z 2a and m have the same meaning as described above. "
(3- 1) (3-1)
一般式 [lc]の化合物は、還元剤の存在下、一般式 [5]の化合物を一般式 [6]の 化合物と反応させることにより製造することができる。 この反応は、 WO02Z50061号公報、 WO02Z56882号公報およびジエリ一'マ ーチ（Jerry March)、アドバンスド 'オーガニック 'ケミストリー（Advanced Organic Che mistry)第 4版、第 898〜900頁、 1992年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)などに記載された方法またはそれに準じた方法で行えばよ!、。 The compound of the general formula [lc] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [6] in the presence of a reducing agent. This reaction is described in WO02Z50061, WO02Z56882 and Jerry March, Advanced Organic Chemistry 4th edition, pages 898-900, 1992, John Willie. You can do it by the method described in 'And' Sons, Inc. (John Wiley & Sons, INC.) Or a similar method!
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロ ゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジ ォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテル、ジェ チレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルおよび エチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなど のスルホキシド類；酢酸ェチルなどのエステル類ならびに水などが挙げられ、これら は混合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Halogenated hydrocarbons such as form and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, azole, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Examples thereof include ethers such as monomethyl ether; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate and water. These may be used as a mixture.
この反応に使用される還元剤としては、たとえば、水素化アルミニウムリチウム、トリ ァセトキシ水素化ホウ素ナトリウム、水素化シァノホウ素ナトリウムおよび水素化ホウ素 ナトリウムなどの水素化錯ィ匕合物、ボラン、ナトリウムならびにナトリウムアマルガムな どが挙げられる。また、銅または白金を陰極に用いた電解還元;ラネーニッケル、酸 化白金またはパラジウム黒を用いる接触還元ならびに「亜鉛 酸」を用いる還元など を用いることちでさる。  Examples of the reducing agent used in this reaction include lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride complex compounds such as borane, sodium and sodium. Examples include amalgam. In addition, electrolytic reduction using copper or platinum as a cathode; catalytic reduction using Raney nickel, platinum oxide or palladium black and reduction using “zinc acid” can be used.
この反応において、一般式 [6]の化合物のおよび還元剤の使用量は、一般式 [5] の化合物に対して 1〜50倍モル、好ましくは 1〜5倍モルであればよい。  In this reaction, the amount of the compound of the general formula [6] and the reducing agent used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [5].
この反応は、 30〜150°C、好ましくは 0〜100°Cで 30分間〜 120時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 120 hours.
(3 - 2)  (3-2)
一般式 [lc]の化合物は、塩基の存在下または不存在下、一般式 [5]の化合物を 一般式 [7]の化合物と反応させることにより製造することができる。  The compound of the general formula [lc] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [7] in the presence or absence of a base.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロ ゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジ ォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテル、ジェ チレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルおよび エチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなど のスルホキシド類；酢酸ェチルなどのエステル類ならびに水などが挙げられ、これら は混合して使用してもよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, methanol, ethanol, 2-propanol and 2-methyl-2-propano Alcohols such as alcohol; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; dioxane, tetrahydrofuran, alcohol, ethylene glycol dimethyl ether, Examples include ethers such as polyethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate and water, and these may be used as a mixture.
この反応において所望により使用される塩基としては、たとえば、ピリジン、ジメチル アミノビリジンおよびトリェチルァミンなどの有機塩基;水酸ィ匕ナトリウム、水酸ィ匕カリウ ム、炭酸水素ナトリウム、炭酸カリウムおよび炭酸ナトリウムなどの無機塩基などが挙 げられる。  Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminoviridine and triethylamine; sodium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate. Examples include inorganic bases.
この反応において、所望により使用される塩基および一般式 [7]の化合物の使用 量は、一般式 [5]の化合物に対して 1〜50倍モル、好ましくは 1〜5倍モルであればよ い。  In this reaction, the amount of the base and the compound of the general formula [7] used as desired may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [5]. Yes.
この反応は、 30〜150°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
[0042] [製造法 4]  [0042] [Production Method 4]
Figure imgf000029_0001
Figure imgf000029_0001
[8] [ 1 d]  [8] [1 d]
「式中、
Figure imgf000029_0002
R2a、 R3a、 R4a、 R5a、 R6a、 Zlaおよび Z2aは、前記と同様の意味を有する。」 [0043] 一般式 [Id]の化合物は、還元剤の存在下、一般式 [8]の化合物を一般式 [4]の 化合物と反応させることにより製造することができる。 "In the formula,
Figure imgf000029_0002
R 2a , R 3a , R 4a , R 5a , R 6a , Z la and Z 2a have the same meaning as described above. [0043] The compound of the general formula [Id] can be produced by reacting the compound of the general formula [8] with the compound of the general formula [4] in the presence of a reducing agent.
この反応は、製造法 3—1に準じて行えばよい。  This reaction may be carried out according to production method 3-1.
[0044] [製造法 5]
Figure imgf000030_0001
[0044] [Production Method 5]
Figure imgf000030_0001
[5] [ 1 e] [5] [1 e]
「式中、 R は、置換されていてもよいシクロアルキル、シクロアルケ-ル、アルアルキ ル、ァリールまたは複素環式基を; R15は、 C R2a、 R3a、 R4a
Figure imgf000030_0002
"Wherein R is an optionally substituted cycloalkyl, cycloalkyl, alkyl, aryl, or heterocyclic group; R 15 is CR 2a , R 3a , R 4a
Figure imgf000030_0002
、 R5a、 Q\ X1、 X2、 X3、 Zlaおよび Z2aは、前記と同様の意味を有する。」 , R 5a , Q \ X 1 , X 2 , X 3 , Z la and Z 2a have the same meaning as described above. "
[0045] 一般式 [le]の化合物は、一般式 [5]の化合物を一般式 [9]の化合物と反応させる ことにより製造することができる。この反応は、バイオオーガニック'アンド'メディシナ ル 'ケミストリ^ ~ ·レター（Bioorganic. Med. Chem. Lett.)、第 13卷、第 241〜245頁、 20 03年などに記載された方法またはそれに準じた方法で行えばよい。 [0045] The compound of the general formula [le] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [9]. This reaction is the same as or similar to the method described in Bioorganic. Med. Chem. Lett., Vol. 13, pages 241-245, 2003. You can do this by
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロ ゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジ ォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテル、ジェ チレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルおよび エチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなど のスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類；酢酸ェチルなどのエス テル類ならびに水などが挙げられ、これらは混合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Halogenated hydrocarbons such as form and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, azole, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Ethers such as monomethyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; esters such as ethyl acetate; and water. Mixed and may also be used.
この反応において、一般式 [9]の化合物の使用量は、一般式 [5]の化合物に対し て 1〜50倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of the compound of the general formula [9] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [5]!
この反応は、 30〜150°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
[0046] [製造法 6]
Figure imgf000031_0001
[0046] [Production method 6]
Figure imgf000031_0001
[5] [ 1 f] [5] [1 f]
「式中、 R\ R2a、 R3a、 R4a、 R5a、 R14d、 Q\ X1、 X2、 X3、 Zlaおよび Z2aは、前記と同様 の意味を有する。」 “In the formula, R \ R 2a , R 3a , R 4a , R 5a , R 14d , Q \ X 1 , X 2 , X 3 , Z la and Z 2a have the same meaning as described above.
[0047] 一般式 [If]の化合物は、溶媒の存在下または不存在下、一般式 [5]の化合物を 一般式 [10]の化合物と反応させることにより製造することができる。この反応は、日 本化学会編、新実験科学講座 14、有機化合物の合成と反応 III、第 1628〜1644頁、 1 978年、丸善などに記載された方法またはそれに準じた方法で行えばよ!、。  [0047] The compound of the general formula [If] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [10] in the presence or absence of a solvent. This reaction may be carried out by the method described in the Chemical Society of Japan, New Experimental Science Course 14, Synthesis and Reaction of Organic Compounds III, pp. 1628-1644, 1978, Maruzen, etc. !
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロゲン化炭化水 素類;ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類;ジォキサン、テト ラヒドロフラン、ァニソール、エチレングリコールジメチルエーテル、ジエチレングリコー ルジメチルエーテルおよびジエチレングリコールジェチルエーテルなどのエーテル 類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよび 2—ブタノンなどのケト ン類ならびに酢酸ェチルなどのエステル類などが挙げられ、これらは混合して使用し てもよい。  Solvents used in this reaction are not particularly limited as long as they do not adversely influence the reaction.For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatics such as benzene, toluene and xylene. Hydrocarbons; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol jetyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone and ethyl acetate These esters may be used, and these may be used as a mixture.
この反応において、一般式 [10]の化合物の使用量は、一般式 [5]の化合物に対し て 1〜50倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of the compound of the general formula [10] used is 1 to 50 times mol, preferably 1 to 5 times mol of the compound of the general formula [5]!
この反応は、 30〜200°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
[0048] [製造法 7]  [0048] [Production method 7]
Figure imgf000031_0002
「式中、 T1は、酸素原子、硫黄原子または NR8a「式中、 R8aは、前記と同様の意味を 有する。」を; R R2a、 R3a、 R4a、 R5a、 R6a、 Zlaおよび Z2aは、前記と同様の意味を有す る。」
Figure imgf000031_0002
“Wherein T 1 is an oxygen atom, a sulfur atom or NR 8a ” wherein R 8a has the same meaning as described above; RR 2a , R 3a , R 4a , R 5a , R 6a , Z la and Z 2a have the same meaning as described above. "
[0049] 一般式 [lg]または [lh]の化合物は、一般式 [11]の化合物を一般式 [4]の化合 物と反応させることにより製造することができる。この反応は、ジャーナル'ォブ 'ォー ガ-ック.ケミストリー（J. Org. Chem.)、第 56卷、第 5939〜5942頁、 1991年などに記載 された方法またはそれに準じた方法で行えばよい。  [0049] The compound of the general formula [lg] or [lh] can be produced by reacting the compound of the general formula [11] with a compound of the general formula [4]. This reaction is carried out according to the method described in the journal 'Ob' Oga. Chem., Vol. 56, pages 5939 to 5942, 1991, or the like. Just do it.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類； N, N ジメチルホルムアミド、 N, N ジメチルァセトアミド および 1ーメチルー 2—ピロリドンなどのアミド 塩化メチレン、クロ口ホルムおよびジ クロロェタンなどのハロゲン化炭化水素類；ベンゼン -—、トルエンおよびキシレンなどの 芳香族炭化水素類;ジォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコール ジメチルエーテル、ジエチレングリコールジメチルエーテル、ジエチレングリコールジ ェチルエーテルおよびエチレングリコールモノメチルエーテルなどのエーテル類；ジ メチルスルホキシドなどのスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類； 酢酸ェチルなどのエステル類ならびに水などが挙げられ、これらは混合して使用して ちょい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N dimethylformamide Amides such as N, N dimethylacetamide and 1-methyl-2-pyrrolidone Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene--, toluene and xylene; Dioxane , Tetrahydrofuran, ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ether glycol such as ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; Ketones such as emissions and 2-butanone; and esters and water, such as acetic Echiru the like, Choi and used these were mixed.
この反応において、一般式 [4]の化合物の使用量は、一般式 [11]の化合物に対し て 1〜50倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of the compound of the general formula [4] used may be 1 to 50 times mol, preferably 1 to 5 times mol of the compound of the general formula [11]!
この反応は、 30〜150°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
[0050] [製造法 8]  [0050] [Production method 8]
Figure imgf000032_0001
Figure imgf000032_0001
[28] 「式中、 R\ R2a、 R3a、 R4a、 R5a、 R6a、 Zlaおよび Z2aは、前記と同様の意味を有する。」 [0051] 一般式 [li]の化合物は、溶媒の存在下または不存在下、一般式 [28]の化合物を 一般式 [4]の化合物と反応させることにより製造することができる。この反応は、 W02 004Z058144号公報などに記載された方法またはそれに準じた方法で行えばよい この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類； N, N ジメチルホルムアミド、 N, N ジメチルァセトアミド および 1ーメチルー 2—ピロリドンなどのアミド類;塩化メチレン、クロ口ホルムおよびジ クロロェタンなどのハロゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの 芳香族炭化水素類;ジォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコール ジメチルエーテル、ジエチレングリコールジメチルエーテル、ジエチレングリコールジ ェチルエーテルおよびエチレングリコールモノメチルエーテルなどのエーテル類；ジ メチルスルホキシドなどのスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類； 酢酸ェチルなどのエステル類ならびに水などが挙げられ、これらは混合して使用して ちょい。 [28] “In the formula, R \ R 2a , R 3a , R 4a , R 5a , R 6a , Z la and Z 2a have the same meaning as described above.” [0051] The compound of the general formula [li] is a solvent It can be produced by reacting the compound of general formula [28] with the compound of general formula [4] in the presence or absence of. This reaction may be carried out by the method described in W02 004Z058144 or the like, or a method according thereto. Solvents used in this reaction may be those which do not adversely affect the reaction. For example, methanol, ethanol , Alcohols such as 2-propanol and 2-methyl-2-propanol; amides such as N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone; methylene chloride, black mouth form and di Halogenated hydrocarbons such as chloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, azole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol Ethers such as methyl ether; sulfoxides such as di-methyl sulfoxide; ketones such as acetone and 2-butanone; and esters and water, such as acetic Echiru the like, Choi and used these were mixed.
この反応において、一般式 [4]の化合物の使用量は、一般式 [28]の化合物に対し て 1〜50倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of the compound of the general formula [4] to be used is 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [28]!
この反応は、 30〜150°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
[0052] [製造法 9]  [0052] [Production method 9]
Figure imgf000033_0001
Figure imgf000033_0001
[5]  [Five]
「式中、 R\ R2a、 R° R4a、 R5a、 R"、 Q\ X1、 X2、 Zlaおよび Z2aは、前記と同様 の意味を有する。」 [0053] 一般式 [lj]の化合物は、溶媒の存在下または不存在下、一般式 [5]の化合物を一 般式 [29]の化合物と反応させることにより製造することができる。この反応は、 WOO 3Z010138号公報などに記載された方法またはそれに準じた方法で行えばよい。 この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロゲン化炭化水 素類;ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類;ジォキサン、テト ラヒドロフラン、ァニソール、エチレングリコールジメチルエーテル、ジエチレングリコー ルジメチルエーテルおよびジエチレングリコールジェチルエーテルなどのエーテル 類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよび 2—ブタノンなどのケト ン類ならびに酢酸ェチルなどのエステル類などが挙げられ、これらは混合して使用し てもよい。 “Wherein R \ R 2a , R ° R 4a , R 5a , R", Q \ X 1 , X 2 , Z la and Z 2a have the same meaning as described above. " [0053] The compound of the general formula [lj] can be produced by reacting the compound of the general formula [5] with a compound of the general formula [29] in the presence or absence of a solvent. This reaction may be carried out by a method described in WOO 3Z010138 or the like or a method analogous thereto. Solvents used in this reaction are not particularly limited as long as they do not adversely influence the reaction.For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatics such as benzene, toluene and xylene. Hydrocarbons; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol jetyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone and ethyl acetate These esters may be used, and these may be used as a mixture.
この反応において、一般式 [29]の化合物の使用量は、一般式 [5]の化合物に対し て 1〜50倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of the compound of the general formula [29] used is 1 to 50 times mol, preferably 1 to 5 times mol of the compound of the general formula [5]!
この反応は、 30〜200°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C., preferably 0 to 150 ° C. for 30 minutes to 48 hours.
[0054] [製造法 10]  [0054] [Production method 10]
Figure imgf000034_0001
Figure imgf000034_0001
[1 5] [ 1 k]  [1 5] [1 k]
「式中、 U1は、ハロゲン原子、アルカンスルホ -ルォキシ基またはァリールスルホ-ル
Figure imgf000034_0002
R2a、 R3a、 R4a、 R5a、 R6、 X3、 Zlaおよび Z2aは、前記と同様の意味を 有する。」 “In the formula, U 1 represents a halogen atom, an alkanesulfoxy group or an arylsulfol.
Figure imgf000034_0002
R 2a , R 3a , R 4a , R 5a , R 6 , X 3 , Z la and Z 2a have the same meaning as described above. "
[0055] 一般式 [lk]の化合物は、塩基および触媒の存在下、ホスフィンの存在下または 不存在下、一般式 [15]の化合物を一般式 [30]の化合物と反応させることにより製 造することができる。  [0055] The compound of the general formula [lk] is produced by reacting the compound of the general formula [15] with the compound of the general formula [30] in the presence of a base and a catalyst and in the presence or absence of phosphine. can do.
この反応は、オーガニック 'レターズ（Organic. Letters.)、第 1卷、第 35〜38頁、 1999 年などに記載された方法またはそれに準じた方法で行えばよい。 This reaction is described in Organic 'Letters., 1st pp. 35-38, 1999. What is necessary is just to carry out by the method described in the year etc. or the method according to it.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、 N, N ジメチルホルムアミド、 N, N ジメチルァセトアミドおよび 1—メチ ルー 2—ピロリドンなどのアミド類;塩化メチレン、クロ口ホルムおよびジクロロェタンな どのハロゲンィ匕炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水 素類；ジォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテ ル、ジエチレングリコールジメチルエーテルおよびジエチレングリコールジェチルェ 一テルなどのエーテル類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよ び 2—ブタノンなどのケトン類ならびに酢酸ェチルなどのエステル類などが挙げられ、 これらは混合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, amides such as N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; dioxane, tetrahydrofuran, carsol, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol dimethyl ether Examples include ethers such as ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; esters such as ethyl acetate; and the like.
この反応に使用される塩基としては、たとえば、ナトリウム =tert—ブトキシド、ピリジ ン、ジメチルァミノピリジンおよびトリェチルァミンなどの有機塩基;水酸ィ匕ナトリウム、 水酸ィ匕カリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸ナトリウムおよび炭酸セシゥ ムなどの無機塩基などが挙げられる。  Examples of the base used in this reaction include organic bases such as sodium tert-butoxide, pyridine, dimethylaminopyridine, and triethylamine; sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate And inorganic bases such as sodium carbonate and cesium carbonate.
この反応に使用される触媒としては、たとえば、テトラキス（トリフエニルホスフィン)パ ラジウム、酢酸パラジウム（11)、塩ィ匕パラジウム（II)およびトリス（ジベンジリデンァセト ン）二パラジウム (0)などが挙げられる。  Examples of the catalyst used in this reaction include tetrakis (triphenylphosphine) palladium, palladium acetate (11), sodium chloride palladium (II), and tris (dibenzylideneacetone) dipalladium (0). Can be mentioned.
この反応において所望により使用されるホスフィンとしては、たとえば、トリフエ-ルホ スフイン、トリ一 tert ブチルホスフィン、ジフエ-ル（オルトトリル）ホスフィン、トリ（トリ ル）ホスフィンおよび 2, 2，一ビス（ジフエ-ルホスフイノ）一 1, 1，一ビナフチルなどが 挙げられる。  Examples of the phosphine optionally used in this reaction include triphenylphosphine, tritert-butylbutylphosphine, diphenyl (orthotolyl) phosphine, tri (tolyl) phosphine and 2,2,1bis (diphenylphosphino). ) 1, 1, 1 and 1 binaphthyl.
この反応において、使用される塩基、一般式 [30]の化合物の使用量は、一般式 [1 5]の化合物に対して 1〜50倍モル、好ましくは 1〜5倍モルであればよい。  In this reaction, the used amount of the base and the compound of the general formula [30] may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [15].
この反応にお 、て、使用される触媒の使用量は一般式 [15]の化合物に対して 0.00 1〜 10倍モル、好ましくは 0.01〜 2倍モルであればよ 、。  In this reaction, the amount of catalyst used is 0.001 to 10 times mol, preferably 0.01 to 2 times mol, of the compound of the general formula [15].
この反応において、所望により使用されるホスフィンの使用量は、一般式 [15]の化 合物に対して 0.001〜40倍モル、好ましくは 0.01〜8倍モルであればよい。  In this reaction, the amount of phosphine used as desired may be 0.001 to 40 times mol, preferably 0.01 to 8 times mol, of the compound of general formula [15].
この反応は、 30〜150°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。 This reaction may be carried out at 30 to 150 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours. Yes.
[製造法 11] [Production method 11]
Figure imgf000036_0001
Figure imgf000036_0001
「式中、 U2は、ハロゲン原子、アルカンスルホ -ルォキシ基またはァリールスルホ-ル ォキシ基を; R16は、カルボキシル基の保護基を; R R2a、 R3a、 R5a、 R6、 X1、 X2、 X3 、 Zlaおよび Z2aは、前記と同様の意味を有する。」 "In the formula, U 2 represents a halogen atom, an alkanesulfo-oxy group or an aryl sulfo-oxy group; R 16 represents a protecting group for a carboxyl group; RR 2a , R 3a , R 5a , R 6 , X 1 , X 2 , X 3 , Z la and Z 2a have the same meaning as described above.
一般式 [lm]の化合物は、触媒の存在下、塩基の存在下または不存在下、ホスフィ ンの存在下または不存在下、一般式 [11]の化合物を一般式 [14]の化合物と反応さ せること〖こより製造することができる。この反応は、たとえば、辻ら、遷移金属が拓く有 機合成、第 19〜22頁、 1997年、丸善などに記載された方法またはそれに準じた方法 で行えばよい。  A compound of general formula [lm] can be reacted with a compound of general formula [11] in the presence of a catalyst, in the presence or absence of a base, or in the presence or absence of phosphine. It can be manufactured from Sasako. This reaction may be performed, for example, by the method described in, for example, Organic Synthesis Opened by Transition Metals, pp. 19-22, 1997, Maruzen et al.
一般式 [14]の化合物としては、メチル =アタリラート、ェチル =アタリラートおよび t ert—ブチル =アタリラートなどが挙げられる。  Examples of the compound of the general formula [14] include methyl acrylate, ethyl acrylate, tert-butyl acrylate.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2— プロパノールなどのアルコール類； N, N—ジメチルホルムアミド、 N, N—ジメチルァ セトアミドおよび 1ーメチルー 2—ピロリドンなどのアミド類;塩化メチレン、クロ口ホルム およびジクロロェタンなどのハロゲン化炭化水素類；ベンゼン、トルエンおよびキシレ ンなどの芳香族炭化水素類;ジォキサン、テトラヒドロフラン、ァ-ソール、エチレング リコールジメチルエーテル、ジエチレングリコールジメチルエーテル、ジエチレングリコ 一ルジェチルエーテルおよびエチレングリコールモノメチルエーテルなどのエーテル 類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよび 2—ブタノンなどのケト ン類；酢酸ェチルなどのエステル類；ァセトニトリルなどの-トリル類ならびに水などが 挙げられ、これらは混合して使用してもよい。 この反応に使用される触媒としては、たとえば、ビス（トリフエ-ルホスフィン)パラジゥ ムジクロリド（π)、テトラキス（トリフエ-ルホスフィン)パラジウム、酢酸パラジウム（11)、 塩ィ匕パラジウム（II)、ビス（トリ tert ブチルホスフィン)パラジウム（0)およびトリス（ ジベンジリデンアセトン）二パラジウム（0)などが挙げられる。 The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene, and xylene; Dioxane , Tetrahydrofuran, ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, and ethers such as ethylene glycol monomethyl ether; sulfoxy such as dimethyl sulfoxide Ketones such as acetone and 2-butanone; esters such as ethyl acetate; -tolyls such as acetonitrile; and water. These may be used as a mixture. Examples of the catalyst used in this reaction include bis (triphenylphosphine) paradichloride (π), tetrakis (triphenylphosphine) palladium, palladium acetate (11), salty palladium (II), bis ( And tri-tert-butylphosphine) palladium (0) and tris (dibenzylideneacetone) dipalladium (0).
この反応において所望により使用されるホスフィンとしては、たとえば、トリフエ-ルホ スフイン、トリ一 tert ブチルホスフィン、ジフエ-ル（オルトトリル）ホスフィン、トリ（トリ ル）ホスフィンおよび 2, 2， 一ビス（ジフエ-ルホスフイノ）一 1, 1， 一ビナフチルなどが 挙げられる。  The phosphine optionally used in this reaction includes, for example, triphenylphosphine, tritertbutylbutylphosphine, diphenyl (orthotolyl) phosphine, tri (tolyl) phosphine and 2,2,1bis (diphenylphosphino). ) 1, 1, 1 binaphthyl.
この反応において所望により使用される塩基としては、たとえば、ピリジン、ジメチル アミノビリジン、トリエチルァミン、 N, N ジメチルベンジルァミン、酢酸ナトリウムおよ び酢酸カリウムなどの有機塩基;水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウ ム、炭酸カリウムおよび炭酸ナトリウムなどの無機塩基などが挙げられる。  Examples of bases optionally used in this reaction include organic bases such as pyridine, dimethylaminoviridine, triethylamine, N, N dimethylbenzylamine, sodium acetate and potassium acetate; Examples thereof include inorganic bases such as potassium hydroxide, sodium hydrogen carbonate, potassium carbonate and sodium carbonate.
この反応において、一般式 [14]の化合物の使用量は、一般式 [11]の化合物に対 して 1〜 10倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of the compound of the general formula [14] used may be 1 to 10 times mol, preferably 1 to 5 times mol of the compound of the general formula [11]!
この反応において、触媒の使用量は、一般式 [11]の化合物に対して 0.001〜10倍 モル、好ましくは 0.01〜2倍モルであればよい。  In this reaction, the amount of the catalyst used may be 0.001 to 10 times mol, preferably 0.01 to 2 times mol for the compound of the general formula [11].
この反応において、所望により使用されるホスフィンの使用量は、一般式 [11]の化 合物に対して 0.001〜40倍モル、好ましくは 0.01〜8倍モルであればよい。  In this reaction, the amount of phosphine used as desired may be 0.001 to 40 times mol, preferably 0.01 to 8 times mol, of the compound of general formula [11].
この反応において、塩基の使用量は、一般式 [11]の化合物に対して 1〜10倍モル 、好ましくは 1〜5倍モルであればよい。  In this reaction, the amount of the base used may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [11].
この反応は、 30〜200°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
このようにして得られた一般式 [la]、 [lb]ゝ [lc]、 [Id] , [le]、 [If]ゝ [lg]、 [lh ]、 [li]、 [lj]、 [lk]ゝ [11]および [lm]の化合物またはそれらの塩は、たとえば、縮 合、付加、酸化、還元、転位、置換、ハロゲン化、脱水もしくは加水分解などの自体 公知の反応に付すことによって、またはそれらの反応を適宜組み合わせることによつ て、他の一般式 [1]の化合物またはその塩に誘導することができる。  The general formulas [la], [lb] ゝ [lc], [Id], [le], [If] ゝ [lg], [lh], [li], [lj], [ lk] ゝ [11] and [lm] or a salt thereof is subjected to a reaction known per se, for example, condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis. Or by appropriately combining these reactions, it can be derived into other compounds of the general formula [1] or salts thereof.
また、上記した製造法における化合物において、異性体 (たとえば、光学異性体、 幾何異性体および互変異性体など)が存在する場合、これらの異性体も使用すること ができ、また、溶媒和物、水和物および種々の形状の結晶も使用することができる。 In the compound in the above production method, an isomer (for example, an optical isomer, If present, such as geometric isomers and tautomers, these isomers can also be used, and solvates, hydrates and various forms of crystals can also be used.
[0058] 次に、本発明化合物の製造の原料である一般式 [2]、 [3]、 [4]、 [5]、 [8]、 [9]、  [0058] Next, general formulas [2], [3], [4], [5], [8], [9], which are raw materials for the production of the compound of the present invention,
[11]、 [28]、 [29]および [30]の化合物の製造法について説明する。  A method for producing the compounds [11], [28], [29] and [30] will be described.
[0059] 一般式 [2]の化合物として、たとえば、 8 アミノー 2—メチルキノリンおよび 8 アミ ノ 2—メトキシキノリン [ジャーナノレ ·ォブ ·アメリカン'ケミカノレ ·ソサエティ一 (j.Am.C hem.So ）、第 68卷、第 1553〜1556頁、 1946年およびオーストラリアン'ジャーナル' ォブ 'ケミストリー（Aus. J. Org. Chem.)、第 56卷、第 39〜44頁、 2003年]などが知られ ている。また、一般式 [2]の化合物は、自体公知の方法を組み合わせることにより製 造されるが、たとえば、次に示す製造法により製造することができる。  [0059] Examples of the compound represented by the general formula [2] include 8 amino-2-methylquinoline and 8 amino-2-methoxyquinoline [Janano Reb American American Chemicanor Society (j.Am.Chem.So) 68, pp. 1553-1556, 1946 and Australian 'Journal' of Chemistry (Aus. J. Org. Chem.), Verse 56, pp. 39-44, 2003] It has been. Further, the compound of the general formula [2] is produced by combining methods known per se, and can be produced, for example, by the production method shown below.
[0060] [製造法 A]  [0060] [Production method A]
Figure imgf000038_0001
Figure imgf000038_0001
[0061] 一般式 [12]の化合物として、たとえば、 7—メトキシイソキノリン [オーガニック 'リアク シヨン（Org.React.)、第 VI卷、第 191〜206頁]および 2 シァノキノリンなどが知られ ている。  [0061] As compounds of the general formula [12], for example, 7-methoxyisoquinoline [Organic Reaction (Org. React.), VI VI, pp. 191 to 206] and 2 cyanoquinoline are known.
[0062] (A- 1)  [0062] (A- 1)
一般式 [2a]の化合物は、一般式 [12]の化合物をナトリウムアミドと反応させること により製造することができる。この反応は、たとえば、ジャーナル'ォブ 'オーガニック' ケミストリー (J. Org. Chem.)、第 11卷、第 239〜246頁、 1946年などに記載された方法 またはそれに準じた方法で行えばょ 、。 The compound of the general formula [2a] can be produced by reacting the compound of the general formula [12] with sodium amide. This reaction is described, for example, in the method described in Journal 'Ob' Organic 'Chemistry (J. Org. Chem.), Vol. 11, pages 239-246, 1946, etc. Or if you follow a similar method.
この反応に使用される溶媒としては、たとえば、反応に悪影響を及ぼさないものであ ればよぐたとえば、ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類;ジ メチルァ-リンおよびジェチルァ-リンなどの芳香族ァミン類ならびに液体アンモニア などが挙げられ、これらは混合して使用してもよい。  Examples of the solvent used in this reaction include those that do not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; Aromatic amines and liquid ammonia may be mentioned, and these may be used as a mixture.
この反応において、ナトリウムアミドの使用量は、一般式 [12]の化合物に対して 1〜 10倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of sodium amide to be used is 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [12]!
この反応は、 100〜150°Cで 30分間〜 48時間実施すればよい。  This reaction may be carried out at 100 to 150 ° C. for 30 minutes to 48 hours.
[0063] (A- 2) [0063] (A-2)
一般式 [13]の化合物は、一般式 [12]の化合物をニトロ化することにより製造する ことができる。  The compound of the general formula [13] can be produced by nitration of the compound of the general formula [12].
一般式 [12]の化合物の-トロ化は、たとえば、ジエリ一'マーチ（Jerry March)、アド バンスド 'オーガニック 'ケミストリー（Advanced Organic Chemistry)第 4版、第 522〜52 5頁、 1992年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)などに記載 された方法またはそれに準じた方法で行えばよい。  The -trolation of compounds of general formula [12] is described, for example, by Jerry March, Advanced Organic Chemistry, 4th edition, pages 522-525, 1992, John The method described in John Wiley & Sons, INC. Or a method similar thereto may be used.
[0064] (A— 3) [0064] (A— 3)
一般式 [2a]の化合物は、一般式 [13]の化合物を還元することにより製造すること ができる。  The compound of the general formula [2a] can be produced by reducing the compound of the general formula [13].
一般式 [13]の化合物の還元は、たとえば、ジエリ一'マーチ（Jerry March)、アドバ ンスド 'オーガニック 'ケミストリー（Advanced Organic Chemistry)第 4版、第 1026〜121 7頁、 1992年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)などに記載 された方法またはそれに準じた方法で行えばよい。  Reduction of the compound of general formula [13] can be performed, for example, by Jerry March, Advanced 'Organic' Advanced Organic Chemistry, 4th edition, pp. 1026-1121, 1992, John 'Willy. The method described in “And” Sands (John Wiley & Sons, INC.) Or the like may be used.
[0065] [製造法 B] [0065] [Production Method B]
Figure imgf000040_0001
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0002
「式中、 R4bは、
Figure imgf000040_0003
R2a、 R3a、 R16、 Zlaおよび Z2aは、前記と同様の 意味を有する。」 “In the formula, R 4b is
Figure imgf000040_0003
R 2a , R 3a , R 16 , Z la and Z 2a have the same meaning as described above. "
[0066] 一般式 [2b]の化合物として、たとえば、 8 アミノー 2—メチルキノリンおよび 8 ァ ミノ 2—メトキシキノリン [ジャーナル ·ォブ ·アメリカン'ケミカル ·ソサエティ一 (j.Am. Chem.So ）、第 68卷、第 1553〜1556頁、 1946年およびオーストラリアン'ジャーナル' ォブ 'ケミストリー（Aus. J. Chem.)、第 56卷、第 39〜44頁、 2003年]などが知られてい る。  [0066] Examples of the compound of the general formula [2b] include, for example, 8 amino-2-methylquinoline and 8 amino-2-methoxyquinoline [Journal of American Chemical Society (j. Am. Chem.So), 68, 1553-1556, 1946 and Australian 'Journal' of Chemistry (Aus. J. Chem., 56, 39-44, 2003) are known. .
[0067] (B- 1)  [0067] (B- 1)
一般式 [2c]の化合物は、一般式 [2b]の化合物をハロゲンィ匕することにより製造す ることができる。この反応は、たとえば、ジエリ一'マーチ (Jerry March)、アドバンスド' オーガニック 'ケミストリー（Advanced Organic Chemistry)第 4版、第 531〜534頁、 199 2年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)などに記載された方 法またはそれに準じた方法で行えばょ 、。  The compound of the general formula [2c] can be produced by halogenating the compound of the general formula [2b]. This reaction is described, for example, by Jerry March, Advanced Organic Chemistry 4th Edition, pp. 531-534, 1992, John Wiley & And Sons (John Wiley). & Sons, INC.), Etc., or a method similar to that.
[0068] (B- 2) [0068] (B-2)
一般式 [2d]の化合物は、触媒の存在下、塩基の存在下または不存在下、ホスフィ ンの存在下または不存在下、一般式 [2c]の化合物を一般式 [14]の化合物と反応さ せることにより製造することができる。この反応は、製造法 11に準じて行えばよい。  The compound of the general formula [2d] can be reacted with the compound of the general formula [14] in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of phosphine. Can be manufactured. This reaction may be carried out according to production method 11.
[0069] (B- 3) [0069] (B- 3)
一般式 [2e]の化合物は、一般式 [2d]の化合物を還元することにより製造することが できる。この反応は、たとえば、ジエリ一'マーチ (Jerry March)、アドバンスド 'オーガ ニック'ケミストリー（Advanced Organic Chemistry)第 4版、第 771〜780頁、 1992年、ジ ヨン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.) The compound of the general formula [2e] can be produced by reducing the compound of the general formula [2d]. it can. This reaction is described, for example, by Jerry March, Advanced Organic Chemistry 4th edition, pp. 771-780, 1992, John Y'Willy 'And'Sands (John (Wiley & Sons, INC.)
などに記載された方法またはそれに準じた方法で行えばよい。 The method described in the above or the like may be performed.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素 類；ジォキサン、テトラヒドロフラン、ァニソール、エチレングリコールジメチルエーテル 、ジエチレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルお よびエチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシド などのスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類；酢酸ェチルなどの エステル類ならびに水などが挙げられ、これらは混合して使用してもよ 、。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; benzene, toluene and xylene Aromatic hydrocarbons such as: dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethers such as ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; acetone and 2-butanone Ketones: Esters such as ethyl acetate and water, etc., and these may be used as a mixture.
この反応に使用される還元剤としては、たとえば、水素化シァノホウ素ナトリウムおよ び水素化ホウ素ナトリウムなどの水素化錯ィ匕合物ならびにボランなどが挙げられる。 この反応において、還元剤の使用量は、一般式 [2d]の化合物に対して 0.5〜10倍 モノレであればよい。  Examples of the reducing agent used in this reaction include hydrogenated complex compounds such as sodium cyanoborohydride and sodium borohydride, and borane. In this reaction, the reducing agent may be used in an amount of 0.5 to 10 times that of the compound of the general formula [2d].
また、酸性条件下で亜鉛などの金属を用いる還元;銅または白金を陰極に用いる 電解還元;ラネーニッケル、酸化白金、ノラジウム炭素またはパラジウム黒を触媒に 用いる接触還元などを用いることもできる。  Further, reduction using a metal such as zinc under acidic conditions; electrolytic reduction using copper or platinum as a cathode; catalytic reduction using Raney nickel, platinum oxide, noradium carbon or palladium black as a catalyst can also be used.
この反応において、触媒の使用量は、一般式 [2d]の化合物に対して 0.001〜5倍モ ルであればよい。  In this reaction, the amount of the catalyst used may be 0.001 to 5 times mol of the compound of the general formula [2d].
この反応は、 30〜200°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
[製造法 C] [Production method C]
Figure imgf000042_0001
Figure imgf000042_0001
[ 1 5]  [1 5]
「式中、
Figure imgf000042_0002
R2a、 R3a、 R4a、 R5a、 Zlaおよび Z2aは、前記と同様の意味を有する。"In the formula,
Figure imgf000042_0002
R 2a , R 3a , R 4a , R 5a , Z la and Z 2a have the same meaning as described above.
J J
[0071] (C- 1)  [0071] (C-1)
一般式 [2f]の化合物は、一般式 [2b]の化合物をジァゾィ匕した後、ィォゥ化合物 A と反応させた後、加水分解することにより製造することができる。  The compound of the general formula [2f] can be produced by diazotizing the compound of the general formula [2b], reacting with the thio compound A, and then hydrolyzing.
この反応に使用される溶媒としては、通常、水などが挙げられる。  As a solvent used in this reaction, water is usually used.
この反応に使用されるィォゥ化合物 Aとしては、たとえば、チォ尿素およびキサント ゲン酸カリウムなどが挙げられる。  Examples of the sulfur compound A used in this reaction include thiourea and potassium xanthate.
この反応において、ィォゥ化合物 Aの使用量は、一般式 [2b]の化合物に対して 1 〜20倍モルであればよ!、。  In this reaction, the amount of io compound A used should be 1 to 20 moles compared to the compound of general formula [2b]!
この反応は、 30〜200°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C., preferably 0 to 150 ° C. for 30 minutes to 48 hours.
[0072] (C- 2)  [0072] (C-2)
一般式 [2f]の化合物は、一般式 [15]の化合物をィォゥ化合物 Bと反応させた後、 必要に応じて脱保護することにより製造することができる。  The compound of the general formula [2f] can be produced by reacting the compound of the general formula [15] with the thio compound B and then deprotecting as necessary.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロ ゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジ ォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテル、ジェ チレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルおよび エチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなど のスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類；酢酸ェチルなどのエス テル類ならびに水などが挙げられ、これらは混合して使用してもよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Halogenated hydrocarbons such as form and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as oxane, tetrahydrofuran, ether, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; And the like, and these may be used as a mixture.
この反応に使用されるィォゥ化合物 Bとしては、たとえば、硫ィ匕ナトリウムなどの無機 ィォゥ化合物およびフエ-ルメタンチオールおよび 1, 1ージメチルエタンチオールな どの有機ィォゥ化合物が挙げられる。  Examples of thio compound B used in this reaction include inorganic thio compounds such as sodium sulfate and organic thio compounds such as methane thiol and 1,1-dimethylethane thiol.
この反応において、ィォゥ化合物 Bの使用量は、一般式 [15]の化合物に対して 1 〜20倍モルであればよ!、。  In this reaction, the amount of iodo compound B used should be 1 to 20 moles compared to the compound of general formula [15]!
この反応は、 0〜200°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよい。  This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
[0073] [製造法 D] [0073] [Production Method D]
Figure imgf000043_0001
Figure imgf000043_0001
[1 5]  [1 5]
「式中、 R17は、
Figure imgf000043_0002
R2a、 R3a、 R4a、 R5a、 Zlaおよび Z2aは、前 記と同様の意味を有する。」 `` Where R 17 is
Figure imgf000043_0002
R 2a , R 3a , R 4a , R 5a , Z la and Z 2a have the same meaning as described above. "
[0074] (D— 1) [0074] (D— 1)
一般式 [2g]の化合物は、一般式 [2b]の化合物をジァゾ化した後、酸で処理するこ とにより製造することができる。  The compound of the general formula [2g] can be produced by diazotizing the compound of the general formula [2b] and then treating with an acid.
この反応に使用される溶媒としては、通常、水などが挙げられる。  As a solvent used in this reaction, water is usually used.
この反応に使用される酸としては、たとえば、塩酸、硫酸および硝酸などが挙げられ る。 Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid and nitric acid. The
この反応において、酸の使用量は、一般式 [2b]の化合物に対して 1〜100倍モル であればよい。  In this reaction, the acid may be used in an amount of 1 to 100 moles compared to the compound of the general formula [2b].
この反応は、 30〜200°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C., preferably 0 to 150 ° C. for 30 minutes to 48 hours.
[0075] (D- 2)  [0075] (D-2)
一般式 [2g]の化合物は、一般式 [15]の化合物を一般式 [16]の化合物と反応さ せた後、脱保護することにより製造することができる。  The compound of the general formula [2g] can be produced by reacting the compound of the general formula [15] with the compound of the general formula [16] and then deprotecting it.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロ ゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジ ォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテル、ジェ チレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルおよび エチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなど のスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類；酢酸ェチルなどのエス テル類ならびに水などが挙げられ、これらは混合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Halogenated hydrocarbons such as form and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, azole, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Ethers such as monomethyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; esters such as ethyl acetate; and water. Mixed and may also be used.
この反応に使用される一般式 [16]の化合物としては、たとえば、ナトリウムメトキシド およびナトリウムエトキシドなどの金属アルコキシド類が挙げられる。  Examples of the compound of the general formula [16] used in this reaction include metal alkoxides such as sodium methoxide and sodium ethoxide.
この反応において、一般式 [16]の化合物の使用量は、一般式 [15]の化合物に対 して 1〜20倍モルであればよ!、。  In this reaction, the amount of the compound of the general formula [16] used may be 1 to 20 times the mole of the compound of the general formula [15]!
この反応は、 0〜200°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよい。 This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
R17で示される基の除去は、たとえば、 W.グリーン (W.Green)ら、プロテクティブ 'グ ノレープス'イン'オーガニック 'シンセシス (Protective Groups in Organic Synthesis)第 3版、第 246〜292頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,IN C.)に記載された方法で行えばよい。 Removal of the group represented by R 17 is described, for example, by W. Green et al., Protective Groups in Organic Synthesis, 3rd edition, pages 246-292, 1999. The method described in John Wiley & Sons, INC. May be used.
[0076] 一般式 [3]の化合物は、自体公知の方法を組み合わせることにより製造されるが、 たとえば、次に示す製造法により製造することができる。 [製造法 E] [0076] The compound of the general formula [3] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below. [Production method E]
HOC_(CH2)m—厂 X4— R14 [6] HOC_ (CH 2 ) m — 厂 X 4 — R 14 [6]
H0 C-XLQLH H0 CX L Q L H
[ 1 7]  [1 7]
' -(CH9) [7] '-(CH 9 ) [7]
_ ^ H02C-X3-Q -(CH2)m-X4-R14 _ ^ H0 2 CX 3 -Q-(CH 2 ) m -X 4 -R 14
[3a]  [3a]
「式中、 R14、
Figure imgf000045_0001
X3、 X4および mは、前記と同様の意味を有する。」 [0077] 一般式 [17]の化合物として、たとえば、 4ーピペリジンカルボン酸などが知られてい る。 "Where R 14 ,
Figure imgf000045_0001
X 3 , X 4 and m have the same meaning as described above. [0077] As a compound of the general formula [17], for example, 4-piperidinecarboxylic acid is known.
[0078] (E- 1)  [0078] (E- 1)
一般式 [6]の化合物として、たとえば、 2, 3 （メチレンジォキシ)ベンズアルデヒド 、 1, 4一べンゾジォキサンー6 カルバルデヒドおよび（2, 3 ジヒドロ [1, 4]ジォキ シン一 6 ィル）ァセトアルデヒド [WO02Z50061号公報]などが知られて!/、る。 一般式 [3a]の化合物は、還元剤の存在下、一般式 [17]の化合物を一般式 [6]の 化合物と反応させることにより製造することができる。  Examples of the compound of the general formula [6] include 2,3 (methylenedioxy) benzaldehyde, 1,4 monobenzodioxane-6 carbaldehyde and (2,3 dihydro [1,4] dioxin monoyl). WO02Z50061 publication] is known! The compound of the general formula [3a] can be produced by reacting the compound of the general formula [17] with the compound of the general formula [6] in the presence of a reducing agent.
この反応は、製造法 3—1に準じて行えばよい。  This reaction may be carried out according to production method 3-1.
[0079] (E- 2) [0079] (E-2)
一般式 [7]の化合物として、たとえば、 2- (3 ォキソ 3, 4 ジヒドロー 2H べ ンゾチアジン 6 ィル）ェチル =メタンスルホナートおよび 2 （ベンゾ [1, 3]ジォキ ソールー 5—ィル）ェチル =メタンスルホナートなどが知られている。  As compounds of general formula [7], for example, 2- (3 oxo 3,4 dihydro-2H benzothiazine 6 yl) ethyl = methanesulfonate and 2 (benzo [1,3] dioxol-5 yl) ethyl = Methane sulfonate and the like are known.
一般式 [3a]の化合物は、一般式 [17]の化合物を一般式 [7]の化合物と反応させ ること〖こより製造することができる。  The compound of the general formula [3a] can be produced by reacting the compound of the general formula [17] with the compound of the general formula [7].
この反応は、製造法 3— 2に準じて行えばよい。  This reaction may be carried out according to production method 3-2.
[0080] 一般式 [4]の化合物は、自体公知の方法を組み合わせることにより製造されるが、 たとえば、次に示す製造法により製造することができる。 [0080] The compound of the general formula [4] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.
[製造法 F] Y[Production Method F] Y
Figure imgf000046_0001
Figure imgf000046_0001
2) 脱保護  2) Deprotection
[4a]  [4a]
「式中、 Q2は、 "Where Q 2 is
Figure imgf000046_0002
は
Figure imgf000046_0002
Is
「式中、 1、 Rlla、 Rllb、 Rlleおよび R13は、前記と同様の意味を有する。」 “ Wherein , 1 , R lla , R llb , R lle and R 13 have the same meaning as described above.
を; Yeは、ァミノ基の保護基を; R14、 L\ X4および mは、前記と同様の意味を有する。Y e is a protecting group for an amino group; R 14 , L \ X 4 and m have the same meaning as described above.
J J
[0081] 一般式 [18]の化合物として、たとえば、 tert—ブチル =ピペラジンカルボキシラー トなどが知られている。  [0081] As a compound of the general formula [18], for example, tert-butyl = piperazinecarboxylate is known.
[0082] (F- 1) [0082] (F- 1)
一般式 [6]の化合物として、たとえば、 2, 3—（メチレンジォキシ)ベンズアルデヒド 、 1, 4一べンゾジォキサンー6—カルバルデヒドおよび（2, 3—ジヒドロ [1, 4]ジォキ シン一 6—ィル）ァセトアルデヒド [WO02Z50061号公報]などが知られて!/、る。 一般式 [4a]の化合物は、一般式 [18]の化合物を一般式 [6]の化合物と反応させ た後、脱保護することにより製造することができる。  Examples of the compound of the general formula [6] include 2,3- (methylenedioxy) benzaldehyde, 1,4-monobenzodioxane-6-carbaldehyde and (2,3-dihydro [1,4] dioxin-6-yl). Acetaldehyde [WO02Z50061] is known! The compound of the general formula [4a] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [6] and then deprotecting it.
一般式 [18]の化合物と一般式 [6]の化合物の反応は、製造法 3— 1に準じて行え ばよい。  The reaction of the compound of general formula [18] and the compound of general formula [6] may be carried out according to production method 3-1.
Y°で示されるァミノ基の保護基の除去は、たとえば、 W.グリーン (W.Green)ら、プロ テクティブ'グノレープス'イン'オーガニック 'シンセシス (Protective Groups in Organic Synthesis)第 3版、第 494〜653頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wi ley & Sons,INC.)に記載された方法で行えばよい。  For example, W. Green et al., Protective Groups in Organic Synthesis, 3rd edition, 494-- 653, 1999, as described by John Wiley & Sons, INC.
[0083] (F- 2) 一般式 [7]の化合物として、たとえば、 2- (3 ォキソ 3, 4 ジヒドロー 2H べ ンゾチアジン 6 ィル）ェチル =メタンスルホナートおよび 2 （ベンゾ [1 , 3]ジォキ ソールー 5—ィル）ェチル =メタンスルホナートなどが知られている。 [0083] (F-2) As compounds of general formula [7], for example, 2- (3 oxo 3,4 dihydro-2H benzothiazine 6 yl) ethyl = methanesulfonate and 2 (benzo [1,3] dioxol-5 yl) ethyl = Methane sulfonate and the like are known.
一般式 [4a]の化合物は、一般式 [18]の化合物を一般式 [7]の化合物と反応させ た後、脱保護することにより製造することができる。  The compound of the general formula [4a] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [7] and then deprotecting it.
一般式 [18]の化合物と一般式 [7]の化合物の反応は、製造法 3— 2に準じて行え ばよい。  The reaction of the compound of general formula [18] and the compound of general formula [7] may be carried out according to production method 3-2.
Y°で示されるァミノ基の保護基の除去は、たとえば、 W.グリーン (W.Green)ら、プロ テクティブ'グノレープス'イン'オーガニック 'シンセシス (Protective Groups in Organic Synthesis)第 3版、第 494〜653頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wi ley & Sons,INC.)に記載された方法で行えばよい。  For example, W. Green et al., Protective Groups in Organic Synthesis, 3rd edition, 494-- 653, 1999, as described by John Wiley & Sons, INC.
[0084] 一般式 [5]の化合物は、自体公知の方法を組み合わせることにより製造されるが、 たとえば、次に示す製造法により製造することができる。 [0084] The compound of the general formula [5] is produced by a combination of methods known per se. For example, the compound can be produced by the following production method.
[製造法 G]  [Production method G]
Figure imgf000047_0001
Figure imgf000047_0001
[2]  [2]
「式中、 Ydは、ァミノ基の保護基を;
Figure imgf000047_0002
Wherein Y d is a protecting group for the amino group;
Figure imgf000047_0002
z2aは、前記と同様の意味を有する。 z 2a has the same meaning as described above.
[0085] 一般式 [19]の化合物として、たとえば、 4一（tert ブトキシカルボ-ル）ピぺリジン カルボン酸などが知られて 、る。  [0085] As the compound of the general formula [19], for example, 4- (tert-butoxycarbol) piperidinecarboxylic acid is known.
一般式 [5a]の化合物は、一般式 [2]の化合物を一般式 [19]の化合物の反応性 誘導体と反応させた後、脱保護することにより製造することができる。  The compound of the general formula [5a] can be produced by reacting the compound of the general formula [2] with a reactive derivative of the compound of the general formula [19] and then deprotecting it.
一般式 [2]の化合物と一般式 [19]の化合物の反応性誘導体の反応は、製造法 1 に準じて行えばよい。  The reaction of the compound of the general formula [2] and the reactive derivative of the compound of the general formula [19] may be carried out according to production method 1.
で示されるァミノ基の保護基の除去は、たとえば、 W.グリーン (W.Green)ら、プ ロテクティブ'グノレープス'イン'オーガニック 'シンセシス（Protective Groups in Organ ic Synthesis)第 3版、第 494〜653頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)に記載された方法で行えばよい。 Removal of the protecting group of the amino group shown by, for example, W. Green et al. Protective Groups in Organic Synthesis, 3rd edition, pages 494-653, 1999, described in John Wiley & Sons, INC. You can do this by
[製造法 H]  [Production method H]
Figure imgf000048_0001
Figure imgf000048_0001
[2] [5b] [2] [5b]
「式中、 Yeは、ァミノ基の保護基を; R1 R2a、 R3a、 R4a、 R5a、 Q2、 Xla、 Zlaおよび Z2a は、前記と同様の意味を有する。 “In the formula, Y e represents a protecting group for an amino group; R 1 R 2a , R 3a , R 4a , R 5a , Q 2 , X la , Z la and Z 2a have the same meaning as described above.
[0087] 一般式 [20]の化合物として、たとえば、 1 tert ブトキシカルボ-ルビペラジンお よび 4 ( (tert ブトキシカルボ-ル）ァミノ）ピぺリジンなどが知られて!/、る。 [0087] Examples of the compound represented by the general formula [20] include 1 tert butoxycarborubiperazine and 4 ((tertbutoxycarboro) amino) piperidine.
一般式 [5b]の化合物は、塩基の存在下または不存在下、一般式 [2]の化合物を カルボニル化合物と反応させた後、一般式 [20]の化合物と反応させ、次いで脱保護 することにより製造することができる。また、一般式 [5b]の化合物は、塩基の存在下ま たは不存在下、一般式 [20]の化合物をカルボニル化合物と反応させた後、一般式 [ 2]の化合物と反応させ、次いで脱保護することにより製造することができる。  The compound of general formula [5b] must be deprotected after reacting the compound of general formula [2] with a carbonyl compound in the presence or absence of a base, followed by reaction with the compound of general formula [20]. Can be manufactured. In addition, the compound of the general formula [5b] is reacted with the compound of the general formula [2] after reacting the compound of the general formula [20] with a carbonyl compound in the presence or absence of a base. It can be manufactured by deprotection.
一般式 [2]の化合物と一般式 [20]の化合物の反応は、製造法 2に準じて行えばよ い。  The reaction of the compound of the general formula [2] and the compound of the general formula [20] may be performed according to the production method 2.
Y6で示されるァミノ基の保護基の除去は、たとえば、 W.グリーン (W.Green)ら、プ ロテクティブ'グノレープス'イン'オーガニック 'シンセシス (Protective groups in Organi c synthesis)、第 3版、第 494〜653頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)に記載された方法で行えばよい。 Removal of the protecting group of the Amino group represented by Y 6 is, for example, W. Green (W.Green) et flop Rotekutibu 'Gunorepusu' in 'Organic' Synthesis (Protective groups in Organi c synthesis) , third edition, 494-653, 1999, John Wiley & Sons, INC ..
[0088] [製造法 I]
Figure imgf000049_0001
[0088] [Production Method I]
Figure imgf000049_0001
[5c]  [5c]
「式中、 L2は、
Figure imgf000049_0002
Zlaおよび Z2aは、前記 と同様の意味を有する。」 `` Where L 2 is
Figure imgf000049_0002
Z la and Z 2a have the same meaning as described above. "
一般式 [21]の化合物として、たとえば、（1一（tert ブトキシカルボ-ル）ピベリジ ンー4 ィル)メチル =メタンスルホナートなどが知られている。  As a compound of the general formula [21], for example, (1 (tert-butoxycarbol) piberidin-4-yl) methyl methanesulfonate is known.
一般式 [5c]の化合物は、塩基の存在下または不存在下、一般式 [2]の化合物を 一般式 [21]の化合物と反応させた後、脱保護することにより製造することができる。 この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロ ゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジ ォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテル、ジェ チレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルおよび エチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなど のスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類；酢酸ェチルなどのエス テル類ならびに水などが挙げられ、これらは混合して使用してもよい。  The compound of the general formula [5c] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [21] in the presence or absence of a base and then deprotecting the compound. The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Halogenated hydrocarbons such as form and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, azole, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Ethers such as monomethyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; esters such as ethyl acetate; and water. Mixed and may also be used.
この反応において所望により使用される塩基としては、たとえば、ピリジン、ジメチル アミノビリジンおよびトリェチルァミンなどの有機塩基;水酸ィ匕ナトリウム、水酸ィ匕カリウ ム、炭酸水素ナトリウム、炭酸カリウムおよび炭酸ナトリウムなどの無機塩基などが挙 げられる。  Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminoviridine and triethylamine; sodium hydroxide, sodium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate. Examples include inorganic bases.
この反応において、一般式 [21]の化合物および塩基の使用量は、一般式 [2]の 化合物に対して 1〜20倍モルであればよい。  In this reaction, the compound and the base used in the general formula [21] may be used in an amount of 1 to 20 moles compared to the compound of the general formula [2].
この反応は、 0〜200°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよい。 Y6で示されるァミノ基の保護基の除去は、たとえば、 W.グリーン (W.Green)ら、プ ロテクティブ'グノレープス'イン'オーガニック 'シンセシス (Protective groups in Organi c synthesis)、第 3版、第 494〜653頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)に記載された方法で行えばよい。 This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours. Removal of the protecting group of the Amino group represented by Y 6 is, for example, W. Green (W.Green) et flop Rotekutibu 'Gunorepusu' in 'Organic' Synthesis (Protective groups in Organi c synthesis), 3rd edition, pp. 494-653, 1999, John Wiley & Sons, INC. may be used.
[製造 ¾[]  [Manufacturing ¾ []
Figure imgf000050_0001
Figure imgf000050_0001
[1 1 ] [5d] [1 1] [5d]
「式中、 R R2a、 R3a、 R4a、 R5a、 Q2、 T\ Ye、 Zlaおよび Z2aは、前記と同様の意味を 有する。」 “Wherein, RR 2a , R 3a , R 4a , R 5a , Q 2 , T \ Y e , Z la and Z 2a have the same meaning as described above.
[0091] 一般式 [5d]の化合物は、一般式 [11]の化合物を一般式 [20]の化合物と反応さ せた後、脱保護することにより製造することができる。  [0091] The compound of the general formula [5d] can be produced by reacting the compound of the general formula [11] with the compound of the general formula [20], followed by deprotection.
一般式 [11]の化合物と一般式 [20]の化合物の反応は、製造法 7に準じて行えば よい。  The reaction of the compound of the general formula [11] and the compound of the general formula [20] may be performed according to the production method 7.
Y6で示されるァミノ基の保護基の除去は、たとえば、 W.グリーン (W.Green)ら、プ ロテクティブ'グノレープス'イン'オーガニック 'シンセシス (Protective groups in Organi c synthesis)、第 3版、第 494〜653頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)に記載された方法で行えばよい。 Removal of the protecting group of the Amino group represented by Y 6 is, for example, W. Green (W.Green) et flop Rotekutibu 'Gunorepusu' in 'Organic' Synthesis (Protective groups in Organi c synthesis) , third edition, 494-653, 1999, John Wiley & Sons, INC ..
[0092] [製造法 K] [0092] [Production method K]
Figure imgf000051_0001
Figure imgf000051_0001
[23]  [twenty three]
「式中、 R18および R19は、ハロゲン原子を; nは、 2—
Figure imgf000051_0002
R2a、 R3a、 R4a、 R 5a、 Q\ Yd、 zlaおよび z2aは、前記と同様の意味を有する。」 "Wherein R 18 and R 19 are halogen atoms; n is 2—
Figure imgf000051_0002
R 2a , R 3a , R 4a , R 5a , Q \ Y d , z la and z 2a have the same meaning as described above. "
(K- 1) (K- 1)
一般式 [22]の化合物として、たとえば、 4ーブロモメチルー 1一（tert ブトキシカ ルポ-ル）ピぺリジンおよび 4ーブロモメチルー 1 （ベンジルォキシカルボ-ル）ピぺ リジンなどが知られて 、る。  As compounds of the general formula [22], for example, 4-bromomethyl-1-piperidine and 4-bromomethyl-1 (benzyloxycarbo) piperidine are known.
一般式 [5e]の化合物は、一般式 [8]の化合物を一般式 [22]の化合物力 製造さ れるゥイツティッヒ (Wittig)試薬と反応させた後、還元、脱保護することにより製造する ことができる。  The compound of the general formula [5e] can be produced by reacting the compound of the general formula [8] with the Wittig reagent produced by the compound power of the general formula [22], followed by reduction and deprotection. it can.
ゥイツティッヒ反応は、たとえば、ジエリ一'マーチ（Jerry March)、アドバンスド'ォー ガ-ック.ケミストリー（Advanced Organic Chemistry)第 4版、第 956〜963頁、 1992年、 ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & SonsJNC.)などに記載された方法また はそれに準じた方法で行えばよい。一般式 [22]の化合物から製造されるウイッテイツ ヒ (Wittig)試薬は、たとえば、一般式 [22]の化合物をトリフエニルホスフィンと反応さ せること〖こより製造することができる。  The Witztig reaction can be described, for example, by Jerry March, Advanced Organic Chemistry, 4th edition, pages 956-963, 1992, John 'Willie' and'Sands. The method described in the company (John Wiley & SonsJNC.) Or the like may be used. The Wittig reagent produced from the compound of the general formula [22] can be produced, for example, by reacting the compound of the general formula [22] with triphenylphosphine.
還元は、たとえば、触媒を用いる接触還元などを用いればよい。この反応に使用さ れる触媒としては、たとえば、ラネーニッケル、酸化白金、ノラジウム炭素またはパラ ジゥム黒などが挙げられる。この反応は、たとえば、ジエリ一'マーチ (Jerry March)、 アドバンスド 'オーガニック 'ケミストリー（Advanced Organic Chemistry)第 4版、第 771 〜780頁、 1992年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.) などに記載された方法またはそれに準じた方法で行えばよい。 For the reduction, for example, catalytic reduction using a catalyst may be used. Examples of the catalyst used in this reaction include Raney nickel, platinum oxide, noradium carbon, and paraffin. For example, Jim Black. This reaction is described, for example, by Jerry March, Advanced Organic Chemistry, 4th edition, pp. 771-780, 1992, John Wiley & Sons (John Wiley & Sons, INC.) Etc. or a method based thereon.
で示されるァミノ基の保護基の除去は、たとえば、 W.グリーン (W.Green)ら、プ ロテクティブ'グノレープス'イン'オーガニック 'シンセシス (Protective groups in Organi c synthesis)、第 3版、第 494〜653頁、 1999年、ジョン'ウイリイ 'アンド'サンズ社 (John Wiley & Sons,INC.)に記載された方法で行えばよい。  For example, W. Green et al., Protective groups in Organi c synthesis, 3rd edition, 494- 653, 1999, as described in John Wiley & Sons, INC.
[0094] (K- 2) [0094] (K-2)
一般式 [5e]の化合物は、一般式 [24]の化合物を一般式 [23]の化合物力 製造 されるゥイツティッヒ (Wittig)試薬と反応させた後、還元、脱保護することにより製造す ることがでさる。  The compound of the general formula [5e] is prepared by reacting the compound of the general formula [24] with the Wittig reagent produced by the compound power of the general formula [23], followed by reduction and deprotection. It is out.
一般式 [23]の化合物は、たとえば、炭素鎖の伸張反応を用いることにより一般式 [ 8]の化合物力 製造することができる。  The compound of the general formula [23] can be produced, for example, by using a carbon chain extension reaction.
一般式 [24]の化合物として、たとえば、 1 ベンジルピペリジン 4 カルバルデヒ ド、 l—(tert—ブトキシカルボ-ル）ピぺリジン— 4—カルバルデヒド、 1—ァセチルビ ペリジン— 4 カルバルデヒドおよび 1―トリフルォロアセチルビペリジン 4 力ルバ ルデヒドなどが知られて 、る。  Compounds of general formula [24] include, for example, 1 benzylpiperidine 4 carbaldehyde, l- (tert-butoxycarbol) piperidine-4 carbaldehyde, 1-acetylbiperidine 4 carbaldehyde and 1-trifluoro Loacetylbiperidine 4 strength rubaldehyde is known.
この反応は、製造法 K 1に準じて行えばよい。  This reaction may be performed according to the production method K1.
[0095] 一般式 [8]の化合物として、たとえば、 7—メトキシイソキノリン 1 カルバルデヒド [0095] As a compound of the general formula [8], for example, 7-methoxyisoquinoline 1 carbaldehyde
[ジャーナル'ォブ.メデイシナル 'ケミストリー（J. Med. Chem.)、第 13卷、第 1117〜11 24頁、 1970年]などが知られている。また、一般式 [8]の化合物は、自体公知の方法 を組み合わせることにより製造されるが、たとえば、次に示す製造法により製造するこ とがでさる。  [Journal 'Ob. Medicinal' Chemistry (J. Med. Chem.), VIII, 1117-1124, 1970] is known. The compound of the general formula [8] can be produced by a combination of methods known per se, for example, by the production method shown below.
[0096] [製造法 L]
Figure imgf000053_0001
[0096] [Production method L]
Figure imgf000053_0001
[25] [8]  [25] [8]
「式中、
Figure imgf000053_0002
R2a、 R3a、 R4a、 R5a、 Zlaおよび Z2aは、前記と同様の意味を有する。」 [0097] 一般式 [25]の化合物として、たとえば、 2—クロロー 8—メチルキノリン [ (ジャーナル "In the formula,
Figure imgf000053_0002
R 2a , R 3a , R 4a , R 5a , Z la and Z 2a have the same meaning as described above. [0097] As a compound of the general formula [25], for example, 2-chloro-8-methylquinoline [(journal
'ォブ 'オーガニック 'ケミストリー（J.Org.Chem.)、第 37卷、第 4410〜4415頁、 1972年） ]、 7—メトキシ一 1—メチノレイソキノリンおよび 7, 8—ジメトキシ一 1—メチノレイソキノリ ンなどが知られている。  'Ob' Organic 'Chemistry (J. Org. Chem.), 37th, 4410-4415, 1972)], 7-methoxy-1-methoxy-isoquinoline and 7,8-dimethoxy-1-methi Noreisoquinoline is known.
一般式 [8]の化合物は、一般式 [25]の化合物を酸化することにより製造することが できる。  The compound of the general formula [8] can be produced by oxidizing the compound of the general formula [25].
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロゲン化炭化水 素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジメチルスルホキ シドなどのスルホキシド類、酢酸などの酸類ならびに水などが挙げられ、これらは混 合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; aromatics such as benzene, toluene and xylene. Hydrocarbons; sulfoxides such as dimethyl sulfoxide; acids such as acetic acid; water and the like. These may be used in combination.
この反応に使用される酸化剤としては、たとえば、三酸化クロム、二酸化マンガン、 塩ィ匕クロミルおよび二酸ィ匕セレンなどが挙げられる。  Examples of the oxidizing agent used in this reaction include chromium trioxide, manganese dioxide, salt-chromyl, and diacid-selenium.
この反応において、酸化剤の使用量は、一般式 [25]の化合物に対して 0.5〜10倍 モノレであればよい。  In this reaction, the oxidant may be used in an amount of 0.5 to 10 times that of the compound of the general formula [25].
この反応は、 0〜200°C、好ましくは 0〜150°Cで 30分間〜 48時間実施すればよい。  This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.
[0098] 一般式 [9]の化合物は、自体公知の方法を組み合わせることにより製造されるが、 たとえば、次に示す製造法により製造することができる。 [0098] The compound of the general formula [9] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.
[製造法 M]  [Production method M]
^2 14d NH ^ 2 14d NH
SCN . R . r15— s人 N S CN . R. R15 — s people N
[26] H H  [26] H H
[27] [9]  [27] [9]
「式中、 R14dおよび R15は、前記と同様の意味を有する。」 [0099] 一般式 [26]の化合物として、たとえば、 2, 3 ジヒドロー 1, 4一べンゾジォキシン 6—ィル =イソチオシアナートなどが知られている。 “Wherein R 14d and R 15 have the same meaning as described above.” [0099] As the compound of the general formula [26], for example, 2,3 dihydro-1,4 monobenzodioxin 6-yl isothiocyanate and the like are known.
[0100] (M— 1) [0100] (M— 1)
一般式 [27]の化合物は、一般式 [26]の化合物をアンモニアと反応させることによ り製造することがでさる。  The compound of the general formula [27] can be produced by reacting the compound of the general formula [26] with ammonia.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロゲン化炭化水 素類;ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類;ジォキサン、テト ラヒドロフラン、ァニソール、エチレングリコールジメチルエーテル、ジエチレングリコー ルジメチルエーテルおよびジエチレングリコールジェチルエーテルなどのエーテル 類；アセトンおよび 2—ブタノンなどのケトン類ならびに酢酸ェチルなどのエステル類 などが挙げられ、これらは混合して使用してもよい。また、溶媒としてアンモニア水を 使用してちょい。  Solvents used in this reaction are not particularly limited as long as they do not adversely influence the reaction.For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatics such as benzene, toluene and xylene. Hydrocarbons; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol dimethyl ether; ketones such as acetone and 2-butanone; and esters such as ethyl acetate; These may be used as a mixture. Use ammonia water as the solvent.
この反応において、アンモニアの使用量は、一般式 [26]の化合物に対して等モル 以上であればよい。  In this reaction, the amount of ammonia used may be equimolar or more with respect to the compound of the general formula [26].
この反応は、 30〜200°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
[0101] (M-2)  [0101] (M-2)
一般式 [9]の化合物は、一般式 [27]の化合物をアルキル剤と反応させることにより 製造することができる。この反応はたとえば、 DE10Z061541号公報などに記載さ れた方法またはそれに準じた方法で行えばよい。  The compound of the general formula [9] can be produced by reacting the compound of the general formula [27] with an alkyl agent. This reaction may be performed, for example, by a method described in DE10Z061541 or a similar method.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロ ゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジ ォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテル、ジェ チレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルおよび エチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなど のスルホキシド類；アセトンおよび 2—ブタノンなどのケトン類；酢酸ェチルなどのエス テル類ならびに水などが挙げられ、これらは混合して使用してもよい。 The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Halogenated hydrocarbons such as form and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, azole, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Ethers such as monomethyl ether; dimethyl sulfoxide, etc. Sulfoxides; ketones such as acetone and 2-butanone; esters such as ethyl acetate and water, and the like. These may be used as a mixture.
この反応に使用されるアルキル化剤としては、たとえば、ヨウ化メチルおよびヨウィ匕 ェチルなどのハロゲン化アルキルが挙げられる。  Examples of the alkylating agent used in this reaction include alkyl halides such as methyl iodide and yowiethyl.
この反応において、アルキル化剤の使用量は、一般式 [27]の化合物に対して 1〜 10倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the alkylating agent may be used in an amount of 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [27]!
この反応は、 30〜200°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
[0102] 一般式 [11]の化合物として、たとえば、 7—メトキシー1—(ォキシランー2 ィル)ィ ソキノリン [ジャーナル'ォブ 'メデイシナル 'ケミストリー (J. Med. Chem.)、第 13卷、第 1 117〜1124頁、 1970年]などが知られている。また、一般式 [11]の化合物は、自体公 知の方法を組み合わせることにより製造される力 たとえば、次に示す製造法により 製造することができる。  [0102] As a compound of the general formula [11], for example, 7-methoxy-1- (oxosilane-2-yl) soquinoline [Journal 'Ob' Medicinal 'Chemistry (J. Med. Chem.), No. 13, 1 117 to 1124, 1970]. Further, the compound of the general formula [11] can be produced by a method produced by combining methods known per se, for example, by the production method shown below.
[0103] [製造法 N]  [0103] [Production method N]
Figure imgf000055_0001
Figure imgf000055_0001
[8] [1 1 a] [1 1 b] [8] [1 1 a] [1 1 b]
「式中、
Figure imgf000055_0002
R2a、 R3a、 R4a、 R5a、 Zlaおよび Z2aは、前記と同様の意味を有する。」 [0104] (N- 1) "In the formula,
Figure imgf000055_0002
R 2a , R 3a , R 4a , R 5a , Z la and Z 2a have the same meaning as described above. [0104] (N- 1)
一般式 [11a]の化合物は、一般式 [8]の化合物を硫黄イリドと反応させることにより 製造することができる。  The compound of the general formula [11a] can be produced by reacting the compound of the general formula [8] with sulfur ylide.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロゲン化炭化水 素類;ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類;ジォキサン、テト ラヒドロフラン、ァニソール、ジエチレングリコールジメチルエーテル、ジエチレングリコ 一ルジェチルエーテルおよびエチレングリコールモノメチルエーテルなどのエーテル 類；ジメチルスルホキシドなどのスルホキシド類ならびに水などが挙げられ、これらは 混合して使用してもよい。 Solvents used in this reaction are not particularly limited as long as they do not adversely influence the reaction.For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatics such as benzene, toluene and xylene. Hydrocarbons; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide and water. You may mix and use.
この反応に使用される硫黄イリドとしては、通常のォキシラン合成に使用される硫黄 イリドが挙げられ、たとえば、ジメチルスルホ-ゥムメチリド、ジメチルォキソスルホ-ゥ ムメチリド、ジメチルァミノ (メチル)ォキソスルホユウムメチリドおよびジメチルァミノ（フ ェニル)ォキソスルホユウムメチリドなどが挙げられる。  Examples of the sulfur ylide used in this reaction include sulfur ylides used in ordinary oxosilane synthesis. For example, dimethylsulfo-methyl methacrylate, dimethyloxosulfo-methyl methacrylate, dimethylamino (methyl) oxosulfo-methyl ester. And dimethylamino (phenyl) oxosulfoium methylide.
この反応において、硫黄イリドの使用量は、一般式 [8]の化合物に対して 1〜50倍 モル、好ましくは 1〜5倍モルであればよい。  In this reaction, the amount of sulfur ylide used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [8].
この反応は、 30〜150°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
[0105] (N- 2)  [0105] (N-2)
一般式 [l ib]の化合物は、一般式 [11a]の化合物をイソシアン酸カリウムと反応さ せること〖こより製造することができる。  The compound of the general formula [l ib] can be produced by reacting the compound of the general formula [11a] with potassium isocyanate.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2—プロパノ ールなどのアルコール類；塩化メチレン、クロ口ホルムおよびジクロロェタンなどのハロ ゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジ ォキサン、テトラヒドロフラン、ァ-ソール、エチレングリコールジメチルエーテル、ジェ チレングリコールジメチルエーテル、ジエチレングリコールジェチルエーテルおよび エチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなど のスルホキシド類ならびに水などが挙げられ、これらは混合して使用してもよ 、。 この反応において、イソシアン酸カリウムの使用量は、一般式 [11a]の化合物に対 して 1〜50倍モル、好ましくは 1〜5倍モルであればよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Halogenated hydrocarbons such as form and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, azole, ethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol Examples include ethers such as monomethyl ether; sulfoxides such as dimethyl sulfoxide, and water. These may be used as a mixture. In this reaction, the amount of potassium isocyanate used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [11a].
この反応は、 30〜150°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.
[0106] [製造法 O]
Figure imgf000057_0001
[0106] [Production method O]
Figure imgf000057_0001
[1 5] [28]  [1 5] [28]
「式中、
Figure imgf000057_0002
Zlaおよび Z2aは、前記と同様の意味を有する。」 [0107] 一般式 [28]の化合物は、触媒の存在下、塩基の存在下または不存在下、一般式 [ 15]の化合物をビュル金属化合物と反応させることにより製造することができる。 "In the formula,
Figure imgf000057_0002
Z la and Z 2a have the same meaning as described above. [0107] The compound of the general formula [28] can be produced by reacting the compound of the general formula [15] with a bulure metal compound in the presence of a catalyst, in the presence or absence of a base.
この反応に使用されるビニル金属化合物としては、たとえば、（トリプチル）（ビュル） スズなどの有機スズィ匕合物およびビュルボラン酸ピナコールエステルなどの有機ホウ 素化合物が挙げられる。  Examples of the vinyl metal compound used in this reaction include organic tin compounds such as (triptyl) (bulu) tin and organoboron compounds such as bulboronic acid pinacol ester.
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよぐ たとえば、たとえば、メタノール、エタノール、 2—プロパノールおよび 2—メチルー 2— プロパノールなどのアルコール類； N, N ジメチルホルムアミド、 N, N ジメチルァ セトアミドおよび 1ーメチルー 2—ピロリドンなどのアミド類;塩化メチレン、クロ口ホルム およびジクロロェタンなどのハロゲン化炭化水素類；ベンゼン、トルエンおよびキシレ ンなどの芳香族炭化水素類;ジォキサン、テトラヒドロフラン、ァ-ソール、エチレング リコールジメチルエーテル、ジエチレングリコールジメチルエーテル、ジエチレングリコ 一ルジェチルエーテルおよびエチレングリコールモノメチルエーテルなどのエーテル 類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよび 2—ブタノンなどのケト ン類；酢酸ェチルなどのエステル類；ァセトニトリルなどの-トリル類ならびに水などが 挙げられ、これらは混合して使用してもよい。  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N dimethylformamide Amides such as N, N dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Dioxane, Tetrahydrofuran , Ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide ; Ketone such as acetone and 2-butanone; esters such as acetic Echiru; Asetonitoriru etc. - tolyl ethers and water, and the like, may be used which are mixed.
[0108] この反応に使用される触媒としては、たとえば、ビス（トリフエ-ルホスフィン)パラジゥ ムジクロリド（11)、テトラキス（トリフエ-ルホスフィン)パラジウム、酢酸パラジウム（11)、 塩ィ匕パラジウム（II)、ビス（トリ tert—ブチルホスフィン)パラジウム（0)およびトリス（ ジベンジリデンアセトン）二パラジウム（0)などが挙げられる。 [0108] Examples of the catalyst used in this reaction include bis (triphenylphosphine) paradichloride dichloride (11), tetrakis (triphenylphosphine) palladium, palladium acetate (11), and sodium chloride palladium (II). Bis (tri tert-butylphosphine) palladium (0) and tris (dibenzylideneacetone) dipalladium (0).
この反応に所望により使用される塩基としては、たとえば、ピリジン、ジメチルアミノビ リジン、トリエチルァミン、 N, N ジメチルベンジルァミン、酢酸ナトリウムおよび酢酸 カリウムなどの有機塩基;水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウム、炭 酸カリウムおよび炭酸ナトリウムなどの無機塩基などが挙げられる。 Bases optionally used in this reaction include, for example, pyridine, dimethylaminopyridine, triethylamine, N, N dimethylbenzylamine, sodium acetate and acetic acid. Organic bases such as potassium; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate.
この反応において、ビニル金属化合物の使用量は、一般式 [15]の化合物に対し て 1〜 10倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of vinyl metal compound used should be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of general formula [15]!
この反応において、触媒の使用量は、一般式 [15]の化合物に対して 0.001〜10倍 モル、好ましくは 0.01〜2倍モルであればよい。  In this reaction, the amount of the catalyst used may be 0.001 to 10 times mol, preferably 0.01 to 2 times mol, of the compound of the general formula [15].
この反応において、所望により使用される塩基の使用量は、一般式 [15]の化合物 に対して 1〜 10倍モル、好ましくは 1〜5倍モルであればよ!、。  In this reaction, the amount of the base used as required may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [15]!
この反応は、 30〜200°C、好ましくは 0〜100°Cで 30分間〜 48時間実施すればよ い。  This reaction may be carried out at 30 to 200 ° C, preferably at 0 to 100 ° C for 30 minutes to 48 hours.
[0109] [製造法 P]  [0109] [Production method P]
ビニル金属化合物 14d Vinyl metal compound 14d
U3-R14d » CH2 = CH-RMd U 3 -R 14d »CH 2 = CH-R Md
[31 ] [29]  [31] [29]
「式中、 U3は、ハロゲン原子、アルカンスルホ-ルォキシ基およびァリールスルホ- ルォキシ基を; R14dは、前記と同様の意味を有する。」 “In the formula, U 3 represents a halogen atom, an alkanesulfooxy group and an arylsulfooxy group; R 14d has the same meaning as described above.”
[0110] 一般式 [29]の化合物は、触媒の存在下、塩基の存在下または不存在下、一般式 [[0110] The compound of the general formula [29] can be synthesized in the presence of a catalyst in the presence or absence of a base.
31]の化合物をビュル金属化合物と反応させることにより製造することができる。この 反応は、製造法 Oに準じて行えばよい。 The compound of [31] can be produced by reacting with a bur metal compound. This reaction may be performed according to production method O.
[0111] [製造法 Q] [0111] [Production method Q]
H02C-X3-R6 [3] の反応性誘導体 H2NOC- X3- 6 [30] H0 2 CX 3 reactive derivative of -R 6 [3] H 2 NOC- X 3 - 6 [30]
「式中、 R6および X3は、前記と同様の意味を有する。」 “Wherein R 6 and X 3 have the same meaning as described above.”
[0112] 一般式 [30]の化合物は、塩基の存在下または不存在下、一般式 [3]の化合物の 反応性誘導体とアンモニアを反応させることにより製造することができる。この反応は[0112] The compound of the general formula [30] can be produced by reacting a reactive derivative of the compound of the general formula [3] with ammonia in the presence or absence of a base. This reaction is
、製造法 1に準じて行えばよい。 The production method 1 may be performed.
[0113] [製造法 R] [0113] [Production method R]
Figure imgf000059_0001
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0002
「式中、
Figure imgf000059_0003
Zlaおよび Z2aは、前記と同様の意 味を有する。」 "In the formula,
Figure imgf000059_0003
Zla and Z2a have the same meaning as described above. "
[0114] (R- 1) [0114] (R-1)
一般式 [5f]の化合物は、一般式 [11c]の化合物を一般式 [20]の化合物と反応さ せることにより製造することができる。この反応は、製造法 7に準じて行えばよい。  The compound of the general formula [5f] can be produced by reacting the compound of the general formula [11c] with the compound of the general formula [20]. This reaction may be performed according to production method 7.
[0115] (R- 2) [0115] (R-2)
一般式 [5g]の化合物は、触媒および塩基の存在下、ホスフィンの存在下または不 存在下、一般式 [5f]の化合物を一般式 [14]の化合物と反応させた後、脱保護する ことにより製造することができる。この反応は、製造法 11に準じて行えばよい。  The compound of general formula [5g] should be deprotected after reacting the compound of general formula [5f] with the compound of general formula [14] in the presence of a catalyst and a base, in the presence or absence of phosphine. Can be manufactured. This reaction may be carried out according to production method 11.
[0116] このようにして得られた一般式 [2a]、 [2b]ゝ [2c]ゝ [2d] , [2e]、 [2f]、 [2g]、 [3a] 、 [4a]ゝ [5a]ゝ [5b]ゝ [5c]ゝ [5d]、 [5e]、 [5f]、 [5g]、 [8]、 [9]、 [11a]ゝ [l ib]ゝ [13]、 [27]、 [28]、 [29]および [30]の化合物は、たとえば、縮合、付加、酸化、還 元、転位、置換、ハロゲン化、脱水もしくは加水分解などの自体公知の反応に付すこ とによって、またはそれらの反応を適宜組み合わせることによって、他の化合物に誘 導することができる。 [0116] General formula [2a], [2b] ゝ [2c] ゝ [2d], [2e], [2f], [2g], [3a], [4a] ゝ [5a ] ゝ [5b] ゝ [5c] ゝ [5d], [5e], [5f], [5g], [8], [9], [11a] ゝ [l ib] ゝ [13], [27] The compounds of [28], [29] and [30] are subjected to a reaction known per se, such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, for example. Or it can induce to other compounds by combining those reactions suitably.
[0117] 本明細書において、
Figure imgf000059_0004
R 9、 R9a、 R10、 R10\ R11 Rlla、 Rllbおよび Rllcの各基は、ハロゲン原子、保護されてい てもよ 、ヒドロキシルおよびカルボキシル基、置換されて!、てもよ 、アルカンスルホ- ル基、保護されて 、てもよ 、カルボキシル基で置換されて 、るアルキル基ならびに置 換されていてもよいアルキル、ァルケ-ル、アルキ -ル、アルコキシおよびァリール基 など力 選ばれる 1つ以上の基で置換されてもよい。好ましい置換基としては、ハロゲ ン原子；保護されて 、てもよ 、ヒドロキシルおよびカルボキシル基;ノヽロゲン原子で置 換されて!/、てもよ!/、アルカンスルホ -ル基；保護されて!、てもよ!/、カルボキシル基で 置換されて ヽるアルキル基；ならびにハロゲン原子、保護されて ヽてもよ ヽヒドロキシ ル基または保護されて 、てもよ 、カルボキシル基で置換されて 、てもよ 、アルキル、 ァルケ-ル、アルキ -ル、アルコキシおよびァリール基が挙げられる。より好ましい置 換基としては、ハロゲン原子；ヒドロキシル基；カルボキシル基；ハロゲン原子で置換さ れて 、てもよ 、メタンスルホ -ル基；ならびにハロゲン原子、ヒドロキシル基および力 ルボキシル基力 選ばれる 1つ以上の基で置換されていてもよいメチル、ェチル、プ 口ピル、ビニル、ァリル、ェチニル、メトキシ、エトキシおよびフエ-ル基が挙げられる。 [0117] In this specification,
Figure imgf000059_0004
R 9, R 9a , R 10 , R 10 \ R 11 R lla , R llb and R llc groups may be halogen atoms, protected, hydroxyl and carboxyl groups, substituted! Alkanesulfo- Alkyl group, protected or substituted by carboxyl group, alkyl group and optionally substituted alkyl, alkyl, alkyl, alkoxy and aryl groups, etc. One or more selected May be substituted. Preferred substituents include halogen atoms; protected, hydroxyl and carboxyl groups; substituted with nitrogen atoms! /, May! /, Alkanesulfonyl groups; protected! , May! /, An alkyl group substituted with a carboxyl group; and a halogen atom, protected or a hydroxyl group or protected, may be substituted with a carboxyl group, Of course, alkyl, alkyl, alkyl, alkoxy and aryl groups are mentioned. More preferred substituents are halogen atom; hydroxyl group; carboxyl group; substituted with halogen atom, methanesulfol group; and halogen atom, hydroxyl group and force ruxyl group force one or more selected And methyl, ethyl, propyl, vinyl, allyl, ethynyl, methoxy, ethoxy and phenyl groups which may be substituted with these groups.
[0118] R13および R13a、は、置換されて!、てもよ 、アルキル、ァルケ-ル、アルキ -ル、アル コキシおよびァリール基など力 選ばれる 1つ以上の基で置換されてもよい。好ましい 置換基としては、ハロゲン原子、保護されていてもよいヒドロキシル基または保護され ていてもよいカルボキシル基で置換されていてもよいアルキル、ァルケ-ル、アルキ -ル、アルコキシおよびァリール基が挙げられる。より好ましい置換基としては、ハロ ゲン原子、ヒドロキシル基およびカルボキシル基力 選ばれる 1つ以上の基で置換さ れていてもよいメチル、ェチル、プロピル、ビニル、ァリル、ェチニル、メトキシおよび フエニル基が挙げられる。 [0118] R 13 and R 13a may be substituted !, or may be substituted with one or more groups selected from forces such as alkyl, alkaryl, alkyl, alkoxy and aryl groups. . Preferred substituents include halogen atoms, optionally protected hydroxyl groups or optionally protected alkyl groups, alkyl, alkyl, alkyl, alkoxy and aryl groups which may be substituted. . More preferred substituents include methyl, ethyl, propyl, vinyl, aryl, ethynyl, methoxy and phenyl groups which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group and a carboxyl group. It is done.
[0119] R"、 R14a、 R14b、 R14cおよび R14dは、ハロゲン原子、ニトロ基、シァノ基、ォキソ基、 保護されて 、てもよ 、ヒドロキシ、ァミノおよびカルボキシル基ならびに置換されて！ヽ てもよいアルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、ァシル、ァリ ール、複素環式、ァミノおよび力ルバモイル基など力 選ばれる 1つ以上の基で置換 されてもよい。好ましい置換基としては、ハロゲン原子;ニトロ基;シァノ基;ォキソ基； 保護されて ヽてもよ ヽヒドロキシ、ァミノおよびカルボキシル基；ならびにハロゲン原子 、保護されていてもよいヒドロキシル基、保護されていてもよいカルボキシル基、低級 アルキル基、ァリール基またはァリールスルフィエル基で置換されて 、てもよ 、アルキ ル、ァルケ-ル、アルキ -ル、アルコキシ、アルキルチオ、ァシル、ァリール、複素環 式、ァミノおよび力ルバモイル基が挙げられる。より好ましい置換基としては、ハロゲン 原子;ニトロ基;シァノ基；ォキソ基；ヒドロキシル基；アミノ基；カルボキシル基；ならび にハロゲン原子、ヒドロキシル基、カルボキシル基、メチル基、ェチル基、フエニル基[0119] R ", R 14a , R 14b , R 14c and R 14d are halogen atom, nitro group, cyano group, oxo group, protected, hydroxy, amino and carboxyl groups and substituted! The alkyl group may be substituted with one or more groups which may be optionally selected, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, aryl, heterocyclic, amino and rubamoyl groups. Is a halogen atom, a nitro group, a cyan group, an oxo group, a protected hydroxy group, an amino group and a carboxyl group; and a halogen atom, an optionally protected hydroxyl group, an optionally protected carboxyl group Substituted with a lower alkyl group, an aryl group or an aryl reel group, an alkyl group may be substituted. , Alkyl, alkyl, alkoxy, alkylthio, acyl, aryl, heterocyclic, amino and force rubamoyl groups. More preferred substituents are halogen atom; nitro group; cyano group; oxo group; hydroxyl group; amino group; carboxyl group; and halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, and phenyl group.
、フエ-ルスルフィエルメチル基から選ばれる 1つ以上の基で置換されて 、てもよ 、メ チル、ェチル、プロピル、ビニル、ァリル、ェチニル、メトキシ、エトキシ、メチルチオ、 ェチルチオ、ァセチル、プロピオニル、フエニル、フリル、チェニル、チアゾリル、ォキ サゾリル、ピリジル、ピリミジ -ル、ァミノおよび力ルバモイル基が挙げられる。 May be substituted with one or more groups selected from a phenylsulfurmethyl group, and may be methyl, ethyl, propyl, vinyl, allyl, ethynyl, methoxy, ethoxy, methylthio, ethylthio, acetyl, propionyl, phenyl , Furyl, chenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, amino and force rubamoyl groups.
[0120] X5、 X6、 X6a、 X6bおよび X7は、ハロゲン原子、保護されて 、てもよ ヽヒドロキシ、アミ ノおよびカルボキシル基ならびに置換されていてもよいアルキル、ァルケ-ル、アル キニル、アルコキシ、ァリール、ァミノおよび力ルバモイル基など力 選ばれる 1っ以 上の基で置換されてもよい。好ましい置換基としては、ハロゲン原子;保護されていて もよぃヒドロキシル、ァミノおよびカルボキシル基;ならびにハロゲン原子、保護されて[0120] X 5 , X 6 , X 6a , X 6b and X 7 are each a halogen atom, a protected, optionally substituted hydroxy, amino and carboxyl group, and an optionally substituted alkyl, alkenyl, It may be substituted with one or more groups selected by force, such as alkynyl, alkoxy, aryl, amino and force rubamoyl groups. Preferred substituents include halogen atoms; optionally protected hydroxyl, amino and carboxyl groups; and halogen atoms, protected
V、てもよ 、ヒドロキシル基または保護されて!、てもよ!/、カルボキシル基で置換されて いてもよいアルキル、ァルケ-ル、アルキ -ル、アルコキシおよびァリール基が挙げら れる。より好ましい置換基としては、ハロゲン原子；ヒドロキシル基;アミノ基;カルボキ シル基；ならびにハロゲン原子、ヒドロキシル基およびカルボキシル基から選ばれる 1 つ以上の基で置換されていてもよいメチル、ェチル、プロピル、ビュル、ァリル、ェチ -ル、メトキシ、エトキシおよびフエ-ル基が挙げられる。 V, may be a hydroxyl group or protected !, may! /, Alkyl, alkaryl, alkyl, alkoxy, and aryl groups optionally substituted with a carboxyl group. More preferable substituents include a halogen atom; a hydroxyl group; an amino group; a carboxy group; and methyl, ethyl, propyl, which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group, and a carboxyl group. Examples include bur, aryl, ethyl, methoxy, ethoxy and phenol groups.
[0121] 本発明化合物を医薬として用いる場合、通常、製剤化に使用される賦形剤、担体 および希釈剤などの製剤補助剤を適宜混合してもよい。これらは、常法にしたがって 、錠剤、カプセル剤、散剤、シロップ剤、顆粒剤、丸剤、懸濁剤、乳剤、液剤、粉体製 剤、坐剤、点眼剤、点鼻剤、点耳剤、貼付剤、軟膏剤または注射剤などの形態で、 経口または非経口で投与することができる。また投与方法、投与量および投与回数 は、患者の年齢、体重および症状に応じて適宜選択することができる。通常、成人に 対しては、経口または非経口（たとえば、注射、点滴および直腸部位への投与など） 投与により、 1日、 0.01〜1000mgZkgを 1回力も数回に分割して投与すればよい。  [0121] When the compound of the present invention is used as a medicine, formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powders, suppositories, eye drops, nasal drops, ear drops according to conventional methods. It can be administered orally or parenterally in the form of a patch, ointment or injection. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg Zkg may be administered in several divided doses once a day.
[0122] 次に、本発明化合物の有用性を、以下の試験例で説明する。 [0123] 試験例 1 感受性試験 1 [0122] Next, the usefulness of the compounds of the present invention will be described in the following test examples. [0123] Test Example 1 Sensitivity test 1
日本化学療法学会が推奨する微量液体希釈法で抗菌力 (MIC)を測定した。  Antibacterial activity (MIC) was measured by the micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
菌体として、黄色ブドウ球菌（S.aureus FDA209)を用いた。ミュラーヒントンァガー（ Mueller- Hinton agar:MHA)平板上、 35°Cで一夜培養した菌体を 0.5McFarland相当 になるように滅菌生理食塩水に懸濁した。この懸濁液を 10倍希釈し、接種菌液とした 。接種菌液約 0.005mLを、被験物質を含むカチオン調整ミュラーヒントン培地 (Cation -adjusted Mueller- Hinton broth (CAMHB) )に接種し、 35°Cで一夜培養した。肉眼的 に菌の発育が認められな 、最も低 、薬剤濃度を MICとした。結果を表 4に示す。  Staphylococcus aureus (S. aureus FDA209) was used as the cells. Cells cultured overnight at 35 ° C on a Mueller-Hinton agar (MHA) plate were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculum solution was inoculated into a cation-adjusted Mueller-Hinton broth (CAMHB) containing a test substance and cultured overnight at 35 ° C. The lowest microbial growth was not observed macroscopically, and the drug concentration was MIC. The results are shown in Table 4.
[0124] [表 4] 被験物質 被験物質[0124] [Table 4] Test substance Test substance
IC(/ g/mL) IC(/ g/mL) IC (/ g / mL) IC (/ g / mL)
(実施例番号） (実施例番号）  (Example number) (Example number)
1 0. 125 93 0. 125 1 0. 125 93 0. 125
4 0. 0625 99 0. 1254 0. 0625 99 0. 125
5 0. 0625 104 0. 0313 5 0. 0625 104 0. 0313
6 0. 0156 105 0. 125 6 0. 0156 105 0. 125
8 0. 25 107 0. 1258 0. 25 107 0. 125
9 0. 25 111 0. 1259 0. 25 111 0. 125
15 2 123 0. 062515 2 123 0. 0625
20 0. 0313 124 0. 12520 0. 0313 124 0. 125
23 0. 0625 125 0. 062523 0. 0625 125 0. 0625
29 2 126 0. 12529 2 126 0. 125
40 0. 125 135 0. 12540 0. 125 135 0. 125
44 0. 125 156 0. 2544 0. 125 156 0. 25
49 0. 0625 159 0. 12549 0. 0625 159 0. 125
50 0. 125 161 0. 12550 0. 125 161 0. 125
55 0. 125 170 0. 12555 0. 125 170 0. 125
59 0. 0625 176 0. 12559 0. 0625 176 0. 125
67 0. 25 186 0. 12567 0. 25 186 0. 125
69 0. 0313 189 0. 12569 0. 0313 189 0. 125
74 0. 0625 197 0. 2574 0. 0625 197 0. 25
78 0. 125 229 0. 2578 0. 125 229 0. 25
81 0. 0313 230 0. 2581 0. 0313 230 0. 25
84 0. 0625 231 0. 0625 84 0. 0625 231 0. 0625
[0125] 試験例 2 感受性試験 2 菌体として、メチシリン耐性黄色ブドウ球菌（S.aureus F3095)を用い、試験例 1と同 様な方法で、抗菌力（MIC)を測定した。結果を表 5に示す。 [0125] Test Example 2 Sensitivity Test 2 Using methicillin-resistant Staphylococcus aureus (S. aureus F3095) as the microbial cell, antimicrobial activity (MIC) was measured in the same manner as in Test Example 1. The results are shown in Table 5.
[表 5] 被験物質[Table 5] Test substance
ICCju g/mL)  ICCju g / mL)
(実施例番号）  (Example number)
1 0.25  1 0.25
8 1  8 1
20 0.0313  20 0.0313
50 0.25  50 0.25
59 0.125  59 0.125
69 0.0625  69 0.0625
74 0.125  74 0.125
81 0.125  81 0.125
99 0.125  99 0.125
104 0.0625  104 0.0625
124 0.125  124 0.125
125 0.125  125 0.125
126 0.5  126 0.5
231 0.125 試験例 3 細胞毒性試験 1  231 0.125 Test Example 3 Cytotoxicity test 1
被験物質として、実施例 8、 9および 15の化合物を選択した。  The compounds of Examples 8, 9, and 15 were selected as test substances.
被験物質をジメチルスルホキシドに溶解し、 10%フェイタル'ボーバイン'セ一ラム（ Fetal Bovine Serum :FBS)を添カ卩したイーグルズ'ミニマム'エッセンシャル'メディウム (E'MEM)で希釈し、被験物質溶液 (51.2 μ g/mL)を調製した。被験物質溶液 100 μ L /wellおよび 10%FBSを含む E'MEMに懸濁したベロ（Vero)細胞 3 X 103cells/100 μ L/ wellを合わせ、 5%COインキュベーターで、 37°C、 3日間培養した。培養後、 lmg/mL Dissolve the test substance in dimethyl sulfoxide, dilute it with Eagles 'Minimum'Essential'Medium(E'MEM) supplemented with 10% Fatal Bovine Serum (FBS), and add the test substance solution ( 51.2 μg / mL) was prepared. Vero cells suspended in E'MEM containing 100 μL / well of test substance solution and 10% FBS, combine 3 X 10 3 cells / 100 μL / well in a 5% CO incubator at 37 ° C, Cultured for 3 days. Lmg / mL after incubation
2  2
2, 3—ビス一 [2—メトシキ一 4— -トロ一 5—スルホ -ル]—2H—テトラゾリゥム一 5— カルボキシァ -リド（XTT)および 25 μ mol/Lフエナジンメトサルフェート（PMS)を含む E'MEM50 Lを各ゥエルに添カ卩した。 37°C、 2時間培養後、 450nmの吸光度をマイク 口プレートリーダーを用いて測定し、被験物質処理ゥエルの値と被験物質非添加ゥェ ルの値の比 (T/C)を計算した。結果を表 6に示す。 [表 6] 被験物質 2,3-bis- [2-methoxy 4--tro 5-sulfol] —2H-tetrazolium 5-carboxyl-lide (XTT) and 25 μmol / L phenazine methosulfate (PMS) Including E'MEM50 L was attached to each well. After culturing at 37 ° C for 2 hours, the absorbance at 450 nm was measured using a microphone plate reader, and the ratio (T / C) between the value of the test substance treated well and the value of the test substance-free well was calculated. The results are shown in Table 6. [Table 6] Test substances
T/C (%)  T / C (%)
(実施例番号）  (Example number)
8 >50  8> 50
9 >50  9> 50
1 5 >50  1 5> 50
[0129] 試験例 4 細胞毒性試験 2 [0129] Test Example 4 Cytotoxicity test 2
被験物質をジメチルスルホキシドに溶解し、 10%フェイタル'ボーバイン'セ一ラム（ Fetal Bovine Serum : FBS)を添カ卩したイーグルズ'ミニマム'エッセンシャル'メディウム (E'MEM)で希釈し、被験物質溶液を調製した。被験物質溶液 100 L/wellおよび 10 %FBSを含む E'MEMに懸濁したベロ（Vero)細胞 3 X 103cells/100 μ L/wellを合わせ、 5%COインキュベーターで、 37°C、 3日間培養した。培養後、 lmg/mL2, 3—ビス一 [Dissolve the test substance in dimethyl sulfoxide, dilute it with Eagles 'Minimum'Essential'medium(E'MEM) supplemented with 10% Fatal Bovine Serum (FBS), and Prepared. Vero cells suspended in E'MEM containing 100 L / well of test substance solution and 10% FBS 3 X 10 3 cells / 100 μL / well are combined in a 5% CO incubator at 37 ° C, 3 Cultured for days. After incubation, lmg / mL2, 3-bis
2 2
2—メトシキ一 4— -トロ一 5—スルホフエ-ル]— 2H—テトラゾリゥム一 5—カルボキ ンァニリト (2,3— bis[2— Methoxy— 4— nitro— 5— sulfophenyl]— 2H— tetrazolium— 5— carboxanil id : XTT)および 25mmol/Lフエナジンメトサルフェート（phenazine methosulfate： PMS) を含む E'MEM50 Lを各ゥエルに添カ卩した。 37°C、 2時間培養後、 450nmの吸光度を マイクロプレートリーダーを用いて測定し、被験物質処理ゥエルの値と被験物質非添 力ロウェルの値から、 50%の阻害率を示す被験物質濃度 (CC 、 /z g/mL)を計算した。  2—Metoshiki 4—-Toro 1—5-sulfophenol] — 2H—Tetrazolium 1—5-Carbonylanito (2,3-—bis [2—Methoxy— 4—nitro— 5—sulfophenyl] — 2H—tetrazolium— 5— E'MEM50 L containing carboxanil id (XTT) and 25 mmol / L phenazine methosulfate (PMS) was added to each well. After culturing at 37 ° C for 2 hours, the absorbance at 450 nm was measured using a microplate reader, and the concentration of the test substance showing a 50% inhibition rate from the value of the test substance-treated well and the value of the test substance non-added lowell ( CC, / zg / mL).
50  50
結果を表 7に示す。  The results are shown in Table 7.
[0130] [表 7] [0130] [Table 7]
被験物質 Test substance
CC50 ( / g/mL) CC 50 (/ g / mL)
(実施例番号） (Example number)
50 29.5  50 29.5
59 >6.4  59> 6.4
69 >6.4  69> 6.4
74 6.4  74 6.4
81 26.7  81 26.7
99 >1 2.8  99> 1 2.8
1 04 >6.4  1 04> 6.4
1 24 >6.4  1 24> 6.4
1 25 6.2  1 25 6.2
1 26 >300  1 26> 300
231 >1 2.8 試験例 5 感染実験 1  231> 1 2.8 Test example 5 Infection experiment 1
被験物質として、実施例 8の化合物を選択した。  The compound of Example 8 was selected as the test substance.
ミュラーヒントンァガー（Mueller- Hinton agar:MHA)平板上、 37。Cで一夜培養した 黄色ブドウ球菌スミス（S.aureus Smith)を終濃度 109CFU/mLになるように懸濁した。こ の懸濁液を 5.6%ムチンを含む l/15mol/Lリン酸緩衝液 (pH7)で 10倍希釈し、接種菌 液とした。マウス (ICR系、 4週齢、雄性、 5匹/群）に感染を惹起するため、接種菌液 0. 4mLをマウスの腹腔内に接種した（4 X 107CFU/匹）。 37 on the Mueller-Hinton agar (MHA) plate. S. aureus Smith cultured overnight in C was suspended to a final concentration of 10 9 CFU / mL. This suspension was diluted 10-fold with a l / 15 mol / L phosphate buffer (pH 7) containing 5.6% mucin to prepare an inoculum. In order to induce infection in mice (ICR line, 4 weeks old, male, 5 mice / group), 0.4 mL of the inoculum was inoculated intraperitoneally (4 × 10 7 CFU / mouse).
被験物質を終濃度 lOmg/mLになるように 22.5%2 ヒドロキシプロピル βーシクロ デキストリン (HP- -CD)に溶解した。被験物質の溶液を感染 1時間後に 1回皮下投 与（100mg/kg)した。コントロール群には、 22.5%HP- j8 - CDを投与した。マウスを毎 日観察し、感染 3日後の生存匹数を記録した。結果を表 8に示す。  The test substance was dissolved in 22.5% 2 hydroxypropyl β-cyclodextrin (HP-CD) to a final concentration of 10 mg / mL. The test substance solution was administered subcutaneously (100 mg / kg) once 1 hour after infection. The control group received 22.5% HP-j8-CD. Mice were observed daily and the number of surviving animals 3 days after infection was recorded. The results are shown in Table 8.
[表 8] 被験物質 生存匹数 [Table 8] Number of test animals surviving
実施例 8 5  Example 8 5
コントロール 0 試験例 6 感染実験 2  Control 0 Test example 6 Infection experiment 2
被験物質として、実施例 50および 126の化合物を選択した。 ミュラーヒントンァガー（Mueller- Hinton agar:MHA)平板上、 37。Cで一夜培養した 黄色ブドウ球菌スミス（S.aureus Smith)を終濃度 109CFU/mLになるように懸濁した。こ の懸濁液を 5.6%ムチンを含む l/15mol/Lリン酸緩衝液 (pH7)で 10倍希釈し、接種菌 液とした。マウス (ICR系、 4週齢、雄性、 5匹/群）に感染を惹起するため、接種菌液 0. 4mLをマウスの腹腔内に接種した（4 X 107CFU/匹）。 The compounds of Examples 50 and 126 were selected as test substances. 37 on the Mueller-Hinton agar (MHA) plate. S. aureus Smith cultured overnight in C was suspended to a final concentration of 10 9 CFU / mL. This suspension was diluted 10-fold with a l / 15 mol / L phosphate buffer (pH 7) containing 5.6% mucin to prepare an inoculum. In order to induce infection in mice (ICR line, 4 weeks old, male, 5 mice / group), 0.4 mL of the inoculum was inoculated intraperitoneally (4 × 10 7 CFU / mouse).
被験物質を O.lmol/L水酸ィ匕ナトリウム水溶液に溶解し、濃度 lmg/mLに調整した。 被験物質の溶液を感染 1時間後に 1回皮下投与した。コントロール群には、 22.5%H P- β -CDを投与した。マウスを毎日観察し、感染 3日後の生存匹数を記録した。結果 を表 9に示す。  The test substance was dissolved in O.lmol / L sodium hydroxide aqueous solution and adjusted to a concentration of 1 mg / mL. The test substance solution was administered subcutaneously once 1 hour after infection. The control group was administered 22.5% HP-β-CD. Mice were observed daily and the number of surviving animals 3 days after infection was recorded. The results are shown in Table 9.
[0134] [表 9] 被験物質 生存匹数 [0134] [Table 9] Test substance Number of surviving animals
実施例 50 3  Example 50 3
実施例 1 26 5  Example 1 26 5
コントロール 0  Control 0
[0135] 試験例 7 細菌を用いる復帰突然変異試験 [0135] Test Example 7 Reverse mutation test using bacteria
被験物質として、実施例 1の化合物を選択した。  The compound of Example 1 was selected as the test substance.
不ス チフス歯 almonella typhimunum TA98および Salmonella typhimunum TA10 0)を用い、プレインキュベーション法により、遺伝子突然変異誘発能の有無を調べた 。被験物質を水に溶解または懸濁し、ガラス試験管を用いて所定の被験物質濃度に なるように希釈系列を作製した。直接法の場合は、リン酸緩衝液を、代謝活性化法の 場合は、ラット肝臓由来 S9mixを添加した。前培養したネズミチフス菌の 2菌株をそれ ぞれ添加した後、ガラス試験管を温浴で 37°C、 20分間プレインキュベーションした。 その後、各ガラス試験管に軟寒天をカ卩え、この全量を半径 10cmシャーレ (テスメディ ァ平板プレート）に播種し、 37°Cで 48時間培養した。培養終了後、コロニー計数装置 を用いて、各プレートにおける復帰変異コロニー数を測定した。陰性対照群の 2倍以 上の復帰変異コロニー数がみられる場合を陽性とした。  The presence or absence of gene mutagenesis was examined by preincubation using non-stiff teeth, almonella typhimunum TA98 and Salmonella typhimunum TA100). A test substance was dissolved or suspended in water, and a dilution series was prepared using a glass test tube so as to obtain a predetermined test substance concentration. In the direct method, phosphate buffer was added, and in the case of metabolic activation, rat liver-derived S9mix was added. After adding two pre-cultured Salmonella typhimurium strains, glass test tubes were preincubated in a warm bath at 37 ° C for 20 minutes. Thereafter, soft agar was placed in each glass test tube, and the entire amount was seeded on a 10 cm radius petri dish (Tesmedia flat plate) and cultured at 37 ° C for 48 hours. After completion of the culture, the number of revertant colonies in each plate was measured using a colony counter. A case where the number of revertant colonies more than twice that of the negative control group was observed was regarded as positive.
実施例 1の化合物は、陰性であった。  The compound of Example 1 was negative.
[0136] 試験例 8 マウスを用いる骨髄小核試験 被験物質として、実施例 1の化合物を選択した。 Test Example 8 Bone marrow micronucleus test using mice The compound of Example 1 was selected as the test substance.
マウス (ICR系、 8週齢、雄性、 5匹/群）に被験物質 100mg/kgを 2日間反復皮下投与 した。陰性対照群には、生理食塩液を皮下投与した。最終投与の 24時間後に、マウ スを頸椎脱臼により安楽死させ、両側の大腿骨を採取した。大腿骨の骨髄を子牛血 清で洗い出し、骨髄塗抹標本を作製し、メイ 'ダリユンワルド染色を施して小核標本と した。この小核標本を顕微鏡下 (倍率 600倍)で観察し、多染性赤血球 1000個当たり の小核赤血球数 (小核を有する多染性赤血球数)の出現頻度 (小核出現頻度)を算 出した。続いてカステンバウムとボウマン（Kastenbaum and Bowman)の数表を用いる 条件付き二項検定法により、陰性対照群と被験物質投与群の間における小核出現 頻度の統計学的有意差検定を実施した。陰性対照群に比較して、小核出現頻度の 有意な増加がみられる場合を陽性とした。  Mice (ICR system, 8 weeks old, male, 5 / group) were repeatedly subcutaneously administered with 100 mg / kg of the test substance for 2 days. To the negative control group, physiological saline was administered subcutaneously. 24 hours after the last dose, the mice were euthanized by cervical dislocation and bilateral femurs were collected. The bone marrow of the femur was washed with calf serum, and a bone marrow smear was prepared. This micronucleus sample is observed under a microscope (600 times magnification), and the number of micronucleated red blood cells per 1000 polychromatic erythrocytes (the number of polychromatic erythrocytes having micronuclei) is calculated (micronucleus appearance frequency). I put it out. Subsequently, a statistically significant test of the frequency of micronucleus appearance between the negative control group and the test substance-administered group was performed by a conditional binomial test using the Kastenbaum and Bowman number table. Positive cases were observed where there was a significant increase in the frequency of micronucleus appearance compared to the negative control group.
実施例 1の化合物は、陰性であった。  The compound of Example 1 was negative.
実施例  Example
[0137] 次に、本発明を参考例および実施例を挙げて説明するが、本発明はこれらに限定 されるものではない。  [0137] Next, the present invention will be described with reference to reference examples and examples, but the present invention is not limited thereto.
溶離液における混合比は、容量比である。特に記載のない場合、シリカゲルカラム クロマトグラフィーにおける担体は、富士シリシァ化学株式会社、 B. W.シリカゲル、 BW— 127ZH ;逆相シリカゲルカラムクロマトグラフィーにおける担体は、株式会社ヮ イエムシィ、 ODS—AM120— S50である。  The mixing ratio in the eluent is a volume ratio. Unless otherwise specified, the carrier in silica gel column chromatography is Fuji Silica Chemical Co., Ltd., B. W. Silica Gel, BW-127ZH; the carrier in reverse phase silica gel column chromatography is Seki YMC, ODS-AM120-S50.
各実施例において各略号は、以下の意味を有する。  In each example, each abbreviation has the following meaning.
Ac :ァセチル、 Boc :tert—ブトキシカルボニル、 Bu:ブチル、 tBu:tert—ブチル、 Et:ェチル、 Me :メチル、 Ms :メタンスルホ -ル、 Ph:フエ-ル、 Tf :トリフルォロメチ ノレスノレホニノレ  Ac: acetyl, Boc: tert-butoxycarbonyl, Bu: butyl, tBu: tert-butyl, Et: ethyl, Me: methyl, Ms: methanesulfol, Ph: phenol, Tf: trifluoromethyl nolesnorehoninore
DMSO-d：重ジメチルスルホキシド  DMSO-d: Heavy dimethyl sulfoxide
6  6
[0138] 参考例 1  [0138] Reference Example 1
'Bu02G、
Figure imgf000067_0001
l—(tert ブトキシカルボ-ル）ピぺラジン 2.1g、 (2, 3 ジヒドロべンゾ [b] [1, 4] ジォキシン 6 ィル）ァセトアルデヒド 2.4gおよび酢酸 0.64mLの塩化メチレン 55mL 溶液に、水冷下、トリァセトキシ水素化ホウ素ナトリウム 2.9gを加え、 25時間攪拌した。 反応混合物に水 50mLおよび酢酸ェチル lOOmLを加えた。有機層を分取し、飽和塩 化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留 去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢 酸ェチル = 1 : 1]で精製し、淡黄色油状物の tert ブチル =4— (2— (2, 3 ジヒド 口べンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル）ピぺラジン 1 カルボキシラート 4.5gを得た。 'Bu0 2 G,
Figure imgf000067_0001
l- (tert-butoxycarbol) piperazine 2.1 g, (2,3 dihydrobenz [b] [1, 4] dioxin 6 yl) acetaldehyde 2.4 g and acetic acid 0.64 mL in 55 mL of methylene chloride Under water cooling, 2.9 g of sodium triacetoxyborohydride was added and stirred for 25 hours. To the reaction mixture, 50 mL of water and lOOmL of ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 1: 1], and tert-butyl 4- (2- (2,3-dihydrate) was obtained as a pale yellow oil. Zo [b] [1,4] dioxin 6yl) ethyl) piperazine 1 carboxylate (4.5 g) was obtained.
'H-NMRCCDCl ) δ値： 1.46(9H,s),2.40- 2.50(4H,m),2.50- 2.60(2H,m),2.65- 2.75(2Η,  'H-NMRCCDCl) δ value: 1.46 (9H, s), 2.40-2.50 (4H, m), 2.50-2.60 (2H, m), 2.65- 2.75 (2Η,
3  Three
m),3.40-3.50(4H,m),4.24(4H,s),6.66(lH,dd,J=8.2,2.0Hz),6.71(lH,d,J=2.0Hz),6.78(l H,d,J=8.2Hz)  m), 3.40-3.50 (4H, m), 4.24 (4H, s), 6.66 (lH, dd, J = 8.2, 2.0Hz), 6.71 (lH, d, J = 2.0Hz), 6.78 (l H, d, J = 8.2Hz)
[0139] 参考例 2
Figure imgf000068_0001
[0139] Reference Example 2
Figure imgf000068_0001
tert ブチル =4一（2—（2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン 6 ィル） ェチル）ピぺラジン 1 カルボキシラート 4.5gの塩化メチレン溶液 13mLに、トリフル ォロ酢酸 13mLを加え、 2時間攪拌した。減圧下で溶媒を留去し、 1.6mol/L塩ィ匕水素/ 酢酸ェチル 30mLを加え、減圧下で溶媒を留去し、淡橙色固体の 1一（2— (2, 3 ジ ヒドロべンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル）ピぺラジンの塩酸塩 3.2gを得 た。  tert butyl = 4 (2- (2, 3 dihydrobenz [b] [1, 4] dioxin 6 yl) ethyl) piperazine 1 carboxylate 4.5 g of methylene chloride solution in 13 mL of trifluoroacetic acid 13 mL was added and stirred for 2 hours. Evaporate the solvent under reduced pressure, add 1.6 mL / L salt / hydrogen chloride / ethyl acetate 30 mL, evaporate the solvent under reduced pressure, and remove 1- (2- (2,3 dihydrobenzene) as a pale orange solid. Zo [b] [1,4] dioxin 6yl) ethyl) piperazine hydrochloride 3.2g was obtained.
'H-NMRCDMSO-d ) δ値： 2.90- 3.00(2H,m),3.20- 3.60(10H,m),4.21(4H,s),6.70- 6.75(  'H-NMRCDMSO-d) δ value: 2.90-3.00 (2H, m), 3.20-3.60 (10H, m), 4.21 (4H, s), 6.70-6.75 (
6  6
lH,m),6.75-6.85(2H,m),9.79(2H,broad)  lH, m), 6.75-6.85 (2H, m), 9.79 (2H, broad)
[0140] 参考例 3
Figure imgf000068_0002
[0140] Reference Example 3
Figure imgf000068_0002
イソ-ペコチン酸 0.30gの N, N ジメチルホルムアミド 13mL溶液に、 25°Cで（2, 3 ージヒドロべンゾ [b] [1, 4]ジォキシン 6 ィル）ァセトアルデヒド 0.21gおよび酢酸 0 .13mLをカ卩え、攪拌後、トリァセトキシ水素化ホウ素ナトリウム 0.37gをカ卩え、 2時間 10分 間攪拌した。減圧下で溶媒を留去し、得られた残留物をシリカゲルカラムクロマトダラ フィー [溶離液；クロ口ホルム：メタノール：トリフルォロ酢酸 = 40： 10： 1 ]で精製した。 得られた物質に水 2mLおよび水酸ィ匕ナトリウム 96mgをカ卩え、炭酸ガスを吹き込んだ。 ついで、 6.0mol/L塩酸で pH3.0に調整し、炭酸ガスを吹き込んだ。析出物をろ取し、 白色固体の 1一（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル )ピペリジンー4一力ルボン酸 0.17gを得た。ろ液を水酸化ナトリウム水溶液で pH7.5に 調整し、逆相シリカゲルカラムクロマトグラフィー [溶離液；ァセトニトリル：水 = 1： 4]で 精製し、ジェチルエーテルをカ卩え、析出物をろ取し、白色固体の 1— (2— (2, 3 ジ ヒドロべンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル）ピぺリジン 4一力ルボン酸 61 mgを得た。 To a solution of 0.30 g of iso-pecotic acid in 13 mL of N, N dimethylformamide at 25 ° C (2, 3 Dihydrobenzo [b] [1, 4] dioxin 6yl) acetaldehyde 0.21g and acetic acid 0.13mL were added, and after stirring, sodium triacetoxyborohydride 0.37g was added, and 2 hours 10 Stir for minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: chloroform-form: methanol: trifluoroacetic acid = 40: 10: 1]. 2 mL of water and 96 mg of sodium hydroxide were added to the obtained substance, and carbon dioxide gas was blown into the material. Next, the pH was adjusted to 3.0 with 6.0 mol / L hydrochloric acid, and carbon dioxide gas was blown into the system. The precipitate was collected by filtration to obtain 0.17 g of 1- (2- (2,3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piperidine-4 monostrengthene rubonic acid as a white solid. The filtrate was adjusted to pH 7.5 with an aqueous sodium hydroxide solution and purified by reverse-phase silica gel column chromatography [eluent: acetonitrile: water = 1: 4], the jet ether was collected, and the precipitate was collected by filtration. As a result, 61 mg of white solid 1- (2- (2,3 dihydrobenzo [b] [1,4] dioxin 6 yl) ethyl) piperidine 4strength rubonic acid was obtained.
'H-NMRCDMSO-d ) δ値： 1.45— 1.55(2H,m),1.70— 1.80(2H,m),1.90— 2.00(2H,m),2.10—  'H-NMRCDMSO-d) δ value: 1.45—1.55 (2H, m), 1.70—1.80 (2H, m), 1.90—2.00 (2H, m), 2.10—
6  6
2.20(lH,m),2.35-2.45(2H,m),2.55-2.60(2H,m),2.75-2.85(2H,m),4.19(4H,s),6.60-6.7 5(3H,m)  2.20 (lH, m), 2.35-2.45 (2H, m), 2.55-2.60 (2H, m), 2.75-2.85 (2H, m), 4.19 (4H, s), 6.60-6.7 5 (3H, m)
参考例 4
Figure imgf000069_0001
Reference example 4
Figure imgf000069_0001
(2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ァセトアルデヒド 3.5gのジク ロロエタン 17.5mL溶液に、室温でイソ-ペコチン酸ェチルエステル 3.0mLをカ卩え、 20 分間攪拌した。ついで、酢酸 l.lmLを加え、 30分間攪拌した後、同温度でトリァセトキ シ水素化ホウ素ナトリウム 6.2gをカ卩え、 1時間攪拌した。反応混合物に水 20mL、クロ口 ホルム 20mLおよび 6.0mol/L塩酸をカ卩え、 pHl.Oに調整した。有機層を分取し、水およ び飽和炭酸水素ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、 減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶 離液；へキサン：酢酸ェチル = 1： 1]で精製した。得られた油状物を酢酸ェチルに溶 解させ、水および 6.0mol/L塩酸をカ卩え、 pHl.Oに調整した。水層を分取し、有機層を 1 .Omol/L塩酸で抽出した。水層および抽出液を合わせ、酢酸ヱチルで洗浄した。水 層に酢酸ェチルおよび飽和炭酸水素ナトリウム水溶液を加え、 pH7.8に調整した。有 機層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わせ、飽和 塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を 留去し、黄色油状物のェチル = 1一（2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシ ン一 6 ィル）ェチル）ピぺリジン 4—カルボキシラート 2.1 gを得た。 (2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) Acetaldehyde 3.5 g of dichloroethane in 17.5 mL solution at room temperature with 3.0 mL of iso-pecotic acid ethyl ester for 20 minutes Stir. Then, 1 mL of acetic acid was added and stirred for 30 minutes, and then 6.2 g of sodium triacetoxyborohydride was added at the same temperature and stirred for 1 hour. Water (20 mL), black mouth form (20 mL) and 6.0 mol / L hydrochloric acid were added to the reaction mixture and adjusted to pHl.O. The organic layer was separated, washed successively with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1]. The obtained oil was dissolved in ethyl acetate, and water and 6.0 mol / L hydrochloric acid were added to adjust to pHl.O. The aqueous layer was separated, and the organic layer was extracted with 1.Omol / L hydrochloric acid. The aqueous layer and the extract were combined and washed with acetyl acetate. water Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the layer to adjust the pH to 7.8. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oily substance ethyl = 1 (2- (2, 3 dihydroben Zo [b] [1,4] dioxin-6 yl) ethyl) piperidine 4-carboxylate (2.1 g) was obtained.
1H-NMR(CDC1 ) δ値： 1.25(3H,t,J=7.1Hz),1.74- 1.83(2H,m),1.85- 1.95(2H,m),2.00- 2  1H-NMR (CDC1) δ value: 1.25 (3H, t, J = 7.1Hz), 1.74- 1.83 (2H, m), 1.85- 1.95 (2H, m), 2.00-2
3  Three
.15(2H,m),2.25-2.35(lH,m),2.50-2.60(2H,m),2.65-2.75(2H,m),2.90-3.00(2H,m),4.1 3(2H,q,J=7.1Hz),4.23(4H,s),6.66(lH,dd,J=8.2,2.1Hz),6.71(lH,d,J=2.1Hz),6.77(lH,d ,J=8.2Hz)  .15 (2H, m), 2.25-2.35 (lH, m), 2.50-2.60 (2H, m), 2.65-2.75 (2H, m), 2.90-3.00 (2H, m), 4.1 3 (2H, q , J = 7.1Hz), 4.23 (4H, s), 6.66 (lH, dd, J = 8.2,2.1Hz), 6.71 (lH, d, J = 2.1Hz), 6.77 (lH, d, J = 8.2Hz )
[0142] 参考例 5
Figure imgf000070_0001
[0142] Reference Example 5
Figure imgf000070_0001
ェチル = 1— (2— (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル） ピぺリジン一 4—カルボキシラート 2.0gのエタノール 10mL溶液に、室温で 1.0mol/L水 酸ィ匕ナトリウム水溶液 12.5mLを加え、 1時間攪拌した。減圧下で溶媒を留去し、水お よび酢酸ェチルを加えた。水層を分取し、有機層を水で抽出した。水層と抽出液を 合わせ、酢酸ェチルで洗浄した。水層に 6.0mol/L塩酸をカ卩え、 pH7.0に調整した後、 減圧下で溶媒を留去した。得られた残留物を逆相シリカゲルカラムクロマトグラフィー [溶離液;ァセトニトリル:水 = 1 : 9]で精製し、白色固体の 1— (2— (2, 3 ジヒドロべ ンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル）ピぺリジン 4一力ルボン酸 1.4gを得 た。  Ethyl = 1— (2— (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) Piperidine mono 4-carboxylate 1.0 g in ethanol 10 mL solution at room temperature 12.5 mL of / L sodium hydroxide aqueous solution was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and water and ethyl acetate were added. The aqueous layer was separated and the organic layer was extracted with water. The aqueous layer and the extract were combined and washed with ethyl acetate. 6.0 mol / L hydrochloric acid was added to the aqueous layer and adjusted to pH 7.0, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by reversed-phase silica gel column chromatography [eluent: acetonitrile: water = 1: 9] to give a white solid 1— (2— (2,3 dihydrobenzo [b] [1, 4] Dioxin 6yl) ethyl) piperidine 4
1H- NMRは、参考例 3のデータと一致した。  1H-NMR was consistent with the data in Reference Example 3.
[0143] 参考例 6
Figure imgf000070_0002
[0143] Reference Example 6
Figure imgf000070_0002
8 アミノー 2—メトキシキノリン l.Ogの酢酸 21mL溶液に、氷冷下、臭素 0.39mLの酢 酸 15mL溶液を分割して添加した。反応混合物に飽和チォ硫酸ナトリウム水溶液 10m Lおよび酢酸ェチル 50mLをカ卩え、 20%水酸化ナトリウム水溶液で pH5.6に調整した。 有機層を分取し、水層を酢酸ェチル 50mLで 2回抽出した。有機層および抽出液を合 わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留 物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 10： 1]で精 製し、へキサンを加え、析出物をろ取し、白色固体の 5—ブロモ—2—メトキシキノリン — 8 ァミン 0.56gを得た。 8 Amino-2-methoxyquinoline l.Og A solution of bromine 0.39 mL of acetic acid 15 mL was dividedly added to a solution of 21 mL of acetic acid under ice-cooling. To the reaction mixture, saturated sodium thiosulfate aqueous solution 10m L and 50 mL of ethyl acetate were added and adjusted to pH 5.6 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted twice with 50 mL of ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 10: 1], hexane was added, the precipitate was collected by filtration, and white solid 5-bromo-2-— Methoxyquinoline — 0.56 g of 8 amine was obtained.
'H-NMRCCDCl ) δ fg： 4.07(3H,s),4.76(2H,s),6.79(lH,d,J=8.2Hz),6.98(lH,d,J=9.0Hz  'H-NMRCCDCl) δ fg: 4.07 (3H, s), 4.76 (2H, s), 6.79 (lH, d, J = 8.2Hz), 6.98 (lH, d, J = 9.0Hz)
3  Three
),7.41(lH,d,J=8.2Hz),8.29(lH,d,J=9.0Hz)  ), 7.41 (lH, d, J = 8.2Hz), 8.29 (lH, d, J = 9.0Hz)
[0144] 参考例 7
Figure imgf000071_0001
[0144] Reference Example 7
Figure imgf000071_0001
8 アミノー 2—メトキシキノリン 0.20gのピリジン 2.2mL溶液に、氷冷下、 1.0mol/L— 塩化ヨウ素/塩化メチレン l.lmLを加え、 30分間攪拌した。反応混合物に酢酸ェチル 20mLおよび飽和チォ硫酸ナトリウム水溶液 10mLを加え、 20%水酸ィ匕ナトリウム水溶 液で pHll.Oに調整した。有機層を分取し、水および飽和塩ィ匕ナトリウム水溶液で順 次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残 留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 10： 1]で 精製し、へキサンを加え、析出物をろ取し、白色固体の 5—ョード—2—メトキシキノリ ンー8 ァミン 0.21gを得た。  8 L-lmL of 1.0mol / L-iodine chloride / methylene chloride was added to a solution of 0.2mL of amino-2-methoxyquinoline in 2.2mL of pyridine under ice-cooling and stirred for 30 minutes. Ethyl acetate (20 mL) and saturated sodium thiosulfate aqueous solution (10 mL) were added to the reaction mixture, and adjusted to pHll.O with 20% aqueous sodium hydroxide solution. The organic layer was separated, washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 10: 1], hexane was added, and the precipitate was collected by filtration to give a white solid, 5-hydroxy-2— 0.21 g of methoxyquinolin-8amine was obtained.
'H-NMRCCDCl ) δ値： 4.07(3H,s),4.80(2H,s),6.69(lH,d,J=8.1Hz),6.94(lH,d,J=9.0Hz  'H-NMRCCDCl) δ value: 4.07 (3H, s), 4.80 (2H, s), 6.69 (lH, d, J = 8.1Hz), 6.94 (lH, d, J = 9.0Hz)
3  Three
),7.67(lH,dd,J=8.1,0.74Hz),8.15(lH,dd,J=9.0,0.74Hz)  ), 7.67 (lH, dd, J = 8.1,0.74Hz), 8.15 (lH, dd, J = 9.0,0.74Hz)
[0145] 参考例 8  [0145] Reference Example 8
Figure imgf000071_0002
。2'Bu
Figure imgf000071_0002
. 2 'Bu
5 ョード 2—メトキシキノリン一 8 ァミン 0.21gの N, N ジメチルァセトアミド 2.0 mL溶液に、トリェチルァミン 0.29mL、 tert ブチル =アタリラート 0.15mLおよび酢酸 ノ ラジウム (II) 16mgを加え、窒素気流下、 100〜110°Cで 6時間加熱した。反応混合物 に水 10mLおよび酢酸ェチル 10mLをカ卩えた。有機層を分取し、飽和塩化ナトリウム水 溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られ た残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 5： 1 ]で精製し、黄色油状物の tert—ブチル = (E) - 3- (8—ァミノ 2—メトキシキノリン — 5 ィル)アタリラー卜 0.16gを得た。 5) 2-methoxyquinoline 8-amamine 0.21 g of N, N dimethylacetamide 2.0 mL solution, triethylamine 0.29 mL, tert butyl = talylate 0.15 mL and acetic acid 16 mg of noradium (II) was added, and the mixture was heated at 100 to 110 ° C. for 6 hours under a nitrogen stream. To the reaction mixture, 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 5: 1] and tert-butyl = (E) -3- (8-amino-2-methoxyquinoline as a yellow oily substance. — 5 il) Atarilar g 0.16g was obtained.
'H-NMRCCDCl ) δ値： 1.55(9H,s),4.06(3H,s),5.04(2H,s),6.32(lH,d,J=15.6Hz),6.89(l  'H-NMRCCDCl) δ value: 1.55 (9H, s), 4.06 (3H, s), 5.04 (2H, s), 6.32 (lH, d, J = 15.6Hz), 6.89 (l
3  Three
H,d,J=8.4Hz),6.98(lH,d,J=9.0Hz),7.58(lH,d,J=8.4Hz),8.20(lH,d,J=15.6Hz),8.39(lH ,d,J=9.0Hz)  H, d, J = 8.4Hz), 6.98 (lH, d, J = 9.0Hz), 7.58 (lH, d, J = 8.4Hz), 8.20 (lH, d, J = 15.6Hz), 8.39 (lH, d, J = 9.0Hz)
[0146] 参考例 9 [0146] Reference Example 9
Figure imgf000072_0001
Figure imgf000072_0001
tert—ブチル = (E) - 3- (8—ァミノ一 2—メトキシキノリン一 5—ィル）アタリラート 0 .16gのエタノール 2.7mL溶液に、 10%パラジウム 炭素 32mgを加え、水素雰囲気下、 1時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去し、黄色固体の tert ブチル = 3— (8 アミノー 2—メトキシキノリンー5 ィル）プロピオナート 0.13gを得た。  tert-Butyl = (E) -3- (8-Amino 2-methoxyquinoline 1-yl) attalylate Add 0.16 g of ethanol in 2.7 mL of a solution with 10% palladium on carbon 32 mg, in a hydrogen atmosphere for 1 hour Stir. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.13 g of tertbutyl = 3- (8-amino-2-methoxyquinolin-5-yl) propionate as a yellow solid.
1H-NMR(CDC1 ) δ値： 1.43(9H,s),2.56(2H,t,J=7.9Hz),3.19(2H,t,J=7.9Hz),4.07(3H,s)  1H-NMR (CDC1) δ value: 1.43 (9H, s), 2.56 (2H, t, J = 7.9Hz), 3.19 (2H, t, J = 7.9Hz), 4.07 (3H, s)
3  Three
,6.94(lH,d,J=9.2Hz),6.99(lH,d,J=7.6Hz),7.07(lH,d,J=7.6Hz),8.17(lH,d,J=9.2Hz) [0147] 参考例 10
Figure imgf000072_0002
, 6.94 (lH, d, J = 9.2Hz), 6.99 (lH, d, J = 7.6Hz), 7.07 (lH, d, J = 7.6Hz), 8.17 (lH, d, J = 9.2Hz) [0147 ] Reference Example 10
Figure imgf000072_0002
( 1) 1一（tert ブトキシカルボ-ル）ピぺリジン 4一力ルボン酸 0.79gおよび 8 アミ ノー 2—メトキシキノリン 0.50gの N, N ジメチルホルムアミド 6mL溶液に、室温でトリエ チルァミン 1.2mLおよび O— (7 ァザべンゾトリアゾール 1—ィル） 1, 1, 3, 3— テトラメチルゥロニゥム =へキサフルォロホスフェート 1.7gをカ卩え、 2時間 10分間攪拌し た。 O— (7 ァザべンゾトリァゾールー 1ーィル） 1, 1, 3, 3—テトラメチルゥ口-ゥ ム=へキサフルォロホスフェート 0.55gをカ卩え、 30分間攪拌した。反応混合物を酢酸 ェチル 20mLおよび水 20mL混液に加えた。有機層を分取し、水層を酢酸ェチル 20m Lで抽出した。有機層および抽出液を合わせ、飽和塩化アンモ-ゥム水溶液、飽和 炭酸水素ナトリウム水溶液および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸 マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物の tert ブチル =4 - (2—メトキシキノリン一 8—ィルカルバモイル）ピぺリジン一 1 カルボキシラートを 得た。 (1) 1 (tert-butoxycarbol) piperidine 4 monostrength rubonic acid 0.79g and 8 amino 2-methoxyquinoline 0.50g in N, N dimethylformamide 6mL solution, triethylamine 1.2mL and O at room temperature — (7 Azabenzotriazole 1-yl) 1, 1, 3, 3— Tetramethyluronium hexafluorophosphate (1.7 g) was added and stirred for 2 hours and 10 minutes. O— (7 Azabenzotriazole 1-yl) 1, 1, 3, 3—Tetramethylol Mu-hexafluorophosphate (0.55 g) was added and stirred for 30 minutes. The reaction mixture was added to a mixture of 20 mL of ethyl acetate and 20 mL of water. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. An oily tertbutyl 4- (2-methoxyquinoline-1-ylcarbamoyl) piperidine-1-carboxylate was obtained.
(2)得られた tert ブチル =4— (2—メトキシキノリンー8—ィルカルバモイル）ピペリ ジン 1 カルボキシラートのエタノール 10mL溶液に、 10mol/L塩化水素/メタノール 10mLを加え、 1時間 30分間攪拌した後、減圧下で溶媒を留去した。得られた残留物 をクロ口ホルム、酢酸ェチル、ジェチルエーテルおよびメタノールの混液に溶解し、 炭酸カリウムを加え、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムク 口マトグラフィー [溶離液;クロ口ホルム:メタノール = 10 : 1]で精製し、白色固体の N — (2—メトキシキノリン一 8—ィル)ピぺリジン一 4—カルボキサミド l.Ogを得た。  (2) 10 mL of 10 mol / L hydrogen chloride / methanol was added to 10 mL of ethanol solution of tert butyl = 4- (2-methoxyquinoline-8-ylcarbamoyl) piperidine 1 carboxylate obtained and stirred for 1 hour and 30 minutes Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a mixed solution of black mouth form, ethyl acetate, jetyl ether and methanol, potassium carbonate was added, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 10: 1], and N — (2-methoxyquinoline 1-yl) piperidine 1 4-Carboxamide l.Og was obtained.
'H-NMRCDMSO-d ) δ値： 1.85— 1.95(2H,m),2.10— 2.15(2H,m),2.90— 3.05(3H,m),3.30— 'H-NMRCDMSO-d) δ value: 1.85— 1.95 (2H, m), 2.10— 2.15 (2H, m), 2.90—3.05 (3H, m), 3.30—
6  6
3.70(2H,m),4.11(3H,s),7.11(lH,d,J=9.0Hz),7.41(lH,t,J=7.6Hz),7.62(lH,d,J=7.6Hz), 8.29(lH,d,J=9.0Hz),8.46(lH,d,J=7.6Hz),9.69(lH,s)  3.70 (2H, m), 4.11 (3H, s), 7.11 (lH, d, J = 9.0Hz), 7.41 (lH, t, J = 7.6Hz), 7.62 (lH, d, J = 7.6Hz), 8.29 (lH, d, J = 9.0Hz), 8.46 (lH, d, J = 7.6Hz), 9.69 (lH, s)
参考例 11
Figure imgf000073_0001
Reference Example 11
Figure imgf000073_0001
2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルァミン 3. Ogのクロ口ホルム 80m L溶液に、 N, N，一カルボ-ルジイミダゾール 4.2gをカ卩え、 45分間加熱還流した。反 応混合物を室温まで冷却し、ェチル =イソ-ペコタート 3. lgのクロ口ホルム 20mL溶液 を加え、室温で 30分間攪拌し、トリェチルァミン 2.8mLを加え、 1時間 25分間攪拌した 。析出物をろ去し、塩ィ匕アンモニゥム水溶液 50mLを加えた。有機層を分取し、飽和 塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を 留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム ：アセトン = 50 : 1]で精製し、褐色泡状物のェチル = 1— ( (2, 3 ジヒドロべンゾ [b] '(ω'Ηΐ)08·9— SZ'9'C"'HI)SZ'9— ( '9'(S'H )^ · '(δ'Η θε·ε:ϋ 9 ( P-OS a)H N-HT 2, 3 Dihydrobenzo [b] [l, 4] Dioxin 6 Illamine 3. Add 4.2 g of N, N, monocarbodiimidazole to 80 ml L-form of Og and heat reflux for 45 minutes. did. The reaction mixture was cooled to room temperature, ethyl = iso-pecotate 3. lg of 20 mL of chloroform solution was added, stirred at room temperature for 30 minutes, 2.8 mL of triethylamine was added, and stirred for 1 hour and 25 minutes. The precipitate was removed by filtration, and 50 mL of a salt / ammonium aqueous solution was added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: acetone = 50: 1], and ethyl = 1— ((2, 3 dihydrobenzo [b] '(ω'Ηΐ) 08 · 9— SZ'9'C "' HI) SZ'9— ('9' ( S 'H) ^ ·' ( δ 'Η θε · ε: ϋ 9 (P-OS a ) H NH T
。 §0·ΐ ^( / 9一べ ^:^^ [ Ί] [q]
Figure imgf000074_0001
、つ ¾9¾呦 ffl措、 " ¥ 一ェ ^エ . § 0 · ΐ ^ (/ 9 whole ^: ^^ [Ί] [q]
Figure imgf000074_0001
¾9¾ 呦 ffl measures
^ 。 ·η# ^ οε n^' ΐベ ^^ ¾¾ατ¾πω9· ΐ氺 ¾ベ  ^. · Η # ^ οε n ^ 'ΐBe ^^ ¾¾ατ¾πω9 · ΐ 氺 ¾Be
O)S0'W— ^ ^ = /
Figure imgf000074_0002
O) S0'W— ^ ^ = /
Figure imgf000074_0002
SIp}% [OSTO]
Figure imgf000074_0003
SIp}% [OSTO]
Figure imgf000074_0003
·8=ΓΡΡ'Ηΐ)38·9'(ζΗ8·8=ΓΡ'Ηΐ)69·9'(ω'Η^)02^-3ΐ^'(ω'Η2)00^-36·ε'(ω'Η2)06·2 ・ 8 = ΓΡΡ'Ηΐ) 38 ・ 9 '( ζ Η8 ・ 8 = ΓΡ'Ηΐ) 69 ・ 9'(ω'Η ^) 02 ^ -3ΐ ^ '(ω'Η2) 00 ^ -36 · ε' ( ω'Η2) 06
- 08 ' (ra'HI)SS - 0 'S'(ra'HS)S8'I- SZ'I'(ra'HS)OS'I- 0 ·ΐ :軍 9 ( OS ) 顺- Ητ -08 '(ra'HI) SS-0' S '(ra'HS) S8'I- SZ'I'(ra'HS)OS'I- 0ΐ: Army 9 (OS) 顺-Η τ
。 ¾·ΐ邈べ ^ / 一  . ¾ · ΐ 邈 ^ /
)
Figure imgf000074_0004
)
Figure imgf000074_0004
Λ ^^- ^ °-^mw^ ^m ni^swoマ rw 濯氺、止^^、  Λ ^^-^ °-^ mw ^ ^ m ni ^ swo ma rw rinse, stop ^^,
Figure imgf000074_0005
Figure imgf000074_0005
(zH S=f'P'HI)S6'9'(ra'HS)08'9— ( '9'(S'HI)6 9 (zH S = f'P'HI) S6'9 '(ra'HS) 08'9— (' 9 '( S ' HI) 6 9
'(ω'Η^)52^-02^'(ζΗ2· =Γ¾Ή2)9Γ^'(ω'Η2)00^-06·ε'(ω'Η2)50·ε-36·2'(ω'Ηΐ)½·
Figure imgf000074_0006
'(ω'Η ^) 52 ^ -02 ^' (ζΗ2 · = Γ¾Ή2) 9Γ ^ '(ω'Η2) 00 ^ -06 · ε'(ω'Η2) 50 · ε-36-2 '(ω' Ηΐ) ½
Figure imgf000074_0006
98S6T0/S00Zdf/X3d ZL 6.85-6.95(lH,m),9.46(lH,s) 98S6T0 / S00Zdf / X3d ZL 6.85-6.95 (lH, m), 9.46 (lH, s)
[0151] 参考例 14
Figure imgf000075_0001
[0151] Reference Example 14
Figure imgf000075_0001
1 - (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6 ィル）チォゥレア l.Ogのァセト ン 5.0mLおよびメタノール 10mL混液に、ヨウ化メチル 0.30mLを加え、 1時間 50分間加 熱還流した。反応混合物を室温まで冷却し、減圧下で溶媒を留去し、淡橙色泡状物 の 1ー（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィル） 2—メチルイソチォ ゥレアのヨウ化水素酸塩 1.8gを得た。  1-(2, 3 Dihydrobenzo [b] [l, 4] dioxin-6 yl) thiourea Add 0.30 mL of methyl iodide to 5.0 mL of acetonitrile and 10 mL of methanol for 1 hour and 50 minutes Heated to reflux. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and a pale orange foam 1- (2,3 dihydrobenz [b] [l, 4] dioxin 6-yl) 2-methylisothio 1.8 g of urea hydroiodide was obtained.
'H-NMRCDMSO-d ) δ値： 2.65(3H,s),4.27(4H,s),6.78(lH,dd,J=8.5,2.4Hz),6.88(lH,d  'H-NMRCDMSO-d) δ values: 2.65 (3H, s), 4.27 (4H, s), 6.78 (lH, dd, J = 8.5, 2.4 Hz), 6.88 (lH, d
6  6
,J=2.4Hz),6.97(lH,d,J=8.5Hz)  , J = 2.4Hz), 6.97 (lH, d, J = 8.5Hz)
[0152] 参考例 15
Figure imgf000075_0002
[0152] Reference Example 15
Figure imgf000075_0002
1— (tert—ブトキシカルボ-ル）ピぺリジン— 4—カルボン酸 0.14gの N, N ジメチ ルホルムアミド 2mL溶液に、氷冷下、 N, N，—カルボ-ルジイミダゾール 0.10gをカロえ 、室温で 1時間攪拌した後、 7—メトキシイソキノリン一 1—ァミン 0.10gをカ卩え、同温度 で 1時間、 40°Cで 1時間、 50°Cで 1時間攪拌した。反応混合物に酢酸ェチル 20mLおよ び水 20mLをカ卩えた後、 1.0mol/L塩酸をカ卩え、 pH3.0に調整した。有機層を分取し、 水層を酢酸ェチル 10mLで抽出した。有機層および抽出液を合わせ、飽和炭酸水素 ナトリウム水溶液および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシ ゥムで乾燥させ、減圧下で溶媒を留去し、淡褐色固体の tert ブチル =4一（（7—メ トキシイソキノリン一 1—ィル）力ルバモイル）ピぺリジン一 1 カルボキシラート 0.17gを 得た。  1- (tert-Butoxycarbol) piperidine-4-carboxylic acid 0.14 g of N, N dimethylformamide in 2 mL solution under ice-cooling, 0.10 g of N, N, -carbodidiimidazole After stirring at room temperature for 1 hour, 0.10 g of 7-methoxyisoquinoline mono-amine was added and stirred at the same temperature for 1 hour, at 40 ° C for 1 hour, and at 50 ° C for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and 1.0 mol / L hydrochloric acid was added to adjust the pH to 3.0. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove a light brown solid tert butyl = 0.17 g of 4-((7-methoxyisoquinoline 1-1-yl) strength rubermoyl) piperidine-1-carboxylate was obtained.
'H-NMRCDMSO-d ) δ値： 1.41(9H,s),1.51— 1.61(2H,m),1.89— 1.92(2H,m),2.70— 2.90(3  'H-NMRCDMSO-d) δ value: 1.41 (9H, s), 1.51— 1.61 (2H, m), 1.89—1.92 (2H, m), 2.70—2.90 (3
6  6
H,m),3.86(3H,s),4.00-4.04(2H,m),7.15-7.20(lH,m),7.44(lH,dd,J=9.0,2.4Hz),7.67(l H,d,J=5.6Hz),7.92(lH,d,J=9.0Hz),8.19(lH,d,J=5.6Hz),10.41(lH,s) H, m), 3.86 (3H, s), 4.00-4.04 (2H, m), 7.15-7.20 (lH, m), 7.44 (lH, dd, J = 9.0, 2.4Hz), 7.67 (l H, d, J = 5.6Hz), 7.92 (lH, d, J = 9.0Hz), 8.19 (lH, d, J = 5.6Hz), 10.41 (lH, s)
[0153] 参考例 16
Figure imgf000076_0001
[0153] Reference Example 16
Figure imgf000076_0001
tert—ブチル =4— ( (7—メトキシイソキノリン一 1—ィル）力ルバモイル）ピぺリジン 1 カルボキシラート 150mgの塩化メチレン 3mL溶液に、室温でトリフルォロ酢酸 1.5 mLを加え、同温度で 1時間攪拌した後、減圧下で溶媒を留去した。得られた残留物 にクロ口ホルム 30mLおよび飽和炭酸水素ナトリウム水溶液 30mLをカ卩え、水層を分取 した。水層にクロ口ホルム 30mLをカ卩えた後、 20%水酸化ナトリウム水溶液をカ卩え、 pHl 0.0に調整した。有機層を分取し、水層をクロ口ホルム 10mLで抽出した。有機層およ び抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾 燥させ、減圧下で溶媒を留去し、淡褐色固体の N— (7—メトキシイソキノリン 1ーィ ル）ピぺリジン 4 カルボキサミド 70mgを得た。  tert-Butyl = 4— ((7-methoxyisoquinoline 1-yl) rubamoyl) piperidine 1 carboxylate 150 mL of methylene chloride in 1.5 mL of trifluoroacetic acid at room temperature was added at room temperature and stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of black mouth form and 30 mL of saturated aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was separated. After 30 mL of black mouth form was added to the aqueous layer, 20% aqueous sodium hydroxide solution was added to adjust the pH to 0.0. The organic layer was separated, and the aqueous layer was extracted with 10 mL of black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a light brown solid N— (7-methoxyisoquinoline 1-yl). ) Piperidine 4 carboxamide 70 mg was obtained.
1H-NMR(CDC1 ) δ fg: 1.77-1.86(2H,m),2.03-2.06(2H,m),2.69-2.75(3H,m),3.18-3.2  1H-NMR (CDC1) δ fg: 1.77-1.86 (2H, m), 2.03-2.06 (2H, m), 2.69-2.75 (3H, m), 3.18-3.2
3  Three
l(2H,m),3.93(3H,s),7.00-8.50(5H,m)  l (2H, m), 3.93 (3H, s), 7.00-8.50 (5H, m)
[0154] 参考例 17
Figure imgf000076_0002
[0154] Reference Example 17
Figure imgf000076_0002
2, 4ージクロ口キノリン l.Ogの濃硫酸 5.0mL溶液に、氷冷下、発煙硝酸 224 Lを滴 下し、 30分間攪拌した。室温で 2時間攪拌した後、反応混合物を氷水に注ぎ、トルェ ン 10mLをカ卩えた後、 20%水酸化ナトリウム水溶液をカ卩え、 pH12.0に調整した。不溶 物をろ去し、ろ滓をトルエン 10mLで洗浄した。有機層を分取し、水層をトルエン 10mL で抽出した。有機層および抽出液を合わせ、水 10mLおよび飽和塩ィ匕ナトリウム水溶 液 10mLで順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した 。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチ ル = 5 : 1]で精製し、淡黄色固体の 2, 4 ジクロロ 8 二トロキノリン 0.32gを得た。 H-NMR(CDC1 ) δ値： 7.66(lH,s),7.72- 7.76(lH,m),8.11(lH,dd,J=7.6,1.2Hz),8.44(l To a 5.0 mL concentrated sulfuric acid solution of 2,4-dichloroquinoline l.Og, 224 L of fuming nitric acid was added dropwise under ice cooling and stirred for 30 minutes. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, 10 mL of toluene was prepared, 20% aqueous sodium hydroxide solution was added, and the pH was adjusted to 12.0. Insoluble materials were removed by filtration, and the filter cake was washed with 10 mL of toluene. The organic layer was separated, and the aqueous layer was extracted with 10 mL of toluene. The organic layer and the extract were combined, washed sequentially with 10 mL of water and 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1] to obtain 0.32 g of 2,4 dichloro 8 ditroquinoline as a pale yellow solid. H-NMR (CDC1) δ value: 7.66 (lH, s), 7.72-7.76 (lH, m), 8.11 (lH, dd, J = 7.6, 1.2 Hz), 8.44 (l
3  Three
H,dd,J=8.5,1.2Hz)  (H, dd, J = 8.5,1.2Hz)
[0155] 参考例 18
Figure imgf000077_0001
[0155] Reference Example 18
Figure imgf000077_0001
28%ナトリウムメトキシド /メタノール 0.30gにメタノール lOmLをカ卩えた後、 2, 4—ジク ロロー8— -トロキノリン 0.15gをカ卩え、 1時間 30分間加熱還流した。さらに、 28%ナトリ ゥムメトキシド /メタノール 0.15gを加え、 2時間加熱還流した。さらに、 28%ナトリウムメト キシド /メタノール 0.15gをカ卩え、 1時間加熱還流した後、室温まで冷却した。反応混合 物に酢酸ェチル 30mLおよび水 30mLをカ卩えた。有機層を分取し、水層を酢酸ェチル 10mLで抽出した。有機層および抽出液を合わせ、水 10mLおよび飽和塩ィ匕ナトリウム 水溶液 10mLで順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留 去した。得られた残留物にへキサンを加え、析出物をろ取し、淡褐色固体の 2, 4— ジメトキシー 8—二トロキノリン 0.14gを得た。  After adding methanol 10 mL to 28% sodium methoxide / methanol 0.30 g, 2,5-dichloro 8--troquinoline 0.15 g was added and heated under reflux for 1 hour 30 minutes. Further, 0.15 g of 28% sodium methoxide / methanol was added and heated to reflux for 2 hours. Further, 0.15 g of 28% sodium methoxide / methanol was added, heated under reflux for 1 hour, and then cooled to room temperature. To the reaction mixture, 30 mL of ethyl acetate and 30 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed sequentially with 10 mL of water and 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Hexane was added to the resulting residue, and the precipitate was collected by filtration to obtain 0.14 g of 2,4-dimethoxy-8-nitroquinoline as a light brown solid.
1H-NMR(CDC1 ) δ fg:4.03(3H,s),4.04(3H,s),6.31(lH,s),7.36(lH,dd,J=8.2,7.6Hz),7.  1H-NMR (CDC1) δ fg: 4.03 (3H, s), 4.04 (3H, s), 6.31 (lH, s), 7.36 (lH, dd, J = 8.2, 7.6 Hz), 7.
3  Three
93(lH,dd,J=7.6,1.5Hz),8.24(lH,dd,J=8.2,1.5Hz)  93 (lH, dd, J = 7.6,1.5Hz), 8.24 (lH, dd, J = 8.2,1.5Hz)
[0156] 参考例 19
Figure imgf000077_0002
[0156] Reference Example 19
Figure imgf000077_0002
2, 4ージメトキシー 8— -トロキノリン 0.14gの酢酸 lOmL懸濁液に、室温で 10%パラ ジゥム—炭素 28mgを加え、水素雰囲気下で 2時間攪拌した。不溶物をろ去し、減圧 下で溶媒を留去した。得られた残留物に酢酸ェチル 30mLおよび飽和炭酸水素ナトリ ゥム水溶液 30mLをカ卩えた。有機層を分取し、水層を酢酸ェチル 20mLで抽出した。有 機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無 水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカ ゲルカラムクロマトグラフィー [溶離液;へキサン:酢酸ェチル = 3 : 1]で精製し、白色 固体の 2, 4 ジメトキシキノリン一 8 ァミン 52mgを得た。 2,4-Dimethoxy-8--troquinoline 0.14 g of acetic acid in lOmL was added with 10% para-carbon-28 mg at room temperature, and stirred for 2 hours under a hydrogen atmosphere. Insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of ethyl acetate and 30 mL of saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 3: 1] and white. 52 mg of solid 2,4 dimethoxyquinoline monoamine was obtained.
1H-NMR(CDC1 ) δ値： 3.97(3H,s),4.03(3H,s),4.69(2H,s),6.21(lH,s),6.90(lH,dd,J=7.  1H-NMR (CDC1) δ value: 3.97 (3H, s), 4.03 (3H, s), 4.69 (2H, s), 6.21 (lH, s), 6.90 (lH, dd, J = 7.
3  Three
6,1.2Hz),7.13(lH,dd,J=8.3,7.6Hz),7.40(lH,dd,J=8.3,1.2Hz)  6,1.2Hz), 7.13 (lH, dd, J = 8.3,7.6Hz), 7.40 (lH, dd, J = 8.3,1.2Hz)
[0157] 参考例 20
Figure imgf000078_0001
[0157] Reference Example 20
Figure imgf000078_0001
2 クロロー 3—メチルキノリン 2.0gの濃硫酸 10mL溶液に、氷冷下、発煙硝酸 0.5mL を滴下し、室温で 5時間攪拌した。反応混合物を氷水に注ぎ、析出物をろ取し、水 50 mLで洗浄し、橙色固体を得た。得られた固体にクロ口ホルム 30mLおよび水 20mLをカロ え、 20%水酸ィ匕ナトリウム水溶液を加え、 pH12.0に調整した。有機層を分取し、水層 をクロ口ホルム 20mLで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕 ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を 留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン： 酢酸ェチル = 3 : 1]で精製し、橙色固体の 2 クロ口 3—メチル—8 二トロキノリン 0.62gを得た。  2 Chloro-3-methylquinoline 2.0 g of concentrated sulfuric acid 10 mL solution was added dropwise with 0.5 mL of fuming nitric acid under ice cooling and stirred at room temperature for 5 hours. The reaction mixture was poured into ice water, and the precipitate was collected by filtration and washed with 50 mL of water to obtain an orange solid. To the obtained solid, 30 mL of black mouth form and 20 mL of water were added, and 20% aqueous sodium hydroxide solution was added to adjust the pH to 12.0. The organic layer was separated, and the aqueous layer was extracted with 20 mL of black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1] to obtain 0.62 g of 2-chloro 3-methyl-8 ditroquinoline as an orange solid.
^-NMRCCDCl ) δ値： 2.58(3H,s),7.58- 7.62(lH,m),7.97(lH,d,J=8.3Hz),8.03(lH,d,J=  ^ -NMRCCDCl) δ value: 2.58 (3H, s), 7.58-7.62 (lH, m), 7.97 (lH, d, J = 8.3Hz), 8.03 (lH, d, J =
3  Three
7.6Hz),8.07(lH,s)  7.6Hz), 8.07 (lH, s)
[0158] 参考例 21
Figure imgf000078_0002
[0158] Reference Example 21
Figure imgf000078_0002
2 クロ口一 3—メチル 8 二トロキノリン 0.30gのメタノール lOmL懸濁液に、 28% ナトリウムメトキシド /メタノール 0.39gをカ卩え、 2時間加熱還流した。反応混合物を室温 まで冷却し、酢酸ェチル 30mLおよび水 20mLをカ卩えた。有機層を分取し、水層を酢酸 ェチル 10mLで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウ ム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し た。得られた残留物にへキサンをカ卩え、不溶物をろ取し、淡桃色固体の 2—メトキシ - 3—メチノレー 8 ニトロキノリン 0.25gを得た。 H-NMR(CDC1 ) δ値： 2.36(3H,s),4.09(3H,s),7.36-7.40(lH,m),7.83-7.85(2H,m),7.91 2 Black mouth 3-methyl-8 ditroquinoline 0.30 g of methanol 10 mL was charged with 28% sodium methoxide / methanol 0.39 g and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and charged with 30 mL of ethyl acetate and 20 mL of water. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, and the insoluble matter was collected by filtration to obtain 0.25 g of 2-methoxy-3-methynole 8 nitroquinoline as a pale pink solid. H-NMR (CDC1) δ value: 2.36 (3H, s), 4.09 (3H, s), 7.36-7.40 (lH, m), 7.83-7.85 (2H, m), 7.91
3  Three
(lH,dd,J=7.6,1.2Hz)  (lH, dd, J = 7.6,1.2Hz)
[0159] 参考例 22
Figure imgf000079_0001
[0159] Reference Example 22
Figure imgf000079_0001
2—メトキシー3—メチルー 8 -トロキノリン 0.22gの酢酸 lOmL懸濁液に、室温で 10 %パラジウム—炭素 44mgを加え、水素雰囲気下で 2時間攪拌した。不溶物をろ去し、 ろ滓をクロ口ホルム 20mLで 2回洗浄し、減圧下で溶媒を留去した。得られた残留物に 酢酸ェチル 30mLおよび飽和炭酸水素ナトリウム水溶液 20mLをカ卩え、有機層を分取 し、水層を酢酸ェチル 20mLで抽出した。有機層および抽出液を合わせ、水および飽 和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で 溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキ サン:酢酸ェチル = 3 : 1]で精製し、淡黄緑色固体の 2—メトキシ— 3—メチルキノリン — 8 ァミン 0.18gを得た。  To a suspension of 0.22 g of 2-methoxy-3-methyl-8-troquinoline in 10 mL of acetic acid was added 44 mg of 10% palladium-carbon at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filter cake was washed twice with 20 mL of black mouth form, and the solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of ethyl acetate and 20 mL of saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 3: 1] to obtain 0.18 g of 2-methoxy-3-methylquinoline-8-amine as a pale yellowish green solid. .
1H-NMR(CDC1 ) δ値： 2.32(3H,d,J=0.98Hz),4.08(3H,s),4.50- 4.90(2H,broad),6.86(l  1H-NMR (CDC1) δ value: 2.32 (3H, d, J = 0.98Hz), 4.08 (3H, s), 4.50-4.90 (2H, broad), 6.86 (l
3  Three
H,dd,J=7.6,1.2Hz),7.04(lH,dd,J=8.0,1.2Hz),7.13-7.17(lH,m),7.70(lH,d,J=0.98Hz) H, dd, J = 7.6,1.2Hz), 7.04 (lH, dd, J = 8.0,1.2Hz), 7.13-7.17 (lH, m), 7.70 (lH, d, J = 0.98Hz)
[0160] 参考例 23
Figure imgf000079_0002
[0160] Reference Example 23
Figure imgf000079_0002
7—メトキシイソキノリン 1 カルバルデヒド 0.50gのジメチルスルホキシド 5mL溶液 に、室温でトリメチルスルホニムョージド 0.71gおよび水酸化カリウム 0.19gをカ卩え、 60 °Cで 1時間攪拌した。反応混合物を室温まで冷却し、水 10mLおよび酢酸ェチル 10m Lを加えた。有機層を分取し、水層を酢酸ェチル 5mLで抽出した。有機層および抽出 液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた 残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 1 : 1] で精製し、淡黄色油状物の 7—メトキシ— 1— (ォキシラン— 2—ィル)イソキノリン 0.44 gを得た。 H-NMR(CDC1 ) δ fg: 3.30(lH,dd,J=5.9,4.1Hz),3.37(lH,dd,J=5.9,2.6Hz),3.97(3H,s)To a solution of 0.50 g of 7-methoxyisoquinoline 1 carbaldehyde in 5 mL of dimethyl sulfoxide was added 0.71 g of trimethylsulfonimide and 0.19 g of potassium hydroxide at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature and 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with 5 mL of ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 1: 1], and light yellow oily 7-methoxy-1- (oxylan-2-yl) isoquinoline 0.44 g Got. H-NMR (CDC1) δ fg: 3.30 (lH, dd, J = 5.9,4.1Hz), 3.37 (lH, dd, J = 5.9,2.6Hz), 3.97 (3H, s)
3 Three
4.56(lH,dd,J=4.1,2.6Hz),7.36(lH,dd,J=8.9,2.5Hz),7.53(lH,d,J=5.6Hz),7.61(lH,d,J =2.5Hz),7.74(lH,d,J=8.9Hz),8.39(lH,d,J=5.6Hz)  4.56 (lH, dd, J = 4.1,2.6Hz), 7.36 (lH, dd, J = 8.9,2.5Hz), 7.53 (lH, d, J = 5.6Hz), 7.61 (lH, d, J = 2.5Hz) ), 7.74 (lH, d, J = 8.9Hz), 8.39 (lH, d, J = 5.6Hz)
参考例 24
Figure imgf000080_0001
Reference Example 24
Figure imgf000080_0001
7—メトキシ一 1— (ォキシラン一 2—ィル)イソキノリン 0.30gの N, N ジメチルホル ムアミド 6mL溶液に、室温で 4 （（tert ブトキシカルボ-ル）ァミノ）ピぺリジン 0.36g および過塩素酸リチウム 0.16gを加え、 80°Cで 1時間攪拌した。反応混合物を室温ま で冷却し、水 10mLおよび酢酸ェチル 20mLを加え、有機層を分取し、水層を酢酸ェ チル 10mLで抽出した。有機層および抽出液を合わせ、飽和塩ィ匕ナトリウム水溶液で 洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留 物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 9： 1]で精 製し、白色固体の tert—ブチル = 1— (2 ヒドロキシ一 2— (7—メトキシイソキノリン 1 ィル）ェチル）ピぺリジンー4ーィルカルバマート 0.46gを得た。  7-Methoxy-1- (oxylan-2-yl) isoquinoline 0.30 g in 6 mL of N, N dimethylformamide at room temperature with 4 ((tert-butoxycarb) amino) piperidine 0.36 g 0.16g was added and it stirred at 80 degreeC for 1 hour. The reaction mixture was cooled to room temperature, 10 mL of water and 20 mL of ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 9: 1] and tert-butyl = 1- (2 hydroxy-1- (7-methoxyisoquinoline 1) as a white solid. 0.46 g of yl) ethyl) piperidine-4-ylcarbamate was obtained.
'H-NMRCCDCl ) δ値： 1.46- 1.61(2H,m),1.46(9H,m),1.93- 2.01(2H,m),2.30- 2.40(2Η, 'H-NMRCCDCl) δ value: 1.46-1.61 (2H, m), 1.46 (9H, m), 1.93-2.01 (2H, m), 2.30-2.40 (2Η,
3  Three
m),2.76-2.80(2H,m),3.01-3.13(2H,m),3.40-3.70(lH,m),3.95(3H,s),4.45-4.70(lH,m) ,5.50(lH,dd,J=8.4,3.2Hz),7.36(lH,dd,J=8.8,2.2Hz),7.43(lH,d,J=2.2Hz),7.53(lH,d,J =5.4Hz),7.76(lH,d,J=8.8Hz),8.35(lH,d,J=5.4Hz) m), 2.76-2.80 (2H, m), 3.01-3.13 (2H, m), 3.40-3.70 (lH, m), 3.95 (3H, s), 4.45-4.70 (lH, m), 5.50 (lH, dd, J = 8.4, 3.2 Hz), 7.36 (lH, dd, J = 8.8, 2.2 Hz), 7.43 (lH, d, J = 2.2 Hz), 7.53 (lH, d, J = 5.4 Hz), 7.76 ( lH, d, J = 8.8Hz), 8.35 (lH, d, J = 5.4Hz)
参考例 25
Figure imgf000080_0002
Reference Example 25
Figure imgf000080_0002
7—メトキシ一 1— (ォキシラン一 2—ィル)イソキノリン 0.22gの N, N ジメチルホル ムアミド 3mL溶液に、室温で 1一（tert ブトキシカルボ-ル）ピぺラジン 0.22gおよび 過塩素酸リチウム 0.1 lgを加え、 60°Cで 1時間、 90°Cで 1時間攪拌した。反応混合物を 室温まで冷却し、水 10mLおよび酢酸ェチル 10mLをカ卩えた。有機層を分取し、水層を 酢酸ェチル lOmLで 2回抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウ ム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。 得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム]で精製し7-Methoxy-1- (oxylan-2-yl) isoquinoline 0.22 g N, N dimethylformamide in 3 mL solution at room temperature, 1- (tert-butoxycarbol) piperazine 0.22 g and lithium perchlorate 0.1 lg And stirred at 60 ° C for 1 hour and at 90 ° C for 1 hour. The reaction mixture was cooled to room temperature, and 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted twice with lOmL of ethyl acetate. Combine the organic layer and the extract. The solution was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form].
、褐色油状物の tert ブチル =4一（2 ヒドロキシ 2—（7—メトキシイソキノリン 1 ィル）ェチル）ピぺラジンカルボキシラート 0.33gを得た。 As a result, 0.33 g of tert butyl 4- (2-hydroxy 2- (7-methoxyisoquinoline 1 yl) ethyl) piperazinecarboxylate as a brown oily substance was obtained.
1H-NMR(CDC1 ) δ値： 1.47(9H,s),2.55- 2.70(4H,m),2.74- 2.88(2H,m),3.44- 3.60(4Η,  1H-NMR (CDC1) δ value: 1.47 (9H, s), 2.55- 2.70 (4H, m), 2.74-2.88 (2H, m), 3.44- 3.60 (4Η,
3  Three
m),3.96(3H,s),5.12(lH,s),5.53(lH,dd,J=8.4,2.8Hz),7.37(lH,dd,J=9.2,2.4Hz), 7.41(1 H,d,J=2.4Hz),7.54(lH,d,J=5.6Hz),7.77(lH,d,J=9.2Hz),8.36(lH,d,J=5.6Hz)  m), 3.96 (3H, s), 5.12 (lH, s), 5.53 (lH, dd, J = 8.4, 2.8Hz), 7.37 (lH, dd, J = 9.2, 2.4Hz), 7.41 (1 H, d, J = 2.4Hz), 7.54 (lH, d, J = 5.6Hz), 7.77 (lH, d, J = 9.2Hz), 8.36 (lH, d, J = 5.6Hz)
[0163] 参考例 26
Figure imgf000081_0001
[0163] Reference Example 26
Figure imgf000081_0001
tert—ブチル =4— (2 ヒドロキシ一 2— (7—メトキシイソキノリン一 1—ィル）ェチ ル）ピぺラジンカルボキシラート 0.33gの塩化メチレン 6mL溶液に、氷冷下、トリフルォ 口酢酸 2mLを加え、室温で 1時間攪拌した後、減圧下で溶媒を留去した。得られた残 留物にクロ口ホルム 20mLおよび水 10mLをカ卩え、 20%水酸化ナトリウム水溶液をで pH 12.5に調整した。有機層を分取し、水層をクロ口ホルム 10mLで 2回抽出した。有機層 および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、炭酸カリウムで乾燥さ せ、減圧下で溶媒を留去し、褐色油状物の 1— (7—メトキシイソキノリン— 1—ィル） 2 （ピペラジン 1 ィル）エタノール 0.21gを得た。  tert-Butyl = 4— (2 Hydroxy-1- (7-methoxyisoquinoline-1-yl) ethyl) Piperazinecarboxylate 0.33 g of methylene chloride in 6 mL In addition, after stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The obtained residue was charged with 20 mL of black mouth form and 10 mL of water, and adjusted to pH 12.5 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of black mouth form. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over potassium carbonate, evaporated under reduced pressure to give a brown oily 1- (7-methoxyisoquinoline-1-yl) 2 0.21 g of (piperazine 1 yl) ethanol was obtained.
'H-NMRCCDCl ) δ値： 2.66- 2.87(6H,m),2.94- 3.03(4H,m),3.97(3H,s),5.54(lH,dd,J=8  'H-NMRCCDCl) δ value: 2.66- 2.87 (6H, m), 2.94-3.03 (4H, m), 3.97 (3H, s), 5.54 (lH, dd, J = 8
3  Three
.6,3.0Hz),7.37(lH,dd,J=8.9,2.5Hz),7.48(lH,d,J=2.5Hz),7.54(lH,d,J=5.6Hz),7.77(lH ,d,J=8.9Hz),8.36(lH,d,J=5.6Hz)  .6,3.0Hz), 7.37 (lH, dd, J = 8.9,2.5Hz), 7.48 (lH, d, J = 2.5Hz), 7.54 (lH, d, J = 5.6Hz), 7.77 (lH, d , J = 8.9Hz), 8.36 (lH, d, J = 5.6Hz)
[0164] 参考例 27
Figure imgf000081_0002
[0164] Reference Example 27
Figure imgf000081_0002
ェチル = 1, 2 ジヒドロー 2 ォキソキノリンー3 カルボキシラート l.Ogに、ォキシ 塩化リン 5.0mLを加え、加熱還流下、 1時間攪拌した。反応混合物を室温まで冷却し 、減圧下で溶媒を留去した。得られた残留物に水 20mLおよび酢酸ェチル 20mLを加 えた。有機層を分取し、水層を酢酸ェチル 10mLで 2回抽出した。有機層および抽出 液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ 、減圧下で溶媒を留去した。得られた残留物にへキサンおよびジェチルエーテルを 加え、不溶物をろ取し、褐色固体のェチル = 2 クロ口キノリン 3 カルボキシラー ト 0.86gを得た。 Ethyl = 1, 2 Dihydro-2-oxoquinoline-3 Carboxylate l.Og was added with 5.0 mL of phosphorus oxychloride and stirred for 1 hour while heating under reflux. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Add 20 mL of water and 20 mL of ethyl acetate to the residue. Yeah. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane and jetyl ether were added to the obtained residue, and the insoluble matter was collected by filtration to obtain 0.86 g of brown solid ethyl = 2 black mouth quinoline 3 carboxylate.
1H-NMR(CDC1 ) δ値： 1.47(3H,t,J=7.2Hz),4.49(2H,q,J=7.2Hz),7.65- 7.69(lH,m),7.8  1H-NMR (CDC1) δ value: 1.47 (3H, t, J = 7.2Hz), 4.49 (2H, q, J = 7.2Hz), 7.65-7.69 (lH, m), 7.8
3  Three
5-7.91(lH,m),7.93-7.95(lH,m),8.12-8.14(lH,m),8.75(lH,s)  5-7.91 (lH, m), 7.93-7.95 (lH, m), 8.12-8.14 (lH, m), 8.75 (lH, s)
[0165] 参考例 28
Figure imgf000082_0001
[0165] Reference Example 28
Figure imgf000082_0001
ェチル = 2 クロ口キノリンー3 カルボキシラート 0.80gの濃硫酸 4mL溶液に、 5°C で発煙硝酸 0.2mLを加え、室温で 3時間攪拌した。反応混合物を氷水に注ぎ、酢酸 ェチル 20mLをカ卩えた。有機層を分取し、水層を酢酸ェチル 10mLで抽出した。有機 層および抽出液を合わせ、水、飽和炭酸水素ナトリウム水溶液および飽和塩ィ匕ナトリ ゥム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去 した。得られた残留物にジェチルエーテルをカ卩え、不溶物をろ取し、褐色固体のェ チル = 2 クロロー 8 二トロキノリンー3 カルボキシラート 0.49gを得た。  Ethyl = 2 Black-mouthed quinoline-3 carboxylate To a solution of 0.80 g of concentrated sulfuric acid in 4 mL of concentrated sulfuric acid was added 0.2 mL of fuming nitric acid at 5 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and 20 mL of ethyl acetate was collected. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Jetyl ether was added to the resulting residue, and the insoluble matter was collected by filtration to obtain 0.49 g of brown solid ethyl = 2 chloro-8 ditroquinoline-3 carboxylate.
1H-NMR(CDC1 ) δ値： 1.47(3H,t,J=7.2Hz),4.50(2H,q,J=7.2Hz),7.69- 7.74(lH,m),8.1  1H-NMR (CDC1) δ value: 1.47 (3H, t, J = 7.2Hz), 4.50 (2H, q, J = 7.2Hz), 7.69-7.74 (lH, m), 8.1
3  Three
3(lH,dd,J=8.4,1.2Hz),8.19(lH,dd,J=7.4,1.2Hz),8.72(lH,s)  3 (lH, dd, J = 8.4,1.2Hz), 8.19 (lH, dd, J = 7.4,1.2Hz), 8.72 (lH, s)
[0166] 参考例 29
Figure imgf000082_0002
[0166] Reference Example 29
Figure imgf000082_0002
ェチル = 2 クロロー 8 二トロキノリンー3 カルボキシラート 0.49gのメタノール 5m L懸濁液に、 28%ナトリウムメトキシド /メタノール 0.40gをカ卩え、加熱還流下、 1時間攪 拌した。反応混合物に 6mol/L塩酸 0.5mL、酢酸ェチル 20mL、水 20mLおよび飽和炭 酸水素ナトリウム水溶液 5mLを加えた。有機層を分取し、水層を酢酸ェチル 10mLで 抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水 硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。残留物にジェチルエーテ ルをカ卩え、不溶物をろ取した。得られた固体をシリカゲルカラムクロマトグラフィー [溶 離液;へキサン:酢酸ェチル =3： 1 ]で精製し、褐色固体のメチル = 2—メトキシ 8— ニトロキノリンー3 カルボキシラート 0.23gを得た。 Ethyl = 2 Chloro-8 Nitroquinoline-3 Carboxylate 0.49 g of methanol in a 5 mL suspension of methanol was charged with 0.40 g of 28% sodium methoxide / methanol and stirred for 1 hour under heating to reflux. To the reaction mixture were added 0.5 mL of 6 mol / L hydrochloric acid, 20 mL of ethyl acetate, 20 mL of water, and 5 mL of a saturated aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. Combine the organic layer and the extract, wash with saturated aqueous sodium chloride, It was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Jetyl ether was added to the residue, and insolubles were collected by filtration. The obtained solid was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 3: 1] to obtain 0.23 g of methyl 2-methoxy 8-nitroquinoline-3 carboxylate as a brown solid.
1H-NMR(CDC1 ) δ値： 3.98(3H,s),4.16(3H,s),7.49(lH,t,J=8.0Hz),8.00(lH,dd,J=8.0,l  1H-NMR (CDC1) δ value: 3.98 (3H, s), 4.16 (3H, s), 7.49 (lH, t, J = 8.0 Hz), 8.00 (lH, dd, J = 8.0, l
3  Three
.4Hz),8.09(lH,dd,J=8.0,1.4Hz),8.67(lH,s)  .4Hz), 8.09 (lH, dd, J = 8.0,1.4Hz), 8.67 (lH, s)
[0167] 参考例 30
Figure imgf000083_0001
[0167] Reference Example 30
Figure imgf000083_0001
メチル = 2—メトキシ 8 -トロキノリン 3 カルボキシラート 0.22gの酢酸 4mL懸 濁液に、室温で 10%パラジウム—炭素 50mgをカ卩え、水素雰囲気下、 1時間攪拌した 。不溶物をろ去し、減圧下で溶媒を留去した。酢酸ェチル、水および飽和炭酸水素 ナトリウム水溶液を加え、 pH8.0に調整した。有機層を分取し、水層を酢酸ェチルで 抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水 硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲ ルカラムクロマトグラフィー [溶離液；へキサン:酢酸ェチル = 3 : 1]で精製し、黄色固 体のメチル = 8 アミノー 2—メトキシキノリン 3 カルボキシラート 0.18gを得た。 1H-NMR(CDC1 ) δ fg: 3.96(3H,s),4.15(3H,s),4.74(2H,s),6.99(lH,dd,J=7.3,1.5Hz),7.  Methyl = 2-methoxy 8 -troquinoline 3 carboxylate 0.22 g of acetic acid (4 mL) was suspended in 10 mL of palladium-carbon (50 mg) at room temperature and stirred for 1 hour in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to 8.0. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1] to obtain 0.18 g of yellow solid methyl = 8 amino-2-methoxyquinoline 3 carboxylate. 1H-NMR (CDC1) δ fg: 3.96 (3H, s), 4.15 (3H, s), 4.74 (2H, s), 6.99 (lH, dd, J = 7.3, 1.5 Hz), 7.
3  Three
17(lH,dd,J=8.0,1.5Hz),7.21-7.25(lH,m),8.58(lH,s)  17 (lH, dd, J = 8.0,1.5Hz), 7.21-7.25 (lH, m), 8.58 (lH, s)
[0168] 参考例 31
Figure imgf000083_0002
[0168] Reference Example 31
Figure imgf000083_0002
1, 4一べンゾジォキサンー6 カルバルデヒド 0.20gのジクロロェタン 5mL溶液に、 室温で 4 ( (tert ブトキシカルボ-ル）ァミノ）ピぺリジン 0.27gおよび酢酸 77 μ Lを 加え、同温度で 20分間攪拌した。ついで、同温度でトリァセトキシ水素化ホウ素ナトリ ゥム 0.39gを加え、 2時間 10分間攪拌した。さらに、 4— ( (tert ブトキシカルボニル） ァミノ)ピぺリジン 49mgをカ卩え、 55分間攪拌した後、トリァセトキシ水素化ホウ素ナトリウ ム 0.13gを加え、 50分間攪拌した。反応混合物に水 10mLおよびクロ口ホルム 10mLを "¾^ij¾s8 / -ェ — {^ ^J^{^—^c ^^ i-^%))- z^ 、^继 ^i^oiベ έ ΰ、 ;½4 )§ο·ΐベ ^ ； ^べ Ν
Figure imgf000084_0001
1,4 Monobenzodioxane-6 Carbaldehyde 0.20 g of dichloroethane in 5 mL solution was added 0.27 g of 4 ((tert-butoxycarbol) amino) piperidine and 77 μL of acetic acid at room temperature and stirred at the same temperature for 20 minutes . Then, 0.39 g of sodium triacetoxyborohydride was added at the same temperature and stirred for 2 hours and 10 minutes. Further, 49 mg of 4-((tert-butoxycarbonyl) amino) piperidine was added and stirred for 55 minutes, and then 0.13 g of sodium triacetoxyborohydride was added and stirred for 50 minutes. Add 10 mL of water and 10 mL of black mouth form to the reaction mixture. "¾ ^ ij¾ s 8 / -e — (^ ^ J ^ {^ — ^ c ^^ i-^%))-z ^, ^ 继 ^ i ^ oi έ ΰ,; ½4) §ο · ΐ ^; ^
Figure imgf000084_0001
SSp}% [ΟΖΐΟ] ( Ώοα Ήΐ)56 ΐ-3 ΐ'(ωΉε)03·8-32·8'(8Ήΐ)9Γ '(ΖΗ ·8=ΓΡΉΐ SSp}% [ΟΖΐΟ] (Ώοα Ήΐ) 56 ΐ-3 ΐ '(ωΉε) 03 · 8-32 · 8' ( 8 Ήΐ) 9Γ '(ΖΗ · 8 = ΓΡΉΐ
)ιο· '(ζΗΓ8=ί"'ρ'Ηΐ)ΐ6·9'(δ'Η 9S' C"'Hs)sr— so' (ω'Η ο ·ε— οε·ε'(ω'Ηΐ)οε·ε ) ιο · '( ζ ΗΓ8 = ί "'ρ'Ηΐ) ΐ6 · 9 '( δ ' Η 9S 'C"' Hs) sr— so '(ω'Η ο · ε— οε · ε'(ω'Ηΐ ) οε · ε
— 3ΐ·ε'(ω'Η ΟΟ·ε— S8 ' (ra'HS)SrS— 00 ' (m'HS)OO — S8'I :軍 9 ( P-OS a)H N-HT — 3ΐ · ε '(ω'Η ΟΟ · ε— S8'(ra'HS) SrS— 00 '(m'HS) OO — S8'I: Military 9 (P-OS a) H NH T
。 ¾¾ S'0^邈 ^O)ベ ^ →-ベ fi (^ ( 一 9 - ^^ \ ' I m - ^ m辛爵¾瀚缀 止 ϊί教 ^n ^^m u m辛爵¾瀚 缀、 止 s教 ^w ^^ ^m^ -M^ ·η辛爵 瀚缀、 止 s教 a  . ¾¾ S'0 ^ 邈 ^ O) Be ^ → -Be fi (^ (1 9-^^ \ 'I m-^ m s teaching ^ w ^^ ^ m ^ -M ^
。 ·η辛爵 瀚缀、 止 ϊί教、つ 翻 ¾累 ^w ^m ^^^ . · Η Tsura爵瀚缀, stop ϊί Christian, one transliteration ¾ cumulative ^ w ^ m ^^^
瑰
Figure imgf000084_0002
瑰
Figure imgf000084_0002
Ζ£\ ^ [6910]  Ζ £ \ ^ [6910]
)00" -06"9'(zH8" =rP'HT)e8"9'(PBO-i 'HT)09^-0e^'(s'H^)92^'(ra'HS)08"S-e^-S'(ra ) 00 "-06" 9 '( z H8 "= rP'HT) e8"9' (P BO -i 'HT) 09 ^ -0e ^'(s'H ^) 92 ^ '(ra'HS) 08 "Se ^ -S '(ra
'HS)0S'S- S6 ' C"'H 0S - ' (ω'Η )0ΐ - 0Ζ·ΐ'(δ'Η6)ε ·ΐ :軍 9 ( !DaD)H N-HT 'HS) 0S'S- S6' C "'H 0S-'(ω'Η) 0ΐ-0Ζ · ΐ '( δ ' Η6) εΐΐ: Army 9 (! DaD) H NH T
。 會| ^ '(H—ム  .會 | ^ '(H—M
'ζ))
Figure imgf000084_0003
'ζ))
Figure imgf000084_0003
Figure imgf000084_0004
。 ·η辛恩 瀚缀、 止
Figure imgf000084_0005
、つ 斜萆
Figure imgf000084_0004
. · Η
Figure imgf000084_0005
The
98S6T0/S00Zdf/X3d 38 ZSS9^0/900Z OAV 、 20分間攪拌した。ついで、トリェチルァミン 1.7mLを加え、室温で 14時間攪拌し、減 圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [シリカ ゲル；富士シリシァ化学株式会社、 NH— DM1020、溶離液；クロ口ホルム：メタノー ル =40： 1]およびシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノー ル = 3 : 1]で精製し、黄色油状物の tert ブチル = 3 （メチルァミノ）プロピルカル バマート 0.36gを得た。 98S6T0 / S00Zdf / X3d 38 ZSS9 ^ 0 / 900Z OAV And stirred for 20 minutes. Then, 1.7 mL of triethylamine was added and stirred at room temperature for 14 hours, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [silica gel; Fuji Silicon Chemical Co., Ltd., NH-DM1020, eluent; black mouth form: methanol = 40: 1] and silica gel column chromatography [eluent: black mouth form] : Methanol = 3: 1] to obtain 0.36 g of tert-butyl = 3 (methylamino) propylcarbamate as a yellow oily substance.
^-NMRCCDCl ) δ値： 1.44(9H,s),1.45- 1.55(lH,broad),1.65(2H,quintet,J=6.6Hz),2.  ^ -NMRCCDCl) δ value: 1.44 (9H, s), 1.45-1.55 (lH, broad), 1.65 (2H, quintet, J = 6.6Hz), 2.
3  Three
42(3H,s),2.63(2H,t,J=6.6Hz),3.10-3.25(2H,m),4.90-5.10(lH,broad)  42 (3H, s), 2.63 (2H, t, J = 6.6Hz), 3.10-3.25 (2H, m), 4.90-5.10 (lH, broad)
[0171] 参考例 34
Figure imgf000085_0001
[0171] Reference Example 34
Figure imgf000085_0001
tert ブチル = 3 （メチルァミノ）プロピル力ルバマート 0.14gの N, N ジメチルホ ルムアミド 2mL溶液に、 7—メトキシ一 1— (ォキシラン一 2—ィル)イソキノリン 0.10gの N, N ジメチルホルムアミド lmL溶液および過塩素酸リチウム 53mgを加え、 80°Cで 1 時間 50分間攪拌した。反応混合物を室温まで冷却し、水 5mLおよび酢酸ェチル 5mL を加え、 6.0mol/L塩酸をカ卩え、 pH4.0に調整した。有機層を分取し、水層に 20%水酸 化ナトリウム水溶液を加え、酢酸ェチルで抽出した。有機層および抽出液を合わせ、 飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶 媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液;クロロホ ルム：メタノール = 10 : 1]で精製し、黄色油状物の tert ブチル = 3—（（ 2 ヒドロキ シ 2—（7—メトキシイソキノリン 1 ィル）ェチル）（メチル）ァミノ）プロピル力ルバ マート 0.13gを得た。  tert butyl = 3 (methylamino) propyl strength rubamate 0.14 g of N, N dimethylformamide in 2 mL solution, 7-methoxy-1- (oxylan-2-yl) isoquinoline 0.10 g of N, N dimethylformamide in lmL and perchlorine 53 mg of lithium acid was added, and the mixture was stirred at 80 ° C for 1 hour and 50 minutes. The reaction mixture was cooled to room temperature, 5 mL of water and 5 mL of ethyl acetate were added, 6.0 mol / L hydrochloric acid was added, and the pH was adjusted to 4.0. The organic layer was separated, 20% aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 10: 1], and tert-butyl 3-(((2 hydroxy 2- (7-methoxyisoquinoline 1 0.13 g of le) ethyl) (methyl) amino) propyl strength rubamate was obtained.
1H-NMR(CDC1 ) δ値： 1.45(9H,s),1.65- 1.75(2H,m),2.50(3H,s),2.55- 2.75(2H,m),2.75  1H-NMR (CDC1) δ value: 1.45 (9H, s), 1.65- 1.75 (2H, m), 2.50 (3H, s), 2.55- 2.75 (2H, m), 2.75
3  Three
-2.90(2H,m),3.10-3.30(2H,m),3.97(3H,s),5.25-5.35(lH,broad),5.54(lH,dd,J=8.2,2.6 Hz),7.37(lH,dd,J=8.8,2.4Hz),7.42(lH,d,J=2.4Hz),7.55(lH,d,J=5.6Hz),7.77(lH,d,J=8 .8Hz),8.36(lH,d,J=5.6Hz)  -2.90 (2H, m), 3.10-3.30 (2H, m), 3.97 (3H, s), 5.25-5.35 (lH, broad), 5.54 (lH, dd, J = 8.2,2.6 Hz), 7.37 (lH , dd, J = 8.8,2.4Hz), 7.42 (lH, d, J = 2.4Hz), 7.55 (lH, d, J = 5.6Hz), 7.77 (lH, d, J = 8.8Hz), 8.36 ( lH, d, J = 5.6Hz)
[0172] 参考例 35
Figure imgf000086_0001
[0172] Reference Example 35
Figure imgf000086_0001
tert—ブチル = 3— ( (2 ヒドロキシ一 2— (7—メトキシイソキノリン一 1—ィル）ェチ ル）（メチル）ァミノ）プロピル力ルバマート 0.13gの塩化メチレン 2mL溶液に、氷冷下、ト リフルォロ酢酸 lmLを加え、室温で 30分間攪拌した。減圧下で溶媒を留去し、得られ た残留物にクロ口ホルム 10mL、水 10mLおよび 20%水酸化ナトリウム水溶液を加え、 p H11.5に調整した。有機層を分取し、水層をクロ口ホルムで抽出した。有機層および 抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥 させ、減圧下で溶媒を留去し、褐色油状物の 2—（（3 ァミノプロピル）（メチル)ァミノ )— 1— (7—メトキシイソキノリン一 1 ィル）エタノール 0.10gを得た。  tert-Butyl = 3— ((2 Hydroxy-2- (7-methoxyisoquinoline-1-yl) ethyl) (methyl) amino) propyl-powered rubamate To a solution of 0.13 g of methylene chloride in 2 mL of 1 mL of rifluoroacetic acid was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and 10 mL of chloroform, 10 mL of water and 20% aqueous sodium hydroxide solution were added to the resulting residue to adjust the pH to 11.5. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a brown oily 2-(((3 aminopropyl) (methyl) amino))-1 — 0.10 g of (7-methoxyisoquinoline monoyl) ethanol was obtained.
'H-NMRCCDCl ) δ値： 1.65- 1.72(2H,m),2.46(3H,s),2.50- 2.90(6H,m),3.96(3H,s),5.50 'H-NMRCCDCl) δ value: 1.65-1.72 (2H, m), 2.46 (3H, s), 2.50-2.90 (6H, m), 3.96 (3H, s), 5.50
3  Three
(lH,dd,J=7.8,3.7Hz),7.34-7.37(lH,m),7.48-7.49(lH,m),7.53(lH,d,J=5.6Hz),7.76(lH ,d,J=9.0Hz),8.35(lH,d,J=5.6Hz)  (lH, dd, J = 7.8,3.7Hz), 7.34-7.37 (lH, m), 7.48-7.49 (lH, m), 7.53 (lH, d, J = 5.6Hz), 7.76 (lH, d, J = 9.0Hz), 8.35 (lH, d, J = 5.6Hz)
参考例 36
Figure imgf000086_0002
Reference Example 36
Figure imgf000086_0002
2- (2 ブロモェチルチオ）チォフェン 0.10gの N, N ジメチルホルムアミド 3mL溶 液に、 4一（（tert ブトキシカルボ-ル）ァミノ）ピぺリジン 99mgおよび炭酸カリウム 68 mgをカ卩え、 60°Cで 3時間 30分間攪拌した。反応混合物を室温まで冷却し、水 10mLお よび酢酸ェチル 10mLをカ卩えた。有機層を分取し、水層を酢酸ェチルで抽出した。有 機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネ シゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロ マトグラフィー [溶離液;クロ口ホルム:メタノール = 50 : 1]で精製し、白色固体の tert ブチル = 1一（2 （チォフェン 2—ィルチオ）ェチル）ピぺリジンー4ーィルカル バマート 0.12gを得た。  2- (2 Bromoethylthio) thiophene In a solution of 0.10 g of N, N dimethylformamide in 3 mL, add 99 mg of (1- (butoxycarbonyl) amino) piperidine and 68 mg of potassium carbonate at 60 ° C. Stir for 3 hours 30 minutes. The reaction mixture was cooled to room temperature, and 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; black mouth form: methanol = 50: 1], and tert butyl = 1 (2 (thiophene-2-ylthio) ethyl) piperidine as a white solid. 0.12 g of 4-ilcal bamat was obtained.
'H-NMRCCDCl ) δ値： 1.35- 1.50(2H,m),1.44(9H,s),1.85- 1.95(2H,m),2.05- 2.15(2Η,  'H-NMRCCDCl) δ value: 1.35- 1.50 (2H, m), 1.44 (9H, s), 1.85- 1.95 (2H, m), 2.05- 2.15 (2 (,
3  Three
m),2.58-2.62(2H,m), 2.75— 2.85(2H,m),2.88— 2.92(2H,m),3.35— 3.50(lH,m),4.30— 4.50 (lH,m),6.96(lH,dd,J=5.3,3.5Hz),7.11(lH,dd,J=3.5,1.2Hz),7.33(lH,dd,J=5.3,1.2Hz) [0174] 参考例 37
Figure imgf000087_0001
m), 2.58-2.62 (2H, m), 2.75― 2.85 (2H, m), 2.88― 2.92 (2H, m), 3.35― 3.50 (lH, m), 4.30― 4.50 (lH, m), 6.96 ( lH, dd, J = 5.3,3.5Hz), 7.11 (lH, dd, J = 3.5,1.2Hz), 7.33 (lH, dd, J = 5.3,1.2Hz) [0174] Reference Example 37
Figure imgf000087_0001
tert ブチル = 1一（2 （チォフェン一 2—ィルチオ）ェチル）ピぺリジン一 4ーィル 力ルバマート llOmgの塩化メチレン 2mL溶液に、氷冷下、トリフルォロ酢酸 lmLを加え 、室温で 40分間攪拌し、減圧下で溶媒を留去した。得られた残留物にクロ口ホルム 10 mL、水 10mLおよび 20%水酸化ナトリウム水溶液を加え、 pHll.Oに調整した。有機層 を分取し、水層をクロ口ホルムで抽出した。有機層および抽出液を合わせ、飽和塩化 ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去 し、無色油状物の 1一（2 （チォフェン 2—ィルチオ）ェチル）ピぺリジンー4 アミ ン 70mgを得た。  tert Butyl = 1 (2 (thiophene-2-ylthio) ethyl) piperidine 1- 4il Forced rubamate llOmg in methylene chloride (2 mL) was added with trifluoroacetic acid (1 mL) under ice-cooling, stirred at room temperature for 40 minutes, and reduced in pressure. The solvent was distilled off under. To the obtained residue, 10 mL of chloroform, 10 mL of water and 20% aqueous sodium hydroxide solution were added to adjust to pHll.O. The organic layer was separated and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oily 1- (2 (thiophene-2-ylthio) ethyl) pipette. 70 mg of lysine-4 amine was obtained.
^-NMRCCDCl ) δ値： 1.20- 1.55(2H,m),1.46(2H,s),1.75- 1.85(2H,m),2.05(2H,td,J=l  ^ -NMRCCDCl) δ value: 1.20-1.55 (2H, m), 1.46 (2H, s), 1.75-1.85 (2H, m), 2.05 (2H, td, J = l
3  Three
1.5,2.1Ηζ),2.55-2.70(3H,m),2.75-2.95(4H,m),6.96(lH,dd,J=5.4,3.5Hz),7.12(lH,dd, J=3.5,1.2Hz),7.33(lH,dd,J=5.4,1.2Hz)  1.5,2.1Ηζ), 2.55-2.70 (3H, m), 2.75-2.95 (4H, m), 6.96 (lH, dd, J = 5.4,3.5Hz), 7.12 (lH, dd, J = 3.5,1.2Hz) ), 7.33 (lH, dd, J = 5.4,1.2Hz)
[0175] 参考例 38 0。W N¾ *~
Figure imgf000087_0002
[0175] Reference Example 38 0. W N ¾ * ~
Figure imgf000087_0002
1— (tert ブトキシカルボ-ル）ピぺリジン— 4—カルボン酸 0.15gの N, N ジメチ ルホルムアミド 2mL溶液に、氷冷下、 N, N，—カルボ-ルジイミダゾール O.llgをカロえ 、室温で 80分間攪拌した。ついで、 ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 —ィル)メチル）ァミン 0.10gの N, N ジメチルホルムアミド lmL溶液をカ卩え、室温で 1 時間、 50°Cで 1時間攪拌した。反応混合物を室温まで冷却し、水 10mLおよび酢酸ェ チル 10mLをカ卩え、 6.0mol/L塩酸をカ卩え、 pH3.5に調整した。有機層を分取し、水層を 酢酸ェチルで抽出した。有機層および抽出液を合わせ、水で洗浄し、 20%水酸化ナ トリウム水溶液を加え、 ρΗΙΟ.Οに調整した。有機層を分取し、飽和塩ィ匕ナトリウム水溶 液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた 残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 50： 1 ]で精製し、淡黄色泡状物の tert—ブチル =4— ( (2, 3 ジヒドロべンゾ [b] [1, 4] Ί 邈^ 廳
Figure imgf000088_0001
、つ止縱 Ί 1
Figure imgf000088_0002
1— (tert-butoxycarbol) piperidine—4-carboxylic acid 0.15 g of N, N dimethylformamide in 2 mL solution under ice-cooling, N, N, -carbodidiimidazole O.llg Stir at room temperature for 80 minutes. Next, ((2, 3 dihydrobenz [b] [l, 4] dioxin 6 —yl) methyl) amine 0.10 g of N, N dimethylformamide in 1 mL was added and stirred at room temperature for 1 hour, 50 ° Stir at C for 1 hour. The reaction mixture was cooled to room temperature, and 10 mL of water and 10 mL of ethyl acetate were added, 6.0 mol / L hydrochloric acid was added, and the pH was adjusted to 3.5. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with water, and 20% aqueous sodium hydroxide solution was added to adjust to ρΗΙΟ.Ο. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 50: 1], and tert-butyl = 4— ((2, 3 dihydrobenzo [ b] [1, 4] Ί 邈 ^ 廳
Figure imgf000088_0001
つ 縱1
Figure imgf000088_0002
0¾^ [ΖΖΐΟ] 0¾ ^ [ΖΖΐΟ]
(zHS'8=f'P'HI)I8'9'(zH0 =ί"'Ρ'Ηΐ)9Γ9'(ζΗ0 ' S'8=f'PP'HI)Sr9'(s'HI)Z8'S'(z (zHS'8 = f'P'HI) I8'9 '( z H0 = ί "'Ρ'Ηΐ) 9Γ9 '( ζ Η0'S'8 = f'PP'HI) Sr9 '( s ' HI) Z8'S '(z
H9"e=rP'H2)TS^'(s'H^^'(ui'H2)02-S-0rS'(zH9"2'S"2T=rpVH2)S9"2'(s'HT)0^"2 H9 "e = rP'H2) TS ^ '(s'H ^^'(ui'H2) 02-S-0rS '(z H9"2'S"2T = rpVH2) S9"2'(s' HT) 0 ^ "2
'(zH8'S l
Figure imgf000088_0003
ODaD)H N-H.
Figure imgf000088_0004
'(zH8'S l
Figure imgf000088_0003
ODaD) H NH.
Figure imgf000088_0004
Figure imgf000088_0005
、つ辛爵 瀚缀、 止 ϊί教 マ /^
Figure imgf000088_0006
Figure imgf000088_0005
, Spicy 爵 、 ϊ ϊί 教 Ma / ^
Figure imgf000088_0006
つ辛爵 瀚缀、 止 教
Figure imgf000088_0007
、止^^
Figure imgf000088_0008
( / ¾ Spicy spear, stop
Figure imgf000088_0007
, Stop ^^
Figure imgf000088_0008
(/ ¾
Figure imgf000088_0009
Figure imgf000088_0009
6Sp}% [9ΖΪ0] 6Sp}% [9ΖΪ0]
(ZHS'8=f'P'HI)S8'9'(zHZ'I=f'P'HI)ZZ'9'(zHZ'I'S'8=rPP'HI)Sr9'(PBOJq
Figure imgf000088_0010
(ZHS'8 = f'P'HI) S8'9 '( z HZ'I = f'P'HI) ZZ'9' ( z HZ'I'S'8 = rPP'HI) Sr9 '(P BO Jq
Figure imgf000088_0010
'HI)0S - OS ' (ω'Η 06·ΐ- 08·ΐ'(ω'Η 3Ζ·ΐ- SS'I'(s'H6)S 'I :軍 9 ( !DaD)H N-HT 'HI) 0S-OS'(ω'Η 06 · ΐ- 08 · ΐ '(ω'Η 3Ζ · ΐ- SS'I'(s'H6) S 'I: Army 9 (! DaD) H NH T
¾§ ΐ 4— I
Figure imgf000088_0011
¾§ ΐ 4— I
Figure imgf000088_0011
98S6T0/S00Zdf/X3d 98 口ホルム 10mLで抽出した。有機層および抽出液を合わせ、水 10mLおよび飽和塩ィ匕 ナトリウム水溶液 10mLで順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で 溶媒を留去した。得られた残留物にジェチルエーテルおよびへキサンをカ卩え、析出 物をろ取し、淡褐色固体の 2 クロロー 7 フルォロ 8 -トロキノリン 66mgを得た。 1H-NMR(CDC1 ) δ fg: 7.48-7.53(2H,m),7.99(lH,dd,J=9.3,5.4Hz),8.18(lH,d,J=8.5Hz 98S6T0 / S00Zdf / X3d 98 Extracted with 10 mL oral form. The organic layer and the extract were combined, washed successively with 10 mL of water and 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Jetyl ether and hexane were added to the obtained residue, and the precipitate was collected by filtration to obtain 66 mg of 2-chloro-7-fluoro 8 -troquinoline as a light brown solid. 1H-NMR (CDC1) δ fg: 7.48-7.53 (2H, m), 7.99 (lH, dd, J = 9.3,5.4Hz), 8.18 (lH, d, J = 8.5Hz)
3  Three
)  )
[0178] 参考例 41
Figure imgf000089_0001
[0178] Reference Example 41
Figure imgf000089_0001
28%ナトリウムメトキシド /メタノール 72mgにメタノール 3mLをカ卩えた後、 2 クロ口一 7 フルオロー 8 -トロキノリン 56mgをカ卩え、 1時間加熱還流した。反応混合物に酢酸 ェチル 20mLおよび水 20mLをカ卩え、有機層を分取し、水層を酢酸ェチル 10mLで抽出 した。有機層および抽出液を合わせ、水 10mLおよび飽和塩ィ匕ナトリウム水溶液 10mL で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られ た残留物をシリカゲルカラムクロマトグラフィー [溶離液;へキサン:酢酸ェチル = 1： 1 ]で精製し、淡褐色固体の 2, 7 ジメトキシ— 8 -トロキノリン 25mgを得た。  After adding 3 mL of methanol to 28 mg of 28% sodium methoxide / methanol, 56 mg of 2 7-fluoro-8-troquinoline was added and heated to reflux for 1 hour. To the reaction mixture, 20 mL of ethyl acetate and 20 mL of water were added, the organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed sequentially with 10 mL of water and 10 mL of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 1: 1] to obtain 25 mg of 2,7 dimethoxy-8-troquinoline as a light brown solid.
'H-NMRCCDCl ) δ fg:4.01(3H,s),4.03(3H,s),6.84(lH,d,J=9.0Hz),7.17(lH,d,J=9.0Hz  'H-NMRCCDCl) δ fg: 4.01 (3H, s), 4.03 (3H, s), 6.84 (lH, d, J = 9.0Hz), 7.17 (lH, d, J = 9.0Hz
3  Three
),7.78(lH,d,J=9.0Hz),7.93(lH,d,J=9.0Hz)  ), 7.78 (lH, d, J = 9.0Hz), 7.93 (lH, d, J = 9.0Hz)
[0179] 参考例 42
Figure imgf000089_0002
[0179] Reference Example 42
Figure imgf000089_0002
2, 7 ジメトキシー 8 -トロキノリン 25mgの酢酸 3mL懸濁液に、室温で 10%パラジ ゥム—炭素 5mgを加え、水素雰囲気下で 1時間攪拌した。不溶物をろ去し、減圧下で 溶媒を留去した。得られた残留物に酢酸ェチル 30mLおよび飽和炭酸水素ナトリウム 水溶液 20mLをカ卩えた。有機層を分取し、水層を酢酸ェチル 10mLで抽出した。有機 層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水 硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物の 2, 7 ジメトキ シキノリン一 8 ァミン 22mgを得た。 H-NMR(CDC1 ) δ値： 3.97(3H,s),4.06(3H,s),4.67(2H,s),6.75(lH,d,J=9.0Hz),7.06- 7. To a suspension of 25 mg of 2,7 dimethoxy-8-troquinoline in 3 mL of acetic acid was added 5 mg of 10% palladium-carbon at room temperature, and the mixture was stirred for 1 hour under a hydrogen atmosphere. Insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of ethyl acetate and 20 mL of saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to give a brown oily 2,7-dimethoxyquinoline-l-amamine 22 mg Got. H-NMR (CDC1) δ value: 3.97 (3H, s), 4.06 (3H, s), 4.67 (2H, s), 6.75 (lH, d, J = 9.0 Hz), 7.06- 7.
3  Three
ll(2H,m),7.87(lH,d,J=8.8Hz)  ll (2H, m), 7.87 (lH, d, J = 8.8Hz)
[0180] 参考例 43
Figure imgf000090_0001
[0180] Reference Example 43
Figure imgf000090_0001
(1) 4— (tert -ブトキシカルボ-ル）アミノシクロへキサン— 1 カルボン酸 0.15gの N , N ジメチルホルムアミド 2mL溶液に、氷冷下、 N, N，一カルボ-ルジイミダゾール O.llgを加え、室温で 1時間攪拌した後、 7—メトキシイソキノリン一 1—ァミン 0.10gをカロ え、 50°Cで 3時間攪拌した。反応混合物に酢酸ェチル 20mLおよび水 20mLを加えた 後、 6.0mol/L塩酸をカ卩え、 pH3.0に調整した。有機層を分取し、水層を酢酸ェチル 10 mLで抽出した。有機層および抽出液を合わせ、飽和炭酸水素ナトリウム水溶液およ び飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧 下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液； へキサン：酢酸ェチル = 1 : 1]で精製し、淡黄色泡状物の tert ブチル =4— ( (7— メトキシイソキノリン 1 ィル）力ルバモイル）シクロへキシルカルバマート 0.21gを得 た。  (1) 4- (tert-Butoxycarbol) aminocyclohexane-1 carboxylic acid 0.15 g of N, N dimethylformamide in 2 mL solution under ice-cooling, N, N, monocarbodiimidazole O.llg In addition, after stirring at room temperature for 1 hour, 0.10 g of 7-methoxyisoquinoline mono-amine was added and stirred at 50 ° C for 3 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and 6.0 mol / L hydrochloric acid was added to adjust the pH to 3.0. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1], and tert-butyl 4-((7-methoxyisoquinoline 1 yl) force of pale yellow foam. 0.21 g of rubamoyl) cyclohexyl carbamate was obtained.
(2)得られた tert ブチル =4— ( (7—メトキシイソキノリン 1 ィル）力ルバモイル） シクロへキシルカルバマート 0.20gの塩化メチレン lmL溶液に、室温でトリフルォロ酢 酸 lmLを加え、同温度で 1時間 30分間攪拌した後、減圧下で溶媒を留去した。得られ た残留物に水 10mLおよびクロ口ホルム 10mLを加え、 20%水酸化ナトリウム水溶液を 加え、 pH12.0に調整した。有機層を分取し、水層をクロ口ホルム 10mLで 2回抽出した (2) Obtained tertbutyl 4-((7-methoxyisoquinoline 1 yl) rubamoyl) Cyclohexylcarbamate 0.20 g of methylene chloride in lmL solution was added trifluoroacetic acid lmL at room temperature. After stirring for 1 hour and 30 minutes, the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of water and 10 mL of black mouth form were added, and a 20% aqueous sodium hydroxide solution was added to adjust the pH to 12.0. The organic layer was separated and the aqueous layer was extracted twice with 10 mL of black mouth form.
。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグ ネシゥムで乾燥させ、減圧下で溶媒を留去し、淡黄色の 4 アミノー N— (7—メトキシ イソキノリン 1 ィル）シクロへキサンカルボキサミド 0.16gを得た。 . The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to give pale yellow 4 amino-N- (7-methoxyisoquinoline 1 yl) cyclohexane. 0.16 g of hexanecarboxamide was obtained.
'H-NMRCCDCl ) δ値： 1.10— 2.30(8H,m),2.50— 3.10(2H,m),3.90(3H,s),6.95— 8.20(5Η,  'H-NMRCCDCl) δ value: 1.10— 2.30 (8H, m), 2.50— 3.10 (2H, m), 3.90 (3H, s), 6.95—8.20 (5Η,
3  Three
m)  m)
[0181] 参考例 44
Figure imgf000091_0001
[0181] Reference Example 44
Figure imgf000091_0001
5—ョード一 2—メトキシキノリン一 8—ァミン 4.0gの N, N -ジメチルホルムアミド 26m L溶液に、シアン化銅 (I) 2.4gおよびテトラキス（トリフエ-ルホスフィン)ノ《ラジウム 1.6g を加え、窒素気流下、 100〜110°Cで 4時間 20分間加熱した。反応混合物に水 50mL、 25%アンモニア水 20mLおよび酢酸ェチル 50mLをカ卩え、ろ過し、不溶物とろ液を分離 した。  To a solution of 4.0 g of N-, N-dimethylformamide, 2.4 g of copper cyanide and 1.6 g of tetrakis (triphenylphosphine) no << radium 1.6 g The mixture was heated at 100 to 110 ° C for 4 hours and 20 minutes under a nitrogen stream. To the reaction mixture, 50 mL of water, 20 mL of 25% aqueous ammonia and 50 mL of ethyl acetate were filtered and filtered to separate the insoluble material and the filtrate.
ろ液の有機層を分取し、水層を酢酸ェチル 20mLで 2回抽出した。有機層および抽 出液を合わせ、 25%アンモニア水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、 無水硫酸マグネシウムで乾燥させた。  The organic layer of the filtrate was separated, and the aqueous layer was extracted twice with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with 25% aqueous ammonia and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
不溶物に 25%アンモニア水 20mLおよび酢酸ェチル 50mLを加え、不溶物をろ去し た。有機層を分取し、水層を酢酸ェチル 20mLで 2回抽出した。有機層および抽出液 を合わせ、 25%アンモニア水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水 硫酸マグネシウムで乾燥させた。  To the insoluble material, 20 mL of 25% aqueous ammonia and 50 mL of ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer was separated, and the aqueous layer was extracted twice with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed sequentially with 25% aqueous ammonia and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
乾燥されたすベての溶液を合わせ、減圧下で溶媒を留去した。得られた残留物を シリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル =4： 1]で精製し、 へキサンを加え、析出物をろ取し、褐色固体の 8—ァミノ一 2—メトキシキノリン一 5— カルボ-トリル 1.6gを得た。  All the dried solutions were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 4: 1], hexane was added, the precipitate was collected by filtration, and 8-Bramino-2-methoxy as a brown solid. 1.6 g of quinoline 1-carbo-tolyl was obtained.
'H-NMRCCDCl ) δ fg:4.07(3H,s),5.29(2H,s),6.82(lH,d,J=8.0Hz),7.08(lH,d,J=8.9Hz  'H-NMRCCDCl) δ fg: 4.07 (3H, s), 5.29 (2H, s), 6.82 (lH, d, J = 8.0Hz), 7.08 (lH, d, J = 8.9Hz
3  Three
),7.58(lH,d,J=8.0Hz),8.27(lH,d,J=8.9Hz)  ), 7.58 (lH, d, J = 8.0Hz), 8.27 (lH, d, J = 8.9Hz)
参考例 45
Figure imgf000091_0002
Reference Example 45
Figure imgf000091_0002
8—ァミノ一 2—メトキシキノリン一 5—カルボ-トリル 0.10gの 75%エタノール水 0.50m L溶液に、水酸ィ匕ナトリウム 80mgをカ卩え、 3時間 10分間加熱還流した。エチレングリコ ール 0.50mLを加え、 8時間 40分間加熱還流した。反応混合物に水 20mLおよび酢酸 ェチル 20mLをカ卩えた。有機層を分取し、水層を酢酸ェチル 10mLで抽出した。有機 層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシゥ ムで乾燥させた。減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロ マトグラフィー [溶離液；クロ口ホルム：メタノール = 25 : 1]で精製し、ジェチルエーテ ルをカ卩え、析出物をろ取し、淡褐色固体の 8 ァミノ 2—メトキシキノリン— 5—カル ボキサミド 14mgを得た。 8-Amino-2-methoxyquinoline 5-Carbo-tolyl 80 mg of sodium hydroxide was added to a solution of 0.10 g of 75% ethanol in 0.50 mL and heated to reflux for 3 hours and 10 minutes. Ethylene glycol (0.50 mL) was added, and the mixture was heated to reflux for 8 hours and 40 minutes. 20 mL of water and acetic acid in the reaction mixture I got 20mL of ethyl. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 25: 1], the jetty ether was collected, the precipitate was collected by filtration, and the pale brown solid 8 amino 2 14 mg of methoxyquinoline-5-carboxamide was obtained.
'H-NMRCCDCl ) δ値： 4.06(3H,s),5.10(2H,s),6.81(lH,d,J=8.0Hz),7.00(lH,d,J=9.3Hz  'H-NMRCCDCl) δ value: 4.06 (3H, s), 5.10 (2H, s), 6.81 (lH, d, J = 8.0Hz), 7.00 (lH, d, J = 9.3Hz
3  Three
),7.51(lH,d,J=8.0Hz),8.95(lH,d,J=9.3Hz)  ), 7.51 (lH, d, J = 8.0Hz), 8.95 (lH, d, J = 9.3Hz)
[0183] 参考例 46
Figure imgf000092_0001
[0183] Reference Example 46
Figure imgf000092_0001
2 クロ口キノリン— 8—オール 65mgの N, N ジメチルホルムアミド 3mL溶液に、氷 冷下、 60%水素化ナトリウム 17mg加え、 10分間攪拌した後、（1— (tert—ブトキシカ ルポ-ル）ピぺリジンー4 ィル)メチル =メタンスルホナート O.llgをカ卩え、室温で 30 分間、 80°Cで 3時間攪拌した。 60%水素化ナトリウム 8.6mgをカ卩え、 80〜100°Cで 1時 間攪拌した。反応混合物に酢酸ェチル 20mLおよび水 10mLをカ卩え、 Imol/mL塩酸を 加えて PH4.0に調整した。有機層を分取し、水層を酢酸ヱチル 10mLで抽出した。有 機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無 水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカ ゲルカラムクロマトグラフィー [溶離液;へキサン:酢酸ェチル = 2 : 1]で精製し、黄色 油状物の tert ブチル =4— ( (2 クロ口キノリンー8 ィルォキシ)メチル）ピベリジ ン 1 カルボキシラート 82mgを得た。  2 Black mouth quinolin-8-ol To a solution of 65 mg N, N dimethylformamide in 3 mL, add 17 mg of 60% sodium hydride under ice-cooling, stir for 10 minutes, and then add (1- (tert-butoxypolyol) pipette. Lysine-4-yl) methyl methanesulfonate O.llg was added and stirred at room temperature for 30 minutes and at 80 ° C. for 3 hours. 8.6 mg of 60% sodium hydride was added and stirred at 80-100 ° C for 1 hour. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction mixture, and Imol / mL hydrochloric acid was added to adjust the pH to 4.0. The organic layer was separated and the aqueous layer was extracted with 10 mL of acetyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 2: 1], and yellow oily matter tert butyl = 4 — (((2 quinoline-8 yloxy) methyl) piveridi 82 mg of carboxylate 1 was obtained.
'H-NMRCCDCl ) δ fg: 1.23-1.36(2H,m),1.47(9H,s),1.94-2.02(2H,m),2.20-2.32(lH,  'H-NMRCCDCl) δ fg: 1.23-1.36 (2H, m), 1.47 (9H, s), 1.94-2.02 (2H, m), 2.20-2.32 (lH,
3  Three
m),2.73-2.85(2H,m),4.02-4.08(2H,m),4.11-4.25(2H,m),7.09(lH,dd,J=7.9,1.0Hz),7.3 8(lH,dd,J=7.9,1.0Hz),7.39(lH,d,J=8.7Hz),7.46(lH,t,J=7.9Hz),8.06(lH,d,J=8.7Hz) m), 2.73-2.85 (2H, m), 4.02-4.08 (2H, m), 4.11-4.25 (2H, m), 7.09 (lH, dd, J = 7.9, 1.0Hz), 7.3 8 (lH, dd , J = 7.9,1.0Hz), 7.39 (lH, d, J = 8.7Hz), 7.46 (lH, t, J = 7.9Hz), 8.06 (lH, d, J = 8.7Hz)
[0184] 参考例 47
Figure imgf000092_0002
tert -ブチル =4— ( (2—クロ口キノリン一 8—ィルォキシ）メチル）ピぺリジン 1— カルボキシラート 80mgにトルエン 3mLおよびメタノール 3mLをカ卩え、 28%ナトリウムメト キシド /メタノール 62mgをカ卩えた後、 1時間加熱還流した。さらに、 28%ナトリウムメトキ シド /メタノール 124mgおよびトルエン 2mLをカ卩え、 2時間加熱還流した。さらに、 28% ナトリウムメトキシド /メタノール 124mgおよびトルエン 2mLを加え、 3時間加熱還流した 。反応混合物に酢酸ェチル 10mLおよび水 10mLを加え、有機層を分取し、水層を酢 酸ェチル lOmLで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリ ゥム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去 し、淡褐油状物の tert—ブチル =4— ( (2—メトキシキノリン— 8—ィルォキシ)メチル )ピぺリジン 1 カルボキシラート 62mgを得た。 [0184] Reference example 47
Figure imgf000092_0002
tert-Butyl = 4— ((2-Chronoquinoquinone 8-yloxy) methyl) piperidine 1—carboxylate 80 mg of toluene and 3 mL of methanol were added, and 28% sodium methoxide / methanol 62 mg was added. And then heated to reflux for 1 hour. Further, 124 mg of 28% sodium methoxide / methanol and 2 mL of toluene were added and heated under reflux for 2 hours. Furthermore, 28% sodium methoxide / methanol 124 mg and toluene 2 mL were added, and the mixture was heated to reflux for 3 hours. To the reaction mixture, 10 mL of ethyl acetate and 10 mL of water were added, the organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and tert-butyl = 4— 62 mg of ((2-methoxyquinoline-8-yloxy) methyl) piperidine 1 carboxylate was obtained.
'H-NMRCCDCl ) δ値： 1.30- 1.50(2H,m),1.47(9H,s),1.94- 2.02(2H,m),2.10- 2.25(1Η,  'H-NMRCCDCl) δ value: 1.30-1.50 (2H, m), 1.47 (9H, s), 1.94-2.02 (2H, m), 2.10-2.25 (1Η,
3  Three
m),2.75-2.88(2H,m),4.03-4.09(2H,m),4.09(3H,s),4.12-4.25(2H,m),6.92(lH,d,J=8.9m), 2.75-2.88 (2H, m), 4.03-4.09 (2H, m), 4.09 (3H, s), 4.12-4.25 (2H, m), 6.92 (lH, d, J = 8.9
Hz),7.05(lH,dd,J=7.8,1.5Hz),7.27(lH,t,J=7.8Hz),7.33(lH,dd,J=7.8,1.5Hz),7.96(lH, d,J=8.9Hz) Hz), 7.05 (lH, dd, J = 7.8, 1.5 Hz), 7.27 (lH, t, J = 7.8 Hz), 7.33 (lH, dd, J = 7.8, 1.5 Hz), 7.96 (lH, d, J = 8.9Hz)
参考例 48
Figure imgf000093_0001
Reference Example 48
Figure imgf000093_0001
tert -ブチル = 4— ( ( 2—メトキシキノリン一 8 ィルォキシ)メチル）ピぺリジン 1 カルボキシラート 60mgの塩化メチレン 3mL溶液に、トリフルォロ酢酸 lmLをカ卩え、室 温で 1時間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸ェチル 30mLお よび水 lOmLをカ卩え、 20%水酸化ナトリウム水溶液をカ卩え、 pH12.0に調整した。有機 層を分取し、水層を酢酸ェチル lOmLで抽出した。有機層および抽出液を合わせ、飽 和塩ィ匕ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒 を留去し、淡黄色油状物の 8— ( (ピペリジン— 4—ィル)メトキシ）—2—メトキシキノリ ン 42mgを得た。  tert-Butyl = 4-((2-methoxyquinoline-l-8yloxy) methyl) piperidine 1 carboxylate 60 mL of methylene chloride was added to 1 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and 30 mL of ethyl acetate and 10 mL of water were added to the resulting residue, and 20% aqueous sodium hydroxide solution was added to adjust the pH to 12.0. The organic layer was separated, and the aqueous layer was extracted with lOmL of ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow oily 8- ((piperidine-4-yl). 42 mg of) methoxy) -2-methoxyquinoline was obtained.
'H-NMRCCDCl ) δ値： 1.34- 1.46(2H,m),1.80- 2.06(2H,m),2.10- 2.24(lH,m),2.26- 2.3  'H-NMRCCDCl) δ value: 1.34- 1.46 (2H, m), 1.80-2.06 (2H, m), 2.10-2.24 (lH, m), 2.26-2.3
3  Three
5(lH,m),2.68-2.77(2H,m),3.16-3.24(2H,m),4.04(2H,d,J=6.6Hz),4.10(3H,s),6.91(lH, d,J=8.8Hz),7.06(lH,dd,J=7.9,1.6Hz),7.27(lH,t,J=7.8Hz),7.32(lH,dd,J=7.8,1.5Hz),7. 95(lH,d,J=8.8Hz) 5 (lH, m), 2.68-2.77 (2H, m), 3.16-3.24 (2H, m), 4.04 (2H, d, J = 6.6Hz), 4.10 (3H, s), 6.91 (lH, d, J = 8.8Hz), 7.06 (lH, dd, J = 7.9,1.6Hz), 7.27 (lH, t, J = 7.8Hz), 7.32 (lH, dd, J = 7.8,1.5Hz), 7. 95 (lH, d, J = 8.8Hz)
[0186] 参考例 49
Figure imgf000094_0001
[0186] Reference Example 49
Figure imgf000094_0001
2 クロ口キノリンー4一力ルボン酸 2.0gの塩化メチレン 20mL懸濁液に、室温でォキ サリルクロリド l.OmLおよび N, N ジメチルホルムアミド 2滴を加え、室温で 2時間攪 拌した。ついで、メタノール 2mLを滴下し、室温で 1時間攪拌した。反応混合物を氷水 で冷却し、飽和炭酸水素ナトリウム水溶液 30mLを加えた。有機層を分取し、水層をク ロロホルム 20mLで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナト リウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留 去した。得られた残留物にへキサンを加え、不溶物をろ取し、淡黄色固体のメチル = 2—クロ口キノリン 4 カルボキシラート 1.4gを得た。  2 Chlo-mouth quinoline-4 monostrength rubonic acid 2.0 g of methylene chloride in 20 mL suspension was added with oxalyl chloride l.OmL and 2 drops of N, N dimethylformamide at room temperature and stirred at room temperature for 2 hours. Subsequently, 2 mL of methanol was added dropwise and stirred at room temperature for 1 hour. The reaction mixture was cooled with ice water, and 30 mL of saturated aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of chloroform. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Hexane was added to the resulting residue, and insoluble matter was collected by filtration to obtain 1.4 g of methyl-2-chloroquinoline 4 carboxylate as a pale yellow solid.
'H-NMRCCDCl ) δ値： 4.05(3H,s),7.64- 7.70(lH,m),7.77- 7.82(lH,m),7.91(lH,s),8.06  'H-NMRCCDCl) δ value: 4.05 (3H, s), 7.64- 7.70 (lH, m), 7.77-7.82 (lH, m), 7.91 (lH, s), 8.06
3  Three
-8.10(lH,m),8.71-8.76(lH,m)  -8.10 (lH, m), 8.71-8.76 (lH, m)
[0187] 参考例 50
Figure imgf000094_0002
[0187] Reference Example 50
Figure imgf000094_0002
メチル = 2 クロ口キノリンー4 カルボキシラート 1.3gの濃硫酸 6.0mL溶液に、氷冷 下、発煙硝酸 0.27mLを滴下し、室温で 30分間、 50°Cで 1時間攪拌した。反応混合物 を氷水に注ぎ、酢酸ェチル 50mLをカ卩えた。有機層を分取し、水層を酢酸ェチル 30m Lで抽出した。有機層および抽出液を合わせ、水、飽和炭酸水素ナトリウム水溶液お よび飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減 圧下で溶媒を留去した。得られた残留物をジイソプロピルエーテルで抽出し、減圧下 で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へ キサン:酢酸ェチル = 2 : 1]で精製し、淡黄白色固体のメチル = 2 クロ口一 8 二ト 口キノリンー4 カルボキシラート 0.25gを得た。  Methyl = 2 Chloroquinoline-4 carboxylate To a solution of 1.3 g of concentrated sulfuric acid in 6.0 mL of concentrated sulfuric acid was added dropwise 0.27 mL of fuming nitric acid under ice cooling, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C for 1 hour. The reaction mixture was poured into ice water and 50 mL of ethyl acetate was collected. The organic layer was separated, and the aqueous layer was extracted with 30 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was extracted with diisopropyl ether, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 2: 1], and a pale yellowish white solid of methyl = 2 was obtained, and 0.25 g of quinoline-4 carboxylate was obtained. Obtained.
'H-NMRCCDCI ) δ fg:4.08(3H,s),7.74(lH,dd,J=8.6,7.6Hz),8.06(lH,s),8.08(lH,dd,J =7.6,1.3Hz),9.03(lH,dd,J=8.6,1.3Hz) 'H-NMRCCDCI) δ fg: 4.08 (3H, s), 7.74 (lH, dd, J = 8.6,7.6Hz), 8.06 (lH, s), 8.08 (lH, dd, J = 7.6,1.3Hz), 9.03 (lH, dd, J = 8.6,1.3Hz)
[0188] 参考例 51
Figure imgf000095_0001
[0188] Reference Example 51
Figure imgf000095_0001
メチル = 2 クロロー 8 二トロキノリンー4 カルボキシラート 0.20gのメタノール 5mL 懸濁液に 28%ナトリウムメトキシド /メタノール 0.22gを加え、 1時間加熱還流した。反応 混合物に酢酸ェチル 30mLおよび水 20mLをカ卩えた。有機層を分取し、水層を酢酸ェ チル 20mLで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム 水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、 淡褐色固体のメチル = 2—メトキシー8 -トロキノリンー4 カルボキシラート O.llgを 得た。  Methyl = 2 Chloro-8 ditroquinoline-4 carboxylate 0.22 g of methanol was added to 0.20 g of a suspension of methanol, and 0.22 g of 28% sodium methoxide / methanol was added, and the mixture was heated to reflux for 1 hour. To the reaction mixture, 30 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to give a light brown solid methyl = 2-methoxy-8-troquinoline-4 Carboxylate O.llg was obtained.
^-NMRCCDCl ) δ fg:4.04(3H,s),4.08(3H,s),7.51(lH,dd,J=8.5,7.9Hz),7.57(lH,s),7.  ^ -NMRCCDCl) δ fg: 4.04 (3H, s), 4.08 (3H, s), 7.51 (lH, dd, J = 8.5, 7.9 Hz), 7.57 (lH, s), 7.
3  Three
97(lH,dd,J=7.9,1.4Hz),8.88(lH,dd,J=8.5,1.4Hz)  97 (lH, dd, J = 7.9,1.4Hz), 8.88 (lH, dd, J = 8.5,1.4Hz)
[0189] 参考例 52
Figure imgf000095_0002
[0189] Reference Example 52
Figure imgf000095_0002
メチル = 2—メトキシ 8 二トロキノリン一 4—カルボキシラート 1 OOmgの酢酸 3mL溶 液に、室温で 10%パラジウム—炭素 20mgを加え、水素雰囲気下で 1時間攪拌した。 不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物に酢酸ェチル 20mLおよ び水 10mLをカ卩え、氷冷下、飽和炭酸水素ナトリウム水溶液で pH9.0に調整した。有 機層を分取し、水層を酢酸ェチル 10mLで抽出した。有機層および抽出液を合わせ、 飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶 媒を留去し、褐色油状物のメチル =8-ァミノ 2—メトキシキノリン 4 カルボキシ ラート 79mgを得た。  Methyl = 2-methoxy 8 ditroquinoline 4-carboxylate 1 To 10 mL of acetic acid in 3 mL of acetic acid was added 10 mg of palladium-carbon 20 mg at room temperature, and the mixture was stirred under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 20 mL of ethyl acetate and 10 mL of water were added, and the mixture was adjusted to pH 9.0 with a saturated aqueous solution of sodium bicarbonate under ice cooling. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methyl = 8-amino-2-methoxyquinoline 4 carboxylate as a brown oily substance 79 mg Got.
'H-NMRCCDCl ) δ値： 4.00(3H,s),4.08(3H,s),4.72- 4.82(2H,broad),6.96(lH,dd,J=7.6,  'H-NMRCCDCl) δ value: 4.00 (3H, s), 4.08 (3H, s), 4.72- 4.82 (2H, broad), 6.96 (lH, dd, J = 7.6,
3  Three
1.2Hz),7.27(lH,dd,J=8.5,7.6Hz),7.41(lH,s),7.89(lH,dd,J=8.5,1.2Hz) [0190] 参考例 53
Figure imgf000096_0001
1.2Hz), 7.27 (lH, dd, J = 8.5,7.6Hz), 7.41 (lH, s), 7.89 (lH, dd, J = 8.5,1.2Hz) [0190] Reference Example 53
Figure imgf000096_0001
2 クロロー 8—メチルキノリン 1.50gのメタノール 12mL溶液に、室温でナトリウムメト キシド 1.96gおよびテトラプチルアンモ-ゥムブロミド 1.36gをカ卩え、 6日間加熱還流した 。放冷後、反応混合物に水 50mLおよびクロ口ホルム 50mLを加えた。有機層を分取し 、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシ リカゲルカラムクロマトグラフィー [シリカゲル；関東ィ匕学株式会社、シリカゲル 60、溶 離液;へキサン:酢酸ェチル = 20 : 1]で精製し、無色油状物の 2—メトキシ 8—メチ ルキノリン 1.25gを得た。  2 Chloro-8-methylquinoline 1.50 g of a methanol 12 mL solution was charged with 1.96 g of sodium methoxide and 1.36 g of tetraptyl ammonium bromide at room temperature, and heated to reflux for 6 days. After allowing to cool, 50 mL of water and 50 mL of black mouth form were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Ltd., silica gel 60, eluent; hexane: ethyl acetate = 20: 1] to give 2-methoxy 8 -1.25 g of methylquinoline was obtained.
1H-NMR(CDC1 ) δ値： 2.72(3H,s),4.08(3H,s),6.90(lH,d,J=8.8Hz),7.24(lH,d,J=7.5Hz  1H-NMR (CDC1) δ value: 2.72 (3H, s), 4.08 (3H, s), 6.90 (lH, d, J = 8.8Hz), 7.24 (lH, d, J = 7.5Hz)
3  Three
),7.28(lH,d,J=7.5Hz),7.44-7.60(lH,m),7.94(lH,d,J=8.8Hz)  ), 7.28 (lH, d, J = 7.5Hz), 7.44-7.60 (lH, m), 7.94 (lH, d, J = 8.8Hz)
[0191] 参考例 54
Figure imgf000096_0002
[0191] Reference Example 54
Figure imgf000096_0002
2—メトキシ 8—メチルキノリン 20. lgの四塩化炭素 500mL溶液に、室温で N ブロ モコハク酸イミド 20.6gおよびベンゾィル =ペルォキシド（75%) 3.64gを加え、 1時間加 熱還流した。反応混合物を放冷後、不溶物をろ去し、ろ液を減圧下で濃縮し、クロ口 ホルム 300mLおよび 10%炭酸ナトリウム水溶液 300mLをカ卩えた。有機層を分取し、水 300mLで洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄 色固体の 8 ブロモメチルー 2—メトキシキノリン 30.1gを得た。  2-methoxy 8-methylquinoline 20.0.6 g of carbon tetrachloride in 500 mL was added with 20.6 g of N-bromosuccinimide and 3.64 g of benzoyl peroxide (75%) at room temperature, and heated to reflux for 1 hour. The reaction mixture was allowed to cool, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 300 mL of chloroform and 300 mL of a 10% aqueous sodium carbonate solution. The organic layer was separated, washed with 300 mL of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 30.1 g of 8 bromomethyl-2-methoxyquinoline as a pale yellow solid.
'H-NMRCCDCl ) δ fg:4.12(3H,s),5.12(2H,s),6.93(lH,d,J=8.9Hz),7.32(lH,dd,J=8.1,  'H-NMRCCDCl) δ fg: 4.12 (3H, s), 5.12 (2H, s), 6.93 (lH, d, J = 8.9Hz), 7.32 (lH, dd, J = 8.1,
3  Three
7.2Hz),7.68(lH,dd,J=8.1,1.6Hz),7.72(lH,dd,J=7.2,1.4Hz),7.96(lH,d,J=8.9Hz)  7.2Hz), 7.68 (lH, dd, J = 8.1,1.6Hz), 7.72 (lH, dd, J = 7.2,1.4Hz), 7.96 (lH, d, J = 8.9Hz)
[0192] 参考例 55
Figure imgf000096_0003
[0192] Reference Example 55
Figure imgf000096_0003
8 ブロモメチル 2—メトキシキノリン 29.0gのァセトニトリル 900mL溶液に、室温で N メチルモルホリン N—ォキシド 38.5gおよび 4Aモレキュラーシーブス 1.50gをカロ え、室温で 2時間 30分間攪拌した。反応混合物を少量のシリカゲルを用いてろ過し、 ろ液を減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィ 一 [シリカゲル；関東ィ匕学株式会社、シリカゲル 60、溶離液；へキサン：酢酸ェチル = 7 : 1]で精製し、淡黄色固体の 2—メトキシキノリン— 8—カルバルデヒド 11.4gを得た。 1H-NMR(CDC1 ) δ値： 4.12(3H,s),7.00(lH,d,J=8.8Hz),7.49(lH,t,J=7.9Hz),7.98(lH,d 8 Bromomethyl 2-methoxyquinoline 29.0 g of acetonitrile in 900 mL solution at room temperature 38.5 g of N-methylmorpholine N-oxide and 1.50 g of 4A molecular sieves were added and stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was filtered using a small amount of silica gel, and the solvent was distilled off from the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography 1 [silica gel; Kanto Chemical Co., Ltd., silica gel 60, eluent; hexane: ethyl acetate = 7: 1] to give 2-methoxyquinoline-8 as a pale yellow solid. -11.4 g of carbaldehyde was obtained. 1H-NMR (CDC1) δ value: 4.12 (3H, s), 7.00 (lH, d, J = 8.8Hz), 7.49 (lH, t, J = 7.9Hz), 7.98 (lH, d
3  Three
d,J=7.9,1.5Hz),8.05(lH,d,J=8.8Hz),8.24(lH,dd,J=7.5,1.5Hz),11.37(lH,d,J=0.7Hz) d, J = 7.9,1.5Hz), 8.05 (lH, d, J = 8.8Hz), 8.24 (lH, dd, J = 7.5,1.5Hz), 11.37 (lH, d, J = 0.7Hz)
[0193] 参考例 56
Figure imgf000097_0001
[0193] Reference Example 56
Figure imgf000097_0001
2—メトキシキノリン— 8—カルバルデヒド 2.00gのァセトニトリル 20mL溶液に、室温で トリメチルスルホ-ゥムョージド 2.18g、水酸化カリウム 1.20gおよび水 48mgを加え、 60 °Cで 5時間攪拌した。反応混合物をろ過後、ろ液を減圧濃縮し、得られた残留物に酢 酸ェチル 50mLおよび水 20mLを加えた。有機層を分取し、飽和塩化ナトリウム水溶液 20mLで 2回洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄 色油状物の 2—メトキシ一 8— (ォキシラン一 2—ィル)キノリン 2.35gを得た。  To a solution of acetonitrile in 2.00 g of 2-methoxyquinoline-8-carbaldehyde in 2.20 g of acetonitrile, 2.18 g of trimethylsulfo-methanolide, 1.20 g of potassium hydroxide and 48 mg of water were added at room temperature, followed by stirring at 60 ° C for 5 hours. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure, and 50 mL of ethyl acetate and 20 mL of water were added to the resulting residue. The organic layer was separated, washed twice with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-methoxy-1-8- (oxysilane-2- Yl) 2.35 g of quinoline was obtained.
1H-NMR(CDC1 ) δ fg: 2.82(lH,dd,J=5.8,2.7Hz),3.34(lH,dd,J=5.8,4.2Hz),4.10(3H,s)  1H-NMR (CDC1) δ fg: 2.82 (lH, dd, J = 5.8,2.7Hz), 3.34 (lH, dd, J = 5.8,4.2Hz), 4.10 (3H, s)
3  Three
,5.01(lH,dd,J=4.2,2.7Hz),6.94(lH,d,J=8.9Hz),7.36(lH,t,J=7.3Hz),7.49(lH,dd,J=7.3, 1.6Hz),7.66(lH,dd,J=7.9,1.4Hz),8.00(lH,d,J=9.0Hz)  , 5.01 (lH, dd, J = 4.2,2.7Hz), 6.94 (lH, d, J = 8.9Hz), 7.36 (lH, t, J = 7.3Hz), 7.49 (lH, dd, J = 7.3, 1.6 Hz), 7.66 (lH, dd, J = 7.9,1.4Hz), 8.00 (lH, d, J = 9.0Hz)
[0194] 参考例 57
Figure imgf000097_0002
[0194] Reference Example 57
Figure imgf000097_0002
2—メトキシ一 8— (ォキシラン一 2—ィル）キノリン 0.70gの N, N—ジメチルホルムァ ミド 10mL溶液に、室温で 1 tert ブトキシカルボ-ルビペラジン 0.78gおよび過塩 素酸リチウム 0.44gを加え、 80°Cで 1時間 30分間攪拌した。放冷後、反応混合物に酢 酸ェチル 40mLおよび水 40mLを加えた。有機層を分取し、水層を酢酸ェチル 40mLで 抽出した。有機層および抽出液を合わせ、飽和塩ィ匕ナトリウム水溶液 40mLで洗浄し 、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシ リカゲルカラムクロマトグラフィー [シリカゲル；関東ィ匕学株式会社、シリカゲル 60、溶 離液;へキサン：酢酸ェチル = 2 : 3]で精製し、無色ガム状の tert ブチル =4 (2 ーヒドロキシー2—（2—メトキシキノリンー8 ィル）ェチル）ピぺラジンカルボキシラー ト 0.51gを得た。 To a solution of 0.70 g of 2-methoxy-1-8- (oxylan-1-yl) quinoline in 10 mL of N, N-dimethylformamide at room temperature is added 0.78 g of 1 tert-butoxycarborubiperazine and 0.44 g of lithium perchlorate. The mixture was stirred at 80 ° C for 1 hour and 30 minutes. After allowing to cool, 40 mL of ethyl acetate and 40 mL of water were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with 40 mL of ethyl acetate. Combine the organic layer and the extract, and wash with 40 mL of saturated sodium chloride aqueous solution. And dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Ltd., silica gel 60, eluent; hexane: ethyl acetate = 2: 3], and colorless gum-like tert butyl = 4 0.51 g of (2-hydroxy-2- (2-methoxyquinoline-8yl) ethyl) piperazinecarboxylate was obtained.
1H-NMR(CDC1 ) δ fg: 1.48(9H,s),2.40-2.54(2H,m),2.60(lH,dd,J=12.5,9.9Hz),2.68- 1H-NMR (CDC1) δ fg: 1.48 (9H, s), 2.40-2.54 (2H, m), 2.60 (lH, dd, J = 12.5, 9.9Hz), 2.68-
3 Three
2.84(2H,m),2.98(lH,dd,J=12.5,3.3Hz),3.45-3.55(4H,m),4.04(3H,s),5.75(lH,dd,J=9. 9,3.3Hz),6.90(lH,d,J=8.8Hz),7.34-7.44(lH,m),7.62(lH,dd,J=8.1,1.5Hz),7.78-7.86( lH,m),7.98(lH,d,J=8.8Hz)  2.84 (2H, m), 2.98 (lH, dd, J = 12.5,3.3Hz), 3.45-3.55 (4H, m), 4.04 (3H, s), 5.75 (lH, dd, J = 9, 9.3.3 Hz), 6.90 (lH, d, J = 8.8Hz), 7.34-7.44 (lH, m), 7.62 (lH, dd, J = 8.1, 1.5Hz), 7.78-7.86 (lH, m), 7.98 (lH , d, J = 8.8Hz)
[0195] 参考例 58
Figure imgf000098_0001
[0195] Reference Example 58
Figure imgf000098_0001
tert—ブチル =4— (2 ヒドロキシ— 2— (2—メトキシキノリン— 8—ィル）ェチル） ピぺラジンカルボキシラート 0.49gのクロ口ホルム 9mL溶液に、氷冷下、トリフルォロ酢 酸 3mLを滴下し、室温で 40分間攪拌した。反応混合物を減圧濃縮後、クロ口ホルム 20 mLおよび水 10mLを加え、 20%水酸化ナトリウム水溶液で ρΗ11〜12に調整（pH試験 紙)した。有機層を分取し、水層をクロ口ホルム 20mLで抽出した。有機層および抽出 液を合わせ、飽和塩ィ匕ナトリウム水溶液 30mLで洗浄し、無水硫酸マグネシウムで乾 燥させ、減圧下で溶媒を留去し、黄色油状物の 1— (2—メトキシキノリン— 8—ィル） 2 （ピペラジン 1 ィル）エタノール 0.46gを得た。  tert-Butyl = 4— (2 Hydroxy-2- (2-methoxyquinoline-8-yl) ethyl) Piperazinecarboxylate 3 mL of trifluoroacetic acid is added dropwise to 9 mL of 0.49 g of chloroform under ice-cooling. And stirred for 40 minutes at room temperature. After concentration of the reaction mixture under reduced pressure, 20 mL of black mouth form and 10 mL of water were added, and the pH was adjusted to 11-12 with a 20% aqueous sodium hydroxide solution (pH test paper). The organic layer was separated, and the aqueous layer was extracted with 20 mL of black mouth form. The organic layer and the extract were combined, washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- (2-methoxyquinoline-8- Yil) 2 (piperazine 1 yl) ethanol 0.46 g was obtained.
'H-NMRCCDCl ) δ値： 2.44- 2.58(2H,m),2.70- 2.88(2H,m),2.90- 3.06(6H,m),4.04(3H,  'H-NMRCCDCl) δ value: 2.44-2.58 (2H, m), 2.70-2.88 (2H, m), 2.90-3.06 (6H, m), 4.04 (3H,
3  Three
s),5.78(lH,dd,J=9.9,3.3Hz),6.90(lH,d,J=8.9Hz),7.40(lH,t,J=7.9Hz),7.62(lH,dd,J=7. 9,1.4Hz),7.84(lH,dd,J=7.3,1.4Hz),7.98(lH,d,J=8.9Hz)  s), 5.78 (lH, dd, J = 9.9,3.3Hz), 6.90 (lH, d, J = 8.9Hz), 7.40 (lH, t, J = 7.9Hz), 7.62 (lH, dd, J = 7 9,1.4Hz), 7.84 (lH, dd, J = 7.3,1.4Hz), 7.98 (lH, d, J = 8.9Hz)
[0196] 参考例 59
Figure imgf000098_0002
[0196] Reference Example 59
Figure imgf000098_0002
窒素雰囲気下、ォキサリルクロリド 0.93gのジクロロメタン 28mL溶液を 78°Cに冷却 し、ジメチルスルホキシド 2.3gのジクロロメタン 20mL溶液、続けて 1—ベンジル— 4— ピぺリジンメタノール 1.2gのジクロロメタン 20mL溶液をそれぞれ 5分間かけて滴下した 。— 70〜― 60°Cで 1時間攪拌後、トリェチルァミン 2.7mLを 5分間かけて滴下し、—65 °Cで 20分、室温で 10分間攪拌した。反応混合物に水 60mLを加えて有機層を分取し 、水層をクロ口ホルム 50mLで抽出した。有機層および抽出液を合わせ、飽和塩化ナト リウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、 淡黄色油状物の 1 ベンジル 4 ピぺリジンカルバルデヒド 1.3gを得た。 In a nitrogen atmosphere, cool a solution of 0.93 g of oxalyl chloride in 28 mL of dichloromethane to 78 ° C, then add 2.3 g of dimethyl sulfoxide in 20 mL of dichloromethane, followed by 1-benzyl-4- Piperidine methanol (1.2 g) in dichloromethane (20 mL) was added dropwise over 5 minutes. — After stirring at 70 to 60 ° C. for 1 hour, 2.7 mL of triethylamine was added dropwise over 5 minutes, followed by stirring at −65 ° C. for 20 minutes and at room temperature for 10 minutes. 60 mL of water was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with 50 mL of black mouth form. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 1.3 g of 1-benzyl 4-piperidinecarbaldehyde as a pale yellow oil. It was.
'H-NMRCCDCl ) δ値： 1.60- 1.76(2H,m),1.82- 1.94(2H,m),2.04- 2.16(2H,m),2.18- 2.3  'H-NMRCCDCl) δ value: 1.60- 1.76 (2H, m), 1.82- 1.94 (2H, m), 2.04- 2.16 (2H, m), 2.18- 2.3
3  Three
0(lH,m),2.78-2.86(2H,m),3.50(2H,s),7.21-7.37(5H,m),9.64(lH,d,J=l.lHz)  0 (lH, m), 2.78-2.86 (2H, m), 3.50 (2H, s), 7.21-7.37 (5H, m), 9.64 (lH, d, J = l.lHz)
[0197] 参考例 60
Figure imgf000099_0001
[0197] Reference Example 60
Figure imgf000099_0001
8 ブロモメチルー 2—メトキシキノリン 2. lgのトルエン 25mL溶液に、室温でトリフエ -ルホスフィン 2.2gのトルエン 15mL溶液を 10分間かけて滴下し、 30分間攪拌後、 80 °Cで 1時間 30分間攪拌した。反応混合物を放冷後、沈殿物をろ取し、白色粉末の (2 —メトキシキノリン一 8 ィル)メチルトリフエ-ルホスホ-ゥムブロミド 2.19gを得た。 1H-NMR(CDC1 ) δ fg: 3.63(3H,s),6.04(2H,d,J=14.5Hz),6.68(lH,d,J=8.9Hz), 7.12-7.2  8 Bromomethyl-2-methoxyquinoline 2. To a 25 mL solution of lg in toluene, 15 mL of a toluene solution of 2.2 g of triphenylphosphine was added dropwise over 10 minutes, stirred for 30 minutes, and then stirred at 80 ° C for 1 hour and 30 minutes. . The reaction mixture was allowed to cool, and the precipitate was collected by filtration to give 2.19 g of (2-methoxyquinoline monoyl) methyltriphenylphospho-mubromide as a white powder. 1H-NMR (CDC1) δ fg: 3.63 (3H, s), 6.04 (2H, d, J = 14.5Hz), 6.68 (lH, d, J = 8.9Hz), 7.12-7.2
3  Three
9(2H,m),7.48-7.74(15H,m),7.76-7.83(lH,m),7.86(lH,d,J=8.9Hz)  9 (2H, m), 7.48-7.74 (15H, m), 7.76-7.83 (lH, m), 7.86 (lH, d, J = 8.9Hz)
[0198] 参考例 61
Figure imgf000099_0002
[0198] Reference Example 61
Figure imgf000099_0002
窒素雰囲気下、（2 メトキシキノリン— 8 ィル)メチルトリフエ-ルホスホ-ゥムブロ ミド 1.3gのテトラヒドロフラン 15mL溶液を— 78°Cに冷却し、 2.6mol/Lのブチルリチウム 1 .lmLを 3分間かけて滴下し、 50分間攪拌した。 1—ベンジル— 4 ピぺリジン力ルバ ルデヒド 0.52gのテトラヒドロフラン 6mL溶液を 4分間かけて滴下した。反応混合物を室 温で 1時間 40分間攪拌した後に減圧下で濃縮した。得られた残留物をシリカゲルカラ ムクロマトグラフィー [シリカゲル；関東ィ匕学株式会社、シリカゲル 60、溶離液;酢酸ェ チル]で精製し、淡黄色油状物の 8— [2—（1 ベンジルピペリジンー4 ィル)ビ- ル ]ー2—メトキシキノリン 0.67gを得た。得られた生成物は E体、 Z体の混合物であり、 このまま次工程に用いた。 Under nitrogen atmosphere, (2 methoxyquinoline-8-yl) methyltriphenylphosphorobromide 1.3 g tetrahydrofuran solution in 15 mL was cooled to -78 ° C and 2.6 mol / L butyllithium 1.lmL was added dropwise over 3 min. And stirred for 50 minutes. A solution of 0.52 g of 1-benzyl-4 piperidine strength rubaldehyde in 6 mL of tetrahydrofuran was added dropwise over 4 minutes. The reaction mixture was stirred at room temperature for 1 hour and 40 minutes and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [silica gel; Kanto Chemical Co., Ltd., silica gel 60, eluent: acetate Purification by chill] gave 0.67 g of 8- [2- (1 benzylpiperidine-4-yl) vinyl] -2-methoxyquinoline as a pale yellow oil. The obtained product was a mixture of E-form and Z-form and used in the next step as it was.
[0199] 参考例 62
Figure imgf000100_0001
[0199] Reference Example 62
Figure imgf000100_0001
8— [2— (1—ベンジルピペリジン一 4—ィル）ビュル」一 2—メトキシキノリン 0.65gの エタノール 20mL溶液に、室温で 10%パラジウム 炭素 0.21gをカ卩え、水素雰囲気下、 2時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去して黄色油状物の 8— [2— ( 1—ベンジルピペリジン一 4—ィル）ェチル ]—2—メトキシキノリン 0.63gを得た。  8— [2— (1-Benzylpiperidine 4-yl) bule] 2-methoxyquinoline 0.65 g of ethanol in 20 mL solution was charged with 0.21 g of 10% palladium on carbon at room temperature for 2 hours in a hydrogen atmosphere. Stir. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.63 g of 8- [2- (1-benzylpiperidine-l-yl) ethyl] -2-methoxyquinoline as a yellow oily substance.
'H-NMRCCDCl ) δ値： 1.32- 1.92(7H,m),1.94- 2.18(2H,m),2.92- 3.08(2H,m),3.10- 3.2  'H-NMRCCDCl) δ value: 1.32- 1.92 (7H, m), 1.94- 2.18 (2H, m), 2.92-3.08 (2H, m), 3.10-3.2
3  Three
5(2H,m),3.61(2H,s),4.04(3H,s),6.88(lH,d,J=8.8Hz),7.22-7.48(7H,m),7.52-7.59(lH, m),7.95(lH,d,J=8.8Hz)  5 (2H, m), 3.61 (2H, s), 4.04 (3H, s), 6.88 (lH, d, J = 8.8Hz), 7.22-7.48 (7H, m), 7.52-7.59 (lH, m) , 7.95 (lH, d, J = 8.8Hz)
[0200] 参考例 63
Figure imgf000100_0002
[0200] Reference Example 63
Figure imgf000100_0002
8— [2— (1—ベンジルピペリジン一 4—ィル）ェチル ]—2—メトキシキノリン 0.63gの エタノール 50mL溶液に、室温で 10%パラジウム 炭素 0.22gをカ卩え、水素添加（3.4k gf/cm2)した。 12時間攪拌後、不溶物をろ去し、減圧下で溶媒を留去して、淡黄色油 状物の 2—メトキシー8— (2- (ピペリジンー4 ィル）ェチル）キノリン 0.44gを得た。 'H-NMRCCDCl ) δ値： 1.36(2H,dt,J=12.4,3.7Hz),1.43- 1.57(lH,m),1.68- 1.78(2H,m), 8- [2- (1-Benzylpiperidine-4-yl) ethyl] -2-2-methoxyquinoline 0.63 g in 50 mL of ethanol was charged with 0.22 g of 10% palladium on carbon at room temperature and hydrogenated (3.4 kgf) / cm 2 ). After stirring for 12 hours, the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.44 g of 2-methoxy-8- (2- (piperidine-4-yl) ethyl) quinoline as a pale yellow oil. . 'H-NMRCCDCl) δ value: 1.36 (2H, dt, J = 12.4,3.7Hz), 1.43-1.57 (lH, m), 1.68-1.78 (2H, m),
3  Three
1.82-1.93(2H,m),2.67(2H,t,J=12.1Hz),3.12-3.24(4H,m),4.05(3H,s),6.89(lH,d,J=8.7 Hz),7.29(lH,t,J=7.9Hz),7.46(lH,d,J=7.0Hz),7.57(lH,d,J=8.1Hz),7.96(lH,d,J=8.7Hz )  1.82-1.93 (2H, m), 2.67 (2H, t, J = 12.1Hz), 3.12-3.24 (4H, m), 4.05 (3H, s), 6.89 (lH, d, J = 8.7 Hz), 7.29 (lH, t, J = 7.9Hz), 7.46 (lH, d, J = 7.0Hz), 7.57 (lH, d, J = 8.1Hz), 7.96 (lH, d, J = 8.7Hz)
[0201] 参考例 64
Figure imgf000100_0003
キノリンー8 オール 5.0gの硫酸 15mL溶液に、 5°Cで臭素 1.85mLを滴下し、 3時間 攪拌した。反応混合物を氷 100gに注ぎ、氷が溶解するまで放置した。不溶物をろ去 し、ろ液を 20%水酸ィ匕ナトリウム水溶液で pH6.0に調整し、析出物をろ取した。析出物 をクロ口ホルムに溶解し、有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧 下で溶媒を留去し、褐色固体 6.9gを得た。得られた褐色固体 2.0gのテトラヒドロフラン 20mL溶液に、氷冷下、 60%水素化ナトリウム 0.36gをカ卩え、 10分間攪拌した。テトラヒ ドロフラン 20mLおよびベンジルブロミド l.lmLを順次加え、室温で 1時間、還流下 2時 間攪拌した。 N, N ジメチルホルムアミド 20mLをカ卩え、還流下 1時間攪拌した。反応 混合物に酢酸ェチル 20mLおよび水 20mLをカ卩えた。有機層を分取し、水層を酢酸ェ チル 20mLで抽出した。有機層および抽出液を合わせ、飽和塩ィ匕ナトリウム水溶液で 洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留 物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 5： 1]で精 製し、白色固体の 8 -ベンジルォキシ 5 ブロモキノリン 1.5gを得た。 [0201] Reference Example 64
Figure imgf000100_0003
To a solution of quinolin-8ol 5.0 g in sulfuric acid 15 mL was added dropwise 1.85 mL of bromine at 5 ° C. and stirred for 3 hours. The reaction mixture was poured into 100 g of ice and allowed to stand until the ice melted. Insolubles were removed by filtration, and the filtrate was adjusted to pH 6.0 with 20% aqueous sodium hydroxide solution, and the precipitate was collected by filtration. The precipitate was dissolved in chloroform and the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.9 g of a brown solid. To a solution of the obtained brown solid (2.0 g) in tetrahydrofuran (20 mL) was added 60% sodium hydride (0.36 g) under ice cooling, and the mixture was stirred for 10 minutes. Tetrahydrofuran (20 mL) and benzyl bromide (1 mL) were sequentially added, and the mixture was stirred at room temperature for 1 hour and under reflux for 2 hours. 20 mL of N, N dimethylformamide was added and stirred for 1 hour under reflux. To the reaction mixture, 20 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1] to obtain 1.5 g of 8-benzyloxy-5-bromoquinoline as a white solid.
^-NMRCCDCl ) δ値： 5.44(2H,s),6.91(lH,d,J=8.5Hz),7.28-7.65(7H,m),8.50(lH,dd,J ^ -NMRCCDCl) δ value: 5.44 (2H, s), 6.91 (lH, d, J = 8.5Hz), 7.28-7.65 (7H, m), 8.50 (lH, dd, J
3  Three
=8.5,1.7Hz),9.00(lH,dd,J=4.2,1.7Hz)  = 8.5,1.7Hz), 9.00 (lH, dd, J = 4.2,1.7Hz)
参考例 65
Figure imgf000101_0001
Reference Example 65
Figure imgf000101_0001
8 -ベンジルォキシ 5 ブ口モキノリン 0.50gのクロ口ホルム 4mL溶液に、 5°Cでメタ クロ口過安息香酸 0.44gをカ卩え、室温で 6時間攪拌した。メタクロ口過安息香酸 0.44gを 加え、 1時間攪拌した。反応混合物にクロ口ホルム 10mLおよび水 10mLを加え、飽和 炭酸水素ナトリウム水溶液で PH8.4に調整した。有機層を分取し、水層をクロ口ホルム 10mLで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄 し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を シリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム]で精製し、褐色固体の 8 - ペンジノレオキシ 5 ブロモキノリン = 1 ォキシド 0.41 gを得た。  To a solution of 0.50 g of 8-benzyloxy-5-bumoquinoline in 4 mL of black mouth form was added 0.44 g of metabenzoic perbenzoic acid at 5 ° C., and the mixture was stirred at room temperature for 6 hours. 0.44 g of metabenzoic perbenzoic acid was added and stirred for 1 hour. To the reaction mixture, 10 mL of black mouth form and 10 mL of water were added, and the pH was adjusted to pH 8.4 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with 10 mL of black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form] to obtain 0.41 g of 8-pentinoreoxy 5 bromoquinoline = 1 oxide as a brown solid.
1H-NMR(CDC1 ) δ値： 5.28(2H,s),6.99(lH,d,J=8.6Hz), 7.28- 7.41(4H,m),7.57- 7.63(2 H,m),7.71(lH,d,J=8.6Hz),8.04(lH,dd,J=8.8,0.7Hz),8.51(lH,dd,J=6.1,1.0Hz) 1H-NMR (CDC1) δ value: 5.28 (2H, s), 6.99 (lH, d, J = 8.6Hz), 7.28-7.41 (4H, m), 7.57-7.63 (2 H, m), 7.71 (lH, d, J = 8.6Hz), 8.04 (lH, dd, J = 8.8,0.7Hz), 8.51 (lH, dd, J = 6.1,1.0Hz)
[0203] 参考例 66
Figure imgf000102_0001
[0203] Reference Example 66
Figure imgf000102_0001
8 ベンジルォキシ一 5 ブロモキノリン = 1—ォキシド 1.9gのクロ口ホルム 15mL溶 液に、ォキシ塩化リン 0.65mLをカ卩え、室温で 1時間攪拌した。ォキシ塩化リン 0.65mL を加え、 30分間攪拌した。減圧下で溶媒を留去し、酢酸ェチル 15mLおよび飽和炭酸 水素ナトリウム水溶液 15mLを加え、 20%水酸ィ匕ナトリウム水溶液で pH7.5に調整した 。有機層を分取し、水層を酢酸ェチル 10mLで抽出した。有機層および抽出液を合わ せ、飽和塩ィ匕ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下 で溶媒を留去し、褐色油状物の 8 ベンジルォキシ 5 ブロモ 2 クロ口キノリン 1.9gを得た。  8 Benzyloxy-5 Bromoquinoline = 1-oxide Into a 15 mL solution of 1.9 g of black mouth form, 0.65 mL of phosphorus oxychloride was added and stirred at room temperature for 1 hour. 0.65 mL of phosphorus oxychloride was added and stirred for 30 minutes. The solvent was distilled off under reduced pressure, 15 mL of ethyl acetate and 15 mL of saturated aqueous sodium bicarbonate were added, and the pH was adjusted to 7.5 with 20% aqueous sodium hydroxide. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and 1.9 g of 8 benzyloxy-5 bromo-2-chloroquinoline as a brown oily substance. Obtained.
^-NMRCCDCl ) δ値： 5.43(2H,s),6.93(lH,d,J=8.6Hz),7.26-7.52(6H,m),7.62(lH,d,J=  ^ -NMRCCDCl) δ value: 5.43 (2H, s), 6.93 (lH, d, J = 8.6Hz), 7.26-7.52 (6H, m), 7.62 (lH, d, J =
3  Three
8.3Hz),8.43(lH,dd,J=8.8,1.7Hz)  8.3Hz), 8.43 (lH, dd, J = 8.8,1.7Hz)
[0204] 参考例 67
Figure imgf000102_0002
[0204] Reference Example 67
Figure imgf000102_0002
8 ベンジルォキシ 5 ブロモ 2 クロ口キノリン 1.9gから参考例 18と同様にし て、白色固体の 8 ベンジルォキシ 5 ブロモー 2—メトキシキノリン 1.6gを得た。 'H-NMRCCDCl ) δ値： 4.13(3H,s),5.34(2H,s),6.96- 7.03(2H,m),7.28- 7.58(6H,m),8.33  In the same manner as in Reference Example 18, benzyloxy-5-bromo-2-chloroquinoline (1.9 g) was obtained in the same manner as in Reference Example 18 to obtain 1.6 g of 8-benzyloxy-5-bromo-2-methoxyquinoline as a white solid. 'H-NMRCCDCl) δ value: 4.13 (3H, s), 5.34 (2H, s), 6.96-7.03 (2H, m), 7.28-7.58 (6H, m), 8.33
3  Three
(lH,d,J=9.0Hz)  (lH, d, J = 9.0Hz)
[0205] 参考例 68
Figure imgf000102_0003
[0205] Reference Example 68
Figure imgf000102_0003
8 ベンジルォキシ 5 ブロモ 2—メトキシキノリン 0.50gのブタノール 4mLおよ びトリエチルァミン 4mL混合溶液に、ビス（トリフエ-ルホスフィン）パラジウムジクロリド 0 .10gを加え、一酸化炭素雰囲気下で 4時間加熱還流した。反応混合物をろ過し、残 渣をクロ口ホルムで洗净した。ろ液および洗液を合わせ、減圧下で溶媒を留去した。 得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 10 : 1]で精製し、白色固体のブチル =8 べンジルォキシー2—メトキシキノリン 5 カルボキシラート 0.38gを得た。 8 Benzyloxy 5 bromo 2-methoxyquinoline 0.50 g butanol 4 mL Bis (triphenylphosphine) palladium dichloride (0.10 g) was added to 4 mL of triethylamine mixed solution, and the mixture was heated to reflux for 4 hours in a carbon monoxide atmosphere. The reaction mixture was filtered and the residue was washed with black mouth form. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 10: 1] to obtain 0.38 g of white solid butyl = 8 benzyloxy-2-methoxyquinoline 5 carboxylate.
'H-NMRCCDCl ) δ値： 1.00(3H,t,J=7.3Hz), 1.45- 1.56(2H,m), 1.74- 1.84(2H,m),4.13(3  'H-NMRCCDCl) δ value: 1.00 (3H, t, J = 7.3Hz), 1.45- 1.56 (2H, m), 1.74- 1.84 (2H, m), 4.13 (3
3  Three
H,s),4.35(2H,J=7.1Hz),5.40(2H,s),7.04-7.08(2H,m),7.30-7.42(3H,m),7.54-7.60(2H, m),8.09(lH,d,J=8.3Hz),9.29(lH,d,J=9.3Hz)  H, s), 4.35 (2H, J = 7.1Hz), 5.40 (2H, s), 7.04-7.08 (2H, m), 7.30-7.42 (3H, m), 7.54-7.60 (2H, m), 8.09 (lH, d, J = 8.3Hz), 9.29 (lH, d, J = 9.3Hz)
[0206] 参考例 69
Figure imgf000103_0001
[0206] Reference Example 69
Figure imgf000103_0001
ブチル = 8 ベンジルォキシ 2—メトキシキノリンー 5 カルボキシラート 0.41 gの テトラヒドロフラン 7mL溶液に、 5%パラジウム 炭素 80mgのテトラヒドロフラン 2mL懸濁 液を加え、水素雰囲気下で 4時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去し 、白色固体のブチル =8 ヒドロキシー2—メトキシキノリンー5 カルボキシラート 0.3 3gを得た。  Butyl = 8 benzyloxy 2-methoxyquinoline-5 carboxylate To a solution of 0.41 g of tetrahydrofuran in 7 mL of tetrahydrofuran was added a suspension of 5% palladium on carbon 80 mg of tetrahydrofuran in 2 mL, and the mixture was stirred under a hydrogen atmosphere for 4 hours. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.33 g of butyl = 8 hydroxy-2-methoxyquinoline-5 carboxylate as a white solid.
1H-NMR(CDC1 ) δ値： 1.00(3H,t,J=7.4Hz),1.46- 1.56(2H,m),1.75- 1.83(2H,m),4.08(3  1H-NMR (CDC1) δ value: 1.00 (3H, t, J = 7.4Hz), 1.46-1.56 (2H, m), 1.75- 1.83 (2H, m), 4.08 (3
3  Three
H,s),4.36(2H,t,J=6.6Hz),7.05(lH,d,J=9.3Hz),7.12(lH,d,J=8.3Hz),8.15(lH,d,J=8.3Hz ),8.22(lH,s),9.33(lH,d,J=9.3Hz)  H, s), 4.36 (2H, t, J = 6.6Hz), 7.05 (lH, d, J = 9.3Hz), 7.12 (lH, d, J = 8.3Hz), 8.15 (lH, d, J = 8.3) Hz), 8.22 (lH, s), 9.33 (lH, d, J = 9.3Hz)
[0207] 参考例 70
Figure imgf000103_0002
[0207] Reference Example 70
Figure imgf000103_0002
ブチル = 8 ヒドロキシ 2—メトキシキノリン 5 カルボキシラート 0.16gの塩化メ チレン 5mL溶液に、 2, 6—ルチジン O.lOmLおよび 4ージメチルァミノピリジン 7mgをカロ え、 2°Cに冷却した後、無水トリフルォロメタンスルホン酸 0.1 ImLを滴下し、 1時間攪拌 した。反応混合物に飽和塩ィ匕アンモニゥム水溶液 10mLを加えた。有機層を分取し、 水層を塩化メチレン 5mLで抽出した。有機層および抽出液を合わせ、無水硫酸マグ ネシゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラム クロマトグラフィー [溶離液；へキサン：酢酸ェチル = 30： 1]で精製し、白色油状物の ブチル = 2—メトキシー8 （（トリフルォロメタンスルホ -ル）ォキシ）キノリン 5—力 ルボキシラート 0.17gを得た。 Butyl = 8 Hydroxy 2-methoxyquinoline 5 Carboxylate 0.16 g Methylene chloride in 5 mL solution 2,6-Lutidine O.lOmL and 4-Dimethylaminopyridine 7 mg were added and cooled to 2 ° C, then anhydrous Trifluoromethanesulfonic acid 0.1 ImL was added dropwise and stirred for 1 hour. did. To the reaction mixture was added 10 mL of a saturated aqueous solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 5 mL of methylene chloride. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 30: 1], and white oil butyl = 2-methoxy-8 ((trifluoromethanesulfoyl) oxy) quinoline. 0.17 g of 5-force ruboxylate was obtained.
'H-NMRCCDCl ) δ値： 1.01(3H,t,J=7.4Hz), 1.45- 1.56(2H,m), 1.77- 1.84(2H,m),4.14(3  'H-NMRCCDCl) δ value: 1.01 (3H, t, J = 7.4Hz), 1.45- 1.56 (2H, m), 1.77-1.84 (2H, m), 4.14 (3
3  Three
H,s),4.41(2H,t,J=6.6Hz),7.11(lH,d,J=9.5Hz),7.52(lH,d,J=8.3Hz),8.10(lH,d,J=8.3Hz ),9.20(lH,d,J=9.5Hz)  H, s), 4.41 (2H, t, J = 6.6Hz), 7.11 (lH, d, J = 9.5Hz), 7.52 (lH, d, J = 8.3Hz), 8.10 (lH, d, J = 8.3) Hz), 9.20 (lH, d, J = 9.5Hz)
[0208] 参考例 71
Figure imgf000104_0001
[0208] Reference Example 71
Figure imgf000104_0001
5 ブロモ 2—メトキシ 8—メチルキノリン 1.5gのベンゼン 7.5mL溶液に、室温で N ブロモスクシンイミド l.lgおよび 2, 2，—ァゾビス（イソブチ口-トリル） 58mgをカロえ 、 1時間 50分間加熱還流した。反応混合物を室温まで冷却後、酢酸ェチルおよび水 を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシ ゥムで乾燥させ、減圧下で溶媒を留去し、黄色固体の 5—ブロモー 8—ブロモメチル 2—メトキシキノリン 1.9gを得た。  5 Bromo 2-methoxy 8-methylquinoline 1.5g benzene 7.5mL solution N-bromosuccinimide l.lg and 2,2, -azobis (isobutyor-tolyl) 58mg at room temperature, heated to reflux for 1 hour 50 minutes did. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.9 g of yellow solid 5-bromo-8-bromomethyl 2-methoxyquinoline. It was.
1H-NMR(CDC1 ) δ値： 4.14(3H,s),5.08(2H,s),7.02(lH,d,J=9.0Hz),7.57(lH,d,J=7.8Hz  1H-NMR (CDC1) δ value: 4.14 (3H, s), 5.08 (2H, s), 7.02 (lH, d, J = 9.0Hz), 7.57 (lH, d, J = 7.8Hz)
3  Three
),7.61(lH,d,J=7.8Hz),8.37(lH,d,J=9.0Hz)  ), 7.61 (lH, d, J = 7.8Hz), 8.37 (lH, d, J = 9.0Hz)
[0209] 参考例 72
Figure imgf000104_0002
[0209] Reference Example 72
Figure imgf000104_0002
5 ブロモ 8 ブロモメチル 2—メトキシキノリン 1.9gの酢酸 5mL溶液に、室温で へキサメチレンテトラミン 3.2gの水 5mL溶液を加え、 1時間 30分間加熱還流した。反応 混合物を氷冷下まで冷却後、クロ口ホルムをカ卩え、 20%水酸ィ匕ナトリウム水溶液で pH 7.0に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグ ネシゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラム クロマトグラフィー [溶離液;へキサン:酢酸ェチル = 10 : 1]で精製し、淡黄色固体の 5 ブロモ 2—メトキシキノリン一 8 カルバルデヒド 0.48gを得た。 5 Bromo 8 Bromomethyl 2-methoxyquinoline To a solution of 1.9 g of acetic acid in 5 mL of acetic acid was added 5 mL of water of 3.2 g of hexamethylenetetramine at room temperature, and the mixture was heated to reflux for 1 hour and 30 minutes. After cooling the reaction mixture to ice-cooling, cover with black mouth form and pH with 20% aqueous sodium hydroxide solution. Adjusted to 7.0. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 10: 1] to obtain 0.48 g of 8-bromo-2-methoxyquinoline monocarbaldehyde as a pale yellow solid.
1H-NMR(CDC1 ) δ値： 4.13(3H,s),7.08(lH,d,J=9.3Hz),7.77(lH,d,J=8.0Hz),8.07(lH,d  1H-NMR (CDC1) δ value: 4.13 (3H, s), 7.08 (lH, d, J = 9.3 Hz), 7.77 (lH, d, J = 8.0 Hz), 8.07 (lH, d
3  Three
,J=8.0Hz),8.44(lH,d,J=9.3Hz),11.31(lH,s)  , J = 8.0Hz), 8.44 (lH, d, J = 9.3Hz), 11.31 (lH, s)
[0210] 参考例 73  [0210] Reference Example 73
Figure imgf000105_0001
Figure imgf000105_0001
5 ブロモー 2—メトキシキノリンー8 カルバルデヒド 0.20gのジメチルスルホキシド 5 mL溶液に、室温でトリメチルスルホ-ゥムョージド 0.24g、氷冷下で水酸化カリウム 65m gを加え、 30°Cで 1時間 30分間攪拌した。反応混合物に酢酸ェチルおよび水を加えた 。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾 燥させ、減圧下で溶媒を留去し、橙色固体の 5 プロモー 2—メトキシー 8 （ォキシ ラン一 2—ィル)キノリン 0.20gを得た。  5 Bromo-2-methoxyquinoline-8 Carbaldehyde 0.20 g of dimethyl sulfoxide in 5 mL solution, 0.24 g of trimethylsulfo-methanol at room temperature and 65 mg of potassium hydroxide under ice-cooling, stirred at 30 ° C for 1 hour and 30 minutes did. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an orange solid of 5-promo-2-methoxy-8 (oxylan-2-yl). 0.20 g of quinoline was obtained.
'H-NMRCCDCl ) δ fg: 2.77(lH,dd,J=5.6,2.6Hz),3.30(lH,dd,J=5.6,4.1Hz),4.09(3H,s)  'H-NMRCCDCl) δ fg: 2.77 (lH, dd, J = 5.6,2.6Hz), 3.30 (lH, dd, J = 5.6,4.1Hz), 4.09 (3H, s)
3  Three
,4.90-4.96(lH,m),7.02(lH,d,J=9.0Hz),7.33(lH,d,J=7.9Hz),7.61(lH,d,J=7.9Hz),8.38( lH,d,J=9.0Hz)  , 4.90-4.96 (lH, m), 7.02 (lH, d, J = 9.0Hz), 7.33 (lH, d, J = 7.9Hz), 7.61 (lH, d, J = 7.9Hz), 8.38 (lH, d, J = 9.0Hz)
[0211] 参考例 74  [0211] Reference Example 74
Figure imgf000105_0002
Figure imgf000105_0002
5 ブロモー 2—メトキシ 8 （ォキシラン 2 ィル）キノリン 90mgのジェチルエー テル 3mL溶液に、 20°Cで 5% (トリフルォロボランージェチルエーテル錯体）ジェチ ルエーテル溶液 92 Lを加え、室温で 5時間攪拌した。反応混合物に飽和炭酸水素 ナトリウム水溶液および酢酸ェチルを加えた。有機層を分取し、飽和塩ィ匕ナトリウム水 溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られ た残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 10： 1]で精製し、淡黄色固体の（5 ブロモ—2—メトキシキノリン— 8—ィル)ァセトアル デヒド 35mgを得た。 5 Bromo-2-methoxy 8 (Oxylan 2-yl) quinoline 90 mg of Jetyl Ether 3 mL solution is added 5% (trifluoroborane-jetyl ether complex) jet ether solution 92 L at 20 ° C, and 5 hours at room temperature. Stir. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Obtained The residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 10: 1] to obtain 35 mg of (5 bromo-2-methoxyquinoline-8-yl) acetoaldehyde as a pale yellow solid. .
1H-NMR(CDC1 ) δ値： 4.00(3H,s),4.02- 4.05(2H,m),7.01(lH,d,J=9.0Hz),7.39(lH,d,J=  1H-NMR (CDC1) δ value: 4.00 (3H, s), 4.02- 4.05 (2H, m), 7.01 (lH, d, J = 9.0 Hz), 7.39 (lH, d, J =
3  Three
7.8Hz),7.63(lH,d,J=7.8Hz),8.38(lH,d,J=9.0Hz),9.81-9.84(lH,m)  7.8Hz), 7.63 (lH, d, J = 7.8Hz), 8.38 (lH, d, J = 9.0Hz), 9.81-9.84 (lH, m)
[0212] 参考例 75
Figure imgf000106_0001
[0212] Reference Example 75
Figure imgf000106_0001
メチル = 3 アミノー 4 メチルベンゾアート l.Ogを氷冷下、ピリジン 5.0mLに溶解さ せ、（2E)— 3 エトキシアタリ口イルクロリド 0.90gを滴下した。同温度で 10分間攪拌 後、室温まで昇温し、 4時間攪拌した。反応混合物を氷水に注ぎ、固形物をろ取し、 水で洗浄し、橙色固体のメチル = 3— ( ( (2E)—3—エトキシアタリロイル)ァミノ）—4 メチノレべンゾァート 1.7gを得た。  Methyl = 3 amino-4-methylbenzoate l.Og was dissolved in 5.0 mL of pyridine under ice cooling, and 0.90 g of (2E) -3 ethoxyatyl yl chloride was added dropwise. After stirring at the same temperature for 10 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was poured into ice water and the solid was collected by filtration and washed with water to give 1.7 g of orange solid methyl = 3— (((2E) -3-Ethoxyatalyloyl) amino) —4 methinolevenzoate .
1H-NMR(CDC1 ) δ fg: 1.35(3H,t,J=7.1Hz),2.31(3H,s),3.89(3H,s),3.95(2H,q,J=7.1Hz  1H-NMR (CDC1) δ fg: 1.35 (3H, t, J = 7.1Hz), 2.31 (3H, s), 3.89 (3H, s), 3.95 (2H, q, J = 7.1Hz
3  Three
),5.34(lH,d,J=12.2Hz),6.79(lH,s),7.26(lH,d,J=7.9Hz),7.66(lH,d,J=12.2Hz),7.76(lH ,dd,J=7.9,1.6Hz),8.40(lH,s)  ), 5.34 (lH, d, J = 12.2Hz), 6.79 (lH, s), 7.26 (lH, d, J = 7.9Hz), 7.66 (lH, d, J = 12.2Hz), 7.76 (lH, dd , J = 7.9,1.6Hz), 8.40 (lH, s)
[0213] 参考例 76
Figure imgf000106_0002
[0213] Reference Example 76
Figure imgf000106_0002
濃硫酸 70mLに氷冷下、メチル = 3— ( ( (2E) エトキシアタリロイル)ァミノ）ー4ーメ チルベンゾアート 10gを分割で添加した。同温度で 30分間攪拌後、室温まで昇温し、 6時間攪拌した。反応混合物を氷水 80mLに注ぎ、酢酸ェチルを加えた。水層を分取 し、メタノール 50mLをカ卩えて、 60〜70°Cで 7時間攪拌した。減圧下で溶媒を留去し、 得られた残留物に、水を加えて不溶物をろ取した。得られた不溶物を酢酸ェチルに 懸濁し、 2分間加熱還流した。放冷後、固形物をろ取し、黄白色固体のメチル =8— メチル 2 ォキソ 1 , 2 ジヒドロキノリン 5 カルボキシラート 3.0gを得た。 H-NMR(DMSO-d ) δ値： 2.50(3H,s),3.89(3H,s),6.66(lH,d,J=10.0Hz),7.46(lH,d,J=7 To 70 mL of concentrated sulfuric acid, 10 g of methyl = 3-((((2E) ethoxyatalyloyl) amino) -4-methylbenzoate was added in portions under ice cooling. After stirring for 30 minutes at the same temperature, the temperature was raised to room temperature and stirring was continued for 6 hours. The reaction mixture was poured into 80 mL of ice water and ethyl acetate was added. The aqueous layer was separated, 50 mL of methanol was added, and the mixture was stirred at 60 to 70 ° C. for 7 hours. The solvent was distilled off under reduced pressure, water was added to the obtained residue, and the insoluble material was collected by filtration. The obtained insoluble matter was suspended in ethyl acetate and heated to reflux for 2 minutes. After allowing to cool, the solid was collected by filtration to obtain 3.0 g of methyl = 8-methyl 2-oxo 1,2 dihydroquinoline 5 carboxylate as a pale yellow solid. H-NMR (DMSO-d) δ value: 2.50 (3H, s), 3.89 (3H, s), 6.66 (lH, d, J = 10.0Hz), 7.46 (lH, d, J = 7
6  6
.8Hz),7.65(lH,d,J=7.8Hz),8.69(lH,d,J=10.0Hz),11.02(lH,s)  .8Hz), 7.65 (lH, d, J = 7.8Hz), 8.69 (lH, d, J = 10.0Hz), 11.02 (lH, s)
[0214] 参考例 77
Figure imgf000107_0001
[0214] Reference Example 77
Figure imgf000107_0001
メチル = 8 メチル 2 ォキソ 1 , 2 ジヒドロキノリン 5 カルボキシラート 2.9 gをォキシ塩化リン 18mLに懸濁し、 3時間加熱還流した。放冷後、反応混合物を氷水 に注ぎ、固形物をろ取し、水で洗浄し、黄色固体のメチル = 2 クロ口 8—メチルキ ノリンー 5—力ノレボキシラート 3.7gを得た。  Methyl = 8 Methyl 2 oxo 1,2 Dihydroquinoline 5 Carboxylate (2.9 g) was suspended in 18 mL of phosphorus oxychloride and heated to reflux for 3 hours. After allowing to cool, the reaction mixture was poured into ice water, and the solid matter was collected by filtration and washed with water to obtain 3.7 g of yellow solid methyl = 2-chloroquine 8-methylquinoline-5-force noreboxylate.
'H-NMRCCDCl ) δ値： 2.82(3H,s),3.99(3H,s),7.49(lH,d,J=9.0Hz),7.61(lH,d,J=7.6Hz  'H-NMRCCDCl) δ value: 2.82 (3H, s), 3.99 (3H, s), 7.49 (lH, d, J = 9.0Hz), 7.61 (lH, d, J = 7.6Hz)
3  Three
),8.20(lH,d,J=7.6Hz),9.37(lH,d,J=9.0Hz)  ), 8.20 (lH, d, J = 7.6Hz), 9.37 (lH, d, J = 9.0Hz)
[0215] 参考例 78
Figure imgf000107_0002
[0215] Reference Example 78
Figure imgf000107_0002
参考例 18と同様な方法で、メチル = 2 クロロー 8 メチルキノリン 5 カルボキ シラート 3.5gからメチル = 2—メトキシ一 8—メチルキノリン一 5—カルボキシラート 1.5g を得た。  In the same manner as in Reference Example 18, 1.5 g of methyl-2-chloro-8-methylquinoline-5-carboxylate was obtained from 3.5 g of methyl = 2 chloro-8-methylquinoline-5-carboxylate.
'H-NMRCCDCl ) δ fg: 2.75(3H,s),3.96(3H,s),4.08(3H,s),7.01(lH,d,J=9.3Hz), 7.50(1  'H-NMRCCDCl) δ fg: 2.75 (3H, s), 3.96 (3H, s), 4.08 (3H, s), 7.01 (lH, d, J = 9.3Hz), 7.50 (1
3  Three
H,d,J=7.6Hz),8.01(lH,d,J=7.6Hz),9.20(lH,d,J=9.3Hz)  H, d, J = 7.6Hz), 8.01 (lH, d, J = 7.6Hz), 9.20 (lH, d, J = 9.3Hz)
[0216] 参考例 79  [0216] Reference Example 79
Figure imgf000107_0003
Figure imgf000107_0003
メチル = 2—メトキシー 8—メチルキノリン 5 カルボキシラート 1.5gのベンゼン 12m L溶液に、室温で N ブロモスクシンイミド l.lgおよび 2, 2'—ァゾビス（イソブチロニト リル) 70mgを加え、 2時間加熱還流した。反応混合物を放冷後、水および酢酸ェチル を加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留 去し、黄色固体のメチル = 8 ブロモメチル 2—メトキシキノリン 5 カルボキシラ ート 2. lgを得た。 Methyl 2-methoxy-8-methylquinoline 5 carboxylate To a solution of 1.5 g of benzene in 12 mL of benzene were added N bromosuccinimide l.lg and 70 mg of 2,2′-azobis (isobutyronitrile) at room temperature, and the mixture was heated to reflux for 2 hours. After allowing the reaction mixture to cool, water and ethyl acetate Was added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.lg of methyl solid = 8 bromomethyl 2-methoxyquinoline 5 carboxylate as a yellow solid.
1H-NMR(CDC1 ) δ値： 3.98(3H,s),4.11(3H,s),5.11(2H,s),7.04(lH,d,J=9.4Hz), 7.74(1  1H-NMR (CDC1) δ value: 3.98 (3H, s), 4.11 (3H, s), 5.11 (2H, s), 7.04 (lH, d, J = 9.4 Hz), 7.74 (1
3  Three
H,d,J=7.7Hz),8.02(lH,d,J=7.7Hz),9.15(lH,d,J=9.4Hz)  H, d, J = 7.7Hz), 8.02 (lH, d, J = 7.7Hz), 9.15 (lH, d, J = 9.4Hz)
[0217] 参考例 80  [0217] Reference Example 80
Figure imgf000108_0001
Figure imgf000108_0001
メチル = 8 ブロモメチルー 2—メトキシキノリン 5 カルボキシラート 2.0gの塩化メ チレン 10mL溶液に、氷冷下、ジメチルスルホキシド 20mLおよびトリメチルアミン=N —ォキシド =二水和物 4.3gをカ卩え、 5〜10°Cで 2時間 20分間攪拌した、トリメチルアミ ン=?^—ォキシド =二水和物 4.3gをカ卩え、 1時間 30分間攪拌した。トリメチルアミン= N—ォキシド=二水和物 4.3gを加え、 45分間攪拌した。反応混合物に飽和塩化ナトリ ゥム水溶液、水および酢酸ェチルをカ卩えた。有機層を分取し、無水硫酸マグネシウム で乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグ ラフィー [溶離液；へキサン:酢酸ェチル = 5 : 1]で精製し、黄色固体のメチル = 8— ホルミル 2—メトキシキノリン 5 カルボキシラート 0.61gを得た。  Methyl = 8 Bromomethyl-2-methoxyquinoline 5 Carboxylate 2.0 g of methyl chloride in 10 mL solution, ice-cooled, with dimethyl sulfoxide 20 mL and trimethylamine N-oxide = dihydrate 4.3 g, 5-10 ° After stirring for 2 hours and 20 minutes with C, 4.3 g of trimethylamine =? ^-Oxide = dihydrate was added and stirred for 1 hour and 30 minutes. 4.3 g of trimethylamine = N-oxide = dihydrate was added and stirred for 45 minutes. Saturated aqueous sodium chloride solution, water and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1] to obtain 0.61 g of methyl = 8-formyl 2-methoxyquinoline 5 carboxylate as a yellow solid.
'H-NMRCCDCl ) δ fg:4.02(3H,s),4.12(3H,s),7.08(lH,d,J=9.4Hz),8.11(lH,d,J=7.8Hz  'H-NMRCCDCl) δ fg: 4.02 (3H, s), 4.12 (3H, s), 7.08 (lH, d, J = 9.4Hz), 8.11 (lH, d, J = 7.8Hz
3  Three
),8.20(lH,d,J=7.8Hz),9.13(lH,d,J=9.4Hz),11.38(lH,s)  ), 8.20 (lH, d, J = 7.8Hz), 9.13 (lH, d, J = 9.4Hz), 11.38 (lH, s)
[0218] 参考例 81  [0218] Reference Example 81
Figure imgf000108_0002
Figure imgf000108_0002
メチル = 8 ホルミル 2ーメトキシキノリン 5 カルボキシラート 20mgの N, N— ジメチルホルムアミド lmL溶液に、室温でトリメチルスルホ-ゥムョージド 19mg、氷冷 下で 60%水素化ナトリウム 4mgを加え、同温度で 30分間攪拌した。反応混合物に酢 酸ェチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、 無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色油状物のメチル =Methyl = 8 Formyl 2-Methoxyquinoline 5 Carboxylate Add 20 mg of N, N-dimethylformamide in lmL solution at room temperature, add 19 mg of trimethylsulfo-methanolide, 4 mg of 60% sodium hydride under ice cooling, and stir at the same temperature for 30 minutes did. Ethyl acetate and water were added to the reaction mixture. The organic layer is separated and washed with a saturated aqueous sodium chloride solution, Dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure.
2—メトキシ 8 （ォキシラン 2 ィル）キノリン 5 カルボキシラート 20mgを得た 1H-NMR(CDC1 ) δ fg: 2.77(lH,dd,J=5.9,2.6Hz),3.34(lH,dd,J=5.9,4.4Hz),3.98(3H,s) 1-H NMR (CDC1) δ fg: 2.77 (lH, dd, J = 5.9,2.6Hz), 3.34 (lH, dd, J = 5.9), which gave 20 mg of 2-methoxy 8 (oxylan 2yl) quinoline 5 carboxylate , 4.4Hz), 3.98 (3H, s)
3  Three
,4.09(3H,s),5.02(lH,dd,J=4.4,2.6Hz),7.05(lH,d,J=9.3Hz),7.51(lH,d,J=7.7Hz),8.08(l H,d,J=7.7Hz),9.20(lH,d,J=9.3Hz)  , 4.09 (3H, s), 5.02 (lH, dd, J = 4.4,2.6Hz), 7.05 (lH, d, J = 9.3Hz), 7.51 (lH, d, J = 7.7Hz), 8.08 (l H , d, J = 7.7Hz), 9.20 (lH, d, J = 9.3Hz)
[0219] 参考例 82
Figure imgf000109_0001
[0219] Reference Example 82
Figure imgf000109_0001
2 クロロー 6—メトキシー8 -トロキノリン 0.10gのメタノール 2mL懸濁液に、室温で 28%ナトリウムメトキシド /メタノール 0.24gのメタノール 0.5mL溶液をカ卩え、 5時間加熱 還流した。反応混合物を室温まで冷却し、酢酸ェチルおよび水を加えた。有機層を 分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナ トリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し 、淡黄色固体の 2, 6 ジメトキシー 8 -トロキノリン 50mgを得た。  2 Chloro-6-methoxy-8-troquinoline A solution of 0.10 g of methanol in 2 mL of methanol was charged with a 0.5 mL solution of 28% sodium methoxide / methanol 0.24 g in methanol at room temperature and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 50 mg of 2,6 dimethoxy-8-troquinoline as a pale yellow solid.
1H-NMR(CDC1 ) δ fg: 3.94(3H,s),4.03(3H,s),6.99(lH,d,J=9.0Hz),7.26(lH,s), 7.63(1  1H-NMR (CDC1) δ fg: 3.94 (3H, s), 4.03 (3H, s), 6.99 (lH, d, J = 9.0Hz), 7.26 (lH, s), 7.63 (1
3  Three
H,d,J=2.7Hz),7.94(lH,d,J=9.0Hz)  H, d, J = 2.7Hz), 7.94 (lH, d, J = 9.0Hz)
[0220] 参考例 83
Figure imgf000109_0002
[0220] Reference Example 83
Figure imgf000109_0002
2, 6 ジメトキシー 8 -トロキノリン 45mgの酢酸 5mL溶液に、室温で 10%パラジゥ ム—炭素 9mgを加え、水素雰囲気下で 2時間攪拌した。不溶物をろ去し、減圧下で溶 媒を留去した。得られた残留物に酢酸ェチルおよび飽和炭酸水素ナトリウム水溶液 を加えた。有機層を分取し、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水 硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲ ルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 10 : 1]で精製し、白色 固体の 2, 6 ジメトキシキノリン一 8 ァミン 14mgを得た。 H-NMR(CDC1 ) δ値： 3.85(3H,s),4.03(3H,s),4.66- 4.90(2H,m),6.47(lH,d,J=2.6Hz),6 To a solution of 45 mg of 2,6 dimethoxy-8-troquinoline in 5 mL of acetic acid was added 9 mg of 10% palladium-carbon at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. Insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 10: 1] to obtain 14 mg of 2,6 dimethoxyquinoline monoamine, white solid. H-NMR (CDC1) δ value: 3.85 (3H, s), 4.03 (3H, s), 4.66- 4.90 (2H, m), 6.47 (lH, d, J = 2.6Hz), 6
3  Three
.58(lH,d,J=2.6Hz),6.86(lH,d,J=8.8Hz),7.83(lH,d,J=8.8Hz)  .58 (lH, d, J = 2.6Hz), 6.86 (lH, d, J = 8.8Hz), 7.83 (lH, d, J = 8.8Hz)
[0221] 参考例 84
Figure imgf000110_0001
[0221] Reference Example 84
Figure imgf000110_0001
1— (2— (2, 3 ジヒドロべンゾ [b] [ 1 ,4]ジォキシンー6 ィル）ェチル）ピぺリジン 4一力ルボン酸 0.50gの塩化メチレン 5mL溶液に、氷冷下、塩化チォ -ル 2mLおよ ΧβΝ, Ν ジメチルホルムアミド 1滴をカ卩え、 1時間 20分間加熱還流した。減圧下で溶 媒を留去し、テトラヒドロフラン 2mLを加え、氷冷下、 25%アンモニア水 10mLに滴下し 、室温で 30分間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールをカロ え、不溶物をろ去し、減圧下で溶媒を留去し、黄褐色固体の 1— (2— (2, 3 ジヒド 口べンゾ [b] [ 1 ,4]ベンゾジォキシン 6 ィル）ェチノレ）ピぺリジン 4 力ノレボキサ ミド 0.75gを得た。  1— (2— (2, 3 Dihydrobenzzo [b] [1,4] dioxin-6 yl) ethyl) piperidine 4 Monostrophic rubonic acid 0.50 g methylene chloride in 5 mL solution under ice-cooling 2 mL of thiol and 1 drop of ΧβΝ, Ν dimethylformamide were added and heated to reflux for 1 hour and 20 minutes. The solvent was distilled off under reduced pressure, 2 mL of tetrahydrofuran was added, and the mixture was added dropwise to 10 mL of 25% aqueous ammonia under ice cooling, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, methanol was removed from the resulting residue, the insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and 1- (2- (2,3 dihydride) was obtained as a tan solid. Mouth Benzo [b] [1,4] benzodioxin 6 yl) ethinole) piperidine 4 force novaboxamide 0.75 g was obtained.
'H-NMRCDMSO-d ) δ値： 1.76- 1.98(4H,m),2.24- 2.42(lH,m),2.71- 2.96(4H,m),3.05- 'H-NMRCDMSO-d) δ value: 1.76- 1.98 (4H, m), 2.24- 2.42 (lH, m), 2.71- 2.96 (4H, m), 3.05-
6 6
3.18(2H,m),3.41-3.54(2H,m),4.21(4H,s),6.70(lH,dd,J=8.2, 1.9Hz),6.78(lH,d,J=1.9H z),6.80(lH,d,J=8.2Hz),7.16-7.46(lH,m),7.42(lH,s)  3.18 (2H, m), 3.41-3.54 (2H, m), 4.21 (4H, s), 6.70 (lH, dd, J = 8.2, 1.9Hz), 6.78 (lH, d, J = 1.9H z), 6.80 (lH, d, J = 8.2Hz), 7.16-7.46 (lH, m), 7.42 (lH, s)
[0222] 参考例 85
Figure imgf000110_0002
[0222] Reference Example 85
Figure imgf000110_0002
7—メトキシ一 4—メチルイソキノリン一 1— (2H)—オン 1.8gをォキシ塩化リン 12mL に懸濁し、 1時間 30分間加熱還流した。減圧下で溶媒を留去し、残留物に水および 飽和炭酸水素ナトリウム水溶液を加え、酢酸ェチルを加えた。有機層を分取し、無水 硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲ ルカラムクロマトグラフィー [溶離液;へキサン:酢酸ェチル = 5 : 1]で精製し、淡黄色 固体の 1—クロ口一 7—メトキシ一 4—メチルイソキノリン 1.6gを得た。  1.8 g of 7-methoxy-1-4-methylisoquinoline-1- (2H) -one was suspended in 12 mL of phosphorus oxychloride and heated to reflux for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, water and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and ethyl acetate was added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 5: 1] to obtain 1.6 g of 1-chloro-1-4-methylisoquinoline as a pale yellow solid. It was.
1H-NMR(CDC1 ) δ fg : 2.56(3H,s),3.99(3H,s),7.41(lH,dd,J=9.1 ,2.1Hz),7.55(lH,d,J=  1H-NMR (CDC1) δ fg: 2.56 (3H, s), 3.99 (3H, s), 7.41 (lH, dd, J = 9.1, 2.1 Hz), 7.55 (lH, d, J =
3  Three
2.7Hz),7.85(lH,d,J=9.1Hz),8.00(lH,s) [0223] 参考例 86
Figure imgf000111_0001
2.7Hz), 7.85 (lH, d, J = 9.1Hz), 8.00 (lH, s) [0223] Reference example 86
Figure imgf000111_0001
1—クロ口一 7—メトキシ一 4—メチルイソキノリン 1.7gのベンゼン 13mL溶液に、室温 で N—ブロモスクシンイミド 1.4gおよび 2, 2，—ァゾビス（イソブチ口-トリル） 80mgをカロ え、 6時間加熱還流した。反応混合物を放冷後、水および酢酸ェチルを加えた。有機 層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ 、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶 離液;へキサン:酢酸ェチル =4 : 1]で精製し、淡黄色固体の 4 ブロモメチル 1 クロ口一 7—メトキシイソキノリン 1.8gを得た。  1-Black 7-Methoxy-1-4-Methylisoquinoline 1.7g benzene 13mL solution, N-bromosuccinimide 1.4g and 2, 2, -azobis (isobuty-mouth-tolyl) 80mg at room temperature, heated for 6 hours Refluxed. After allowing the reaction mixture to cool, water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 4: 1] to obtain 1.8 g of 4-bromomethyl 1-chloroisoquinoline as a pale yellow solid.
'H-NMRCCDCl ) δ fg:4.01(3H,s),4.82(2H,s),7.52(lH,dd,J=9.1,2.7Hz),7.63(lH,d,J=  'H-NMRCCDCl) δ fg: 4.01 (3H, s), 4.82 (2H, s), 7.52 (lH, dd, J = 9.1,2.7Hz), 7.63 (lH, d, J =
3  Three
2.7Hz),8.05(lH,d,J=9.2Hz),8.21(lH,s)  2.7Hz), 8.05 (lH, d, J = 9.2Hz), 8.21 (lH, s)
[0224] 参考例 87
Figure imgf000111_0002
[0224] Reference Example 87
Figure imgf000111_0002
4 -ブロモメチル 1 クロ口一 7 メトキシイソキノリン 1.9gの塩化メチレン 7.4mL溶 液に、ジメチルスルホキシド 15mLおよびトリメチルアミン=?^—ォキシド =二水和物 3. 6gをカ卩え、 60〜70°Cで 5時間 20分間攪拌した。トリメチルアミン=?^—ォキシド =二水 和物 1.4gを加え、 65〜75°Cで 1時間攪拌した。反応混合物に飽和炭酸ナトリウム水溶 液、水および酢酸ェチルをカ卩えた。有機層を分取し、水層を酢酸ェチルで抽出した 。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、 無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリ 力ゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 1 : 2]で精製し、淡 黄色固体の 7 メトキシ一 1 ォキソ 1, 2 ジヒドロイソキノリン 4 カルバルデヒ ド 0.38gを得た。  4-Bromomethyl 1 Black mouth 7 Methoxyisoquinoline 1.9 g of methylene chloride 7.4 mL, dimethyl sulfoxide 15 mL and trimethylamine =? ^-Oxide = dihydrate 3.6 g were added at 60-70 ° C. Stir for 5 hours and 20 minutes. 1.4 g of trimethylamine =? ^-Oxide = dihydrate was added and stirred at 65-75 ° C. for 1 hour. A saturated sodium carbonate aqueous solution, water and ethyl acetate were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 1: 2), and 0.38 g of 7-methoxy-1,1-dihydroisoquinoline-4 carbaldehyde as a pale yellow solid was obtained. Obtained.
1H-NMR(CDC1 ) δ fg: 3.96(3H,s),7.42(lH,dd,J=9.0,2.9Hz),7.64-7.68(lH,m),7.82(l H,d,J=2.9Hz),9.01(lH,d,J=9.0Hz),9.79(lH,s),10.67(lH,s) 1H-NMR (CDC1) δ fg: 3.96 (3H, s), 7.42 (lH, dd, J = 9.0, 2.9Hz), 7.64-7.68 (lH, m), 7.82 (l H, d, J = 2.9Hz), 9.01 (lH, d, J = 9.0Hz), 9.79 (lH, s), 10.67 (lH, s)
[0225] 参考例 88  [0225] Reference Example 88
Figure imgf000112_0001
Figure imgf000112_0001
60%水素化ナトリウム 0.35gの N, N ジメチルホルムアミド 5.4mL懸濁液に、氷冷下 、ジェチルホスホノ酢酸ェチル 2.0gを加え、氷冷〜室温で 1時間攪拌した。室温で 7 —メトキシ一 1 ォキソ 1, 2 ジヒドロイソキノリン一 4 カルバルデヒド 0.36gの N, N ジメチルホルムアミド 3mL溶液を滴下し、 60〜70°Cで 6時間 30分間攪拌した。反 応混合物を室温まで冷却後、水を加え、飽和塩ィ匕アンモ-ゥム水溶液で中和し、酢 酸ェチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸 マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に冷ジェチル エーテルを加えて、固形物をろ取し、淡黄白色固体のェチル = (E) - 3- (7—メトキ シ一 1 ォキソ 1, 2 ジヒドロイソキノリン 4 ィル)アタリラート 0.25gを得た。 'H-NMRCCDCl ) δ値： 1.36(3H,t,J=7.0Hz),3.97(3H,s),4.29(2H,q,J=7.0Hz),6.33(lH,d  To a suspension of 60% sodium hydride 0.35 g of N, N dimethylformamide 5.4 mL, 2.0 g of ethyl ethylphosphonoacetate was added under ice cooling, and the mixture was stirred at ice cooling to room temperature for 1 hour. 7-Methoxy-1-oxo-1,2-dihydroisoquinoline-4 carbaldehyde 0.36 g of N, N dimethylformamide 3 mL solution was added dropwise at room temperature, and the mixture was stirred at 60 to 70 ° C. for 6 hours 30 minutes. The reaction mixture was cooled to room temperature, water was added, neutralized with a saturated aqueous solution of ammonium chloride, and ethyl acetate was added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Cold jetyl ether is added to the obtained residue, and the solid is collected by filtration. A light yellowish white solid ethyl = (E)-3- (7-methoxy 1 1 oxo 1, 2 dihydroisoquinoline 4 yl) 0.25 g of attalylate was obtained. 'H-NMRCCDCl) δ value: 1.36 (3H, t, J = 7.0Hz), 3.97 (3H, s), 4.29 (2H, q, J = 7.0Hz), 6.33 (lH, d
3  Three
,J=15.7Hz),7.39(lH,dd,J=9.0,2.5Hz),7.45(lH,s),7.84(lH,d,J=9.0Hz),7.87(lH,d,J=2. 5Hz),8.00(lH,d,J=15.7Hz),11.40(lH,s)  , J = 15.7Hz), 7.39 (lH, dd, J = 9.0,2.5Hz), 7.45 (lH, s), 7.84 (lH, d, J = 9.0Hz), 7.87 (lH, d, J = 2. 5Hz), 8.00 (lH, d, J = 15.7Hz), 11.40 (lH, s)
[0226] 参考例 89  [0226] Reference Example 89
Figure imgf000112_0002
Figure imgf000112_0002
ェチノレ = (E) - 3- (7—メトキシ一 1—ォキソ 1, 2 ジヒドロイソキノリン一 4—ィ ル)アタリラート 0.25gをォキシ塩化リン 3.5mLに懸濁し、 1時間 45分間加熱還流した。 減圧下で溶媒を留去し、残留物に水、飽和炭酸水素ナトリウム水溶液および酢酸ェ チルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグ ネシゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にへキサンを加えて 、固形物をろ取し、淡黄白色固体のェチル = (E) - 3- (1—クロ口 7—メトキシイソ キノリン一 4—ィル)アタリラート 0.30gを得た。 Ethinole = (E) -3- (7-methoxy-1-oxo-1,2-dihydroisoquinoline-4-yl) attalylate 0.25 g was suspended in 3.5 mL of phosphorus oxychloride and heated to reflux for 1 hour 45 minutes. The solvent was distilled off under reduced pressure, and water, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane is added to the obtained residue, and the solid is collected by filtration. The pale yellowish white solid ethyl = (E)-3- (1-black 7-methoxyiso 0.30 g of quinoline 4-yl) attalylate was obtained.
1H-NMR(CDC1 ) δ値： 1.38(3H,t,J=7.2Hz),4.02(3H,s),4.32(2H,q,J=7.2Hz),6.57(lH,d  1H-NMR (CDC1) δ value: 1.38 (3H, t, J = 7.2Hz), 4.02 (3H, s), 4.32 (2H, q, J = 7.2Hz), 6.57 (lH, d
3  Three
,J=16.0Hz),7.50(lH,dd,J=9.3,2.7Hz),7.61(lH,d,J=2.7Hz),8.07(lH,d,J=9.3Hz),8.26(l H,d,J=16.0Hz),8.39(lH,s)  , J = 16.0Hz), 7.50 (lH, dd, J = 9.3,2.7Hz), 7.61 (lH, d, J = 2.7Hz), 8.07 (lH, d, J = 9.3Hz), 8.26 (l H, d, J = 16.0Hz), 8.39 (lH, s)
[0227] 参考例 90  [0227] Reference Example 90
Figure imgf000113_0001
Figure imgf000113_0001
窒素気流下、ェチル = (E) - 3- (1—クロ口一 7—メトキシイソキノリン一 4—ィル） アタリラート 0.20gのトルエン 4mL溶液に、室温でトリブチルビ-ルスズ 0.26gおよびビス (トリー tert ブチルホスフィン）パラジウム（0) 35mgを加え、 100〜105°Cで 30分間攪 拌した。反応混合物を放冷し、水、飽和塩ィ匕ナトリウム水溶液および酢酸ェチルをカロ えた。有機層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わ せ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物 をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 3： 1]で精製し 、黄色固体のェチル = (E)—3— (7—メトキシ— 1—ビュルイソキノリン— 4—ィル）ァ タリラート 42mgを得た。  Under nitrogen flow, ethyl = (E)-3- (1-black mouth 7-methoxyisoquinoline 1-4-yl) Atalylate 0.20 g of toluene in 4 mL of toluene at room temperature with 0.26 g of tributylvinyltin and bis (tree tert butyl) Phosphine) palladium (0) 35 mg was added, and the mixture was stirred at 100 to 105 ° C. for 30 minutes. The reaction mixture was allowed to cool, and water, saturated aqueous sodium chloride solution and ethyl acetate were calorieated. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1] to give a yellow solid ethyl = (E) -3— (7-methoxy-1-bululisoquinoline-4 -Il) 42 mg of taritalate was obtained.
1H-NMR(CDC1 ) δ値： 1.38(3H,t,J=7.1Hz),3.98(3H,s),4.32(2H,q,J=7.1Hz),5.75(lH,d  1H-NMR (CDC1) δ value: 1.38 (3H, t, J = 7.1Hz), 3.98 (3H, s), 4.32 (2H, q, J = 7.1Hz), 5.75 (lH, d
3  Three
,J=10.7Hz),6.56(lH,dd,J=16.8,1.7Hz),6.58(lH,d,J=15.8Hz),7.42(lH,dd,J=9.3,2.4Hz) , J = 10.7Hz), 6.56 (lH, dd, J = 16.8,1.7Hz), 6.58 (lH, d, J = 15.8Hz), 7.42 (lH, dd, J = 9.3,2.4Hz)
,7.49(lH,d,J=2.4Hz),7.55(lH,dd,J=16.8,10.7Hz),8.07(lH,d,J=9.3Hz),8.33(lH,d,J=l, 7.49 (lH, d, J = 2.4Hz), 7.55 (lH, dd, J = 16.8,10.7Hz), 8.07 (lH, d, J = 9.3Hz), 8.33 (lH, d, J = l
5.8Hz),8.65(lH,s) 5.8Hz), 8.65 (lH, s)
[0228] 参考例 91  [0228] Reference Example 91
Figure imgf000113_0002
Figure imgf000113_0002
5 ブロモ 2—メトキシ一 8— (ォキシラン一 2—ィル）キノリン 4.1gの N, N ジメチ ルホルムアミド 25mL溶液に、室温で 4 （（tert ブトキシカルボ-ル）ァミノ）ピベリジ ン 4.1gおよび過塩素酸リチウム 2.2gを加え、 90°Cで 5時間攪拌した。反応混合物を室 温まで冷却し、水 50mLおよび酢酸ェチル 50mLをカ卩えた。有機層を分取し、水層を酢 酸ェチル 20mLで抽出した。有機層および抽出液を合わせ、飽和塩ィ匕ナトリウム水溶 液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた 残留物にジェチルエーテルを加え、固形物をろ取し、白色固体の tert ブチル = (1 - (2- (5 ブロモ 2—メトキシキノリン一 8—ィル） 2 ヒドロキシェチル）ピベリジ ン 4 ィル）力ルバマート 5.7gを得た。 5 Bromo 2-methoxy-1-8- (oxylan-2-yl) quinoline 4.1 g of N, N dimethylformamide in 25 mL of solution at room temperature with 4 ((tert-butoxycarbol) amino) piverid 4.1 g of lithium and 2.2 g of lithium perchlorate were added and stirred at 90 ° C. for 5 hours. The reaction mixture was cooled to room temperature and 50 mL of water and 50 mL of ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Jetyl ether was added to the obtained residue, and the solid was collected by filtration. Then, white solid tert butyl = (1-(2- (5 bromo 2 -methoxyquinoline 1-8 -yl) 2 hydroxyethyl) pipelid 4 il) Obtained 5.7 g of strength rubamate.
'H-NMRCCDCl ) δ fg: 1.39-1.67(HH,m),1.90-2.10(2H,m),2.15-2.30(lH,m),2.30-2.  'H-NMRCCDCl) δ fg: 1.39-1.67 (HH, m), 1.90-2.10 (2H, m), 2.15-2.30 (lH, m), 2.30-2.
3  Three
50(2H,m),2.75-2.85(lH,m),2.94-2.99(lH,m),3.15-3.30(lH,m),3.40-3.60(lH,m),4.03 (3H,s),4.20-4.35(lH,m),4.40-4.55(lH,m),5.70(lH,dd,J=9.8,3.1Hz),6.98(lH,d,J=9.0 Hz),7.65(lH,d,J=8.1Hz),7.71(lH,d,J=8.1Hz),8.37(lH,d,J=9.0Hz)  50 (2H, m), 2.75-2.85 (lH, m), 2.94-2.99 (lH, m), 3.15-3.30 (lH, m), 3.40-3.60 (lH, m), 4.03 (3H, s), 4.20-4.35 (lH, m), 4.40-4.55 (lH, m), 5.70 (lH, dd, J = 9.8,3.1Hz), 6.98 (lH, d, J = 9.0 Hz), 7.65 (lH, d, J = 8.1Hz), 7.71 (lH, d, J = 8.1Hz), 8.37 (lH, d, J = 9.0Hz)
参考例 92 Reference Example 92
Figure imgf000114_0001
Figure imgf000114_0001
tert—ブチル = (1— (2— (5 ブロモ 2—メトキシキノリン一 8—ィル） 2 ヒドロ キシェチル）ピぺリジン— 4—ィル）力ルバマート 5.4gの N, N ジメチルホルムアミド 2 7mL溶液に、トリェチルァミン 2.3mL、ェチル =アタリラート 1.8mLおよびビス（トリー ter t ブチルホスフィン)パラジウム（O) 0.17gをカ卩え、窒素気流下、 96〜100°Cで 1時間 3 0分間攪拌した。反応混合物に水 50mLおよび酢酸ェチル 50mLを加え、不溶物をろ 去した。有機層を分取し、水層を酢酸ェチル 10mLで抽出した。有機層および抽出液 を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、 減圧下で溶媒を留去し、黄色油状物のェチル = (E) 3—（8—（2—（4一（(tert— ブトキシカルボ-ル）ァミノ）ピぺリジン— 1—ィル） - 1—ヒドロキシェチル）— 2—メト キシキノリン一 5—ィル)アタリラート 8.4gを得た。 tert-Butyl = (1— (2— (5 Bromo-2-methoxyquinoline 1-8-yl) 2 Hydrochichetyl) piperidine-4-yl) Power rubamate 5.4 g N, N dimethylformamide 2 in 7 mL solution Triethylamine 2.3 mL, ethyl = atarylate 1.8 mL and bis (tree tert butylphosphine) palladium (O) 0.17 g were added and stirred at 96-100 ° C. for 1 hour 30 minutes under a nitrogen stream. 50 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and insoluble materials were removed by filtration. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl of yellow oil = (E) 3— (8— (2— ( 4 ((tert-Butoxycarbol) amino) piperidine-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5-yl) Atalylate 8.4 g was obtained.
- NMR(CDC1 ) S値：  -NMR (CDC1) S value:
3  Three
1.30-1.70(2H,m),1.37(3H,t,J=7.1Hz),1.45(9H,s),1.90-2.05(2H,m),2.17-2.25(lH,m), ΐ=ί"'ΡΡ'Ηΐ)00·ε'(ω'Η 38 - 09 ' (ra'HS)SS - 0 '(S'H6) ·ΐ :軍 9 ( !DaD)H N-HT
Figure imgf000115_0001
1.30-1.70 (2H, m), 1.37 (3H, t, J = 7.1Hz), 1.45 (9H, s), 1.90-2.05 (2H, m), 2.17-2.25 (lH, m), ΐ = ί "'ΡΡ'Ηΐ) 00 ・ ε' (ω '-38-09'(ra'HS) SS-0 '( S ' H6) ΐΐ: Army 9 (! DaD) H NH T
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0002
(s'HI)SS'0I'(zHS'6=l"'P'HI)S9'8'(ra'HS)09'8— S 8'(zH6'SI=f'P'HI )eS"8'(zHZ"Z=rP'HT)00"8'(zHZ"Z=rP'HT)26"Z'(ZHS"6=rP'HT)9rZ'(ZH6"ST=rP'HT)S Γ9'(ω'Ηΐ)03·9— 0 ·9'(ω'Ηΐ)3ΐ·9— S0'9'(ZH =f'b'HS) ^ (S'HS)80' (ω'Ηΐ)00·— 0
Figure imgf000115_0003
:軍 9 ( p-os a)H N-HT
Figure imgf000115_0004
( s ' HI) SS'0I '( z HS'6 = l "'P'HI)S9'8'(ra'HS)09'8— S 8' ( z H6'SI = f'P'HI) eS "8 '( z HZ" Z = rP'HT) 00 "8' ( z HZ" Z = rP'HT) 26 "Z '(ZHS" 6 = rP'HT) 9rZ' (ZH6 "ST = rP ' HT) S Γ9 '(ω'Ηΐ) 03 · 9— 0 · 9'(ω'Ηΐ) 3ΐ · 9— S0'9 '( Z H = f'b'HS) ^ ( S ' HS) 80 '( ω'Ηΐ) 00 · — 0
Figure imgf000115_0003
: Military 9 (p-os a) H NH T
Figure imgf000115_0004
、つ辛恩 瀚缀、 止 ϊί教 °
Figure imgf000115_0005
辛 辛, 瀚 缀 教 ί ℃
Figure imgf000115_0005
Figure imgf000115_0006
Figure imgf000115_0006
(ZHS"6=rP'HT)8S"8'(zHZ"ST=rP'H T)eS"8'(zH8"Z=rP'HT)Z8"Z'(ZH8"Z=rP'HT)89"Z'(ZHS"6=rP'HT)66"9'(zHZ"ST=rP'HT )SS'9'(zHS'S'0'0I=rPP'HI)9rS'(ZHrZ=f'b'HS)9S' C"'HS)0S'— SS' (s'HS)SO'(ZHS "6 = rP'HT) 8S" 8 '( z HZ "ST = rP'H T) eS"8' ( z H8 "Z = rP'HT) Z8" Z '(ZH8 "Z = rP'HT ) 89 "Z '(ZHS" 6 = rP'HT) 66 "9' ( z HZ" ST = rP'HT) SS'9 '( z HS'S'0'0I = rPP'HI) 9rS' (ZHrZ = f 'b'HS) 9S' C "'HS) 0S'— SS'(s'HS) SO '
Ήΐ)09·ε— ο ·ε'(ω'Ηΐ)οε·ε— 3ΐ·ε'(ω'Ηΐ)εο·ε— ε6 ' C"'Hi)s8 — sz ' C"'Hs)os — Ήΐ) 09 · ε— ο · ε '(ω'Ηΐ) οε · ε— 3ΐ · ε' (ω'Ηΐ) εο · ε— ε6 'C "' Hi) s8 — sz 'C"' Hs) os —
98S6T0/S00Zdf/X3d ε ΓΡΉΐ)9Γ '(ζΗ6·3ΐ=ΓΡΉΐ)ε ·9'(ΡΏΟ^Ήΐ)09·9-32·9'(ω'Ηΐ)02·9-0Γ9'(ζΗΓ =Γ¾' Η '(δ'Ηε)80· '(ω'Η0ΐ · — ο ·ε'(ζΗΐ·ζ=π'Ηε)οε·ΐ :軍 9 ( OS ) Η顺— Ητ
Figure imgf000116_0001
98S6T0 / S00Zdf / X3d ε ΓΡΉΐ) 9Γ '(ζΗ6 · 3ΐ = ΓΡΉΐ) ε · 9' (Ρ ΏΟ ^ Ήΐ) 09 · 9-32 · 9 '(ω'Ηΐ) 02 · 9-0Γ9' (ζ ΗΓ = Γ¾ 'Η' (δ 'Ηε) 80 ·'(ω'Η0ΐ · — ο · ε '( ζ Ηΐ · ζ = π'Ηε) οε · ΐ: Army 9 (OS) Η 顺 — Η τ
Figure imgf000116_0001
y-i
Figure imgf000116_0002
-ζ) -8)— ε— (Ή) = ェ 理 S S Ν ΟΗ Ν OH yi
Figure imgf000116_0002
-ζ) -8) — ε— (Ή) = 理 SS Ν ΟΗ Ν OH
(zH2"6=rP'HT)6S"8'(zH6"eT=rP'HT)SS"8'(zH8"Z=rP'HT)Z8"Z'(zH8"Z=f'P'HT)69"Z
Figure imgf000116_0003
(zH2 "6 = rP'HT) 6S" 8 '( z H6 "eT = rP'HT) SS"8' ( z H8 "Z = rP'HT) Z8" Z '(zH8 "Z = f'P' HT) 69 "Z
Figure imgf000116_0003
S)S8'S-S9'S'(ra'HS)SS'S-0 S'(s'H6 n'(zHrZ=r HS)^'I:l! 9 ( ϋα )Η顺- HT S) S8'S-S9'S '(ra'HS) SS'S-0 S' ( s ' H6 n '( z HrZ = r HS) ^' I: l! 9 (ϋα) Η 顺-H T
Figure imgf000116_0004
Figure imgf000116_0004
(ZHr6=rP'HT)8S"8'(zH6"Z=rP'HT)2Z"Z'(ZH6"Z=rP'HT)99"Z'(ZHr6=rP'H i)66'9'(zHrs'6'6=i"'pp'Hi)ws'(s'Hi)s ^ (s'Hs)w (ω'Η )09·ε— 3ε·ε'(ζΗΐ·ε' (ZHr6 = rP'HT) 8S "8 '( z H6" Z = rP'HT) 2Z "Z'(ZH6" Z = rP'HT) 99 "Z '(ZHr6 = rP'H i) 66'9' ( z Hrs'6'6 = i "'pp'Hi) ws'(s'Hi) s ^ ( s ' Hs) w (ω'Η) 09 · ε— 3ε · ε' ( ζ Ηΐ · ε '
98S6T0/S00Zdf/X3d =9.3Hz),7.93(lH,d,J=7.8Hz),8.00(lH,d,J=7.8Hz),8.35(lH,d,J=15.9Hz),8.61(lH,d,J= 9.3Hz),10.02(2H,s),11.10-11.60(lH,broad) 98S6T0 / S00Zdf / X3d = 9.3Hz), 7.93 (lH, d, J = 7.8Hz), 8.00 (lH, d, J = 7.8Hz), 8.35 (lH, d, J = 15.9Hz), 8.61 (lH, d, J = 9.3 Hz), 10.02 (2H, s), 11.10-11.60 (lH, broad)
[0234] 参考例 97
Figure imgf000117_0001
[0234] Reference Example 97
Figure imgf000117_0001
(7—メトキシイソキノリン 4 ィル）酢酸の塩酸塩 0.80gのメタノール 16mL懸濁液に 、塩ィ匕チォニル 0.54mLを加え、 1時間加熱還流した。減圧下で溶媒を濃縮した後、酢 酸ェチルおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水層を 酢酸ェチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液 で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色固体のメ チル = (7—メトキシイソキノリン一 4—ィル）ァセタート 0.67gを得た。  (7-methoxyisoquinoline 4-yl) acetic acid hydrochloride To a suspension of 0.80 g of methanol in 16 mL of methanol was added 0.54 mL of hydrochloride and heated to reflux for 1 hour. After concentrating the solvent under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. Combine the organic layer and the extract, wash with saturated aqueous sodium chloride, dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and obtain methyl (7-methoxyisoquinoline-4-yl) acetate as a brown solid. 0.67 g was obtained.
'H-NMRCCDCl ) δ値： 3.69(3H,s),3.96(3H,s),3.99(2H,s),7.25(lH,d,J=2.7Hz), 7.40(1  'H-NMRCCDCl) δ value: 3.69 (3H, s), 3.96 (3H, s), 3.99 (2H, s), 7.25 (lH, d, J = 2.7Hz), 7.40 (1
3  Three
H,dd,J=9.3,2.7Hz),7.88(lH,d,J=9.3Hz),8.32(lH,s),9.10(lH,s)  H, dd, J = 9.3,2.7Hz), 7.88 (lH, d, J = 9.3Hz), 8.32 (lH, s), 9.10 (lH, s)
[0235] 参考例 98
Figure imgf000117_0002
[0235] Reference Example 98
Figure imgf000117_0002
メチル = (7—メトキシイソキノリン一 4—ィル）ァセタート 0.65gのクロ口ホルム 20mL溶 液に、 5°Cでメタクロ口過安息香酸 1.6gを加え、室温で 1時間攪拌した。反応混合物に 水 10mLおよび飽和炭酸水素ナトリウム水溶液 10mLをカ卩えた。有機層を分取し、水層 をクロ口ホルム lOmLで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム 水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得ら れた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 10 : 1]で精製し、褐色油状物のメチル = (7—メトキシイソキノリン一 4—ィル)ァセタ 一ト = N—ォキシド 0.70gを得た。  1.6 g of metabenzoic perbenzoic acid was added to a 20 mL solution of 0.65 g of methyl = (7-methoxyisoquinoline-4-yl) acetate at 5 ° C. and stirred at room temperature for 1 hour. To the reaction mixture, 10 mL of water and 10 mL of a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 10: 1], and methyl = (7-methoxyisoquinoline 4-yl) acetate = brown oily substance. 0.70 g of N-oxide was obtained.
1H-NMR(CDC1 ) δ fg: 3.71(3H,s),3.92(2H,s),3.94(3H,s),6.99(lH,d,J=2.4Hz), 7.26(1  1H-NMR (CDC1) δ fg: 3.71 (3H, s), 3.92 (2H, s), 3.94 (3H, s), 6.99 (lH, d, J = 2.4Hz), 7.26 (1
3  Three
H,dd,J=9.3,2.4Hz),7.77(lH,d,J=9.3Hz),8.01(lH,d,J=1.5Hz),8.62(lH,s) [0236] 参考例 99
Figure imgf000118_0001
H, dd, J = 9.3,2.4Hz), 7.77 (lH, d, J = 9.3Hz), 8.01 (lH, d, J = 1.5Hz), 8.62 (lH, s) [0236] Reference Example 99
Figure imgf000118_0001
メチル = (7—メトキシイソキノリン一 4—ィル）ァセタート =N—ォキシド 0.69gのクロ口 ホルム 14mL溶液に、ォキシ塩化リン 0.31mLを加え、室温で 1時間 30分間、還流下で 2 0分間攪拌した。減圧下で溶媒を留去し、酢酸ェチル 10mLおよび飽和炭酸水素ナト リウム 5mLを加えた。有機層を分取し、水層を酢酸ェチル 10mLで抽出した。有機層 および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウム で乾燥させ、減圧下で溶媒を留去し、褐色固体のメチル = (1 クロロー 7—メトキシ イソキノリン一 4—ィル）ァセタート 0.61gを得た。  Methyl = (7-methoxyisoquinoline 1-yl) acetate = N-oxide Add 0.61 g of Chromium Form to 14 mL solution of 0.31 mL of phosphorus oxychloride and stir at room temperature for 1 hour 30 minutes and at reflux for 20 minutes did. The solvent was distilled off under reduced pressure, and 10 mL of ethyl acetate and 5 mL of saturated sodium bicarbonate were added. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. Combine the organic layer and the extract, wash with saturated aqueous sodium chloride, dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, methyl brown solid = (1 Chloro-7-methoxyisoquinoline 4-yl) 0.61 g of acetate was obtained.
'H-NMRCCDCl ) δ fg: 3.69(3H,s),3.96(2H,s),4.00(3H,s),7.45(lH,dd,J=9.2,2.6Hz),7.  'H-NMRCCDCl) δ fg: 3.69 (3H, s), 3.96 (2H, s), 4.00 (3H, s), 7.45 (lH, dd, J = 9.2, 2.6Hz), 7.
3  Three
60(lH,d,J=2.6Hz),7.88(lH,d,J=9.2Hz),8.09(lH,s)  60 (lH, d, J = 2.6Hz), 7.88 (lH, d, J = 9.2Hz), 8.09 (lH, s)
[0237] 参考例 100 [0237] Reference Example 100
Figure imgf000118_0002
Figure imgf000118_0002
メチル = (1—クロ口一 7—メトキシイソキノリン一 4—ィル）ァセタート 0.20gのトルエン 4mL溶液に、トリブチルビ-ルスズ 0.26mLおよびビス（トリー tert ブチルホスフィン） パラジウム (0) 38mgを加え、窒素雰囲気下で 30分間加熱還流した。反応混合物をろ 過し、ろ滓を酢酸ェチルで洗浄した。ろ液および洗液を合わせ、減圧下で溶媒を留 去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢 酸ェチル = 1 : 1]で精製し、褐色油状物のメチル = (7—メトキシ— 1—ビュルイソキノ リン一 4—ィル）ァセタート 0.13gを得た。  Methyl = (1—Black mouth 7-Methoxyisoquinoline 4-yl) acetate 0.20 g of toluene in 4 ml of toluene, 0.26 ml of tributyl beryl tin and 38 mg of bis (tree tert butylphosphine) palladium (0) are added, and nitrogen atmosphere Under reflux for 30 minutes. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate and washings were combined and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1], and the brown oil was methyl = (7-methoxy-1-buluisoquinoline 4-yl) 0.13 g of acetate was obtained.
1H-NMR(CDC1 ) δ fg: 3.67(3H,s),3.96(3H,s),3.99(2H,s),5.69(lH,dd,J=11.0,2.0Hz),6  1H-NMR (CDC1) δ fg: 3.67 (3H, s), 3.96 (3H, s), 3.99 (2H, s), 5.69 (lH, dd, J = 11.0, 2.0 Hz), 6
3  Three
.47(lH,dd,J=16.9,2.0Hz),7.39(lH,dd,J=9.2,2.6Hz),7.49(lH,d,J=2.6Hz),7.53(lH,dd,J =16.9,11.0Hz),7.88(lH,d,J=9.2Hz),8.33(lH,s)  .47 (lH, dd, J = 16.9,2.0Hz), 7.39 (lH, dd, J = 9.2,2.6Hz), 7.49 (lH, d, J = 2.6Hz), 7.53 (lH, dd, J = 16.9 , 11.0Hz), 7.88 (lH, d, J = 9.2Hz), 8.33 (lH, s)
[0238] 参考例 101
Figure imgf000119_0001
[0238] Reference Example 101
Figure imgf000119_0001
1, 2, 3, 4ーテトラヒドロイソキノリン l.Ogのジメチルスルホキシド lOmL溶液に、炭酸 カリウム 1.3gおよび 1ーブロモー 2 クロロェタン 0.94mLをカ卩え、室温で 1時間攪拌し た。反応混合物に水 10mLおよび酢酸ェチル 10mLをカ卩えた。有機層を分取し、水お よび飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減 圧下で溶媒を留去した。得られた残留物に酢酸ェチルおよび 1.0mol/L塩酸をカロえ、 水層を分取した。水層に酢酸ェチルおよび炭酸カリウムを加え、有機層を分取し、無 水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカ ゲルカラムクロマトグラフィー [溶離液;へキサン:酢酸ェチル = 10 : 1]で精製し、無色 油状物の 2— (2 クロ口ェチル）一1, 2, 3, 4—テトラヒドロイソキノリン 0.67gを得た。 1H-NMR(CDC1 ) δ fg: 2.82(2H,t,J=5.5Hz),2.88-2.94(4H,m),3.68(2H,t,J=7.1Hz),3.72  1.3 g of potassium carbonate and 0.94 mL of 1-bromo-2-chloroethane were added to a solution of 1,2,3,4-tetrahydroisoquinoline l.Og in dimethyl sulfoxide lOmL and stirred at room temperature for 1 hour. To the reaction mixture, 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was charged with ethyl acetate and 1.0 mol / L hydrochloric acid, and the aqueous layer was separated. Ethyl acetate and potassium carbonate were added to the aqueous layer, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 10: 1] and obtained as a colorless oily 2- (2-chloroethyl) -1,2,3,4- 0.67 g of tetrahydroisoquinoline was obtained. 1H-NMR (CDC1) δ fg: 2.82 (2H, t, J = 5.5Hz), 2.88-2.94 (4H, m), 3.68 (2H, t, J = 7.1Hz), 3.72
3  Three
(2H,s),6.99-7.04(lH,m),7.07-7.16(3H,m)  (2H, s), 6.99-7.04 (lH, m), 7.07-7.16 (3H, m)
[0239] 参考例 102 [0239] Reference Example 102
Figure imgf000119_0002
Figure imgf000119_0002
ェチル = 3— (8—アミノー 2—メトキシキノリンー5 ィル）プロピオナート 0.60gおよ び 1一（tert ブトキシカルボ-ル）ピぺリジンー4一力ルボン酸 0.55gから実施例 10と 同様にして、淡黄色固体の tert ブチル =4一（（（5—（2 （エトキシカルボ-ル）ェ チル） 2—メトキシキノリン 8 ィル）ァミノ）カルボ-ル）ピぺリジン 1 カルボキ シラート 0.97gを得た。  Ethyl = 3— (8-amino-2-methoxyquinoline-5 yl) propionate 0.60 g and 1 (tert-butoxycarbol) piperidine-4 Light yellow solid tert butyl = 4 -1 (((5- (2 (ethoxycarbol) ethyl) 2-methoxyquinoline 8 yl) amino) carbol) piperidine 1 carboxylate 0.97g It was.
1H-NMR(CDC1 ) δ fg: 1.24(3H,t,J=7.1Hz),1.48(9H,s),1.72-1.88(2H,m),2.00-2.15(2  1H-NMR (CDC1) δ fg: 1.24 (3H, t, J = 7.1Hz), 1.48 (9H, s), 1.72-1.88 (2H, m), 2.00-2.15 (2
3  Three
H,m),2.50-2.62(lH,m),2.67(2H,t,J=7.9Hz),2.80-2.95(2H,m),3.30(2H,t,J=7.9Hz),4.0 9(3H,s),4.10-4.30(2H,m),4.13(2H,q,J=7.1Hz),7.00(lH,d,J=9.0Hz),7.23(lH,d,J=8.0H z),8.25(lH,d,J=9.0Hz),8.61(lH,d,J=8.0Hz),9.58(lH,s)  H, m), 2.50-2.62 (lH, m), 2.67 (2H, t, J = 7.9Hz), 2.80-2.95 (2H, m), 3.30 (2H, t, J = 7.9Hz), 4.0 9 ( 3H, s), 4.10-4.30 (2H, m), 4.13 (2H, q, J = 7.1Hz), 7.00 (lH, d, J = 9.0Hz), 7.23 (lH, d, J = 8.0H z) , 8.25 (lH, d, J = 9.0Hz), 8.61 (lH, d, J = 8.0Hz), 9.58 (lH, s)
[0240] 参考例 103
Figure imgf000120_0001
[0240] Reference Example 103
Figure imgf000120_0001
tert ブチル =4— ( ( (5—（2 （エトキシカルボ-ル）ェチル）ー2—メトキシキノリ ンー8 ィル）ァミノ）カルボ-ル）ピぺリジン 1 カルボキシラート 0.96gから参考例 16と同様にして、白色固体のェチル = 3— (2—メトキシ一 8— ( (ピペリジン一 4—ィ ル）カルボ-ル）ァミノキノリン 5 ィル）プロピオナート 0.89gを得た。  tert butyl = 4— (((5— (2 (ethoxycarbol) ethyl) -2-methoxyquinoline-8 yl) amino) carbol) piperidine 1 Carboxylate Thus, 0.89 g of white solid ethyl = 3- (2-methoxy-1-8-((piperidine-1-4-yl) carbol) aminoquinoline-5-yl) propionate was obtained.
'H-NMRCCDCl ) δ値： 1.24(3H,t,J=7.2Hz),2.15- 2.40(4H,m),2.68(2H,t,J=7.9Hz),2.71 'H-NMRCCDCl) δ value: 1.24 (3H, t, J = 7.2Hz), 2.15-2.40 (4H, m), 2.68 (2H, t, J = 7.9Hz), 2.71
3  Three
-2.80(lH,m),3.07-3.17(2H,m),3.30(2H,t,J=7.9Hz),3.52-3.62(2H,m),4.09(3H,s),4.13 (2H,q,J=7.2Hz),7.01(lH,d,J=9.3Hz),7.22-7.27(lH,m),8.26(lH,d,J=9.3Hz),8.57(lH,d ,J=8.1Hz),9.59(lH,s)  -2.80 (lH, m), 3.07-3.17 (2H, m), 3.30 (2H, t, J = 7.9Hz), 3.52-3.62 (2H, m), 4.09 (3H, s), 4.13 (2H, q , J = 7.2Hz), 7.01 (lH, d, J = 9.3Hz), 7.22-7.27 (lH, m), 8.26 (lH, d, J = 9.3Hz), 8.57 (lH, d, J = 8.1Hz ), 9.59 (lH, s)
参考例 104
Figure imgf000120_0002
Reference Example 104
Figure imgf000120_0002
2, 3 ジヒドロ [1, 4]ジォキシノ [2, 3— c]ピリジンー7 カルバルデヒド 0.20gの N , N—ジメチルホルムアミド 2.4mL溶液に、 4 アミノシクロへキサンカルボン酸 0.35g および酢酸 0.24mLを加え、室温で 15分間攪拌した。水素化トリァセトキシホウ素ナトリ ゥム 0.31gを加え、室温で 10時間攪拌した。減圧下で溶媒を留去し、得られた残留物 をジォキサン 5.0mLおよび水 3.0mLの溶液に懸濁し、 5mol/L水酸化ナトリウム水溶液 1. lmLおよびジー tert ブチル =ジカルボナート 0.93gをカ卩え、室温で 6時間 30分間 攪拌した。酢酸ェチル、水および飽和塩ィ匕アンモ-ゥム水溶液をカ卩え、 pH8.0に調整 した。有機層を分取し、水層を 6.0mol/L塩酸で pH4.0に調整し、酢酸ェチルで抽出し た。有機層および抽出液を合わせ、飽和塩化アンモ-ゥム水溶液で洗浄し、無水硫 酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲル カラムクロマトグラフィー [溶離液;クロ口ホルム:メタノール = 20 : 1]で精製し、白色固 体の 4一（（tert ブトキシカルボ-ル）（2, 3 ジヒドロ [1, 4]ジォキシノ [2, 3— c]ピ リジン 7 ィルメチル）ァミノ）シクロへキサンカルボン酸 0.25gを得た。 2,3 dihydro [1,4] dioxino [2,3-c] pyridine-7 carbaldehyde 0.20 g of N, N-dimethylformamide in 2.4 mL solution was added 0.35 g of 4-aminocyclohexanecarboxylic acid and 0.24 mL of acetic acid And stirred at room temperature for 15 minutes. 0.31 g of sodium triacetoxyborohydride was added and stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in a solution of 5.0 mL of dioxane and 3.0 mL of water, and 1 mL of 5 mol / L sodium hydroxide aqueous solution and 0.93 g of di-tert-butyl dicarbonate were added. The mixture was stirred at room temperature for 6 hours and 30 minutes. Ethyl acetate, water, and saturated saline aqueous solution were added and adjusted to pH 8.0. The organic layer was separated, the aqueous layer was adjusted to pH 4.0 with 6.0 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; black mouth form: methanol = 20: 1], and the white solid 4 ((tert-butoxycarbol) (2,3 dihydro [1,3 4] Dioxino [2, 3— c] pi 0.25 g of lysine 7ylmethyl) amino) cyclohexanecarboxylic acid was obtained.
1H-NMR(CDC1 ) δ値： 1.32— 1.58(13H,m),1.70— 1.81(2H,m),2.00— 2.10(2H,m),2.15— 2.  1H-NMR (CDC1) δ value: 1.32—1.58 (13H, m), 1.70—1.81 (2H, m), 2.00—2.10 (2H, m), 2.15—2.
3  Three
26(lH,m),4.00-4.08(lH,m),4.24-4.45(6H,m),6.78(lH,s),8.06(lH,s)  26 (lH, m), 4.00-4.08 (lH, m), 4.24-4.45 (6H, m), 6.78 (lH, s), 8.06 (lH, s)
参考例 105
Figure imgf000121_0001
Reference Example 105
Figure imgf000121_0001
2 メトキシキノリン一 8 -ァミン 0.35gの N, N -ジメチルホルムアミド 8.0mL溶液に S トリフノレオロメチノレ - 3, 7-ジ-トロジベンゾチォフエ-ゥム =トリフノレオロメタンス ルホナート 0.91gを加え、室温で 1時間攪拌した。反応混合物に水 5mLおよび酢酸ェ チル 5mLを加え、ろ過し、 5. Omol/L水酸化ナトリウム水溶液で pH 13に調整した。有機 層を分取し、水層を酢酸ェチル 10mLで抽出した。有機層および抽出液を合わせ、飽 和塩ィ匕ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒 を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン： トルエン = 3 : 1]で精製し、へキサンを加え、固形物をろ取し、白色固体の 2—メトキシ 5 （トリフルォロメチル）キノリン 8 ァミン 48mgを得た。  2 Methoxyquinoline 8-amino amine 0.35 g N, N -dimethylformamide 8.0 mL solution The mixture was further stirred at room temperature for 1 hour. To the reaction mixture were added 5 mL of water and 5 mL of ethyl acetate, filtered, and adjusted to pH 13 with 5. Omol / L sodium hydroxide aqueous solution. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: toluene = 3: 1], hexane was added, the solid was collected by filtration, and white solid 2-methoxy-5 (trifluoro) 48 mg of methyl) quinoline 8amine was obtained.
1H-NMR(CDC1 ) δ値： 4.07(3H,s),5.00— 5.15(2H,m),6.83(lH,d,J=8.1Hz),7.02(lH,d,J=  1H-NMR (CDC1) δ value: 4.07 (3H, s), 5.00—5.15 (2H, m), 6.83 (lH, d, J = 8.1Hz), 7.02 (lH, d, J =
3  Three
9.3Hz),7.53(lH,d,J=8.1Hz),8.25-8.30(lH,m)  9.3Hz), 7.53 (lH, d, J = 8.1Hz), 8.25-8.30 (lH, m)
[0243] 参考例 106
Figure imgf000121_0002
[0243] Reference Example 106
Figure imgf000121_0002
ブチル = 8 ベンジルォキシー 2—メトキシキノリン 5 カルボキシラート 0.50gから 実施例 33と同様にして、白色固体の 8 ベンジルォキシ一 2—メトキシキノリン一 5— カルボン酸 0.34gを得た。  Butyl = 8 benzyloxy-2-methoxyquinoline 5 carboxylate 0.50 g In the same manner as in Example 33, white solid 8-benzyloxy-2-methoxyquinoline-1-5-carboxylic acid 0.34 g was obtained.
1H-NMR(CDC1 ) δ値： 4.14(3H,s),5.42(2H,s),7.07-7.11(2H,m),7.30-7.45(3H,m),7.56  1H-NMR (CDC1) δ value: 4.14 (3H, s), 5.42 (2H, s), 7.07-7.11 (2H, m), 7.30-7.45 (3H, m), 7.56
3  Three
-7.61(2H,m),8.25(lH,d,J=8.8Hz),9.36(lH,d,J=10.0Hz)  -7.61 (2H, m), 8.25 (lH, d, J = 8.8Hz), 9.36 (lH, d, J = 10.0Hz)
[0244] 参考例 107
Figure imgf000122_0001
[0244] Reference Example 107
Figure imgf000122_0001
(1) 8 -ベンジルォキシ 2—メトキシキノリン一 5 カルボン酸 0.20gの塩化メチレン 3 .OmL溶液に、塩化ォキサリル 0.18mLおよび N, N ジメチルホルムアミド 1滴をカロえ、 室温で 1時間 15分間攪拌した。塩ィ匕ォキサリル 0.18mLをカ卩え、 30分間攪拌した。減 圧下で溶媒を留去し、 8 -ベンジルォキシ - 2—メトキシキノリン— 5 カルボ-ルクロ リドを得た。  (1) To a solution of 0.20 g of 8-benzyloxy-2-methoxyquinoline monocarboxylic acid 0.20 g of methylene chloride was added 0.18 mL of oxalyl chloride and 1 drop of N, N dimethylformamide, and the mixture was stirred at room temperature for 1 hour and 15 minutes. 0.18 mL of salt oxalil was added and stirred for 30 minutes. The solvent was distilled off under reduced pressure to obtain 8-benzyloxy-2-methoxyquinoline-5-carbochloride.
(2)水酸化カリウム 2.6gの水 7.8mL溶液に、ジェチルエーテル 7.8mLをカ卩え、氷冷下 、 N—-トロソメチルゥレア 0.67gをカ卩え、有機層を分取した。氷冷下、 8 ベンジルォ キシ一 2—メトキシキノリン一 5—カルボ-ルクロリドの塩化メチレン 5.0mL溶液を加え、 室温で 30分間攪拌した。減圧下で溶媒を留去し、トルエンを加え、固形物をろ取し、 淡褐色固体の 1— (8—ベンジルォキシ一 2—メトキシキノリン一 5—ィル） 2 ジァ ゾエタノン 90mgを得た。  (2) Into a solution of potassium hydroxide (2.6 g) in water (7.8 mL) was added dimethyl ether (7.8 mL). Under ice-cooling, N-trosomethylurea (0.67 g) was added, and the organic layer was separated. Under ice-cooling, 5.0 mL of methylene chloride in 8 benzyloxy-2-methoxyquinoline 5-carbonyl chloride was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, toluene was added, and the solid was collected by filtration to obtain 90 mg of 1- (8-benzyloxy-2-methoxyquinoline-5-yl) 2 diazoethanone as a light brown solid.
1H-NMR(CDC1 ) δ値： 4.13(3H,s),5.40(2H,s),5.75(lH,s),7.01-7.05(2H,m),7.31-7.40(  1H-NMR (CDC1) δ value: 4.13 (3H, s), 5.40 (2H, s), 5.75 (lH, s), 7.01-7.05 (2H, m), 7.31-7.40 (
3  Three
3H,m),7.49(lH,d,J=8.0Hz),7.54-7.59(2H,m),8.94(lH,d,J=9.2Hz)  3H, m), 7.49 (lH, d, J = 8.0Hz), 7.54-7.59 (2H, m), 8.94 (lH, d, J = 9.2Hz)
参考例 108 Reference Example 108
Figure imgf000122_0002
Figure imgf000122_0002
トリェチルァミン 0.45mLに安息香酸銀 31mgをカ卩え、水冷下、 1一（8 べンジルォキ シ一 2—メトキシキノリン一 5—ィル） 2 ジァゾエタノン 90mgのテトラヒドロフラン 0.90 mLおよびエタノール 0.90mL懸濁液を加え、室温で 1時間攪拌した。減圧下で溶媒を 留去し、得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢 酸ェチル = 10 : 1]で精製し、無色油状物のェチル = (8 ベンジルォキシー 2—メト キシキノリン一 5—ィル）ァセタート 63mgを得た。  Add 31 mg of silver benzoate to 0.45 mL of triethylamine, add 1 (8 benzyloxy-2-methoxyquinoline 1-5-yl) 2 diazoethanone 90 mg of tetrahydrofuran 0.90 mL and ethanol 0.90 mL under water cooling. And stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 10: 1] to give a colorless oily substance ethyl = (8 benzyloxy 2-metho 63 mg of xyquinoline 1-yl) acetate was obtained.
'H-NMRCCDCl ) δ fg: 1.20(3H,t,J=7.1Hz),3.91(2H,s),4.13(3H,s),4.13(2H,q,J=7.1Hz  'H-NMRCCDCl) δ fg: 1.20 (3H, t, J = 7.1Hz), 3.91 (2H, s), 4.13 (3H, s), 4.13 (2H, q, J = 7.1Hz
3  Three
),5.35(2H,s),6.98(lH,d,J=9.0Hz),7.06(lH,d,J=7.8Hz),7.18(lH,d,J=7.8Hz),7.25-7.42( —エ /^ェ O)Sui094— έίί^ （ —S べ ίί,^Ρ ー S / ベ:^— ), 5.35 (2H, s), 6.98 (lH, d, J = 9.0Hz), 7.06 (lH, d, J = 7.8Hz), 7.18 (lH, d, J = 7.8Hz), 7.25 to 7.42 ( —D / ^ e O) Sui094— έίί ^ （—S べ ίί, ^ Ρ ー S / Be: ^ —
8)— ε— (Ή)
Figure imgf000123_0001
8) — ε— (Ή)
Figure imgf000123_0001
Figure imgf000123_0002
Figure imgf000123_0002
(ZHS"6=f'P'HT)S2"8'(zHZ"Z=rP'HT)9^"Z'(ZHZ"Z=rP'HT)0S"Z'(ZHS"6=rP'HT)S0"Z'(
Figure imgf000123_0003
(ZHS "6 = f'P'HT) S2" 8 '( z HZ "Z = rP'HT) 9 ^"Z' (ZHZ "Z = rP'HT) 0S" Z '(ZHS "6 = rP' HT) S0 "Z '(
Figure imgf000123_0003
。 S — ( 、^ （ . S — (, ^ (
Figure imgf000123_0004
Figure imgf000123_0004
拳^ Q!SuiOS — ¾· （ / — S  Fist ^ Q! SuiOS — ¾ · (/ — S
Figure imgf000123_0005
Figure imgf000123_0006
Figure imgf000123_0005
Figure imgf000123_0006
'Ρ'Ηΐ) ·8'(δ'Ηΐ)89·Ζ'(ζΗ0·8=ί"'Ρ'Ηΐ) ·Ζ'(ζΗ0·8=ί"'Ρ'Ηΐ)60·Ζ'(ζΗ0·6=ί"'Ρ'Ηΐ)66·9'(
Figure imgf000123_0007
'Ρ'Ηΐ) · 8' ( δ 'Ηΐ) 89 · Ζ' ( ζ Η0 · 8 = ί "'Ρ'Ηΐ) · Ζ' ( ζ Η0 · 8 = ί"'Ρ'Ηΐ) 60 · Ζ' ( ζ Η0 · 6 = ί "'Ρ'Ηΐ) 66 · 9' (
Figure imgf000123_0007
。 ¾¾Sra0w— （ — s . ¾¾Sra 0 w— (— s
Figure imgf000123_0008
Figure imgf000123_0008
60Ip}% [9 WO] (ZH0"6=rP'HT)8r8'(zH2"Z=f'P'H2)8S"Z'(ra'He 60Ip}% [9 WO] (ZH0 "6 = rP'HT) 8r8 '( z H2" Z = f'P'H2) 8S "Z'(ra'He
98S6T0/S00Zdf/X3d 1-31. テル 0.34mL溶液に、窒素気流下、酢酸パラジウム 1.2mgを加え、氷冷下、分取した有 機層を滴下し、 30分間攪拌した。反応混合物に酢酸 0.79mLを加え、減圧下で溶媒を 留去し、得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢 酸ェチル = 15 : 1]で精製し、無色油状物のメチル = 2—（8 べンジルォキシ 2— メトキシキノリン 5—ィル）シクロプロパンカルボキシラート 35mgを得た。 98S6T0 / S00Zdf / X3d 1-31. To a 0.34 mL solution of Teru, 1.2 mg of palladium acetate was added under a nitrogen stream, and the separated organic layer was added dropwise under ice cooling, followed by stirring for 30 minutes. 0.79 mL of acetic acid was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 15: 1] to give a colorless oil 35 mg of methyl 2- (8-benzyloxy 2-methoxyquinoline 5-yl) cyclopropanecarboxylate was obtained.
1H-NMR(CDC1 ) δ値： 1.33- 1.40(lH,m),1.63- 1.68(lH,m),1.86- 1.92(lH,m),2.81- 2.8 1H-NMR (CDC1) δ value: 1.33- 1.40 (lH, m), 1.63- 1.68 (lH, m), 1.86- 1.92 (lH, m), 2.81- 2.8
3  Three
7(lH,m),3.79(3H,s),4.13(3H,s),5.34(2H,s),6.98-7.05(3H,m),7.28-7.41(3H,m),7.57(2 H,d,J=7.6Hz),8.35(lH,d,J=9.0Hz)  7 (lH, m), 3.79 (3H, s), 4.13 (3H, s), 5.34 (2H, s), 6.98-7.05 (3H, m), 7.28-7.41 (3H, m), 7.57 (2 H , d, J = 7.6Hz), 8.35 (lH, d, J = 9.0Hz)
参考例 112 Reference Example 112
Figure imgf000124_0001
Figure imgf000124_0001
メチル = 2— (8—ベンジルォキシ一 2—メトキシキノリン一 5—ィル）シクロプロパン カルボキシラート 35mgから参考例 69と同様にして、無色油状物のメチル = 2— (8— ヒドロキシー 2—メトキシキノリンー5 ィル）シクロプロパンカルボキシラート 23mgを得 た。  Methyl = 2- (8-benzyloxy-1-2-methoxyquinoline-5-yl) cyclopropanecarboxylate 35 mg in the same manner as in Reference Example 69, methyl oil as a colorless oil = 2- (8-hydroxy-2-methoxyquinoline 5 mg) Cyclopropanecarboxylate 23 mg was obtained.
'H-NMRCCDCl ) δ値： 1.36- 1.41(lH,m),1.62- 1.68(lH,m),1.85- 1.91(lH,m),2.80- 2.8  'H-NMRCCDCl) δ value: 1.36- 1.41 (lH, m), 1.62- 1.68 (lH, m), 1.85- 1.91 (lH, m), 2.80-2.8
3  Three
6(lH,m),3.78(3H,s),4.08(3H,s),7.01(lH,d,J=9.2Hz),7.03-7.08(2H,m),7.62(lH,s),8.3 6 (lH, m), 3.78 (3H, s), 4.08 (3H, s), 7.01 (lH, d, J = 9.2Hz), 7.03-7.08 (2H, m), 7.62 (lH, s), 8.3
5(lH,d,J=9.2Hz) 5 (lH, d, J = 9.2Hz)
参考例 113 Reference Example 113
Figure imgf000124_0002
Figure imgf000124_0002
メチル = 2— (8—ヒドロキシー2—メトキシキノリンー5 ィル）シクロプロパンカルボ キシラート 23mgから参考例 70と同様にして、無色油状物のメチル = 2— (2—メトキシ
Figure imgf000124_0003
シクロプロパン カルボキシラート 26mgを得た。 0^ ¾§es 4-6fi^ (,^ （ / ^ ΰ /
Figure imgf000125_0001
、つ辛爵 瀚 缀、 止 s教 ^^m^w^ ^ ^m^wo (ο ^½Ε^Τ¾:§82 Methyl = 2- (8-hydroxy-2-methoxyquinoline-5-yl) cyclopropanecarboxylate 23 mg in the same manner as in Reference Example 70.
Figure imgf000124_0003
26 mg of cyclopropanecarboxylate was obtained. 0 ^ ¾§es 4-6fi ^ (, ^ (/ ^ ΰ /
Figure imgf000125_0001
, Spicy 瀚 缀, stop s teaching ^^ m ^ w ^ ^ ^ m ^ wo (ο ^ ½Ε ^ Τ¾: §82
(ベ ^ / ェ (Η) ^^1 、止^蹈 峯暴
Figure imgf000125_0002
(Be ^ / e (Η) ^^ 1
Figure imgf000125_0002
'ΝΟ)¾·ΐ4— έίί^ （ - ^ ^ : (H) -Ζ = Λ^ ίΙ^^\'\ ^ （ / 一 8—ベ ίί,^Ρ ^ EH 一 S―、 E— g)— Ν— ΰ / fH— S 'Z 'Z  'ΝΟ) ¾ · ΐ4— έίί ^ (-^ ^: (H) -Ζ = Λ ^ ίΙ ^^ \' \ ^ (/ 1—8 ベ ίί, ^ Ρ ^ EH 1 S—, E—g) — Ν— ΰ / fH— S 'Z' Z
Figure imgf000125_0003
Figure imgf000125_0003
(s'HI)9S'0r(zHS'8=rP'HI)8S'8'(zHS'6=f' P'HT)92"8'(zH2-8=rP'HT)96" '(zH2-6=rP'HT)S0" '(s'HS)2r^:i!} 9 ( Iつ αつ) WN— Ητ —ベ
Figure imgf000125_0004
( s 'HI) 9S'0r ( z HS'8 = rP'HI) 8S'8' ( z HS'6 = f 'P'HT) 92 "8' ( z H2-8 = rP'HT) 96"'(zH2-6 = rP'HT) S0 "'(s'HS) 2r ^: i!} 9 (I and α) WN— Η τ —Be
Figure imgf000125_0004
^w ^^^m ^^ m辛爵¾瀚缀 止 s教  ^ w ^^^ m ^^ m
¾、 マ
Figure imgf000125_0005
、つ ¾ »斜萆 °
Figure imgf000125_0006
。： ¾, Ma
Figure imgf000125_0005
, ¾ »
Figure imgf000125_0006
. :
Figure imgf000125_0007
Figure imgf000125_0008
Figure imgf000125_0007
Figure imgf000125_0008
ί"'Ρ'Ηΐ)ΐ ·Ζ'(ΖΗΐ·8=ΓΡ'Ηΐ)^ (ζΗΐ·6=ί"'Ρ'Ηΐ)Ζ0 (δ'Ηε)ΐ· '(δ'Ηε)08·ε'(ω'Ηΐ) 6 - 88 ' (ω'Ηΐ)ΟΟ - 36·ΐ'(ω'Ηΐ)9Ζ·ΐ- 0Ζ·ΐ'(ω'Ηΐ) ·ΐ- 8ε·ΐ :軍 9 ( !DaD)H N-HT ί "'Ρ'Ηΐ) ΐ · Ζ' (ΖΗΐ · 8 = ΓΡ'Ηΐ) ^ ( ζ Ηΐ · 6 = ί"'Ρ'Ηΐ) Ζ0 ( δ ' Ηε) ΐ · '( δ ' Ηε) 08 ε '(ω'Ηΐ) 6-88'(ω'Ηΐ) ΟΟ-36 · ΐ '(ω'Ηΐ) 9Ζ · ΐ- 0Ζ · ΐ'(ω'Ηΐ) · ΐ-8ε · ΐ: Army 9 ( ! DaD) H NH T
98S6T0/S00Zdf/X3d
Figure imgf000126_0001
-ζ- (a))-9))-s)→= Λ^ - ^α) ^Μ^、ェっ^薄 f$SOS'(H— έίί^ （ 一 S ベ ίί,^Ρ ^ EH ー S 一 8)— ε— (Ή) = ェ 98S6T0 / S00Zdf / X3d
Figure imgf000126_0001
-ζ- (a))-9))-s) → = Λ ^-^ α) ^ Μ ^, ^^ thin f $ SOS '(H— έίί ^ （一 S ベ ίί, ^ Ρ ^ EH ーS 1 8) — ε— (Ή) =
13 ¾0 1ョ 'οο  13 ¾0 1
Figure imgf000126_0002
Figure imgf000126_0002
(ΖΗΐ·6=ΓΡ'Ηΐ)ε^8'(ζΗ6·Ζ=ί"'Ρ'Ηΐ)3ΐ·Ζ'(ΖΗΐ·6=ί"'Ρ'Ηΐ) 6·9'(ζΗ6·Ζ=ΓΡ'Ηΐ)68·9'(
Figure imgf000126_0003
9 ( Iつ dつ) WN- Ητ (ΖΗΐ · 6 = ΓΡ'Ηΐ) ε ^ 8 '(ζ Η6 · Ζ = ί "'Ρ'Ηΐ) 3ΐ · Ζ '(ΖΗΐ · 6 = ί"'Ρ'Ηΐ) 6 · 9 '(ζ Η6 · Ζ = ΓΡ'Ηΐ) 68 · 9 '(
Figure imgf000126_0003
9 (I d) WN- Η τ
。 ¾¾§0ΐ·(Η— ( / —S べ fi,^ ^E ー S— 8) -Z
Figure imgf000126_0004
、つ辛爵 瀚缀 止 ϊί教。 翻 S っ。 of、止^蹈 峯氺、" Hf Su¾s峯^—マ 0 /Οοΐ
Figure imgf000126_0005
. ¾¾§0ΐ · (Η— (/ —S all fi, ^ ^ E ー S— 8) -Z
Figure imgf000126_0004
つ 辛 ϊ ϊ 教 ί. Transform S of, 蹈 ^ 蹈 峯 氺, "Hf Su ¾s 峯 ^ —MA 0 / Ο οΐ
Figure imgf000126_0005
Figure imgf000126_0006
Figure imgf000126_0006
mベ ^^ · ΜΜ ~]
Figure imgf000126_0007
、つ辛爵 ¾瀚缀 止 s教 、止^蹈 峯氺 ^w ^v^^ ^^ ui0S峯^ マ ο/ο0ΐ、コ)继鼸疆 Τϋθΐ继缀氺 /— ^ 0/ o06O)¾S'(H— έίί^ mbe ^^ · ΜΜ ~]
Figure imgf000126_0007
つ 爵 瀚 缀 止 s 教 、 止 蹈 ^ 蹈 w ^ w ^ v ^^ ^^ ui 0S 峯 ^ Ma ο / ο0ΐ , 继 鼸 疆) 继 鼸 疆 Τϋθΐ 继 缀 氺 / — ^ 0 / o 06O) ¾S '(H— έίί ^
Figure imgf000126_0008
Figure imgf000126_0008
I'(zHS'8=f'P'HI)I9'8'(zH8'8=f'P'HI)S6 '(zHS'8=f'P'HI)IS '(zH8'8=f'P'HI)66'9'( ζΗ9·ΐ=ί"'Ρ'Ηΐ) Ζ·9'(ζΗ9·ΐ=ί"'Ρ'Ηΐ)ΐ6·3'(δ'Ηε)0ΐ· (s'HS)SZ'S:m 9 ( !DaD)H N-HT I '(zHS'8 = f'P'HI) I9'8' ( z H8'8 = f'P'HI) S6 '( z HS'8 = f'P'HI) IS' ( z H8'8 = f'P'HI) 66'9 '(ζΗ9 · ΐ = ί "'Ρ'Ηΐ) Ζ9 '( ζ Η9 · ΐ = ί"'Ρ'Ηΐ) ΐ6.3 '(δ'Ηε) 0ΐ ( S 'HS) SZ'S: m 9 (! DaD) H NH T
98S6T0/S00Zdf/X3d 1731- H-NMR(CDC1 ) δ値： 1.15- 1.35(2H,m),l.36(3H,t,J=7.2Hz),1.45(9H,s), 1.78- 1.90(2 98S6T0 / S00Zdf / X3d 1731- H-NMR (CDC1) δ value: 1.15- 1.35 (2H, m), l.36 (3H, t, J = 7.2Hz), 1.45 (9H, s), 1.78-1.90 (2
3  Three
H,m),2.09-2.20(lH,m),2.40-2.50(2H,m),2.70-2.85(2H,m),4.05-4.20(2H,m),4.11(3H ,s),4.30(2H,q,J=7.2Hz),6.51(lH,d,J=15.9Hz),7.06(lH,d,J=9.0Hz),7.72(lH,d,J=8.2Hz ),8.30(lH,d,J=15.9Hz),8.44(lH,d,J=9.0Hz),8.73(lH,d,J=8.2Hz),9.50(lH,s)  H, m), 2.09-2.20 (lH, m), 2.40-2.50 (2H, m), 2.70-2.85 (2H, m), 4.05-4.20 (2H, m), 4.11 (3H, s), 4.30 ( 2H, q, J = 7.2Hz), 6.51 (lH, d, J = 15.9Hz), 7.06 (lH, d, J = 9.0Hz), 7.72 (lH, d, J = 8.2Hz), 8.30 (lH, d, J = 15.9Hz), 8.44 (lH, d, J = 9.0Hz), 8.73 (lH, d, J = 8.2Hz), 9.50 (lH, s)
[0255] 参考例 118 [0255] Reference Example 118
Figure imgf000127_0001
Figure imgf000127_0001
tert—ブチル =4— (2- ( (5- ( (E)—2— (エトキシカルボ-ル）ビュル）—2—メト キシキノリン一 8—ィル）ァミノ） 2—ォキソェチル）ピぺリジン一 1 カルボキシラート 0.15gから参考例 16と同様にして、淡黄色固体のェチル = (E)—3— (2—メトキシ— 8 （（ピペリジンー4ーィルァセチル）ァミノ）キノリン 5 ィル）アタリラート 0.10gを得 た。  tert—Butyl = 4— (2- ((5- ((E) —2— (Ethoxycarbol) bur) —2—Methoxyquinoline 8-yl) amino) 2-Oxoethyl) piperidine 1 In the same manner as in Reference Example 16 from 0.15 g of carboxylate, 0.10 g of ethyl of pale yellow solid = (E) -3- (2-methoxy-8 ((piperidine-4-ylacetyl) amino) quinoline 5 yl) talylate was obtained. .
1H-NMR(DMSO-d ) δ値： 1.29(3H,t,J=7.1Hz),1.38- 1.50(2H,m),1.86- 1.94(2H,m),2.0  1H-NMR (DMSO-d) δ value: 1.29 (3H, t, J = 7.1Hz), 1.38-1.50 (2H, m), 1.86-1.94 (2H, m), 2.0
6  6
5-2.15(lH,m),2.59-2.63(2H,m),2.86-2.95(2H,m),3.26-3.30(2H,m),4.14(3H,s),4.23(2 H,q,J=7.1Hz),6.68(lH,d,J=15.7Hz),7.19(lH,d,J=9.3Hz),7.96(lH,d,J=8.3Hz),8.21-8. 29(lH,m),8.30(lH,d,J=15.7Hz),8.54(lH,d,J=8.3Hz),8.64(lH,d,J=9.3Hz),9.74(lH,s) [0256] 参考例 119
Figure imgf000127_0002
5-2.15 (lH, m), 2.59-2.63 (2H, m), 2.86-2.95 (2H, m), 3.26-3.30 (2H, m), 4.14 (3H, s), 4.23 (2 H, q, J = 7.1Hz), 6.68 (lH, d, J = 15.7Hz), 7.19 (lH, d, J = 9.3Hz), 7.96 (lH, d, J = 8.3Hz), 8.21-8.29 (lH, m), 8.30 (lH, d, J = 15.7Hz), 8.54 (lH, d, J = 8.3Hz), 8.64 (lH, d, J = 9.3Hz), 9.74 (lH, s) [0256] Reference examples 119
Figure imgf000127_0002
E F ？  E F?
濃硫酸 5.0mLに、氷冷下、（E)—3—エトキシー N— (3—フルオロフヱ-ル）アクリル アミド 1.5gを分割添加し、室温で 20分間攪拌した。反応混合物を氷水に注ぎ、固形物 をろ取し、メタノールおよびジェチルエーテルで洗浄し、淡褐色固体の 7—フルォロ キノリン 2 (1H) オンおよび 5 フルォロキノリン 2 (1H) オンの混合物 0.73gを 得た。  To 5.0 mL of concentrated sulfuric acid, 1.5 g of (E) -3-ethoxy N- (3-fluorophenyl) acrylamide was added in portions under ice cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture is poured into ice water, and the solid is collected by filtration and washed with methanol and jetyl ether to obtain 0.73 g of a mixture of 7-fluoroquinolin 2 (1H) on and 5 fluoroquinolin 2 (1H) on as a light brown solid. It was.
[0257] 参考例 120
Figure imgf000128_0001
[0257] Reference Example 120
Figure imgf000128_0001
7 フルォロキノリン一 2 (1H)—オンおよび 5 フルォロキノリン一 2 (1H)—オンの 混合物 0.70gに、ォキシ塩化リン 7.0mLをカ卩え、 2時間加熱還流した。反応混合物を室 温まで冷却し、減圧下で溶媒を留去した。得られた残留物を氷水に注ぎ、酢酸ェチ ルを加え、 20%水酸ィ匕ナトリウム水溶液で pH12に調整した。有機層を分取し、水層を 酢酸ェチルで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウ ム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し た。得られた残留物に 2—プロパノールを加え、不溶物をろ去し、減圧下で溶媒を留 去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢 酸ェチル = 10 : 1]で精製し、白色固体の 2 クロ口 7 フルォロキノリンおよび 2 - クロ口 5 フルォロキノリンの混合物 0.25gを得た。  To 0.70 g of a mixture of 7 fluoroquinoline 1 2 (1H) —one and 5 fluoroquinoline 1 2 (1H) —one was added 7.0 mL of phosphorus oxychloride and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was poured into ice water, ethyl acetate was added, and the pH was adjusted to 12 with 20% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. 2-Propanol was added to the obtained residue, the insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 10: 1] to obtain 0.25 g of a mixture of 2 black-mouth 7 fluoroquinoline and 2-black mouth 5 fluoroquinoline as white solids. It was.
[0258] 参考例 121
Figure imgf000128_0002
[0258] Reference Example 121
Figure imgf000128_0002
2 クロロー 7 フルォロキノリンおよび 2 クロロー 5 フルォロキノリンの混合物 0. 25gに、メタノール 5mLおよび 28%ナトリウムメトキシド /メタノール 0.81gをカ卩え、 2時間 加熱還流した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた 残留物に水および酢酸ェチルを加えた。有機層を分取し、水層を酢酸ェチルで抽出 した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸 マグネシウムで乾燥させ、無色油状物の 7 フルォロ 2—メトキシキノリンおよび 5— フルオロー 2—メトキシキノリンの混合物 0.19gを得た。 To 0.25 g of a mixture of 2 chloro-7 fluoroquinoline and 2 chloro-5 fluoroquinoline was added 5 mL of methanol and 0.81 g of 28% sodium methoxide / methanol, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate to obtain 0.19 g of a colorless oily mixture of 7-fluoro-2-methoxyquinoline and 5-fluoro-2-methoxyquinoline.
[0259] 参考例 122
Figure imgf000128_0003
[0259] Reference Example 122
Figure imgf000128_0003
7 フルォロ 2—メトキシキノリンおよび 5 フルォロ 2—メトキシキノリンの混合 物 0.19gに、濃硫酸 2mLおよび発煙硝酸 Lを加え、室温で 1時間攪拌した。反応 混合物を氷水に注ぎ、固形物をろ取し、水で 2回洗浄し、淡黄色固体を得た。得られ た淡黄色固体にクロ口ホルムおよび水を加え、 1.0mol/L水酸ィ匕ナトリウム水溶液で pH 10に調整した。有機層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出 液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシゥ ムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマト グラフィー [溶離液；へキサン:酢酸ェチル = 2 : 1]で精製し、淡黄色固体の 7 フル ォロ 2 メトキシ 8 -トロキノリン 48mgおよび淡黄色固体の 5 フルォロ 2 メ トキシー 8 -トロキノリン 20mgを得た。 Mixing of 7 fluoro 2-methoxyquinoline and 5 fluoro 2-methoxyquinoline Concentrated sulfuric acid (2 mL) and fuming nitric acid (L) were added to 0.19 g of the product, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and the solid was collected by filtration and washed twice with water to give a pale yellow solid. To the obtained pale yellow solid, black mouth form and water were added, and the pH was adjusted to 10 with a 1.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 2: 1], and the pale yellow solid 7 fluoro 2 methoxy 8 -troquinoline 48 mg and the pale yellow solid 5 fluoro 2 20 mg of methoxy 8 -troquinoline was obtained.
7 フルォロ一 2—メトキシ一 8 ニトロキノリン 7 Fluoro 2 -Methoxy 1 8 Nitroquinoline
'H-NMRCCDCl ) δ値： 4.04(3H,s),6.98(lH,d,J=8.8Hz),7.24-7.28(lH,m),7.83(lH,dd,J  'H-NMRCCDCl) δ value: 4.04 (3H, s), 6.98 (lH, d, J = 8.8Hz), 7.24-7.28 (lH, m), 7.83 (lH, dd, J
3  Three
=9.0,5.9Hz),8.01(lH,d,J=8.8Hz)  = 9.0, 5.9Hz), 8.01 (lH, d, J = 8.8Hz)
5 フルォロ一 2—メトキシ一 8 ニトロキノリン  5 Fluoro 2 -Methoxy 1 8 Nitroquinoline
'H-NMRCCDCl ) δ fg:4.09(3H,s),7.06-7.12(2H,m),8.04(lH,dd,J=8.5,5.4Hz),8.29(l  'H-NMRCCDCl) δ fg: 4.09 (3H, s), 7.06-7.12 (2H, m), 8.04 (lH, dd, J = 8.5,5.4Hz), 8.29 (l
3  Three
H,d,J=9.3Hz)  (H, d, J = 9.3Hz)
参考例 123
Figure imgf000129_0001
Reference Example 123
Figure imgf000129_0001
7 フルオロー 2—メトキシー8 -トロキノリン 45mgに、室温で酢酸 4mLおよび 10% パラジウム—炭素 9mgを加え、水素雰囲気下で 1時間攪拌した。不溶物をろ去し、ろ 滓を酢酸ェチルで 3回洗浄した。ろ液および洗液を合わせ、減圧下で溶媒を留去し た。得られた残留物に酢酸ェチルおよび飽和炭酸水素ナトリウム水溶液を加えた。 有機層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わせ、水 および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、 減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶 離液;へキサン:酢酸ェチル = 3 : 1]で精製し、淡褐色固体の 7 フルォロ 2—メト キシキノリン一 8—ァミン 33mgを得た。  7 To 45 mg of fluoro-2-methoxy-8-troquinoline, 4 mL of acetic acid and 9 mg of 10% palladium-carbon were added at room temperature, and the mixture was stirred for 1 hour under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filter cake was washed 3 times with ethyl acetate. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 3: 1] to obtain 33 mg of 7-fluoro-2-methoxyquinoline 8-aminomine as a light brown solid.
^-NMRCCDCl ) δ fg:4.08(3H,s),6.85(lH,d,J=8.8Hz),7.05(lH,dd,J=8.9,5.7Hz),7.13 (lH,dd,J=10.4,8.9Hz),7.92(lH,d,J=8.8Hz) ^ -NMRCCDCl) δ fg: 4.08 (3H, s), 6.85 (lH, d, J = 8.8Hz), 7.05 (lH, dd, J = 8.9,5.7Hz), 7.13 (lH, dd, J = 10.4,8.9Hz), 7.92 (lH, d, J = 8.8Hz)
[0261] 参考例 124
Figure imgf000130_0001
[0261] Reference Example 124
Figure imgf000130_0001
5 フルォロ一 2—メトキシ一 8 -トロキノリン 20mgから参考例 123と同様にして、 濃紫色固体の 5 -フルォロ 2 メトキシキノリン一 8 -ァミン 18mgを得た。 In the same manner as in Reference Example 123, 20 mg of 5-fluoro-2-methoxy-1-8-tromine was obtained in the same manner as in Reference Example 123.
1H-NMR(CDC1 ) δ値： 4.07(3H,s),4.56(2H,broad),6.79(lH,dd,J=8.4,5.1Hz),6.88(lH  1H-NMR (CDC1) δ value: 4.07 (3H, s), 4.56 (2H, broad), 6.79 (lH, dd, J = 8.4, 5.1 Hz), 6.88 (lH
3  Three
dd,J=9.6,8.4Hz),6.94(lH,d,J=9.0Hz),8.19(lH,d,J=9.0Hz)  dd, J = 9.6,8.4Hz), 6.94 (lH, d, J = 9.0Hz), 8.19 (lH, d, J = 9.0Hz)
参考例 125
Figure imgf000130_0002
Reference Example 125
Figure imgf000130_0002
2—メトキシー4ーメチルー 8 -トロキノリン 0.50gのジォキサン 5mL溶液に、室温で 二酸ィ匕セレン 0.31gを加え、 3時間加熱還流した。減圧下で溶媒を留去し、キシレン 5 mLを加え、 6時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去 し、ろ滓をクロ口ホルムで 3回洗浄した。ろ液および洗液を合わせ、減圧下で溶媒を留 去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢 酸ェチル = 3 : 1]で精製し、淡黄色固体の 2—メトキシ— 8 -トロキノリン— 4—カル バルデヒド 0.15gを得た。  To a solution of 2-methoxy-4-methyl-8-troquinoline 0.50 g in dioxane 5 mL was added 0.31 g of biselenium selenium at room temperature, and the mixture was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, 5 mL of xylene was added, and the mixture was heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and the filter cake was washed 3 times with black mouth form. The filtrate and washings were combined and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1] to obtain 0.15 g of 2-methoxy-8-troquinoline-4-carbaldehyde as a pale yellow solid. .
'H-NMRCCDCl ) δ fg:4.13(3H,s),7.45(lH,s),7.58(lH,dd,J=8.4,7.6Hz),8.02(lH,dd,J  'H-NMRCCDCl) δ fg: 4.13 (3H, s), 7.45 (lH, s), 7.58 (lH, dd, J = 8.4, 7.6 Hz), 8.02 (lH, dd, J
3  Three
=7.6,1.4Hz),9.12(lH,dd,J=8.4,1.4Hz),10.34(lH,s)  = 7.6,1.4Hz), 9.12 (lH, dd, J = 8.4,1.4Hz), 10.34 (lH, s)
[0263] 参考例 126 [0263] Reference Example 126
Figure imgf000130_0003
Figure imgf000130_0003
ジェチルホスホノ酢酸ェチル O.lOmLの N, N ジメチルホルムアミド 2mL溶液に、室 温で 60%水素化ナトリウム 19mgを加え、 30分間攪拌した。 2—メトキシ— 8 二トロキノ リン— 4—カルバルデヒド 0.10gの N, N ジメチルホルムアミド 2mL溶液を加え、 30分 間攪拌した。反応混合物を氷水および酢酸ェチルの混液に注ぎ、 lmol/L塩酸で pH 3に調整した。有機層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液 を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウム で乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグ ラフィー [溶離液;へキサン:酢酸ェチル = 2 : 1]で精製し、淡褐色固体のェチル = ( E) - 3- (2—メトキシ一 8 二トロキノリン一 4—ィル）アタリラート 85mgを得た。 19 mg of 60% sodium hydride was added at room temperature to 2 mL of N, N dimethylformamide in 0.10 mL of ethyl ethyl phosphonoacetate O.10 mL and stirred for 30 minutes. 2-Methoxy-8 Nitroquino A solution of 0.10 g of phosphorus-4-carbaldehyde in 2 mL of N, N dimethylformamide was added and stirred for 30 minutes. The reaction mixture was poured into a mixture of ice water and ethyl acetate and adjusted to pH 3 with lmol / L hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 2: 1], and the pale brown solid ethyl = (E) -3- (2-methoxy-1-8 ditroquinoline-1-4 -Il) 85 mg of attalylate was obtained.
'H-NMRCCDCl ) δ値： 1.38(3H,t,J=7.1Hz),4.07(3H,s),4.34(2H,q,J=7.1Hz),6.60(lH,d  'H-NMRCCDCl) δ value: 1.38 (3H, t, J = 7.1Hz), 4.07 (3H, s), 4.34 (2H, q, J = 7.1Hz), 6.60 (lH, d
3  Three
,J=15.9Hz),7.14(lH,s),7.46-7.51(lH,m),7.97(lH,dd,J=7.6,1.2Hz),8.18(lH,dd,J=8.3, 1.2Hz),8.23(lH,d,J=15.9Hz)  , J = 15.9Hz), 7.14 (lH, s), 7.46-7.51 (lH, m), 7.97 (lH, dd, J = 7.6,1.2Hz), 8.18 (lH, dd, J = 8.3, 1.2Hz) , 8.23 (lH, d, J = 15.9Hz)
[0264] 参考例 127 [0264] Reference Example 127
Figure imgf000131_0001
Figure imgf000131_0001
ェチル = (E) - 3- (2—メトキシ一 8 二トロキノリン一 4—ィル）アタリラート 80mgに 、室温で酢酸 3mLおよび 10%パラジウム 炭素 32mgを加え、水素雰囲気下、 40°Cで 5時間攪拌した。不溶物をろ去し、ろ滓をクロ口ホルムで 3回洗浄した。ろ液および洗 液を合わせ、減圧下で溶媒を留去した。得られた残留物に酢酸ェチルおよび飽和炭 酸水素ナトリウム水溶液を加えた。有機層を分取し、水層を酢酸ェチルで抽出した。 有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグ ネシゥムで乾燥させ、減圧下で溶媒を留去し、褐色油状物のェチル = 3—（8—ァミノ — 2—メトキシキノリン一 4—ィル）プロピオナ一ト 64mgを得た。  Ethyl = (E)-3- (2-Methoxy-1,8-troquinoline-1,4-yl) attalylate Add 80mL of acetic acid, 3mL of acetic acid and 32mg of 10% palladium on carbon at room temperature, and stir at 40 ° C for 5 hours under hydrogen atmosphere did. The insoluble material was removed by filtration, and the filter cake was washed three times with black mouth form. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract are combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to give a brown oily substance ethyl = 3- (8-amino--2-methoxyquinoline. 1 4-yl) Propionato 64 mg was obtained.
^-NMRCCDCl ) δ値： 1.25(3H,t,J=7.2Hz),2.74(2H,t,J=7.9Hz),3.29(2H,t,J=7.9Hz),4.  ^ -NMRCCDCl) δ value: 1.25 (3H, t, J = 7.2Hz), 2.74 (2H, t, J = 7.9Hz), 3.29 (2H, t, J = 7.9Hz), 4.
3  Three
04(3H,s),4.16(2H,q,J=7.2Hz),4.77(2H,s),6.76(lH,s),6.92(lH,dd,J=7.6,1.2Hz),7.20(l H,t,J=7.6Hz),7.24-7.27(lH,m)  04 (3H, s), 4.16 (2H, q, J = 7.2Hz), 4.77 (2H, s), 6.76 (lH, s), 6.92 (lH, dd, J = 7.6,1.2Hz), 7.20 (l H, t, J = 7.6Hz), 7.24-7.27 (lH, m)
[0265] 参考例 128
Figure imgf000132_0001
[0265] Reference Example 128
Figure imgf000132_0001
ェチル = (E) - 3- (2—メトキシ一 8 二トロキノリン一 4—ィル）アタリラート 48mgに 、室温で酢酸 4mLおよびリンドラー触媒 9.6mgを加え、水素雰囲気下、同温で 30分間 、 50°Cで 1時間攪拌した。リンドラー触媒 29mgを加え、水素雰囲気下、 50°Cで 6時間 攪拌した。不溶物をろ去し、ろ滓をクロ口ホルムで3回洗浄した。ろ液および洗液を合 わせ、減圧下で溶媒を留去した。得られた残留物に酢酸ェチルおよび飽和炭酸水 素ナトリウム水溶液を加えた。有機層を分取し、水層を酢酸ェチルで抽出した。有機 層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水 硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物のェチル = (E) —3— (8—ァミノ一 2—メトキシキノリン一 4—ィル）アタリラートの 43mgを得た。 Ethyl = (E)-3- (2-Methoxy-1 8 ditroquinoline 1-yl) Atalylate 48mg, Acetic acid 4mL and Lindlar's catalyst 9.6mg are added at room temperature, 30 minutes at the same temperature under hydrogen atmosphere, 50 ° Stir at C for 1 hour. Lindlar catalyst (29 mg) was added, and the mixture was stirred at 50 ° C for 6 hours under hydrogen atmosphere. The insoluble material was removed by filtration, and the filter cake was washed three times with black mouth form. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and ethyl ether of brown oil = (E) —3— ( 43 mg of 8-amino-1,2-methoxyquinoline 4-yl) attalylate was obtained.
^-NMRCCDCl ) δ値： 1.37(3H,t,J=7.2Hz),4.07(3H,s),4.31(2H,q,J=7.2Hz),4.79(2H,b ^ -NMRCCDCl) δ value: 1.37 (3H, t, J = 7.2Hz), 4.07 (3H, s), 4.31 (2H, q, J = 7.2Hz), 4.79 (2H, b
3  Three
road),6.55(lH,d,J=15.9Hz),6.96(lH,dd,J=7.6,1.2Hz),7.04(lH,s),7.22-7.28(lH,m),7. 35(lH,dd,J=8.3,1.2Hz),8.26(lH,d,J=15.9Hz) road), 6.55 (lH, d, J = 15.9Hz), 6.96 (lH, dd, J = 7.6,1.2Hz), 7.04 (lH, s), 7.22-7.28 (lH, m), 7.35 (lH , dd, J = 8.3,1.2Hz), 8.26 (lH, d, J = 15.9Hz)
参考例 129
Figure imgf000132_0002
Reference Example 129
Figure imgf000132_0002
1 （トリフルォロアセチル）ピぺリジンー4ーァミンの塩酸塩 0.50gの塩化メチレン 10 mL懸濁液に、 2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 スルホユルクロリド 0.5 0gをカ卩え、氷冷下、トリェチルァミン 0.59mLを滴下し、室温まで昇温し、 1時間攪拌し た。反応混合物にクロ口ホルムおよび水をカ卩えた。有機層を分取し、水層をクロロホ ルムで抽出した。有機層および抽出液を合わせ、 l.Omol/L塩酸、水および飽和塩化 ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を 留去し、淡褐色泡状物の N— (1 （トリフルォロアセチル）ピぺリジンー4 ィル） - 2 , 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—スルホンアミド 0.30gを得た。  1 (Trifluoroacetyl) piperidine-4-amine hydrochloride 0.50 g in methylene chloride 10 mL suspension with 2, 3 dihydrobenz [b] [l, 4] dioxin 6 sulfourel chloride 0.5 0 g Under cooling and ice cooling, 0.59 mL of triethylamine was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was charged with black mouth form and water. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed sequentially with l.Omol / L hydrochloric acid, water, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to give N- (1 (Trifluoroacetyl) piperidine-4-yl) -2,3 dihydrobenzo [b] [l, 4] dioxin 6-sulfonamide 0.30 g was obtained.
1H-NMR(CDC1 ) δ fg: 1.37-1.53(2H,m),1.86-1.98(2H,m),2.95-3.02(lH,m),3.16-3.2 4(lH,m),3.39-3.46(lH,m),3.84-3.92(lH,m),4.20-4.40(5H,m),4.48(lH,d,J=7.3Hz),6. 97(lH,d,J=8.5Hz),7.36(lH,dd,J=8.5,2.2Hz),7.40(lH,d,J=2.2Hz) 1H-NMR (CDC1) δ fg: 1.37-1.53 (2H, m), 1.86-1.98 (2H, m), 2.95-3.02 (lH, m), 3.16-3.2 4 (lH, m), 3.39-3.46 (lH, m), 3.84-3.92 (lH, m), 4.20-4.40 (5H, m), 4.48 (lH, d, J = 7.3Hz), 6.97 ( lH, d, J = 8.5Hz), 7.36 (lH, dd, J = 8.5,2.2Hz), 7.40 (lH, d, J = 2.2Hz)
[0267] 参考例 130
Figure imgf000133_0001
[0267] Reference Example 130
Figure imgf000133_0001
N- (1 （トリフルォロアセチル）ピぺリジンー4 ィル）—2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン一 6—スルホンアミド 0.29gのメタノール 2mL溶液に、水 0.5mLおよび 炭酸カリウム 0.12gをカ卩え、室温で 1時間攪拌した。反応混合物にクロ口ホルムおよび 水を加え、 lmol/L塩酸で pH8.0に調整した。有機層を分取し、水層をクロ口ホルムで 2 回抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減 圧下で溶媒を留去した。得られた残留物にへキサンを加え、固形物をろ取し、淡褐 色固体の N—(ピペリジンー4ーィル） 2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン - 6 スノレホンアミド 0.1 lgを得た。  N- (1 (trifluoroacetyl) piperidine-4-yl) -2,3 dihydrobenzo [b] [1,4] dioxin 6-sulfonamide 0.29 g of methanol in 2 mL of solution and water 0.5 mL And, potassium carbonate 0.12g was added and stirred at room temperature for 1 hour. To the reaction mixture was added black mouthform and water, and the pH was adjusted to 8.0 with lmol / L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with black mouth form. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the resulting residue, and the solid was collected by filtration. N— (piperidine-4-yl) 2, 3 dihydrobenzo [b] [l, 4] dioxin-6 snolehonamide 0.1 got lg.
1H-NMR(DMSO-d ) δ値： 1.12— 1.30(2H,m),1.44— 1.52(2H,m),2.26— 2.35(2H,m),2.74—  1H-NMR (DMSO-d) δ value: 1.12— 1.30 (2H, m), 1.44—1.52 (2H, m), 2.26—2.35 (2H, m), 2.74—
6  6
2.84(2H,m),2.88-2.98(lH,m),4.27-4.38(4H,m),6.98-7.04(lH,m),7.23-7.30(2H,m) [0268] 参考例 131
Figure imgf000133_0002
2.84 (2H, m), 2.88-2.98 (lH, m), 4.27-4.38 (4H, m), 6.98-7.04 (lH, m), 7.23-7.30 (2H, m) [0268] Reference Example 131
Figure imgf000133_0002
tert ブチル =4 アミノー 4 メチルビペリジン 1 カルボキシラート 0.50gの塩 化メチレン 5mL溶液に、 2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 カルバルデ ヒド 0.38gおよび酢酸 0.13mLを加え、室温で 3時間攪拌した。反応混合物に水素化トリ ァセトキシホウ素ナトリウム 0.74gを加え、同温度で 30分間攪拌した。さらに、水素化ト リアセトキシホウ素ナトリウム 0.74gを加え、同温度で 30分間攪拌した後、 1時間加熱還 流した。反応混合物にクロ口ホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。 有機層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出液を合わせ、飽 和塩ィ匕ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒 を留去し、淡褐色油状物の tert ブチル =4一（（2, 3 ジヒドロべンゾ [b] [1, 4]ジ ォキシン一 6 ィルメチル）ァミノ）一 4 メチルビペリジン 1 カルボキシラート 0.81 gを得た。 tert Butyl = 4 Amino-4 Methylbiperidine 1 Carboxylate Add 0.50 g of methylene chloride to a solution of 0.50 g with 2,3 dihydrobenzo [b] [l, 4] dioxin 6 carbaldehyde 0.38 g and acetic acid 0.13 mL at room temperature. Stir for 3 hours. To the reaction mixture, 0.74 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 minutes. Further, 0.74 g of sodium triacetoxyborohydride was added, stirred at the same temperature for 30 minutes, and then heated to reflux for 1 hour. To the reaction mixture, black mouth form and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Dihydrobenzo [b] [1, 4] dioxin 6-ylmethyl) amino) 1 4 methylbiperidine 1 carboxylate 0.81 g was obtained.
1H-NMR(CDC1 ) δ値： 1.17(3H,s),1.46(9H,s),1.36- 1.60(4H,m),3.35- 3.55(3H,m),3.58  1H-NMR (CDC1) δ value: 1.17 (3H, s), 1.46 (9H, s), 1.36-1.60 (4H, m), 3.35-3.55 (3H, m), 3.58
3  Three
(2H,s),4.20-4.30(6H,m),6.80-6.90(3H,m)  (2H, s), 4.20-4.30 (6H, m), 6.80-6.90 (3H, m)
[0269] 参考例 132
Figure imgf000134_0001
[0269] Reference Example 132
Figure imgf000134_0001
6 ーブチル=4ー（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルメチル )ァミノ）ー4ーメチルビペリジン 1 カルボキシラート 0.66gの塩化メチレン 5mL溶液 に、トリフルォロ酢酸 5mLを加え、室温で 1時間攪拌した。減圧下で溶媒を留去し、ク ロロホルム、水および 6mol/L塩酸をカ卩えた。水層を分取し、水層をクロ口ホルムで洗 浄した。水層にクロ口ホルムをカ卩え、 20%水酸ィ匕ナトリウム水溶液で pH13に調整した 。有機層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出液を合わせ、 無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、無色油状物の N— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン 6 ィルメチル）ー4ーメチルビペリジンー4 —ァミン 0.26gを得た。  6-Butyl = 4-((2,3 dihydrobenz [b] [l, 4] dioxin 6-ylmethyl) amino) -4-methylbiperidine 1 carboxylate Trifluoroacetic acid in 0.66 g methylene chloride solution 5 mL was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain chloroform, water and 6 mol / L hydrochloric acid. The aqueous layer was separated, and the aqueous layer was washed with black mouth form. A black mouth form was placed in the aqueous layer and adjusted to pH 13 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and colorless oil N- (2, 3 dihydrobenzo [b] [1, 4] dioxin 6ylmethyl) 0.26 g of -4-methylbiperidine-4-ammine was obtained.
1H-NMR(CDC1 ) δ fg: 1.16(3H,s),1.47-1.60(4H,m),2.73-2.79(2H,m),2.93-3.01(2H,  1H-NMR (CDC1) δ fg: 1.16 (3H, s), 1.47-1.60 (4H, m), 2.73-2.79 (2H, m), 2.93-3.01 (2H,
3  Three
m),3.59(2H,s),4.24(4H,s),6.80-6.82(2H,m),6.88-6.90(lH,m)  m), 3.59 (2H, s), 4.24 (4H, s), 6.80-6.82 (2H, m), 6.88-6.90 (lH, m)
[0270] 参考例 133
Figure imgf000134_0002
κ O [0270] Reference Example 133
Figure imgf000134_0002
κ O
HCI  HCI
1— (トリフルォロアセチル）ピぺリジン— 4—ァミンの塩酸塩 1.5gの N, N ジメチル ホルムアミド 15mL溶液に、 2 ブロモ N— (ピリジン— 2—ィル）ァセトアミド 1.4gおよ び炭酸カリウム 1.8gを加え、室温で 4時間攪拌した。反応混合物に酢酸ェチルおよび 水を加えた。有機層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液 を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウム で乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグ ラフィー [溶離液;クロ口ホルム:メタノール = 10 : 1]で精製し、淡褐色油状物の N— ( ピリジン 2 ィル） N2— (1 （トリフルォロアセチル）ピぺリジンー4 ィル）グリシ ンアミド、 l.lgを得た。 1- (Trifluoroacetyl) piperidine-4-hydroamine hydrochloride 1.5 g in N, N dimethylformamide 15 mL solution, 2 bromo N- (pyridine-2-yl) acetamide 1.4 g and potassium carbonate 1.8 g was added and stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 10: 1] to give N— ( Pyridine 2yl) N 2 — (1 (trifluoroacetyl) piperidine-4-yl) glycinamide, l.lg was obtained.
1H-NMR(CDC1 ) δ値： 1.35— 1.55(2H,m),2.00— 2.10(2H,m),2.77— 2.98(2H,m),3.15— 3.2  1H-NMR (CDC1) δ value: 1.35—1.55 (2H, m), 2.00—2.10 (2H, m), 2.77—2.98 (2H, m), 3.15—3.2
3  Three
3(lH,m),3.48(2H,s),3.97-4.05(lH,m),4.42-4.50(lH,m),7.06(lH,ddd,J=7.3,4.9,1.0Hz 3 (lH, m), 3.48 (2H, s), 3.97-4.05 (lH, m), 4.42-4.50 (lH, m), 7.06 (lH, ddd, J = 7.3,4.9,1.0Hz
),7.72(lH,td,J=7.9,1.9Hz),8.23(lH,d,J=8.3Hz),8.31(lH,ddd,J=4.9,1.9,1.0Hz),9.59(l), 7.72 (lH, td, J = 7.9, 1.9 Hz), 8.23 (lH, d, J = 8.3 Hz), 8.31 (lH, ddd, J = 4.9, 1.9, 1.0 Hz), 9.59 (l
H,s) H, s)
[0271] 参考例 134
Figure imgf000135_0001
[0271] Reference Example 134
Figure imgf000135_0001
N- (ピリジン 2 ィル） N2— (1 （トリフルォロアセチル）ピぺリジンー4ーィル )グリシンアミド l.lgの塩化メチレン 10mL溶液に、ジ—tert ブチル =ジカルボナート 0.87gを加え、室温で 1時間攪拌した。ジー tert ブチル =ジカルボナート 0.87gをカロ え、 2時間加熱還流した。ジー tert ブチル =ジカルボナート 1.75gをカ卩え、 1時間加 熱還流した。減圧下で溶媒を留去し、得られた残留物をシリカゲルカラムクロマトダラ フィー [溶離液；へキサン：酢酸ェチル = 1 : 1]で精製し、白色泡状物の tert -ブチル = (2—ォキソ 2—（ピリジン 2—ィルァミノ）ェチル）（1 （トリフルォロアセチル） ピぺリジン 4 ィル）力ルバマート 0.84gを得た。 N- (pyridine 2-yl) N 2 — (1 (trifluoroacetyl) piperidine-4-yl) glycinamide l.lg in 10 mL of methylene chloride was added 0.87 g of di-tert butyl dicarbonate at room temperature. Stir for 1 hour. 0.87 g of di-tert-butyl dicarbonate was added and heated to reflux for 2 hours. 1.75 g of di-tert-butyl dicarbonate was added and heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 1: 1] to give white foam tert-butyl = (2— 0.84 g of oxo-2- (pyridine-2-ylamino) ethyl) (1 (trifluoroacetyl) piperidine 4 yl) force rubamate was obtained.
'H-NMRCCDCl ) δ値： 1.47(9H,s),1.55- 1.70(2H,m),1.90- 2.00(2H,m),2.79(lH,t,J=12.  'H-NMRCCDCl) δ value: 1.47 (9H, s), 1.55- 1.70 (2H, m), 1.90-2.00 (2H, m), 2.79 (lH, t, J = 12.
3  Three
6Hz),3.18(lH,t,J=12.7Hz),3.88(2H,s),4.05-4.13(lH,m),4.15-4.50(lH,m),4.62-4.70( lH,m),7.06(lH,ddd,J=7.3,5.0,0.9Hz),7.69-7.74(lH,m),8.17(lH,d,J=8.3Hz),8.28(lH, ddd,J=5.0,2.0,0.9Hz)  6Hz), 3.18 (lH, t, J = 12.7Hz), 3.88 (2H, s), 4.05-4.13 (lH, m), 4.15-4.50 (lH, m), 4.62-4.70 (lH, m), 7.06 (lH, ddd, J = 7.3,5.0,0.9Hz), 7.69-7.74 (lH, m), 8.17 (lH, d, J = 8.3Hz), 8.28 (lH, ddd, J = 5.0,2.0,0.9Hz )
[0272] 参考例 135
Figure imgf000135_0002
[0272] Reference Example 135
Figure imgf000135_0002
tert ブチル = (2—ォキソ 2—（ピリジン 2—ィルァミノ）ェチル）（1 （トリフル ォロアセチル）ピぺリジンー4 ィル）力ルバマート 0.80gのメタノール 8mL溶液に、水 2 mLおよび炭酸カリウム 0.31gを加え、室温で 1時間攪拌した。反応混合物にクロ口ホル ムおよび水を加えた。有機層を分取し、水層をクロ口ホルムで抽出した。有機層およ び抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾 燥させ、減圧下で溶媒を留去し、淡褐色泡状物の tert ブチル = (2—ォキソ 2— (ピリジン 2 ィルァミノ）ェチル）（ピペリジンー4 ィル）力ルバマート 0.61gを得た。 1H-NMR(CDC1 ) δ fg: 1.46(9H,s),1.40-1.60(2H,m),1.76-1.83(2H,m),2.65-2.71(2H, tert Butyl = (2-oxo-2- (pyridine-2-ylamino) ethyl) (1 (trifluoroacetyl) piperidine-4-yl) strength rubamate 0.80 g of methanol in 8 mL of solution, add 2 mL of water and 0.31 g of potassium carbonate And stirred at room temperature for 1 hour. Black mouth form and water were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with black mouth form. Organic layer and And the extracts, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and tert-butyl = (2-oxo-2- (pyridine-2-ylamino) as a light brown foam. ) Ethyl) (piperidine-4-yl) strength rubamate 0.61 g was obtained. 1H-NMR (CDC1) δ fg: 1.46 (9H, s), 1.40-1.60 (2H, m), 1.76-1.83 (2H, m), 2.65-2.71 (2H,
3  Three
m),3.10-3.18(2H,m),3.92(2H,s),4.00-4.25(lH,m),7.04(lH,ddd,J=7.3,4.9,0.9Hz),7.67m), 3.10-3.18 (2H, m), 3.92 (2H, s), 4.00-4.25 (lH, m), 7.04 (lH, ddd, J = 7.3, 4.9, 0.9Hz), 7.67
-7.73(lH,m),8.20(lH,d,J=8.3Hz),8.27(lH,ddd,J=4.9,2.0,0.8Hz) -7.73 (lH, m), 8.20 (lH, d, J = 8.3Hz), 8.27 (lH, ddd, J = 4.9,2.0,0.8Hz)
参考例 136
Figure imgf000136_0001
Reference Example 136
Figure imgf000136_0001
tert ブチル =4 ( ( (ベンジルォキシ）カルボニル）ァミノ） 4 （（メチルァミノ） カルボ-ル）ピぺリジン 1 カルボキシラート 0.75gのエタノール 10mL溶液に、室温 で 20%水酸化パラジウム—炭素 75mgをカ卩え、水素雰囲気下、 40°Cで 2時間攪拌した 。 20%水酸化パラジウム—炭素 75mgをカ卩え、水素雰囲気下、 40°Cで 3時間攪拌した 。不溶物をろ去し、ろ滓をクロ口ホルムで 3回洗浄した。ろ液および洗液を合わせ、減 圧下で溶媒を留去し、淡灰色泡状物の tert ブチル =4 アミノー 4 （(メチルアミ ノ）カルボ-ル）ピぺリジン 1 カルボキシラート 0.62gを得た。  tert Butyl = 4 (((Benzyloxy) carbonyl) amino) 4 ((Methylamino) carbol) piperidine 1 Carboxylate Add 0.75 g of ethanol in 10 mL solution of 20% palladium hydroxide-carbon at room temperature. The mixture was stirred at 40 ° C for 2 hours in a hydrogen atmosphere. 20% palladium hydroxide-carbon (75 mg) was added, and the mixture was stirred at 40 ° C. for 3 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filter cake was washed three times with black mouth form. The filtrate and washing solution were combined and the solvent was distilled off under reduced pressure to obtain 0.62 g of light gray foam tertbutyl = 4 amino-4 ((methylamino) carbol) piperidine 1 carboxylate.
1H-NMR(CDC1 ) δ値： 1.45(9H,s), 1.40- 3.80(8H,m),2.84(3H,d,J=4.6Hz),7.75- 7.85(1 1H-NMR (CDC1) δ value: 1.45 (9H, s), 1.40-3.80 (8H, m), 2.84 (3H, d, J = 4.6Hz), 7.75-7.85 (1
3  Three
H, broad)  H, broad)
参考例 137
Figure imgf000136_0002
Reference Example 137
Figure imgf000136_0002
tert ブチル =4 アミノー 4 （（メチルァミノ）カルボ-ル）ピぺリジン 1 カルボ キシラート 0.30gの塩化メチレン 5mL溶液に、 2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシ ンー6 カルバルデヒド 0.16gおよび酢酸 57 Lをカ卩え、室温で 2時間攪拌した。反応 混合物に水素化トリァセトキシホウ素ナトリウム 0.32gを加え、同温度で 30分間攪拌し た。反応混合物にクロ口ホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。有機 層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出液を合わせ、水およ び飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧 (H) 、¾QT¾n rf8Zベ ^ ^エ fH ι 1 ΐ94— έίί^ ^エ -2M ^mZA^ . tert Butyl = 4 Amino-4 ((Methylamino) carbol) piperidine 1 Carboxylate Add 0.30 g of methylene chloride to a solution of 2,3 dihydrobenz [b] [1, 4] dioxin-6 carbaldehyde 0.16 g and 57 L of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 0.32 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 minutes. To the reaction mixture, black mouth form and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated and the aqueous layer was extracted with black mouth form. Combine the organic layer and the extract, wash sequentially with water and saturated aqueous sodium chloride solution, dry over anhydrous magnesium sulfate, and vacuum (H), ¾QT¾n rf 8Z base ^ ^ E fH ι 1 ΐ94— έίί ^ ^ E -2M ^ m ZA ^.
Figure imgf000137_0001
Figure imgf000137_0001
6SIp}% [9Z20] (ω'Ηΐ)8ε· — SS' ' C"'HS) 8·9— 8·9'(ζΗ8·ΐ'0· 8=rPP'HT) -9'(s'H^) 2^'(ra'H2)02^-00^'(s'H2) ^-S'(ra'H2) 0"S-T0"S'(zHrS=f'P 6SIp}% [9Z20] (ω'Ηΐ) 8ε · — SS '' C "'HS) 8 · 9— 8 · 9' ( ζ Η8 · ΐ'0 · 8 = rPP'HT) -9 '( s ' H ^) 2 ^ '(ra'H2) 02 ^ -00 ^' ( s ' H2) ^ -S '(ra'H2) 0 "S-T0"S' ( z HrS = f'P
'HS)S8 ' C"'HS) 8 — 9 ' C"'HS) rS— SO ' (ω'ΗΖ)89·ΐ— 8S'I :軍 9 ( Iつ dつ) WN— Ητ 'HS) S8' C "'HS) 8 — 9'C"'HS) rS— SO'(ω'ΗΖ) 89 · ΐ— 8S'I: Army 9 (I d) WN— Η τ
。 會| ^ S'0、 ^ ^^ 一 一べ ^ ー N—（ ^ （ ^ / 9一べ^^^^ [ Ί]
Figure imgf000137_0002
— 0)呦^ ^ .會 | ^ S'0, ^ ^^ All in one ^ ー N— (^ (^ / 9 All in ^^^^ [Ί]
Figure imgf000137_0002
— 0) 呦 ^^
、π辛爵 瀚缀 止 s教 ^^m^ ^^^m ^ ^^ nm  , Pi piju 瀚 缀 s teaching ^^ m ^ ^^^ m ^ ^^ nm
m¾鱸 εΐΗ¾_
Figure imgf000137_0003
、つ辛恩 瀚缀 止 sm °^^ ^ ^ ^ ^ZWB^^ C ^继缀 τ¾ペm¾ 鱸 εΐΗ¾_
Figure imgf000137_0003
, Spicy 瀚 缀 Stop sm ° ^^ ^ ^ ^ ^ ZWB ^^ C ^ 继 缀 τ¾
Figure imgf000137_0004
(
Figure imgf000137_0005
Figure imgf000137_0004
(
Figure imgf000137_0005
(ra'HT)62"Z-T2-Z'(ra'H2)06"9-S8"9'(zH (ra'HT) 62 "Z-T2-Z '(ra'H2) 06" 9-S8 "9' ( z H
0 'S'8=1"'PP'HI)SZ'9'(S'H )9S' (ω'Η 88·ε— Z S'(s'HS)8 S'(ra'HS)SS'S— εΐ·ε'(ζΗ6 0 'S'8 = 1 "'PP'HI)SZ'9'( S ' H) 9S '(ω'Η 88 · ε— Z S' ( s 'HS) 8 S'(ra'HS)SS'S— εΐ · ε '( ζ Η6
· =【'Ρ'Ηε)ε8 ' C"'H SrS- SO ' (ω'Η Ζ9·ΐ- WI'(s'H6)9 'I :軍 9 (OQDWH-H^
Figure imgf000137_0006
' z))→= ^ -^°^^ ^Μ^、つ ¾H [τ:(Η= /—,^ マ / crn^· = 【'Ρ'Ηε) ε8' C "'H SrS- SO'(ω'Η Ζ9 · ΐ- WI '(s'H6) 9' I: Military 9 (OQDWH-H ^
Figure imgf000137_0006
'z)) → = ^-^ ° ^^ ^ Μ ^, ¾H (τ: (Η = / —, ^ Ma / crn ^
Figure imgf000137_0007
Figure imgf000137_0007
98S6T0/S00Zdf/X3d 981- H9"eT=rP'HT)eS"8'(zH8"Z=f'P'HT)^9"Z'(ZH8"Z=f'P'HT)6^"Z'(ZHr6=rP'HT)S0"Z'(ZH 98S6T0 / S00Zdf / X3d 981- H9 "eT = rP'HT) eS" 8 '( z H8 "Z = f'P'HT) ^ 9"Z' (ZH8 "Z = f'P'HT) 6 ^" Z '(ZHr6 = rP' HT) S0 "Z '(ZH
9'SI=f'P'HI)SS'9'(zHS 'r =f'PP'HI)00'S'(ZHrZ=f'b'HS)IS' (S'HS)60' (ζΗΐ· 8
Figure imgf000138_0001
） -
Figure imgf000138_0002
9'SI = f'P'HI) SS'9 '( z HS' r = f'PP'HI) 00'S '(ZHrZ = f'b'HS) IS' ( S 'HS) 60' ( ζ Ηΐ 8
Figure imgf000138_0001
-
Figure imgf000138_0002
^^ ^m ^ ^ 。 >η辛恩 瀚缀、 止 ϊί教 ^^m^ ^^^m 斜萆 m^^-^^ ^ 、つ 斜萆。 ^ 一ェ  ^^ ^ m ^ ^. > η 恩 瀚 缀, ϊ ϊί 教 ^^ m ^ ^^^ m 萆 萆 m ^^-^^ ^, 萆 萆. ^
§ε ·ο、 — Eマ - ^
Figure imgf000138_0003
 § ε · ο, E Ma-^
Figure imgf000138_0003
§03 4— § 03 4—
Figure imgf000138_0004
Figure imgf000138_0004
O^Ip}% [ΖΖ20] O ^ Ip}% [ΖΖ20]
(δ'Ηΐ)9ε·π'(ζΗΐ·6= rP'HT)S^"8'(zH6"eT=rP'HT)9S"8'(zH8"Z=rP'HT)S2"8'(zH8"Z=rP'HT)SZ"Z'(ZHr6=f 'Ρ'Ηΐ)80 (ζΗ6·3ΐ=ί"'Ρ'Ηΐ)09·9'(ζΗΓΖ=Γ&'Η εε· (s'HS)Sr (ζΗΓΖ=ί"'νΗε)8ε·ΐ( δ 'Ηΐ) 9ε · π' ( ζ Ηΐ · 6 = rP'HT) S ^ "8 '( z H6" eT = rP'HT) 9S "8' ( z H8" Z = rP'HT) S2 " 8 '( z H8 "Z = rP'HT) SZ"Z' (ZHr6 = f 'Ρ'Ηΐ) 80 ( ζ Η6 · 3ΐ = ί "'Ρ'Ηΐ) 09 · 9 '( ζ ΗΓΖ = Γ &' Η εε · ( s 'HS) Sr ( ζ ΗΓΖ = ί "' νΗε) 8ε · ΐ
Figure imgf000138_0005
Figure imgf000138_0005
。 ¾¾§69·(Η— έίί^ （ —S—べ ίί,^Ρ ^Ε ー S— /  . ¾¾§69 · (Η— έίί ^ (—S—Be ίί, ^ Ρ ^ Ε ー S— /
¾
Figure imgf000138_0006
瀚缀 止 s教 ¾
Figure imgf000138_0006
止 Stop s teaching
^ ^mm。 ·η辛爵¾瀚缀 止 ϊί教、^ ^ mm. · Ηpion ¾ 瀚 缀
z^o0oe、止^蹈 峯暴、"¾^i Sui6's(o)マ (ベ ^ /^ I— — z ^ o 0 oe, 蹈 ^ 蹈 峯 激, "¾ ^ i Sui 6's (o) ma (be ^ / ^ I— —
98S6T0/S00Zdf/X3d 9ε ΐ· zrnm^ [6 20] 98S6T0 / S00Zdf / X3d 9ε ΐ zrnm ^ [6 20]
(δ'Ηΐ)38·0ΐ'(δ'Ηΐ)90·6'(ζΗΐ·ΐ'6·Ζ=ΓΡΡ'Ηΐ)ΐε·8'(ζΗ8·8=ί"'Ρ (δ'Ηΐ) 38 · 0ΐ '( δ ' Ηΐ) 90 · 6 '( ζ Ηΐ · 6'6 · Ζ = ΓΡΡ'Ηΐ) ΐε · 8' ( ζ Η8 · 8 = ί "'Ρ
'HT) 2"8'(zHrr6" =rPP'HT)2S" '(ZH6" =r HT)6S" '(ZH8"8=rP'HT)0r '(ra'He)S 'HT) 2 "8' ( z Hrr6" = rPP'HT) 2S "'(ZH6" = r HT) 6S "'(ZH8" 8 = rP'HT) 0r '(ra'He) S
8·9-0 ·9'(ω'Η¾5ε^-02^'(ω'Η^^-02^'(8Ήε)60^'(ω'Η2)0 ·ε-09·ε'(ω'Η¾55·ε8 · 9-0 · 9 '(ω'Η¾5ε ^ -02 ^'(ω'Η ^^-02 ^ '( 8 Ήε) 60 ^'(ω'Η2) 0 · ε-09 · ε '(ω' Η¾55 · ε
— 3 ·ε'(ω'Η„·ε— sWC"'Hs)os's— 3θ·ε'(ω'Η οο·ε— 06 ：軍 9 ( oswa) Ν— ΗΤ — 3 · ε '(ω'Η „· ε— sWC"' Hs) os's— 3θ · ε '(ω'Η οο · ε— 06: Army 9 (oswa) Ν— Η Τ
。 ¾¾Sui99^r邈 ^r ^^ ^^ 一 I一べ . ¾¾ Sui 99 ^ r 邈 ^ r ^^ ^^
-N- ( /^ - ^J ^ Ί]
Figure imgf000139_0001
、つ1 §:Μ Πωο·3氺 一 ^ェ0 /0 -N- (/ ^-^ J ^ Ί]
Figure imgf000139_0001
, One 1 §: Μ Πωο · 3氺one ^ E 0/0
06¾§0ΐ θ)¾ζ )^ °^¾¾s6s'o^邈 ^ )、 ^ ^^ 一 τ -^ό^ (^ -06¾§0ΐ θ) ¾ζ) ^ ° ^ ¾¾ s 6s'o ^ 邈 ^), ^ ^^ One τ-^ ό ^ (^-
S
Figure imgf000139_0002
、
Figure imgf000139_0003
、つ ¾9¾呦 措 ェ邈 呦爵 ¾、つ 辛爵 瀚缀、 止 s教
Figure imgf000139_0004
Figure imgf000139_0005
。 ·η辛恩 瀚缀、 止 S
Figure imgf000139_0002
,
Figure imgf000139_0003
¾9¾ 呦 Measures 呦 呦, つ 爵
Figure imgf000139_0004
Figure imgf000139_0005
. · Η
m ^^ ^ ^^^m ^ ^^ ^m ^ mM^。 つ 回  m ^^ ^ ^^^ m ^ ^^ ^ m ^ mM ^. Times
Figure imgf000139_0006
Figure imgf000139_0006
ε 'ζ) -ζ)-ι、τ" ·οベ ^ ェ fw ^ ^ ^ ^ ^ ^ ε 'ζ) -ζ) -ι 、 τ "· ο be ^ fw ^ ^ ^ ^ ^ ^
翻 ΐ っ。 ss〜os ^w^zz^^— ^y^—^c - {N ' Γ0ベ;^ fiTranslation. ss〜os ^ w ^ zz ^^ — ^ y ^ — ^ c- { N 'Γ0Be; ^ fi
^ ^ 一  ^ ^ One
Figure imgf000139_0007
Figure imgf000139_0007
(ζΗΓ6'Ρ'Ηΐ)0 ·8'(ζ (ζΗΓ6'Ρ'Ηΐ) 0 8 '( ζ
98S6T0/S00Zdf/X3d l£l ZSS9^0/900Z OAV
Figure imgf000140_0001
98S6T0 / S00Zdf / X3d l £ l ZSS9 ^ 0 / 900Z OAV
Figure imgf000140_0001
8 アミノー 2—メチルキノリン 0.10gおよび 1— (2— (2, 3 ジヒドロべンゾ [b] [l, 4 ]ジォキシン 6 ィル）ェチル）ピぺラジンの塩酸塩 0.20gから実施例 1と同様にして 、淡黄色固体の 4一（2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン 6 ィル）ェ チル） N— (2—メチルキノリンー8 ィル）ピぺラジン 1 カルボキサミドの塩酸塩 0.20gを得た。  8 Example 1 from 0.10 g of amino-2-methylquinoline and 0.20 g of 1- (2- (2,3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piperazine hydrochloride In the same manner, a light yellow solid 4 (2— (2,3 dihydrobenz [b] [1,4] dioxin 6 yl) ethyl) N— (2-methylquinoline-8 yl) piperazine 1 0.20 g of carboxamide hydrochloride was obtained.
'H-NMRCDMSO-d ) δ値： 2.75(3H,s),2.90— 3.00(2H,m),3.10— 3.30(2H,m),3.30— 3.80(6  'H-NMRCDMSO-d) δ value: 2.75 (3H, s), 2.90—3.00 (2H, m), 3.10—3.30 (2H, m), 3.30—3.80 (6
6  6
H,m),4.22(4H,s),4.15-4.40(2H,m),6.75-6.90(3H,m),7.50-7.60(3H,m),8.25-8.35(2H, m)  H, m), 4.22 (4H, s), 4.15-4.40 (2H, m), 6.75-6.90 (3H, m), 7.50-7.60 (3H, m), 8.25-8.35 (2H, m)
実施例 3 Example 3
Figure imgf000140_0002
Figure imgf000140_0002
l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ン— 4—カルボン酸 82mgの N, N ジメチルホルムアミド 1.6mL溶液に、 N, N，—カル ボニルジイミダゾール 75mgを加え、室温で 50分間攪拌した。 8 アミノー 2—メトキシ キノリン 81mgをカ卩え、 2時間 45分間攪拌した。ジフエ-ルホスホン酸アジド 67 Lをカロ え、 60〜70°Cで 6時間攪拌した。反応混合物に水 10mLおよび酢酸ェチル 10mLをカロ え、 6.0mol/L塩酸で pHl.Oに調整した。有機層を分取し、水層に炭酸カルシウムを飽 和するまで加え、酢酸ェチル 10mLで抽出した。有機層および抽出液を合わせ、飽和 塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を 留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム ：メタノール =20 : 1]で精製し、褐色油状物の 1— (1— (2— (2, 3 ジヒドロべンゾ [b ] [1, 4]ジォキシン一 6—ィル）ェチル）ピぺリジン一 4—ィル） 3— (2—メトキシキノ リン— 8—ィル）ゥレア llmgを得た。  l-(2- (2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piberidine-4-carboxylic acid 82 mg N, N dimethylformamide in 1.6 mL solution, N, N , -Carbonyldiimidazole (75 mg) was added, and the mixture was stirred at room temperature for 50 minutes. 8 81 mg of amino-2-methoxyquinoline was added and stirred for 2 hours and 45 minutes. 67 L of diphenylphosphonic acid azide was added and stirred at 60 to 70 ° C. for 6 hours. The reaction mixture was charged with 10 mL of water and 10 mL of ethyl acetate, and adjusted to pHl.O with 6.0 mol / L hydrochloric acid. The organic layer was separated, calcium carbonate was added to the aqueous layer until saturated, and extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1] to give a brown oily 1- (1— (2— (2, 3 dihydrobenzo [b ] [1, 4] Dioxin-6-yl) ethyl) piperidine-4-yl) 3- (2-methoxyquinoline-8-yl) urea llmg was obtained.
1H-NMR(CDC1 ) δ値： 1.55- 1.65(2H,m),2.05- 2.25(4H,m),2.50- 2.75(4H,m),2.90- 3.0
Figure imgf000141_0001
1H-NMR (CDC1) δ value: 1.55- 1.65 (2H, m), 2.05- 2.25 (4H, m), 2.50-2.75 (4H, m), 2.90- 3.0
Figure imgf000141_0001
S圏第 [2820] (S'HT)S9"6 S-zone [2820] ( S 'HT) S9 "6
'(ζΗ9·Ζ=ί"'Ρ'Ηΐ)εΓ8'(ζΗ0·6=ί"'Ρ'Ηΐ)ΐ0·8'(ω'Ηζ)03·Ζ— 3ε·Ζ'(ζΗ0·6=ί"'Ρ'Ηΐ)96·9'(ω'Η ε)38·9-39·9'(ω'Η^)82^-ε2^'(8'Ηε)0ΐ^'(ω'Η2)02·ε-0Γε'(ω'Η2)08·2-0 ·2'(ω'Η2)0 '(ζΗ9 · Ζ = ί "'Ρ'Ηΐ) εΓ8 '( ζ Η0 · 6 = ί"'Ρ'Ηΐ) ΐ0 · 8 '(ω'Ηζ) 03 · Ζ— 3ε · Ζ' ( ζ Η0 · 6 = ί "'Ρ'Ηΐ) 96 · 9'(ω'Η ε) 38 · 9-39 · 9 '(ω'Η ^) 82 ^ -ε2 ^'(8'Ηε) 0ΐ ^ '(ω'Η2 ) 02 ・ ε-0Γε '(ω'Η2) 08 ・ 2-0 2'(ω'Η2) 0
Ζ - 09 ' (ω'Ηΐ)03 - 0 ' (ω'Η - 0rS'C"'HS)0rS- 06·ΐ :軍 9 ( !DaD)H N-HT
Figure imgf000141_0002
、つ ¾9¾呦 ffl措、" ¥Hf 继 Ζ-09 '(ω'Ηΐ) 03-0'(ω'Η-0rS'C"'HS) 0rS-06 06: Army 9 (! DaD) H NH T
Figure imgf000141_0002
, ¾9¾ 呦 ffl measures, "\ Hf 继
^ベ ^ 一 / 一ェ ^エ 、 ^ ^- [ 1 : 001 = — ^： ^Λ^ ^ ί ψΜ
Figure imgf000141_0003
。 ·η辛恩 瀚缀、 止 s教 mmm^ ^。 _nffl 回 τ"0Μ/ ェ邈 氺、つ 斜萆。：ふ^ Be ^ 1 / 1e ^ D, ^ ^-[1 : 001 = — ^: ^ Λ ^ ^ ί ψΜ
Figure imgf000141_0003
. · Η 辛 恩, s teaching mmm ^ ^. _nffl times τ " 0Μ / Μ邈, 萆. ： ふ
Figure imgf000141_0004
Figure imgf000141_0004
^Μ ^'Κ^^ ^ w ベ ^ ^エ fH、 T?iSu¾ベ ίί,^ρ ^E ー s— ^ Μ ^ 'Κ ^^ ^ w Bee ^^ E fH, T? I Su ¾Be ίί, ^ ρ ^ E ー s—
8 \ 、 。 _n辛爵¾瀚缀、 止 s教、 ： a ^w ^^ ^ ^ ^ 止 ¾教。 D 翻 ΐ  8 \,. _n 爵 瀚 缀 瀚 缀, 教 教 、: a ^ w ^^ ^ ^ ^ ¾ 教. D translation
Figure imgf000141_0005
Figure imgf000141_0005
m^ [1820] m ^ [1820]
(ω'Η 03·8- 0 ·8'(ΖΗ (ω'Η 03 / 8- 0 8 '( Ζ Η
8·8=ΓΡΉΐ)66· '(ω'Η2)0^· -0ε· '(ζΗ8·8=Γ'ΡΉΐ)ε6·9'(ζΗ0·8=ΓΡΉΐ)8 ·9'(ω'Η2)5 8 · 8 = ΓΡΉΐ) 66 · '(ω'Η2) 0 ^ · -0ε ·' (ζΗ8 · 8 = Γ'ΡΉΐ) ε6 · 9 '( ζ Η0 · 8 = ΓΡΉΐ) 8 · 9'(ω'Η2 )Five
Ζ·9— 39·9'(ζΗ9·Ζ=ί"'Ρ'Ηΐ)6Ζ· (ω'Η SS' —SS (S'HS)60' (ω'Ηΐ)08·ε— ( 'S'(ra'HS)O 9 · 9— 39 · 9 '( ζ Η9 · Ζ = ί "'Ρ'Ηΐ) 6Ζ · (ω'Η SS '—SS ( S ' HS) 60 '(ω'Ηΐ) 08 · ε— (' S '(ra'HS) O
98S6T0/S00Zdf/X3d 6ε ΐ· ン 4 カルボン酸 0.83gに塩化チォ -ル 5.4mLおよび N, N ジメチルホルムアミド 3 0 /z Lを加え、 50分間加熱還流した。反応混合物を室温まで冷却し、減圧下で溶媒を 留去した。得られた残留物に塩化メチレン 5.4mLを加え、氷冷下、 5 ブロモー 2—メ トキシキノリン一 8 ァミン 0.69gおよびトリェチルァミン 0.38mLの塩化メチレン 5.4mL溶 液を加え、室温で 20分間攪拌した。水 20mLおよび酢酸ェチル 20mLを加え、析出物 をろ取し、白色固体の N— (5 ブロモ 2—メトキシキノリン一 8—ィル） 1— (2— ( 2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピぺリジン 4 カル ボキサミド 1.3gを得た。 98S6T0 / S00Zdf / X3d 6ε ΐ To 0.83 g of 4-carboxylic acid, 5.4 mL of thiol chloride and N, N dimethylformamide 30 / zL were added, and the mixture was heated to reflux for 50 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. To the obtained residue, 5.4 mL of methylene chloride was added, and under ice cooling, a solution of 0.69 g of 5-bromo-2-methoxyquinoline monoamine and 0.68 g of methylene chloride of 0.38 mL of triethylamine was added and stirred at room temperature for 20 minutes. Water (20 mL) and ethyl acetate (20 mL) were added, and the precipitate was collected by filtration. White solid N— (5 bromo-2-methoxyquinoline 1-8-yl) 1— (2— (2, 3 dihydrobenzo [b] 1.3 g of [l, 4] dioxin 6yl) ethyl) piperidine 4 carboxamide was obtained.
^-NMRCDMSO-d ) δ値： 1.95— 2.10(2H,m),2.10— 2.30(2H,m),2.85— 3.15(5H,m),3.20—  ^ -NMRCDMSO-d) δ value: 1.95— 2.10 (2H, m), 2.10— 2.30 (2H, m), 2.85— 3.15 (5H, m), 3.20—
6  6
3.50(2H,m),3.60-3.70(2H,m),4.16(3H,s),4.20-4.25(4H,m),6.70-6.85(3H,m),7.27(lH ,d,J=9.0Hz),7.76(lH,d,J=8.4Hz),8.39(lH,d,J=9.0Hz),8.40(lH,d,J=8.4Hz),9.78(lH,s) 実施例 6  3.50 (2H, m), 3.60-3.70 (2H, m), 4.16 (3H, s), 4.20-4.25 (4H, m), 6.70-6.85 (3H, m), 7.27 (lH, d, J = 9.0 Hz), 7.76 (lH, d, J = 8.4 Hz), 8.39 (lH, d, J = 9.0 Hz), 8.40 (lH, d, J = 8.4 Hz), 9.78 (lH, s) Example 6
Figure imgf000142_0001
Figure imgf000142_0001
N— (5 ブロモ 2—メトキシキノリン一 8—ィル） 1— (2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル）ピぺリジン 4 カルボキサミド 0.10gのへ キサメチルリン酸トリアミド 2.0mL溶液に、テトラメチルスズ (IV) 53 Lおよびジクロロビ ス（トリフエ-ルホスフィン）パラジウム（II) 13mgをカ卩え、窒素気流下、 100〜110°Cで 5 時間加熱した。ジクロロビス（トリフエ-ルホスフィン）パラジウム（II) 13mgをカ卩え、 100 〜110°Cで 7時間加熱した。反応混合物に水 10mLをカ卩え、 20%水酸ィ匕ナトリウム水溶 液で pHll.Oに調整し、酢酸ェチル 20mLをカ卩えた。有機層を分取し、飽和塩化ナトリ ゥム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。 得られた残留物をアルミナカラムクロマトグラフィー [アルミナ;メルク株式会社、アルミ ユウムォキシド 60、溶離液;へキサン:酢酸ェチル = 2 : 1]および高速液体クロマトグ ラフィー [担体;株式会社ヮイエムシィ、 ODS AM、溶離液;ァセトニトリル: 0.1%トリ フルォロ酢酸水溶液 = 3 : 7]で精製した。得られた物質をクロ口ホルム 2. OmLに溶解し 、 3.2mol/L塩ィ匕水素/ジォキサン l.OmLをカ卩えた。減圧下で溶媒を留去し、酢酸ェチ
Figure imgf000143_0001
N— (5 Bromo 2-methoxyquinoline 8-yl) 1— (2— (2, 3 Dihydrobenzo [b] [1, 4] dioxin 6 yl) ethyl) piperidine 4 Carboxamide 0.10 g To a 2.0 mL solution of hexamethylphosphoric triamide, add 53 L of tetramethyltin (IV) and 13 mg of dichlorobis (triphosphinephosphine) palladium (II), and heat at 100 to 110 ° C for 5 hours under nitrogen flow. did. 13 mg of dichlorobis (triphenylphosphine) palladium (II) was added and heated at 100 to 110 ° C. for 7 hours. 10 mL of water was added to the reaction mixture, adjusted to pHll.O with 20% aqueous sodium hydroxide solution, and 20 mL of ethyl acetate was added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to alumina column chromatography [Alumina; Merck & Co., Aluminium oxide 60, eluent; Hexane: Ethyl acetate = 2: 1] and high-performance liquid chromatography [Carrier; Tsubaki YMC, ODS AM, elution Solution; acetonitrile: 0.1% aqueous trifluoroacetic acid = 3: 7]. The obtained substance was dissolved in 2.OmL of black mouth form, and 3.2 mol / L of sodium chloride / dioxane / OmL was collected. Evaporate the solvent under reduced pressure and
Figure imgf000143_0001
(8Ήΐ)ε9·6'(ζΗΟ·8=ΓΡ'Ηΐ)29·8'(ζΗ2·6=ΓΡ'Ηΐ)^·8'(ω'Ηΐ)οε· -3Γ '(ζΗ2 ·6=ί"'Ρ'Ηΐ)66·9'(ω'Ηε)08·9- S9'9'(S'H )W (s'HS)Or (zH6 =l"' HS)SS'S'(ra'HS)0 ( 8 Ήΐ) ε9 ・ 6 '( ζ ΗΟ · 8 = ΓΡ'Ηΐ) 29 ・ 8' ( ζ Η2 ・ 6 = ΓΡ'Ηΐ) ^ · 8 '(ω'Ηΐ) οε · -3Γ' (ζΗ2 = ί "'Ρ'Ηΐ) 66 · 9'(ω'Ηε) 08 · 9- S9'9 '( S ' H) W ( s ' HS) Or ( z H6 = l"'HS)SS'S' (ra 'HS) 0
S'S- 0ΐ·ε'(ω'Η 08 - OrS'(zH6 =f' HS)6S ' C"'HS)( - SS ' (ra'HI)SS - (^ ' S'S-0ΐ · ε '(ω'Η 08-OrS' ( z H6 = f 'HS) 6S' C "'HS) (-SS'(ra'HI) SS-(^ '
'H SS - OrS'C"'H SO - 06·ΐ 'C"'HS)( 'I- 0S'I'(s'H6)S 'I :軍 9 (OQDWH-H^ 'H SS-OrS'C "' H SO-06 · ΐ 'C"' HS) ('I-0S'I' (s'H6) S 'I: Army 9 (OQDWH-H ^
(H— -
Figure imgf000143_0002
(
Figure imgf000143_0003
(H—-
Figure imgf000143_0002
(
Figure imgf000143_0003
Figure imgf000143_0004
Figure imgf000143_0004
Ζ圏第 [画]  Ninth Region [Picture]
T)Z9"6'(zH8"8=rP'HT)8S"8'(zH8"Z=rP'HT)SS"8'(zH8"Z=rP'HT)S2"Z'(zH8"8=rP'HT)S ΐ·Ζ'(ω'Ηε)38·9— 0r9'(s'H )SS ' (s'HS)ir (ω'Η ΟΖ·ε— Ο9·ε'(ω'Η Ο ·ε— 0S'S'(ra'H T) Z9 "6 '( z H8" 8 = rP'HT) 8S "8' ( z H8" Z = rP'HT) SS "8 '( z H8" Z = rP'HT) S2 "Z' (zH8 "8 = rP'HT) S ΐ · Ζ '(ω'Ηε) 38 · 9— 0r9' ( s 'H) SS' ( s 'HS) ir (ω'Η ΟΖ · ε— Ο9 · ε' (ω 'Η Ο · ε— 0S'S'(ra'H
3)0ΐ·ε— 08 '(s'HS)8S'S'(ra'H SS SrS'C"'H S0 — 06·ΐ :軍 9 ( OSW I) 顺—
Figure imgf000143_0005
3) 0ΐ · ε— 08 '( s ' HS) 8S'S '(ra'H SS SrS'C "' H S0 — 06 · ΐ: Army 9 (OSW I) 顺 —
Figure imgf000143_0005
9、つ 呦 ffl措
Figure imgf000143_0006
9, 呦 ffl measures
Figure imgf000143_0006
98S6T0/S00Zdf/X3d 6 ーブチル= 3—（8—（1ー（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィル）ェチル）ピぺリジン— 4—カルボキサミド）— 2—メトキシキノリン— 5—ィル） プロピオナート 0.16gの塩化メチレン 2.0mL溶液に、トリフルォロ酢酸 2.0mLをカ卩え、 3 時間攪拌した。減圧下で溶媒を留去し、得られた残留物をクロ口ホルム 5.0mLに溶解 し、 3.2mol/L塩ィ匕水素/ジォキサン 5.0mLをカ卩えた。減圧下で溶媒を留去し、得られ た残留物にクロ口ホルム 5.0mL、 3.2mol/L塩化水素/ジォキサン 5.0mLをカ卩えた。減圧 下で溶媒を留去した後、クロ口ホルム 5.0mLおよびジェチルエーテル 5.0mLをカロえ、 析出物をろ取し、淡褐色固体の 3—（8— (1—（2— (2, 3 ジヒドロべンゾ [b] [l, 4] ジォキシン 6 ィル）ェチル）ピぺリジン 4 カルボキサミド） - 2—メトキシキノリン 5 ィル）プロピオン酸の塩酸塩 0.1 lgを得た。 98S6T0 / S00Zdf / X3d 6-Butyl = 3- (8- (1- (2- (2,3 Dihydrobenzo [b] [l, 4] dioxin 6-yl) ethyl) piperidine- 4-carboxamide)-2-methoxy Quinoline-5-yl) Propionate To a solution of 0.16 g of methylene chloride in 2.0 mL was added 2.0 mL of trifluoroacetic acid and stirred for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 5.0 mL of chloroform and 5.0 mL of 3.2 mol / L sodium chloride / dioxane was collected. The solvent was distilled off under reduced pressure, and 5.0 mL of chloroform and 5.0 mL of 3.2 mol / L hydrogen chloride / dioxane were added to the obtained residue. After the solvent was distilled off under reduced pressure, 5.0 mL of black mouth form and 5.0 mL of jetyl ether were removed, and the precipitate was collected by filtration to give a light brown solid 3— (8— (1— (2— (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6yl) ethyl) piperidine 4carboxamide) -2-methoxyquinoline 5yl) propionic acid hydrochloride 0.1 lg was obtained.
'H-NMRCDMSO-d ) δ値： 1.90— 2.00(2H,m),2.15— 2.30(2H,m),2.40— 2.60(2H,m),2.80—  'H-NMRCDMSO-d) δ value: 1.90—2.00 (2H, m), 2.15—2.30 (2H, m), 2.40—2.60 (2H, m), 2.80—
6  6
3.15(5H,m),3.15-3.40(4H,m),3.60-3.70(2H,m),4.11(3H,s),4.22(4H,s),6.70-6.85(3H, m),7.10-7.15(lH,m),7.25-7.30(lH,m),8.30-8.40(lH,m),8.40-8.50(lH,m),9.70(lH,s) ,12.20(lH,s)  3.15 (5H, m), 3.15-3.40 (4H, m), 3.60-3.70 (2H, m), 4.11 (3H, s), 4.22 (4H, s), 6.70-6.85 (3H, m), 7.10- 7.15 (lH, m), 7.25-7.30 (lH, m), 8.30-8.40 (lH, m), 8.40-8.50 (lH, m), 9.70 (lH, s), 12.20 (lH, s)
実施例 9
Figure imgf000144_0001
Example 9
Figure imgf000144_0001
1, 4 ベンゾジォキサン一 6 ァミン 26mgのクロ口ホルム 1.8mL溶液に、 N, N，一力 ルポニルジイミダゾール 44mgを加え、 55分間加熱還流した。反応混合物を室温まで 冷却し、 N— (2—メトキシキノリン— 8—ィル）ピぺリジン— 4—カルボキサミド 50mgの クロ口ホルム l.OmL溶液をカ卩え、室温で 20分間攪拌した。反応混合物に水 20mLおよ び酢酸ェチル 20mLをカ卩えた。有機層を分取し、塩ィ匕アンモ-ゥム水溶液および飽和 塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶 媒を留去した。得られた残留物を塩基性アルミナカラムクロマトグラフィー [アルミナ； メルク株式会社、アルミニウムォキシド 60、溶離液；へキサン：酢酸ェチル = 1： 2]で 精製し、白色泡状物の 1— ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン一 6—ィル） 力ルバモイル） -N- (2—メトキシキノリンー8 ィル）ピぺリジンカルボキサミド 26mg
Figure imgf000145_0001
To a 1.8 mL solution of 1,4 benzodioxane 1-6 amamine 26 mg in Kuroguchi form, 44 mg of N, N, olponyldiimidazole was added and heated to reflux for 55 minutes. The reaction mixture was cooled to room temperature, and a solution of N- (2-methoxyquinoline-8-yl) piperidine-4-carboxamide 50 mg in chloroform-form l.OmL was added and stirred at room temperature for 20 minutes. 20 mL of water and 20 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with aqueous salt ammonium solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic alumina column chromatography [alumina; Merck Ltd., aluminum oxide 60, eluent; hexane: ethyl acetate = 1: 2], and white foam 1— (( 2, 3 Dihydrobenzo [b] [l, 4] Dioxin 6-yl) Forced rubermoyl) -N- (2-Methoxyquinoline-8 yl) piperidinecarboxamide 26mg
Figure imgf000145_0001
(δ'Ηΐ)Ζ9·6'(ζΗΐ·8=ΓΡ'Ηΐ)ΐ9·8'(ζΗΖ·6=ΓΡ'Ηΐ)9^8'(ω'Ηΐ)0ε·Ζ— 0S (ZHS'6= ί"'Ρ'Ηΐ)00· '(ZHS =l"'P'HI)S6'9'(ra'HS)08'9— Sr9'(s'HI)IS'9'C"'H OS'f— 0 ^ (ω'Η 0 ト 0ΐ· (S'HS)60'
Figure imgf000145_0002
( δ 'Ηΐ) Ηΐ9 · 6' ( ζ Ηΐ · 8 = ΓΡ'Ηΐ) ΐ9 · 8 '( ζ ΗΖ · 6 = ΓΡ'Ηΐ) 9 ^ 8'(ω'Ηΐ) 0ε · Ζ— 0S ( Z HS '6 = ί "'Ρ'Ηΐ) 00 · '( Z HS = l"'P'HI)S6'9'(ra'HS)08'9—Sr9' ( s ' HI) IS'9'C "'HOS'f— 0 ^ (ω'Η 0 to 0ΐ · ( S ' HS) 60 '
Figure imgf000145_0002
'HI)( - SS ' C"'H 0S - 0rS'(ra'HS)00 - 06·ΐ'(δ'Η6)ε ·ΐ :軍 9 (OQDWH-H^
Figure imgf000145_0003
'HI) (-SS' C "'H 0S-0rS'(ra'HS) 00-06 · ΐ '( δ ' Η6) εΐΐ: Army 9 (OQDWH-H ^
Figure imgf000145_0003
。 _n辛爵¾瀚缀 止 s教
Figure imgf000145_0004
氺、つ 斜单。 ιΐί^Ίωοΐ>ι¾ατ¾πωοΜ/^ェ邈 呦^^ 。 _n ^翻 、"¾^i s 9 一ェ ^ =マ ^ ^ί^— ε 'ε. _n
Figure imgf000145_0004
氺 、 つ tilt south. ιΐί ^ Ίωοΐ> ι¾ατ¾πωοΜ / ^ 邈 呦 ^^. _n ^ Translation, "¾ ^ i s 9 1e ^ = Ma ^ ^ ί ^ — ε 'ε
Ί Ί - ( /y- 1
Figure imgf000145_0005
^エ fHΊ Ί-(/ y- 1
Figure imgf000145_0005
^ D fH
、^继缀 τ¾·ο、 ^ マ ^ ー Ν 'Ν )§ωοε4— ΰ : ( / —g—べ , ^ 继 缀 τ¾ · ο, ^ Ma ^ ー Ν 'Ν) §ωοε4— ΰ: (/ —g—
Figure imgf000145_0006
Figure imgf000145_0006
(s'HI)S9'6'(zH9'I'S'6=rPP'HI)0r8'(zHS'6=f'P'HI)S0'8'(ra'HS)0S'Z— '(ω'Η ΟΟ·Ζ—Ο6·9'(ω'Η Ο8·9— 0r9'(s'HI)SS'9'C"'H9)0S' — 0ΐ· (s'HS)0r C"'HS)0 ΐ·ε— 00·ε'(ω'Ηΐ)0Ζ — 09 ' C"'H 0S SrS'(ra'HS)00 — S8'I :軍 9 (OQDWH-H^ ( s ' HI) S9'6 '( z H9'I'S'6 = rPP'HI) 0r8' ( z HS'6 = f'P'HI) S0'8 '(ra'HS) 0S'Z—' ( ω'Η ΟΟ · Ζ—Ο6 · 9 '(ω'Η Ο8 · 9— 0r9' ( s ' HI) SS'9'C "'H9) 0S' — 0ΐ · ( s ' HS) 0r C"'HS ) 0 ΐ · ε— 00 · ε '(ω'Ηΐ) 0Ζ — 09' C "'H 0S SrS'(ra'HS) 00 — S8'I: Military 9 (OQDWH-H ^
98S6T0/S00Zdf/X3d
Figure imgf000146_0001
98S6T0 / S00Zdf / X3d
Figure imgf000146_0001
tert—ブチル = 3— (8— (1— ( (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン一 6— ィル）力ルバモイル）ピぺリジン 4 カルボキサミド） - 2—メトキシキノリン一 5 ィル )プロピオナート 62mgの塩化メチレン 0.20mL溶液に、トリフルォロ酢酸 0.20mLをカロえ 、 1時間 10分間攪拌した。減圧下で溶媒を留去し、ジェチルエーテルを加え、析出物 をろ取し、喑黄色固体の 3—（8— (1 - ( (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン — 6 ィル）力ルバモイル）ピぺリジン 4 カルボキサミド） - 2—メトキシキノリン一 5 ィル）プロピオン酸のトリフルォロ酢酸塩 40mgを得た。  tert-Butyl = 3— (8— (1— ((2, 3 Dihydrobenz [b] [1, 4] Dioxin 6-yl) Strengthened rubamoyl) Piperidine 4 Carboxamide)-2-Methoxyquinoline To a 0.20 mL solution of 62 mg of propionate in 62 mg of methylene chloride was added 0.20 mL of trifluoroacetic acid and stirred for 1 hour and 10 minutes. The solvent was distilled off under reduced pressure, jetyl ether was added, the precipitate was collected by filtration, and the pale yellow solid 3- (8- (1-((2, 3 dihydrobenzo [b] [1, 4 ] Dioxin-6yl) Strong rubermoyl) Piperidine 4 carboxamide)-2-methoxyquinoline 1-5yl) Propionic acid trifluoroacetate 40mg was obtained.
1H-NMR(DMSO-d ) δ値： 1.55- 1.70(2H,m),1.95- 2.00(2H,m),2.58(2H,t,J=7.7Hz),2.8  1H-NMR (DMSO-d) δ value: 1.55- 1.70 (2H, m), 1.95-2.00 (2H, m), 2.58 (2H, t, J = 7.7Hz), 2.8
6  6
0-2.95(3H,m),3.20(2H,t,J=7.7Hz),4.10(3H,s),4.10-4.20(6H,m),6.70(lH,d,J=8.7Hz), 6.88(lH,dt,J=8.7,2.6Hz),7.06(lH,t,J=2.6Hz),7.12(lH,d,J=9.0Hz),7.26(lH,d,J=8.0Hz ),8.32(lH,s),8.38(lH,d,J=8.0Hz),8.44(lH,d,J=9.0Hz),9.64(lH,s)  0-2.95 (3H, m), 3.20 (2H, t, J = 7.7Hz), 4.10 (3H, s), 4.10-4.20 (6H, m), 6.70 (lH, d, J = 8.7Hz), 6.88 (lH, dt, J = 8.7,2.6Hz), 7.06 (lH, t, J = 2.6Hz), 7.12 (lH, d, J = 9.0Hz), 7.26 (lH, d, J = 8.0Hz), 8.32 (lH, s), 8.38 (lH, d, J = 8.0Hz), 8.44 (lH, d, J = 9.0Hz), 9.64 (lH, s)
実施例 12
Figure imgf000146_0002
Example 12
Figure imgf000146_0002
N— (2—メトキシキノリンー8 ィル）ピぺリジンー4 カルボキサミド 0.10gのァセトニ トリル 0.70mL溶液に、 N, N ジイソプロピルェチルァミン 0.18mLおよび 1— (2, 3— ジヒドロべンゾ [b] [1, 4]ジォキシンー6 ィル） 2 メチルイソチォゥレアのヨウ化 水素酸塩 0.18gをカ卩え、室温で 30分間攪拌後、 50分間加熱還流した。さらに、 N, N ージメチルホルムアミド 2.0mLをカ卩え、 120〜130°Cで 2時間 15分間攪拌した。反応混 合物を室温まで冷却し、酢酸ェチル 50mLをカ卩え、 20%水酸ィ匕ナトリウム水溶液で pH 13.0に調整した。有機層を分取し、水層を酢酸ェチル 10mLで 2回抽出した。有機層 および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し た。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー [シリカゲル；富士シリ ΐ圏第 N— (2-Methoxyquinoline-8-yl) piperidine-4-carboxamide In a solution of 0.10 g of acetonitrile with 0.18 mL of N, N diisopropylethylamine and 1- (2, 3-dihydrobenzo [ b] [1, 4] dioxin-6 yl) 2 Methylisothiourea hydroiodide 0.18 g was added and stirred at room temperature for 30 minutes and then heated to reflux for 50 minutes. Further, 2.0 mL of N, N-dimethylformamide was added and stirred at 120 to 130 ° C. for 2 hours and 15 minutes. The reaction mixture was cooled to room temperature, 50 mL of ethyl acetate was added, and the pH was adjusted to 13.0 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography [silica gel; Fuji Siri No. 1
(s'HT)^Z"6'(zH0"8=rP'HT)^Z"8'(zH2"6=rP'H I)S 8'(zH8'SI=f'P'HI)IS'8'(zH0'8=f'P'HI)0rZ'(zHS'6=f'P'HI)W) '(zH0'8=f'P'HI )8Γ9'(ΖΗ0 =1"'Ρ'Ηΐ)εΓ9'(ζΗ0 ' 0·8=ΓΡΡ'Ηΐ)89·9'(ζΗ8·3ΐ=ί"'Ρ'Ηΐ)„·9'(δ'Η S ' (s'HS)ir (ω'Ηζ)3ΐ·ε— S0'S'C"'HS)08 — ( 'S'C"'HS)S9 — SS'S'C"'HI)OS — O S'C" 'HS)SS - SO ' C"'HS)SO - 06 (S'H6)9S'I '(ω'Ηΐ)ΟΖ·ΐ- OS'I :軍 9 ( ϋα )Η顺- Ητ ( s 'HT) ^ Z "6' ( z H0" 8 = rP'HT) ^ Z "8 '( z H2" 6 = rP'H I) S 8' ( z H8'SI = f'P'HI ) IS'8 '( z H0'8 = f'P'HI) 0rZ'(zHS'6 = f'P'HI) W) '( z H0'8 = f'P'HI) 8Γ9' ( Ζ Η0 = 1 "'Ρ'Ηΐ) εΓ9' ( ζ Η0 '0 · 8 = ΓΡΡ'Ηΐ) 89 · 9' ( ζ Η8 · 3ΐ = ί"'Ρ'Ηΐ) „· 9' ( δ 'Η S' ( s 'HS) ir (ω'Ηζ) 3ΐ · ε— S0'S'C "' HS) 08 — ('S'C"' HS) S9 — SS'S'C "'HI) OS — O S'C"' HS ) SS-SO 'C "' HS) SO-06 ( S 'H6) 9S'I'(ω'Ηΐ) ΟΖ ・ ΐ- OS'I: Army 9 (ϋα) Η 顺-Η τ
Figure imgf000147_0001
Ί]
Figure imgf000147_0001
Ί]
^i^-Z- ^ .-S)— ε— (Ή) = ^ :— 9¾QT?is9S'0邈ベ^ / — —ベ
Figure imgf000147_0002
^ i ^ -Z- ^ .-S) — ε— (Ή) = ^: — 9 ¾QT? i s 9S'0 邈 Be ^ / — —Be
Figure imgf000147_0002
ει圏第 ει zone number
(δ'Ηΐ) 9·6'(ζΗ3·ΐ'9·Ζ=ΓΡΡ'Ηΐ)ΐΖ·8'(ζΗ8·8=ί"'Ρ( δ 'Ηΐ) 9 · 6' ( ζ Η3 · ΐ'9 · Ζ = ΓΡΡ'Ηΐ) ΐΖ · 8 '( ζ Η8 · 8 = ί "' Ρ
Ήΐ)20·8'(ω'Η2)5^· -3ε· '(ζΗ8·8=ΓΡΉΐ) 6·9'(ζΗ3·8=ΓΡΉΐ)8 ·9'(ζΗ^·2=ΓΡΉΐ)ε ·9'(ζΗ '3·8=ΓΡΡ'Ηΐ)6ε·9'(ω'Η OS' 0S (s'HS)0r C"'HS)Sr SO' C"'HS)SΉΐ) 20 ・ 8 '(ω'Η2) 5 ^ ・ -3ε ・' (ζΗ8 ・ 8 = ΓΡΉΐ) 6 ・ 9 '( ζ Η3 ・ 8 = ΓΡΉΐ) 8 ・ 9' ( ζ Η ^ ・ 2 = ΓΡΉΐ) ε 9 '( ζ Η' 3 8 = Γ ΡΡ '6) 6ε 9' (ω 'Η OS' 0S ( s 'HS) 0r C "' HS) Sr SO 'C"' HS) S
0·ε- S6 ' ( 1)0 - 09 ' C"'H 0S - OrS'(ra'HS)00 - 06·ΐ :軍 9 ( <3つ) Η顺- Ητ 0 · ε- S6 '(1) 0-09' C "'H 0S-OrS'(ra'HS) 00-06 · ΐ: Army 9 (<3) Η 顺-Η τ
。 §ω0ε、 ^^ / — —ベ （ — 8—ベ ίί,^Ρ ^^ — -Ν- ( ^ (/ . §Ω 0ε , ^^ / — —Be (— 8—Be ίί, ^ Ρ ^^ — -Ν- (^ (/
'χ]
Figure imgf000147_0003
、つ 'χ]
Figure imgf000147_0003
, One
X： 01 = — ^^： ^Λ^ ^ ί ψΜ 、Χαθ(ΗΉ / f 、 、  X: 01 = — ^^: ^ Λ ^ ^ ί ψΜ, Χαθ (ΗΉ / f,,
98S6T0/S00Zdf/X3d
Figure imgf000148_0001
98S6T0 / S00Zdf / X3d
Figure imgf000148_0001
tert—ブチノレ = (E) - 3- (8— (1— (2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキ シンー6 ィル）ェチル）ピぺリジンー4 カルボキサミド）ー2—メトキシキノリンー5— ィル）アタリラート 28mgの塩化メチレン 0.20mL溶液に、トリフルォロ酢酸 0.20mLをカロえ 、 2時間 50分間攪拌した。減圧下で溶媒を留去し、得られた残留物を酢酸ェチル 1.0 mLに溶解し、 4.0mol/L塩ィ匕水素/酢酸ェチル l.OmLをカ卩えた。減圧下で溶媒を留去 し、酢酸ェチルをカ卩え、析出物をろ取し、淡褐色固体の (E) - 3- (8—（1— (2— (2 , 3—ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィル）ェチル）ピぺリジンー4 カルボ キサミド） 2—メトキシキノリン一 5 ィル)アクリル酸の塩酸塩 23mgを得た。  tert-Butinore = (E)-3- (8— (1— (2— (2, 3 Dihydrobenzo [b] [1, 4] dioxin-6 yl) ethyl) piperidine-4 carboxamide)- 2-Methoxyquinoline-5-yl) Atalylate 0.20 mL of trifluoroacetic acid was added to a solution of 28 mg of methylene chloride in 28 mg and stirred for 2 hours and 50 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 1.0 mL of ethyl acetate to obtain 4.0 mol / L of hydrogen chloride / ethyl acetate. The solvent was distilled off under reduced pressure, ethyl acetate was removed, the precipitate was collected by filtration, and (E) -3- (8— (1— (2— (2,3, dihydroben Zo [b] [l, 4] dioxin 6-yl) ethyl) piperidine-4carboxamide) 2-methoxyquinoline 1-5yl) acrylic acid hydrochloride 23 mg was obtained.
1H-NMR(DMSO-d ) δ値： 1.90— 2.10(2H,m),2.20— 2.30(2H,m),2.50— 3.20(7H,m),3.60— 1H-NMR (DMSO-d) δ value: 1.90— 2.10 (2H, m), 2.20— 2.30 (2H, m), 2.50— 3.20 (7H, m), 3.60—
6  6
3.75(2H,m),4.14(3H,s),4.22(4H,s),6.60(lH,d,J=15.6Hz),6.70-6.85(3H,m),7.20(lH,d, 3.75 (2H, m), 4.14 (3H, s), 4.22 (4H, s), 6.60 (lH, d, J = 15.6Hz), 6.70-6.85 (3H, m), 7.20 (lH, d,
J=9.3Hz),7.94(lH,d,J=8.2Hz),8.25(lH,d,J=15.6Hz),8.54(lH,d,J=8.2Hz),8.64(lH,d,JJ = 9.3Hz), 7.94 (lH, d, J = 8.2Hz), 8.25 (lH, d, J = 15.6Hz), 8.54 (lH, d, J = 8.2Hz), 8.64 (lH, d, J
=9.3Hz),9.87(lH,s) = 9.3Hz), 9.87 (lH, s)
実施例 15
Figure imgf000148_0002
Example 15
Figure imgf000148_0002
7—メトキシイソキノリン一 1—ァミン 0.30gのクロ口ホルム 5mL溶液に、室温で N, N— ジメチルァミノピリジン 0.23gおよび N, N'—カルボ-ルジイミダゾール 0.45gを加え、 室温で 1時間攪拌した。減圧下で溶媒を留去し、得られた残留物に N, N ジメチル ホノレムアミド 7mL、 1— (2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン— 6—ィル） ェチル）ピぺラジンの塩酸塩 0.61gおよびトリェチルァミン 0.53mLをカ卩えた。反応混合 物を室温で 30分間攪拌した後、酢酸ェチル 30mLおよび水 30mLをカ卩えた。有機層を 分取し、水層を酢酸ェチル 20mLで抽出した。有機層および抽出液を合わせ、水およ び飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧 下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液； クロ口ホルム：メタノール = 50 : 1]で精製し、淡褐色固体の 4 (2- (2, 3 ジヒドロ ベンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル） N— (7—メトキシイソキノリン 1 —ィル)ピぺラジン一 1 カルボキサミド 0.48gを得た。 7-Methoxyisoquinoline 1-Amin 0.30 g of Kro-Form 5 mL solution, add 0.23 g of N, N-dimethylaminopyridine and 0.45 g of N, N'-carbodidiimidazole at room temperature, and stir at room temperature for 1 hour did. Evaporate the solvent under reduced pressure, and add 7 mL of N, N dimethyl honolemamide, 1— (2— (2,3 dihydrobenz [b] [1, 4] dioxin-6-yl) to the residue. Ethyl) Piperazine hydrochloride (0.61 g) and triethylamine (0.53 mL) were added. The reaction mixture was stirred at room temperature for 30 minutes, and then 30 mL of ethyl acetate and 30 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. Combine the organic layer and the extract, wash sequentially with water and saturated aqueous sodium chloride solution, dry over anhydrous magnesium sulfate, and vacuum The solvent was distilled off under. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 50: 1] to give 4 (2- (2, 3 dihydrobenzo [b] [1, 4] Dioxin 6yl) ethyl) N— (7-methoxyisoquinoline 1-yl) piperazine 1 carboxamide 0.48 g was obtained.
1H-NMR(CDC1 ) δ値： 2.55— 2.65(6H,m),2.70— 2.80(2H,m),3.70— 3.75(2H,m),3.95(3H,  1H-NMR (CDC1) δ value: 2.55— 2.65 (6H, m), 2.70— 2.80 (2H, m), 3.70— 3.75 (2H, m), 3.95 (3H,
3  Three
s),4.05-4.10(2H,m),4.24(4H,s),6.65(lH,d,J=6.8Hz),6.69(lH,dd,J=8.2,2.0Hz),6.74(l H,d,J=2.0Hz),6.79(lH,d,J=8.2Hz),7.06-7.09(lH,m),7.30(lH,dd,J=8.5,2.7Hz), 7.48(1 H,d,J=8.5Hz),8.01(lH,d,J=2.7Hz),14.5(lH,s) s), 4.05-4.10 (2H, m), 4.24 (4H, s), 6.65 (lH, d, J = 6.8Hz), 6.69 (lH, dd, J = 8.2, 2.0Hz), 6.74 (l H, d, J = 2.0Hz), 6.79 (lH, d, J = 8.2Hz), 7.06-7.09 (lH, m), 7.30 (lH, dd, J = 8.5,2.7Hz), 7.48 (1 H, d, J = 8.5Hz), 8.01 (lH, d, J = 2.7Hz), 14.5 (lH, s)
実施例 16
Figure imgf000149_0001
Example 16
Figure imgf000149_0001
N- (7—メトキシイソキノリン一 1 ィル）ピぺリジン 4 カルボキサミド 60mgのメタ ノール 2mL溶液に、室温で（2, 3 ジヒドロべンゾ [1, 4]ジォキシン 6 ィル）ァセト アルデヒド 38mgのメタノール lmL溶液および酢酸 40 Lをカ卩え、同温度で 3時間攪拌 した。反応混合物に水素化シァノホウ素ナトリウム 13mgを加え、室温で 30分間攪拌し 、減圧下で溶媒を留去した。水 10mLおよびクロ口ホルム 10mLをカ卩えた後、 20%水酸 化ナトリウム水溶液をカ卩え、 PH12.5に調整した。有機層を分取し、水層をクロ口ホルム 10mLで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶 液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得ら れた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 10 : 1]で精製し、淡褐色固体の 1一（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシ ン一 6—ィル）ェチル） -N- (7—メトキシイソキノリン一 1—ィル）ピぺリジン一 4—力 ルボキサミド 10mgを得た。  N- (7-methoxyisoquinoline 1-yl) piperidine 4 carboxamide 60 mg methanol in 2 mL solution at room temperature (2,3 dihydrobenzzo [1,4] dioxin 6 yl) acetaldehyde 38 mg methanol An lmL solution and 40 L of acetic acid were added and stirred at the same temperature for 3 hours. To the reaction mixture, 13 mg of sodium cyanoborohydride was added, stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. After adding 10 mL of water and 10 mL of black mouth form, 20% aqueous sodium hydroxide solution was added and adjusted to PH12.5. The organic layer was separated, and the aqueous layer was extracted with 10 mL of black mouth form. The organic layer and the extract were combined, washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 10: 1] to obtain a light brown solid 1 1 (2- (2, 3 dihydrobenzo [b] [ l, 4] dioxin 1-yl) ethyl) -N- (7-methoxyisoquinoline 1-yl) piperidine 1-power lboxamide 10 mg was obtained.
'H-NMRCDMSO-d ) δ値： 1.68— 1.76(2H,m), 1.88— 1.91(2H,m), 1.99— 2.05(2H,m),2.45—  'H-NMRCDMSO-d) δ value: 1.68— 1.76 (2H, m), 1.88— 1.91 (2H, m), 1.99— 2.05 (2H, m), 2.45—
6  6
2.65(5H,m),2.95-3.05(2H,m),3.86(3H,s),4.20(4H,s),6.65-6.75(3H,m),7.15-7.20(lH, m),7.44(lH,dd,J=8.9,2.4Hz),7.66(lH,d,J=5.5Hz),7.91(lH,d,J=8.9Hz),8.19(lH,d,J=5. 5Hz),10.3(lH,s) [0294] 実施例 17 2.65 (5H, m), 2.95-3.05 (2H, m), 3.86 (3H, s), 4.20 (4H, s), 6.65-6.75 (3H, m), 7.15-7.20 (lH, m), 7.44 ( lH, dd, J = 8.9,2.4Hz), 7.66 (lH, d, J = 5.5Hz), 7.91 (lH, d, J = 8.9Hz), 8.19 (lH, d, J = 5.5Hz), 10.3 (lH, s) [0294] Example 17
Figure imgf000150_0001
Figure imgf000150_0001
l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ンー4一力ルボン酸 53mgに、室温で 2, 4 ジメトキシキノリン 8 ァミン 37mgの N, N ジメチルホルムアミド 3mL溶液を加えた。室温で O— (7—ァザべンゾトリアゾール — 1—ィル） 1, 1, 3, 3—テトラメチルゥ口-ゥム =へキサフルォロホスフェート 0.10 gおよびトリェチルァミン 76 Lをカ卩え、 30分間攪拌し、 60°Cで 3時間攪拌した後、室温 まで冷却した。反応混合物に酢酸ェチル 20mLおよび水 20mLを加えた。有機層を分 取し、水層を酢酸ェチル 10mLで抽出した。有機層および抽出液を合わせ、水および 飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下 で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；ク ロロホルム：メタノール = 10 : 1]で精製し、淡褐色固体の 1 （2— (2, 3 ジヒドロべ ンゾ [b] [l, 4]ジォキシン一 6—ィル）ェチル）一 N— (2, 4—ジメトキシキノリン一 8— ィル）ピぺリジン 4 カルボキサミド 40mgを得た。  l-(2- (2, 3 dihydrobenzzo [b] [l, 4] dioxin 6 yl) ethyl) piberidin-4 monolithic rubonic acid 53 mg, 2, 4 dimethoxyquinoline 8 ammine 37 mg N at room temperature , N Dimethylformamide 3mL solution was added. At room temperature, O- (7-azabenzotriazole — 1-yl) 1, 1, 3, 3-tetramethyl oxalate-hexafluorophosphate 0.10 g and triethylamine 76 L were prepared. The mixture was stirred for 30 minutes, stirred at 60 ° C for 3 hours, and then cooled to room temperature. To the reaction mixture was added 20 mL of ethyl acetate and 20 mL of water. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 10: 1] to give 1 (2- (2, 3 dihydrobenzo [b] [l, 4 ] Dioxin 1-yl) ethyl) 1 N- (2,4-dimethoxyquinoline 1-yl) piperidine 4 carboxamide 40 mg was obtained.
1H-NMR(CDC1 ) δ値： 1.80- 2.90(llH,m),3.10- 3.30(2H,m),4.01(3H,s),4.07(3H,s),4.2  1H-NMR (CDC1) δ value: 1.80-2.90 (llH, m), 3.10-3.30 (2H, m), 4.01 (3H, s), 4.07 (3H, s), 4.2
3  Three
4(4H,s),6.27(lH,s),6.67-6.80(3H,m),7.30-7.34(lH,m),7.74(lH,d,J=8.0Hz),8.68(lH, d,J=7.6Hz),9.65(lH,s)  4 (4H, s), 6.27 (lH, s), 6.67-6.80 (3H, m), 7.30-7.34 (lH, m), 7.74 (lH, d, J = 8.0Hz), 8.68 (lH, d, J = 7.6Hz), 9.65 (lH, s)
[0295] 実施例 18
Figure imgf000150_0002
[0295] Example 18
Figure imgf000150_0002
2 メトキシ 3 メチルキノリン一 8 -ァミン 70mgの N, N -ジメチルホルムアミド 3m L溶液に、室温で 1ー（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェ チル）ピぺリジン— 4—カルボン酸 0.11g、 0- (7—ァザべンゾトリアゾール—1—ィル )— 1, 1, 3, 3—テトラメチルゥ口-ゥム =へキサフルォロホスフェート 0.21gおよびトリ ェチルァミン 0.16mLを加え、 60°Cで 2時間攪拌した。反応混合物を室温まで冷却し、 酢酸ェチル 30mLおよび水 20mLを加えた。有機層を分取し、水層を酢酸ェチル 20mL で抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で 順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた 残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 20： 1 ]で精製し、淡褐色固体 1— (2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン— 6— ィル）ェチル） -N- (2—メトキシ一 3—メチルキノリン一 8—ィル）ピぺリジン一 4—力 ルボキサミド 85mgを得た。 2-Methoxy-3-methylquinoline 1- (2- (2,3 dihydrobenzo [b] [l, 4] dioxin 6 yl) in room temperature 70 mg of N, N-dimethylformamide 3 mL Ethyl) piperidine—4-carboxylic acid 0.11 g, 0- (7-azabenzotriazole—1-yl) — 1, 1, 3, 3—tetramethyl hex-hexafluoro 0.21 g of lophosphate and 0.16 mL of triethylamine were added and stirred at 60 ° C. for 2 hours. Cool the reaction mixture to room temperature, Ethyl acetate 30 mL and water 20 mL were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1] to give a light brown solid 1— (2— (2,3 dihydrobenzo [b] [1, 4] Dioxin-6-yl) ethyl) -N- (2-methoxy-1-3-methylquinoline-1-yl) piperidine-1-4-ruboxamide 85 mg was obtained.
'H-NMRCCDCl ) δ値： 1.96- 2.05(2H,m),2.14- 2.17(4H,m),2.35(3H,s),2.40- 2.50(1Η,  'H-NMRCCDCl) δ value: 1.96-2.05 (2H, m), 2.14-2.17 (4H, m), 2.35 (3H, s), 2.40-2.50 (1Η,
3  Three
m),2.59-2.61(2H,m),2.71-2.75(2H,m),3.09-3.15(2H,m),4.12(3H,s),4.24(4H,s),6.68( lH,dd,J=8.3,2.0Hz),6.73(lH,d,J=2.0Hz),6.79(lH,d,J=8.3Hz),7.34-7.36(2H,m),7.79( lH,s),8.64-8.66(lH,m),9.63(lH,s) m), 2.59-2.61 (2H, m), 2.71-2.75 (2H, m), 3.09-3.15 (2H, m), 4.12 (3H, s), 4.24 (4H, s), 6.68 (lH, dd, J = 8.3,2.0Hz), 6.73 (lH, d, J = 2.0Hz), 6.79 (lH, d, J = 8.3Hz), 7.34-7.36 (2H, m), 7.79 (lH, s), 8.64- 8.66 (lH, m), 9.63 (lH, s)
実施例 19
Figure imgf000151_0001
Example 19
Figure imgf000151_0001
(1) tert ブチル = 1— (2 ヒドロキシ一 2— (7—メトキシイソキノリン一 1—ィル）ェ チル）ピぺリジン 4ーィルカルバマート 0.45gの塩化メチレン 2mL溶液に、室温でトリ フルォロ酢酸 lmLを加え、 1時間攪拌した後、減圧下で溶媒を留去した。得られた残 留物に水 10mLおよび酢酸ェチル 20mLをカ卩え、炭酸カリウムをカ卩えて pH9.5に調整し た。有機層を分取し、水層を酢酸ヱチル 10mLで 4回抽出した。有機層および抽出液 を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、 減圧下で溶媒を留去し、黄色泡状物の 2—（4 アミノビペリジン 1 ィル） 1一（ 7—メトキシイソキノリン一 1—ィル）エタノールを得た。  (1) tert butyl = 1- (2 hydroxy-1- (7-methoxyisoquinoline-1-yl) ethyl) piperidine 4-ylcarbamate 0.45 g in methylene chloride in 2 mL solution at room temperature After adding 1 mL of acetic acid and stirring for 1 hour, the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of water and 20 mL of ethyl acetate were added, and potassium carbonate was added to adjust the pH to 9.5. The organic layer was separated, and the aqueous layer was extracted four times with 10 mL of acetyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a yellow foam 2- (4 aminobiperidine 1) 1 (7 -Methoxyisoquinoline 1-yl) ethanol was obtained.
(2)得られた 2— (4 アミノビペリジン一 1—ィル） 1— (7—メトキシイソキノリン一 1 ィル）エタノールの塩化メチレン 9mL懸濁液に、室温でメタノール 3mL、 1, 4 ベン ゾジォキサン 6 カルバルデヒド 0.14gおよび 4Aモレキュラーシーブス 1.5gをカロえ、 終夜攪拌した。反応混合物に水素化ホウ素ナトリウム 98mgを加え、室温で 2時間攪拌 した。水 10mLをカ卩え、 6mol/L塩酸で pH3.0に調整し、ついで、 20%水酸化ナトリウム 水溶液で ρΗΙΟ.Οに調整した。酢酸ェチル 10mLを加え、有機層を分取し、水層を酢
Figure imgf000152_0001
(2) Obtained 2- (4 aminobiperidine 1-yl) 1- (7-methoxyisoquinoline 1-yl) Ethanol in 9 mL of methylene chloride suspension, 3 mL of methanol at room temperature, 1, 4 Benzodioxane 6 Carobaldehyde 0.14g and 4A molecular sieves 1.5g were prepared and stirred overnight. To the reaction mixture, 98 mg of sodium borohydride was added and stirred at room temperature for 2 hours. 10 mL of water was added, adjusted to pH 3.0 with 6 mol / L hydrochloric acid, and then adjusted to ρΗΙΟ.Ο with 20% aqueous sodium hydroxide solution. Add 10 mL of ethyl acetate, separate the organic layer,
Figure imgf000152_0001
(zH2"9=rP'HT)SS"8'(zH2"6=rP'HT)S0"8'(zH2"9=rP'HT)Z6"Z'(s'H ΐ)99· '(ω'Ηΐ)09· - 3· '(ω'Ηε)00· - 8·9'(ω'Ηΐ)02·9- 6·3'(8'Η^)6ΐ^'(ω'Η2)0ΐ^-3(zH2 "9 = rP'HT) SS" 8 '( z H2 "6 = rP'HT) S0"8' ( z H2 "9 = rP'HT) Z6" Z '(s'H ΐ) 99 ·'(ω'Ηΐ) 09 ·-3 · '(ω'Ηε) 00 ·-8 · 9'(ω'Ηΐ) 02 · 9- 6 · 3 '(8'Η ^) 6ΐ ^'(ω'Η2) 0ΐ ^ -3
6·ε'(δΉε)36·ε'(ω'Ηΐ)06·ε— ε8·ε'(ω'Ηΐ)08·ε— srs'C"'Hs)89's— 03·ε'(ω'Ηΐ)3 ·ε— εε·ε ^Ήζ) ζ - ν£ ^Ήζ) £τ-8ζτ ^Ήζ) οτ-£6Ί· ϊ 9 (o2a-9p-os a)H N-HT 6 · ε '( δ Ήε) 36 · ε'(ω'Ηΐ) 06 · ε— ε8 · ε '(ω'Ηΐ) 08 · ε— srs'C "' Hs) 89's— 03 · ε '(ω' Ηΐ) 3 · ε— εε · ε ^ Ήζ) ζ-ν £ ^ Ήζ) £ τ-8ζτ ^ Ήζ) οτ- £ 6Ί · ϊ 9 (o 2 a- 9 p-os a) H NH T
Figure imgf000152_0002
Figure imgf000152_0002
Figure imgf000152_0003
Figure imgf000152_0004
Figure imgf000152_0003
Figure imgf000152_0004
(zwe=f'P'HT)9S"8'(zH8"8=rP'HT)9 " '(ra'H2)es- -TS" '(zW2'8"8=rPP'HT)9S" ' (zH8"T=f'P'HT)^8"9'(zH2-8=rP'HT)28"9'(zH8T2"8=rPP'HT)6 -9'WS'2-8=rPP'H I)6 S'(s'H )SS (s'HS)96'S'(s'HS)^'S'(ra'HS)SrS— 60'S'C"'HS)S8 — 9Ζ '(ω'Ηΐ)6 S — S ' (ω'Η Ζε ' (ω'Η 36·ΐ— S6 (ra'HS)8S'I— :軍 9 ( !DaD)H N-HT (zwe = f'P'HT) 9S "8 '( z H8" 8 = rP'HT) 9 "'(ra'H2) es- -TS"'(zW2'8"8 = rPP'HT) 9S"'(zH8"T = f'P'HT) ^ 8"9' ( z H2-8 = rP'HT) 28 "9 '( z H8T2" 8 = rPP'HT) 6 -9'WS'2-8 = rPP'H I) 6 S '(s'H) SS ( s ' HS) 96'S '( s ' HS) ^ 'S'(ra'HS) SrS— 60'S'C "'HS) S8 — 9Ζ' ( ω'Ηΐ) 6 S — S '(ω'Η Ζε'(ω'Η 36 · ΐ— S6 (ra'HS) 8S'I—: Army 9 (! DaD) H NH T
。 Sui02 /—, ェ（ / — I—ベ fi ^ ^ . Sui 0 2 / —, é (/ — I—be fi ^ ^
Ί] [q] 、ベ
Figure imgf000152_0005
べ^ 厶 Ί] [q]
Figure imgf000152_0005
^
¾ 。 ·η辛爵 瀚缀、 止 ϊί教 ^^m^ ^^^m ^ ^ ^mm^ マ (H 靱 ^^mn mM^。 ·ηί¾ 回 τ"0Μ/ ェ邈 ¾. · Η 辛 爵 止 止 教 ϊ 教 ^ ^^ m ^ ^^^ m ^ ^ ^ mm ^ Ma (H tough ^^ mn mM ^. · Ηί¾ times τ " 0Μ / 邈
98S6T0/S00Zdf/X3d 091- 1— (7—メトキシイソキノリン一 1—ィル） 2— (ピペラジン一 1—ィル）エタノール 0. 21gの塩化メチレン 3mL懸濁液に、室温で酢酸 42 L、 (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン— 6 ィル）ァセトアルデヒド 0.14gおよびトリァセトキシ水素化ホウ素ナト リウム 0.15gを加え、室温で 2時間攪拌した。さらに、（2, 3 ジヒドロべンゾ [b] [l, 4] ジォキシン 6 ィル）ァセトアルデヒド 27mgおよびトリァセトキシ水素化ホウ素ナトリ ゥム 30mgをカ卩え、室温で 1時間攪拌した。反応混合物にクロ口ホルム 10mLおよび水 1 OmLをカ卩え、 20%水酸ィ匕ナトリウム水溶液で pHl 1.5に調整した。有機層を分取し、水 層をクロ口ホルム lOmLで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウ ム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、淡黄色油状物の 2—（4 (2 一（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピぺラジン 1 ィル） 1一（7—メトキシイソキノリン 1 ィル）エタノール 0.23gを得た。 98S6T0 / S00Zdf / X3d 091- 1- (7-methoxyisoquinoline 1-yl) 2- (piperazine 1-yl) ethanol 0.21 g of methylene chloride in 3 mL suspension of acetic acid 42 L, (2, 3 dihydrobenzo [b] [1, 4] dioxin-6yl) acetaldehyde (0.14 g) and triacetoxy sodium borohydride (0.15 g) were added, and the mixture was stirred at room temperature for 2 hours. Further, 27 mg of (2, 3 dihydrobenz [b] [l, 4] dioxin 6yl) acetaldehyde and 30 mg of triacetoxyborohydride were added and stirred at room temperature for 1 hour. To the reaction mixture, 10 mL of black mouth form and 1 OmL of water were added, and the pH was adjusted to 1.5 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with 10 mL of black mouth form. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and washed with 2- (4 (2 1 (2, 3 dihydrobenzo [b] [l, 4] Dioxin 6 yl) Ethyl) Piperazine 1 yl) 1 (7-methoxyisoquinoline 1 yl) Ethanol 0.23 g was obtained.
'H-NMRCCDCl ) δ値： 2.55- 2.90(14H,m),3.96(3H,s),4.24(4H,s),5.53(lH,dd,J=8.4,3. 'H-NMRCCDCl) δ value: 2.55- 2.90 (14H, m), 3.96 (3H, s), 4.24 (4H, s), 5.53 (lH, dd, J = 8.4, 3.
3  Three
2Hz),6.68(lH,dd,J=8.2,2.2Hz),6.73(lH,d,J=2.2Hz),6.78(lH,d,J=8.2Hz),7.36(lH,dd,J =9.0,2.2Hz),7.46(lH,d,J=2.2Hz),7.53(lH,d,J=5.6Hz),7.76(lH,d,J=9.0Hz),8.36(lH,d, J=5.6Hz)  2Hz), 6.68 (lH, dd, J = 8.2,2.2Hz), 6.73 (lH, d, J = 2.2Hz), 6.78 (lH, d, J = 8.2Hz), 7.36 (lH, dd, J = 9.0 , 2.2Hz), 7.46 (lH, d, J = 2.2Hz), 7.53 (lH, d, J = 5.6Hz), 7.76 (lH, d, J = 9.0Hz), 8.36 (lH, d, J = 5.6) Hz)
実施例 22
Figure imgf000153_0001
Example 22
Figure imgf000153_0001
7—メトキシ一 1— (ォキシラン一 2—ィル）イソキノリン 85mgの N, N ジメチルホル ムアミド 5mL溶液に、室温で 1一（2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシンー6 ィル）ェチル）ピぺラジンの塩酸塩 0.16g、過塩素酸リチウム 45mgおよび炭酸力リウ ム 0.13gを加え、 80°Cで 1時間攪拌した。反応混合物を室温まで冷却し、水 lOmLおよ び酢酸ェチル lOmLを加えた。有機層を分取し、水層を酢酸ェチル 5mLで抽出した。 有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグ ネシゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラム クロマトグラフィー [溶離液；クロ口ホルム：メタノール = 50： 1]で精製し、淡黄色油状 物の 2—（4ー（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル） ピぺラジン一 1—ィル） 1— (7—メトキシイソキノリン一 1—ィル）エタノール 60mgを得 た。 7-Methoxy-1- (oxylan-2-yl) isoquinoline 85 mg of N, N dimethylformamide in 5 mL of a solution of 1- (2- (2, 3 dihydrobenz [b] [1, 4] dioxin 6yl) ethyl) piperazine hydrochloride (0.16 g), lithium perchlorate (45 mg) and carbonated lithium (0.13 g) were added, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature and 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with 5 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 50: 1], and 2- (4- (2- (2,3-dihydrobenzo [ b] [l, 4] dioxin 6 yl) ethyl) Piperazine 1-yl) 1- (7-methoxyisoquinoline 1-yl) ethanol 60 mg was obtained.
1H-NMRは、実施例 21のデータと一致した。  1H-NMR was consistent with the data in Example 21.
[0300] 実施例 23
Figure imgf000154_0001
[0300] Example 23
Figure imgf000154_0001
2- (4- (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピぺ ラジン一 1 ィル） 1— (7—メトキシイソキノリン一 1 ィル）エタノール 0.23gの酢酸 ェチル 3mL溶液に、室温で 4.0mol/L塩化水素/酢酸ェチル 0.55mLをカ卩え、減圧下で 溶媒を留去した。残留物に酢酸ェチルを加え、不溶物をろ取し、淡黄色固体の 2— ( 4- (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピぺラジン 1ーィル） 1 7—メトキシイソキノリン 1 ィル）エタノールの塩酸塩 0.23gを得 た。  2- (4- (2- (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piperazine 1 yl) 1— (7-methoxyisoquinoline 1 yl ) Ethanol acetate (3 mL) in ethanol (3 mL) was charged with 4.0 mol / L hydrogen chloride / ethyl acetate (0.55 mL) at room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the insoluble material was collected by filtration to give a pale yellow solid 2— (4- (2- (2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) Piperazine 1-yl) 17-methoxyisoquinoline 1-yl) Ethanol hydrochloride 0.23 g was obtained.
'H-NMRCDMSO-d - D 0) δ値： 2.85- 2.90(2H,m),3.00- 3.35(12H,m),4.03(3H,s),4.21(  'H-NMRCDMSO-d-D 0) δ value: 2.85-2.90 (2H, m), 3.00-3.35 (12H, m), 4.03 (3H, s), 4.21 (
6 2  6 2
4H,s),6.00-6.03(lH,s),6.74-6.84(3H,m),7.74-7.79(2H,m),8.19-8.22(2H,m),8.40(lH, d,J=6.4Hz)  4H, s), 6.00-6.03 (lH, s), 6.74-6.84 (3H, m), 7.74-7.79 (2H, m), 8.19-8.22 (2H, m), 8.40 (lH, d, J = 6.4 Hz)
[0301] 実施例 24 [0301] Example 24
Figure imgf000154_0002
Figure imgf000154_0002
l - ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル)メチル）ピぺリジンー4 —ァミンの塩酸塩 0.18gの N, N ジメチルホルムアミド 3mL溶液に、炭酸カリウム 0.15 gを加え、 50°Cで 40分間攪拌した。 40°Cまで冷却し、過塩素酸リチウム 53mgおよび 7 —メトキシ一 1— (ォキシラン一 2—ィル）イソキノリン lOOmgの N, N ジメチルホルム アミド 2mL溶液をカ卩え、 80°Cで 2時間 30分間攪拌した。反応混合物を室温まで冷却し 、水 5mLおよび酢酸ェチル 5mLをカ卩えた。有機層を分取し、水層を酢酸ェチルで抽 出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次 洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留 物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 5： 1]で精 製し、褐色油状物の 2— (1— ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン— 6—ィ ル)メチル）ピぺリジン一 4—ィル）ァミノ一 1― (7—メトキシイソキノリン一 1—ィル）エタ ノール 63mgを得た。 l-((2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) methyl) piperidine-4-hydroamine hydrochloride 0.18 g of N, N dimethylformamide in 3 mL of potassium carbonate 0.15 g was added and stirred at 50 ° C for 40 minutes. Cool to 40 ° C, add 53 mg of lithium perchlorate and 2 mL of 7-methoxy-1- (oxysilane-1-yl) isoquinoline lOOmg of N, N dimethylformamide at 80 ° C for 2 hours 30 Stir for minutes. The reaction mixture was cooled to room temperature and 5 mL of water and 5 mL of ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. Combine the organic layer and the extract, and sequentially add water and saturated aqueous sodium chloride solution. It was washed and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 5: 1] to give 2- (1— ((2, 3 dihydrobenzo [b] 63 mg of [l, 4] dioxin-6-yl) methyl) piperidine-4-yl) amino-1- (7-methoxyisoquinoline-1-yl) ethanol was obtained.
1H-NMR(CDC1 ) δ値： 1.45- 1.60(2H,m),1.85- 2.00(2H,m),2.00- 2.10(2H,m),2.55- 2.9  1H-NMR (CDC1) δ value: 1.45- 1.60 (2H, m), 1.85-2.00 (2H, m), 2.00-2.10 (2H, m), 2.55-2.9
3  Three
0(4H,m),3.20-3.24(lH,m),3.41(2H,s),3.96(3H,s),4.25(4H,s),5.54(lH,dd,J=8.5,2.7Hz 0 (4H, m), 3.20-3.24 (lH, m), 3.41 (2H, s), 3.96 (3H, s), 4.25 (4H, s), 5.54 (lH, dd, J = 8.5,2.7Hz
),6.77-6.83(3H,m),7.35-7.38(2H,m),7.55(lH,d,J=5.6Hz),7.77(lH,d,J=9.8Hz),8.34(l), 6.77-6.83 (3H, m), 7.35-7.38 (2H, m), 7.55 (lH, d, J = 5.6Hz), 7.77 (lH, d, J = 9.8Hz), 8.34 (l
H,d,J=5.6Hz) (H, d, J = 5.6Hz)
[0302] 実施例 25  [0302] Example 25
Figure imgf000155_0001
Figure imgf000155_0001
2- (l - ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル)メチル）ピベリジ ン一 4—ィルァミノ）一 1— (7—メトキシイソキノリン一 1 ィル）エタノール 63mgの酢酸 ェチル 2mL溶液に、室温で 4.0mol/L塩化水素/酢酸ェチル 0.12mLをカ卩えた。同温度 で 1時間 10分間攪拌した後、氷冷下で 20分間攪拌した。析出物をろ取し、淡黄色固 体の 2—（1ー（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル)メチル）ピペリ ジンー4 ィルァミノ） 1 7—メトキシイソキノリン 1 ィル）エタノールの塩酸塩 5 2mgを得た。  2- (l-((2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) methyl) piberidin 1 4-ylamino) 1 1- (7-methoxyisoquinoline 1 yl) ethanol To a 2 mL solution of 63 mg of ethyl acetate, 4.0 mol / L hydrogen chloride / 0.12 mL of ethyl acetate was added at room temperature. The mixture was stirred at the same temperature for 1 hour and 10 minutes, and then stirred for 20 minutes under ice cooling. The precipitate was collected by filtration to give a pale yellow solid 2- (1-((2,3 dihydrobenz [b] [l, 4] dioxin 6 yl) methyl) piperidine-4 ilamino) 1 7-methoxy Isoquinoline 1yl) ethanol hydrochloride 5 2 mg was obtained.
1H-NMR(DMSO-d ) δ値： 2.00— 2.40(4H,m),2.85— 3.00(2H,m),3.20— 3.70(4H,m),4.03(  1H-NMR (DMSO-d) δ value: 2.00— 2.40 (4H, m), 2.85—3.00 (2H, m), 3.20—3.70 (4H, m), 4.03 (
6  6
3H,s),4.10-4.15(2H,m),4.20-4.30(5H,m),6.05-6.20(lH,m),6.92(lH,d,J=8.2Hz),7.01( lH,d,J=8.2Hz),7.16(lH,s),7.60-7.75(lH,m),7.85-7.95(lH,m),8.00-8.20(2H,m),8.42( lH,d,J=5.9Hz)  3H, s), 4.10-4.15 (2H, m), 4.20-4.30 (5H, m), 6.05-6.20 (lH, m), 6.92 (lH, d, J = 8.2Hz), 7.01 (lH, d, J = 8.2Hz), 7.16 (lH, s), 7.60-7.75 (lH, m), 7.85-7.95 (lH, m), 8.00-8.20 (2H, m), 8.42 (lH, d, J = 5.9Hz )
[0303] 実施例 26
Figure imgf000155_0002
09·ε— οε·ε'(ω'Η ) so's— 06 '(s'HS)OS ' C"'Hs)ss si ：軍 g (9p— oswa) N— HT [0303] Example 26
Figure imgf000155_0002
09 · ε— οε · ε '(ω'Η) so's— 06' ( s ' HS) OS 'C "' Hs) ss si ： Military g ( 9 p— oswa) N— H T
。
Figure imgf000156_0001
.
Figure imgf000156_0001
I] [4] > ^、 ー ε '2))-ε))-2θ)φ}@^^、つ辛恩 瀚缀 止 S教 I] [4]> ^, ー ε '2))-ε))-2θ) φ} @ ^^
一ェ "^エ^ QT¾ /— エ^ mm ^。 ·η辛爵 瀚缀 止 。 >n辛爵¾瀚缀 止 s教 一, ェ
Figure imgf000156_0002
ェ "^ e ^ QT¾ / — é ^ mm ^.
Figure imgf000156_0002
M。 " 1 88 ^エ邈 4S/峯 >^ ^π/ΐ。ωο· ¾累 ^ ^ΖΛ^^Μ^  M. "1 88 ^ d 4S / 峯> ^ ^ π / ΐ.ωο · ¾ ^ ^ ^ ΖΛ ^^ Μ ^
o)§ui„ /—,^ェ ( / - 1
Figure imgf000156_0003
-I- ( ^ （ ）（ Λ o) §ui „/ —, ^ e (/-1
Figure imgf000156_0003
-I- (^ () (Λ
[画]
Figure imgf000156_0004
[Picture]
Figure imgf000156_0004
•8'(zH6"8=rP'HT)9Z"Z'(ZHZ"e=f'P'HT)2e"Z'(zW2=f'P'HT)TS"Z'(zW2'6"8=rPP'HT) SS '(ra'HS)S8'9— 9Ζ·9'(ΖΗ8· 9=l"'PP'HI)Z S'(s'H )SS ' (s'HS) 6'S'(s'HS)99'S'(ra • 8 '( z H6 "8 = rP'HT) 9Z"Z' (ZHZ "e = f'P'HT) 2e" Z '(zW2 = f'P'HT) TS "Z'(zW2'6" 8 = rPP'HT) SS '(ra'HS) S8'9— 9Ζ · 9' ( Ζ Η8 · 9 = l "'PP'HI) Z S'(s'H) SS '( s ' HS) 6'S '( s ' HS) 99'S' (ra
'HS)S8 — Ϊ8 ' (ω'Η 9 — SS '(s'HS)S S'(ra'HS)Sri— 89·ΐ :軍 9 ( !DaD)H N-HT 'HS) S8 — Ϊ8'(ω'Η 9 — SS '( s ' HS) S S'(ra'HS) Sri— 89 · ΐ: Military 9 (! DaD) H NH T
。 ¾¾su^M/— , ェ {^y- 1 - 1 . ¾¾su ^ M / —, é {^ y- 1-1
(/ （ ^ ）（ /^ ^ ( / 9一べ/^^^^ [ 'x][ ] ^>^ci^  (/ (^) (/ ^ ^ (/ 9 all / ^^^^ ['x] [] ^> ^ ci ^
'Ζ))-£))
Figure imgf000156_0005
ί
Figure imgf000156_0006
。 ·η辛恩 瀚缀、 止 'Ζ))-£))
Figure imgf000156_0005
ί
Figure imgf000156_0006
. · Η
Figure imgf000156_0007
m辛恩 瀚缀、 止 s教
Figure imgf000156_0007
m
Figure imgf000156_0008
Figure imgf000156_0008
翻 ε9 ¾累、" Hfi¾Suiss、
Figure imgf000156_0009
Ε9 ¾, "Hfi¾ Sui ss,
Figure imgf000156_0009
Figure imgf000156_0010
/— ^ェ
Figure imgf000156_0010
/ — ^
-I- ( ^( /^) ( ΰ :,^ 一 ε))— s  -I- (^ (/ ^) (ΰ:, ^ one ε)) — s
98S6T0/S00Zdf/X3d 9V H,m),4.00-4.10(5H,m),4.25(4H,s),6.15-6.30(lH,m),6.90(lH,d,J=8.4Hz),7.02(lH,d,J =8.4Hz),7.14(lH,s),7.60-7.70(lH,m),7.90-7.95(lH,m),8.00-8.20(2H,m),8.35-8.45(l H,m) 98S6T0 / S00Zdf / X3d 9V H, m), 4.00-4.10 (5H, m), 4.25 (4H, s), 6.15-6.30 (lH, m), 6.90 (lH, d, J = 8.4Hz), 7.02 (lH, d, J = 8.4Hz), 7.14 (lH, s), 7.60-7.70 (lH, m), 7.90-7.95 (lH, m), 8.00-8.20 (2H, m), 8.35-8.45 (l H, m)
[0305] 実施例 28
Figure imgf000157_0001
[0305] Example 28
Figure imgf000157_0001
1— (2 （チォフェン 2—ィルチオ）ェチル）ピぺリジンー4ーァミン 70mgの N, N —ジメチルホルムアミド 2mL溶液に、 7—メトキシ一 1— (ォキシラン一 2—ィル)イソキ ノリン 58mgおよび過塩素酸リチウム 31mgを加え、 85°Cで 4時間攪拌した。反応混合物 を室温まで冷却し、水 10mLおよび酢酸ェチル 10mLをカ卩えた。有機層を分取し、水層 を酢酸ェチルで抽出した。有機層および抽出液を合わせ、飽和塩ィ匕ナトリウム水溶 液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた 残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 5 : 1] で精製し、無色油状物の 2— (1— (2— (チォフェン— 2—ィルチオ)ェチル)ピベリジ ン一 4—ィルァミノ）一 1— (7—メトキシイソキノリン一 1 ィル）エタノール 65mgを得た  1- (2 (thiophen-2-ylthio) ethyl) piperidine-4-amine 70 mg in 2 mL of N, N-dimethylformamide, 58 mg of 7-methoxy-1- (oxylan-2-yl) isoquinoline and perchloric acid 31 mg of lithium was added and stirred at 85 ° C for 4 hours. The reaction mixture was cooled to room temperature, and 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 5: 1], and the colorless oily 2- (1— (2- (thiophen-2-ylthio) ethyl) piveridi 1- (7-methoxyisoquinoline 1-yl) ethanol 65 mg was obtained.
1H-NMR(CDC1 ) δ値： 1.40- 1.50(2H,m),1.80- 1.95(2H,m),2.00- 2.06(2H,m),2.50- 2.6 1H-NMR (CDC1) δ value: 1.40-1.50 (2H, m), 1.80-1.95 (2H, m), 2.00-2.06 (2H, m), 2.50-2.6
3  Three
5(3H,m),2.74-2.92(5H,m),3.17(lH,dd,J=12.0,2.9Hz),3.95(3H,s),5.50(lH,dd,J=8.7,2. 8Hz),6.96(lH,dd,J=5.4,3.5Hz),7.11(lH,dd,J=3.5,1.2Hz),7.32(lH,dd,J=5.4,1.2Hz),7. 34-7.38(2H,m),7.55(lH,d,J=5.5Hz),7.77(lH,d,J=8.8Hz),8.34(lH,d,J=5.5Hz)  5 (3H, m), 2.74-2.92 (5H, m), 3.17 (lH, dd, J = 12.0,2.9Hz), 3.95 (3H, s), 5.50 (lH, dd, J = 8.7,2.8 Hz ), 6.96 (lH, dd, J = 5.4, 3.5 Hz), 7.11 (lH, dd, J = 3.5, 1.2 Hz), 7.32 (lH, dd, J = 5.4, 1.2 Hz), 7. 34-7.38 ( 2H, m), 7.55 (lH, d, J = 5.5Hz), 7.77 (lH, d, J = 8.8Hz), 8.34 (lH, d, J = 5.5Hz)
[0306] 実施例 29
Figure imgf000157_0002
[0306] Example 29
Figure imgf000157_0002
2- (1— (2 （チォフェン 2—ィルチオ）ェチル）ピぺリジンー4 ィルァミノ） 1 一（7—メトキシイソキノリン 1 ィル）エタノール 65mgの酢酸ェチル 2mL溶液に、室 温で 4.0mol/L塩ィ匕水素/酢酸ェチル 0.13mLをカ卩えた。同温度で 30分間攪拌し、減圧 下で溶媒を留去した。得られた残留物に酢酸ェチルおよび 4.0mol/L塩ィ匕水素/酢酸 ェチル 0.13mLをカ卩え、析出物をろ取し、白色固体の 2— (1— (2— (チォフェン— 2— ィルチオ）ェチル）ピぺリジンー4 ィルァミノ） 1一（7—メトキシイソキノリン 1ーィ ル）エタノールの塩酸塩 53mgを得た。 2- (1— (2 (thiophene 2-ylthio) ethyl) piperidine-4-ylamino) 1 (7-methoxyisoquinoline 1-yl) ethanol In a solution of 65 mg of ethyl acetate in 2 mL of 4.0 mol / L salt at room temperature Hydrogen / ethyl acetate 0.13 mL was added. Stir at the same temperature for 30 minutes and decompress The solvent was distilled off under. To the obtained residue, ethyl acetate and 4.03 mol / L salt / hydrogen acetate / ethyl acetate (0.13 mL) were added, and the precipitate was collected by filtration to give a white solid 2— (1— (2— (thiophene 2— (Ilthio) ethyl) piperidine-4-ylamino) 1- (7-methoxyisoquinoline 1-yl) ethanol hydrochloride 53 mg was obtained.
1H-NMR(DMSO-d ) δ値： 1.95— 2.35(6H,m),2.95— 3.05(2H,m),3.10— 3.80(7H,m),4.07(  1H-NMR (DMSO-d) δ value: 1.95— 2.35 (6H, m), 2.95—3.05 (2H, m), 3.10—3.80 (7H, m), 4.07 (
6  6
3H,s),6.20-6.40(lH,m),7.10(lH,dd,J=5.2,3.5Hz),7.31(lH,dd,J=3.5,1.2Hz),7.71(lH, dd,J=5.2,1.2Hz),7.65-7.80(lH,m),7.90-8.05(lH,m),8.10-8.30(2H,m),8.45(lH,d,J=6. 3H, s), 6.20-6.40 (lH, m), 7.10 (lH, dd, J = 5.2, 3.5Hz), 7.31 (lH, dd, J = 3.5, 1.2Hz), 7.71 (lH, dd, J = 5.2, 1.2 Hz), 7.65-7.80 (lH, m), 7.90-8.05 (lH, m), 8.10-8.30 (2H, m), 8.45 (lH, d, J = 6.
1Hz) 1Hz)
実施例 30 Example 30
Figure imgf000158_0001
Figure imgf000158_0001
N- ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル)メチル）ピぺリジン 4 カルボキサミド 0.12gのジクロロェタン 3mL溶液に、室温で 7—メトキシイソキノリン 1 カルバルデヒド 53mgおよび酢酸 24 Lを加え、同温度で 20分間攪拌した。つ いで、同温度でトリァセトキシ水素化ホウ素ナトリウム 0.13gをカ卩え、 1時間 20分間攪拌 した。反応混合物に水およびクロ口ホルムを加えた。有機層を分取し、水層をクロロホ ルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し 、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシ リカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 10： 1]で精製し 、無色泡状物の N—（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル)メチル )— 1—( (7—メトキシイソキノリン一 1 ィル)メチル)ピぺリジン一 4—カルボキサミド 0. 10gを得た。  N- ((2,3 dihydrobenz [b] [l, 4] dioxin 6 yl) methyl) piperidine 4 carboxamide 0.12 g in dichloroethane 3 mL at room temperature with 7-methoxyisoquinoline 1 carbaldehyde 53 mg and Acetic acid 24 L was added and stirred at the same temperature for 20 minutes. Next, 0.13 g of sodium triacetoxyborohydride was added at the same temperature and stirred for 1 hour and 20 minutes. Water and black mouth form were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 10: 1] to give N-((2,3 dihydrobenzo [b] [l , 4] dioxin 6yl) methyl) -1-((7-methoxyisoquinoline 1-yl) methyl) piperidine 4-carboxamide 0.10 g.
'H-NMRCCDCl ) δ値： 1.70- 1.90(4H,m),2.10- 2.25(3H,m),2.95- 3.05(2H,m),3.96(3H,  'H-NMRCCDCl) δ value: 1.70-1.90 (4H, m), 2.10-2.25 (3H, m), 2.95-3.05 (2H, m), 3.96 (3H,
3  Three
s),4.05(2H,s),4.23(4H,s),4.31(2H,d,J=5.4Hz),5.55-5.65(lH,m),6.71(lH,dd,J=8.3,2.1 Hz),6.75(lH,d,J=2.1Hz),6.80(lH,d,J=8.3Hz),7.34(lH,dd,J=8.9,2.5Hz),7.51(lH,d,J=5 .7Hz),7.72(lH,d,J=8.9Hz),7.92(lH,d,J=2.5Hz),8.32(lH,d,J=5.7Hz) s), 4.05 (2H, s), 4.23 (4H, s), 4.31 (2H, d, J = 5.4Hz), 5.55-5.65 (lH, m), 6.71 (lH, dd, J = 8.3, 2.1 Hz) ), 6.75 (lH, d, J = 2.1Hz), 6.80 (lH, d, J = 8.3Hz), 7.34 (lH, dd, J = 8.9,2.5Hz), 7.51 (lH, d, J = 5. 7Hz), 7.72 (lH, d, J = 8.9Hz), 7.92 (lH, d, J = 2.5Hz), 8.32 (lH, d, J = 5.7Hz)
実施例 31 ^^ / 一 一べ fi （ ^エ（ 9一べ ^:^^ [ Ί] [ ]
Figure imgf000159_0001
Example 31 ^^ / one one fi (^ one (9 one ^: ^^ [Ί] []
Figure imgf000159_0001
— ε 'ζ) -ζ)-ι) -2= ^α> ^、つ ¾9¾呦 ffl措。 ·Π#¾^ ΟΪ D¥ ^ m。 " ^tif i^^i^sベ ^?^ ^ π 1 ΐ9ベ ^ ^エ fH、 T?iSu¾84—— Ε 'ζ) -ζ) -ι) -2 = ^ α> ^, ¾9¾ 呦 ffl measures. · Π # ¾ ^ ΟΪ D ¥ ^ m. "^ tif i ^^ i ^ s base ^? ^ ^ π 1 ΐ9 base ^ ^ d fH, T? i Su ¾84—
Δ^^ ^— ε ベ /^^- 2- ^-8 = 、止^^ 1119ベΔ ^^ ^ — ε / ^^-2- ^ -8 =, Stop ^^ 11 19
^ ェ (H ^^m ^n^^^^ ^ mw^ ^。 ·η辛爵 瀚缀 止 ^ É (H ^^ m ^ n ^^^^ ^ mw ^ ^.
Figure imgf000159_0002
Figure imgf000159_0002
z m  z m
(zwe=rP'HT) ^"8'(zH6"8=rP'HT)S0"8'(We=rP'HT)88" '(zHS"2'6(zwe = rP'HT) ^ "8 '( z H6" 8 = rP'HT) S0 "8' (We = rP'HT) 88"'(zHS"2'6
•8=f'PP'HT)WZ'(zHS"2=rP'HT)0S"Z'(zH2"8=rP'HT)6Z"9'(zH0"2=rP'HT)SZ"9'(zH0"2• 8 = f'PP'HT) WZ '(zHS "2 = rP'HT) 0S"Z' (zH2 "8 = rP'HT) 6Z" 9 '( z H0 "2 = rP'HT) SZ" 9 '( z H0 "2
'2'8=f'PP'HI)0r9'(s'HS)0rS'(s'H IS ' (zH9'S=f'P'HS)9r (s'HS)66'S'(ra'HS)( 'S'2'8 = f'PP'HI) 0r9' ( s ' HS) 0rS '(s'H IS' ( z H9'S = f'P'HS) 9r ( s ' HS) 66'S '(ra'HS) ( 'S
— Ο9·ε'(ω'Η 3ε·ε— 0S'S'C"'HI)S9 — S ' (ω'Η ) SI'S— S6'I :軍 9 ( P-OS a)H N-HT — Ο9 · ε '(ω'Η 3ε · ε— 0S'S'C "' HI) S9 — S '(ω'Η) SI'S— S6'I: Military 9 (P-OS a) H NH T
。 ¾¾Suq Z ^邈^ r ^^ ^^ →_ ^^ . ¾¾Suq Z ^ 邈 ^ r ^^ ^^ → _ ^^
Ί]
Figure imgf000159_0003
、つ ¾9¾呦 ffl措 ェ邈 4S )Soro、 ^ ^^ 一 一べ fi （ ^ ( τ一べ ^ Ί]
Figure imgf000159_0003
¾9¾ 呦 ffl measures 4S) Soro, ^ ^^ all fi (^ (τ all ^
Figure imgf000159_0004
Figure imgf000159_0004
98S6T0/S00Zdf/X3d 191 ZSS9^0/900Z OAV m^ [πεο] 98S6T0 / S00Zdf / X3d 191 ZSS9 ^ 0 / 900Z OAV m ^ [πεο]
(S'HI)I ( S 'HI) I
9"6'(zH9"Z=f'P'HT)e^"8'(s'HT)Z2"8'(zH9"Z=f'P'HT)8S"Z'(ra'HT)8S"Z-^"Z'(ra'H2)SZ" 9— ΖΓ9'(ζΗ8·ΐ'^8=ΓΡΡ'Ηΐ)99·9'(δ'Η OS' (S'HS)Z(T (ra'HS)SO'S— S6 ' C"'HS)( 9 "6 '( z H9" Z = f'P'HT) e ^ "8' ( s ' HT) Z2" 8 '( z H9 "Z = f'P'HT) 8S"Z'(ra'HT ) 8S "Z-^" Z '(ra'H2) SZ "9— ΖΓ9' ( ζ Η8 · ΐ '^ 8 = ΓΡΡ'Ηΐ) 99 · 9' ( δ 'Η OS' ( S 'HS) Z ( T (ra'HS) SO'S— S6 'C "' HS) (
- 0 ' (ra'HS)SrS- 00 ' C"'HS)00 - 06·ΐ'(ω'Η 08·ΐ- S9'I :軍 9 ( OSWd) N- Ητ -0 '(ra'HS) SrS- 00' C "'HS) 00-06 · ΐ'(ω'Η 08 · ΐ- S9'I: Army 9 (OSWd) N- Η τ
。 ¾¾§ωΐε^べ^ . ¾¾§ω ΐε ^
ε べ fi ,^Ρ ^ EH ー S 01^ ^^ 一 一べ ίί （ ^エ（ 9一べ/^  ε be fi, ^ Ρ ^ EH ー S 01 ^ ^^
Ί]
Figure imgf000160_0001
、つ ¾9¾呦 ffl 措 ^m^^ mm ^。 ·η辛爵¾瀚缀 止 s教 ^w ^w^ Ί]
Figure imgf000160_0001
¾9¾ 呦 ffl measures ^ m ^^ mm ^.・ Η
Ύ^ΖΛ^/^- \ mm ^。 ·η辛爵¾瀚缀、 止 s教、 : ·η¾鱸コ 91^、
Figure imgf000160_0002
ェ邈 4§
Figure imgf000160_0003
。 つ ε— ^^- ζ ^ →-ベ ίί Ύ ^ ΖΛ ^ / ^-\ mm ^. · Ηpion ¾ 瀚 缀, stop suk, · · η¾ 鱸 コ 91 ^,
Figure imgf000160_0002
4§
Figure imgf000160_0003
. Ε— ^^-ζ ^ → -Be ίί
Figure imgf000160_0004
Figure imgf000160_0004
εε圏第 [οτεο] εε range [οτεο]
( BOjq'HT)(BOjq'HT)
09·0ΐ— 0ε·0ΐ'(δ'Ηΐ)^·6'(δ'Ηΐ)ΐ8·8'(ω'Ηΐ)¾·8— 03·8'(ω'Ηΐ)6Ζ·Ζ— (ω'Ηΐ)ΐ3·Ζ—09 · 0ΐ— 0ε · 0ΐ '( δ ' Ηΐ) ^ · 6 '( δ ' Ηΐ) ΐ8 · 8 '(ω'Ηΐ) ¾ · 8— 03 · 8'(ω'Ηΐ) 6Ζ · Ζ— (ω 'Ηΐ) ΐ3 · Ζ—
·Ζ'(ω'Η ε8·9— 8Γ9'(ω'Ηΐ) Γ9— Sr9'(s'H )SS ' (s'HS r (s'HS)68'S'(ra'HS)( 'S — Ο9·ε'(ω'Η Ο ·ε— 0S'S'(ra'HS)0rS— S8 ' (ω'Η )θε — 00 ：！^ 9 ( P-OS a)H N-HT · Ζ '(ω'Η ε8 · 9— 8Γ9'(ω'Ηΐ) Γ9— Sr9 '( s ' H) SS' ( s ' HS r ( s ' HS) 68'S '(ra'HS) (' S — Ο9 · ε '(ω'Η ε · ε— 0S'S'(ra'HS) 0rS— S8 '(ω'Η) θε — 00 ：! ^ 9 (P-OS a) H NH T
。 Su¾8^r濯 ^r ^— 、^^ 一 ε—ベ ,^: 、^ ^ ー s (、 . Su¾ 8 ^ r rinse ^ r ^ —, ^^ one ε — be, ^:, ^ ^ ー s (,
98S6T0/S00Zdf/X3d 891-
Figure imgf000161_0001
98S6T0 / S00Zdf / X3d 891-
Figure imgf000161_0001
2, 7 ジメトキシキノリン— 8 ァミン 22mgの N, N ジメチルホルムアミド 2mL溶液 に、室温で 1一（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル） ピぺリジン— 4—カルボン酸 31mg、 0- (7 ァザべンゾトリアゾール—1—ィル）—1, 1, 3, 3—テトラメチルゥ口-ゥム =へキサフルォロホスフェート 62mgおよびトリェチル ァミン 45 μ Lを加え、 60°Cで 1時間、 90°Cで 1時間攪拌した。 O—（7 ァザべンゾトリア ゾールー 1ーィル）ー1, 1, 3, 3—テトラメチルゥ口-ゥム =へキサフルォロホスフエ一 ト 62mgおよびトリェチルァミン 45 /z Lをカ卩え、 70°Cで 1時間攪拌した。反応混合物に酢 酸ェチル 30mLおよび水 20mLを加えた。有機層を分取し、水層を酢酸ェチル 10mLで 抽出した。有機層および抽出液を合わせ、水 10mLおよび飽和塩ィ匕ナトリウム水溶液 10mLで洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得ら れた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 20 : 1]で精製し、得られた残留物にジェチルエーテルおよびジイソプロピルエーテ ルを加えた。不溶物をろ取し、淡褐色固体の 1一（2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン— 6—ィル）ェチル）— N—(2, 7 ジメトキシキノリン— 8—ィル）ピペリ ジン 4 カルボキサミド 3mgを得た。  2, 7 Dimethoxyquinoline— 8 Amine In a solution of 22 mg of N, N dimethylformamide in 2 mL, add 1 (2- (2, 3 dihydrobenz [b] [l, 4] dioxin 6 yl) ethyl) Peridine—4-carboxylic acid 31 mg, 0- (7-azabenzotriazole-1-yl) -1,1,3,3-tetramethylthio-hexafluorophosphate 62 mg and triethylamine 45 μL was added, and the mixture was stirred at 60 ° C for 1 hour and at 90 ° C for 1 hour. O— (7 Azabenzotriazole 1-yl) -1, 1, 3, 3—Tetramethylu-um-hexafluorophosphite 62 mg and triethylamine 45 / z L, 70 ° Stir at C for 1 hour. To the reaction mixture, 30 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with 10 mL of water and 10 mL of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1], and jetyl ether and diisopropyl ether were added to the obtained residue. The insoluble material was collected by filtration and collected as a light brown solid 1 (2— (2,3 dihydrobenzo [b] [1, 4] dioxin-6-yl) ethyl) —N— (2, 7 dimethoxyquinoline — 8—yl) piperidine 4 carboxamide 3 mg was obtained.
1H-NMR(CDC1 ) δ値： 1.95- 2.20(6H,m),2.40- 2.65(3H,m),2.70- 2.80(2H,m),3.05- 3.1  1H-NMR (CDC1) δ value: 1.95-2.20 (6H, m), 2.40-2.65 (3H, m), 2.70-2.80 (2H, m), 3.05-3.1
3  Three
5(2H,m),3.99(3H,s),4.03(3H,s),4.24(4H,s),6.65-6.80(4H,m),7.18(lH,d,J=9.0Hz),7.5 5(lH,s),7.60(lH,d,J=9.0Hz),7.91(lH,d,J=8.8Hz)  5 (2H, m), 3.99 (3H, s), 4.03 (3H, s), 4.24 (4H, s), 6.65-6.80 (4H, m), 7.18 (lH, d, J = 9.0Hz), 7.5 5 (lH, s), 7.60 (lH, d, J = 9.0Hz), 7.91 (lH, d, J = 8.8Hz)
実施例 35
Figure imgf000161_0002
Example 35
Figure imgf000161_0002
4 ァミノ一 N— (7—メトキシイソキノリン一 1 ィル）シクロへキサンカルボキサミド 8 Omgのジクロロェタン 2mL溶液に、室温で 1, 4一べンゾジォキサン 6 カルバルデ ヒド 44mgおよび酢酸 16 /z Lをカ卩え、同温度で 1時間攪拌した。ついで、同温度でトリア セトキシ水素化ホウ素ナトリウム 84mgを加え、 3時間攪拌した。反応混合物に水 lOmL および酢酸ェチル 40mLをカ卩えた。 20%水酸化ナトリウム水溶液をカ卩え、 pH12.0に調 整した。有機層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合 わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧 下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液； クロ口ホルム：メタノール = 20 : 1]で精製し、白色固体の 4— ( (2, 3 ジヒドロベンゾ[ b] [l, 4]ジォキシン— 6—ィル)メチルァミノ）— N— (7—メトキシイソキノリン— 1—ィ ル）シクロへキサンカルボキサミド 17mgを得た。 4 Amino N- (7-methoxyisoquinoline 1 yl) cyclohexanecarboxamide 8 Omg of dichloroethane in 2 mL solution was charged with 1,4 monobenzodioxane 6 carbaldehyde 44 mg and acetic acid 16 / z L at room temperature, The mixture was stirred at the same temperature for 1 hour. Then, Tria at the same temperature 84 mg of sodium cetoxyborohydride was added and stirred for 3 hours. To the reaction mixture was added 10 mL of water and 40 mL of ethyl acetate. A 20% aqueous sodium hydroxide solution was prepared and adjusted to pH 12.0. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; black mouth form: methanol = 20: 1] to give 4- ((2, 3 dihydrobenzo [b] [l, 4] dioxin— 6-yl) methylamino) -N- (7-methoxyisoquinoline-1-yl) cyclohexanecarboxamide 17 mg was obtained.
'H-NMRCDMSO-d ) δ値： 1.06— 1.20(2H,m),1.42— 1.74(3H,m),1.96— 2.03(4H,m),2.40—  'H-NMRCDMSO-d) δ value: 1.06— 1.20 (2H, m), 1.42—1.74 (3H, m), 1.96—2.03 (4H, m), 2.40—
6  6
2.70(lH,m),3.60-3.70(2H,m),3.85(3H,s),4.21(4H,s),6.76-6.88(3H,m),7.16-7.20(lH, m),7.43(lH,dd,J=9.0,2.4Hz),7.65(lH,d,J=5.5Hz),7.90(lH,d,J=9.0Hz),8.18(lH,d,J=5. 5Hz),10.23-10.28(lH,m)  2.70 (lH, m), 3.60-3.70 (2H, m), 3.85 (3H, s), 4.21 (4H, s), 6.76-6.88 (3H, m), 7.16-7.20 (lH, m), 7.43 ( lH, dd, J = 9.0,2.4Hz), 7.65 (lH, d, J = 5.5Hz), 7.90 (lH, d, J = 9.0Hz), 8.18 (lH, d, J = 5.5Hz), 10.23 -10.28 (lH, m)
実施例 36 Example 36
Figure imgf000162_0001
Figure imgf000162_0001
8 -ァミノ 2 メトキシキノリン一 5 -カルボキサミド 13mgの N, N -ジメチルホルム アミド 0.60mL溶液に、室温で 1— (2— (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン— 6 ィル）ェチル）ピぺリジンー4一力ルボン酸 21mg、トリェチルァミン 34 Lおよび O — (7 ァザべンゾトリアゾール—1—ィル）—1, 1, 3, 3—テトラメチルゥ口-ゥム = へキサフルォロホスフェート 46mgを加え、室温で 2時間 35分間、 60〜70°Cで 40分間 攪拌した。反応混合物を室温まで冷却し、 O— (7—ァザべンゾトリアゾール—1—ィ ル） 1, 1, 3, 3—テトラメチルゥ口-ゥム =へキサフルォロホスフェート 46mgおよびト リエチルァミン 34 Lを加え、室温で 55分間、 100〜110°Cで 1時間攪拌した。反応混 合物を室温まで冷却し、酢酸ェチル 10mLおよび水 10mLをカ卩えた。有機層を分取し、 水層を酢酸ェチル 10mLで抽出した。有機層および抽出液を合わせ、無水硫酸マグ ネシゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラム クロマトグラフィー [溶離液;クロ口ホルム:メタノール = 10 : 1]で精製し、褐色固体の 8 - N 'ΝΟ)§ω 4— 1- (2- (2,3 Dihydrobenzo [b] [1, 4] dioxin— 6) in a solution of 8-amino 2 methoxyquinoline mono 5-carboxamide 13 mg in 0.60 mL N, N -dimethylformamide at room temperature Yl) ethyl) piperidine-4strength rubonic acid 21 mg, triethylamine 34 L and O — (7 azabenzotriazole-1-yl) —1, 1, 3, 3—tetramethylol-um = Hexafluorophosphate (46 mg) was added, and the mixture was stirred at room temperature for 2 hours and 35 minutes and at 60 to 70 ° C for 40 minutes. The reaction mixture was cooled to room temperature and O— (7-azabenzotriazole-1-yl) 1, 1, 3, 3-tetramethyl oxalate-hexafluorophosphate 46 mg and triethylamine 34 L was added, and the mixture was stirred at room temperature for 55 minutes and at 100 to 110 ° C for 1 hour. The reaction mixture was cooled to room temperature and 10 mL of ethyl acetate and 10 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; black form: methanol = 10: 1]. -N 'ΝΟ) §ω 4—
Figure imgf000163_0001
Figure imgf000163_0001
(ZH6"8=rP'HT)96"Z'(ZHeT8"Z=rPP'HT)2S"Z'(ZH8"Z=rVHT)82"Z'(ZHST8"Z=rPP'H ΐ)90·Ζ'(ζΗ6·8=ί"'Ρ'Ηΐ)ΐ6·9'(ζΗΓ8=ί"'Ρ'Ηΐ)8Γ9'(ζΗΐ =ί"'Ρ'Ηΐ)εΓ9'(ζΗΓ^Γ8=ΓΡΡ 'Ηΐ)89·9'(ω'Η )8^— IS (s'HS)Or (ZH9'9=1"'P'HS)S(T (ω'Η ΐΐ·ε— SO'S'(ra'HS) — U ' C"'HS)S9 — SS ' C"'HS)9rS— 00 ' C"'HS)8S'I— ΐ :軍 9 (OQDWH-^ (ZH6 "8 = rP'HT) 96" Z '(ZHeT8 "Z = rPP'HT) 2S"Z' (ZH8 "Z = rVHT) 82" Z '(ZHST8 "Z = rPP'H ΐ) 90 · Ζ '( ζ Η6 · 8 = ί "'Ρ'Ηΐ) ΐ6 · 9 '( ζ ΗΓ8 = ί"'Ρ'Ηΐ) 8Γ9 '( ζ Ηΐ = ί "'Ρ'Ηΐ) εΓ9 '( ζ ΗΓ ^ Γ8 = ΓΡΡ 'Ηΐ) 89 · 9'(ω'Η) 8 ^ — IS ( s ' HS) Or ( Z H9'9 = 1 "'P'HS) S (T (ω'Η ΐΐ · ε— SO'S' ( ra'HS) — U 'C "' HS) S9 — SS 'C"' HS) 9rS— 00 'C "' HS) 8S'I— ΐ: Army 9 (OQDWH- ^
。 §ω6ΐベ fi,^^^ ー (^i^ z) -z) -D) -s > ^mWw、つ if慰、 [τ : = /— ^ マ / cm ^ 鍋缀
Figure imgf000163_0002
m ^ mM^。 ·πί¾¾ Ίωοΐマ ^ mc^^ (氺 ^ ^ mM^ ° つ ¾鱸 . §Ω 6ΐbe fi, ^^^ ー (^ i ^ z) -z) -D) -s> ^ mWw, if consolation, (τ: = / — ^ ma / cm ^
Figure imgf000163_0002
m ^ mM ^. · Πί¾¾ Ίωοΐ マ ^ mc ^^ (氺 ^ ^ mM ^ ° ¾ 鱸
Figure imgf000163_0003
Figure imgf000163_0003
圏第 No. 1
(ΖΗε·6=ί"'Ρ'Ηΐ) Ζ·8'(ζΗ0·8=ί"'Ρ'Ηΐ)Ζ3·8'(ζΗ0·8=ί"'Ρ'Ηΐ)Ζ9·Ζ'(ζΗε·6=ί"'Ρ'Ηΐ)0ΐ ·Ζ'(ω'Ηε)08·9- ( '9'(S'H ) ' (s'HS)Sr (ra'HSI)( 'S- 08·ΐ :軍 9 (QO^QDWH-H^ °^ ¾SuiS · S、 ^ ^^ -9- d/^W- Z - (、 ^ →- ^
Figure imgf000163_0004
(ΖΗε · 6 = ί "'Ρ'Ηΐ) Ζ8' ( ζ Η0 · 8 = ί"'Ρ'Ηΐ) Ζ3 / 8' ( ζ Η0 · 8 = ί "'Ρ'Ηΐ) Ζ9 · Ζ' ( ζ Ηε · 6 = ί "'Ρ'Ηΐ) 0ΐ · Ζ'(ω'Ηε) 089- ('9' ( S 'H)' ( s 'HS) Sr (ra'HSI) (' S -08 · ΐ: Army 9 (QO ^ QDWH-H ^ ° ^ ¾SuiSS, ^ ^^ -9- d / ^ W- Z-(, ^ →-^
Figure imgf000163_0004
98S6T0/S00Zdf/X3d 1-91. q]
Figure imgf000164_0001
一エ /98S6T0 / S00Zdf / X3d 1-91. q]
Figure imgf000164_0001
I
、回 ¾ Ίω0ΐ氺 q¾ ¾<¾?ffi¾。 つ 鱸 ) S'SHd、 難^ Π/ριιιθ'ΐ ^ΰί ( , ¾ Ίω 0ΐ氺 q¾ ¾ <¾? Ffi¾. Tsu 鱸) S'SHd, Difficulty ^ Π / ριιιθ'ΐ ^ ΰί (
uios氺、つ辛爵 瀚缀 止 s教
Figure imgf000164_0002
uios つ
Figure imgf000164_0002
rfss 缀氺マ fw 濯氺0 /oos 、
Figure imgf000164_0003
z i
Figure imgf000164_0004
r f ss 缀 氺 fw rinse 0 / oos,
Figure imgf000164_0003
zi
Figure imgf000164_0004
一 ^^- ζ ^ →-ベ n (^-έ  One ^^-ζ ^ → -Be n (^ -έ
Figure imgf000164_0005
Figure imgf000164_0005
6ε圏第 [9ΐεο]
Figure imgf000164_0006
6ε-zone [9ΐεο]
Figure imgf000164_0006
q'HT)89"6-S9"6'(zH9"Z=f'P'HT)8Z"8'(zHS"8=f'P'HT)e2"8'(ui'H2)TS-Z-^"Z'(ra'He)28"q'HT) 89 "6-S9" 6 '( z H9 "Z = f'P'HT) 8Z"8' ( z HS "8 = f'P'HT) e2" 8 '( u i'H2) TS-Z-^ "Z '(ra'He) 28"
9— 99'9'(S'H )W (s'HS)Sr (s'HS)SO' (ω'Η 9ΐ·ε— ΖΟ·ε'(ω'Η 8Ζ — ( ' WHS) 9—99'9 '( S ' H) W ( s ' HS) Sr (s'HS) SO '(ω'Η 9ΐ · ε— ΖΟεε (ω'Η 8Ζ — (' WHS)
9·2— 9S'2'(UI'HI)0S - 0 ' (ω'Η WS- OrS'(ra'HS)W) - 06·ΐ :軍 9 ( !DaD)H N-HT 9 · 2- 9S '2' ( UI'HI) 0S - 0 '(ω'Η WS- OrS'(ra'HS) W) - 06 · ΐ: army 9 (! DaD) H NH T
。 Sra0w— ^^ / 一
Figure imgf000164_0007
( / ェ ( / 9—ベ 、^ . Sra 0 w— ^^ / One
Figure imgf000164_0007
(/ É (/ 9—be, ^
'I][q]
Figure imgf000164_0008
、っ^'I] [q]
Figure imgf000164_0008
...
^-^^^ ^^。 ·η辛爵¾瀚缀、 止 ϊί教、つ i ^ / 一ェ ΰ ^-^^^ ^^. · Η 爵 克 ¾ 瀚 缀 、 ϊ ϊί 教 、 つ i ^ / 一 ェ
^ ^ ^W^ ^ ^Ψ,、っ攝慰、 [I:OS= /— ^ マ fm  ^ ^ ^ W ^ ^ ^ Ψ, 攝 consolation, [I: OS = / — ^ ma fm
、 止 s教 ^^m^ ^^^m ^ ^ wi^mm^ ^^ ^ 斜, Stop s teaching ^^ m ^ ^^^ m ^ ^ wi ^ mm ^ ^^ ^
w 、
Figure imgf000164_0009
w,
Figure imgf000164_0009
ΰ / ^ =マ - ΰ /^ ^！ ー 'ε 'ε 'χ 'i （ / "[一 /— 、
Figure imgf000164_0010
マ ^ ΰ / ^ = Ma-ΰ / ^ ^!ー 'ε' ε 'χ' i (/ "[One / —,
Figure imgf000164_0010
Ma ^
98S6T0/S00Zdf/X3d 391- ] [1, 4]ジォキシンー6 ィル）ェチル）ピぺリジンー4 カルボキサミド）ー2—メトキ シキノリン 4 カルボン酸 23mgを得た。 98S6T0 / S00Zdf / X3d 391- ] [1,4] dioxin-6yl) ethyl) piperidine-4carboxamide) -2-methoxyquinoline 4 carboxylic acid 23 mg was obtained.
1H-NMR(DMSO-d ) δ値： 1.80— 1.95(2H,m),2.00— 2.15(2H,m),2.65— 2.90(5H,m),3.20—  1H-NMR (DMSO-d) δ value: 1.80— 1.95 (2H, m), 2.00— 2.15 (2H, m), 2.65— 2.90 (5H, m), 3.20—
6  6
3.50(4H,m),4.07(3H,s),4.21(4H,s),6.67-6.72(lH,m),6.76-6.79(2H,m),7.20(lH,s),7.3 3.50 (4H, m), 4.07 (3H, s), 4.21 (4H, s), 6.67-6.72 (lH, m), 6.76-6.79 (2H, m), 7.20 (lH, s), 7.3
5-7.43(lH,m),8.18(lH,d,8.5Hz),8.47(lH,d,J=7.8Hz),9.72(lH,s) 5-7.43 (lH, m), 8.18 (lH, d, 8.5Hz), 8.47 (lH, d, J = 7.8Hz), 9.72 (lH, s)
実施例 40
Figure imgf000165_0001
Example 40
Figure imgf000165_0001
N- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6 ィル）ピぺリジンー4 カル ボキサミド 0.26gの N, N—ジメチルホルムアミド 10mL溶液に、室温で 7—メトキシ— 1 （ォキシランー2 ィル)イソキノリン 0.20gおよび過塩素酸リチウム O.llgをカ卩え、 80 °Cで 2時間攪拌した。反応混合物を室温まで冷却し、水 10mLおよび酢酸ェチル 20m Lをカ卩えた。 lmol/L塩酸で pHl.lに調整し、水層を分取し、水層を酢酸ェチルで洗浄 した。水層に酢酸ェチル 20mLをカ卩え、 20%水酸化ナトリウム水溶液をカ卩え、 pHll.7 に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネ シゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロ マトグラフィー [溶離液;クロ口ホルム:メタノール = 9 : 1]で精製し、淡黄白色固体の N 一（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6—ィル）ー1ー（2 ヒドロキシー2 - (7—メトキシイソキノリン一 1—ィル）ェチル）ピぺリジン一 4—カルボキサミド 49mgを 得た。  N- (2, 3 Dihydrobenzo [b] [l, 4] dioxin-6 yl) piperidine-4 carboxamide 0.26 g of N, N-dimethylformamide in 10 mL solution at room temperature with 7-methoxy-1 ( Oxylan-2yl) Isoquinoline (0.20 g) and lithium perchlorate (O.llg) were added and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature and 10 mL of water and 20 mL of ethyl acetate were collected. The pH was adjusted to 1 with lmol / L hydrochloric acid, the aqueous layer was separated, and the aqueous layer was washed with ethyl acetate. Ethyl acetate (20 mL) was added to the aqueous layer, and 20% aqueous sodium hydroxide solution was added to adjust to pHll.7. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 9: 1] to give N 1 (2,3 dihydrobenzo [b] [l, 4] Dioxin-6-yl) -1- (2 hydroxy-2- (7-methoxyisoquinoline-1-yl) ethyl) piperidine-1-4-carboxamide 49 mg was obtained.
'H-NMRCCDCl ) δ値： 1.85— 2.05(4H,m),2.15— 2.40(3H,m),2.75— 2.93(2H,m),3.13— 3.3  'H-NMRCCDCl) δ value: 1.85— 2.05 (4H, m), 2.15— 2.40 (3H, m), 2.75— 2.93 (2H, m), 3.13— 3.3
3  Three
3(2H,m),3.97(3H,s),4.24(4H,s),5.50-5.52(lH,m),6.80(lH,d,J=8.6Hz),6.90(lH,dd,J=8 .6,2.1Hz),7.00-7.12(lH,m),7.16(lH,d,J=2.3Hz),7.37(lH,dd,J=8.9,2.3Hz),7.49-7.53( lH,m),7.54(lH,d,J=5.6Hz),7.77(lH,d,J=8.9Hz),8.36(lH,d,J=5.6Hz)  3 (2H, m), 3.97 (3H, s), 4.24 (4H, s), 5.50-5.52 (lH, m), 6.80 (lH, d, J = 8.6Hz), 6.90 (lH, dd, J = 8.6, 2.1 Hz), 7.00-7.12 (lH, m), 7.16 (lH, d, J = 2.3 Hz), 7.37 (lH, dd, J = 8.9, 2.3 Hz), 7.49-7.53 (lH, m ), 7.54 (lH, d, J = 5.6Hz), 7.77 (lH, d, J = 8.9Hz), 8.36 (lH, d, J = 5.6Hz)
実施例 41
Figure imgf000165_0002
'(zH6'8=f'P'HI)80 '(ra'HS)S8'9— 6Γ9'(ζΗ6·ΐ'^8=ΓΡΡ'Ηΐ) Ζ·9'(ζΗ8·6=ί"'Ρ'Ηΐ)εΐ·9'Example 41
Figure imgf000165_0002
'(zH6'8 = f'P'HI) 80'(ra'HS)S8'9— 6Γ9 '( ζ Η6 · ΐ' ^ 8 = ΓΡΡ'Ηΐ) Ζ · 9 '( ζ Η8 · 6 = ί "'Ρ'Ηΐ)εΐ9'
(S'H '(s'HS o' 'C"'Hsi)oo' - ΐ·ε'(ω ) ο·ε- 06 ： iH(9p- OS ) 顺- ΗΤ ( S 'H' ( s 'HS o''C"' Hsi) oo '-ΐ · ε' (ω) ο · ε- 06: iH ( 9 p- OS) 顺-Η Τ
Figure imgf000166_0001
（ ^エ（ / 9一べ ^^^^ [ Ί]
Figure imgf000166_0002
'ζ) -Ζ)→) -Ζ
Figure imgf000166_0003
Figure imgf000166_0001
(^ E (/ 9 all ^^^^ [Ί]
Figure imgf000166_0002
'ζ) -Ζ) →) -Ζ
Figure imgf000166_0003
薦第 [6ΐεο]
Figure imgf000166_0004
Recommended [6ΐεο]
Figure imgf000166_0004
HT)86" '(zwr2" =f'PP'HT)^8" '(zwr6" =rPP'HT)^9" '(zH8" =rVHT)6S" '(zH6  HT) 86 "'(zwr2" = f'PP'HT) ^ 8 "' (zwr6" = rPP'HT) ^ 9 "'(zH8" = rVHT) 6S "' (zH6
·8=ί"'Ρ'Ηΐ)06·9'(ζΗΓ8=ί"'Ρ'Ηΐ)6Γ9'(ω'Ηζ)3Ζ·9— S9'9'(zH0'S'6'6=rPP'HI)8rS'(s'H· 8 = ί "'Ρ'Ηΐ) 06 · 9' ( ζ ΗΓ8 = ί"'Ρ'Ηΐ)6Γ9'(ω'Ηζ) 3Ζ · 9—S9'9 '( z H0'S'6'6 = rPP' HI) 8rS '(s'H
^ (s'HS)SO' (ζΗΐ·ε' ΐ=ΓΡΡ'Ηΐ)Ζ0·ε'(ω'Ηεΐ)96 — fS'S:!! 9 ( !DaD)H N-HT ^ (s'HS) SO '( ζ Ηΐ · ε' ΐ = ΓΡΡ'Ηΐ) Ζ0 · ε '(ω'Ηεΐ) 96 — fS'S: !! 9 (! DaD) H NH T
。 ¾¾Su¾ /— ^ェ（ / — 8—ベ ίί,^Ρ ^^ — ΐ— (  . ¾¾Su¾ / — ^ e （/ — 8—Be ίί, ^ Ρ ^^ — ΐ— (
)-Ζ)→)
Figure imgf000166_0005
- 、HN- xsJo uKiq /) -Ζ) →)
Figure imgf000166_0005
-, HN- xsJo uKiq /
f 、、¾ 、 ( 、平囂： ίί/¾ατ?ίτ Ό： I： os = ^ .—^ .%SZ - ^^¾^^車阖： (^]— 0 f, ¾, (, flat: ίί / ¾ατ? ίτ Ό: I: os = ^ .— ^.% SZ-^^ ¾ ^^ vehicle: (^] — 0
Figure imgf000166_0006
。 >n辛爵 瀚缀 止 ϊί教 、 マ
Figure imgf000166_0007
Figure imgf000166_0006
. > n
Figure imgf000166_0007
Ύ^ΟΖ^Λ^ η^ ^ ^。 ^翻 S、 ¾累 Hf Sui εマ (H 峯
Figure imgf000166_0008
( / Ύ ^ ΟΖ ^ Λ ^ η ^ ^ ^. ^ F, S ¾ Hf Sui ε (H 峯
Figure imgf000166_0008
(/
98S6T0/S00Zdf/X3d 9V 7.47-7.56(lH,m),7.84-7.93(2H,m),8.29(lH,d,J=8.9Hz) 98S6T0 / S00Zdf / X3d 9V 7.47-7.56 (lH, m), 7.84-7.93 (2H, m), 8.29 (lH, d, J = 8.9Hz)
[0320] 実施例 43
Figure imgf000167_0001
[0320] Example 43
Figure imgf000167_0001
2—メトキシ一 8— (2— (ピペリジン一 4—ィル）ェチル）キノリン 0.42g、 (2, 3 ジヒド 口べンゾ [b] [1, 4]ジォキシン 6 ィル）ァセトアルデヒド 0.36gおよび酢酸 0.09mL のジクロロメタン 10mL—メタノール lmL溶液に、室温でトリァセトキシ水素化ホウ素ナト リウム 0.52gをカ卩え、 40分間攪拌した。反応混合物に水 10mLおよびクロ口ホルム 20mL を加えた。有機層を分取し、水層をクロ口ホルム 20mLで抽出した。有機層および抽出 液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ 、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [シ リカゲル；富士シリシァ化学株式会社、 Chromatorex-NH、溶離液；酢酸ェチル]で精 製し、無色油状物の 8—（2— (1— (2— (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン —6—ィル）ェチル）ピぺリジン一 4—ィル）ェチル） 2—メトキシキノリン 0.16gを得た  2-methoxy-1-8- (2- (piperidine-4-yl) ethyl) quinoline 0.42 g, (2,3 dihydr benzo [b] [1, 4] dioxin 6 yl) acetaldehyde 0.36 g Then, 0.52 g of sodium triacetoxyborohydride was added to a solution of 0.09 mL of acetic acid in 10 mL of dichloromethane and 1 mL of methanol at room temperature and stirred for 40 minutes. To the reaction mixture, 10 mL of water and 20 mL of black mouth form were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silicon Chemical Co., Ltd., Chromatorex-NH, eluent: ethyl acetate] to give a colorless oily 8- (2— (1— (2— (2,3 dihydrobenzo [b] [l, 4] dioxin-6-yl) ethyl) piperidine-4-yl) ethyl) 2-methoxyquinoline 0.16g was obtained.
1H-NMR(CDC1 ) δ値： 1.30- 1.50(2H,m),1.54- 2.06(7H,m),2.46- 2.61(2H,m),2.63- 2.8 1H-NMR (CDC1) δ value: 1.30-1.50 (2H, m), 1.54-2.06 (7H, m), 2.46-2.61 (2H, m), 2.63- 2.8
3  Three
0(2H,m),3.01(2H,d,J=11.0Hz),3.17(2H,t,J=8.1Hz),4.06(3H,s),4.23(4H,s),6.67(lH,dd ,J=7.9,2.0Hz),6.71(lH,d,J=1.8Hz),6.78(lH,d,J=8.1Hz),6.88(lH,d,J=8.8Hz),7.30(lH, t,J=7.3Hz),7.47(lH,dd,J=7.0,1.3Hz),7.56(lH,dd,J=7.9,1.5Hz),7.95(lH,d,J=8.8Hz) 0 (2H, m), 3.01 (2H, d, J = 11.0Hz), 3.17 (2H, t, J = 8.1Hz), 4.06 (3H, s), 4.23 (4H, s), 6.67 (lH, dd , J = 7.9, 2.0 Hz), 6.71 (lH, d, J = 1.8 Hz), 6.78 (lH, d, J = 8.1 Hz), 6.88 (lH, d, J = 8.8 Hz), 7.30 (lH, t , J = 7.3Hz), 7.47 (lH, dd, J = 7.0,1.3Hz), 7.56 (lH, dd, J = 7.9,1.5Hz), 7.95 (lH, d, J = 8.8Hz)
[0321] 実施例 44
Figure imgf000167_0002
[0321] Example 44
Figure imgf000167_0002
8- (2- (l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル )ピペリジンー4 ィル）ェチル）ー2—メトキシキノリン 0.14gの酢酸ェチル 3mL溶液に 、室温で 4mol/L塩ィ匕水素/酢酸ェチル 0.36mLを加え、減圧下で溶媒を留去した。得 られた残留物をジェチルエーテルに懸濁させた後、ろ取し、淡黄色固体の 8— (2- ( 1一（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピぺリジン ,¾))))入y入プ^^T 4 V6、 v I、v7 VYY; t rr rrH?ノIIII 11ノ 8- (2- (l-(2- (2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piperidine-4-yl) ethyl) -2-methoxyquinoline 0.14 g acetic acid To a 3 mL solution of ethyl, 0.36 mL of 4 mol / L sodium hydrogen chloride / ethyl acetate was added at room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in jetyl ether and collected by filtration. As a pale yellow solid, 8— (2- (1 1 (2— (2,3 dihydrobenzo [b] [l, 4 ] Dioxin 6 yl) ethyl) piperidine , ¾)))) Input y ^^ T 4 V6, v I, v7 VYY; t rr rrH?
Figure imgf000168_0001
Figure imgf000168_0001
〔0322 ォロ酢酸 lmLを加え、 2時間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢 酸ェチルおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水層を 酢酸ェチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液 で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色固体のメ チル = (1一（2—（4一（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルメチル )ァミノ）ピぺリジン一 1—ィル）ェチル） 7—メトキシイソキノリン一 4—ィル）ァセター ト 83mgを得た。 [0322 1 mL of chloroacetic acid was added and stirred for 2 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methyl yellow solid = (1 1 (2-(4 1 ((2 , 3 Dihydrobenzo [b] [l, 4] dioxin 6-ylmethyl) amino) Piperidine-1-yl) ethyl) 7-methoxyisoquinoline 4-yl) acetate 83 mg was obtained.
'H-NMRCCDCl ) δ値： 1.50- 1.65(2H,m),1.92- 2.10(2H,m),2.20- 2.50(lH,m),2.53- 2.7  'H-NMRCCDCl) δ value: 1.50-1.65 (2H, m), 1.92-2.10 (2H, m), 2.20-2.50 (lH, m), 2.53-2.7
3  Three
5(2H,m),2.90-3.30(4H,m),3.45-3.63(2H,m),3.68(3H,s),3.71(2H,s),3.95(2H,s),3.97(3 H,s),4.25(4H,s),6.76-6.85(3H,m),7.39(lH,dd,J=9.2,2.6Hz),7.43(lH,d,J=2.6Hz),7.87 (lH,d,J=9.2Hz),8.21(lH,s)  5 (2H, m), 2.90-3.30 (4H, m), 3.45-3.63 (2H, m), 3.68 (3H, s), 3.71 (2H, s), 3.95 (2H, s), 3.97 (3 H , s), 4.25 (4H, s), 6.76-6.85 (3H, m), 7.39 (lH, dd, J = 9.2, 2.6Hz), 7.43 (lH, d, J = 2.6Hz), 7.87 (lH, d, J = 9.2Hz), 8.21 (lH, s)
実施例 47 Example 47
Figure imgf000169_0001
Figure imgf000169_0001
5 ブロモ 2—メトキシ一 8— (ォキシラン一 2—ィル）キノリン 0.20gの N, N ジメ チルホルムアミド 5mL溶液に、室温で tert ブチル = (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン 6 ィルメチル）（ピペリジン 4 ィル）力ルバマート 0.32gおよび過 塩素酸リチウム 98mgを加え、 90°Cで 2時間 40分間攪拌した。反応混合物を室温まで 冷却後、酢酸ェチルおよび水を加えた。有機層を分取し、水層を酢酸ェチルで抽出 した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸 マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲル力 ラムクロマトグラフィー [溶離液;クロ口ホルム:メタノール =80 : 1]で精製し、淡黄色泡 状物の tert—ブチル = (1— (2— (5 ブロモ 2—メトキシキノリン一 8—ィル） 2— ヒドロキシェチル）ピぺリジンー4 ィル）（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルメチル）力ルバマート 0.30gを得た。  5 Bromo 2-methoxy-1-8- (oxylan-1-yl) quinoline 0.20 g of N, N dimethylformamide in 5 mL solution at room temperature with tert butyl = (2, 3 dihydrobenzo [b] [1, 4 ] 0.32 g of dioxin 6-ylmethyl) (piperidine 4-yl) strength rubamate and 98 mg of lithium perchlorate were added, and the mixture was stirred at 90 ° C for 2 hours and 40 minutes. After cooling the reaction mixture to room temperature, ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; black form: methanol = 80: 1], and tert-butyl = (1— (2— (5 bromo 2— Methoxyquinoline 1-yl) 2-hydroxyethyl) piperidine-4-yl) (2,3 dihydrobenz [b] [l, 4] dioxin 6-ylmethyl) force rubamate 0.30 g was obtained.
'H-NMRCCDCl ) δ fg: 1.43(9H,s),1.55-1.84(4H,m),2.04-2.20(lH,m),2.22-2.35(lH,  'H-NMRCCDCl) δ fg: 1.43 (9H, s), 1.55-1.84 (4H, m), 2.04-2.20 (lH, m), 2.22-2.35 (lH,
3  Three
m),2.38(lH,dd,J=12.3, 10.3Hz),2.79-2.87(lH,m),2.93(lH,dd,J=12.3,2.9Hz),3.28-3.3 •6=f'P'HT)ZS"8'(zHS"9T=rP'HT "8'(zHZ"Z=rP'HT)98"Z'(ZHZ"Z=rP'HT)Z9"Z'(ZHS"6 =1"'Ρ'Ηΐ)86·9'(ω'Ηε)ΐ8·9— 69·9'(ζΗε·9ΐ=ί"'Ρ'Ηΐ)ΐ3·9'(ζΗ6 ' rOI=f'PP'HI)SrS'(zHI •Z=f'b'HS)OS' (S'H )SS ' (ω'Ηε) Γ OS ' (s'HS)00' (ω'Ηΐ)6ε·ε— 8S'S'(ZH6 ^ ΐ=ΓΡΡ'Ηΐ)36·2'(ω'Ηΐ) 8·2-6 ·2'(ζΗΐ ΐ^·2ΐ=ΓΡΡ'Ηΐ)0^·2'(ω'Ηΐ)5ε·2-22·2'(υι'Η
Figure imgf000170_0001
m), 2.38 (lH, dd, J = 12.3, 10.3Hz), 2.79-2.87 (lH, m), 2.93 (lH, dd, J = 12.3,2.9Hz), 3.28-3.3 • 6 = f'P'HT) ZS "8 '( z HS" 9T = rP'HT "8' ( z HZ" Z = rP'HT) 98 "Z '(ZHZ" Z = rP'HT) Z9 " Z '(ZHS "6 = 1"'Ρ'Ηΐ) 86 · 9 '(ω'Ηε) ΐ8 · 9— 69 · 9' ( ζ Ηε · 9ΐ = ί "'Ρ'Ηΐ) ΐ3 · 9' ( ζ Η6 'rOI = f'PP'HI) SrS' (zHI • Z = f'b'HS) OS '( S ' H) SS '(ω'Ηε) Γ OS' ( s ' HS) 00 '(ω' Ηΐ) 6ε · ε— 8S'S '( Z H6 ^ ΐ = ΓΡΡ'Ηΐ) 36.2'(ω'Ηΐ) 8-2-6 2 '(ζΗΐ ΐ ^ · 2ΐ = ΓΡΡ'Ηΐ) 0 ^ · 2 '(ω'Ηΐ) 5ε ・ 2-222 ・ 2'(υι'Η
Figure imgf000170_0001
。 ^ΐ·(Η— έίί^ (
Figure imgf000170_0002
、つ攝慰、 [τ:ζ= ェ. ^ ΐ · (Η— έίί ^ (
Figure imgf000170_0002
, 攝 攝, [τ: ζ =
χαοοππ、 /、f 、平囂]— 4ム マ / f 、 χαοοππ, /, f, flat]] — 4 mmma / f,
^m - ^ 。 >n辛爵 瀚缀 止 ϊί教 ^^m^ ^^^m ^ 、つ
Figure imgf000170_0003
( /-^Δ /^-Ζ) fw、 T?iSi¾ do ^ ^ ^^ m WM
Figure imgf000170_0004
翻 ε、 つ。 οοι〜ο6、止^蹈 峯暴、"¾^ί^¾ΐ·ο、 ^ΰ :マ ¾べ ^ : 4 ^ if-Q (π) ^^^
Figure imgf000170_0005
、 S'0マ fi
Figure imgf000170_0006
- N 'Νθ)3οε·(Η—ム （ ^ / ^ m-^. > n 爵 爵 ϊ ϊ 教 ί 教 ^^ m ^ ^^^ m ^
Figure imgf000170_0003
(/-^ Δ / ^-Ζ) fw, T? I Si ¾ do ^ ^ ^^ m WM
Figure imgf000170_0004
Ε. οοι〜ο6, 蹈 ^ 蹈 峯 rio, “¾ ^ ί ^ ¾ΐ · ο, ^ ΰ: Ma ¾ total ^: 4 ^ if-Q (π) ^^^
Figure imgf000170_0005
, S'0 ma fi
Figure imgf000170_0006
-N 'Νθ) 3οε · (Η—
Figure imgf000170_0007
Figure imgf000170_0007
(ΖΗΐ·6=ΓΡ'Ηΐ)9ε·8'(ζΗ6·Ζ=ί"'Ρ'Ηΐ)0ΓΖ'(ΖΗ6·Ζ=ί"'Ρ'Ηΐ ) 9·Ζ'(ζΗΓ6=ί"'Ρ'Ηΐ)Ζ6·9'(ζΗε·8=ί"'Ρ'Ηΐ)08·9'(δ'Ηΐ)9Γ9'(ω'Ηΐ) Ζ·9— 9·9'(ΖΗ6 'ε ·0ΐ=ΓΡΡ'Ηΐ)Ζ9·3'(ω'Ηε)9ε· 8S (S'H )SS (ω'Ηΐ)9ε· —^· (s'HS)00' (ω'Ηΐ)8 (ΖΗΐ · 6 = ΓΡ'Ηΐ) 9ε · 8 '( ζ Η6 · Ζ = ί "'Ρ'Ηΐ) 0ΓΖ '(ΖΗ6 · Ζ = ί"'Ρ'Ηΐ) 9 · Ζ '( ζ ΗΓ6 = ί "'Ρ'Ηΐ) Ζ6 · 9' ( ζ Ηε · 8 = ί "'Ρ'Ηΐ) 08 · 9' ( δ 'Ηΐ) 9Γ9'(ω'Ηΐ) Ζ · 9— 9 · 9 '( Ζ Η6' ε · 0ΐ = ΓΡΡ'Ηΐ) Ζ9 · 3 '(ω'Ηε) 9ε · 8S ( S ' H) SS (ω'Ηΐ) 9ε · — ^ · ( s 'HS) 00'(ω'Ηΐ) 8
98S6T0/S00Zdf/X3d 891· 3Hz) 98S6T0 / S00Zdf / X3d 891 (3Hz)
実施例 49 Example 49
Figure imgf000171_0001
Figure imgf000171_0001
ェチル = (E) - 3- (8— (2- (4— ( (tert ブトキシカルボ-ル）（2, 3 ジヒドロ ベンゾ [b] [1, 4]ジォキシン 6 ィルメチル）ァミノ）ピぺリジン 1ーィル） 1ーヒ ドロキシェチル） 2—メトキシキノリン一 5—ィル）アタリラート 0.14gの塩化メチレン 2m L溶液に、氷冷下、トリフルォロ酢酸 lmLを滴下し、同温度で 40分間攪拌した。減圧 下で溶媒を留去し、酢酸ェチルおよび水をカ卩え、 1.0mol/L水酸ィ匕ナトリウム水溶液で pHllに調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マ グネシゥムで乾燥させ、減圧下で溶媒を留去し、黄色泡状物のェチル = (E)— 3—（ 8—（2—（4ー（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルメチル）ァミノ） ピぺリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）アタリ ラート 0.1 lgを得た。  Ethyl = (E)-3- (8— (2- (4— ((tert-butoxycarbol) (2, 3 dihydrobenzo [b] [1, 4] dioxin 6 ylmethyl) amino) piperidine 1 yl 1) Hydroxetyl) 2-Methoxyquinoline 1-5-yl) Atalylate 1 mL of trifluoroacetic acid was added dropwise to 2 mL of 0.14 g of methylene chloride under ice-cooling, and the mixture was stirred at the same temperature for 40 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added and adjusted to pHll with 1.0 mol / L sodium hydroxide aqueous solution. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the yellow foam ethyl = (E) — 3— (8— (2 — (4-((2, 3 dihydrobenz [b] [l, 4] dioxin 6-ylmethyl) amino) piperidine 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 5- Le) Atarilate 0.1 lg was obtained.
'H-NMRCCDCl ) δ値： 1.37(3H,t,J=7.1Hz),1.44- 1.60(3H,m),1.86- 2.00(2H,m),2.10- 2  'H-NMRCCDCl) δ value: 1.37 (3H, t, J = 7.1Hz), 1.44-1.60 (3H, m), 1.86-2.00 (2H, m), 2.10-2
3  Three
.30(lH,m),2.32-2.64(2H,m),2.78-2.90(lH,m),2.98-3.07(lH,m),3.24-3.33(lH,m),3.7 .30 (lH, m), 2.32-2.64 (2H, m), 2.78-2.90 (lH, m), 2.98-3.07 (lH, m), 3.24-3.33 (lH, m), 3.7
2(2H,s),4.03(3H,s),4.25(4H,s),4.30(2H,q,J=7.1Hz),5.75-5.82(lH,m),6.52(lH,d,J=15.2 (2H, s), 4.03 (3H, s), 4.25 (4H, s), 4.30 (2H, q, J = 7.1Hz), 5.75-5.82 (lH, m), 6.52 (lH, d, J = 15.
7Hz),6.74-6.86(3H,m),6.98(lH,d,J=9.3Hz),7.69(lH,d,J=7.7Hz),7.90(lH,d,J=7.7Hz),7Hz), 6.74-6.86 (3H, m), 6.98 (lH, d, J = 9.3Hz), 7.69 (lH, d, J = 7.7Hz), 7.90 (lH, d, J = 7.7Hz),
8.35(lH,d,J=15.7Hz),8.38(lH,d,J=9.3Hz) 8.35 (lH, d, J = 15.7Hz), 8.38 (lH, d, J = 9.3Hz)
実施例 50 Example 50
Figure imgf000171_0002
Figure imgf000171_0002
ェチル= ）ー3—（8—（2—（4ー（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルメチル）ァミノ）ピぺリジン— 1—ィル）—1—ヒドロキシェチル）—2—メトキシキ ノリンー 5 ィル）アタリラート 50mgの 90%エタノール水 2mL溶液に、氷冷下、 20%水 =ΓνΗ¾^·ε'(ω'Ηΐ)82·ε-^Γε'(ζΗ0·ε'ε·2ΐ=Γ'ΡΡΉΐ)68·2'(ω'Ηΐ)28·2-ε ·2'(ζΗ6· = ΓνΗ2)ΐ9·2'(ω'Ηΐ)½·2-^·2'(ζΗ6·6'ε·2ΐ=Γ'ΡΡΉΐ)0^·2'(ω'Ηΐ)ΐε·2-ε2·2'(υιΉΐ)2Γ
Figure imgf000172_0001
Ethyl =) −3− (8− (2− (4 − ((2, 3 dihydrobenz [b] [l, 4] dioxin 6-ylmethyl) amino) piperidine-1-yl) -1 -Hydroxyethyl) -2-methoxyquinoline-5yl) Atalylate 50mg of 90% ethanol in 2mL solution under ice-cooling, 20% water = ΓνΗ¾ ^ · ε '(ω'Ηΐ) 82 · ε- ^ Γε' ( ζ Η0 · ε'ε · 2ΐ = Γ'ΡΡΉΐ) 68 · 2 '(ω'Ηΐ) 28 · 2-ε · 2' ( ζΗ6 · = ΓνΗ2) ΐ9 · 2 '(ω'Ηΐ) ½ · 2- ^ · 2' (ζΗ6 · 6'ε · 2ΐ = Γ'ΡΡΉΐ) 0 ^ · 2 '(ω'Ηΐ) ΐε · 2-ε2 2 '(υιΉΐ) 2Γ
Figure imgf000172_0001
。 ¾¾Sra0 w— ( / S—べ fi ,^Ρ ^Ε ー ί^ Ί][¾ ^>-^^-ε 'ζ))→) -ζ) -8) -£= ^^α>^ ^Μ、つ 辛爵 瀚缀 止 ϊί教 ^^m^ ^^^m ^ ^ ^mm^ ^c^
Figure imgf000172_0002
. ¾¾Sra 0 w— (/ S—be fi, ^ Ρ ^ Ε ー ί ^ Ί] [¾ ^>-^^-ε 'ζ)) →) -ζ) -8)-£ = ^^ α> ^ ^教, 瀚 缀 教 ϊ ϊ ϊί 教 ί ^^ m ^ ^^^ m ^ ^ ^ mm ^ ^ c ^
Figure imgf000172_0002
^^n ^-^ ^。 ·η#¾^翻 8、 ao9〜ss、止^蹈 峯氺 ^n Smz ΐ峯^ マ
Figure imgf000172_0003
^^ n ^-^ ^. · Η # ¾ ^ Translation 8, ao9〜ss, stop ^ 蹈 峯 氺 ^ n Sm z ΐ 峯 ^
Figure imgf000172_0003
—ベ/ —Be /
Figure imgf000172_0004
Figure imgf000172_0004
IS圏第 (ΖΗ0·6= IS-zone number (ΖΗ0 ・ 6 =
ΓΡΉΐ)ε3·8'(ζΗ3·3ΐ=Γ'ΡΉΐ)8Γ8'(ω'Η2)58· -08· '(ΖΗ0·6=ΓΡΉΐ)80· '(ωΉε)58·9-
Figure imgf000172_0005
ΓΡΉΐ) ε3 ・ 8 '( ζ Η3 ・ 3ΐ = Γ'ΡΉΐ) 8Γ8'(ω'Η2) 58 ・ -08 ・ '(ΖΗ0 ・ 6 = ΓΡΉΐ) 80 ・' (ωΉε) 58 ・ 9-
Figure imgf000172_0005
ε'(ω'Ηΐ)9ΐ·ε— 80·ε'(ω'Ηΐ)Ζ6 — '(ΖΗ9 ' S ΐ=ί"'ΡΡ'Ηΐ)99 '(ZH(T6'S I=f'PP'HSε '(ω'Ηΐ) 9ΐ · ε— 80 · ε'(ω'Ηΐ) Ζ6 — '( Ζ Η9' S ΐ = ί "'ΡΡ'Ηΐ) 99' ( Z H (T6'S I = f'PP ' HS
)0， ' C"'HS)OS — ε0 '(ω )88·ΐ— εζ·ΐ'(ω )0 ·ΐ— OS'I :軍 9 (9P— OS ) 顺— Ητ ) 0, 'C "' HS) OS — ε0 '(ω) 88 · ΐ— εζ · ΐ' (ω) 0 · ΐ— OS'I: Army 9 ( 9 P— OS) 顺 — Η τ
。 ¾¾Sui^邈 . ¾¾Sui ^ 邈
( ^ （ ^ / 9一べ^^ 、 [
Figure imgf000172_0006
'Ζ))→)-Ζ)-(^ (^ / 9 all ^^, [
Figure imgf000172_0006
' Ζ )) → ) -Ζ )-
)— ε— ^m^u^ ^ ^ m my 濯^ ^n ^ 辛爵 ¾瀚缀、 止 s教。 ¾^ 0 翻 π揮 ^w ^^m ^^^m ) — Ε— ^ m ^ u ^ ^ ^ m my Rin ^^ n ^ ¾ ^ 0 translation π vol ^ w ^^ m ^^^ m
98S6T0/S00Zdf/X3d Oil .9Hz),3.64(2H,s),3.95(3H,s),4.06(2H,q,J=7.2Hz),4.17(4H,s),5.66(lH,dd,J=9.9,2.8Hz ),6.68-6.80(3H,m),6.86(lH,d,J=9.1Hz),7.18(lH,d,J=7.7Hz),7.69(lH,d,J=7.7Hz),8.14 (lH,d,J=9.1Hz) 98S6T0 / S00Zdf / X3d Oil .9Hz), 3.64 (2H, s), 3.95 (3H, s), 4.06 (2H, q, J = 7.2Hz), 4.17 (4H, s), 5.66 (lH, dd, J = 9.9, 2.8Hz) , 6.68-6.80 (3H, m), 6.86 (lH, d, J = 9.1Hz), 7.18 (lH, d, J = 7.7Hz), 7.69 (lH, d, J = 7.7Hz), 8.14 (lH, d, J = 9.1Hz)
[0329] 実施例 52 [0329] Example 52
Figure imgf000173_0001
Figure imgf000173_0001
ェチル = 3— (8— (2— (4— ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6—ィ ルメチル）ァミノ）ピぺリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン 5 ィル）プロピオナート 35mgの 90%エタノール水 2mL溶液に、氷冷下、 20%水酸 化ナトリウム水溶液 54 Lを加え、室温で 1時間攪拌した。減圧下で溶媒を留去し、水 を加え、炭酸ガスを導入した。減圧下で溶媒を留去し、得られた残留物を逆相シリカ ゲルカラムクロマトグラフィー [溶離液；ァセトニトリル：水 = 3： 7]で精製し、白色固体 の3—（8—（2—（4ー（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルメチル )ァミノ）ピぺリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィ ル)プロピオン酸 23mgを得た。  Ethyl = 3— (8— (2— (4— ((2, 3 Dihydrobenzo [b] [l, 4] dioxin-6-ylmethyl) amino) piperidine 1-yl) 1-hydroxy Ethyl) 2-methoxyquinoline 5yl) propionate To a 2 mL solution of 35 mg of 90% aqueous ethanol, 54 L of 20% aqueous sodium hydroxide was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reversed-phase silica gel column chromatography [eluent: acetonitrile: water = 3: 7] to give a white solid 3- (8- (2- ( 4-((2,3 dihydrobenz [b] [l, 4] dioxin 6-ylmethyl) amino) piperidine 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 1-yl ) 23 mg of propionic acid was obtained.
'H-NMRCDMSO-d ) δ値： 1.20— 1.36(2H,m),1.72— 1.84(2H,m),2.00— 2.40(6H,m),2.60—  'H-NMRCDMSO-d) δ value: 1.20— 1.36 (2H, m), 1.72—1.84 (2H, m), 2.00—2.40 (6H, m), 2.60—
6  6
2.70(lH,m),2.81-2.90(lH,m),3.06-3.20(3H,m),3.58(2H,s),3.96(3H,s),4.20(4H,s),5.7 l-5.79(lH,m),6.72-6.86(3H,m),6.99(lH,d,J=9.1Hz),7.25(lH,d,J=7.3Hz),7.66(lH,d,J =7.3Hz),8.38(lH,d,J=9.1Hz)  2.70 (lH, m), 2.81-2.90 (lH, m), 3.06-3.20 (3H, m), 3.58 (2H, s), 3.96 (3H, s), 4.20 (4H, s), 5.7 l-5.79 (lH, m), 6.72-6.86 (3H, m), 6.99 (lH, d, J = 9.1Hz), 7.25 (lH, d, J = 7.3Hz), 7.66 (lH, d, J = 7.3Hz) , 8.38 (lH, d, J = 9.1Hz)
[0330] 実施例 53 [0330] Example 53
Figure imgf000173_0002
Figure imgf000173_0002
5 ブロモ 2—メトキシ一 8— (ォキシラン一 2—ィル）キノリン 0.13gの N, N ジメ チルホルムアミド 2.5mL溶液に、室温で 1一（2—（2, 3 ジヒドロべンゾ [b] [1, 4]ジ ォキシン— 6—ィル）ェチル）ピぺラジン O.llgの N, N ジメチルホルムアミド 2.5mL溶 液および過塩素酸リチウム 47mgを加え、 90〜100°Cで 10時間攪拌した。反応混合物 を室温まで冷却後、酢酸ェチルおよび水を加えた。有機層を分取し、飽和塩ィ匕ナトリ ゥム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。 得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノー ル = 100 : 1]で精製し、橙色油状物の 1— (5—ブロモ—2—メトキシキノリン— 8—ィ ル）ー2—（4 (2- (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル） ピぺラジン 1 ィル）エタノール 93mgを得た。 5 Bromo 2-methoxy-1-8- (oxylan-1-yl) quinoline In a solution of 0.13 g of N, N-dimethylformamide in 2.5 mL of 1- (2- (2,3-dihydrobenzo [b] [b] [ 1,4] Dioxin-6-yl) ethyl) piperazine O.llg N, N dimethylformamide 2.5mL The solution and 47 mg of lithium perchlorate were added and stirred at 90-100 ° C for 10 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 100: 1], and 1- (5-bromo-2-methoxyquinoline-8-yl) as an orange oil. -2- (4 (2- (2,3 dihydrobenz [b] [1,4] dioxin 6 yl) ethyl) piperazine 1 yl) ethanol 93 mg was obtained.
'H-NMRCCDCl ) δ値： 2.44- 2.75(9H,m),3.03(lH,dd,J=12.4,3.1Hz),3.40(2H,t,J=5.1H  'H-NMRCCDCl) δ value: 2.44- 2.75 (9H, m), 3.03 (lH, dd, J = 12.4,3.1Hz), 3.40 (2H, t, J = 5.1H
3  Three
z),3.58(2H,t,J=5.1Hz),4.04(3H,s),4.24(4H,s),5.74(lH,dd,J=10.2,3.1Hz),6.63-6.80(3 H,m),6.98(lH,d,J=9.0Hz),7.66(lH,d,J=7.8Hz),7.74(lH,d,J=7.8Hz),8.37(lH,d,J=9.0H z) z), 3.58 (2H, t, J = 5.1Hz), 4.04 (3H, s), 4.24 (4H, s), 5.74 (lH, dd, J = 10.2, 3.1Hz), 6.63-6.80 (3 H, m), 6.98 (lH, d, J = 9.0 Hz), 7.66 (lH, d, J = 7.8 Hz), 7.74 (lH, d, J = 7.8 Hz), 8.37 (lH, d, J = 9.0 Hz) )
実施例 54 Example 54
Figure imgf000174_0001
Figure imgf000174_0001
1— (5 ブロモ 2—メトキシキノリン一 8—ィル） 2— (4— (2- (2, 3 ジヒドロ ベンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル）ピぺラジン 1 ィル）エタノール 82 mgの N, N—ジメチルホルムアミド 2mL溶液に、酢酸カリウム 76mg、アクリル酸ェチル 2 5 ;z L、トリス（2 メチルフエ-ル）ホスフィン 4.7mg、酢酸パラジウム（11) 3.5mgおよびテ トラブチルアンモ-ゥムブロミド 50mgをカ卩え、窒素雰囲気下、 90〜95°Cで 2時間 10分 間攪拌した。酢酸パラジウム（II) 7.0mg、トリス（2—メチルフエ-ル)ホスフィン 9.4mgお よびアクリル酸ェチル 50 Lを分割してカ卩え、 95°Cで 9時間 30分間攪拌した。ビス（トリ — tert—ブチルホスフィン)パラジウム（0) 4mgを加え、同温で 40分間攪拌した。反応 混合物を室温まで冷却後、減圧下で溶媒を留去した。得られた残留物をシリカゲル カラムクロマトグラフィー [富士シリシァ、 FL100DX、溶離液;クロ口ホルム]で精製し、 褐色泡状物のェチル = (E) 3—（8—（2—（4一（2— (2, 3 ジヒドロべンゾ [b] [1 , 4]ジォキシン 6 ィル）ェチル）ピぺラジン 1—ィル） 1 ヒドロキシェチル）
Figure imgf000175_0001
1— (5 Bromo 2-methoxyquinoline 1-8-yl) 2— (4-— (2- (2, 3 dihydrobenzo [b] [1, 4] dioxin 6 yl) ethyl) piperazine 1 yl ) Ethanol 82 mg N, N-dimethylformamide in 2 mL solution, potassium acetate 76 mg, ethyl acrylate 25; z L, tris (2 methylphenol) phosphine 4.7 mg, palladium acetate (11) 3.5 mg and tetrabutyl Ammonium bromide (50 mg) was added, and the mixture was stirred at 90 to 95 ° C for 2 hours and 10 minutes under a nitrogen atmosphere. Palladium (II) acetate (7.0 mg), tris (2-methylphenol) phosphine (9.4 mg), and ethyl acrylate (50 L) were divided and stirred, and the mixture was stirred at 95 ° C for 9 hours and 30 minutes. 4 mg of bis (tri-tert-butylphosphine) palladium (0) was added and stirred at the same temperature for 40 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia, FL100DX, eluent: black mouth form], and ethyl brown foam = (E) 3— (8— (2— (4 1 (2 — (2, 3 dihydrobenzo [b] [1, 4] dioxin 6 yl) ethyl) piperazine 1-yl) 1 hydroxyethyl)
Figure imgf000175_0001
99\ Μ [εεεο] 99 \ Μ [εεεο]
(ΖΗε·6=ί"'Ρ'Ηΐ)6 ·8'(ζΗ9·3ΐ=ί"'Ρ'Ηΐ)90·8'(ζΗΖ·Ζ=ί"'Ρ'Ηΐ)6ΓΖ'(ΖΗΖ (ΖΗε · 6 = ί "'Ρ'Ηΐ) 6 8' ( ζ Η9 · 3ΐ = ί"'Ρ'Ηΐ) 90 · 8' ( ζ ΗΖ · Ζ = ί "'Ρ'Ηΐ) 6ΓΖ' (ΖΗΖ
·Ζ=ί"'Ρ'Ηΐ)99·Ζ'(ζΗε·6=ί"'Ρ'Ηΐ)96·9'(ω'Ηε)0Γ9— 8S'9'(zH9'SI=f'P'HI)SS'9'(ra'HI)00 •9— I6'S'(s'H ) SI (s'HS)IO' (s'H 0S'S'(ra'HSI)98 — 9 ： 3} 9 (QO^QDWH-H^ 。 邈 fi （ — S—ベ ίί,^Ρ ^ ー ( ^^^ ^-Ι - y-i-
Figure imgf000175_0002
）— s)— · Ζ = ί "'Ρ'Ηΐ) 99 · Ζ' ( ζ Ηε · 6 = ί"'Ρ'Ηΐ) 96 · 9'(ω'Ηε) 0Γ9— 8S'9 '( z H9'SI = f'P'HI)SS'9'(ra'HI) 00 • 9- I6'S'(s'H) SI (s'HS) IO '(s' H 0S'S'(ra'HSI) 98 - 9: 3} 9 (QO ^ QDWH-H ^. 邈 fi (— S—Be ίί, ^ Ρ ^ ー (^^^ ^ -Ι-yi-
Figure imgf000175_0002
) — S ) —
) -z) -8) -ε- a) m^M、つ攝慰 \ ·ι=^·Λ ( -Λ^ -· m ^\―
Figure imgf000175_0003
呦爵 ) -z) -8) -ε- a) m ^ M, \\ ι = ^ · Λ (-Λ ^-· m ^ \ ―
Figure imgf000175_0003
Marquis
¾ 、π辛爵 瀚缀 止 s教 呦
Figure imgf000175_0004
¾, pi
Figure imgf000175_0004
¾瀚缀、 止 s教。
Figure imgf000175_0005
¾ 瀚 缀, Stop sect.
Figure imgf000175_0005
^%0Z、止^^、^继缀 Τ¾氺 一 ^ェ0/ o06O)Su¾S4— έίί^ （ S べ ίί, ^% 0Z, stop ^^, ^继缀Τ¾氺one ^ E 0 / o 06O) Su¾S4- έίί ^ (S base ίί,
'χ] [q] 、 Εΐ、 ¾^—ε 'ζ) -ζ)→) -ζ) -8)— ε— (Ή) = ^エ 'χ] [q], Εΐ, ¾ ^ —ε' ζ) -ζ) →) -ζ) -8) — ε— (Ή) = ^
Figure imgf000175_0006
Figure imgf000175_0006
Ηΐ·6=ί"'Ρ'Ηΐ)6ε·8'(ζΗΖ·3ΐ=ί"'Ρ'Ηΐ)3ε·8'(ζΗΖ·Ζ=ί"'Ρ'Ηΐ)68·Ζ'(ζΗΖ·Ζ=ί"'Ρ'Ηΐ)69·Ζ'(ζΗ ΐ·6=ί"'Ρ'Ηΐ)66·9'(ω'Ηε)08·9— 9'9'(zHZ'SI=f'P'HI)SS'9'(zH8 ' 0·0ΐ=ί"'ΡΡ'Ηΐ)08·3'(
Figure imgf000175_0007
6 · 6 = ί "'Ρ'Ηΐ) 6ε · 8' ( ζ ΗΖ · 3ΐ = ί"'Ρ'Ηΐ) 3ε · 8' ( ζ ΗΖ · Ζ = ί "'Ρ'Ηΐ) 68 · Ζ' ( ζ ΗΖ · Ζ = ί "'Ρ'Ηΐ) 69 · Ζ' ( ζ Η ΐ · 6 = ί"'Ρ'Ηΐ) 66 · 9'(ω'Ηε) 08 · 9— 9'9 '( z HZ 'SI = f'P'HI) SS'9' ( z H8 '0 · 0ΐ = ί "'ΡΡ'Ηΐ) 08 · 3 '(
Figure imgf000175_0007
H8 ' S ΐ=ΓΡΡ'Ηΐ)90·ε'(ω'Η6)8Ζ -^ '(ζΗΟ·Ζ=Π'Ηε ε·ΐ :軍 9 (OQDWH-H^ H8 'S ΐ = ΓΡΡ'Ηΐ) 90 ・ ε'(ω'Η6) 8Ζ-^ '( ζ ΗΟ ・ Ζ = Π'Ηε ε ・ ΐ: Military 9 (OQDWH-H ^
98S6T0/S00Zdf/X3d mL溶液に、室温で tert ブチル = (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシンー6 ィルメチル）（ピペリジン 4 ィル）力ルバマート 0.24gの塩化メチレン lmL溶液およ び酢酸 31 Lを加え、同温度で 1時間攪拌した。氷冷下、トリァセトキシ水素化ホウ素 ナトリウム O.llgを分割添加し、室温で 1時間攪拌し、一晩放置した。反応混合物に水 および酢酸ェチルを加えた。有機層を分取し、飽和塩ィ匕ナトリウム水溶液で洗浄し、 無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリ 力ゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 30： 1]で精製し、 白色泡状物の tert ブチル = (1 - (2- (5 ブロモー 2—メトキシキノリンー8—ィル )ェチル）ピぺリジンー4 ィル）（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6—ィ ルメチル）力ルバマート 0.24gを得た。 98S6T0 / S00Zdf / X3d In room temperature, add tert butyl = (2, 3 dihydrobenz [b] [1, 4] dioxin-6 ylmethyl) (piperidine 4 yl) strength rubamate 0.24 g methylene chloride in lmL and acetic acid 31 L And stirred at the same temperature for 1 hour. Under ice cooling, sodium triacetoxyborohydride O.llg was added in portions, stirred at room temperature for 1 hour, and left overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 30: 1], and white foam tertbutyl = (1-(2- (5 bromo-2-methoxy Quinoline-8-yl) ethyl) piperidine-4-yl) (2,3 dihydrobenz [b] [l, 4] dioxin-6-methyl) rubamate 0.24 g was obtained.
'H-NMRCCDCl ) δ値： 1.22- 3.70(12H,m),4.05(3H,s),4.18- 4.27(lH,m),4.24(4H,s),4.2  'H-NMRCCDCl) δ value: 1.22- 3.70 (12H, m), 4.05 (3H, s), 4.18-4.27 (lH, m), 4.24 (4H, s), 4.2
3  Three
9-4.36(2H,m),6.69-6.80(3H,m),6.99(lH,d,J=9.0Hz),7.37-7.46(lH,m),7.57(lH,d,J=7 .9Hz),8.37(lH,d,J=9.0Hz)  9-4.36 (2H, m), 6.69-6.80 (3H, m), 6.99 (lH, d, J = 9.0Hz), 7.37-7.46 (lH, m), 7.57 (lH, d, J = 7.9Hz ), 8.37 (lH, d, J = 9.0Hz)
実施例 57 Example 57
Figure imgf000176_0001
Figure imgf000176_0001
tert—ブチル = (1— (2— (5 ブロモ—2—メトキシキノリン— 8—ィル）ェチル）ピ ペリジンー4 ィル）（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルメチル）力 ルバマート 0.12gの N, N—ジメチルホルムアミド 2mL溶液に、室温でビス（トリ— tert— ブチルホスフィン）パラジウム（0) 5mgおよびアクリル酸ェチル 32 μ Lを加え、窒素雰 囲気下、 90°Cで 1時間攪拌した。反応混合物を室温まで冷却後、水および酢酸ェチ ルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネ シゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロ マトグラフィー [富士シリシァ、 FL100DX、溶離液；へキサン：酢酸ェチル = 2 : 1]で精 製し、褐色泡状物のェチル = (E) - 3- (8- (2- (4— ( (tert ブトキシカルボ-ル ) (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルメチル）ァミノ）ピぺリジン 1 69\ Μ [9εεο]
Figure imgf000177_0001
tert-butyl = (1— (2— (5 bromo-2-methoxyquinoline-8-yl) ethyl) piperidine-4-yl) (2,3 dihydrobenzo [b] [l, 4] dioxin 6 In addition, add 2 mg of N, N-dimethylformamide solution of 0.12 g of rubamate to 5 mL of bis (tri-tert-butylphosphine) palladium (0) and 32 μL of ethyl acrylate at room temperature, and in a nitrogen atmosphere, 90 ° Stir at C for 1 hour. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia, FL100DX, eluent; hexane: ethyl acetate = 2: 1] to give a brown foam, ethyl = (E)-3- (8 -(2- (4— ((tert-butoxycarbol)) (2, 3 dihydrobenzo [b] [l, 4] dioxin 6-ylmethyl) amino) piperidine 1 69 \ Μ [9εεο]
Figure imgf000177_0001
·3ΐ=ΓΡΉΐ ·8'(ζΗ9· =ΓΡΉΐ)83· '(ΖΗ9· =ΓΡΉΐ)23· '(ΖΗ2·6=Γ'Ρ'Ηΐ)86·9'(ω'Η · 3ΐ = ΓΡΉΐ 8 '( ζ Η9 · = ΓΡΉΐ) 83 ·' (ΖΗ9 · = ΓΡΉΐ) 23 · '(ΖΗ2 · 6 = Γ'Ρ'Ηΐ) 86.9'(ω'Η
S)e8"9- "9'(zH "eT=rP'HT)6^"9'(zH2"=rb'H2)0S^'(s'H^)S2^'(s'He) 0^'(s'H2)2S) e8 "9-" 9 '( z H "eT = rP'HT) 6 ^"9' ( z H2 "= rb'H2) 0S ^ '( s ' H ^) S2 ^'(s'He) 0 ^ '( s ' H2) 2
·ε'(ω'Η2)^·ε-6ε·ε'(ω'Η2)5Γε-90·ε'(ω'Η2)88·2-9 ·2'(ω'Ηΐ)39·2-ε3·2'(ω'Η2)9ε· 2- 8rs'C"'H S0 - ε6·ΐ'(ω'Η 63·ΐ- Ζ ·ΐ'(ζΗ^Ζ=Π'Ηε ε·ΐ :軍 9 (OQDWH-H^  · Ε '(ω'Η2) ^ · ε-6ε · ε' (ω'Η2) 5Γε-90 · ε '(ω'Η2) 88.2-9 · 2' (ω'Ηΐ) 39 · 2-ε3 2 '(ω'Η2) 9ε2-8rs'C "' H S0-ε6 · ΐ '(ω'Η 63 · ΐ- Ζ · ΐ' (ζΗ ^ Ζ = Π'Ηε ε (OQDWH-H ^
。 SuiOW—
Figure imgf000177_0002
- ( / ェ（ / — I—ベ ζ) 8)— ε— (a) =^^a) ^ ^ 、つ辛爵 瀚缀 止 ϊί教 '^^m^ . SuiOW—
Figure imgf000177_0002
-(/ É (/ — I—Be ζ) 8) — ε— (a) = ^^ a) ^ ^, 辛 爵 ϊ ϊ 教 ί 教 '^^ m ^
^•^^ ^ ^ ^m ^^^ ^m、つ 斜萆。 ·η¾ ^ • ^^ ^ ^ ^ m ^^^ ^ m. · Η¾
Figure imgf000177_0003
m¾鷇、 止
Figure imgf000177_0004
、つ止縱 0邈 、止
Figure imgf000177_0003
m¾ 鷇, stop
Figure imgf000177_0004
, Stop 0 , stop
Figure imgf000177_0005
Figure imgf000177_0005
m^ [esso] m ^ [esso]
(ζΗΐ·6= rP'HT)ZS"8'(zHZ"eT=rP'HT)SS"8'(zH9"Z=rP'HT)8S"Z'(ZH9"Z=rP'HT)Se"Z'(ZHr6=f Ρ'Ηΐ)86·9'(ω'Ηε)08·9— 89·9'(ζΗΖ·3ΐ=ί"'Ρ'Ηΐ)6 ·9'(ζΗΓΖ=Γ&'Η θε· (ω'Ηε)9ε· 9 ( ζ Ηΐ · 6 = rP'HT) ZS "8 '( z HZ" eT = rP'HT) SS "8' ( z H9" Z = rP'HT) 8S "Z '(ZH9" Z = rP'HT ) Se "Z '(ZHr6 = f Ρ'Ηΐ) 86 · 9'(ω'Ηε) 08 · 9— 89 · 9 '( ζ ΗΖ · 3ΐ = ί"'Ρ'Ηΐ) 6 9 '( ζ ΗΓΖ = Γ &'Η θε · (ω'Ηε) 9ε
(s'H )W (S'HS)SO' (ω'Η )93·ε— οΐ·ε'(ω'Η οο·ε— WS'WHS) — OS ' (ω'Η( s 'H) W (S'HS) SO'(ω'Η) 93 · ε— οΐ · ε '(ω'Η οο · ε— WS'WHS) — OS'(ω'Η
90 - 8·ΐ'(ω'Η 8Ζ·ΐ- 9·ΐ'(δ'Η6)ε ·ΐ'(ζΗΓΖ=Π'Ηε)9ε·ΐ :軍 9 (OQDWH-H^ 90-8 · ΐ '(ω'Η 8Ζ · ΐ- 9 · ΐ' ( δ 'Η6) εΐΐ ( ζ ΗΓΖ = Π'Ηε) 9ε · ΐ: Army 9 (OQDWH-H ^
°-M^SmLH-^ . ( ^-9- ίι/^^-Ζ- ( ^エ ( - ° -M ^ Sm LH- ^. (^ -9- ίι / ^^-Ζ- (^ d (-
98S6T0/S00Zdf/X3d 9LV
Figure imgf000178_0001
98S6T0 / S00Zdf / X3d 9LV
Figure imgf000178_0001
ェチル = (E)— 3— (8— (2— (4— ( (2, 3 ジヒドロ一 1, 4 ベンゾジォキシン一 6 —ィルメチル）ァミノ）ピぺリジン— 1—ィル）ェチル） 2—メトキシキノリン— 5 ィル） アタリラート 40mgの 90%エタノール水 2mL溶液に、氷冷下、 20%水酸化ナトリウム水 溶液 63 Lを加え、水冷〜室温で 2時間攪拌した。 20%水酸ィ匕ナトリウム水溶液 31 μ Lを加え、室温で 30分間攪拌した。減圧下で溶媒を留去し、水を加え、炭酸ガスを導 入した。固形物をろ取し、淡黄色固体の (Ε) - 3- (8- (2- (4- ( (2, 3 ジヒドロ - 1, 4 ンゾジォキシンー6 ィルメチル）ァミノ）ピぺリジンー1 ィル）ェチル） 2—メトキシキノリンー5 ィル）アクリル酸 30mgを得た。  Ethyl = (E) — 3— (8— (2— (4— ((2, 3 dihydro-1,4 benzodioxin 6 —ylmethyl) amino) piperidine—1-yl) ethyl) 2-methoxyquinoline — 5 yl) To 2 ml of 90% ethanol solution of 40 mg of attalylate was added 63 L of 20% aqueous sodium hydroxide solution under ice cooling, and the mixture was stirred for 2 hours from water cooling to room temperature. A 20% aqueous sodium hydroxide solution (31 μL) was added, and the mixture was stirred at room temperature for 30 min. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. The solid was collected by filtration to give a pale yellow solid (Ε)-3- (8- (2- (4- ((2, 3 dihydro-1,4 nzodioxin-6 ylmethyl) amino) piperidine-1 yl) ethyl ) 2-Methoxyquinoline-5yl) 30 mg of acrylic acid was obtained.
'H-NMRCDMSO-d ) δ値： 1.20— 1.33(3H,m),1.75— 1.84(2H,m),1.97— 2.07(2H,m),2.30—  'H-NMRCDMSO-d) δ value: 1.20—1.33 (3H, m), 1.75—1.84 (2H, m), 1.97—2.07 (2H, m), 2.30—
6  6
2.40(2H,m),2.58-2.69(2H,m),2.90-2.97(2H,m),3.59(2H,s),4.01(3H,s),4.20(4H,s),6.5 KlH,d,J=15.8Hz),6.74-6.84(3H,m),7.07(lH,d,J=9.2Hz),7.57(lH,d,J=7.7Hz),7.70(l H,d,J=7.7Hz),8.07(lH,d,J=15.8Hz),8.50(lH,d,J=9.2Hz)  2.40 (2H, m), 2.58-2.69 (2H, m), 2.90-2.97 (2H, m), 3.59 (2H, s), 4.01 (3H, s), 4.20 (4H, s), 6.5 KlH, d , J = 15.8Hz), 6.74-6.84 (3H, m), 7.07 (lH, d, J = 9.2Hz), 7.57 (lH, d, J = 7.7Hz), 7.70 (l H, d, J = 7.7 Hz), 8.07 (lH, d, J = 15.8Hz), 8.50 (lH, d, J = 9.2Hz)
実施例 60 Example 60
Figure imgf000178_0002
Figure imgf000178_0002
(1) 5 -ブロモ 2 メトキシ 8 (ォキシラン 2 ィル）キノリン 0.69gの N, N ジ メチルホルムアミド 9mL溶液に、室温で tert ブチル = (2, 3 ジヒドロべンゾ [b] [1 , 4]ジォキシン 6 ィルメチル）（ピペリジンー4 ィル）力ルバマート 0.94gの N, N ージメチルホルムアミド 3mL溶液および過塩素酸リチウム 0.29gを加え、 80 85°Cで 5 時間 40分間攪拌した。反応混合物を室温まで冷却後、酢酸ェチルおよび水を加えた 。有機層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わせ、 飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶 媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液;クロロホ ルム：メタノール =40 : 1]で精製し、淡黄色泡状物の tert ブチル = (1一（1一（5— ブロモ 2 メトキシキノリン 8 ィル） - 2-ヒドロキシェチル）ピぺリジン 4 ィル ) (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルメチル）力ルバマートおよび t ert—ブチル = (1— (2— (5 ブロモ 2—メトキシキノリン一 8—ィル） 2 ヒドロキ シェチル）ピぺリジン 4 ィル）（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6—ィ ルメチル）力ルバマートの混合物 l.lgを得た。 (1) 5 -Bromo 2 methoxy 8 (oxylan 2 yl) quinoline 0.69 g N, N dimethylformamide in 9 mL solution at room temperature with tert butyl = (2, 3 dihydrobenzo [b] [1, 4] Dioxin 6-ylmethyl) (piperidine-4-yl) strength rubamate 0.94 g of N, N-dimethylformamide 3 mL solution and 0.29 g of lithium perchlorate were added, and the mixture was stirred at 85 ° C. for 5 hours and 40 minutes. After cooling the reaction mixture to room temperature, ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. Combine the organic layer and the extract, The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 40: 1], and tert-butyl = (1 1 (5- (bromo-1 methoxyquinoline) 8 Yl) -2-hydroxyethyl) piperidine 4 yl) (2, 3 dihydrobenz [b] [l, 4] dioxin 6 ylmethyl) force rubamate and tert-butyl = (1— (2 — (5 Bromo-2-methoxyquinoline 1-yl) 2 Hydrochetyl) Piperidine 4 Gil) (2, 3 Dihydrobenz [b] [l, 4] dioxin-6-ylmethyl) A mixture l.lg was obtained.
(2)得られた混合物 l.Ogの N, N—ジメチルホルムアミド 12mL溶液に、ビス（トリー tert ブチルホスフィン）パラジウム（0) 41mg、アクリル酸ェチル 0.26mLおよびトリェチル ァミン 0.33mLを加え、窒素雰囲気下、 90°Cで 1時間 30分間攪拌した。反応混合物を 室温まで冷却後、酢酸ェチルおよび水を加え、減圧下で溶媒を留去した。得られた 残留物をシリカゲルカラムクロマトグラフィー [溶離液；へキサン：酢酸ェチル = 2： 1] で精製し、淡黄色泡状物のェチル = (E) - 3- (8—（2—（4— ( (tert ブトキシカル ボ -ル） (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルメチル）ァミノ）ピペリ ジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）アタリラート 0.65gおよび黄色固体のェチル = (E) - 3- (8—（1— (4— ( (tert ブトキシカルボ -ル）（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルメチル）ァミノ）ピぺリジン — 1—ィル） 2 ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）アタリラート 0.16 gを得た。  (2) The resulting mixture l.Og in 12 mL of N, N-dimethylformamide was added 41 mg of bis (tri-tert-butylphosphine) palladium (0), 0.26 mL of ethyl acrylate and 0.33 mL of triethylamine, and a nitrogen atmosphere. The mixture was stirred at 90 ° C for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 2: 1], and ethyl of pale yellow foam = (E)-3- (8— (2— (4 — ((Tert-butoxycal) (2, 3 dihydrobenz [b] [l, 4] dioxin 6-ylmethyl) amino) piperidine 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 1 5-yl) atarylate 0.65 g and yellow solid ethyl = (E)-3- (8— (1— (4— ((tert-butoxycarbol) (2,3 dihydrobenzo [b] [l , 4] dioxin 6-ylmethyl) amino) piperidine-1-yl) 2-hydroxyethyl) 2-methoxyquinoline 5-yl) attalylate 0.16 g was obtained.
ェチル = (E) - 3- (8— (2- (4— ( (tert ブトキシカルボ-ル）（2, 3 ジヒドロ ベンゾ [b] [1, 4]ジォキシン 6 ィルメチル）ァミノ）ピぺリジン 1ーィル） 1ーヒ ドロキシェチル） 2—メトキシキノリン一 5—ィル）アタリラートの 1H-NMRは、実施例 4 8のデータと一致した。  Ethyl = (E)-3- (8— (2- (4— ((tert-butoxycarbol) (2, 3 dihydrobenzo [b] [1, 4] dioxin 6 ylmethyl) amino) piperidine 1 yl 1) -Hydroxychetyl) 1-NMR of 2-methoxyquinoline 1-yl) atalylate was consistent with the data of Example 48.
ェチル = (E) 3—（8—（1— (4— ( (tert ブトキシカルボ-ル）（2, 3 ジヒドロ ベンゾ [b] [1, 4]ジォキシン 6 ィルメチル）ァミノ）ピぺリジン 1 ィル）ー2 ヒ ドロキシェチル） 2—メトキシキノリン 5 ィル）アタリラート  Ethyl = (E) 3— (8— (1— (4— ((tert-butoxycarbol) (2,3 dihydrobenzo [b] [1, 4] dioxin 6 ylmethyl) amino) piperidine 1 yl ) -2 Hydroxetyl) 2-Methoxyquinoline 5) Atalylate
'H-NMRCCDCI ) δ値： 1.30- 1.90(13H,m),1.38(3H,t,J=7.1Hz),2.00- 2.36(2H,m),2.75- 圏第'H-NMRCCDCI) δ value: 1.30-1.90 (13H, m), 1.38 (3H, t, J = 7.1Hz), 2.00-2.36 (2H, m), 2.75- No. 1
(ΖΗΓ6=ΓΡΉΐ)6ε·8'(ζΗ8·3ΐ=ΓΡΉΐ)3ε·8'(ζΗ3· =ΓΡΉΐ)ΐ9· '(ΖΗ3· =ΓΡΉΐ)ΐ 3·Ζ'(ΖΗΓ6=ί"'Ρ'Ηΐ)00·Ζ'(ζΗε·8=ί"'Ρ'Ηΐ)3Ζ·9'(ζΗ0 =f'P'HI)SZ'9'(zH0 'ε·8=ΓΡΡ'Ηΐ
Figure imgf000180_0001
(ΖΗΓ6 = ΓΡΉΐ) 6ε ・ 8 '( ζ Η8 ・ 3ΐ = ΓΡΉΐ) 3ε ・ 8' ( ζ · 3 ・ ΓΓ) ΐ9 · '(ΖΗ3 · = ΓΡΉΐ) ΐ 3 · Ζ' (ΖΗΓ6 = ί "'Ρ' Ηΐ) 00 · Ζ '( ζ Ηε8 = ί "'Ρ'Ηΐ) 3Ζ9 '( ζ = 0 = f'P'HI) SZ'9' ( z H0 'ε8 = ΓΡΡ'Ηΐ
Figure imgf000180_0001
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2-0Γ2'(ΐΐι'Ηε)00·2-28·ΐ'(ω'Η2)93·ΐ-2^·ΐ'(ζΗ2· =Γ'νΗε) ε·ΐ:ΐ!} 9 ( !DaD)H N-HT 2-0Γ2 '(ΐΐι'Ηε) 00 · 2-28 · ΐ'(ω'Η2) 93 · ΐ-2 ^ · ΐ '(ζΗ2 · = Γ'νΗε) ε · ΐ: ΐ!} 9 (! DaD ) H NH T
- 9 -
Figure imgf000180_0002
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Figure imgf000180_0002
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Figure imgf000180_0003
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Figure imgf000180_0003
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Figure imgf000180_0004
Figure imgf000180_0004
(zH2"6=rP'HT)6S"8'(zH9"9T=rP'HT)SS"8'(zH8"Z=rP'HT)09"Z'(zH8"Z=rP'HT )8 ·Ζ'(ζΗ^6=ί"'Ρ'Ηΐ)00·Ζ'(ζΗε·8=ί"'Ρ'Ηΐ)ΖΖ·9'(δ'Ηΐ)ΐΖ·9'(ζΗε·8=ί"'Ρ'Ηΐ)99·9'(ζΗ9· 9ΐ=ΓΡΉΐ)ΐ3·9'(ω'Ηΐ)5ε·5-22·5'(ΖΗΓ =Γ¾Ή2)ΐε^'(8'Η2)52^'(8'Η^·^'(ΐΐι'Ηΐ)5 ε·— ο ^ (s'Hs)w (ω'Ηΐ)ζο·— 96·ε'(ω'Ηΐ)0Γε— 83·ε'(ω'Ηΐ)9^ε— 8ΐ·ε'(ω'Η οο·ε (zH2 "6 = rP'HT) 6S" 8 '( z H9 "9T = rP'HT) SS"8' ( z H8 "Z = rP'HT) 09" Z '(zH8 "Z = rP'HT) 8 · Ζ '( ζ Η ^ 6 = ί "'Ρ'Ηΐ) 00 · Ζ '( ζ Ηε8 = ί"'Ρ'Ηΐ) ΖΖ · 9 '( δ ' Ηΐ) ΐΖ · 9 '( ζ Ηε · 8 = ί "'Ρ'Ηΐ) 99 · 9' ( ζ Η9 · 9ΐ = ΓΡΉΐ) ΐ3 · 9 '(ω'Ηΐ) 5ε · 5-22 / 5' (ΖΗΓ = Γ¾Ή2) ΐε ^ '(8' Η2) 52 ^ '(8'Η ^ · ^'(ΐΐι'Ηΐ) 5 ε · — ο ^ ( s 'Hs) w (ω'Ηΐ) ζο · — 96 · ε'(ω'Ηΐ) 0Γε— 83 · Ε '(ω'Ηΐ) 9 ^ ε— 8ΐ · ε'(ω'Η οο · ε
98S6T0/S00Zdf/X3d 8Ζ V ZSS9^0/900Z OAV
Figure imgf000181_0001
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Figure imgf000181_0002
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Figure imgf000181_0001
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Figure imgf000181_0003
4—M (/ all fi)-9-
Figure imgf000181_0003
Figure imgf000181_0004
Figure imgf000181_0004
ε9圏第 [ο εο] ε9 category [ο εο]
(ΖΗΓ6=ΓΡΉΐ)23·8'(ζΗ ·3ΐ=ΓΡΉΐ)^Γ8'(ω'Η2)0 · -39· '(ΖΗΐ (ΖΗΓ6 = ΓΡΉΐ) 23 · 8 '( ζ Η3Η = ΓΡΉΐ) ^ Γ8'(ω'Η2) 0
·6=ί"'Ρ'Ηΐ)ΐΟ·Ζ'(ω'Ηε)86·9— 08'9'(zHZ'SI=f'P'HI)ZS'9'C"'HI)0 S— IS'S'(s'H ^ · 6 = ί "'Ρ'Ηΐ) ΐΟ · Ζ'(ω'Ηε) 86 · 9— 08'9 '( z HZ'SI = f'P'HI) ZS'9'C"' HI) 0 S — IS'S '(s'H ^
(8Ήε)80^'(8Ή2)ΐ6·ε'(ω'Η2)02^-06·ε'(ω'Ηΐ)55·ε-9^·ε'(ω'Ηΐ)^·ε-^Γε'(ω'Ηΐ)06 ( 8 Ήε) 80 ^ '( 8 Ή2) ΐ6 · ε'(ω'Η2) 02 ^ -06 · ε '(ω'Ηΐ) 55 · ε-9 ^ · ε'(ω'Ηΐ) ^ · ε- ^ Γε '(ω'Ηΐ) 06
·2-8 ·2'(ω'Η2)^·2-9Γ2'(ω'Η2)^Γ2-86·ΐ'(ω'Η2)88·ΐ- 3·ΐ:ΐ!} 9 (QO aD)H N-HT · 2-8 · 2 '(ω'Η2) ^ · 2-9Γ2'(ω'Η2) ^ Γ2-86 · ΐ '(ω'Η2) 88 · ΐ-3 · ΐ: ΐ!} 9 (QO aD ) H NH T
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98S6T0/S00Zdf/X3d 61V S9圏第 98S6T0 / S00Zdf / X3d 61V S9 category
(ΖΗ ·( Ζ Η ·
6=rP'HT)02"6'(zHZ"Z=f'P'HT)2r8'(zHZ"Z=f'P'HT)26"Z'(zW6=rP'HT)T0"Z'(ra'He)9 8"9-^ -9'(zHO"SO T=rPP'HT)28"e'(s'H^)e2^'(s'He)eo^'(s'HS) 6"S'(s'H2)2 -S'(ra' Ηΐ ·ε-^·ε'(ζΗ0·ε^·2ΐ=ΓΡΡ'Ηΐ)90·ε'(ω'Ηΐ)06·2-08·2'(ω'Ηΐ)^9·2-½·2'(ω'Η2)0 S - ' (m'HI)SS - rS'C"'H SO - S8 (ra'HS)S9'I- S 'I :軍 9 (OQDWH-H^6 = rP'HT) 02 "6 '( z HZ" Z = f'P'HT) 2r8' ( z HZ "Z = f'P'HT) 26" Z '(zW6 = rP'HT) T0 "Z '(ra'He) 9 8 "9- ^ -9' ( z HO" SO T = rPP'HT) 28 "e '(s'H ^) e2 ^'(s'He) eo ^ '( s ' HS) 6 "S '( s ' H2) 2 -S '(ra' Ηΐε- ^ · ε '(ζΗ0 · ε ^ · 2ΐ = ΓΡΡ'Ηΐ) 90 · ε'(ω'Ηΐ) 06 -08 2 '(ω'Ηΐ) ^ 9 2-½ · 2'(ω'Η2) 0 S-'(m'HI) SS-rS'C "' H SO-S8 (ra'HS) S9 'I-S'I: Military 9 (OQDWH-H ^
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^ ^m ^ ^^ ^ 斜单 °:_n¾鱸 nma、 继
Figure imgf000182_0002
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Figure imgf000182_0002
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Figure imgf000182_0003
Figure imgf000182_0003
9圏第 9th area
(ΖΗε·6=ΓΡ'Ηΐ)6ΐ·6'(ζΗΓΖ=ί"'Ρ'Ηΐ)π·8'(ζΗΓΖ=ί"'Ρ'Ηΐ)68·Ζ'(ζΗε· 6=rP'HT)00" '(ra'HS)28"9-29"9'(zH8"2O T=rPP'HT)e -e'(s'H2)ie^'(s'H^)S2^'(s'(ΖΗε · 6 = ΓΡ'Ηΐ) 6ΐ · 6 '( ζ ΖΓΖ = ί "'Ρ'Ηΐ) π · 8 '( ζ ΗΓΖ = ί"'Ρ'Ηΐ) 68 · Ζ '( ζ Ηε · 6 = rP 'HT) 00 "'(ra'HS)28" 9-29 "9 '( z H8" 2O T = rPP'HT) e -e'(s'H2) ie ^ '(s'H ^) S2 ^ '(s'
Ηε)00· (S'HS) 6·ε'(ω'Ηΐ)0 ·ε— 0S'S'(ZH8 ' S ΐ=ί"'ΡΡ'Ηΐ)66 ' (ω'Ηΐ)88 — 08 ' 'Η ε - W ' (ω'Ηΐ) - 60 ' (ω'Η3)06·ΐ- 9S (s'H6) n :軍 9 (OQDWH-H^
Figure imgf000182_0004
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Figure imgf000182_0004
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Figure imgf000182_0005
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Figure imgf000182_0005
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98S6T0/S00Zdf/X3d 081·
Figure imgf000183_0001
98S6T0 / S00Zdf / X3d 081
Figure imgf000183_0001
メチル =8— (2— (4— ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルメチ ル）ァミノ）ピぺリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5— カルボキシラート llmgの 90%エタノール水 2mL溶液に、室温で 20%水酸化ナトリウム 水溶液 0.22mLを加え、室温で 2時間攪拌し、一晩放置した。減圧下で溶媒を留去し 、水を加え、炭酸ガスを導入した。固形物をろ取し、橙色固体の 8— (2- (4- ( (2, 3 ージヒドロべンゾ [b] [1, 4]ジォキシンー6 ィルメチル）ァミノ）ピぺリジン 1ーィル )—1—ヒドロキシェチル） 2—メトキシキノリン一 5—カルボン酸 3.2mgを得た。  Methyl = 8— (2— (4— ((2, 3 dihydrobenz [b] [l, 4] dioxin 6-ylmethyl) amino) piperidine 1-yl) 1-hydroxyethyl) To a 2 mL solution of 2-methoxyquinoline 1-carboxylate llmg in 90% aqueous ethanol, 0.22 mL of 20% aqueous sodium hydroxide solution was added at room temperature, stirred at room temperature for 2 hours, and left overnight. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. The solid was collected by filtration to give an orange solid 8— (2- (4- ((2, 3-dihydrobenz [b] [1, 4] dioxin-6-ylmethyl) amino) piperidine 1-yl) —1— Hydroxyethyl) 2-methoxyquinoline mono-5-carboxylic acid 3.2 mg was obtained.
'H-NMRCCD OD) δ値： 1.50— 1.80(2H,m),1.90— 2.20(2H,m),2.35— 2.60(2H,m),2.70— 3. 'H-NMRCCD OD) δ value: 1.50— 1.80 (2H, m), 1.90— 2.20 (2H, m), 2.35— 2.60 (2H, m), 2.70— 3.
3  Three
10(3H,m),3.10-3.22(lH,m),3.40-3.60(lH,m),3.87(2H,s),4.03(3H,s),4.23(4H,s),5.92- 6.04(lH,m),6.80-7.00(4H,m),7.68(lH,d,J=7.6Hz),7.78(lH,d,J=7.6Hz),8.86(lH,d,J=9 •3Hz)  10 (3H, m), 3.10-3.22 (lH, m), 3.40-3.60 (lH, m), 3.87 (2H, s), 4.03 (3H, s), 4.23 (4H, s), 5.92-6.04 ( lH, m), 6.80-7.00 (4H, m), 7.68 (lH, d, J = 7.6Hz), 7.78 (lH, d, J = 7.6Hz), 8.86 (lH, d, J = 9 • 3Hz)
実施例 66
Figure imgf000183_0002
Example 66
Figure imgf000183_0002
l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ンー 4一力ルボン酸 24mgの塩化メチレン懸濁液 2mLに、氷冷下、塩化チォ -ル 0.1m Lおよび N, N ジメチルホルムアミド 1滴を加え、 1時間 15分間加熱還流した。減圧下 で溶媒を留去し、クロ口ホルム 2mLをカ卩えた。 2, 6 ジメトキシキノリン一 8 ァミン 14 mgおよびトリェチルァミン 0.20mLを加え、室温で 2時間 10分間攪拌した。  l-(2- (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piberidin 4 4 strength rubonic acid 24 mg of methylene chloride suspension in 2 mL of ice-cold solution 0.1 mL of thiol and 1 drop of N, N dimethylformamide were added, and the mixture was heated to reflux for 1 hour and 15 minutes. The solvent was distilled off under reduced pressure, and 2 mL of black mouth form was collected. 14 mg of 2,6 dimethoxyquinoline and 14 mg of triethylamine were added, and the mixture was stirred at room temperature for 2 hours and 10 minutes.
1 - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ンー 4一力ルボン酸 60mgの塩化メチレン溶液 2mLに、氷冷下、塩化チォ -ル 0.6mL および N, N—ジメチルホルムアミド 1滴をカ卩え、 30分間加熱還流した。減圧下で溶媒 を留去した。得られた残留物、クロ口ホルム lmLおよびトリェチルァミン 0.2mLを上記 の反応混合物に加え、室温で 2日間放置した。反応混合物に水およびクロ口ホルムを 。 §ω 94— ^^^ 1-(2- (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piberidin 4 4 strength rubonic acid 60 mg of methylene chloride solution in 2 mL of ice-cooled thiochloride- 0.6 mL of N and 1 drop of N, N-dimethylformamide were added and heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure. The resulting residue, 1 mL of black mouth form and 0.2 mL of triethylamine were added to the above reaction mixture and left at room temperature for 2 days. Add water and black mouth form to the reaction mixture. . §Ω 94 — ^^^
(,^ ( /-^ /^ {Λ^→- /^(^0Ά ( ェ（ (, ^ (/-^ / ^ {Λ ^ →-/ ^ (^ 0 Ά (ｅ （
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Figure imgf000185_0001
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ΓΡ'Ηΐ)2Γ8'(ζΗε·6=ΓΡ'Ηΐ)^·Ζ'(ΖΗΓ8=ΓΡ'Ηΐ)^Ζ·9'(ζΗ6·ΐ=ΓΡ'Ηΐ)εΖ·9'(ζΗ6·ΐ'Γ8 ΓΡ'Ηΐ) 2Γ8 '( ζ Ηε · 6 = ΓΡ'Ηΐ) ^ · Ζ' (ΖΗΓ8 = ΓΡ'Ηΐ) ^ Ζ · 9 '( ζ Η6 · ΐ = ΓΡ'Ηΐ) εΖ · 9' ( ζ Η6 ΐ'Γ8
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'Ηΐ)89·9'(ζΗΖ·9=ί"'νΗ Ζε· (S'H )W (s'HS)ir (ω'Η 3ΐ·ε— S0'S'(zHZ'S'S'0I=f 'ΡΡΉ2)ε ·2'(ζΗ ·3'2 ΐ=ΓΡΡ'Η2)09·2'(ω'Ηΐ)25·2-0^·2'(ω'Η^·2-0Γ2'(ω'Η2)^0· 2- Ζ6·ΐ'(ω'Η 38·ΐ- SZ'I'(ra'H 8S'I- 3 ·ΐ'(ζΗε·Ζ=Π'Ηε)00·ΐ :軍 9 (OQDWH-H^ 'Ηΐ) 89 · 9' ( ζ ΗΖ · 9 = ί "'νΗ Ζε · ( S ' H) W ( s ' HS) ir (ω'Η 3ΐ · ε— S0'S '( z HZ'S'S'0I = f' ΡΡΉ2 ) ε 2 '(ζΗ 3'2 ΐ = ΓΡΡ'Η2) 092'(ω'Ηΐ) 25-2-0 ^ 2 '(ω'Η ^ · 2-0Γ2'(ω'Η2) ^ 0 · 2- Ζ6 · ΐ '(ω'Η 38 · ΐ- SZ'I'(ra'H8S'I-3 · ΐ '(ζΗε · Ζ = Π'Ηε) 00 · ΐ: Army 9 (OQDWH -H ^
98S6T0/S00Zdf/X3d 881- ラジウム（0) 3.1mgおよび rac— 2, 2，一ビス（ジフエ-ルホスフイノ）一 1, 1，一ビナフ タレン 6.4mgのジォキサン 1.5mL溶液を、窒素雰囲気下、 10分間超音波処理した。室 温で 2 シァノキノリン一 8—ィル =トリフルォロメタンスルホナート 51mgをカ卩え、 1時間 加熱還流した。反応混合物を室温まで冷却後、水および酢酸ェチルを加えた。有機 層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わせ、飽和塩 化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留 去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム： メタノール = 10 : 1]で精製し、淡黄色固体の N— (2—シァノキノリン一 8—ィル） 1 一（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピぺリジン 4 カルボキサミド 52mgを得た。 98S6T0 / S00Zdf / X3d 881- A solution of 3.1 mg of radium (0) and rac-2,2,1, bis (diphenylphosphino) -1,1,1, binaphthalene 6.4 mg in 1.5 mL of dioxane was sonicated for 10 minutes in a nitrogen atmosphere. At room temperature, 51 mg of 2-cyanoquinoline-1-yl = trifluoromethanesulfonate was added and heated to reflux for 1 hour. After cooling the reaction mixture to room temperature, water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent; black mouth form: methanol = 10: 1], and a pale yellow solid N— (2-cyanoquinoline 1-8-yl) 1 1 (2— ( 2,3 Dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piperidine 4 carboxamide 52 mg was obtained.
'H-NMRCCDCl ) δ値： 1.92- 2.24(6H,m),2.48- 2.65(3H,m),2.70- 2.79(2H,m),3.08- 3.1  'H-NMRCCDCl) δ value: 1.92-2.24 (6H, m), 2.48-2.65 (3H, m), 2.70-2.79 (2H, m), 3.08-3.1
3  Three
7(2H,m),4.24(4H,s),6.70(lH,dd,J=8.2,2.0Hz),6.74(lH,d,J=2.0Hz),6.79(lH,d,J=8.2H z),7.56(lH,d,J=7.2Hz),7.70(lH,t,J=7.2Hz),7.76(lH,d,J=8.5Hz),8.32(lH,d,J=8.5Hz), 8.93(lH,d,J=7.2Hz),9.61(lH,s)  7 (2H, m), 4.24 (4H, s), 6.70 (lH, dd, J = 8.2,2.0Hz), 6.74 (lH, d, J = 2.0Hz), 6.79 (lH, d, J = 8.2H z), 7.56 (lH, d, J = 7.2 Hz), 7.70 (lH, t, J = 7.2 Hz), 7.76 (lH, d, J = 8.5 Hz), 8.32 (lH, d, J = 8.5 Hz) , 8.93 (lH, d, J = 7.2Hz), 9.61 (lH, s)
実施例 70 Example 70
Figure imgf000186_0001
Figure imgf000186_0001
tert—ブチノレ = (ピペリジン 4ーィノレ） (2- (2 チェ二ノレチォ）ェチノレ）カノレバマ ート 43mgの N, N ジメチルホルムアミド 2mL溶液に、室温でェチル = (E)—3— (2 —メトキシ一 8— (ォキシラン一 2—ィル)キノリン一 5—ィル)アタリラート 38mgおよび過 塩素酸リチウム 15mgを加え、 80°Cで 3時間 30分間攪拌した。過塩素酸リチウム 5mgを 加え、同温度で 3時間攪拌した。反応混合物を室温まで冷却後、酢酸ェチルおよび 水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネ シゥムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロ マトグラフィー [溶離液;クロ口ホルム]で精製し、黄色油状物のェチル = (E)— 3— (8 一（2—（4— ( (tert ブトキシカルボ-ル）（2—（2 チェ-ルチオ）ェチル）ァミノ）ピ ペリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）ァクリラ ート 52mgを得た。 tert-Butinole = (piperidine 4-inole) (2- (2 cheninoreio) ethinore) canolebamate 43 mg of N, N dimethylformamide in 2 mL of solution at room temperature with ethyl = (E) —3— (2 —methoxy 1 8 — (Oxylan 2-yl) quinoline 5-yl) Atarylate (38 mg) and lithium perchlorate (15 mg) were added, and the mixture was stirred at 80 ° C. for 3 hours and 30 minutes. 5 mg of lithium perchlorate was added and stirred at the same temperature for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form], and the yellow oily substance ethyl = (E) — 3— (8 1 (2— (4— ((tert butoxycarbo- Le) (2- (2 Chertio) ethyl) amino) Pi Peridine 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 1-yl) acrylate 52 mg was obtained.
1H-NMR(CDC1 ) δ値： 1.30- 1.46(12H,m),1.52- 1.72(4H,m),2.09- 2.20(lH,m),2.24- 2.  1H-NMR (CDC1) δ value: 1.30-1.46 (12H, m), 1.52-1.72 (4H, m), 2.09-2.20 (lH, m), 2.24- 2.
3  Three
36(lH,m),2.42(lH,dd,J=12.3,10.0Hz),2.74-3.02(3H,m),3.18-3.40(3H,m),4.01(3H,s), 4.00-4.10(2H,m),4.31(2H,q,J=7.2Hz),5.74(lH,dd,J=10.0,2.8Hz),6.52(lH,d,J=16.3H z),6.94-7.04(2H,m),7.16-7.20(lH,m),7.35-7.40(lH,m),7.69(lH,d,J=7.6Hz),7.88(lH, d,J=7.6Hz),8.35(lH,d,J=16.3Hz),8.38(lH,d,J=9.3Hz)  36 (lH, m), 2.42 (lH, dd, J = 12.3,10.0Hz), 2.74-3.02 (3H, m), 3.18-3.40 (3H, m), 4.01 (3H, s), 4.00-4.10 ( 2H, m), 4.31 (2H, q, J = 7.2Hz), 5.74 (lH, dd, J = 10.0,2.8Hz), 6.52 (lH, d, J = 16.3H z), 6.94-7.04 (2H, m), 7.16-7.20 (lH, m), 7.35-7.40 (lH, m), 7.69 (lH, d, J = 7.6Hz), 7.88 (lH, d, J = 7.6Hz), 8.35 (lH, d , J = 16.3Hz), 8.38 (lH, d, J = 9.3Hz)
[0348] 実施例 71  [0348] Example 71
Figure imgf000187_0001
Figure imgf000187_0001
ェチル = (E)一 3—（8— (2- (4一（（tert ブトキシカルボニル）（2—（2 チェ二 ルチオ）ェチル）ァミノ）ピぺリジン一 1—ィル） - 1—ヒドロキシェチル） 2—メトキシ キノリン— 5—ィル）アタリラート 50mgの塩化メチレン lmL溶液に、氷冷下、トリフルォロ 酢酸 0.35mLを滴下し、室温で一晩放置した。減圧下で溶媒を留去し、酢酸ェチルお よび水を加え、 20%水酸ィ匕ナトリウム水溶液で pH12に調整した。有機層を分取し、飽 和塩ィ匕ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒 を留去し、褐色油状物のェチル = (E) - 3- (8- (1—ヒドロキシ— 2— (4- ( (2- ( 2—チェ-ルチオ）ェチル）ァミノ）ピぺリジン— 1—ィル）ェチル）— 2—メトキシキノリ ン 5 ィル）アタリラート 42mgを得た。  Ethyl = (E) 1 3— (8— (2- (4 1 ((tert butoxycarbonyl) (2— (2 cherylthio) ethyl) amino) piperidine 1 1-yl) -1-hydroxy (Chill) 2-methoxyquinoline-5-yl) attalylate To a solution of 50 mg of methylene chloride in lmL was added dropwise 0.35 mL of trifluoroacetic acid under ice cooling, and the mixture was allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 12 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a brown oily substance ethyl = (E)-3- (8- ( 1-Hydroxy-2- (4-((2- (2-Certhio) ethyl) amino) piperidine-1-yl) ethyl) -2-methoxyquinolin 5yl) atarylate 42 mg was obtained.
'H-NMRCCDCl ) δ値： 1.37(3H,t,J=7.1Hz),1.44- 1.75(2H,m),1.80- 2.00(2H,m),2.16- 2  'H-NMRCCDCl) δ value: 1.37 (3H, t, J = 7.1Hz), 1.44- 1.75 (2H, m), 1.80-2.00 (2H, m), 2.16-2
3  Three
.60(3H,m),2.70-2.96(6H,m),2.98-3.12(lH,m),3.26-3.35(lH,m),4.04(3H,s),4.31(2H, q,J=7.1Hz),5.76-5.86(lH,m),6.52(lH,d,J=15.6Hz),6.95-7.02(2H,m),7.10-7.15(lH,m ),7.33-7.37(lH,m),7.69(lH,d,J=7.7Hz),7.90(lH,d,J=7.7Hz),8.35(lH,d,J=15.6Hz),8.3 9(lH,d,J=9.3Hz)  .60 (3H, m), 2.70-2.96 (6H, m), 2.98-3.12 (lH, m), 3.26-3.35 (lH, m), 4.04 (3H, s), 4.31 (2H, q, J = 7.1Hz), 5.76-5.86 (lH, m), 6.52 (lH, d, J = 15.6Hz), 6.95-7.02 (2H, m), 7.10-7.15 (lH, m), 7.33-7.37 (lH, m ), 7.69 (lH, d, J = 7.7Hz), 7.90 (lH, d, J = 7.7Hz), 8.35 (lH, d, J = 15.6Hz), 8.39 (lH, d, J = 9.3Hz)
[0349] 実施例 72
Figure imgf000188_0001
[0349] Example 72
Figure imgf000188_0001
ェチル = (E) - 3- (8—（1ーヒドロキシー2— (4- ( (2- (2 チェ-ルチオ）ェチ ル)ァミノ）ピぺリジン一 1—ィル)ェチル） 2—メトキシキノリン一 5 ィル)アタリラート 40mgの 90%エタノール水 lmL溶液に、氷冷下、 20%水酸化ナトリウム水溶液 62 Lを 加え、室温で 1時間攪拌した。減圧下で溶媒を留去し、水を加え、炭酸ガスを導入し た。メタノールをカ卩え、 1.0mol/L塩酸で pH7.4に調整し、減圧下で溶媒を留去した。得 られた残留物を逆相シリカゲルカラムクロマトグラフィー [溶離液；ァセトニトリル：水 = 3 : 7]で精製し、淡黄色固体の (E)—3— (8— (1—ヒドロキシ— 2— (4— ( (2— (2— チェ-ルチオ）ェチル）ァミノ）ピぺリジン一 1—ィル）ェチル） 2—メトキシキノリン一 5 ィル)アクリル酸 20mgを得た。  Ethyl = (E)-3- (8— (1-Hydroxy-2— (4- ((2- (2 Chertio) ethyl) amino) piperidine 1-yl) ethyl) 2-methoxyquinoline To a solution of 40 mg of talylate in 90 ml of 90% aqueous ethanol under ice cooling, 62 L of 20% aqueous sodium hydroxide solution was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. Methanol was added, pH was adjusted to 7.4 with 1.0 mol / L hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reversed-phase silica gel column chromatography [eluent: acetonitrile: water = 3: 7] to give (E) —3— (8— (1—hydroxy— 2— (4 — ((2- (2-Chelthio) ethyl) amino) piperidine-1-yl) ethyl) 2-methoxyquinoline-5-yl) acrylic acid 20 mg was obtained.
1H-NMR(CD OD) δ値： 1.37— 1.53(2H,m),1.75— 1.91(2H,m),2.25— 2.42(2H,m),2.48— 2.  1H-NMR (CD OD) δ value: 1.37—1.53 (2H, m), 1.75—1.91 (2H, m), 2.25—2.42 (2H, m), 2.48—2.
3  Three
68(2H,m),2.71-2.88(5H,m),2.98-3.05(lH,m),3.28-3.35(lH,m),3.94(3H,s),5.85-5.92( lH,m),6.46(lH,d,J=15.8Hz),6.86-6.94(2H,m),7.08-7.10(lH,m),7.36-7.41(lH,m),7.5 7-7.60(lH,m),7.74(lH,d,J=7.8Hz),7.99(lH,d,J=15.8Hz),8.39-8.44(lH,m) 実施例 73  68 (2H, m), 2.71-2.88 (5H, m), 2.98-3.05 (lH, m), 3.28-3.35 (lH, m), 3.94 (3H, s), 5.85-5.92 (lH, m), 6.46 (lH, d, J = 15.8Hz), 6.86-6.94 (2H, m), 7.08-7.10 (lH, m), 7.36-7.41 (lH, m), 7.5 7-7.60 (lH, m), 7.74 (lH, d, J = 7.8Hz), 7.99 (lH, d, J = 15.8Hz), 8.39-8.44 (lH, m) Example 73
Figure imgf000188_0002
Figure imgf000188_0002
ェチル = (E) - 3- (7—メトキシ一 1—ビュルイソキノリン一 4—ィル）アタリラート 40 mgのトルエン lmL溶液に、 tert ブチル = 1ー（2, 3 ジヒドロべンゾ [b] [1, 4]ジォ キシン— 6—ィルメチル）（ピペリジン— 4—ィル）力ルバマート 54mgを加え、 80〜100 °Cで 50分間攪拌した。 tert ブチル = 1一（2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシ ンー6 ィルメチル）（ピペリジンー4 ィル）力ルバマート 40mgのトルエン 0.5mL溶液 を加え、 80〜95°Cで 1時間攪拌した。減圧下で溶媒を留去し、得られた残留物をシリ ΓΡ'Ηΐ)ΐε·8'(ζΗε·6=ί"'Ρ'Ηΐ)90·8'(ζΗ =ί"'Ρ'Ηΐ)3 ·Ζ'(ΖΗ ·^ε·6=ΓΡΡ'Ηΐ)ΐ ·Ζ'(ω'Η ε)98·9— Zr9'(zH6'SI=f'P'HI)SS'9'(zHrZ=f'b'HS)IS' (S'H ) S ' (S'HS)86'S'(S'HS)S ·ε'(ω'Η2)½·ε- ^·ε'(ω'Η2)2Γε-90·ε'(ω'Η2)00·ε-½·2'(ω'Ηΐ)ε9·2-33·2'(ω'Η2)0ε· ' C"'H SO - 36·ΐ'(ω'Η 83·ΐ- 8 ·ΐ'(ζΗΓΖ=Π'Ηε)8ε·ΐ :軍 9 (OQDWH-H^Ethyl = (E)-3- (7-Methoxy-1- 1-Buylisoquinoline 4-yl) Atalylate 40 mL of toluene in 1 mL of toluene, tert butyl = 1- (2, 3 dihydrobenzo [b] [1 , 4] dioxin-6-ylmethyl) (piperidine-4-yl) strength rubamate 54 mg was added, and the mixture was stirred at 80 to 100 ° C. for 50 minutes. tert butyl = 1 (2,3 dihydrobenz [b] [1,4] dioxin-6ylmethyl) (piperidine-4-yl) strength rubamate 40 mg of toluene in 0.5 mL solution is added and 1 at 80-95 ° C. Stir for hours. The solvent was distilled off under reduced pressure, and the resulting residue was ΓΡ'Ηΐ) ΐε · 8 '( ζ Ηε · 6 = ί "'Ρ'Ηΐ) 90/8 '( ζ Η = ί"'Ρ'Ηΐ) 3ΖΖ (ΖΗ · ^ ε · 6 = ΓΡΡ ' Ηΐ) ΐ · Ζ '(ω'Η ε) 98 · 9— Zr9' ( z H6'SI = f'P'HI) SS'9 '( z HrZ = f'b'HS) IS' ( S 'H ) S '( S ' HS) 86'S '( S ' HS) S ε '(ω'Η2) ½ · ε- ^ · ε'(ω'Η2) 2Γε-90 · ε '(ω'Η2) 00 ε-½ · 2 '(ω'Ηΐ) ε9-2-3 2'(ω'Η2) 0ε · 'C "' H SO-36 · ΐ '(ω'Η 83 · ΐ-8 · ΐ' ( ζ ΗΓΖ = Π'Ηε) 8εΐ: Army 9 (OQDWH-H ^
。 ¾ Γ (H— έ fi ( — —ベ
Figure imgf000189_0001
( ェ ( / - 1 { iJ. ( ^ / 一 9 ベ 、^
Figure imgf000189_0002
. ¾ Γ (H— έ fi (— —Be
Figure imgf000189_0001
(É (/-1 {iJ. (^ / 9
Figure imgf000189_0002
、つ攝慰 [τ z-si =ベ ^ ェ (H：へ ： ^Λ^ η^ ί , Tsutsu consolation [τ z-si = be ^ ee (H: to: ^ Λ ^ η ^ ί
Figure imgf000189_0003
。 >n辛爵 瀚缀 止 s教、つ粼¾ ^^^^Mw ^^ mM^ m 回 s マ cm ^m^ -^ 、つ辛爵 瀚缀 止 s教 ° つ喜 ^ a 9 Ι ^Ί^Μ/
Figure imgf000189_0004
-ζ)-ι) ε— (Ή) = ェ
Figure imgf000189_0003
. > n 爵 爵 教 教 、 ^ 粼 ^^^^ Mw ^^ mM ^ m times s ma cm ^ m ^-^, 辛 爵 止 教 a ° a 9 9 ^ Ί ^ Μ /
Figure imgf000189_0004
-ζ) -ι) ε— (Ή) =
Figure imgf000189_0005
Figure imgf000189_0005
ζ圏第 ζ range
(s'HT)Se-8'(zH6"ST=rP'HT)TS-8'(zH8"6=rP'HT) 90·8'(ω'Η2)ε^· -0^· '(ωΉε)08·9-89·9'(ζΗ6·3ΐ=ΓΡΉΐ)ε3·9'(ζΗΓ =Γ¾Ή2)ΐε^'(ω 'HZ)SS'— SO' (S'HS)96'S'C"'HS)0S'S— O S'(ra'HS)OS'S— 30·ε'(ω'Ηζ)00·ε— S8 ' (ω'Η(s'HT) Se-8 '( z H6 "ST = rP'HT) TS-8' ( z H8" 6 = rP'HT) 908 '(ω'Η2) ε ^ · -0 ^ ·' (ωΉε) 08 · 9-89 · 9 '( ζ Η6 · 3ΐ = ΓΡΉΐ) ε3 · 9' ( ζ ΗΓ = Γ¾Ή2) ^ ε ^ '(ω' HZ) SS'— SO '( S ' HS) 96'S'C "'HS) 0S'S— O S'(ra'HS)OS'S— 30 · ε '(ω'Ηζ) 00 · ε— S8'(ω'Η
)Η顺- Ητ
Figure imgf000189_0006
( ^エ（ / ζ)
Figure imgf000189_0007
) Η 顺-Η τ
Figure imgf000189_0006
(^ E (/ ζ)
Figure imgf000189_0007
、つ攝慰 [ΐ： ΟΖ=Λ^/^： ^ΓΛ^ ^ ί \— ^ ム マ /  , 攝 攝 [ΐ: ΟΖ = Λ ^ / ^: ^ ΓΛ ^ ^ ί \ — ^ Mu Ma /
98S6T0/S00Zdf/X3d =15.9Hz),8.53(lH,s) 98S6T0 / S00Zdf / X3d = 15.9Hz), 8.53 (lH, s)
[0352] 実施例 75 [0352] Example 75
Figure imgf000190_0001
Figure imgf000190_0001
ェチル= ）ー3—（1ー（2—（4ー（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルメチル）ァミノ）ピぺリジン一 1—ィル）ェチル） 7—メトキシイソキノリン一 4— ィル）アタリラート 90mgのエタノール 3mL溶液に、 20%水酸化ナトリウム水溶液 0.5mL を加え、室温で 2時間攪拌し、一晩放置した。減圧下で溶媒を留去し、得られた残留 物に水および塩酸をカ卩え、 pH8.0に調整した。 2 プロパノールを加え、固形物をろ 取し、黄色固体の（E)— 3— (1— (2— (4— ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォ キシン一 6—ィルメチル）ァミノ）ピぺリジン一 1—ィル）ェチル） 7—メトキシイソキノリ ン— 4—ィル）アクリル酸 46mgを得た。  Ethyl =) −3— (1− (2− (4 − ((2, 3 dihydrobenz [b] [l, 4] dioxin 6-ylmethyl) amino) piperidine 1-yl) ethyl) 7-Methoxyisoquinoline 4-yl) Atalylate To a solution of 90 mg of ethanol in 3 mL of ethanol was added 0.5 mL of 20% aqueous sodium hydroxide solution, stirred at room temperature for 2 hours, and allowed to stand overnight. The solvent was distilled off under reduced pressure, water and hydrochloric acid were added to the obtained residue, and the pH was adjusted to 8.0. 2 Add propanol, filter the solid, and add (E) — 3— (1— (2— (4— ((2, 3 dihydrobenzo [b] [l, 4] dioxin 1-ylmethyl) amino) piperidine 1-yl) ethyl) 7-methoxyisoquinolin-4-yl) acrylic acid 46 mg was obtained.
1H-NMR(DMSO-d ) δ値： 1.26— 1.38(2H,m),1.80— 1.90(2H,m),2.02— 2.12(2H,m),2.40—  1H-NMR (DMSO-d) δ value: 1.26— 1.38 (2H, m), 1.80— 1.90 (2H, m), 2.02— 2.12 (2H, m), 2.40—
6  6
2.60(lH,m),2.77-2.85(2H,m),2.94-3.04(2H,m),3.15-3.55(2H,m),3.67(2H,s),3.97(3H ,s),4.21(4H,s),6.61(lH,d,J=15.9Hz),6.76-6.88(3H,m),7.50(lH,dd,J=9.3,2.4Hz),7.55( lH,d,J=2.4Hz),8.14(lH,d,J=9.3Hz),8.18(lH,d,J=15.9Hz),8.62(lH,s)  2.60 (lH, m), 2.77-2.85 (2H, m), 2.94-3.04 (2H, m), 3.15-3.55 (2H, m), 3.67 (2H, s), 3.97 (3H, s), 4.21 ( 4H, s), 6.61 (lH, d, J = 15.9Hz), 6.76-6.88 (3H, m), 7.50 (lH, dd, J = 9.3, 2.4Hz), 7.55 (lH, d, J = 2.4Hz ), 8.14 (lH, d, J = 9.3Hz), 8.18 (lH, d, J = 15.9Hz), 8.62 (lH, s)
[0353] 実施例 76
Figure imgf000190_0002
[0353] Example 76
Figure imgf000190_0002
窒素気流下、 tert ブチル = (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6—ィ ルメチル）（1— (2 ヒドロキシ一 2— (7—メトキシイソキノリン一 1—ィル）ェチル）ピぺ リジンー4 ィル）力ルバマート 0.29gのテトラヒドロフラン 6mL溶液に、 60%水素化ナト リウム 22mgおよび tert ブチル =ブ口モアセタート 80 μ Lを加え、 4時間 20分間加熱 還流した。 60%水素化ナトリウム 12mgを加え、 1時間加熱還流した。反応混合物を放 冷後、水および酢酸ェチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾 ·8=ί"'Ρ'Ηΐ)06·9'(ω'Ηΐ)0 ·9- SS'9'(S'H )9 (s'HS)SO' (ω'Η ^· 36·ε'(ω'Η9)06·εUnder nitrogen flow, tert butyl = (2, 3 dihydrobenz [b] [l, 4] dioxin-6-ylmethyl) (1- (2 hydroxy-2- (7-methoxyisoquinoline-1-yl) ethyl) ) Piperidine-4-yl) Forced rubamate To 0.29 g of tetrahydrofuran in 6 mL solution was added 60% sodium hydride 22 mg and tert-butyl = buccal moacetate, and the mixture was heated to reflux for 4 hours and 20 minutes. 60 mg sodium hydride (12 mg) was added, and the mixture was heated to reflux for 1 hour. After allowing the reaction mixture to cool, water and ethyl acetate were added. The organic layer is separated and dried over anhydrous magnesium sulfate. · 8 = ί "'Ρ'Ηΐ) 06 · 9'(ω'Ηΐ)09-SS'9'( S ' H) 9 ( s ' HS) SO '(ω'Η ^ · 36 · ε'(ω'Η9) 06
― ·ε'(ω'Ηε)ο ·ε— oWC"'Hs)s — οε ' (ω'Η οε oi ：軍 9 ( oswa) Ν— ΗΤ ― · Ε '(ω'Ηε) ο · ε- oWC "' Hs) s — οε '(ω'Η οε oi: Army 9 (oswa) Ν— Η Τ
Figure imgf000191_0001
Figure imgf000191_0001
、つ攝慰 [ΐ： S = 一, ：
Figure imgf000191_0002
, Consolation [ΐ: S = one, ：
Figure imgf000191_0002
Figure imgf000191_0003
Figure imgf000191_0004
。 ·η¾ [τ :6= 一, ェ：氺
Figure imgf000191_0003
Figure imgf000191_0004
. · Η¾ [τ: 6 = one, f: 氺
■M oes-osmv-sao、 、マエ ^躲]— έ 4ム マ / π
Figure imgf000191_0005
■ M oes-osmv-sao,, Mae ^ 躲] —έ 4 mma / π
Figure imgf000191_0005
Figure imgf000191_0006
Figure imgf000191_0006
(ZH9"e=rP'HT)ZS"8'(zH2"2=rP'HT)26"Z'(ZH0"6=rP'HT)SZ"Z'(ZH9"e=rP'HT)2S ·Ζ'(ΖΗ ·^0·6=1"'ΡΡ'ΗΪ) :· ' (ω'Ηε)08·9— 09'9'C"'HI)0S'S— 0 S'(s'H S ^ (PBQJq'HS )SS' OS (s'HS)S6'S'C"'HS)Sr — 08·ε'(ω'Ηΐ)3ε·ε— 0S'S'(ra'HS)0S'S— 30·ε'(ω'Ηΐ)08 •2— S9'2'(UI'H SS - 0ΐ '(ω'Η )08·ΐ- SS (ra'H8I)S 'I- SS'I :軍 9 (OQDWH-H^ (ZH9 "e = rP'HT) ZS" 8 '( z H2 "2 = rP'HT) 26"Z' (ZH0 "6 = rP'HT) SZ" Z '(ZH9 "e = rP'HT) 2S · Ζ '(ΖΗ · ^ 0 · 6 = 1 "'ΡΡ'ΗΪ): · '(ω'Ηε) 08 · 9— 09'9'C"' HI) 0S'S— 0 S '(s'H S ^ (PBQJq'HS) SS 'OS ( s ' HS) S6'S'C "'HS) Sr — 08 · ε'(ω'Ηΐ) 3ε · ε— 0S'S '(ra'HS) 0S'S— 30 · ε' (ω 'Ηΐ) 08 • 2— S9 ' 2 '(UI'H SS-0ΐ'(ω'Η) 08 · ΐ- SS (ra'H8I) S 'I- SS'I: Military 9 (OQDWH-H ^
° ^ (H— ^
Figure imgf000191_0007
Figure imgf000191_0008
呦^ ^° ^ (H— ^
Figure imgf000191_0007
Figure imgf000191_0008
呦 ^^
M ^ m^ w-z= : · mmmχαοοοππ、 /、f 、平囂]—
Figure imgf000191_0009
。 >n辛爵¾瀚缀 止 s教 M ^ m ^ wz = : · mmmχαοοοππ, /, f, flat]] —
Figure imgf000191_0009
. > n
98S6T0/S00Zdf/X3d 681· (s'H ΐ)3^ ΐ'(ζΗΓΖ=ΓΡ'Ηΐ)9Ζ·8'(ζΗε·8=ΓΡ'Ηΐ)03·8'(ζΗε·8=ΓΡ'Ηΐ)9Γ8'(ζΗΓΖ=ΓΡ'Ηΐ
Figure imgf000192_0001
98S6T0 / S00Zdf / X3d 681 (s'H ΐ) 3 ^ ΐ ' (ζ ΗΓΖ = ΓΡ'Ηΐ) 9Ζ · 8' (ζ Ηε · 8 = ΓΡ'Ηΐ) 03 · 8 '(ζ Ηε · 8 = ΓΡ'Ηΐ) 9Γ8' (ζ ΗΓΖ = ΓΡ'Ηΐ
Figure imgf000192_0001
- 8 ' (ω'Η 0 - 88·ΐ'(ω'Η 6·ΐ- ε8·ΐ'(ω'Η 08·ΐ- S9'I :軍 9 ( OSWd) N- Ητ -8 '(ω'Η 0-88 · ΐ'(ω'Η 6 · ΐ- ε8 · ΐ '(ω'Η 08 · ΐ- S9'I: Army 9 (OSWd) N- Η τ
。 ¾¾Su¾9邈べ^ -S-^fi . ¾¾Su¾ 9邈 ^ -S- ^ fi
^064— (,^ ( /-^ /^ {Λ^→- /^(^0Ά ( ェ ^ 064— (, ^ (/-^ / ^ {Λ ^ →-/ ^ (^ 0 Ά (
Figure imgf000192_0002
Figure imgf000192_0002
圏第  No. 1
(δ'Ηΐ)ΐ0·0ΐ'(ζΗε·Ζ=ΓΡ'Ηΐ)98·8'(ζΗΐ·8=ΓΡ ( δ 'Ηΐ) ΐ0 · 0ΐ' ( ζ Ηε · Ζ = ΓΡ'Ηΐ) 9 8 '( ζ Ηΐ8 = ΓΡ
Ήΐ)0ε·8'(ζΗΓ8=ΓΡΉΐ)02·8'(ζΗΓ8=ΓνΗΐ)39·Ζ'(ζΗε·Ζ=ΓΡΉΐ)33·Ζ'(ζΗΓ8=ΓΡΉ ΐ)6Γ9'(ζΗ0 =ί"'Ρ'Ηΐ) Ζ·9'(ζΗ0 'ΐ·8=ί"'ΡΡ'Ηΐ)69·9'(δ'Η ^ (S'HS)80' C"'HS)9 ΐ·ε- 80·ε'(ω'Η 08 - ( ' (ω'Ηε)ε9 - 8 ' C"'H9)SS - S6'I :軍 9 ( !DaD)H N-HT Ήΐ) 0ε · 8 '(ζ ΗΓ8 = ΓΡΉΐ) 02 · 8' (ζ ΗΓ8 = ΓνΗΐ) 39 · Ζ '(ζΗε · Ζ = ΓΡΉΐ) 33 · Ζ' (ζΗΓ8 = ΓΡΉ ΐ) 6Γ9 '(ζ Η0 = ί "'Ρ'Ηΐ) Ζ · 9' ( ζ Η0 'ΐ · 8 = ί"'ΡΡ'Ηΐ) 69 · 9 '( δ ' Η ^ ( S 'HS) 80' C "'HS) 9 ΐ · ε -80 · ε '(ω'Η 08-('(ω'Ηε) ε9-8 'C "' H9) SS-S6'I: Army 9 (! DaD) H NH T
Figure imgf000192_0003
Figure imgf000192_0003
{Λ^→- ^(.·^0Ά ( /^ {^y-9- ^^ 'χ] [q] 、ベ:^
Figure imgf000192_0004
{Λ ^ →-^ (. · ^ 0 Ά (/ ^ {^ y-9- ^^ 'χ] [q], Be: ^
Figure imgf000192_0004
L \ -Q^ ^C -V- ^(. ^αΆ ( /^ ( / - 9 - ^^ Ί] [q] 、ベ: ^ΰ、 L \ -Q ^ ^ C -V- ^ (. ^ Α Ά (/ ^ (/-9-^^ Ί] [q], Be: ^ ΰ,
Figure imgf000192_0005
Figure imgf000192_0005
mm^ [eeso] mm ^ [eeso]
(zH9"e=rP'HT)8^"8'(zH6"8=rP'HT)2r8'(zH9"S=rP'HT)Z0"8'(zH6"T=rP'H ΐ)68· '(ζΗ6·ΐ'6·8=ΓΡΡ'Ηΐ)^9· '(ζΗ6·ΐ=ΓΡ'Ηΐ)ΐ2· '(ζΗ6·ΐ'2·8=ΓΡΡ'Ηΐ)80· '(ζΗ2 (zH9 "e = rP'HT) 8 ^" 8 '( z H6 "8 = rP'HT) 2r8' ( z H9" S = rP'HT) Z0 "8 '( z H6" T = rP'H ΐ ) 68 · '(ζΗ6 · ΐ'6 · 8 = ΓΡΡ'Ηΐ) ^ 9 ·' (ζΗ6 · ΐ = ΓΡ'Ηΐ) ΐ2 · '(ζΗ6 · ΐ'2 · 8 = ΓΡΡ'Ηΐ) 80 ·' ( ζΗ2
98S6T0/S00Zdf/X3d 061· [0357] 実施例 80
Figure imgf000193_0001
98S6T0 / S00Zdf / X3d 061 [0357] Example 80
Figure imgf000193_0001
N— (2—メトキシキノリンー8 ィル）ピぺリジンー4 カルボキサミド 50mgのジメチ ルスルホキシド 0.90mL溶液に、トリエチルァミン 29 μ Lおよび 2— (2 クロロェチル） — 1, 2, 3, 4—テトラヒドロイソキノリン 34mgを加え、室温で 2時間攪拌した。トリェチル ァミン 58 Lおよび 2— (2 クロ口ェチル）一1, 2, 3, 4—テトラヒドロイソキノリン 68mg を加え、室温で 1時間攪拌した。トリェチルァミン 87 Lおよび 2— (クロ口ェチル）—1 , 2, 3, 4—テトラヒドロイソキノリン 0.10gを加え、室温で 1時間攪拌した。反応混合物 に水および酢酸ェチルを加えた。有機層を分取し、水および飽和塩ィ匕ナトリウム水溶 液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた 残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 50： 1 ]で精製し、白色固体の 1— (2— (3, 4 ジヒドロイソキノリン一 2 (1H)—ィル)ェチル ) -N- (2—メトキシキノリン一 8—ィル）ピぺリジン一 4—カルボキサミド 25mgを得た。 1H-NMR(CDC1 ) δ値： 1.90— 2.25(6H,m),2.40— 2.50(lH,m),2.65— 2.84(6H,m),2.88— 2.9  N— (2-Methoxyquinoline-8-yl) piperidine-4 carboxamide 50 mg of dimethyl sulfoxide in 0.90 mL solution with 29 μL of triethylamine and 2 -— (2 chloroethyl) — 1, 2, 3, 4-tetrahydro 34 mg of isoquinoline was added and stirred at room temperature for 2 hours. Triethylamine 58 L and 2- (2 chloroethyl) ethyl 1,2,3,4-tetrahydroisoquinoline 68 mg were added and stirred at room temperature for 1 hour. Triethylamine 87 L and 2- (black octyl) -1,2,3,4-tetrahydroisoquinoline (0.10 g) were added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 50: 1], and the white solid 1- (2- (3,4 dihydroisoquinoline 1 2 (1H) -yl ) Ethyl) -N- (2-methoxyquinoline-1-8-yl) piperidine-1-4-carboxamide 25 mg was obtained. 1H-NMR (CDC1) δ value: 1.90— 2.25 (6H, m), 2.40— 2.50 (lH, m), 2.65— 2.84 (6H, m), 2.88— 2.9
3  Three
4(2H,m),3.05-3.15(2H,m),3.70(2H,s),4.10(3H,s),6.96(lH,d,J=8.9Hz),6.98-7.05(lH, m),7.08-7.14(3H,m),7.38(lH,t,J=7.6Hz),7.41-7.45(lH,m),8.01(lH,d,J=8.9Hz),8.70- 4 (2H, m), 3.05-3.15 (2H, m), 3.70 (2H, s), 4.10 (3H, s), 6.96 (lH, d, J = 8.9Hz), 6.98-7.05 (lH, m) , 7.08-7.14 (3H, m), 7.38 (lH, t, J = 7.6Hz), 7.41-7.45 (lH, m), 8.01 (lH, d, J = 8.9Hz), 8.70-
8.74(lH,m),9.62(lH,s) 8.74 (lH, m), 9.62 (lH, s)
[0358] 実施例 81
Figure imgf000193_0002
[0358] Example 81
Figure imgf000193_0002
N— (2—メトキシキノリンー8 ィル）ピぺリジンー4 カルボキサミド 35mgのトルエン 0.20mL懸濁液に、 7 ビュル 2, 3 ジヒドロ [1, 4]ジォキシノ [2, 3— c]ピリジン 20 mgをカ卩え、 2時間 30分間加熱還流した。 N, N—ジメチルホルムアミド 0.20mLをカロえ、 1時間加熱還流した。減圧下で溶媒を留去し、得られた残留物をシリカゲルカラムクロ マトグラフィー [溶離液；クロ口ホルム：メタノール = 20： 1]で精製し、褐色油状物の 1 S8圏第 [09S0]N- (2-methoxyquinoline-8yl) piperidine-4 carboxamide 35 mg of toluene in 0.20 mL suspension of 7 bul 2,3 dihydro [1,4] dioxino [2,3-c] pyridine 20 mg Heated to reflux for 2 hours 30 minutes. N, N-dimethylformamide (0.20 mL) was added and heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: black-mouthed form: methanol = 20: 1]. S8 area [09S0]
(s,HT)29"6'(zHr8=rP'HT)29"8'(zH2-6=rP'HT)^-8'(s'HT)80"8'(zHr8=f'P'HT)S2-
Figure imgf000194_0001
( s, HT) 29 "6 '( z Hr8 = rP'HT) 29"8' ( z H2-6 = rP'HT) ^-8 '( s ' HT) 80 "8 '( z Hr8 = f'P'HT) S2-
Figure imgf000194_0001
Z9 ' (ω'Ηΐ)8 - 8S ' C"'H9)SS - 06·ΐ'(ζΗΓΖ=ΓνΗε) ·ΐ :軍 9 ( IDQD^ N-H. ε^ι— ΰ : ( / —g—べ ίί,^ρ ^E ー ( ^ （ / ^ / （ / — 一べ;^
Figure imgf000194_0002
Z9 '(ω'Ηΐ) 8-8S' C "'H9) SS-06 · ΐ' ( ζ ΗΓΖ = ΓνΗε) · ΐ: Military 9 (IDQD ^ NH. Ε ^ ι— ΰ: (/ —g— ίί, ^ ρ ^ E ー (^ (/ ^ / (/ — one; ^
Figure imgf000194_0002
ΐ))) 8)— ε= ^エ Ο)呦^ ^¾ ^ ^H '■ Ζ= ^ ^-Τ ^  ΐ))) 8) — ε = ^ e Ο) 呦 ^^ ¾ ^^ H '■ Ζ = ^^-Τ ^
• mrn
Figure imgf000194_0003
、つ辛恩 瀚缀 止• mrn
Figure imgf000194_0003
, Ceaseless
Figure imgf000194_0004
( ^ （ -
Figure imgf000194_0004
(^ (-
^ / / 一 一べ fl ））ー8— ^EH ー ε= ^エ ^ WT^ZZ^ ^ ^ / / Everything fl)) － 8— ^ EH ー ε = ^ D ^ WT ^ ZZ ^ ^
Figure imgf000194_0005
Figure imgf000194_0005
(δ'Ηΐ)Ζ9·6'(ω'Ηΐ)9Γ8— ( '8'(S'H ΐ)80·8'(ζΗ8·8=ί"'Ρ'Ηΐ)ΐ0·8'(ω'Ηΐ)3 ·Ζ— 0 ·Ζ'(ζΗ8·Ζ=ί^'Ηΐ)Ζε·Ζ'(ζΗ8·8=ί"'Ρ'Ηΐ)96·9 ( δ 'Ηΐ) Ζ9 · 6'(ω'Ηΐ) 9Γ8— ('8' ( S 'H ΐ) 80 · 8' ( ζ Η8 · 8 = ί "'Ρ'Ηΐ) ΐ0 · 8' (ω ' Ζ) 3 · Ζ— 0 · Ζ '( ζ Η8 · Ζ = ί ^' Ηΐ) Ζε · Ζ '( ζ Η8 · 8 = ί "'Ρ'Ηΐ) 96
'(δ'Ηΐ)ΐΖ·9'(ω'Η SS' (s'HS)0r (ra'HS)WS— 90'S'C"'HS)S6 — S8 ' C"'HS)0 '( δ ' Ηΐ) ΐΖ · 9 '(ω'Η SS' ( s 'HS) 0r (ra'HS) WS— 90'S'C "' HS) S6 — S8 'C"' HS) 0
8 - ( ' (ω'Ηΐ)8 - 8S ' (ω'Η - 0rS'C"'HS)S0 - 06·ΐ :軍 9 ( !DaD)H N-HT 8-('(ω'Ηΐ) 8-8S'(ω'Η-0rS'C"'HS) S0-06 · ΐ: Army 9 (! DaD) H NH T
。 Su¾ W ^^^ / — —ベ ( / — 8—ベ fi ,^Ρ ^^ 一 S )—  . Su¾ W ^^^ / — —Be (/ — 8—Be fi, ^ Ρ ^^ One S) —
98S6T0/S00Zdf/X3d 361- (δ'Ηΐ)ΐΖ·6'(ω'Ηΐ)09·6— S 6'(zHZ'Z=f'P'HI)S 8'(zH8' 8=rP'HT)82"8'(zH " =rP'HT)29" '(ZH " =r HT)T^" '(ra'HS - -9r '(ZH8"8=rP' Ηΐ)π·Ζ'(δ'Ηε)ΐΐ· C"'HS)S9'S— ΐ3·ε'(ω'Ηε)3ΐ·ε— 08 ' C"'HS)89 — 6S ' C"'HS)8S — ΐ ' (ω'Η ^Ή0 ' (ω'Η 0 — ΐ6·ΐ'(ω'Η )3Ζ·ΐ— OS'I :軍 9 ( OS ) 顺— Ητ
Figure imgf000195_0001
98S6T0 / S00Zdf / X3d 361- ( δ 'Ηΐ) ΐΖ · 6'(ω'Ηΐ) 09 · 6— S 6 '( z HZ'Z = f'P'HI) S 8' ( z H8 '8 = rP'HT) 82 "8' ( z H "= rP'HT) 29"'(ZH"= r HT) T ^"'(ra'HS--9r'(ZH8"8 = rP' Ηΐ) π · Ζ '(δ'Ηε) ΐΐ · C "'HS) S9'S— ΐ3 · ε'(ω'Ηε) 3ΐ · ε— 08 'C"' HS) 89 — 6S 'C "' HS) 8S — ΐ '(ω'Η ^ Ή0' (ω 'Η 0 — ΐ6 · ΐ'(ω'Η) 3Ζ · ΐ— OS'I: Army 9 (OS) 顺 — Η τ
Figure imgf000195_0001
Figure imgf000195_0002
Figure imgf000195_0002
^ m^ [ΐ9εο] ^ m ^ [ΐ9εο]
(zH2-6=rP'HT)S^-8'(zH2-8=rP'HT)0^"8'(s'HT)86" '(zH2-8 (zH2-6 = rP'HT) S ^ -8 '( z H2-8 = rP'HT) 0 ^ "8' ( s 'HT) 86"' (zH2-8
=rP'HI)ZS (zHS'6=rP'HI)W) (s'HI)98'9'(ra'H )8S' - 9S (s'HS)ir (ra'HS)O ε— (^·ε'(ω'Ηπ)οΐ·ε— ' C"'H ss — rs'C"'H ors— 6·ΐ :軍 9 (αοεαο)Η Ν-Ητ = rP'HI) ZS (zHS'6 = rP'HI) W) (s'HI) 98'9 '(ra'H) 8S'-9S ( s ' HS) ir (ra'HS) O ε— ( ^ · Ε '(ω'Ηπ) οΐ · ε—' C "'H ss — rs'C"' H ors— 6 · ΐ: Military 9 (αο ε αο) Η Ν-Η τ
。  .
ΐ邈べ ΰ : ( / — g—ベ fi,^p ^ ー S—( ^ （ ^ / （ / — —ベ;^ fi
Figure imgf000195_0003
ΐ 邈 be ΰ: (/ — g—be fi, ^ p ^ ー S— (^ (^ / (/ — —be; ^ fi
Figure imgf000195_0003
^αγ^ ^^ ni ，os'o氺、つ辛爵 瀚缀 止 s教。 っ ¾ 翻^ αγ ^ ^^ ni, os'o 氺, つ 爵. ¾ ¾
Figure imgf000195_0004
Figure imgf000195_0004
6 マ fH 邈氺、^继缀 Τ"0·ΐ氺 一 ^ェ0/ o06O)Su¾w— （ / —g 6 Ma fH邈氺, ^继缀Τ "0 · ΐ氺one ^ E 0 / o 06O) Su ¾w- ( / -g
Figure imgf000195_0005
Figure imgf000195_0005
98S6T0/S00Zdf/X3d 861- 圏第
Figure imgf000196_0001
98S6T0 / S00Zdf / X3d 861- No. 1
Figure imgf000196_0001
ΓΖ'(ΖΗε·6=ί"'Ρ'Ηΐ)π·Ζ'(δ'Ηε 0· (zHZ'Z=l^'HS)6rS'(ra'HS)S6 — S8 ' (ω'Η S9 — S ' (ra'HS)SS — 3^(ω'Η )00Ή8·ΐ'(ω'Η9)3Ζ·ΐ— 0 ·ΐ :軍 9 ( OS ) Η顺— Ητ ΓΖ '(ΖΗε · 6 = ί "'Ρ'Ηΐ) π · Ζ '(δ'Ηε 0 · ( z HZ'Z = l ^' HS) 6rS '(ra'HS) S6 — S8'(ω'Η S9 — S '(ra'HS) SS — 3 ^ (ω'Η) 00Ή8 · ΐ'(ω'Η9) 3Ζ · ΐ— 0 · ΐ: Army 9 (OS) Η 顺 — Η τ
。 ^邈べ ( / ベ ίί,^Ρ ( i .
Figure imgf000196_0002
( / （. ^ ((/ Ίί, ^ Ρ (i.
Figure imgf000196_0002
(/ (
Λ^→- ^(.·^0Ά{ ^ ^—·^^→)-Ι)))- -^ -Ζ) ε= ^エ Λ ^ →-^ (. · ^ 0 Ά {^ ^ — · ^^ →) -Ι)))--^ -Ζ) ε = ^
Figure imgf000196_0003
Figure imgf000196_0003
98圏第  98th
(S'HI)S9'6'(ZH0'8= ί"'Ρ'Ηΐ)ε9·8'(ζΗΐ·6=ΓΡ'Ηΐ) ·8'(ω'Η9)0ε·Ζ—9ΐ (ζΗΐ·6=ί"'Ρ'Ηΐ)66·9'(ζΗΐ·Ζ=Γ&'Η( S 'HI) S9'6' ( Z H0'8 = ί "'Ρ'Ηΐ) ε9 · 8' ( ζ Ηΐ · 6 = ΓΡ'Ηΐ) 8 '(ω'Η9) 0ε · Ζ—9ΐ ( ζ Ηΐ · 6 = ί "'Ρ'Ηΐ) 66 · 9' ( ζ Ηΐ · Ζ = Γ &'Η
εΐ· (S'HS)80' (zH8 =l"' H 6S'S'(ra'H S0'S— S6 ' (ω'Η ( — 09 ' (ra'HS)S
Figure imgf000196_0004
:軍 9 ( !DaD)H N-HT εΐ · ( S 'HS) 80' ( z H8 = l "'H 6S'S'(ra'HS0'S— S6 '(ω'Η (— 09'(ra'HS) S
Figure imgf000196_0004
: Military 9 (! DaD) H NH T
。 ¾¾Sra9 . ¾¾ Sra 9
_χ)))
Figure imgf000196_0005
(^^{ ^ ^^Λ^Λ^→- ^(^0Ά))- -^ -Ζ)— ε= ^エ _χ)))
Figure imgf000196_0005
(^^ {^ ^^ Λ ^ Λ ^ →-^ (^ 0 Ά))--^ -Ζ) — ε = ^
Figure imgf000196_0006
Figure imgf000196_0006
S8圏第 [29S0]  S8 area [29S0]
98S6T0/S00Zdf/X3d
Figure imgf000197_0001
ェチル = 3— (8—アミノー 2—メトキシキノリンー5 ィル）プロピオナート 46mgおよ び 4— ( (tert ブトキシカルボ-ル）（2, 3 ジヒドロ [1, 4]ジォキシノ [2, 3 c]ピリ ジン 7 ィルメチル）ァミノ）シクロへキサンカルボン酸 66mgから実施例 10と同様に して、無色油状物のェチル = 3—（8—（（（4一（（tert ブトキシカルボ-ル）（2, 3— ジヒドロ [1, 4]ジォキシノ [2, 3— c]ピリジンー7 ィルメチル）ァミノ）シクロへキシル） カルボ-ル）ァミノ） 2—メトキシキノリン 5 ィル）プロピオナート 80mgを得た。 'H-NMRCCDCl ) δ値： 1.23(3H,t,J=7.1Hz),1.33- 1.60(llH,m),1.60- 1.90(4H,m),2.10-98S6T0 / S00Zdf / X3d
Figure imgf000197_0001
Ethyl = 3— (8-amino-2-methoxyquinoline-5-yl) propionate 46 mg and 4-((tert-butoxycarbol) (2,3 dihydro [1,4] dixino [2,3 c] pyri In the same manner as in Example 10, ethyl = 3- (8-(((4 ((tert-butoxycarbol) (2, 3 — Dihydro [1,4] dioxino [2,3-c] pyridine-7ylmethyl) amino) cyclohexyl) carbol) amino) 2-methoxyquinoline 5yl) propionate 80 mg was obtained. 'H-NMRCCDCl) δ value: 1.23 (3H, t, J = 7.1Hz), 1.33- 1.60 (llH, m), 1.60-1.90 (4H, m), 2.10-
3 Three
2.35(3H,m),2.66(2H,t,J=7.9Hz),3.28(2H,t,J=7.9Hz),4.10(3H,s),4.13(2H,q,J=7.1Hz), 4.20-4.50(7H,m),6.81(lH,s),6.99(lH,d,J=9.0Hz),7.21(lH,d,J=8.0Hz),8.06(lH,s),8.2 3(lH,d,J=9.0Hz),8.60(lH,d,J=8.0Hz),9.49(lH,s)  2.35 (3H, m), 2.66 (2H, t, J = 7.9Hz), 3.28 (2H, t, J = 7.9Hz), 4.10 (3H, s), 4.13 (2H, q, J = 7.1Hz), 4.20-4.50 (7H, m), 6.81 (lH, s), 6.99 (lH, d, J = 9.0Hz), 7.21 (lH, d, J = 8.0Hz), 8.06 (lH, s), 8.2 3 ( lH, d, J = 9.0Hz), 8.60 (lH, d, J = 8.0Hz), 9.49 (lH, s)
実施例 88 Example 88
Figure imgf000197_0002
Figure imgf000197_0002
ェチル = 3—（8— ( ( (4—（（tert ブトキシカルボ-ル）（2, 3 ジヒドロ [1, 4]ジォ キシノ [2, 3— c]ピリジン 7 ィルメチル）ァミノ）シクロへキシル）カルボ-ル）ァミノ） 2—メトキシキノリンー5 ィル）プロピオナート 80mgの塩化メチレン l.OmL溶液に、ト リフルォロ酢酸 0.50mLを加え、 1時間攪拌した。減圧下で溶媒を留去し、得られた残 留物に 90%エタノール水溶液 l.OmLおよび 5.0mol/L水酸化ナトリウム水溶液 0.12mL を加え、室温で 45分間攪拌した。 5.0mol/L水酸ィ匕ナトリウム水溶液 0.24mLをカ卩え、室 温で 25分間攪拌した。減圧下で溶媒を留去し、水 2.0mLを加え、炭酸ガスを導入した 。固形物をろ取し、白色固体の3—（8—（（（4ー（（2, 3 ジヒドロ [1, 4]ジォキシノ [2 , 3— c]ピリジン— 7—ィルメチル）ァミノ）シクロへキシル）カルボ-ル）ァミノ）—2—メ d/^^^-Z- (,^ {Λ^→- /ί(^0 ( ェ（ / 一 9—ベ 、 Ethyl = 3— (8— (((4 — ((tert-butoxycarbol) (2,3 dihydro [1,4] dioxino [2,3-c] pyridine 7-ylmethyl) amino) cyclohexyl) Carbon) amino) 2-methoxyquinoline-5yl) propionate To a solution of 80 mg of methylene chloride in 0.5 mL of trifluoroacetic acid was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, 90% ethanol aqueous solution l.OmL and 5.0 mol / L aqueous sodium hydroxide solution 0.12mL were added to the resulting residue, and the mixture was stirred at room temperature for 45 minutes. A 0.2 mol mL of 5.0 mol / L sodium hydroxide aqueous solution was added and stirred at room temperature for 25 minutes. The solvent was distilled off under reduced pressure, 2.0 mL of water was added, and carbon dioxide gas was introduced. The solid was collected by filtration, and the white solid 3- (8-(((4-((2,3 dihydro [1,4] dioxino [2,3, c] pyridine-7-ylmethyl) amino) cyclohexyl) ) Carbol) Amino) -2 d / ^^^-Z- (, ^ {Λ ^ →-/ ί (^ 0 (
Ί]
Figure imgf000198_0001
Ί]
Figure imgf000198_0001
Figure imgf000198_0002
Figure imgf000198_0002
(S'HT)Z8 ( S 'HT) Z8
·6'(ζΗε·8=ί"'Ρ'Ηΐ)ε9·8'(ω'Ηΐ)0 ·8— 9ε·8'(ζΗε·8=ί"'Ρ'Ηΐ)88·Ζ'(ζΗε·6=ί"'Ρ'Ηΐ)εε·Ζ'(ω · 6 '( ζ Ηε · 8 = ί "'Ρ'Ηΐ) ε9 · 8 '(ω'Ηΐ) 0 · 8— 9ε · 8' ( ζ Ηε · 8 = ί"'Ρ'Ηΐ) 88 · Ζ' ( ζ Ηε · 6 = ί "'Ρ'Ηΐ) εε · Ζ' (ω
Ήε)9Γ9— 9'9'(S'H )0S ' (s'HS) r (ra'HS)SO'S— S6 ' (ω'Ηε)ΟΓΖ— 09 ' C"'HS)SS — 0 ' (ra'HS)SrS— 00 ' C"'HS)00 — 06·ΐ'(ω )08·ΐ— S9'I :軍 9 ( OS ) 顺— Ητ Ήε) 9Γ9— 9'9 '( S ' H) 0S '( s ' HS) r (ra'HS) SO'S— S6 '(ω'Ηε) ΟΓΖ— 09' C "'HS) SS — 0' (ra 'HS) SrS— 00' C "'HS) 00 — 06 · ΐ' (ω) 08 · ΐ— S9'I: Army 9 (OS) 顺 — Η τ
。 ^^ ^^ 一，— /^(^0Ά ( / S- Ci . ^^ ^^ One, — / ^ (^ 0 Ά (/ S- Ci
-N- ( ^エ（ / 9一べ^^ 、 [
Figure imgf000198_0003
-N- (^ e (/ 9 all ^^, [
Figure imgf000198_0003
'Ζ)— — " [、 TfiSuiSベ ^ — 8—ベ ίί,^Ρ ( ^ ci / fH) 'Ζ) — — “[, Tfi Sui S B ^ — 8—B ίί, ^ Ρ (^ ci / fH)
Figure imgf000198_0004
Figure imgf000198_0004
68圏第 [99S0] 'Ηΐ)Ζ9·6'(ζΗε·6=ΓΡ'Ηΐ)Ζ ·8'(ζ 68th category [99S0] 'Ηΐ) Ζ9 · 6' ( ζ Ηε · 6 = ΓΡ'Ρ) Ζ · 8 '( ζ
H2-8=rP'HT)62"8'(s'HT)2r8'(zH2-8=rP'HT) 2- '(zHS-6=rP'HT)Sr '(s'HT)90" '(ra H2-8 = rP'HT) 62 "8 '(s' HT) 2r8' (z H2-8 = rP'HT) 2- '(zHS-6 = rP'HT) Sr'(s'HT)90"'(ra
Ή^)0^^- 2^'(ω'Η3)02^-06·ε'(ω'Η2)02·ε-2Γε'(ω'Ηΐ)ΐ6·2-28·2'(ω'Ηΐ)59·2-3^·2 Ή ^) 0 ^^-2 ^ '(ω'Η3) 02 ^ -06 · ε' (ω'Η2) 02 · ε-2Γε '(ω'Ηΐ) ΐ6-22-28-2' (ω'Ηΐ ) 59-2-3 ^ 2
'(ω'Η ΐ - ε ' (ω'Η )8ΐ·ζ- wrs'(ra'H )09'i- εε·ΐ :軍 9 (〇 a- p-os a)H N-HT '(ω'Η ΐ-ε'(ω'Η) 8ΐ ・ ζ-wrs'(ra'H)09'i- εεΐΐ: Military 9 (〇 a- p-os a) H NH T
。 ¾¾Su¾S^べ (^ - - d/^^ . ¾¾Su¾ S ^ be (^--d / ^^
98S6T0/S00Zdf/X3d 961· ベ ίί,^Ρ ( ^^ ( - ( ^ ΰ / fH)))—8— ^ΕΗ ー -Ζ = Λί^ 98S6T0 / S00Zdf / X3d 961 Ί, ^ Ρ (^^ (-(^ ΰ / fH))) — 8— ^ ΕΗ ー -Ζ = Λί ^
Figure imgf000199_0001
Figure imgf000199_0001
圏第  No. 1
(s'H ΐ)99·6'(ζΗ0·8=ΓΡ'Ηΐ)2^·8'(ζΗ2·6=ΓΡ'Ηΐ ·8'(ζΗ0·8=ΓΡ'Ηΐ)0ε· '(ζΗ2·6=ΓΡ'Ηΐ)^ ΐ·Ζ'(ω'Ηε)08·9— S9'9'(S'H · (s'HS)Or (s'HS)86'S'(ra'HS)0rS— 06 ' (ω'Η ( (s'H ΐ) 99 · 6 '( ζ Η0 · 8 = ΓΡ'Ηΐ) 2 ^ · 8' ( ζ Η2 · 6 = ΓΡ'Ηΐ 8 '( ζ Η0 · 8 = ΓΡ'Ηΐ) 0ε ·' (ζΗ2 · 6 = ΓΡ'Ηΐ) ^ ΐ · Ζ '(ω'Ηε) 08 · 9— S9'9' ( S 'H · ( s ' HS) Or ( s 'HS) 86'S'(ra'HS) 0rS— 06 '(ω'Η (
- 0 ' (ω'Ηΐ)0 - OS ' (ω'Η - 06·ΐ'(ω )08·ΐ- S9'I :軍 9 ( OS ) 顺- Ητ -0 '(ω'Ηΐ) 0-OS'(ω'Η-06 · ΐ '(ω) 08 · ΐ- S9'I: Army 9 (OS) 顺-Η τ
。 ¾¾Sui92邈 (^ - - d/^^-Z- (,^
Figure imgf000199_0002
. ¾¾ Sui 9 2 邈 (^--d / ^^-Z- (, ^
Figure imgf000199_0002
( / -
Figure imgf000199_0003
( ェ (/-
Figure imgf000199_0003
(
Figure imgf000199_0004
Figure imgf000199_0004
16\ Μ [89S0] (δ'Ηΐ)99·6'(ζΗΓ8=ί"'Ρ'16 \ Μ [89S0] ( δ 'Ηΐ) 99 · 6' ( ζ ΗΓ8 = ί "'Ρ'
Ηΐ)Ζ9·8'(ζΗ2·6=ΓΡ'Ηΐ)^·8'(ζΗΓ8=ΓΡ'Ηΐ)62·Ζ'(ΖΗ2·6=ΓΡ'Ηΐ)00·Ζ'(ΖΗε·8=ΓΡ'Ηΐ
Figure imgf000199_0005
Ηΐ) Ζ9 ・ 8 '( ζ Η2 · 6 = ΓΡ'Ρ) ^ · 8' ( ζ ΗΓ8 = ΓΡ'Ηΐ) 62 · Ζ '(ΖΗ2 ・ 6 = ΓΡ'Ηΐ) 00 · Ζ' (ΖΗε8 = ΓΡ'Ηΐ
Figure imgf000199_0005
s'HS)Ol (s'HS)WS'C"'HS)SrS— S0'S'C"'HS)08 — ( ' C"'HS)S9 — SS ' (ω'Ηΐ)03· s'HS) Ol ( s 'HS) WS'C "' HS) SrS— S0'S'C"'HS) 08 — (' C "'HS) S9 — SS'(ω'Ηΐ) 03
0 ' (ω'Η - 0rS'C"'H S0 - 06·ΐ'(ζΗΓΖ=ΓνΗε)0Π :軍 9 ( !DaD)H N-HT 0 '(ω'Η-0rS'C "' H S0-06 · ΐ '( ζ ΗΓΖ = ΓνΗε) 0Π: Army 9 (! DaD) H NH T
。 ¾¾Sra9w— （ / 一 S—ベ . ¾¾Sra 9 w— (/ One S—Be
98S6T0/S00Zdf/X3d 16V
Figure imgf000200_0001
98S6T0 / S00Zdf / X3d 16V
Figure imgf000200_0001
6圏第
Figure imgf000200_0002
6th zone
Figure imgf000200_0002
)ΐ3·8'(ζΗ2·8=ΓΡ'Ηΐ)9ε·8'(ζΗ2·8=ΓΡ'Ηΐ)2ΓΖ'(ζΗ0·6=ΓΡ'Ηΐ)00·Ζ'(ω'Ηε)9Ζ·9-0Ζ·9' (s'H )0S (s'HS)ir (ra'HS)OS'S— 3ε·ε'(ω'Η8)00·ε— 09 ' C"'HS)SS — zrs'C"'Hs)oi •2- 86·ΐ'(ω'Ηΐ)3Ζ·ΐ- S9'I'(ra'HI)SS'I- 8 ·ΐ'(ω'Ηΐ)3ε·ΐ- 0Π :軍 9 (QO aD)H N-HT ) ΐ3 ・ 8 '( ζ Η2 ・ 8 = ΓΡ'Ηΐ) 9ε ・ 8' ( ζ Η2 ・ 8 = ΓΡ'Ηΐ) 2ΓΖ '(ζΗ0 ・ 6 = ΓΡ'Ηΐ) 00 ・ Ζ'(ω'Ηε) 9Ζ · 9-0Ζ · 9 '( s ' H) 0S ( s ' HS) ir (ra'HS) OS'S— 3ε · ε'(ω'Η8) 00 · ε— 09 'C "' HS) SS — zrs' C "'Hs) oi • 2-86 · ΐ'(ω'Ηΐ) 3Ζ · ΐ- S9'I '(ra'HI) SS'I-8 · ΐ'(ω'Ηΐ) 3ε · ΐ- 0Π: Army 9 (QO aD) H NH T
。 ¾¾§ωθ·8邈ベ^ / ベ lE^ /^( / —g—べ (ί,^Ρ ^ EH ー S—（ ^ （ ^ / （ / — 一べ;^ fi
Figure imgf000200_0003
Figure imgf000200_0004
( ェ（ . ¾¾§ωθ · 8 邈 Be ^ / be lE ^ / ^ (/ —g—be (ί, ^ Ρ ^ EH ー S— (^ (^ / (/ — one; ^ fi
Figure imgf000200_0003
Figure imgf000200_0004
(
Figure imgf000200_0005
Figure imgf000200_0005
ε6圏第 ε6 category
(δ'Ηΐ)ε9·6'(ω'Ηΐ) 9·8— SS'8'(ZH0'6= ΓΡ'Ηΐ)6ε·8'(ζΗΓ8=ί"'Ρ'Ηΐ)εΐ·Ζ'(ζΗΟ·6=ί"'Ρ'Ηΐ)εθ·Ζ'(ζΗε·8=ί"'Ρ'Ηΐ)6Γ9'(ω'Η 9— S9'9'(S'H )W (s'HS)0r (s'HS)6Z'S'(ra'HS)0S'S— 00·ε'(ω'Η3)06 — OS ' (ω'Ηΐ)Ο S - 0 ' C"'HZ)SS - 38·ΐ'(ω'Ηΐ)3Ζ·ΐ- 03·ΐ'(ω'Ηΐ)3 ·ΐ- SS'I：掛 9 (OQDW -^ ( δ 'Ηΐ) ε9 · 6'(ω'Ηΐ) 9 · 8— SS'8 '( Z H0'6 = ΓΡ'Ηΐ) 6ε · 8' ( ζ ΗΓ8 = ί "'Ρ'Ηΐ) εΐ · Ζ '( ζ ΗΟ · 6 = ί "'Ρ'Ηΐ) εθ · Ζ '( ζ Ηε · 8 = ί"'Ρ'Ηΐ) 6Γ9 '(ω'Η 9— S9'9' ( S 'H) W ( s ' HS) 0r ( s ' HS) 6Z'S '(ra'HS) 0S'S— 00 · ε'(ω'Η3) 06 — OS '(ω'Ηΐ) Ο S-0' C "'HZ) SS-38 · Ϊ́ '(ω'Ηΐ) 3Ζ · ΐ- 03 · ΐ'(ω'Ηΐ) 3 · ΐ- SS'I ： Kake 9 (OQDW-^
Figure imgf000200_0006
Figure imgf000200_0006
98S6T0/S00Zdf/X3d 861· 96圏第 98S6T0 / S00Zdf / X3d 861 96th
(S'HI)S9'6'(ZH0'6=1"'P'HI)IS'8'(ZH ε·8=ί"'Ρ'Ηΐ)ε ·8'(ζΗε·8=ί"'Ρ'Ηΐ)0ε·Ζ'(ζΗ0·6=ί"'Ρ'Ηΐ)εΐ·Ζ'(ω'Ηε)9Γ9— S9'9'(ZH8'9= f'b'HI)^' (S'H )0S (S'HS)6(T (ra'HS)SO'S— ' C"'HS)( S S'(ra'HS)n — 0 0 ' C"'HS)00 — 38·ΐ'(ω'Η 08·ΐ— 09·ΐ'(ζΗ8·9=ί"'Ρ'Ηε)3 · ΐ :軍 9 ( P-OS a)H N-HT 。 (^邈べ ϋ ( ^-9 - ( i .( S 'HI) S9'6' ( Z H0'6 = 1 "'P'HI) IS'8' ( Z H ε8 = ί"'Ρ'Ηΐ) ε 8' ( ζ Ηε8 = ί "'Ρ'Ηΐ) 0ε · Ζ' ( ζ Η0 · 6 = ί"'Ρ'Ηΐ) εΐ · Ζ'(ω'Ηε) 9Γ9— S9'9 '( Z H8'9 = f'b'HI ) ^ '( S ' H) 0S ( S 'HS) 6 (T (ra'HS) SO'S—' C "'HS) (S S'(ra'HS) n — 0 0 'C"' HS) 00 — 38 · ΐ '(ω'Η 08 · ΐ— 09 · ΐ' ( ζ Η8 · 9 = ί "'Ρ'Ηε) 3 · ΐ: Army 9 (P-OS a) H NH T. ϋ (^ -9-(i.
Figure imgf000201_0001
/ -
Figure imgf000201_0002
( ェ（
Figure imgf000201_0001
/-
Figure imgf000201_0002
(
Figure imgf000201_0003
Figure imgf000201_0003
S6圏第
Figure imgf000201_0004
S6 area first
Figure imgf000201_0004
ΐ)69·8'(ζΗε·6=ί"'Ρ'Ηΐ)ΐε·8'(ζΗ0·8=ί"'Ρ'Ηΐ) :·Ζ'(ζΗε·6=ί"'Ρ'Ηΐ)ΐ0·Ζ'(ζΗΓ8=ί"'Ρ'Ηΐ)8 Ζ·9'(ΖΗ0 =1"'Ρ'Ηΐ)εΓ9'(ζΗ0 'r8=f'PP'HI)89'9'(zHrZ=f'b'HI)0S' (S'H (s' Ηε)0ΐ· (s'HS)S9'S'(ra'HS) ΐ·ε— 90'S'C"'HS)SrS— 0rS'C"'HS)S9 — 9S'S'C"'HI)8ΐ) 69 · 8 '( ζ Ηε · 6 = ί "'Ρ'Ηΐ) ΐε · 8 '( ζ Η0 · 8 = ί"'Ρ'Ηΐ): · ('( ζ Ηε · 6 = ί "' Ρ 'Ηΐ) ΐ0 · Ζ' ( ζ ΗΓ8 = ί "'Ρ'Ηΐ) 8 Ζ9' ( Ζ Η0 = 1 '''Ρ'Ηΐ)εΓ9' ( ζ Η0 'r8 = f'PP'HI) 89' 9 '( z HrZ = f'b'HI) 0S' ( S 'H ( s ' Ηε) 0ΐ · ( s ' HS) S9'S'(ra'HS) ΐ · ε— 90'S'C "'HS) SrS— 0rS'C "'HS) S9 — 9S'S'C"' HI) 8
— 8S ' C"'H )0S 0rS'C"'HS)S0 — 06·ΐ'(ζΗΐ·Ζ=ΓΡ'Ηε)Ζ9·ΐ :軍 9 ( !DaD)H N-HT — 8S 'C "' H) 0S 0rS'C"'HS) S0 — 06 · ΐ' ( ζ Ηΐ · Ζ = ΓΡ'Ηε) Ζ9 · ΐ: Military 9 (! DaD) H NH T
。 .
ci l ( / —g—べ (ί,^Ρ 、 ^ΕΗ ー ( ^ （ ^ / （ / 一 一べ
Figure imgf000201_0005
ci l (/ —g—be (ί, ^ Ρ, ^ ΕΗ ー (^ (^ / (/
Figure imgf000201_0005
ベ
Figure imgf000201_0006
'ζ)-ζ)-1 、 T?iSui0S4— ( / S—べ ίί,^Ρ ^ EH ー S ,^ —8) = ^ Be
Figure imgf000201_0006
'ζ) -ζ) -1, T? i Sui 0S4— (/ S—Be ίί, ^ Ρ ^ EH ー S, ^ —8) = ^
98S6T0/S00Zdf/X3d 661· (s'HT)99"6'(zH2-6=rP'HT)09"8'(zHS-8=rP'HT)½-8'(zHe-ST=f'P'HT)6r8 '(ZHS"8=f'P'HT)68" '(ZH2T2"e=rPP'HT)6e" '(ra'H¾8r -er '(ZH9"S'2"e=rPP'HT) SO' '(zHS'SI=f'P'HI)9S'9'(s'HS)Sr C"'HS)96 — 06 ' C"'HS)S8 — 8rS'(ra'H^) S — Z ' (ω'Η 00 — 38·ΐ'(ω'Ηε)38·ΐ— 39·ΐ'(ω'Η 3ε·ΐ— OS'I :軍 9 ( OS ) 顺— Ητ 98S6T0 / S00Zdf / X3d 661 ( s 'HT) 99 "6' ( z H2-6 = rP'HT) 09" 8 '( z HS-8 = rP'HT) ½-8' ( z He-ST = f'P'HT) 6r8 '(ZHS "8 = f'P'HT) 68"' (ZH2T2 "e = rPP'HT) 6e"'(ra'H¾8r-er' (ZH9 "S'2" e = rPP'HT) SO '' ( z HS'SI = f'P'HI) 9S'9 '( s ' HS) Sr C "' HS) 96 — 06 'C"' HS) S8 — 8rS '(ra'H ^) S — Z'(ω'Η 00 — 38 · ΐ '(ω'Ηε) 38 · ΐ— 39 · ΐ'(ω'Η 3ε · ΐ— OS'I: Army 9 (OS) 顺 — Η τ
Figure imgf000202_0001
Figure imgf000202_0001
αΆ ( /^ (^ /—^ -Ζ) -Ζ) - Ι)) -Ζ) -S- (Ή) = ェ  αΆ (/ ^ (^ / — ^ -Ζ) -Ζ)-Ι)) -Ζ) -S- (Ή) =
Figure imgf000202_0002
Figure imgf000202_0002
圏第 No. 1
(δ'Ηΐ)03·6'(ζΗε·8=ΓΡ'Ηΐ)^·8'(ζΗΓ6=ί"'Ρ'Ηΐ)ε ·8'(ζΗ9 ·3ΐ=ί"'Ρ'Ηΐ)0ε·8'(ζΗε·8=ΓΡ'Ηΐ)ΐΖ·Ζ'(ΖΗ ·ΐ'ε·3=ΓΡΡ'Ηΐ)^ (ζΗ ·ΐ'3·ε=ΓΡΡ'Ηΐ)ΐ Γ '(ΖΗΓ6=ΓΡΉΐ)30· '(ΖΗ3·ε'ε·3=ΓΡΡΉΐ)96·9'(ζΗ9·3ΐ=ΓΡΉΐ)03·9'(ζΗ2· =Γ¾Ή θε· (s'HS)0r (ω'Η S6 — S8 ' C"'HS)S9 — SS ' (ζΗΐ·Ζ=ΓΡ'Η ε ' (ω'Ηε)ΟΓ
Figure imgf000202_0003
:軍 9 ( !DaD)H N-HT 。 ¾¾Sui9w— (^ (,^ （ ^^ / — 一べ
Figure imgf000202_0004
-S- (Ή) ^{ ^ ^^Λ^→- ^(^0Ά))- -^ -Ζ)— ε— (Ή) = ェ (δ'Ηΐ) 03 · 6 '( ζ Ηε8 = ΓΡ'Ηΐ) ^ · 8' ( ζ ΗΓ6 = ί "'Ρ'Ηΐ) ε 8' ( ζ Η9 3 · = ί"'Ρ'Ηΐ ) 0ε · 8 '( ζ Ηε8 = ΓΡ'Ηΐ) ΐΖ · Ζ' (ΖΗ · ΐ'ε · 3 = ΓΡΡ'Ηΐ) ^ ( ζ ΗΐΗ3 · ε = ΓΡΡ'Ηΐ) ΐ Γ ' (ΖΗΓ6 = ΓΡΉΐ) 30 · ' (ΖΗ3 · ε'ε · 3 = ΓΡΡΉΐ) 96 · 9' (ζ Η9 · 3ΐ = ΓΡΉΐ) 03 · 9 '(ζ Η2 · = Γ¾Ή θε · (s' HS) 0r ( ω'Η S6 — S8 'C "' HS) S9 — SS '( ζ Ηΐ · Ζ = ΓΡ'Η ε'(ω'Ηε) ΟΓ
Figure imgf000202_0003
: Military 9 (! DaD) H NH T. ¾¾Sui 9 w— (^ (, ^ (^^ / —
Figure imgf000202_0004
-S- (Ή) ^ {^ ^^ Λ ^ →-^ (^ 0 Ά))--^ -Ζ) — ε— (Ή) = d
Figure imgf000202_0005
Figure imgf000202_0005
98S6T0/S00Zdf/X3d 003 - OS ' (ω'Η ) SO - 36·ΐ'(ω )09·ΐ- 0 'I'(ra'HS)SS'I- ΟΓΐ :軍 9 ( OS ) 顺- Ητ 98S6T0 / S00Zdf / X3d 003 -OS '(ω'Η) SO-36 · ΐ' (ω) 09 · ΐ- 0 'I'(ra'HS)SS'I- ΟΓΐ: Army 9 (OS) 顺-Η τ
。 ¾¾Su¾ 邈 (^ {^y -Q-^fi
Figure imgf000203_0001
. ¾¾Su¾ 邈 (^ {^ y -Q- ^ fi
Figure imgf000203_0001
/—^ /^ ( /^^ ^ ( ^ [o-ε 'ZV^^  / — ^ / ^ (/ ^^ ^ (^ [o-ε 'ZV ^^
Figure imgf000203_0002
Figure imgf000203_0002
66圏第  66th area
(pBOjq'HT)S9"6-09"6'(zH0"8=f'P'HT)2Z" 8'(zH2"6=rP'HT)S^"8'(zHe"eT=rP'HT)0S"8'(s'HT)90"8'(zH0"8=rP'HT)0Z"Z'(zH2"6=f (pBOjq'HT) S9 "6-09" 6 '( z H0 "8 = f'P'HT) 2Z"8' ( z H2 "6 = rP'HT) S ^" 8 '( z He "eT = rP'HT) 0S "8 '(s ' HT) 90" 8 '(z H0 "8 = rP'HT) 0Z"Z' (zH2 "6 = f
'P'HI)S0 (s'HI)I8'9'(zHS'SI=rP'HI)0S'9'(ra'H6)SS' — 0S (s'HS)ir WHS) (^ 'P'HI) S0 ( s ' HI) I8'9 '( z HS'SI = rP'HI) 0S'9'(ra'H6) SS '— 0S ( s ' HS) ir WHS) (^
- srs'C"'H )06'i- 39·ΐ'(ζΗΐ·ζ=π'Ηε)9ε·ΐ'(ω'Ηπ)ε3·ΐ- :軍 9 ( ι α )Η顺- Ητ ¾§εΐ 4-6ίί^ （,^ （ / ^ /-srs'C "'H) 06'i- 39 · ΐ' ( ζ ζ · ζ = π'Ηε) 9ε · ΐ '(ω'Ηπ) ε3 · ΐ-: Military 9 (ι α) Η 顺-Η τ ¾§εΐ 4-6ίί ^ (, ^ (/ ^ /
Figure imgf000203_0003
Figure imgf000203_0003
¾:§Π 4-6ίί^( ^-9-^ίί ^/ ^4^-2- ^-8)— ε— (Ή) = ェ
Figure imgf000203_0004
¾: §Π 4-6ίί ^ (^ -9- ^ ίί ^ / ^ 4 ^ -2- ^ -8) — ε— (Ή) =
Figure imgf000203_0004
86fii¾?第 [SZSO] 86fii¾? Th [SZSO]
98S6T0/S00Zdf/X3d 1-03 ZSS9^0/900Z OAV 。 ¾¾Sui 2邈 fi ( ^- - ^^-Ζ- (,^
Figure imgf000204_0001
98S6T0 / S00Zdf / X3d 1-03 ZSS9 ^ 0 / 900Z OAV . ¾¾ Sui 2 邈 fi (^--^^-Ζ- (, ^
Figure imgf000204_0001
Figure imgf000204_0002
Figure imgf000204_0002
而圏第 Metasphere
(s'HT)0e-6'(W8=rP'HT)2 -8'(zHS-6=rP'HT)S^-8'(zH -ST=rP'HT)0 S"8'(zW8=rP'HT)TZ"Z'(zHS"6=f'P'HT)e0"Z'(ra'He)^8"9-^Z"9'(zHZ"ST=rP'HT)0e"9'(
Figure imgf000204_0003
(s'HT) 0e-6 '(W8 = rP'HT) 2 -8' ( z HS-6 = rP'HT) S ^ -8 '( z H -ST = rP'HT) 0 S "8' ( z W8 = rP'HT) TZ "Z '(zHS" 6 = f'P'HT) e0 "Z'(ra'He) ^ 8" 9- ^ Z "9 '( z HZ" ST = rP' HT) 0e "9 '(
Figure imgf000204_0003
WS'(ui'HS)S0 - 0Ζ·ΐ'(ω'Η 03·ΐ- 8ε·ΐ'(ζΗΐ·Ζ=ΓνΗε)9ε·ΐ :軍 9 ( !DaD)H N-HT WS '(ui'HS) S0-0Ζ · ΐ'(ω'Η 03 · ΐ-8ε · ΐ '( ζ Ηΐ · Ζ = ΓνΗε) 9ε · ΐ: Military 9 (! DaD) H NH T
。 .
( ^ / 9一べ ^^^^ [
Figure imgf000204_0004
'ζ)-χ)))-8)-ε-(Ή ^{ ^ ^^Λ^→- ^(^0Ά))- -^ -Ζ)— ε— (Ή) = ェ (^ / 9 all ^^^^ [
Figure imgf000204_0004
'ζ) -χ)))-8) -ε- (Ή ^ {^ ^^ Λ ^ →-^ (^ 0 Ά))--^ -Ζ) — ε— (Ή) = d
Figure imgf000204_0005
Figure imgf000204_0005
'Ηΐ)0Γ6'
Figure imgf000204_0006
'Ηΐ) 0Γ6'
Figure imgf000204_0006
(δ'Ηΐ)36·9'(ζΗ ·3ΐ=ΓΡ'Ηΐ)¾·9'(ω'Η )0 · — SS (s'HS)ir (S'HS)( 'S'C"'HS)( (δ'Ηΐ) 36 · 9 '( ζ Η · 3ΐ = ΓΡ'Ηΐ) ¾ · 9'(ω'Η) 0 · — SS ( s 'HS) ir ( S ' HS) ('S'C "' HS) (
98S6T0/S00Zdf/X3d 303 ZSS9^0/900Z OAV
Figure imgf000205_0001
（ / 98S6T0 / S00Zdf / X3d 303 ZSS9 ^ 0 / 900Z OAV
Figure imgf000205_0001
(/
- d ^ si^ -Z Ί- -Z)))→)-Z- fi jp/ W-s- ( ^エ {^y- 1 (,^ {Λ(^ ( 一 ε—ベ ίί,^ρ  -d ^ si ^ -Z Ί- -Z)))))-Z- fi jp / W-s- (^ e (^ y- 1 (, ^ {Λ (^ (one ε-be ίί, ^ ρ
Ί- ^-Ζ)))→) -Z-^ ^-l) -8) -£- (Ή) = ェ  Ί- ^ -Ζ))) →) -Z- ^ ^ -l) -8)-£-(Ή) =
Figure imgf000205_0002
Figure imgf000205_0002
εοι闘第 [θ8εο] εοι fight [θ8εο]
(ζΗΓ6=ί"'Ρ'Ηΐ)8ε·8'(ζΗ0·9ΐ=ί"'Ρ'Ηΐ)3ε·8'(ζΗ8·Ζ=ί"'Ρ'Ηΐ)06 • '(s'HT)T8" '(ZH8" =rP'HT)69" '(ra'H2)8S" -^" '(ra'H2)S2- -er '(ZHr6=rP'HT
Figure imgf000205_0003
(ζΗΓ6 = ί "'Ρ'Ηΐ) 8ε · 8' ( ζ Η0 · 9ΐ = ί"'Ρ'Ηΐ) 3ε · 8' ( ζ Η8 · Ζ = ί "'Ρ'Ηΐ) 06 •'(s' HT) T8 "'(ZH8" = rP'HT) 69 "'(ra'H2)8S"-^"'(ra'H2) S2- -er' (ZHr6 = rP'HT
Figure imgf000205_0003
8·ε'(ω'Ηΐ)3ε·ε— SS'S'C"'HI)SO'S— 00·ε'(ω'Ηΐ)06 — S8'S'C"'HI)0rS— SS'S'C"'HS)0S' 2— SS'2'(UI'HI)SS - SrS'8 · ε '(ω'Ηΐ) 3ε · ε—SS'S'C "' HI) SO'S—00 · ε '(ω'Ηΐ) 06 — S8'S'C"' HI) 0rS—SS'S'C "'HS) 0S '2— SS ' 2 '(UI'HI) SS-SrS'
Figure imgf000205_0004
Figure imgf000205_0004
( / ェ ( / - 1 { iJ. {^^{^y-Z- ^ ^ si^-Z Ί- ^
Figure imgf000205_0005
、ェつ 5 (/ É (/-1 {iJ. {^^ {^ yZ- ^ ^ si ^ -Z Ί- ^
Figure imgf000205_0005
, 5
Figure imgf000205_0006
Figure imgf000205_0006
(s'HT)ZS"6'(zH2"6=rP'HT)8^"8'(zHS (s'HT) ZS "6 '( z H2" 6 = rP'HT) 8 ^ "8' ( z HS
·8=ΓΡΉΐ)9^·8'(ζΗ3·3ΐ=ΓΡΉΐ) 9· '(ζΗε·8=ΓΡΉΐ)29· '(ζΗ2·6=Γ'ΡΉΐ)2Γ '(ωΉε
Figure imgf000205_0007
・ 8 = ΓΡΉΐ) 9 ^ ・ 8 '( ζ Η3 ・ 3ΐ = ΓΡΉΐ) 9 ・' (ζΗε ・ 8 = ΓΡΉΐ) 29 ・ '(ζΗ2 ・ 6 = Γ'ΡΉΐ) 2Γ' (ωΉε
Figure imgf000205_0007
— S'C"'HS)( — OS ' C"'HS)S6'I— S9'I'(ra'HS)9S'I— OS'I :軍 9 ( OS ) 顺— HT — S'C "'HS) (— OS'C"'HS)S6'I—S9'I'(ra'HS)9S'I—OS'I: Army 9 (OS) 顺 —H T
98S6T0/S00Zdf/X3d SOS 33mgを得た。 98S6T0 / S00Zdf / X3d SOS 33 mg was obtained.
1H-NMR(DMSO-d— D O) δ値： 1.60— 1.80(2H,m),2.00— 2.20(2H,m),2.30— 2.90(3H,m),  1H-NMR (DMSO-d—D 2 O) δ value: 1.60— 1.80 (2H, m), 2.00— 2.20 (2H, m), 2.30— 2.90 (3H, m),
6 2  6 2
2.95-3.10(2H,m),3.15-3.30(lH,m),3.40-3.52(lH,m),3.94(2H,s),4.03(3H,s),5.90-5.9 7(lH,m),6.61(lH,d,J=15.7Hz),7.15(lH,d,J=9.4Hz),7.27(lH,t,J=7.8Hz),7.39(lH,d,J= 7.8Hz),7.57(lH,t,J=7.8Hz),7.72(lH,d,J=7.8Hz),7.88-7.93(2H,m),8.08(lH,s),8.28(l H,d,J=15.7Hz),8.57(lH,d,J=9.4Hz)  2.95-3.10 (2H, m), 3.15-3.30 (lH, m), 3.40-3.52 (lH, m), 3.94 (2H, s), 4.03 (3H, s), 5.90-5.9 7 (lH, m) , 6.61 (lH, d, J = 15.7Hz), 7.15 (lH, d, J = 9.4Hz), 7.27 (lH, t, J = 7.8Hz), 7.39 (lH, d, J = 7.8Hz), 7.57 (lH, t, J = 7.8Hz), 7.72 (lH, d, J = 7.8Hz), 7.88-7.93 (2H, m), 8.08 (lH, s), 8.28 (l H, d, J = 15.7Hz ), 8.57 (lH, d, J = 9.4Hz)
[0381] 実施例 104
Figure imgf000206_0001
l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ンー4一力ルボン酸 33mgの塩化メチレン 2mL溶液に、塩化チォ -ル lmLおよび N, N ージメチルホルムアミド 20 Lを加え、 2時間加熱還流した。減圧下で溶媒を留去し、 クロ口ホルム 2mL、 5 フルォロ一 2—メトキシキノリン一 8 ァミン 18mgのクロ口ホルム 3mL溶液およびトリェチルァミン 38 Lをカ卩え、室温で 30分間攪拌した。反応混合物 に水およびクロ口ホルムをカ卩えた。有機層を分取し、水層をクロ口ホルムで抽出した。 有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、 無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリ 力ゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 20： 1]で精製し、 淡褐色固体の 1一（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチ ル） N— (5—フルオロー 2—メトキシキノリン一 8—ィル）ピぺリジン一 4—カルボキ サミド 17mgを得た。 [0381] Example 104
Figure imgf000206_0001
l-(2- (2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piberidin-4 monolithic rubonic acid 33 ml of methylene chloride in 2 ml solution of thiol chloride lmL and N , N-dimethylformamide (20 L) was added, and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and 2 mL of black mouth form, 5 mL of 5-fluoro-2-methoxyquinoline 18 mg, 3 mL of black mouth form and 38 L of triethylamine were added and stirred at room temperature for 30 minutes. Water and black mouth form were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1] to obtain a light brown solid 1 1 (2- (2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) 17 mg of N— (5-fluoro-2-methoxyquinoline 8-yl) piperidine 4-carboxamide was obtained.
^-NMRCCDCl ) δ値： 1.90— 2.05(2H,m),2.10— 2.25(4H,m),2.35— 2.50(lH,m),2.55— 2.6  ^ -NMRCCDCl) δ value: 1.90— 2.05 (2H, m), 2.10— 2.25 (4H, m), 2.35— 2.50 (lH, m), 2.55— 2.6
3  Three
5(2H,m),2.70-2.78(2H,m),3.08-3.17(2H,m),4.11(3H,s),4.24(4H,s),6.68(lH,dd,J=8.1, 2.0Hz),6.73(lH,d,J=2.0Hz),6.78(lH,d,J=8.1Hz),6.99-7.07(2H,m),8.27(lH,d,J=9.0H z),8.66(lH,dd,J=8.8,5.4Hz),9.41(lH,s)  5 (2H, m), 2.70-2.78 (2H, m), 3.08-3.17 (2H, m), 4.11 (3H, s), 4.24 (4H, s), 6.68 (lH, dd, J = 8.1, 2.0 Hz), 6.73 (lH, d, J = 2.0Hz), 6.78 (lH, d, J = 8.1Hz), 6.99-7.07 (2H, m), 8.27 (lH, d, J = 9.0H z), 8.66 (lH, dd, J = 8.8,5.4Hz), 9.41 (lH, s)
[0382] 実施例 105
Figure imgf000207_0001
[0382] Example 105
Figure imgf000207_0001
l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ンー4一力ルボン酸 73mgの塩化メチレン 2mL溶液に、塩化チォ -ル lmLおよび N, N ージメチルホルムアミド 20 Lを加え、 2時間加熱還流した。減圧下で溶媒を留去した 。クロ口ホルム 2mL、 7 フルォロ一 2—メトキシキノリン一 8 ァミン 40mgのクロ口ホル ム 3mL溶液およびトリェチルァミン 87 Lをカ卩え、室温で 30分間攪拌した。反応混合 物に水およびクロ口ホルムをカ卩え、 1.0mol/L水酸化ナトリウム水溶液で pHIOに調整し た。有機層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出液を合わせ 、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥さ せ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [ 溶離液;クロ口ホルム:メタノール = 20 : 1]で精製し、淡灰色固体の 1— (2— (2, 3- ジヒドロべンゾ [b] [1, 4]ジォキシン一 6—ィル）ェチル） N— (7 フルオロー 2—メ トキシキノリン 8—ィル）ピぺリジン 4—カルボキサミド 53mgを得た。  l-(2- (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piberidin-4 monostrength rubonic acid 73 ml of methylene chloride in 2 ml of methylene chloride , N-dimethylformamide (20 L) was added, and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure. 2 mL of black mouth form, 7 fluoro-2-methoxyquinoline 1 8 amamine 3 mg solution of black mouth form and 87 L of triethylamine were added and stirred at room temperature for 30 minutes. Water and black mouth form were added to the reaction mixture, and adjusted to pHIO with 1.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1] to obtain a light gray solid 1— (2— (2,3-dihydrobenzo [b] [ 1,4] dioxin 6-yl) ethyl) N— (7 fluoro-2-methoxyquinoline 8-yl) piperidine 4-carboxamide 53 mg was obtained.
'H-NMRCCDCl ) δ値： 1.80— 2.25(6H,m),2.45— 2.65(3H,m),2.68— 2.78(2H,m),3.06— 3.1 'H-NMRCCDCl) δ value: 1.80— 2.25 (6H, m), 2.45— 2.65 (3H, m), 2.68— 2.78 (2H, m), 3.06— 3.1
3  Three
4(2H,m),4.05(3H,s),4.24(4H,s),6.66-6.80(3H,m),6.88(lH,d,J=8.8Hz),7.20-7.30(lH, m),7.54(lH,dd,J=8.8,5.4Hz),7.95-7.97(2H,m)  4 (2H, m), 4.05 (3H, s), 4.24 (4H, s), 6.66-6.80 (3H, m), 6.88 (lH, d, J = 8.8Hz), 7.20-7.30 (lH, m) 7.54 (lH, dd, J = 8.8,5.4Hz), 7.95-7.97 (2H, m)
実施例 106
Figure imgf000207_0002
Example 106
Figure imgf000207_0002
7—メトキシ一 1— (ォキシラン一 2—ィル）イソキノリン 50mgの N, N ジメチルホル ムアミド 3mL溶液に、室温で N— (2 フエ-ルェチル）ピぺリジンー4 カルボキサミ ド 58mgおよび過塩素酸リチウム 27mgを加え、 80〜90°Cで 3時間攪拌した。反応混合 物を室温まで冷却し、水および酢酸ェチルを加えた。有機層を分取し、水層を酢酸 ェチルで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水 溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。 得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノー ル = 9 : 1]で精製し、淡褐色固体の 1— (2 ヒドロキシ一 2— (7—メトキシイソキノリン 1 ィル）ェチル） -N- (2 フエ-ルェチル）ピぺリジンー4 カルボキサミド 90m gを得た。 7-Methoxy-1- (oxylan-2-yl) isoquinoline 50 mg of N, N dimethylformamide in 3 mL solution at room temperature with 58 mg of N- (2-phenyl) piperidine-4 carboxamide and 27 mg of lithium perchlorate In addition, the mixture was stirred at 80 to 90 ° C for 3 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 9: 1], and 1- (2 hydroxy-2- (7-methoxyisoquinoline 1 yl) as a light brown solid. Ethyl) -N- (2 ferroethyl) piperidine-4 carboxamide 90 mg was obtained.
1H-NMR(CDC1 ) δ値： 1.70- 1.90(4H,m),2.00- 2.35(3H,m),2.72- 2.87(4H,m),3.11- 3.2  1H-NMR (CDC1) δ value: 1.70-1.90 (4H, m), 2.00-2.35 (3H, m), 2.72-2.87 (4H, m), 3.11-3.2
3  Three
2(2H,m),3.52-3.57(2H,m),3.96(3H,s),5.44-5.54(2H,m),7.15-7.40(6H,m),7.48(lH,d,J 2 (2H, m), 3.52-3.57 (2H, m), 3.96 (3H, s), 5.44-5.54 (2H, m), 7.15-7.40 (6H, m), 7.48 (lH, d, J
=2.4Hz),7.53(lH,d,J=5.9Hz),7.76(lH,d,J=9.0Hz),8.35(lH,d,J=5.6Hz) = 2.4Hz), 7.53 (lH, d, J = 5.9Hz), 7.76 (lH, d, J = 9.0Hz), 8.35 (lH, d, J = 5.6Hz)
実施例 107 Example 107
Figure imgf000208_0001
Figure imgf000208_0001
8—（（（1一 （2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン一 6 ィル）ェチル）ピ ペリジン一 4 ィル）カルボ-ル）ァミノ） 2—メトキシキノリン 4 カルボン酸 35mg の N, N ジメチルホルムアミド 2mL懸濁液に、室温でグリシン =ェチル =エステルの 塩酸塩 10mg、 O— (7 ァザべンゾトリアゾール 1—ィル） 1, 1, 3, 3—テトラメチ ルゥ口-ゥム =へキサフルォロホスフェート 40mgおよびトリェチルァミン 29 μ Lを加え、 70°Cで 1時間攪拌した。反応混合物を室温まで冷却し、酢酸ェチルおよび水を加え た。有機層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わせ 、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥さ せ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [ 溶離液；クロ口ホルム：メタノール = 20： 1]で精製し、淡褐色固体の N— ( (8— ( ( ( 1— (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピぺリジンー4 ィル）カルボ-ル）ァミノ） 2—メトキシキノリン 4 ィル）カルボニル）グリシン = ェチル =エステル 22mgを得た。  8-((((1- (2- (2,3 Dihydrobenzo [b] [l, 4] dioxin-6 yl) ethyl) piperidine-4-yl) carbol) amino) 2-methoxy Quinoline 4 Carboxylic acid 35 mg in N, N dimethylformamide suspension in 2 mL at room temperature with glycine = ethyl = ester hydrochloride 10 mg, O— (7azabenzotriazole 1-yl) 1, 1, 3, 40 mg of 3-tetramethyl ru-mu-hexafluorophosphate and 29 μL of triethylamine were added, and the mixture was stirred at 70 ° C. for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1], and N— ((8— (((1— (2- (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6yl) ethyl) piperidine-4yl) carbol) amino) 2-methoxyquinoline 4yl) carbonyl) glycine = ethyl = ester 22mg It was.
'H-NMRCCDCl ) δ値： 1.34(3H,t,J=7.2Hz),1.90- 2.05(2H,m),2.10- 2.25(4H,m),2.40- 2  'H-NMRCCDCl) δ value: 1.34 (3H, t, J = 7.2Hz), 1.90-2.05 (2H, m), 2.10-2.25 (4H, m), 2.40-2
3  Three
.50(lH,m),2.58-2.65(2H,m),2.70-2.77(2H,m),3.08-3.16(2H,m),4.10(3H,s),4.24(4H,s ),4.29(2H,q,J=7.2Hz),4.30(2H,d,J=5.2Hz),6.63(lH,t,J=5.2Hz),6.68(lH,dd,J=8.2,2.0 ΰ : ( / 一 g—ベ (ί,^ρ ^ ー 一 8)— ε= ^エ、τ¾マ / crn^、 つ辛爵 瀚缀、 止 教
Figure imgf000209_0001
— N .50 (lH, m), 2.58-2.65 (2H, m), 2.70-2.77 (2H, m), 3.08-3.16 (2H, m), 4.10 (3H, s), 4.24 (4H, s), 4.29 (2H, q, J = 7.2Hz), 4.30 (2H, d, J = 5.2Hz), 6.63 (lH, t, J = 5.2Hz), 6.68 (lH, dd, J = 8.2,2.0 ΰ: (/ 1 g—be (ί, ^ ρ ^ ー 1 8) — ε = ^ d, τ¾ ma / crn ^
Figure imgf000209_0001
— N
Figure imgf000209_0002
Figure imgf000209_0002
60ΐ圏第 [98S0] (s'HT)89"6'(zH8"S=rVHT)80"6'(zH0"8=f'P 60th Region [98S0] ( s ' HT) 89 "6 '( z H8" S = rVHT) 80 "6' ( z H0" 8 = f'P
Ήΐ)ΐ3·8'(ζΗ0·8=Γ'ΡΉΐ)ε8· '(ζΗ0·8=Γ Ηΐ)ε^· '(8'Ηΐ)0Γ '(ω'Η2) ·9-2 ·9'(ω'Η ΐ)0Γ9— S9'9'(S'H )0S ' (s'HS)Sr (zH8'S=l"'P'HS 6'S'(ra'HS)0rS— S6 ' C"'HS)( Ήΐ) ΐ3 ・ 8 '( ζ Η0 ・ 8 = Γ'ΡΉΐ) ε8 ・' (ζΗ0 ・ 8 = Γ Ηΐ) ε ^ ・ '(8'Ηΐ) 0Γ'(ω'Η2) 9-2 9 (ω'Η ΐ) 0Γ9— S9'9 '( S ' H) 0S '( s ' HS) Sr ( z H8'S = l "'P'HS 6'S'(ra'HS) 0rS— S6 'C"' HS ) (
- S ' C"'H 0S - SO ' C"'H S0 - 06·ΐ'(ω'Η 38·ΐ- S9'I :軍 9 ( OS ) 顺- Ητ -S 'C "' H 0S-SO 'C"' H S0-06 · ΐ '(ω'Η 38 · ΐ- S9'I: Army 9 (OS) 顺 -Η τ
Figure imgf000209_0003
ε 'ζ) -s) -I))) -8)) -NO)*}@^g、つ ¾ ^^難 一ェ エ^ ατ¾氺
Figure imgf000209_0003
ε 'ζ) -s) -I))) -8)) -NO) *} @ ^ g, ¾ ^^ difficultly ^ ατ¾ 氺
、つ 呦^圑。 つ 鱸 o'sHd、 難^ n/ioui(n
Figure imgf000209_0004
。 ·Πつ ^ 呦 呦.鱸 o'sHd, Difficulty ^ n / ioui (n
Figure imgf000209_0004
. · Π
Figure imgf000209_0005
Figure imgf000209_0005
^ ^Ι ^α^Δ^、 /— ^ o)§ui8M/ エ = ^エ =ベ （ /  ^ ^ Ι ^ α ^ Δ ^, / — ^ o) §ui8M / d = ^ d = ((/
ェ（ / 9一べ^^ 、 [
Figure imgf000209_0006
'Z)-Z)-I)))-S))-K (9/9 all ^^, [
Figure imgf000209_0006
'Z) -Z) -I)))-S))-K
Figure imgf000209_0007
Figure imgf000209_0008
·8=ί"'ΡΡ' HT)T8"Z'(zH2"8=rVHT)2^"Z'(s'HT)60"Z'(zH2"8=f'P'HT)8Z"9'(zH0"2=rP'HT)SZ"9'(zH
Figure imgf000209_0007
Figure imgf000209_0008
· 8 = ί "'ΡΡ' HT) T8" Z '(zH2 "8 = rVHT) 2 ^"Z'(s'HT) 60 "Z '(zH2" 8 = f'P'HT) 8Z "9' ( z H0 "2 = rP'HT) SZ" 9 '( z H
98S6T0/S00Zdf/X3d Ζ03 オナート 0.28gおよびトリェチルァミン 0.43mLをカ卩え、室温で 1時間攪拌した。反応混 合物に水およびクロ口ホルムをカ卩えた。有機層を分取し、水層をクロ口ホルムで抽出 した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗 浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物 をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 20： 1]で精 製し、淡褐色固体のェチル = 3—（8—（（（1一（2—（2, 3 ジヒドロべンゾ [b] [l, 4] ジォキシン— 6 ィル）ェチル）ピぺリジン— 4 ィル）カルボ-ル）ァミノ） 2—メトキ シキノリン— 5—ィル）プロピオナート 0.41gを得た。 98S6T0 / S00Zdf / X3d Ζ03 0.28 g of onate and 0.43 mL of triethylamine were added and stirred at room temperature for 1 hour. Water and black mouth form were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1], and the light brown solid ethyl = 3— (8 — (((1 1 (2— (2 , 3 Dihydrobenzo [b] [l, 4] Dioxin— 6 yl) Ethyl) Piperidine — 4 yl) Carboyl) Amino) 2-Methoxyquinoline— 5-yl) Propionate 0.41 g Obtained.
'H-NMRCCDCl ) δ値： 1.24(3H,t,J=7.3Hz),1.90- 2.03(2H,m),2.10- 2.20(4H,m),2.37- 2  'H-NMRCCDCl) δ value: 1.24 (3H, t, J = 7.3Hz), 1.90-2.03 (2H, m), 2.10-2.20 (4H, m), 2.37-2
3  Three
.48(lH,m),2.56-2.76(6H,m),3.06-3.14(2H,m),3.26-3.33(2H,m),4.10(3H,s),4.13(2H, q,J=7.3Hz),4.24(4H,s),6.68(lH,dd,J=8.2,2.0Hz),6.73(lH,d,J=2.0Hz),6.78(lH,d,J=8. 2Hz),7.00(lH,d,J=9.1Hz),7.23(lH,d,J=8.0Hz),8.25(lH,d,J=9.1Hz),8.63(lH,d,J=8.0H z),9.63(lH,s)  .48 (lH, m), 2.56-2.76 (6H, m), 3.06-3.14 (2H, m), 3.26-3.33 (2H, m), 4.10 (3H, s), 4.13 (2H, q, J = 7.3Hz), 4.24 (4H, s), 6.68 (lH, dd, J = 8.2,2.0Hz), 6.73 (lH, d, J = 2.0Hz), 6.78 (lH, d, J = 8.2Hz), 7.00 (lH, d, J = 9.1Hz), 7.23 (lH, d, J = 8.0Hz), 8.25 (lH, d, J = 9.1Hz), 8.63 (lH, d, J = 8.0H z), 9.63 (lH, s)
実施例 110 Example 110
Figure imgf000210_0001
Figure imgf000210_0001
3—（8—（（（1一（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチ ル）ピぺリジン— 4—ィル）カルボ-ル）ァミノ） 2—メトキシキノリン— 5—ィル）プロピ オン酸 20mgの N, N ジメチルホルムアミド 2mL溶液に、 N, N，—カルボ-ルジイミダ ゾール 9.4mgをカ卩え、室温で 1時間、 35°Cで 30分間攪拌した。 N, N， 一カルボ-ルジ イミダゾール 19mgをカ卩え、 40〜50°Cで 1時間攪拌した。反応混合物を室温まで冷却し 、メタンスルホンアミド 4.3mgおよび 1, 8 ジァザビシクロ [5. 4. 0]ゥンデク一 7 ェ ン 8.5 Lを加え、 40〜50°Cで 30分間攪拌した。反応混合物を室温まで冷却し、水お よび酢酸ェチルをカ卩え、 1.0mol/L塩酸で pH7.4に調整した。有機層を分取し、水層を 酢酸ェチルで 3回抽出した。有機層および抽出液を合わせ、飽和塩ィ匕ナトリウム水溶 液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた 残留物にメタノールをカ卩え、固形物をろ取し、白色固体の 1 （2— (2, 3 ジヒドロべ ンゾ [b] [1, 4]ジォキシン 6 ィル）ェチル） N— (2—メトキシー5—（3 （（メチ ルスルホ -ル）ァミノ） 3—ォキソプロピル）キノリン一 8—ィル）ピぺリジン一 4—カル ボキサミド 10mgを得た。 3— (8 — (((1 (2— (2, 3 dihydrobenz [b] [l, 4] dioxin 6 yl) ethyl) piperidine—4 yl) carbol ) Amino) 2-Methoxyquinoline-5-yl) propionic acid 20 mg of N, N dimethylformamide in 2 mL of solution, 9.4 mg of N, N, -carbodiimidazole was added, and 1 hour at room temperature, 35 ° Stir at C for 30 minutes. N, N, monocarbodiimidazole (19 mg) was added and stirred at 40-50 ° C for 1 hour. The reaction mixture was cooled to room temperature, 4.3 mg of methanesulfonamide and 8.5 L of 1,8 diazabicyclo [5.4.0] undecene were added, and the mixture was stirred at 40 to 50 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the pH was adjusted to 7.4 with 1.0 mol / L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. Combine the organic layer and the extract, and use saturated sodium chloride aqueous solution. The solution was washed with liquid, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methanol was added to the residue obtained, and the solid was collected by filtration. 1 (2- (2, 3 dihydrobenz [b] [1, 4] dioxin 6 yl) ethyl) N — 10 mg of (2-methoxy-5- (3 ((methylsulfoyl) amino) 3-oxopropyl) quinoline 1-yl) piperidine 1 4-carboxamide was obtained.
1H-NMR(DMSO-d ) δ値： 1.70— 1.85(2H,m),1.95— 2.05(2H,m),2.20— 2.36(2H,m),2.45—  1H-NMR (DMSO-d) δ value: 1.70— 1.85 (2H, m), 1.95—2.05 (2H, m), 2.20—2.36 (2H, m), 2.45—
6  6
2.75(7H,m),3.09(3H,s),3.05-3.25(4H,m),4.09(3H,s),4.20(4H,s),6.65-6.70(lH,m),6.7 2-6.78(2H,m),7.13(lH,d,J=9.1Hz),7.24(lH,d,J=8.0Hz),8.38(lH,d,J=8.0Hz),8.45(lH, d,J=9.1Hz),9.63(lH,s)  2.75 (7H, m), 3.09 (3H, s), 3.05-3.25 (4H, m), 4.09 (3H, s), 4.20 (4H, s), 6.65-6.70 (lH, m), 6.7 2-6.78 (2H, m), 7.13 (lH, d, J = 9.1Hz), 7.24 (lH, d, J = 8.0Hz), 8.38 (lH, d, J = 8.0Hz), 8.45 (lH, d, J = 9.1Hz), 9.63 (lH, s)
実施例 111 Example 111
Figure imgf000211_0001
Figure imgf000211_0001
l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ンー4一力ルボン酸 93mgの塩化メチレン 2mL溶液に、塩化チォ -ル lmLおよび N, N ージメチルホルムアミド 20 Lを加え、 2時間加熱還流した。減圧下で溶媒を留去し、 クロ口ホルム 3mL、 2—メトキシ一 4—メチルキノリン一 8 ァミン 50mgおよびトリェチル ァミン 0.1 lmLをカ卩え、室温で 1時間攪拌した。反応混合物に水およびクロ口ホルムを 加えた。有機層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出液を合 わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾 燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフ ィー [溶離液；クロ口ホルム：メタノール = 20： 1]で精製し、淡褐色固体の 1— (2— (2 , 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6 ィル）ェチル） N— (2—メトキシー4 ーメチルキノリンー8 ィル）ピぺリジンー4 カルボキサミド 15mgを得た。  l-(2- (2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piberidin-4 monostrength rubonic acid 93 mg of methylene chloride in 2 mL solution of thiol chloride lmL and N , N-dimethylformamide (20 L) was added, and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and 3 mL of black mouth form, 50 mg of 2-methoxy-4-methylquinoline and 8 mL of triethylamine were added and stirred at room temperature for 1 hour. Water and black mouth form were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1] to give a light brown solid 1- (2- (2, 3 dihydrobenzo [b] [l, 4] dioxin-6yl) ethyl) N- (2-methoxy-4-methylquinoline-8yl) piperidine-4 carboxamide 15 mg was obtained.
1H-NMR(CDC1 ) δ値： 1.90— 2.05(2H,m),2.10— 2.20(4H,m),2.38— 2.50(lH,m),2.55— 2.6 1H-NMR (CDC1) δ value: 1.90—2.05 (2H, m), 2.10—2.20 (4H, m), 2.38—2.50 (lH, m), 2.55—2.6
3  Three
7(2H,m),2.63(3H,s),2.69-2.78(2H,m),3.06-3.15(2H,m),4.07(3H,s),4.24(4H,s),6.68(l H,dd,J=8.3,2.0Hz),6.73(lH,d,J=2.0Hz),6.78(lH,d,J=8.3Hz),6.81(lH,s),7.39(lH,t,J= 8.1Hz), 7.57(lH,d,J=8.1Hz),8.73(lH,d,J=8.1Hz),9.74(lH,s) [0389] 実施例 112 7 (2H, m), 2.63 (3H, s), 2.69-2.78 (2H, m), 3.06-3.15 (2H, m), 4.07 (3H, s), 4.24 (4H, s), 6.68 (l H , dd, J = 8.3,2.0Hz), 6.73 (lH, d, J = 2.0Hz), 6.78 (lH, d, J = 8.3Hz), 6.81 (lH, s), 7.39 (lH, t, J = 8.1Hz), 7.57 (lH, d, J = 8.1Hz), 8.73 (lH, d, J = 8.1Hz), 9.74 (lH, s) [0389] Example 112
Figure imgf000212_0001
Figure imgf000212_0001
l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ンー4一力ルボン酸 79mgの塩化メチレン 2mL溶液に、塩化チォ -ル lmLおよび N, N ージメチルホルムアミド 20 Lを加え、 1時間加熱還流した。減圧下で溶媒を留去し、 クロ口ホルム 4mL、ェチル = 3— (8—ァミノ一 2—メトキシキノリン一 4—ィル）プロピオ ナート 62mgおよびトリェチルァミン 96 Lをカ卩え、室温で 1時間攪拌した。反応混合物 に水およびクロ口ホルムをカ卩えた。有機層を分取し、水層をクロ口ホルムで抽出した。 有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、 無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリ 力ゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 20： 1]で精製し、 淡褐色油状物のェチル = 3—（8—（（（1一（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジ ォキシン— 6—ィル）ェチル）ピぺリジン— 4—ィル）カルボ-ル）ァミノ）—2—メトキシ キノリンー4 ィル）プロピオナート 55mgを得た。  l-(2- (2, 3 dihydrobenzzo [b] [l, 4] dioxin 6 yl) ethyl) piberidin-4 monostrength rubonic acid 79 mg of methylene chloride in 2 mL solution of thiol chloride lmL and N , N-dimethylformamide (20 L) was added, and the mixture was heated to reflux for 1 hour. Evaporate the solvent under reduced pressure, and add 4 mL of chloroform formaldehyde, 62 mg of ethyl = 3- (8-amino-2-methoxyquinoline-4-yl) propionate and 96 L of triethylamine, and stir at room temperature for 1 hour. did. Water and black mouth form were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1], and ethyl of pale brown oily substance = 3- (8-(((1 (1 (2— (2,3 dihydrobenz [b] [l, 4] dioxin-6-yl) ethyl) piperidine-4-yl) carbol) amino) -2-methoxyquinoline-4-yl) Propionate 55 mg was obtained.
'H-NMRCCDCl ) δ値： 1.25(3H,t,J=7.3Hz),1.90- 2.05(2H,m),2.10- 2.23(4H,m),2.35- 2  'H-NMRCCDCl) δ value: 1.25 (3H, t, J = 7.3Hz), 1.90-2.05 (2H, m), 2.10-2.23 (4H, m), 2.35- 2
3  Three
.50(lH,m),2.55-2.65(2H,m),2.69-2.81(4H,m),3.06-3.15(2H,m),3.30-3.40(2H,m),4.0 7(3H,s),4.16(2H,q,J=7.3Hz),4.24(4H,s),6.66-6.84(4H,m),7.40(lH,t,J=8.1Hz),7.60(l H,d,J=8.1Hz),8.73(lH,d,J=8.1Hz),9.74(lH,s)  .50 (lH, m), 2.55-2.65 (2H, m), 2.69-2.81 (4H, m), 3.06-3.15 (2H, m), 3.30-3.40 (2H, m), 4.0 7 (3H, s ), 4.16 (2H, q, J = 7.3Hz), 4.24 (4H, s), 6.66-6.84 (4H, m), 7.40 (lH, t, J = 8.1Hz), 7.60 (l H, d, J = 8.1Hz), 8.73 (lH, d, J = 8.1Hz), 9.74 (lH, s)
[0390] 実施例 113 [0390] Example 113
Figure imgf000212_0002
Figure imgf000212_0002
ェチル = 3— (8— ( ( (1— (2— (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6— ィル）ェチル）ピぺリジン— 4—ィル）カルボニル）ァミノ） 2—メトキシキノリン— 4—ィ ル）プロピオナート 50mgのエタノール 2mL溶液に、 20%水酸化ナトリウム水溶液 0.11m Lおよび水 0.2mLを加え、 40°Cで 30分間攪拌した。反応混合物を室温まで冷却し、減 圧下で溶媒を留去した。水 2mLをカ卩え、 1.0mol/L塩酸で pH6.8に調整した。固形物を ろ取し、水およびジェチルエーテルで洗浄し、淡褐色固体の 3—（8—（（（1一（2— ( 2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピぺリジン 4ーィル )カルボ-ル）ァミノ） 2—メトキシキノリンー4 ィル）プロピオン酸 30mgを得た。Ethyl = 3— (8— (((1— (2— (2, 3 Dihydrobenzo [b] [l, 4] dioxin-6-yl) ethyl) piperidine-4-yl) carbonyl) Amino) 2-methoxyquinoline 4- E) To a solution of propionate 50 mg in ethanol 2 mL, 20% aqueous sodium hydroxide solution 0.11 mL and water 0.2 mL were added, and the mixture was stirred at 40 ° C. for 30 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. 2 mL of water was added and adjusted to pH 6.8 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water and jetyl ether, and the light brown solid 3— (8 — (((1 ((2— (2,3 dihydrobenzo [b] [l, 4] dioxin 6yl) ethyl) piperidine 4-yl) carbol) amino) 2-methoxyquinoline-4-yl) propionic acid 30 mg was obtained.
- NMR(DMSO- d ) S値：  -NMR (DMSO- d) S value:
6  6
1.64-1.78(2H,m),1.91-2.00(2H,m),2.02-2.14(2H,m),2.44-2.72(7H,m),2.94-3.04(2H, m),3.20-3.30(2H,m),4.06(3H,s),4.20(4H,s),6.66(lH,dd,J=8.3,2.0Hz),6.72(lH,d,J=2. 0Hz),6.74(lH,d,J=8.3Hz),6.95(lH,s),7.42(lH,t,J=8.0Hz),7.71(lH,dd,J=8.0,l.lHz),8. 51(lH,dd,J=8.0,l.lHz),9.70(lH,s)  1.64-1.78 (2H, m), 1.91-2.00 (2H, m), 2.02-2.14 (2H, m), 2.44-2.72 (7H, m), 2.94-3.04 (2H, m), 3.20-3.30 (2H , m), 4.06 (3H, s), 4.20 (4H, s), 6.66 (lH, dd, J = 8.3,2.0Hz), 6.72 (lH, d, J = 2.0Hz), 6.74 (lH, d , J = 8.3Hz), 6.95 (lH, s), 7.42 (lH, t, J = 8.0Hz), 7.71 (lH, dd, J = 8.0, l.lHz), 8.51 (lH, dd, J = 8.0, l.lHz), 9.70 (lH, s)
実施例 114 Example 114
Figure imgf000213_0001
Figure imgf000213_0001
l - (2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィル）ェチル）ピベリジ ンー4一力ルボン酸 51mgの塩化メチレン 2mL溶液に、塩化チォ -ル lmLおよび N, N ージメチルホルムアミド 20 Lを加え、 1時間 30分間加熱還流した。減圧下で溶媒を 留去し、クロ口ホルム 2mL、ェチル = (E) - 3- (8—ァミノ一 2—メトキシキノリン一 4— ィル）アタリラート 40mgのクロ口ホルム 2mL溶液およびトリェチルァミン 63 μ Lを加え、 室温で 3時間攪拌した。反応混合物に水およびクロ口ホルムを加えた。有機層を分取 し、水層をクロ口ホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩 化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒 を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホル ム:メタノール = 20 : 1]で精製し、淡褐色油状物のェチル = (E) - 3- (8- ( ( (l - ( 2- (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシンー6 ィル）ェチル）ピぺリジンー4 ィル)カルボ-ル)ァミノ）一 2—メトキシキノリン一 4—ィル)アタリラート 37mgを得た。 [0392] 実施例 115 l-(2- (2, 3 dihydrobenzo [b] [l, 4] dioxin 6 yl) ethyl) piberidin-4 monostrength rubonic acid 51 ml of methylene chloride in 2 ml of methylene chloride , N-dimethylformamide (20 L) was added, and the mixture was heated to reflux for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, and 2 mL of chloroform was used. Ethyl = (E) -3- (8-Amino-2-methoxyquinoline-4-yl) attalylate 40 mg of 2 mL of chloroform and 6 mL of triethylamine 63 μL And stirred at room temperature for 3 hours. Water and black mouth form were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 20: 1], and ethyl = (E)-3- (8- (((l- (2- (2, 3 dihydrobenzo [b] [l, 4] dioxin-6 yl) ethyl) piperidine -4 yl) carbole) amino) 1 2-methoxyquinoline 1- 4-yl) 37 mg of attalylate was obtained. [0392] Example 115
Figure imgf000214_0001
Figure imgf000214_0001
ェチル= ）ー3—（8—（（（1ー（2—（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン —6—ィル）ェチル）ピぺリジン— 4—ィル）カルボ-ル）ァミノ）—2—メトキシキノリン— 4—ィル）アタリラート 35mgのエタノール lmL、テトラヒドロフラン lmLおよび水 0.5mL溶 液に、 20%水酸ィ匕ナトリウム水溶液 77 Lを加え、 40°Cで 1時間攪拌した。反応混合 物を室温まで冷却し、減圧下で溶媒を留去した。水 10mLをカ卩え、 1.0mol/L塩酸で pH 6.5に調整した。固形物をろ取し、水およびジェチルエーテルで洗浄し、淡褐色固体 の（E)— 3— (8— ( ( (1— (2— (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン一 6—ィ ル）ェチル）ピぺリジン— 4—ィル）カルボ-ル）ァミノ） 2—メトキシキノリン— 4—ィル )アクリル酸 20mgを得た。  Ethyl =) −3− (8 − (((1− (2− (2, 3 dihydrobenz [b] [l, 4] dioxin —6-yl) ethyl) piperidine-4-yl ) Carbol) Amino) -2-Methoxyquinoline-4-yl) Atalylate 35 mg of ethanol lmL, tetrahydrofuran lmL and water 0.5mL are added with 20% sodium hydroxide aqueous solution 77L, 40 ° C For 1 hour. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. 10 mL of water was added and adjusted to pH 6.5 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water and jetyl ether, and (E) — 3— (8— (((1— (2— (2, 3 Dihydrobenzo [b] [l , 4] Dioxin-6-yl) ethyl) piperidine-4-yl) carbol) amino) 2-methoxyquinoline-4-yl) acrylic acid 20 mg was obtained.
1H-NMR(DMSO-d ) δ値： 1.67— 1.82(2H,m),1.92— 2.02(2H,m),2.10— 2.20(2H,m),2.46—  1H-NMR (DMSO-d) δ value: 1.67—1.82 (2H, m), 1.92—2.02 (2H, m), 2.10—2.20 (2H, m), 2.46—
6  6
2.70(5H,m),2.98-3.09(2H,m),4.11(3H,s),4.20(4H,s),6.67(lH,dd,J=8.1,2.0Hz),6.73(l H,d,J=2.0Hz),6.74(lH,d,J=8.1Hz),6.79(lH,d,J=15.7Hz),7.42(lH,s),7.46(lH,t,J=8.0 Hz),7.78(lH,d,J=8.0Hz),8.14(lH,d,J=15.7Hz),8.54(lH,d,J=8.0Hz),9.70(lH,s)  2.70 (5H, m), 2.98-3.09 (2H, m), 4.11 (3H, s), 4.20 (4H, s), 6.67 (lH, dd, J = 8.1,2.0Hz), 6.73 (l H, d , J = 2.0Hz), 6.74 (lH, d, J = 8.1Hz), 6.79 (lH, d, J = 15.7Hz), 7.42 (lH, s), 7.46 (lH, t, J = 8.0 Hz), 7.78 (lH, d, J = 8.0Hz), 8.14 (lH, d, J = 15.7Hz), 8.54 (lH, d, J = 8.0Hz), 9.70 (lH, s)
[0393] 実施例 116 [0393] Example 116
Figure imgf000214_0002
Figure imgf000214_0002
ェチル = (E) - 3- (8—ァミノ一 2—メトキシキノリン一 5—ィル）アタリラート 70mgの クロ口ホルム 3mL溶液に、 N, N，—カルボ-ルジイミダゾール 63mgを加え、 1時間カロ 熱還流した。反応混合物を室温まで冷却し、 tert ブチル = (2, 3 ジヒドロベンゾ[ b] [l, 4]ジォキシン 6 ィルメチル）（ピペリジンー4 ィル）力ルバマート 0.10gのク ロロホルム 2mL溶液およびトリェチルァミン 72 Lをカ卩え、室温で 1時間攪拌した後、 1 時間加熱還流した。反応混合物を室温まで冷却し、水およびクロ口ホルムを加えた。 有機層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出液を合わせ、水 および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、 減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶 離液;へキサン:酢酸ェチル = 1 : 1]で精製し、淡褐色固体のェチル = (E)— 3— (8 一（（（4一（（tert ブトキシカルボ-ル）（2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン - 6 ィルメチル）ァミノ）ピぺリジン— 1—ィル）カルボ-ル）ァミノ） - 2 メトキシキノ リン一 5—ィル)アタリラート 40mgを得た。 Ethyl = (E)-3- (8-Amino-2-methoxyquinoline 5-yl) Atalylate Add 70 mg of N, N, carbodidiimidazole to 3 mL of 70 mg of Kuroguchi Form, and heat for 1 hour. Refluxed. Cool the reaction mixture to room temperature and add tert butyl = (2,3 dihydrobenzo [b] [l, 4] dioxin 6 ylmethyl) (piperidine-4 yl) strength rubamate 0.10 g of chloroform 2 mL and triethylamine 72 L. After stirring for 1 hour at room temperature, 1 Heated to reflux for hours. The reaction mixture was cooled to room temperature and water and black mouth form were added. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 1: 1], and a light brown solid ethyl = (E) — 3— (8 1 (((4 1 ( (Tert-butoxycarbol) (2,3 dihydrobenz [b] [1, 4] dioxin-6-ylmethyl) amino) piperidine-1-yl) carbol) amino) -2 methoxyquinoline 5-yl) Atarylate 40 mg was obtained.
'H-NMRCCDCl ) δ値： 1.36(3H,t,J=7.0Hz),1.44(9H,s), 1.65- 1.85(4H,m),2.90- 3.05(2  'H-NMRCCDCl) δ value: 1.36 (3H, t, J = 7.0Hz), 1.44 (9H, s), 1.65- 1.85 (4H, m), 2.90-3.05 (2
3  Three
H,m),4.01(3H,s),4.10-4.36(5H,m),4.23(4H,s),4.29(2H,q,J=7.0Hz),6.48(lH,d,J=15.6 Hz),6.64-6.78(3H,m),7.03(lH,d,J=9.1Hz),7.72(lH,d,J=8.5Hz),8.30(lH,d,J=15.6Hz), 8.44(lH,d,J=9.1Hz),8.47(lH,d,J=8.5Hz),9.16(lH,s)  H, m), 4.01 (3H, s), 4.10-4.36 (5H, m), 4.23 (4H, s), 4.29 (2H, q, J = 7.0Hz), 6.48 (lH, d, J = 15.6 Hz ), 6.64-6.78 (3H, m), 7.03 (lH, d, J = 9.1Hz), 7.72 (lH, d, J = 8.5Hz), 8.30 (lH, d, J = 15.6Hz), 8.44 (lH , d, J = 9.1Hz), 8.47 (lH, d, J = 8.5Hz), 9.16 (lH, s)
実施例 117 Example 117
Figure imgf000215_0001
Figure imgf000215_0001
ェチル = (E) - 3- (8— ( ( (4— ( (tert—ブトキシカルボ-ル）（2, 3 ジヒドロベン ゾ [b] [1, 4]ジォキシン 6 ィルメチル）ァミノ）ピぺリジン 1 ィル）カルボ-ル） ァミノ）一 2—メトキシキノリン一 5—ィル)アタリラート 39mgの塩化メチレン 2mL溶液に、 トリフルォロ酢酸 lmLを加え、室温で 2時間攪拌した。減圧下で溶媒を留去し、クロ口 ホルムおよび水をカ卩え、 1.0mol/L水酸ィ匕ナトリウム水溶液で pH12に調整した。有機 層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出液を合わせ、水およ び飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧 下で溶媒を留去し、淡褐色油状物のェチル = (E) 3—（8— ( ( (4—（（2, 3 ジヒド 口べンゾ [b] [1, 4]ジォキシン 6 ィルメチル）ァミノ）ピぺリジン 1ーィル））カル ボ -ル)ァミノ）一 2—メトキシキノリン一 5 ィル)アタリラート 33mgを得た。  Ethyl = (E)-3- (8— (((4— ((tert-Butoxycarbol) (2,3 dihydrobenz [b] [1, 4] dioxin 6 ylmethyl) amino) piperidine 1 1) 2-methoxyquinoline 1-5-yl) attalylate To a solution of 39 mg of methylene chloride in 1 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, chloroform and water were added, and the pH was adjusted to 12 with a 1.0 mol / L sodium hydroxide aqueous solution. The organic layer was separated and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to give ethyl = (E) 3 — (8— (((4 — ((2,3 Dihydrin Benzo [b] [1, 4] Dioxin 6-ylmethyl) amino) piperidine 1-yl)) carbo-)) amino) 1 2— 1 mg of methoxyquinoline) 33 mg of attalylate was obtained.
'H-NMRCCDCI ) δ値： 1.36(3H,t,J=7.1Hz),1.44- 1.56(2H,m),1.96- 2.05(2H,m),2.76- 2 ( / -ζ- ^ ^) -s-^i^-z)— ε— (Ή) = ェ 'H-NMRCCDCI) δ value: 1.36 (3H, t, J = 7.1Hz), 1.44-1.56 (2H, m), 1.96-2.05 (2H, m), 2.76-2 (/ -ζ- ^ ^) -s- ^ i ^ -z) — ε— (Ή) =
Figure imgf000216_0001
Figure imgf000216_0001
(s'HT)8r6'W6=f'P'HT)T9"8'(zH2-8=rP'HT)8S"8'(zHZ-ST=rP' Ηΐ)6Γ8'(ζΗ^8=ί"'Ρ'Ηΐ)68·Ζ'(ζΗ ·6=ί"'Ρ'Ηΐ)ΖΓΖ'(ω'Ηΐ)98·9— 8·9'(ω'Η Ο8·9— SZ'9'
Figure imgf000216_0002
( s ' HT) 8r6'W6 = f'P'HT) T9 "8 '( z H2-8 = rP'HT) 8S"8' ( z HZ-ST = rP 'Ηΐ) 6Γ8' ( ζ Η ^ 8 = ί "'Ρ'Ηΐ) 68 · Ζ' ( ζ Η · 6 = ί"'Ρ'Ηΐ)ΖΓΖ'(ω'Ηΐ) 98 · 9— 8 · 9 '(ω'Η Ο8 · 9— SZ' 9 '
Figure imgf000216_0002
- εθ·ε'(ω'Ηΐ)ΟΖ - 09 ' (ω'Η 36·ΐ- 38·ΐ'(ω'Η 0 ·ΐ- SS'I :軍 9 ( P-OS a)H N-HT -εθ · ε '(ω'Ηΐ) ΟΖ-09'(ω'Η 36 · ΐ- 38 · ΐ '(ω'Η 0 · ΐ- SS'I: Army 9 (P-OS a) H NH T
。 Su¾邈 (^ （
Figure imgf000216_0003
. Su¾ 邈 (^ (
Figure imgf000216_0003
^ ¾ ^ 一エ / エ^ QT¾氺 a¾ ¾<¾?^@、つ 鱸 ^8'9Hd
Figure imgf000216_0004
^ ¾ ^ One / D ^ QT¾ 氺 a¾ ¾ <¾? ^ @ 、 つ つ ^ 8'9Hd
Figure imgf000216_0004
Figure imgf000216_0005
Di i rf99 缀氺マ (Η 濯氺0 /oos、： m τ¾·ο>ι¾ατ¾πωΐべ c^ ^i 、 u ^/— ^ェ o)§uios4— έίί^ （ / s— 9
Figure imgf000216_0005
Di i rf 99 缀 氺 (Η Η 0 / oos ,: m τ¾ · ο> ι¾ατ¾πωΐ c ^ ^ i, u ^ / — ^ é o) §uios4— έίί ^ (/ s— 9
Figure imgf000216_0006
Figure imgf000216_0006
(s'HI)6r6'(zHS'8=f'P'HI)0S'8'(zH0'6=f'P'HI)„'8'(zH9'SI=f'P'HI)0S'8'(zHS'8=f'P 'HT)SZ"Z'(zH0"6=rP'HT)S0"Z'(ra'He)98"9-ZZ"9'(zH9"ST=rP'HT)8^"9'(zHrZ=rb'H2) 6S (S'H )SS (ω'Η · εΐ· (S'HS)90' (s'HS)SZ'S'(ra'HS)6rS— 60·ε'(ω'Ηΐ)98· ( s ' HI) 6r6 '( z HS'8 = f'P'HI) 0S'8' ( z H0'6 = f'P'HI) „'8' ( z H9'SI = f'P'HI ) 0S'8 '( z HS'8 = f'P' HT) SZ "Z '(zH0" 6 = rP'HT) S0 "Z'(ra'He)98" 9-ZZ "9 '( z H9 "ST = rP'HT) 8 ^" 9 '( z HrZ = rb'H2) 6S ( S ' H) SS (ω'Η · εΐ · ( S 'HS) 90' ( s 'HS) SZ'S' (ra 'HS) 6rS— 60 · ε'(ω'Ηΐ) 98 ·
98S6T0/S00Zdf/X3d ドロべンゾ [b] [1, 4]ジォキシンー6 ィル）ピぺリジンー4 カルボキサミド 66mgおよ び過塩素酸リチウム 27mgを加え、 90°Cで 3時間攪拌した。反応混合物を室温まで冷 却し、水および酢酸ェチルを加えた。有機層を分取し、水層を酢酸ェチルで抽出し た。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄 し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を シリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 9： 1]で精製し 、褐色泡状物のェチル = (E) 3—（8—（2—（4一（（2, 3 ジヒドロべンゾ [b] [l, 4 ]ジォキシン— 6—ィルァミノ）カルボ-ル）ピぺリジン— 1—ィル） - 1 ヒドロキシェチ ル）一 2 メトキシキノリン一 5 ィル)アタリラート 72mgを得た。 98S6T0 / S00Zdf / X3d Drobenzo [b] [1,4] dioxin-6yl) piperidine-4carboxamide 66mg and lithium perchlorate 27mg were added and stirred at 90 ° C for 3 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 9: 1], and ethyl of brown foam = (E) 3— (8— (2— (4 (2,3 dihydrobenzo [b] [l, 4] dioxin-6-ylamino) carbole) piperidine-1-yl) -1 hydroxyethyl) 1-2 methoxyquinoline-5 yl) attalylate 72 mg was obtained.
'H-NMRCCDCl ) δ値： 1.37(3H,t,J=7.1Hz),1.86- 2.04(4H,m),2.14- 2.42(3H,m),2.44- 2  'H-NMRCCDCl 3) δ value: 1.37 (3H, t, J = 7.1Hz), 1.86-2.04 (4H, m), 2.14-2.42 (3H, m), 2.44-2
3  Three
.54(lH,m),2.90-3.06(2H,m),3.35-3.45(lH,m),4.03(3H,s),4.23(4H,s),4.30(2H,q,J=7.1 Hz),5.75-5.82(lH,m),6.52(lH,d,J=15.7Hz),6.79(lH,d,J=8.7Hz),6.91(lH,dd,J=8.7,2. 5Hz),6.99(lH,d,J=9.3Hz),7.16(lH,d,J=2.5Hz),7.23(lH,broad),7.68(lH,d,J=7.8Hz),7. 88(lH,d,J=7.8Hz),8.34(lH,d,J=15.7Hz),8.38(lH,d,J=9.3Hz)  .54 (lH, m), 2.90-3.06 (2H, m), 3.35-3.45 (lH, m), 4.03 (3H, s), 4.23 (4H, s), 4.30 (2H, q, J = 7.1 Hz ), 5.75-5.82 (lH, m), 6.52 (lH, d, J = 15.7Hz), 6.79 (lH, d, J = 8.7Hz), 6.91 (lH, dd, J = 8.7, 2.5Hz), 6.99 (lH, d, J = 9.3Hz), 7.16 (lH, d, J = 2.5Hz), 7.23 (lH, broad), 7.68 (lH, d, J = 7.8Hz), 7.88 (lH, d , J = 7.8Hz), 8.34 (lH, d, J = 15.7Hz), 8.38 (lH, d, J = 9.3Hz)
実施例 120 Example 120
Figure imgf000217_0001
Figure imgf000217_0001
ェチル= ）ー3—（8—（2—（4ー（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6 ィルァミノ）カルボ-ル）ピぺリジン 1ーィル） 1ーヒドロキシェチル）ー2—メト キシキノリン 5 ィル）アタリラート 70mgのエタノール 2mL溶液に、 20%水酸化ナトリ ゥム水溶液 0.15mLを加え、室温で 5時間攪拌した。減圧下で溶媒を留去し、水 30mL を加え、氷冷下、 1.0mol/L塩酸で pH5.0に調整した。固形物をろ取し、水およびジェ チルエーテルで洗浄し、淡褐色固体の（E)—3—（8—（2— (4- ( (2, 3 ジヒドロべ ンゾ [b] [1, 4]ジォキシンー6 ィルァミノ）カルボ-ル）ピぺリジン 1ーィル） 1 ヒドロキシェチル） 2—メトキシキノリン一 5 ィル）アクリル酸 49mgを得た。  Ethyl =) -3— (8— (2— (4-((2,3 dihydrobenz [b] [l, 4] dioxin 6 ilamino) carbol) piperidine 1 yl) 1-hydroxy (Chill) -2-Methoxyquinoline 5yl) Atarylate To a solution of 70 mg of ethanol in 2 mL of ethanol was added 0.15 mL of 20% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, 30 mL of water was added, and the mixture was adjusted to pH 5.0 with 1.0 mol / L hydrochloric acid under ice cooling. The solid was collected by filtration, washed with water and diethyl ether, and (E) —3— (8— (2— (4- ((2, 3 dihydrobenzo [b] [1, 4 ] Dioxin-6-ilamino) carbol) piperidine 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 5-yl) 49 mg of acrylic acid was obtained.
'H-NMRCDMSO-d ) δ値： 1.60— 1.84(4H,m),2.10— 2.35(3H,m),2.70— 2.85(lH,m),3.00— 3.09(lH,m),3.20-3.50(2H,m),4.02(3H,s),4.15-4.24(4H,m),5.84-5.91(lH,m),6.60(lH ,d,J=15.6Hz),6.75(lH,d,J=8.9Hz),6.97(lH,dd,J=8.9,2.4Hz),7.11(lH,d,J=9.3Hz),7.23 (lH,d,J=2.4Hz),7.87(lH,d,J=7.8Hz),7.91(lH,d,J=7.8Hz),8.29(lH,d,J=15.6Hz),8.57(l H,d,J=9.3Hz),9.68(lH,s) 'H-NMRCDMSO-d) δ value: 1.60— 1.84 (4H, m), 2.10— 2.35 (3H, m), 2.70— 2.85 (lH, m), 3.00— 3.09 (lH, m), 3.20-3.50 (2H, m), 4.02 (3H, s), 4.15-4.24 (4H, m), 5.84-5.91 (lH, m), 6.60 (lH, d, J = 15.6 Hz), 6.75 (lH, d, J = 8.9 Hz), 6.97 (lH, dd, J = 8.9, 2.4 Hz), 7.11 (lH, d, J = 9.3 Hz), 7.23 (lH, d, J = 2.4) Hz), 7.87 (lH, d, J = 7.8Hz), 7.91 (lH, d, J = 7.8Hz), 8.29 (lH, d, J = 15.6Hz), 8.57 (l H, d, J = 9.3Hz) ), 9.68 (lH, s)
[0398] 実施例 121 [0398] Example 121
Figure imgf000218_0001
Figure imgf000218_0001
ェチル = (E) - 3- (2—メトキシ一 8— (ォキシラン一 2—ィル）キノリン一 5—ィル） アタリラート 43mgの N, N ジメチルホルムアミド 3mL溶液に、室温で N— (ピペリジン 4ーィル）ー2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルスルホンアミド 43 mgおよび過塩素酸リチウム 15mgをカ卩え、 45°Cで 1時間、 80°Cで 2時間および 90°Cで 1 時間攪拌した。反応混合物を室温まで冷却し、水および酢酸ェチルを加えた。有機 層を分取し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わせ、水およ び飽和塩ィ匕ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧 下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [溶離液； クロ口ホルム：メタノール = 10 : 1]で精製し、淡褐色油状物のェチル = (E) - 3- (8 - (2- (4- ( (2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルスルホ -ル）アミ ノ）ピぺリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）ァ タリラート 19mgを得た。  Ethyl = (E)-3- (2-Methoxy-1-8- (Oxylan-2-yl) quinoline-1-yl) Atarylate 43 mg of N, N dimethylformamide in 3 mL of N- (piperidine 4-yl) at room temperature ) -2, 3 Dihydrobenzo [b] [l, 4] Dioxin 6-ylsulfonamide 43 mg and Lithium perchlorate 15 mg were added, 1 hour at 45 ° C, 2 hours at 80 ° C And stirred at 90 ° C for 1 hour. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; black mouth form: methanol = 10: 1], and ethyl of pale brown oily substance = (E)-3- (8-(2- (4- ((2, 3 Dihydrobenzo [b] [l, 4] Dioxin 6-ylsulfol) Amino) Piperidine 1-yl) 1-Hydroxyethyl) 2-Methoxyquinoline 1 5- 19 mg of talarilate was obtained.
'H-NMRCCDCl ) δ値： 1.36(3H,t,J=7.1Hz),1.45- 1.70(2H,m),1.77- 1.95(2H,m),2.13- 2  'H-NMRCCDCl) δ value: 1.36 (3H, t, J = 7.1Hz), 1.45- 1.70 (2H, m), 1.77-1.95 (2H, m), 2.13-2
3  Three
.23(lH,m),2.33-2.45(lH,m),2.44(lH,dd,J=12.3,10.1Hz),2.69-2.78(lH,m),2.95(lH,d d,J=12.3,3.0Hz),3.08-3.29(2H,m),4.01(3H,s),4.25-4.40(6H,m),5.70(lH,dd,J=10.1,3. 0Hz),6.51(lH,d,J=15.9Hz),6.95(lH,d,J=8.5Hz),6.99(lH,d,J=9.1Hz),7.37(lH,dd,J=8. 5,2.2Hz),7.41(lH,d,J=2.2Hz),7.67(lH,d,J=7.8Hz),7.84(lH,d,J=7.8Hz),8.34(lH,d,J=l 5.9Hz),8.38(lH,d,J=9.1Hz)  .23 (lH, m), 2.33-2.45 (lH, m), 2.44 (lH, dd, J = 12.3,10.1Hz), 2.69-2.78 (lH, m), 2.95 (lH, dd, J = 12.3, 3.0Hz), 3.08-3.29 (2H, m), 4.01 (3H, s), 4.25-4.40 (6H, m), 5.70 (lH, dd, J = 10.1, 3.0 Hz), 6.51 (lH, d, J = 15.9Hz), 6.95 (lH, d, J = 8.5Hz), 6.99 (lH, d, J = 9.1Hz), 7.37 (lH, dd, J = 8.5,2.2Hz), 7.41 (lH, d, J = 2.2Hz), 7.67 (lH, d, J = 7.8Hz), 7.84 (lH, d, J = 7.8Hz), 8.34 (lH, d, J = l 5.9Hz), 8.38 (lH, d , J = 9.1Hz)
[0399] 実施例 122
Figure imgf000219_0001
[0399] Example 122
Figure imgf000219_0001
ェチル= ）ー3—（8—（2—（4ー（（2, 3 ジヒドロべンゾ [b] [l, 4]ジォキシン 6—ィルスルホ -ル）ァミノ）ピぺリジン— 1—ィル）—1—ヒドロキシェチル）—2—メトキ シキノリン一 5—ィル）アタリラート 19mgのエタノール 2mL溶液に、 20%水酸化ナトリウ ム水溶液 38 Lを加え、室温で 1時間攪拌し、ー晚静置した。減圧下で溶媒を留去し 、水 20mLをカ卩え、氷冷下、 1.0mol/L塩酸で pH5.0に調整した。固形物をろ取し、水お よびジェチルエーテルで洗浄し、淡褐色固体の（E) - 3- (8—（2— (4- ( (2, 3— ジヒドロべンゾ [b] [1, 4]ジォキシン 6—ィルスルホ -ル）ァミノ）ピぺリジン 1ーィ ル） 1 ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）アクリル酸 7mgを得た。 'H-NMRCDMSO-d ) δ値： 1.30— 1.70(4H,m),2.00— 2.30(lH,m),2.40— 3.50(6H,m),3.98(  Ethyl =) −3− (8− (2− (4 − ((2,3 dihydrobenzo [b] [l, 4] dioxin 6-ylsulfo-yl) amino) piperidine-1-yl) -1-hydroxyethyl) -2-methyl quinoline 1-5-yl) attalylate To 2 mL of 19 mg ethanol was added 38 L of 20% aqueous sodium hydroxide solution, stirred at room temperature for 1 hour, and allowed to stand. . The solvent was distilled off under reduced pressure, 20 mL of water was added, and the mixture was adjusted to pH 5.0 with 1.0 mol / L hydrochloric acid under ice cooling. The solid was collected by filtration, washed with water and jetyl ether, and (E)-3- (8— (2— (4- ((2, 3— dihydrobenzo [b] [ 1,4] dioxin 6-ylsulfo) amino) piperidine 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 5-yl) acrylic acid 7 mg was obtained. 'H-NMRCDMSO-d) δ value: 1.30— 1.70 (4H, m), 2.00— 2.30 (lH, m), 2.40—3.50 (6H, m), 3.98 (
6  6
3H,s),4.25-4.40(4H,m),5.74-5.84(lH,m),6.59(lH,d,J=15.7Hz),7.03(lH,d,J=8.0Hz),7 .09(lH,d,J=9.3Hz),7.26-7.28(2H,m),7.83(lH,d,J=7.7Hz),7.89(lH,d,J=7.7Hz),8.27(l H,d,J=15.7Hz),8.55(lH,d,J=9.3Hz)  3H, s), 4.25-4.40 (4H, m), 5.74-5.84 (lH, m), 6.59 (lH, d, J = 15.7Hz), 7.03 (lH, d, J = 8.0Hz), 7.09 (lH, d, J = 9.3Hz), 7.26-7.28 (2H, m), 7.83 (lH, d, J = 7.7Hz), 7.89 (lH, d, J = 7.7Hz), 8.27 (l H, d , J = 15.7Hz), 8.55 (lH, d, J = 9.3Hz)
実施例 123 Example 123
Figure imgf000219_0002
Figure imgf000219_0002
ェチル = (E) - 3- (2—メトキシ一 8— (ォキシラン一 2—ィル）キノリン一 5—ィル） アタリラート 89mgの N, N ジメチルホルムアミド 3mL溶液に、室温で N— (2, 3 ジヒ ドロべンゾ [b] [l, 4]ジォキシン 6—ィルメチル）（4ーメチルビペリジン 4 ィル） ァミン 78mgおよび過塩素酸リチウム 32mgを加え、 85〜95°Cで 5時間攪拌した。反応混 合物を室温まで冷却し、水および酢酸ェチルを加えた。有機層を分取し、水層を酢 酸ェチルで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム 水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した (ΖΗΓ6=ΓΡ'Ηΐ) ·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)^·8'(ω'Η 88·Ζ-ε8 (ζΗΓEthyl = (E)-3- (2-Methoxy-1-8- (Oxylan-2-yl) quinoline-5-yl) Atalylate 89 mg N, N Dimethylformamide in 3 mL solution at room temperature N- (2, 3 Dihydrobenzo [b] [l, 4] dioxin 6-ylmethyl) (4-methylbiperidine 4 yl) Amine 78mg and lithium perchlorate 32mg were added and stirred at 85-95 ° C for 5 hours. . The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. (ΖΗΓ6 = ΓΡ'Ηΐ) 8 '( ζ Η9 · 3ΐ = ΓΡ'Ηΐ) ^ · 8'(ω'Η 88 · Ζ-ε8 ( ζ ΗΓ
6=ί"'Ρ'Ηΐ)60·Ζ'(ζΗΖ·ΐ=ί"'Ρ'Ηΐ)98·9'(ω'Ηΐ)ΐ8·9— 8Ζ·9'(ζΗε·8=ί"'Ρ'Ηΐ)9Γ9'(ζΗ9·3ΐ=ί"' Ρ'Ηΐ)83·9'(ω'Ηΐ)Ζ8·3— 08'S'(s'H^)0S (s'HS)00' (S'HS)SS'S'C"'HS;^8 — SrS'WH ( 19 ' C"'HS)SS — 0 ' (ω'Η )ΟΖ·ΐ— ε ·ΐ'(δ'Ηε)60·ΐ :軍 9 ( OS ) Η顺— Ητ
Figure imgf000220_0001
6 = ί "'Ρ'Ηΐ) 60 · Ζ' ( ζ ΗΖ · ΐ = ί"'Ρ'Ηΐ) 98 · 9'(ω'Ηΐ) ΐ8 · 9—8Ζ · 9 '( ζ Ηε · 8 = ί "'Ρ'Ηΐ) 9Γ9' ( ζ Η9 · 3ΐ = ί"'Ρ'Ηΐ) 83 · 9'(ω'Ηΐ) Ζ8 · 3— 08'S '(s'H ^) 0S ( s ' HS) 00' ( S 'HS) SS'S'C "'HS; ^ 8 — SrS'WH (19 'C"' HS) SS — 0 '(ω'Η) ΟΖ · ΐ— ε · ΐ' ( δ 'Ηε) 60 ΐ: Army 9 (OS) Η 顺 —Η τ
Figure imgf000220_0001
/y-i- ^(^0ΆΛ^ →- { ^j. {Λ^ Λ^-9- ^^ Ί] [q] 、ベ
Figure imgf000220_0002
/ yi- ^ (^ 0 ΆΛ ^ →-{^ j. {Λ ^ Λ ^ -9- ^^ Ί] [q]
Figure imgf000220_0002
、つ辛爵 瀚缀、 止 教
Figure imgf000220_0003
, Spicy shrine, stop
Figure imgf000220_0003
^%oz、^继缀 τ¾ /— ^ェ 0Su¾w— έίί^ （ —S—べ ίί,^Ρ ^E ー s^% oz 、 ^ 继 缀 τ¾ / — ^ é 0 Su ¾w— έίί ^ （—S—Be ίί, ^ Ρ ^ E ー s
- {Λ^^^ ^-Ι - ( / - 1 - ^(.·^0ΆΛ^ →- ( ^ （ ^ / — 9 -{Λ ^^^ ^ -Ι-(/-1-^ (. · ^ 0 ΆΛ ^ →-(^ (^ / — 9
Figure imgf000220_0004
Figure imgf000220_0004
8'(ζΗ6·3ΐ=ί"'Ρ'Ηΐ)3ε·8'(ζΗ8·Ζ=ί"'Ρ'Ηΐ)68·Ζ'(ζΗ8·Ζ=ί"'Ρ'Ηΐ)69·Ζ'(ζΗε·6=ί"'Ρ'Ηΐ)66·9'
Figure imgf000220_0005
8 '( ζ Η6 · 3ΐ = ί "'Ρ'Ηΐ) 3ε8 '( ζ Η8 · Ζ = ί"'Ρ'Ηΐ) 68 · Ζ '( ζ Η8 · Ζ = ί "'Ρ'Ηΐ) 69 · Ζ '( ζ Ηε · 6 = ί "'Ρ'Ηΐ) 66 · 9 '
Figure imgf000220_0005
S ' (s'HS)W (S'HS)6S'S'C"'HI)60'S— S0'S'C"'HS)S6 — 08 ' C"'HI)S9 — SS ' (ω'Η s)ss -^ ' (ω'Η ζζ·ΐ- 03·ΐ'(ζΗΐ·ζ=Γ Ηε)ζε·ΐ'(δ'Ηε)6ΐ·ΐ :軍 9 ( ι α )Η顺- Ητ S '( s ' HS) W ( S 'HS) 6S'S'C "' HI) 60'S— S0'S'C"'HS) S6 — 08' C "'HI) S9 — SS'(ω'Η s) ss- ^ '(ω'Η ζζ · ΐ- 03 · ΐ' (ζΗΐ · ζ = Γ Ηε) ζε · ΐ '( δ ' Ηε) 6ΐ · ΐ: Army 9 (ι α) Η 顺-Η τ
/ -ε 'z))→)-z)-s)-£- =^^ > ^m^^、つ攝慰、 [ΐ :s= :マ / cm ^ 鍋缀 ]— i^Mム！^マ f 、¾<¾爵 ί ^ ° / -ε 'z)) →) -z) -s)-£-= ^^> ^ m ^^, 攝 攝, [ΐ: s =: ma / cm ^ pot 缀] — i ^ M! ^ Ma f, ¾ <¾ ί ^ °
98S6T0/S00Zdf/X3d 81-3
Figure imgf000221_0001
98S6T0 / S00Zdf / X3d 81-3
Figure imgf000221_0001
ェチル = (E) - 3- (8- (2- (4 アミノビペリジン一 1—ィル） 1—ヒドロキシェ チル）ー2—メトキシキノリンー5 ィル）アタリラートの塩酸塩 0.30gの塩化メチレン 5mL 懸濁液に、 2, 3 ジヒドロ [1, 4]ジォキシノ [2, 3— c]ピリジン 7 カルバルデヒド 0 .12gおよび酢酸 をカ卩え、室温で 5時間攪拌した。水素化トリァセトキシホウ素ナ トリウム 0.23gを加え、同温度で 30分間攪拌した。反応混合物に飽和炭酸水素ナトリウ ム水溶液およびクロ口ホルムをカ卩えた。有機層を分取し、水層をクロ口ホルムで抽出し た。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸 マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲル力 ラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 10 : 1]で精製し、淡褐色油 状物のェチル= ）ー3—（8—（2—（4ー（（2, 3 ジヒドロ [1, 4]ジォキシノ [2, 3 —c]ピリジン— 7—ィルメチル）ァミノ）ピぺリジン— 1—ィル） - 1 ヒドロキシェチル） —2—メトキシキノリン一 5—ィル)アタリラート O.llgを得た。  Ethyl = (E)-3- (8- (2- (4 Aminobiperidine 1-yl) 1-hydroxyethyl) -2-methoxyquinoline-5 yl) Atalylate hydrochloride 0.30 g of methylene chloride 5 mL The suspension was charged with 0.12 g of 2,3 dihydro [1,4] dioxino [2,3-c] pyridine 7 carbaldehyde and acetic acid, and stirred at room temperature for 5 hours. 0.23 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution and black mouth form were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 10: 1], and the light brown oily ethyl =) -3- (8- (2- (4- ((2, 3 dihydro [1, 4] dioxino [2, 3 —c] pyridine-7-ylmethyl) amino) piperidine-1-yl) -1 hydroxyethyl) —2-methoxyquinoline 5- Yil) Atarilate O.llg was obtained.
1H-NMR(CDC1 ) δ値： 1.37(3H,t,J=7.1Hz),1.45- 1.65(2H,m),1.85- 2.00(2H,m),2.10- 2  1H-NMR (CDC1) δ value: 1.37 (3H, t, J = 7.1Hz), 1.45-1.65 (2H, m), 1.85-2.00 (2H, m), 2.10-2
3  Three
.20(lH,m),2.30-2.45(lH,m),2.42(lH,dd,J=12.3,10.1Hz),2.51-2.61(lH,m),2.78-2.88( lH,m),3.01(lH,dd,J=12.3,3.2Hz),3.24-3.33(lH,m),3.81(2H,s),4.03(3H,s),4.25-4.35( 6H,m),5.78(lH,dd,J=10.1,3,2Hz),6.52(lH,d,J=16.1Hz),6.84(lH,s),6.98(lH,d,J=9.3H z),7.69(lH,d,J=7.8Hz),7.90(lH,d,J=7.8Hz),8.11(lH,s),8.35(lH,d,J=16.1Hz),8.38(lH ,d,J=9.3Hz)  .20 (lH, m), 2.30-2.45 (lH, m), 2.42 (lH, dd, J = 12.3,10.1Hz), 2.51-2.61 (lH, m), 2.78-2.88 (lH, m), 3.01 (lH, dd, J = 12.3,3.2Hz), 3.24-3.33 (lH, m), 3.81 (2H, s), 4.03 (3H, s), 4.25-4.35 (6H, m), 5.78 (lH, dd , J = 10.1,3,2Hz), 6.52 (lH, d, J = 16.1Hz), 6.84 (lH, s), 6.98 (lH, d, J = 9.3H z), 7.69 (lH, d, J = 7.8Hz), 7.90 (lH, d, J = 7.8Hz), 8.11 (lH, s), 8.35 (lH, d, J = 16.1Hz), 8.38 (lH, d, J = 9.3Hz)
実施例 126 Example 126
Figure imgf000221_0002
Figure imgf000221_0002
ェチル= ）ー3—（8—（2—（4ー（（2, 3 ジヒドロ [1, 4]ジォキシノ [2, 3— c]ピ リジン— 7—ィルメチル）ァミノ）ピぺリジン— 1—ィル）—1—ヒドロキシェチル）—2—メ トキシキノリン一 5 ィル）アタリラート 0.1 lgのエタノール 2mL溶液に、 20%水酸化ナト リウム水溶液 0.23mLを加え、室温で 2時間攪拌した。減圧下で溶媒を留去し、水 10m Lを加え、 1.0mol/L塩酸で pH7.5に調整した。固形物をろ取し、水およびジェチルェ 一テルで洗浄し、淡褐色固体の（E) 3—（8—（2—（4一（（2, 3 ジヒドロ [1, 4]ジ ォキシノ [2, 3— c]ピリジン一 7—ィルメチル）ァミノ）ピぺリジン一 1—ィル） 1—ヒド 口キシェチル） - 2 メトキシキノリン一 5 ィル）アクリル酸 58mgを得た。 Ethyl =) −3− (8− (2− (4 − ((2,3 dihydro [1,4] dioxino [2,3− c] pi Lysine-7-ylmethyl) amino) piperidine-1-yl) -1-hydroxyethyl) -2-methylquinoline 1-5 yl) talylate 20% sodium hydroxide in 2 ml of 0.1 lg ethanol 0.23 mL of an aqueous solution was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, 10 mL of water was added, and the pH was adjusted to 7.5 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water and jetyl ether, and (E) 3— (8— (2— (4 1 ((2,3 dihydro [1,4] dioxino [2, 3-c] pyridine 1-ylmethyl) amino) piperidine 1-yl) 1-hydric quichetil) -2 methoxyquinoline 1-5 yl) 58 mg of acrylic acid was obtained.
'H-NMRCDMSO-d ) δ値： 1.35— 1.50(2H,m),1.80— 1.94(2H,m),2.13— 2.30(2H,m),2.44— 'H-NMRCDMSO-d) δ value: 1.35— 1.50 (2H, m), 1.80— 1.94 (2H, m), 2.13— 2.30 (2H, m), 2.44—
6  6
2.60(2H,m),2.70-2.77(lH,m),2.91-3.00(lH,m),3.16-3.25(lH,m),3.80(2H,s),4.00(3H ,s),4.26-4.37(4H,m),5.81-5.87(lH,m),6.59(lH,d,J=15.9Hz),7.00(lH,s),7.08(lH,d,J= 9.3Hz),7.84-7.88(2H,m),8.05(lH,s),8.23(lH,d,J=15.9Hz),8.54(lH,d,J=9.3Hz) 実施例 127  2.60 (2H, m), 2.70-2.77 (lH, m), 2.91-3.00 (lH, m), 3.16-3.25 (lH, m), 3.80 (2H, s), 4.00 (3H, s), 4.26- 4.37 (4H, m), 5.81-5.87 (lH, m), 6.59 (lH, d, J = 15.9Hz), 7.00 (lH, s), 7.08 (lH, d, J = 9.3Hz), 7.84-7.88 (2H, m), 8.05 (lH, s), 8.23 (lH, d, J = 15.9Hz), 8.54 (lH, d, J = 9.3Hz) Example 127
Figure imgf000222_0001
Figure imgf000222_0001
ェチル = (E) - 3- (2—メトキシ一 8— (ォキシラン一 2—ィル）キノリン一 5—ィル） アタリラート 0.12gの N, N ジメチルホルムアミド 3mL溶液に、室温で tert—ブチル = (2 ォキソ 2 （ピリジン 2 ィルァミノ）ェチル）（ピペリジンー4 ィル）力ルバマ ート 0.13gおよび過塩素酸リチウム 43mgを加え、 90°Cで 9時間攪拌した。反応混合物 を室温まで冷却し、水および酢酸ェチルを加えた。有機層を分取し、水層を酢酸ェ チルで抽出した。有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶 液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得ら れた残留物をシリカゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 20 : 1]で精製し、淡褐色油状物のェチル = (E)— 3—（8— (2—（4一（(tert ブト キシカルボ-ル）（2—ォキソー2—（ピリジン 2—ィルァミノ）ェチル）ァミノ）ピベリジ ン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）アタリラート 0. 24gを得た。 H-NMR(CDC1 ) δ fg: 1.36(3H,t,J=7.2Hz),1.47(9H,s),1.60-1.95(4H,m),2.15-2.55(3 Ethyl = (E)-3- (2-Methoxy-1-8- (Oxylan-2-yl) quinoline-1-yl) Atarylate 0.12 g of N, N dimethylformamide in 3 mL solution at room temperature with tert-butyl = ( 2Oxo 2 (pyridine 2-ylamino) ethyl) (piperidine-4-yl) strength rubamate 0.13 g and lithium perchlorate 43 mg were added, and the mixture was stirred at 90 ° C. for 9 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1], and ethyl = (E) — 3— (8— (2— (4 1-((tert-butoxycarbol) (2-oxo-2- (pyridine 2-ylamino) ethyl) amino) piberidin 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 5-yl) attalylate 0.24 g was obtained. H-NMR (CDC1) δ fg: 1.36 (3H, t, J = 7.2Hz), 1.47 (9H, s), 1.60-1.95 (4H, m), 2.15-2.55 (3
3  Three
H,m),2.87-3.02(2H,m),3.36-3.44(lH,m),3.86-4.07(3H,m),4.01(3H,s),4.30(2H,q,J=7. 2Hz),5.70-5.76(lH,m),6.51(lH,d,J=15.6Hz),6.98(lH,d,J=9.1Hz),7.01-7.08(lH,m),7. 67(lH,d,J=7.8Hz),7.68-7.75(lH,m),7.86(lH,d,J=7.8Hz),8.20-8.30(2H,m),8.34(lH,d, J=15.6Hz),8.38(lH,d,J=9.1Hz)  H, m), 2.87-3.02 (2H, m), 3.36-3.44 (lH, m), 3.86-4.07 (3H, m), 4.01 (3H, s), 4.30 (2H, q, J = 7.2 Hz ), 5.70-5.76 (lH, m), 6.51 (lH, d, J = 15.6Hz), 6.98 (lH, d, J = 9.1Hz), 7.01-7.08 (lH, m), 7.67 (lH, d, J = 7.8Hz), 7.68-7.75 (lH, m), 7.86 (lH, d, J = 7.8Hz), 8.20-8.30 (2H, m), 8.34 (lH, d, J = 15.6Hz), 8.38 (lH, d, J = 9.1Hz)
[0405] 実施例 128 [0405] Example 128
Figure imgf000223_0001
Figure imgf000223_0001
ェチル = (E) - 3- (8— (2- (4— ( (tert ブトキシカルボ-ル）（2 ォキソー2— (ピリジン— 2—ィルァミノ）ェチル）ァミノ）ピぺリジン— 1—ィル） - 1—ヒドロキシェチ ル） 2—メトキシキノリン一 5—ィル)アタリラート 0.23gの塩化メチレン 5mL溶液に、トリ フルォロ酢酸 5mLを加え、室温で 2時間攪拌した。減圧下で溶媒を留去し、酢酸ェチ ルおよび水を加え、 20%水酸ィ匕ナトリウム水溶液で pH12に調整した。有機層を分取 し、水層を酢酸ェチルで抽出した。有機層および抽出液を合わせ、水および飽和塩 化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒 を留去し、淡褐色油状物のェチル = (E) - 3- (8- (1—ヒドロキシ— 2— (4- ( (2 -ォキソ— 2— (ピリジン 2—ィルァミノ）ェチル）ァミノ）ピぺリジン 1—ィル）ェチ ル）一 2 メトキシキノリン一 5 ィル)アタリラート 0.16gを得た。  Ethyl = (E)-3- (8— (2- (4— ((tert butoxycarbol) (2 oxo-2- (pyridine-2-ylamino) ethyl) amino) piperidine 1-yl) -1-hydroxyethyl) 2-methoxyquinoline 1-5-yl) talylate 5 mL of trifluoroacetic acid was added to a solution of 0.23 g of methylene chloride in 5 mL and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 12 with a 20% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed sequentially with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and ethyl = (E)-3- ( 8- (1—Hydroxy— 2— (4- ((2-Oxo—2— (Pyridine 2-ylamino) ethyl) amino) piperidine 1—yl) ethyl) 1 2 methoxyquinoline 1 5 yl ) 0.16 g of attalylate was obtained.
'H-NMRCCDCl ) δ値： 1.37(3H,t,J=7.2Hz),1.45- 1.70(2H,m),1.85- 2.64(6H,m),2.82- 3  'H-NMRCCDCl) δ value: 1.37 (3H, t, J = 7.2Hz), 1.45- 1.70 (2H, m), 1.85- 2.64 (6H, m), 2.82-3
3  Three
.08(2H,m),3.26-3.40(lH,m),3.46(2H,s),4.02(3H,s),4.30(2H,q,J=7.2Hz),5.74-5.82(1 H,m),6.52(lH,d,J=15.9Hz),6.98(lH,d,J=9.3Hz),7.00-7.08(lH,m),7.66-7.74(2H,m),7 .88(lH,d,J=7.6Hz),8.24-8.40(4H,m),9.81(lH,s)  .08 (2H, m), 3.26-3.40 (lH, m), 3.46 (2H, s), 4.02 (3H, s), 4.30 (2H, q, J = 7.2Hz), 5.74-5.82 (1 H, m), 6.52 (lH, d, J = 15.9Hz), 6.98 (lH, d, J = 9.3Hz), 7.00-7.08 (lH, m), 7.66-7.74 (2H, m), 7.88 (lH , d, J = 7.6Hz), 8.24-8.40 (4H, m), 9.81 (lH, s)
[0406] 実施例 129 [0406] Example 129
Figure imgf000223_0002
ェチノレ = (E) - 3- (8—（1ーヒドロキシー2—（4— ( (2 ォキソー2 （ピリジン 2—ィルァミノ）ェチル）ァミノ）ピぺリジン一 1—ィル）ェチル） 2—メトキシキノリン一 5 ィル）アタリラート 0.14gのエタノール 2mL溶液に、 20%水酸化ナトリウム水溶液 0.3 OmLをカ卩え、室温で 2時間攪拌し、ー晚静置した。減圧下で溶媒を留去し、水 20mLを 加え、 1.0mol/L塩酸で pH6.0に調整した。固形物をろ取し、水およびジェチルエーテ ルで洗浄し、淡褐色固体の (E) 3—（8—（2—（4 （(カルボキシメチル)ァミノ)ピ ペリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）アタリ ル酸 48mgを得た。
Figure imgf000223_0002
Ethinore = (E)-3- (8— (1-hydroxy-2- (4— ((2 oxo2 (pyridine 2-ylamino) ethyl) amino) piperidine 1-yl) ethyl) 2-methoxyquinoline 1 5il) Atalylate 0.14 g of ethanol in 2 mL solution was charged with 20% aqueous sodium hydroxide 0.3 OmL, stirred at room temperature for 2 hours, and allowed to stand still. The solvent was distilled off under reduced pressure, 20 mL of water was added, and the pH was adjusted to 6.0 with 1.0 mol / L hydrochloric acid. Filter off the solid, wash with water and jetyl ether, and add (E) 3— (8— (2— (4 ((carboxymethyl) amino) piperidine 1-yl) 1-hydroxy as a light brown solid. Ethyl) 2-methoxyquinoline-5-yl) attalic acid 48 mg was obtained.
'H-NMRCDMSO-d ) δ値： 1.47— 1.62(2H,m),1.86— 1.97(2H,m),2.06— 2.17(2H,m),2.40—  'H-NMRCDMSO-d) δ value: 1.47—1.62 (2H, m), 1.86—1.97 (2H, m), 2.06—2.17 (2H, m), 2.40—
6  6
2.48(lH,m),2.63-2.70(lH,m),2.80-3.00(2H,m),3.15(2H,s),3.10-3.40(lH,m),4.00(3H ,s),5.79-5.84(lH,m),6.60(lH,d,J=15.9Hz),7.09(lH,d,J=9.3Hz),7.84(lH,d,J=7.8Hz),7 .88(lH,d,J=7.8Hz),8.26(lH,d,J=15.9Hz),8.55(lH,d,J=9.3Hz)  2.48 (lH, m), 2.63-2.70 (lH, m), 2.80-3.00 (2H, m), 3.15 (2H, s), 3.10-3.40 (lH, m), 4.00 (3H, s), 5.79- 5.84 (lH, m), 6.60 (lH, d, J = 15.9Hz), 7.09 (lH, d, J = 9.3Hz), 7.84 (lH, d, J = 7.8Hz), 7.88 (lH, d , J = 7.8Hz), 8.26 (lH, d, J = 15.9Hz), 8.55 (lH, d, J = 9.3Hz)
実施例 130 Example 130
Figure imgf000224_0001
Figure imgf000224_0001
ェチル = (E) - 3- (2—メトキシ一 8— (ォキシラン一 2—ィル）キノリン一 5—ィル） アタリラート O.llgの N, N ジメチルホルムアミド 3mL溶液に、室温で 4— ( (2, 3—ジ ヒドロべンゾ [b] [1, 4]ジォキシン一 6—ィルメチル）ァミノ） N—メチルビペリジン一 4 カルボキサミド O.llgおよび過塩素酸リチウム 39mgをカ卩え、 95°Cで 4時間攪拌した 。過塩素酸リチウム 39mgを加え、 95°Cで 3時間攪拌した。反応混合物を室温まで冷却 し、水および酢酸ェチルを加えた。有機層を分取し、水層を酢酸ェチルで抽出した。 有機層および抽出液を合わせ、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄し、 無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリ 力ゲルカラムクロマトグラフィー [溶離液；クロ口ホルム：メタノール = 10： 1]で精製し、 淡褐色油状物のェチル = (E)— 3—（8—（2— (4- ( (2, 3 ジヒドロべンゾ [b] [1, 4]ジォキシン 6—ィルメチル）ァミノ） -4- ( (メチルァミノ）カルボ-ル）ピぺリジン Ζ£1\ Μ [60^0] Ethyl = (E)-3- (2-Methoxy-1-8- (Oxyllan-2-yl) quinoline-1-yl) Atarylate O.llg in 3 mL of N, N dimethylformamide at room temperature, 4— (( 2,3-dihydrobenzzo [b] [1, 4] dioxin 1-ylmethyl) amino) N-methylbiperidine 1 4 carboxamide O.llg and lithium perchlorate 39 mg 4 at 95 ° C Stir for hours. 39 mg of lithium perchlorate was added and stirred at 95 ° C for 3 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography [eluent: black mouth form: methanol = 10: 1], and ethyl of pale brown oil = (E) — 3— (8— (2— ( 4- ((2, 3 Dihydrobenzo [b] [1, 4] Dioxin 6-ylmethyl) amino) -4- ((Methylamino) carbol) piperidine Ζ £ 1 \ Μ [60 ^ 0]
(zHS"6=f'P'HT)ee"8'(zH9"ST=rP'HT)92"8'(zH (zHS "6 = f'P'HT) ee" 8 '( z H9 "ST = rP'HT) 92"8' ( z H
8"Z=rP'HT)68"Z'(ZH8"Z=rP'HT)S8"Z'(ra'HT)9Z"Z-0Z"Z'(ZHS"6=rP'HT)0rZ'(ra'He)^8 •9— 9Γ9'(ζΗ9·3ΐ=ί"'Ρ'Ηΐ)63·9'(ω'Ηΐ)98·3— 08'S'(s'H^)0S ' (S'HS)66'S'C"'H8)0S'S— 08 "Z = rP'HT) 68" Z '(ZH8 "Z = rP'HT) S8"Z'(ra'HT) 9Z "Z-0Z" Z '(ZHS "6 = rP'HT) 0rZ' ( ra'He) ^ 8 • 9— 9Γ9 '( ζ Η9 · 3ΐ = ί "'Ρ'Ηΐ) 63 · 9 '(ω'Ηΐ) 98 · 3— 08'S'(s'H ^) 0S '( S ' HS) 66'S'C "'H8) 0S'S— 0
'(ζΗ · =ΓΡ'Ηε)ε9 '(ω'Η 86·ΐ— 8·ΐ'(ω'Η 89·ΐ— ·ΐ:ΐ! 9 ( OS ) 顺— Ητ '( ζ Η · = ΓΡ'Ηε) ε9'(ω'Η 86 · ΐ— 8 · ΐ '(ω'Η 89 · ΐ— · ΐ: ΐ! 9 (OS) 顺 — Η τ
。 ¾¾§υ¾ε邈 fi （ ^ー S—べ ίί,^Ρ 44 ー  . ¾¾§υ¾ε 邈 fi （^ ー S—Be ίί, ^ Ρ 44 ー
Ζ - {Λ^^^ ^-Ι - ( / - 1 ( /-^ /^ (,^ ^ ） )→ - Ζ-{Λ ^^^ ^ -Ι-(/-1 (/-^ / ^ (, ^ ^)) →-
Figure imgf000225_0001
Figure imgf000225_0001
ωθΐ·0继缀氺マ fH 邈氺0 /oOS
Figure imgf000225_0002
qui ε /— ^ェ o)so ΐ '(Η— έ ίί^ （ s—べ ίί ,^ρ ^E ー s—( ^エ ^ p 、 — ωθΐ · 0 继 缀 氺 ma fH 邈 氺0 / oOS
Figure imgf000225_0002
qui ε / — ^ é o) s o ΐ '(Η— έ ίί ^ (s—be ίί, ^ ρ ^ E ー s— (^ e ^ p, —
I - ( / - 1 ( /-^ /^ (,^ ^ ） )→- (,^ （ ^ / 一 9  I-(/-1 (/-^ / ^ (, ^ ^)) →-(, ^ (^ / 1 9
Figure imgf000225_0003
Figure imgf000225_0003
[sow)] [sow)]
(ΖΗ (ΖΗ
S"6=rP'HT)6S"8'(zHZ"eT=rP'HT)eS"8'(zH9"Z=rP'HT)68"Z'(zH9"Z=f'P'HT)69"Z'(ra'H ΐ)6ε· -εε· '(ζΗε·6=ΓΡ'Ηΐ)66·9'(ω'Η2) 8·9-ε8·9'(ζΗΓ2'2·8=ΓΡΡ'Ηΐ)9 ·9'(ζΗ ·3ΐ
Figure imgf000225_0004
S "6 = rP'HT) 6S" 8 '( z HZ "eT = rP'HT) eS"8' ( z H9 "Z = rP'HT) 68" Z '(zH9 "Z = f'P'HT ) 69''Z '(ra'H ΐ) 6ε · -εε ·' (ζΗε · 6 = ΓΡ'Ηΐ) 66 · 9 '(ω'Η2) 8 · 9-ε8 · 9' ( ζ ΗΓ2'2 · 8 = ΓΡΡ'Ηΐ) 9 9 '( ζ Η3ΐ
Figure imgf000225_0004
'(ω'Ηΐ)6ΐ·ε— π·ε'(ω'Ηΐ)ζο·ε— οο·ε'(ζΗ6· =ί"'ρ'Ηε) 8 ' C"'Hi)s8 — srs'C"'Hs)s9'
Figure imgf000225_0005
:軍 9 ( ιつ αつ) WN- ΗΤ '(ω'Ηΐ) 6ΐ · ε— π · ε'(ω'Ηΐ) ζο · ε— οο · ε '( ζ Η6 · = ί "'ρ'Ηε) 8 'C"' Hi) s8 — srs' C "'Hs) s9'
Figure imgf000225_0005
: Army 9 (ια α) WN- Η Τ
° 靜  ° 靜
ΐ ΐ 4—
Figure imgf000225_0006
- ( / 一 χ - — ΐ 4—
Figure imgf000225_0006
-(/ One χ-
98S6T0/S00Zdf/X3d
Figure imgf000226_0001
98S6T0 / S00Zdf / X3d
Figure imgf000226_0001
ェチル = (E) - 3- (8- (ピペリジン一 4—カルボキサミド） 2—メトキシキノリン一 5 ィル）アタリラート 85mgのメチルイソブチルケトン 4mL溶液に、室温で 6—（2 クロ ロェチル） 2H べンゾ [1, 4]ォキサジン 3 (4H) オン 61mg、ヨウ化ナトリウム 43 mgおよび炭酸ナトリウム 31mgをカ卩え、 120°Cで 2時間 30分間攪拌した。 6— (2 クロ口 ェチル）一4H べンゾ [1, 4]ォキサジンー3 オン 61mg、ヨウ化ナトリウム 43mgおよ び炭酸ナトリウム 31mgを加え、 4時間 30分間攪拌した。反応混合物を室温まで冷却し 、酢酸ェチル 20mLおよび水 20mLを加えた。有機層を分取し、水層を酢酸ェチルで 抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水 硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲ ルカラムクロマトグラフィー [シリカゲル；富士シリシァ社、 Chromatorex-NH、溶離液； 酢酸ェチル]で精製し、黄色固体のェチル = (E) - 3- (2—メトキシー8— (1 - (2 一（3 ォキソ 3, 4 ジヒドロー 2H—べンゾ [1, 4]ォキサジン 6 ィル）ェチル） ピぺリジン一 4—カルボキサミド）キノリン一 5—ィル）アタリラート 41mgを得た。  Ethyl = (E)-3- (8- (piperidine mono 4-carboxamide) 2-methoxyquinoline mono 5-yl) attalylate 85 mg of methyl isobutyl ketone in 4 mL solution at room temperature 6- (2 chloroethyl) 2H benzo 61 mg of [1, 4] oxazine 3 (4H) one, 43 mg of sodium iodide and 31 mg of sodium carbonate were added and stirred at 120 ° C. for 2 hours and 30 minutes. 6- (2 chloroethyl) 1H benzo [1,4] oxazine-3-one 61 mg, sodium iodide 43 mg and sodium carbonate 31 mg were added and stirred for 4 hours 30 minutes. The reaction mixture was cooled to room temperature and 20 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia, Chromatorex-NH, eluent: ethyl acetate], and the yellow solid ethyl = (E)-3- (2-methoxy-8- ( 1- (2 ((3oxo3,4dihydro-2H-benzo [1,4] oxazine-6yl) ethyl) piperidine-1-4-carboxamide) quinoline-5-yl) attalylate 41 mg was obtained.
'H-NMRCCDCl ) δ値： 1.36(3H,t,J=7.2Hz),1.92- 2.07(2H,m),2.09- 2.27(4H,m),2.36- 2 'H-NMRCCDCl) δ value: 1.36 (3H, t, J = 7.2Hz), 1.92-2.07 (2H, m), 2.09-2.27 (4H, m), 2.36-2
3  Three
.53(lH,m),2.53-2.69(2H,m),2.70-2.85(2H,m),3.03-3.19(2H,m),4.12(3H,s),4.30(2H, q,J=7.2Hz),4.59(2H,s),6.51(lH,d,J=15.7Hz),6.66(lH,d,J=1.9Hz),6.82(lH,dd,J=8.2,l .9Hz),6.90(lH,d,J=8.2Hz),7.06(lH,d,J=9.2Hz),7.72(lH,d,J=8.4Hz),7.97(lH,s),8.30( lH,d,J=15.7Hz),8.44(lH,d,J=9.2Hz),8.75(lH,d,J=8.4Hz),9.74(lH,s)  .53 (lH, m), 2.53-2.69 (2H, m), 2.70-2.85 (2H, m), 3.03-3.19 (2H, m), 4.12 (3H, s), 4.30 (2H, q, J = 7.2Hz), 4.59 (2H, s), 6.51 (lH, d, J = 15.7Hz), 6.66 (lH, d, J = 1.9Hz), 6.82 (lH, dd, J = 8.2, l .9Hz), 6.90 (lH, d, J = 8.2Hz), 7.06 (lH, d, J = 9.2Hz), 7.72 (lH, d, J = 8.4Hz), 7.97 (lH, s), 8.30 (lH, d, J = 15.7Hz), 8.44 (lH, d, J = 9.2Hz), 8.75 (lH, d, J = 8.4Hz), 9.74 (lH, s)
実施例 133 Example 133
Figure imgf000226_0002
Figure imgf000226_0002
ェチノレ = (E) - 3- (2—メトキシ一 8— (1— (2— (3—ォキソ 3, 4 ジヒドロ一 2 SSI圏第 [ZIW] (s'HT)^Z"6'(zH2"8=rP'HT)^Z"8'(zH2"6=rP'HT)^"8'(zHZ"ST=rP'H Ethinore = (E)-3- (2-Methoxy-1-8- (1- (2-- (3-Oxo 3, 4 Dihydro- 1 SSI No. [ZIW] ( s 'HT) ^ Z "6' ( z H2" 8 = rP'HT) ^ Z "8 '( z H2" 6 = rP'HT) ^ "8' ( z HZ" ST = rP'H
T)0S"8'(s'HT)6r8'(zH2-8=f'P'HT)2Z-Z'(zH6"Z=f'P'HT)S2-Z'(zH2-6=rP'HT)90"Z'(zH9 T) 0S "8 '(s ' HT) 6r8' (z H2-8 = f'P'HT) 2Z-Z '(zH6" Z = f'P'HT) S2-Z' (zH2-6 = rP 'HT) 90 "Z' (zH9
·ΐ'6·Ζ=Γ'ΡΡ'Ηΐ)88·9'(ζΗ9·ΐ=ΓΡ'Ηΐ)2Ζ·9'(ζΗΖ·3ΐ=ΓΡ'Ηΐ)ΐ3·9'(ζΗΓΖ=Γ¾'Η2)0ε^'( s'HS)ir (s'HS)S S'(ra'HS)OS'S— εθ·ε'(ω'Η 68 — SrS'C"'HS)U — SS ' (ω'Ηΐ) 3·· Ϊ́'6 · Ζ = Γ'ΡΡ'Ηΐ) 88 · 9 '( ζ Η9 · ΐ = ΓΡ'Ηΐ) 2Ζ9' ( ζ ΗΖ · 3ΐ = ΓΡ'Ηΐ) ΐ3 · 9 '( ζ ΗΓΖ = Γ¾ 'Η2) 0ε ^' ( s 'HS) ir ( s ' HS) S S '(ra'HS) OS'S— εθ · ε'(ω'Η 68 — SrS'C "'HS) U — SS' (ω 'Ηΐ) 3.
' (ω'Η - 80 ' (ω'Η 80 - 88·ΐ'(ζΗΐ·Ζ=ΓνΗε)9ε·ΐ :軍 9 ( !DaD)H N-HT '(ω'Η-80'(ω'Η 80-88 · ΐ '( ζ Ηΐ · Ζ = ΓνΗε) 9ε · ΐ: Army 9 (! DaD) H NH T
。 4— έίί^ (、 ^^ 一 一ベ fi ( ^ . 4— έίί ^ (、 ^^ one fi (^
^{^y-9- ^J.-^ ' I ] ^>^ -HZ- si^ - '£- ^-£)-Ζ)-1)  ^ {^ y-9- ^ J .- ^ 'I] ^> ^ -HZ- si ^-' £-^-£) -Ζ) -1)
-8-/ w-s) ε— (Ή) = ^エ ^ ^mM^ m^^^- (H ε
Figure imgf000227_0001
→- ίί -8)— ε— (Ή) = ェ -8- / ws) ε— (Ή) = ^ d ^ ^ mM ^ m ^^^-(H ε
Figure imgf000227_0001
→-ίί -8) — ε— (Ή) =
Figure imgf000227_0002
Figure imgf000227_0002
w [圏第 [1刺
Figure imgf000227_0003
w [Zone No. 1
Figure imgf000227_0003
ΓΡ'Ηΐ)^9·8'(ζΗε·8=ΓΡ'Ηΐ)½·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)^·8'(ζΗε·8=ΓΡ'Ηΐ)½· '(ΖΗ2·6=Γ 'P'HT)6rZ'(zH8"Z=rP'HT)26"9'(zH8"Z=rP'HT)S8"9'(s'HT)8Z-9'(zH9"ST=f'P'HT)6e-9 ΓΡ'Ηΐ) ^ 9 · 8 '( ζ Ηε · 8 = ΓΡ'Ηΐ) ½ · 8' ( ζ Η9 · 3ΐ = ΓΡ'Ηΐ) ^ · 8 '( ζ Ηε · 8 = ΓΡ'Ηΐ) ½ ·' (ΖΗ2 · 6 = Γ 'P'HT) 6rZ' (zH8 "Z = rP'HT) 26" 9 '( z H8 "Z = rP'HT) S8"9' ( s 'HT) 8Z-9' ( z H9 "ST = f'P'HT) 6e-9
'(s'H S' '(s'HS) r„'H6)08'S— ' C"'H )6S — 8Ζ·ΐ :軍 9 ( OS ) Η顺— Ητ '(s'H S''(s'HS) r „' H6) 08'S— 'C"' H) 6S — 8Ζ · ΐ: Military 9 (OS) Η 顺 —Η 顺τ
。 ¾¾Su¾Z邈
Figure imgf000227_0004
. ¾¾Su¾ Z邈
Figure imgf000227_0004
-I) -ε- a) m^ α¾ ¾^@。 ·Π(5蹦^ Hd)¾
Figure imgf000227_0005
辛爵 瀚缀 止 s教 。： ^ →- ^fi^ ( "^ェ 9一 [ ' ΐ ] 、ベ: H -I) -ε- a) m ^ α¾ ¾ ^ @. · Π (5 蹦 ^ Hd) ¾
Figure imgf000227_0005
Sudan 止 s religion. : ^ →-^ fi ^ ("^ é 9 ichi ['ΐ], Bae: H
98S6T0/S00Zdf/X3d 933
Figure imgf000228_0001
:軍 9 ( oswa) Ν— Ητ - ^(^αΆ ( /^ ^ -ζ- ( / 'x][q-s 'ε]、 ίί HS98S6T0 / S00Zdf / X3d 933
Figure imgf000228_0001
: Military 9 (oswa) Ν- Η τ - ^ (^ α Ά (/ ^ ^ -ζ- (/ 'x] [qs' ε], ίί HS
) -8) ε— (Ή) = ^エ ) -8) ε— (Ή) = ^
Figure imgf000228_0002
鍋缀、09 /
Figure imgf000228_0002
Hot pot, 09 /
車阖： ム I ^マ f 、、つ辛爵 瀚缀 止 S教 Vehicle: Mu I ^ Ma f
。 つ ¾累
Figure imgf000228_0003
fi^-HS- {^^J. ^-Z) -9-¾ΰ :- ¾αΤ¾:§ΙΙΙ0824— 6fi^( ^-9 . ¾ cumulative
Figure imgf000228_0003
fi ^ -HS- (^^ J. ^ -Z) -9-¾ΰ:-¾αΤ¾: §ΙΙΙ 0824— 6fi ^ (^ -9
Figure imgf000228_0004
Figure imgf000228_0004
9ει圏第 [εΐΜ)] 9ει-zone [εΐΜ)]
(s'HT)2S r(s'HT)6Z-6'(zH2-6=rP'HT)29"8'(zHS(s'HT) 2S r ( s ' HT) 6Z-6 '( z H2-6 = rP'HT) 29 "8' ( z HS
•8=f'P'HT)ee"8'(zH9"eT=rP'HT)S2"8'(zHS"8=rP'HT)26"Z'(zH8"Z=rP'HT)22"Z'(zH2"6 • 8 = f'P'HT) ee "8 '( z H9" eT = rP'HT) S2 "8' ( z HS" 8 = rP'HT) 26 "Z '(zH8" Z = rP'HT) 22 "Z '(zH2" 6
=rP'HT)ZrZ'(ZH8"Z=rP'HT)98"9'(s'HT)^8"9'(zH9"ST=rP'HT)Ze-9'(s'HS)n^'(s'H2 = rP'HT) ZrZ '(ZH8 "Z = rP'HT) 98"9' ( s 'HT) ^ 8 "9' ( z H9" ST = rP'HT) Ze-9 '( s ' HS) n ^ '(s'H2
) ·ε'(ω'Η6)ζε·ε— ε ' C"'HS)80 — ε6·ΐ'(ω'Η 8·ΐ— S9'i :軍 9 ( oswa) N— HT ) · Ε '(ω'Η6) ζε · ε— ε' C "'HS) 80 — ε6 · ΐ'(ω'Η 8 · ΐ— S9'i: Army 9 (oswa) N— H T
Figure imgf000228_0005
ェ
Figure imgf000228_0006
Figure imgf000228_0005
Ye
Figure imgf000228_0006
fi Jp οι^ ^ →-ベ ίί （ "^ェ — 9 , ム ν Ί] ^>--Η fi Jp οι ^ ^ → -Be ίί ("^ é — 9, mu ν Ί] ^>-Η
Figure imgf000228_0007
Figure imgf000228_0007
98S6T0/S00Zdf/X3d 933 (s'Hi)orn'(s 98S6T0 / S00Zdf / X3d 933 ( s 'Hi) orn' ( s
'HI)8r6'(zHS'6=f'P'HI) 9'8'(zHS'8=f'P'HI)SS'8'(zH0'9I=f'P'HI)IS'8'(s'HI)90'8'( ζΗ2·8=ΓΡΉΐ)96· '(ζΗ2·6=ΓΡΉΐ)6Γ '(ζΗ0·9ΐ=ΓΡΉΐ)89·9'(ω'Η2)9Γ3-ε0·3'(ζΗ6 •9=1 "' HS)SS (s'HS)ir (S'HS)I9'S'(S'HI)S0'S'(S'HI)06 '(S'HS)I9 ' (ω'Ηΐ)6ε - ZS '(s'H 0W(s'H I6'I'(s'H IZ'I'(zH6'9=rVHS)6S'I :軍 9 ( OS ) 顺— Ητ c →- /^(^0Ά {Λ^^^ ^ -z- ( / 'x][q-s 'ε]、 'HI) 8r6' ( z HS'6 = f'P'HI) 9'8 '( z HS'8 = f'P'HI) SS'8' ( z H0'9I = f'P'HI) IS '8' ( s ' HI) 90'8 '(ζΗ2 · 8 = ΓΡΉΐ) 96 ·' (ζΗ2 · 6 = ΓΡΉΐ) 6Γ '(ζΗ0 · 9ΐ = ΓΡΉΐ) 89 · 9'(ω'Η2) 9Γ3-ε0 3 '(ζΗ6 • 9 = 1 "' HS) SS ( s ' HS) ir ( S 'HS) I9'S' ( S 'HI) S0'S' ( S 'HI) 06' ( S 'HS) I9' (ω 'Ηΐ) 6ε-ZS' ( s ' H 0W ( s ' H I6'I '( s ' H IZ'I'(zH6'9 = rVHS) 6S'I: Army 9 (OS) 顺 — Η τ c → -/ ^ (^ 0 Ά {Λ ^^^ ^ -z- (/ 'x] [qs' ε],
-8)— ε— (a) = /
Figure imgf000229_0001
ί ψΜ 、09 / ίί -8) — ε— (a) = /
Figure imgf000229_0001
ί ψΜ, 09 / ίί
¾ m辛爵¾瀚缀 止 ϊί教 n ^) m ^m^mm^ ^c^m^ mij¾Suis'i9マ fw 峯 峯氺、止^^
Figure imgf000229_0002
¾ m Tsura爵¾瀚缀stop ϊί Judaism n ^) m ^ m ^ mm ^ ^ c ^ m ^ mij¾ Sui s'i9 Ma fw Mine Mine氺, stop ^^
Figure imgf000229_0002
→- ^(^αΆ ( /^ ^ -z- ( / 'x][q-s 'ε]、 ίί ー→-^ (^ α Ά (/ ^ ^ -z- (/ 'x] [qs' ε], ίί ー
UZ-
Figure imgf000229_0003
-ζ)-ι) -8)— ε— (Ή) = ェ UZ-
Figure imgf000229_0003
-ζ) -ι) -8) — ε— (Ή) =
Figure imgf000229_0004
Figure imgf000229_0004
(S'HI)ZS'I( S 'HI) ZS'I
I'(s'HI)8r6'(zHS'6=H'P'HI) 9'8'(zHS'8=f'P'HI)9S'8'(zH0'9I=f'P'HI)6S'8'(s'HI) 2"8'(zHS"8=rP'HT)Z6"Z'(zH2"6=rP'HT)6rZ'(zH0"9T=rP'HT)89"9'(zHS"Z=f'b'H2)22" (s'HS)Sr (S'HS)98'S'(S'HS)89'S'C"'HS)S0'S— 6 ' C"'HS)S9 — Ϊ9 ' (ω'Ηΐ)6ε — 8 I '(s' HI) 8r6 ' (z HS'6 = H'P'HI) 9'8 '(z HS'8 = f'P'HI) 9S'8' (z H0'9I = f'P 'HI) 6S'8' ( s 'HI) 2 "8' ( z HS" 8 = rP'HT) Z6 "Z '(zH2" 6 = rP'HT) 6rZ' (zH0 "9T = rP'HT) 89 "9 '(z HS" Z = f'b'H2) 22 "(s' HS) Sr (S 'HS) 98'S' (S 'HS) 89'S'C"' HS) S0'S- 6 'C "' HS) S9 — Ϊ9 '(ω'Ηΐ) 6ε — 8
98S6T0/S00Zdf/X3d LZZ
Figure imgf000230_0001
(Η ε—ベ ^ 98S6T0 / S00Zdf / X3d LZZ
Figure imgf000230_0001
(Η ε—Be ^
- ^^-Ζ- ( ^^ ^→- ^ -8)— ε— (Ή) = ェ -^^-Ζ- (^^ ^ →-^ -8) — ε— (Ή) =
Figure imgf000230_0002
Figure imgf000230_0002
(S'HI)60'II( S 'HI) 60'II
'(s'HT)9Z"6'(zH2"6=rP'HT)6e"8'(zHS"8=rP'HT)9e"8'(zH9"ST=f'P'HT)22"8'(s'HT)90" 8'(ζΗε·8=Γ'ΡΉΐ)26· '(ζΗ2·6=Γ'ΡΉΐ)8Γ '(ζΗ9·3ΐ=ΓΡΉΐ)93·9'(ω'Ηΐ)2Γ5-60·3'(ω 'Ηΐ)96· — S6' (s'HS)ir (S'HS)8S'S'C"'HS)Z0'S— SO'S'C"'HI)SrS— U'S'C"'HS) 9 — ZS ' C"'H S— 8ΐ '(ω'Η 6·ΐ— 68·ΐ'(ω'Η 3Ζ·ΐ— ΐ9·ΐ :軍 9 ( OS ) Η顺—
Figure imgf000230_0003
( ェ 、つ ¾9¾呦^圑
Figure imgf000230_0004
恩 瀚缀 止 m ^α^ι^ε^ ^ ^^n ^ -^ ^。 ·η# ^翻 aos ^w ^ u¾ro继缀氺マ fH 邈氺 ΐ/Ι '(s'HT) 9Z "6' ( z H2" 6 = rP'HT) 6e "8 '( z HS" 8 = rP'HT) 9e "8' ( z H9" ST = f'P'HT) 22 "8 '( s ' HT) 90" 8 '( ζ Ηε · 8 = Γ'ΡΉΐ) 26 ·' (ζΗ2 · 6 = Γ'ΡΉΐ) 8Γ '(ζΗ9 · 3ΐ = ΓΡΉΐ) 93 · 9' (ω 'Ηΐ) 2Γ5-60 · 3' (ω 'Ηΐ) 96 · — S6' ( s ' HS) ir ( S 'HS) 8S'S'C "' HS) Z0'S— SO'S'C"'HI) SrS— U'S' C "'HS) 9 — ZS'C"'HS—8ΐ'(ω'Η 6 · ΐ— 68 · ΐ '(ω'Η 3Ζ · ΐ— ΐ9 · ΐ: Army 9 (OS) Η 顺 —
Figure imgf000230_0003
(Eh, ¾9¾ 呦 ^ 圑
Figure imgf000230_0004
止 m ^ α ^ ι ^ ε ^ ^ ^^ n ^-^ ^. · Η # ^ translation aos ^ w ^ u¾ro 继 缀 氺 ma fH ΐ ΐ / Ι
— ^ェ o/o0Z )§ui6I w— ^
Figure imgf000230_0005
— ^ E o / o0Z) §ui 6I w— ^
Figure imgf000230_0005
- ^(^αΆ {Λ^^^ ^ -ζ- ( / 'ΐ] [q—s 'ε]、 ίί ー-^ (^ α Ά {Λ ^^^ ^ -ζ- (/ 'ΐ] [q—s' ε], ίί ー
UZ-
Figure imgf000230_0006
-ζ)-ι) -8)— ε— (Ή) = ェ UZ-
Figure imgf000230_0006
-ζ) -ι) -8) — ε— (Ή) =
Figure imgf000230_0007
Figure imgf000230_0007
98S6T0/S00Zdf/X3d 833
Figure imgf000231_0001
98S6T0 / S00Zdf / X3d 833
Figure imgf000231_0001
ΐ圏第 No. 1
(s'HT)Z8 r(s'HT)8Z"6'(zHZ"8=rP'HT)e9"8'(zHS"8=rP'HT)Ze"8'(zH9"ST=rP'HT)^ •8'(zHS"8=rP'HT)26"Z'(ZH8"Z=f'P'HT)ZZ"Z'(ZHZ"8=f'P'HT)8rZ'(ZH8"Z=rP'HT)^rZ' (ΖΗ9·3ΐ=ί"'Ρ'Ηΐ)83·9'(ω'Ηΐ)69· S9' (s'HS)Sr (s'HS)8 S'C"'HS)90'S— ΐΟ·ε'(ω'Η ε)99 — ΐ9 '(s'H S'(ra'H S6'I— ΐ6·ΐ'(ω'Η 6Ζ·ΐ— εζ·ΐ :軍 9 (9p-OS a)H N-HT (s'HT) Z8 r ( s 'HT) 8Z "6' ( z HZ" 8 = rP'HT) e9 "8 '( z HS" 8 = rP'HT) Ze "8' ( z H9" ST = rP'HT) ^ • 8 '( z HS "8 = rP'HT) 26"Z' (ZH8 "Z = f'P'HT) ZZ" Z '(ZHZ "8 = f'P'HT) 8rZ' (ZH8 "Z = rP'HT) ^ rZ '(ΖΗ9 · 3ΐ = ί"'Ρ'Ηΐ) 83 · 9 '(ω'Ηΐ) 69 · S9' ( s 'HS) Sr ( s ' HS) 8 S 'C "' HS) 90'S— ΐΟ · ε '(ω'Η ε) 99 — ΐ9' ( s ' H S '(ra'H S6'I— ΐ6 · ΐ'(ω'Η 6Ζ · ΐ— εζ · ΐ: Military 9 ( 9 p-OS a) H NH T
^→- /^(^0Ά ( /^ ( / - 9 - ^J.-^ 'I][q-S 'S]^fi^-HS-cl^
Figure imgf000231_0002
^ →-/ ^ (^ 0 Ά (/ ^ (/-9-^ J .- ^ 'I] [qS' S] ^ fi ^ -HS-cl ^
Figure imgf000231_0002
-v 'ε- ^-ε) -ζ- ^-ζ)-ι) -s-^i^-z) ε (Ή) = ェ -v 'ε- ^ -ε) -ζ- ^ -ζ) -ι) -s- ^ i ^ -z) ε (Ή) =
Figure imgf000231_0003
Figure imgf000231_0003
(s'HT)62"n'(s'HT)6Z-6'(zH2-6=rP 'HI)S9'8'(zHS'8=f'P'HI)8S'8'(zH9'SI=f'P'HI)9S'8'(ra'HI)S0'8— 96 '(zHS'8=f'P'HI )T6"Z'(ra'HT)6e"Z-ee"Z'(zH2"6=rP'HT)02"Z'(zH9"eT=rP'HT)89"9'(zH6"9=f'b'H2)S2" (s'HS)Sr (s'HS)I0' (s'HS)99'S'(ra'HS)WTS— S6 ' C"'HS)I9 — 09 ' (ra'HI)S S— ΐ S'S'(ra'H 86'I— 6'I'(ra'HS)S8'I—SZ'I'(zH6'9=r HS)8S'I:l! 9 ( OS ) 顺— HT ( s ' HT) 62 "n '( s ' HT) 6Z-6' ( z H2-6 = rP 'HI) S9'8' ( z HS'8 = f'P'HI) 8S'8 '( z H9'SI = f'P'HI) 9S'8 '(ra'HI) S0'8— 96' ( z HS'8 = f'P'HI) T6 "Z '(ra'HT) 6e" Z- ee "Z '(zH2" 6 = rP'HT) 02 "Z'(zH9" eT = rP'HT) 89 "9 '(z H6" 9 = f' b 'H2) S2 "(s' HS) Sr ( s 'HS) I0' ( s 'HS) 99'S'(ra'HS) WTS— S6 'C "' HS) I9 — 09 '(ra'HI) SS— ΐ S'S'(ra'H86'I—6'I'(ra'HS)S8'I—SZ'I'(zH6'9 = r HS) 8S'I: l! 9 (OS) 顺 —H T
( ^^ ^→- ^ ( "^ェ — 9—ベ 、 ^ v 'x][q (^^ ^ →-^ ("^ é — 9—be, ^ v 'x] [q
98S6T0/S00Zdf/X3d 633 (s'HT)9rn'(s'HT)6Z-6'(zH2-6=rP'HT)S9"8'(zHS-8=rP'HT)ee-8'(s'HT)2S-8 '(zH9"eT=rP'HT)62"8'(zHS"8=rP'HT)66"Z'(zH2"6=rP'HT)02"Z'(zH9"ST=f'P'HT)89"9
Figure imgf000232_0001
98S6T0 / S00Zdf / X3d 633 ( s ' HT) 9rn '( s ' HT) 6Z-6' ( z H2-6 = rP'HT) S9 "8 '( z HS-8 = rP'HT) ee-8' ( s ' HT) 2S -8 '(zH9 "eT = rP'HT) 62"8' ( z HS "8 = rP'HT) 66" Z '(zH2 "6 = rP'HT) 02"Z' (zH9 "ST = f 'P'HT) 89 "9
Figure imgf000232_0001
SW(s'H SW(s'H 6'I'(s'H Z'I'(zH6'9=r HS)6S'I:l! 9 ( OSW I) N— HT
Figure imgf000232_0002
(、 ^ →- ^(^Α {Λ^^^ ^ -ζ- ( / -9 - ^J.-^ 'x][q-s 'ε]、 ίί HS ΰ、 ¾^—
Figure imgf000232_0003
-ζ)-ι) 8)— ε—（a) = ェ、ェっ SW ( s ' H SW ( s ' H 6'I '( s ' H Z'I'(zH6'9 = r HS) 6S'I: l! 9 (OSW I) N— H T
Figure imgf000232_0002
(, ^ →-^ (^ Α {Λ ^^^ ^ -ζ- (/ -9-^ J .- ^ 'x] [qs' ε], ίί HS ΰ, ¾ ^ —
Figure imgf000232_0003
-ζ) -ι) 8) — ε— (a) = eh, eh
→- ^(^αΆ ( /^ ^ -ζ- ( / 'x][q-s 'ε]、 (ί ー→-^ (^ α Ά (/ ^ ^ -ζ- (/ 'x] [qs' ε], (ί ー
UZ UZ
Figure imgf000232_0004
Figure imgf000232_0004
(s'HT)8Z"6'(zHr6=f'P'HT)e9"8'(zHS"8=rP'HT)Ze"8'(zH9"ST=rP'(s'HT) 8Z "6 '( z Hr6 = f'P'HT) e9"8' ( z HS "8 = rP'HT) Ze" 8 '( z H9 "ST = rP'
HT)62"8'(s'HT)2r8'(zHS-8=rP'HT)Z6"Z'(zHr6=f'P'HT)6rZ'(zH9"ST=f'P'HT)89"9'(z Η6·9=ί "' HS)SS ' (s'HS)ir (s'HS)98'S'(s'HS)0rS'(ra'HS) 6 — S6'S'C"'HS)S9 — ΐ 9 ' (ω'Η 36·ΐ— 06·ΐ'(ω )9Ζ·ΐ— 0Ζ·ΐ'(ζΗ6·9=Π'Ηε)0ε·ΐ :軍 9 ( OS ) Η顺— Ητ HT) 62 "8 '(s ' HT) 2r8' (z HS-8 = rP'HT) Z6" Z '(zHr6 = f'P'HT) 6rZ' (zH9 "ST = f'P'HT) 89 "9 '( z Η6 · 9 = ί"' HS) SS '( s ' HS) ir ( s ' HS) 98'S' ( s ' HS) 0rS '(ra'HS) 6 — S6'S'C "' HS) S9 — ΐ 9 '(ω'Η 36 · ΐ— 06 · ΐ' (ω) 9Ζ · ΐ— 0Ζ · ΐ '( ζ Η6 · 9 = Π'Ηε) 0ε · ΐ: Army 9 (OS) Η 顺 — Η τ
[q-s 'ε]
Figure imgf000232_0005
-ζ)-ι) -8) -ε[qs' ε]
Figure imgf000232_0005
-ζ) -ι) -8) -ε
- (Ή) = ^エ ^ ^mM^ m^^^- (Η ε—ベ ^ [ Ί] [q—-(Ή) = ^ d ^ ^ mM ^ m ^^^-(Η ε—Be ^ [Ί] [q—
Z 'S]^fi^-HS- {^^J. ^-Z) 9— cicu^ ん f?N— έίί^ （ — S Z 'S] ^ fi ^ -HS- {^^ J. ^ -Z) 9— cicu ^ f? N— έίί ^ (— S
98S6T0/S00Zdf/X3d OSS
Figure imgf000233_0001
98S6T0 / S00Zdf / X3d OSS
Figure imgf000233_0001
09 / 車阖： 4ム！ ^マ f 、¾
Figure imgf000233_0002
09 / Vehicle: 4M! ^ Ma f, ¾
Figure imgf000233_0002
薔^翻 s っ。 osi mi s9s'oマ ίί 濯 ¾ ΐτ¾¾ζ·οマ 、 ε·οベ 一 ωοιベ ^ : ^ )§οε·ο^邈^ son— έίί^ （ —s—べ ίί,^ρ ^^薔 ^ 翻 s っ. osi mi s 9s'o ma ίί ¾ ΐτ¾¾ζ · ο, ε · ο be ωοιbe ^: ^) § οε · ο ^ 邈 ^ son— έίί ^ (—s—Be ίί, ^ ρ ^^
-Ζ- ( /^ ( / - 1 - ^·^0Ά) -Z-^ ^-l) -8)-ε-(Ή) = ェ -Ζ- (/ ^ (/-1-^ · ^ 0 Ά) -Z- ^ ^ -l) -8) -ε- (Ή) =
Figure imgf000233_0003
Figure imgf000233_0003
(s'HI)W'n'(s'HI)08'6'(zHS'8( s 'HI) W'n' ( s 'HI) 08'6' ( z HS'8
=f'P'HI)S9'8'(zHS'8=f'P'HI) S'8'(zHS'9I=f'P'HI)ZS'8'(s'HI)S0'8'(zHS'8=f'P'HI)S6 ·Ζ'(ΖΗε·8=ΓΡ'Ηΐ)8ΐ (ζΗ3·9ΐ=ί"'Ρ'Ηΐ)83·9'(ω'Ηΐ)6^3— 0rS'(s'HS)Sl (s'HS)6S'S '(s'HS)00'S'(s'HS)9 S'(ra'HS)n - 00 ' (ω'Η )06·ΐ- 9Ζ·ΐ :軍 9 ( P-OS a)H N-HT c→- /^(^0Ά {Λ^^^ ^ -z- ( / -9 - ^J.-^ 'x][q-s 'ε]^ίί
Figure imgf000233_0004
-Z)-l) -8) -£- (Ή)、ェっ^ - ^(^αΆ {Λ^^^ ^ -ζ- ( / 'ΐ] [q—s 'ε]、 ίί ー = f'P'HI) S9'8 '(z HS'8 = f'P'HI) S'8' (z HS'9I = f'P'HI) ZS'8 '(s' HI) S0' 8 '( z HS'8 = f'P'HI) S6Ζ (' εΖΗ8 = ΓΡ'Ηΐ) 8ΐ ( ζ Η3 · 9ΐ = ί "'Ρ'Ηΐ) 83 · 9'(ω'Ηΐ) 6 ^ 3— 0rS '(s'HS) Sl ( s ' HS) 6S'S'(s'HS)00'S'( s ' HS) 9 S'(ra'HS) n-00 '(ω'Η) 06 ΐ- 9Ζ · ΐ: Military 9 (P-OS a) H NH T c →-/ ^ (^ 0 Ά (Λ ^^^ ^ -z- (/ -9-^ J .- ^ 'x] [qs 'ε] ^ ίί
Figure imgf000233_0004
-Z) -l) -8)-£-(Ή), Yeah ^-^ (^ α Ά {Λ ^^^ ^ -ζ- (/ 'ΐ] [q—s' ε], ίί ー
Figure imgf000233_0005
Figure imgf000233_0005
98S6T0/S00Zdf/X3d
Figure imgf000234_0001
98S6T0 / S00Zdf / X3d
Figure imgf000234_0001
(S'HI)99'0I'(ZHS'6=1"'P'HI) e"8'(zH9"eT=rP'HT)82"8'(zH8"Z=rP'HT)T6"Z'(zH8"Z=rP'HT)Z8"Z'(zH2"6=rP'HT)n
Figure imgf000234_0002
Ζ·9'(ζΗ9·3ΐ=ί"'Ρ'Ηΐ )09'9'(s'HI)88'S'(s'HS)SS' '(s'HS)S0' '(ra'H I)0S'S— S ：軍 9 ( OS ) 顺— Ητ
Figure imgf000234_0003
ェ l- 、 （ ^エ（ / 9一べ 、 ^ [ ' I ] ^>^ - HS - - 'ε- ^( S 'HI) 99'0I' ( Z HS'6 = 1 "'P'HI) e"8' ( z H9 "eT = rP'HT) 82" 8 '( z H8 "Z = rP'HT) T6 "Z '(zH8" Z = rP'HT) Z8 "Z'(zH2" 6 = rP'HT) n
Figure imgf000234_0002
Ζ · 9 '( ζ Η9 · 3ΐ = ί "'Ρ'Ηΐ)09'9'( s ' HI) 88'S'(s'HS) SS ''(s'HS) S0 ''(ra'HI)0S'S—S: Army 9 (OS) 顺 —Η τ
Figure imgf000234_0003
Eh l-, (^ d (/ 9, ^ ['I] ^>^-HS--' ε- ^
-ε) -ζ)→) -ζ- ^ ^-ι) -8) -ε- (Ή) ω^ ^、つ ¾ ^ / ^ェ邈 m
Figure imgf000234_0004
辛恩 瀚缀 止-ε) -ζ) →) -ζ- ^ ^ -ι) -8) -ε- (Ή) ω ^ ^, ¾ ^ / ^
Figure imgf000234_0004
Suddenly
^im ^ ^^n ^ -^ ^。 >n# ^翻 s っ。 os 翻 ¾累 ^ im ^ ^^ n ^-^ ^. > n # ^ Translation s os transliteration
T"9S'0继缀氺マ fH 邈氺 1/Ιου¾、^继缀 Τ¾マ / cm enuioiベ έ ci ^エ ( / - 1 ^·^0Ά ( ^エ（ / 9 Ί] /、,、 -UZ-nT "9S'0 继 缀 氺 ma fH 邈 氺 1 / Ι ου ¾, ^ 继 缀 Τ¾ Ma / cm enuioi έ ci ^ d (/-1 ^ · ^ 0 Ά (^ d (/ 9 Ί] /, ,, -UZ-n
'ε- ^-ε) -ζ)→) -ζ-^ ^-ι) -8) -ε- (Ή) = ェ 'ε-^-ε) -ζ) →) -ζ- ^ ^ -ι) -8) -ε- (Ή) =
Figure imgf000234_0005
Figure imgf000234_0006
Figure imgf000234_0005
Figure imgf000234_0006
HT)6S"8'(zH9"eT=rP'HT)eS"8'(zHS"Z=f'P'HT)88"Z'(s'HT)S8"Z'(zHS"Z=f'P'HT)89"Z'(z Η^6=ί"'Ρ'Ηΐ)00·Ζ'(ζΗε·8=ί"'Ρ'Ηΐ)06·9'(ζΗ8·ΐ'ε·8=ί"'ΡΡ'Ηΐ)Ζ8·9'(ζΗ8·ΐ=ί"'Ρ'Ηΐ)39·9
Figure imgf000234_0007
HT) 6S "8 '( z H9" eT = rP'HT) eS "8' ( z HS" Z = f'P'HT) 88 "Z '(s'HT) S8"Z' (zHS "Z = f'P'HT) 89 "Z '(z Η ^ 6 = ί"'Ρ'Ηΐ) 00 · Ζ '( ζ Ηε · 8 = ί "'Ρ'Ηΐ) 06 · 9 '( ζ ΐ8 · ΐ' ε · 8 = ί "'ΡΡ'Ηΐ) Ζ8 · 9' ( ζ Η8 · ΐ = ί"'Ρ'Ηΐ) 39 · 9
Figure imgf000234_0007
98S6T0/S00Zdf/X3d ェチル = (E)— 3— (8— (1—ヒドロキシ一 2— (ピペラジン一 1—ィル）ェチル） 2— メトキシキノリン一 5—ィル）アタリラートの 2塩酸塩および 6— (2 クロロェチル） - 2H 一べンゾ [1, 4]チアジン 3 (4H) オンから実施例 144と同様にして、ェチル = (E ) - 3- (8—（1ーヒドロキシー2—（4 (2- (3 ォキソ 3, 4 ジヒドロー 2H べ ンゾ [1, 4]チアジン 6 ィル）ェチル）ピぺラジン 1 ィル）ェチル）ー2—メトキシ キノリン一 5—ィル)アタリラートを得た。 98S6T0 / S00Zdf / X3d Ethyl = (E) — 3— (8— (1—Hydroxy-1 2- (piperazine-1 1-yl) ethyl) 2-Methoxyquinoline 1-yl) Atarylate dihydrochloride and 6— (2 Chloroethyl) -2H monobenzo [1, 4] thiazine 3 (4H) from ethyl = (E)-3- (8— (1-hydroxy-2— (4 (2- (3 oxo) 3,4 dihydro-2H benzo [1,4] thiazine 6 yl) ethyl) piperazine 1 yl) ethyl) -2-methoxyquinoline 5-yl) attalylate was obtained.
'H-NMRCCDCl ) δ値： 1.37(3H,t,J=7.2Hz),2.34- 3.18(14H,m),3.42(2H,s),4.04(3H,s),  'H-NMRCCDCl) δ value: 1.37 (3H, t, J = 7.2Hz), 2.34-3.18 (14H, m), 3.42 (2H, s), 4.04 (3H, s),
3  Three
4.31(2H,q,J=7.2Hz),5.75-5.84(lH,m),6.52(lH,d,J=15.6Hz),6.69(lH,d,J=1.8Hz),6.88 (lH,dd,J=7.8,1.8Hz),7.00(lH,d,J=9.2Hz),7.24(lH,d,J=7.8Hz),7.69(lH,d,J=7.8Hz),7. 76(lH,s),7.88(lH,d,J=7.8Hz),8.35(lH,d,J=15.6Hz),8.39(lH,d,J=9.2Hz)  4.31 (2H, q, J = 7.2Hz), 5.75-5.84 (lH, m), 6.52 (lH, d, J = 15.6Hz), 6.69 (lH, d, J = 1.8Hz), 6.88 (lH, dd , J = 7.8,1.8Hz), 7.00 (lH, d, J = 9.2Hz), 7.24 (lH, d, J = 7.8Hz), 7.69 (lH, d, J = 7.8Hz), 7.76 (lH , s), 7.88 (lH, d, J = 7.8Hz), 8.35 (lH, d, J = 15.6Hz), 8.39 (lH, d, J = 9.2Hz)
実施例 147 Example 147
Figure imgf000235_0001
Figure imgf000235_0001
ェチノレ = (E) - 3- (8—（1ーヒドロキシー2—（4 (2- (3 ォキソ 3, 4 ジヒド 口一 2H ベンゾ [1, 4]チアジン 6 ィル）ェチル）ピぺラジン 1—ィル）ェチル） —2—メトキシキノリン一 5—ィル)アタリラートから実施例 145と同様にして、 (E) - 3 一（8—（1ーヒドロキシー2—（4 (2- (3 ォキソ 3, 4 ジヒドロー 2H—ベンゾ[ 1, 4]チアジン 6 ィル）ェチル）ピぺラジン 1 ィル）ェチル）ー2—メトキシキノリ ン 5—ィル)アクリル酸を得た。  Echinore = (E)-3- (8— (1-Hydroxy-2— (4 (2- (3 oxo 3, 4 dihydr) 1H benzo [1, 4] thiazine 6 yl) ethyl) piperazine 1— E) -3 (8- (1-Hydroxy-2- (4 (2- (3 oxo 3, 4)) Dihydro-2H-benzo [1,4] thiazine 6yl) ethyl) piperazine 1yl) ethyl) -2-methoxyquinolin-5-yl) acrylic acid was obtained.
1H-NMR(CD OD) δ値： 2.81- 3.37(13H,m),3.40(2H,s),3.41- 3.48(lH,m),4.09(3H,s),6.  1H-NMR (CD OD) δ value: 2.81-3.37 (13H, m), 3.40 (2H, s), 3.41-3.48 (lH, m), 4.09 (3H, s), 6.
3  Three
14(lH,dd,J=9.9,2.5Hz),6.59(lH,d,J=15.6Hz),6.86(lH,d,J=1.8Hz),6.94(lH,dd,J=7.8, 1.8Hz),7.10(lH,d,J=9.2Hz),7.25(lH,d,J=7.8Hz),7.85(lH,d,J=7.8Hz),7.96(lH,d,J=7.8 Hz),8.40(lH,d,J=15.6Hz),8.53(lH,d,J=9.2Hz)  14 (lH, dd, J = 9.9,2.5Hz), 6.59 (lH, d, J = 15.6Hz), 6.86 (lH, d, J = 1.8Hz), 6.94 (lH, dd, J = 7.8, 1.8Hz ), 7.10 (lH, d, J = 9.2Hz), 7.25 (lH, d, J = 7.8Hz), 7.85 (lH, d, J = 7.8Hz), 7.96 (lH, d, J = 7.8Hz), 8.40 (lH, d, J = 15.6Hz), 8.53 (lH, d, J = 9.2Hz)
実施例 148 f
Figure imgf000236_0001
Figure imgf000236_0002
Example 148 f
Figure imgf000236_0001
Figure imgf000236_0002
Figure imgf000236_0003
-ζ)→) -ζ) -8) ε— (Ή) = ェ
Figure imgf000236_0003
-ζ) →) -ζ) -8) ε— (Ή) =
Figure imgf000236_0004
Figure imgf000236_0004
'(ZH9"eT=rP'HT "8'(s'HT)^"8'(zH8"Z=rP'HT)S6"Z'(ZH8"Z=f'P'HT)S8"Z'(ZH2"6=f'
Figure imgf000236_0005
'(ZH9 "eT = rP'HT"8' ( s 'HT) ^ "8' ( z H8" Z = rP'HT) S6 "Z '(ZH8" Z = f'P'HT) S8 "Z' (ZH2 "6 = f '
Figure imgf000236_0005
H S8'S'(S'H 99'S'C"'H0I)SZ — 9 '(zH6'9=i^'HS)6S'I :軍 9 ( — OSW I) 顺— Ητ H S8'S '( S ' H 99'S'C "'H0I) SZ — 9' ( z H6'9 = i ^ 'HS) 6S'I: Military 9 (— OSW I) 顺 — Η τ
'ε— ^
Figure imgf000236_0006
つ攝慰、
Figure imgf000236_0007
'ε— ^
Figure imgf000236_0006
Consolation,
Figure imgf000236_0007
ί 、]— ^^ム I ^マ 、つ辛爵 瀚缀 止 s教 D^IZZ J^- 'x][q-s 'ε]、 ίί — HS ( ^^ cm^—  ί,] — ^^ Mu I ^ Ma, 辛 辛 D D D D ^ IZZ J ^-'x] [q-s' ε], ίί — HS (^^ cm ^ —
Z— Λ(^ ( / - 1 - ^·^0Ά) -Z-^ ^-l) -8) -£- (Ή) = ェ Z— Λ (^ (/-1-^ · ^ 0 Ά) -Z- ^ ^ -l) -8)-£-(Ή) =
Figure imgf000236_0008
Figure imgf000236_0008
98S6T0/S00Zdf/X3d 1783 (s'HT)80"n'(zH2-6=rP'HT)½-8'(zHe-ST=rP'HT)S2-8'(s'H ΐ)Μ)·8'(ω'Ηζ)68· — S8' '(zHS'6=f'P'HI)80' '(zHS'SI=f'P'HI)8S'9'(ra'HI) 8'S— 6Γ3' (ra'HT)60"e-e0"e'(s'HS)00^'(s'H2) e"S'(ra'H2T)0 "2- S"2： ϊ 9 ( oswa) N— Ητ 98S6T0 / S00Zdf / X3d 1783 ( s 'HT) 80 "n' ( z H2-6 = rP'HT) ½-8 '( z He-ST = rP'HT) S2-8' ( s 'H ΐ) Μ) 8' (ω 'Ηζ) 68 · — S8''( z HS'6 = f'P'HI) 80''( z HS'SI = f'P'HI) 8S'9'(ra'HI)8'S— 6Γ3 '( ra'HT) 60 "e-e0" e '(s'HS) 00 ^' (s 'H2) e "S'(ra'H2T)0" 2- S "2: ϊ 9 (oswa) N- Η τ
。 ¾¾§ω0·92邈 (^ (^ -Q- d/^^-Z- {Λ^^^ ^ -i- ( / - 1 - ^·^0Ά {Λ^^^ ^ -Z- ( / — 9 - ,、 . ¾¾§ω 0 · 92 邈 (^ (^ -Q- d / ^^-Z- {Λ ^^^ ^ -i- (/-1-^ · ^ 0 Ά {Λ ^^^ ^ -Z- ( / — 9-,,
'x][q-s 'ε]、 ίί — HS 、 ¾、—
Figure imgf000237_0001
-ζ'x] [qs' ε], ίί—HS, ¾, —
Figure imgf000237_0001
-ζ
)→) -ζ) 8)— ε— ^ ^m^ ^ ^ m ^m ^ ^n
Figure imgf000237_0002
>n辛爵¾瀚缀、 止 s教 αύ?
Figure imgf000237_0003
) →) -ζ) 8) — ε— ^ ^ m ^ ^ ^ m ^ m ^ ^ n
Figure imgf000237_0002
> n 爵 瀚 缀 瀚 缀, stop s teaching αύ?
Figure imgf000237_0003
{Λ^^^ ^ -ζ- ( / -9 - ^J.-^ 'i][q—s 'ε]、 ίί ー HS— 、 ¾、一
Figure imgf000237_0004
-ζ)→) -ζ) -8) ε— (Ή) = ェ {Λ ^^^ ^ -ζ- (/ -9-^ J .- ^ 'i] [q—s' ε], ίί ー HS—, ¾, Ichi
Figure imgf000237_0004
-ζ) →) -ζ) -8) ε— (Ή) =
Figure imgf000237_0005
Figure imgf000237_0005
(S'HI)60'II( S 'HI) 60'II
'(ω'Ηΐ)^9·8-93·8'(ζΗΓ9ΐ=ΓΡΉΐ)3ε·8'(8Ήΐ) 0·8'(ω'Η2)00·8-38· '(ζΗ ·8=ΓΡΉΐ)
Figure imgf000237_0006
'(ω'Ηΐ) ^ 9 · 8-93 · 8' ( ζ ΗΓ9ΐ = ΓΡΉΐ) 3ε8 '( 8 Ήΐ) 0 · 8'(ω'Η2) 00 · 8-38 '' (ζΗ 8 = (ΓΡΉΐ)
Figure imgf000237_0006
Figure imgf000237_0007
:軍 9 (9p-os a)H N-HT
Figure imgf000237_0007
: Military 9 ( 9 p-os a) H NH T
。 Sui -Z6 . Sui- Z6
Figure imgf000237_0008
Figure imgf000237_0008
^ ^ [ 1 : 01 = Λ^/^： 'η-Λ^ η^ ί Μ 、09 ¾^¾ ^ ¥ -^^c c^^ ^^^ ^^c^^c c^ i- ^。 ·η辛爵¾瀚 ^ ^ [1 : 01 = Λ ^ / ^: 'η-Λ ^ η ^ ί Μ, 09 ¾ ^ ¾ ^ \-^^ cc ^^ ^^^ ^^ c ^^ cc ^ i- ^.・ Η
98S6T0/S00Zdf/X3d 983 [0428] 実施例 151 98S6T0 / S00Zdf / X3d 983 [0428] Example 151
Figure imgf000238_0001
Figure imgf000238_0001
ェチル = (E) - 3- (8- (2- (4 アミノビペリジン一 1—ィル） 1—ヒドロキシェ チル）ー2—メトキシキノリンー5 ィル）アタリラートの 2塩酸塩 0.21gの塩化メチレン 3 mLおよびメタノール 3mL溶液に、 7 ブロモ 3—ォキソ 3, 4 ジヒドロ一 2H ピ リド [3, 2-b] [l, 4]チアジン— 6—カルバルデヒド 0.14g、酢酸 0.05mLおよびトリァセ トキシ水素化ホウ素ナトリウム 0.12gを加え、室温で 4時間攪拌した。反応混合物にクロ 口ホルム 20mLおよび水 10mLをカ卩え、 20%水酸化ナトリウム水溶液で pHllに調整（pH 試験紙)した。有機層を分取し、水層をクロ口ホルムで抽出した。有機層および抽出 液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ 、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー [シ リカゲル；関東ィ匕学株式会社、シリカゲル 60、溶離液;クロ口ホルム:メタノール = 5 : 1 ]で精製し、黄色固体のェチル = (E) - 3- (8- (2- (4— ( (7 ブロモ—3—ォキソ - 3, 4 ジヒドロ一 2H ピリド [3, 2-b] [l, 4]チアジン一 6—ィル)メチルァミノ）ピ ペリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）ァクリラ 一ト。. llgを得た。  Ethyl = (E)-3- (8- (2- (4 Aminobiperidine 1-yl) 1-hydroxyethyl) -2-methoxyquinoline-5-yl) Atalylate dihydrochloride 0.21 g of methylene chloride 3 In a solution of 3 mL of methanol and 3 mL of methanol, 7 Bromo-3-oxo3,4-dihydro-1H chloride [3, 2-b] [l, 4] thiazine-6-carbaldehyde 0.14 g, acetic acid 0.05 mL and triacetoxyborohydride Sodium (0.12 g) was added, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, 20 mL of chloroform and 10 mL of water were added and adjusted to pHll with 20% aqueous sodium hydroxide solution (pH test paper). The organic layer was separated, and the aqueous layer was extracted with black mouth form. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Ltd., silica gel 60, eluent; black-form: methanol = 5: 1], and the yellow solid ethyl = (E)- 3- (8- (2- (4— ((7 bromo-3-oxo-3, 4 dihydro- 1H pyrido [3, 2-b] [l, 4] thiazine-6-yl) methylamino) piperidine 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 1-yl) acrylate. I got llg.
'H-NMRCCD OD) δ値： 1.35(3H,t,J=7.3Hz),1.63- 1.81(2H,m),2.02- 2.11(lH,m),2.11- 'H-NMRCCD OD) δ value: 1.35 (3H, t, J = 7.3Hz), 1.63-1.81 (2H, m), 2.02- 2.11 (lH, m), 2.11-
3 Three
2.19(lH,m),2.57-2.93(3H,m),3.12-3.21(lH,m),3.26-3.29(lH,m),3.32-3.35(lH,m),3. 55(2H,s),3.56-3.64(lH,m),4.02(2H,s),4.07(3H,s),4.29(2H,q,J=7.3Hz),6.07(lH,dd,J= 9.6,2.8Hz),6.62(lH,d,J=16.1Hz),7.07(lH,d,J=9.2Hz),7.83(lH,d,J=7.8Hz),7.93(lH,d, J=7.8Hz),7.96(lH,s),8.41(lH,d,J=16.1Hz),8.51(lH,d,J=9.2Hz)  2.19 (lH, m), 2.57-2.93 (3H, m), 3.12-3.21 (lH, m), 3.26-3.29 (lH, m), 3.32-3.35 (lH, m), 3.55 (2H, s ), 3.56-3.64 (lH, m), 4.02 (2H, s), 4.07 (3H, s), 4.29 (2H, q, J = 7.3Hz), 6.07 (lH, dd, J = 9.6, 2.8Hz) , 6.62 (lH, d, J = 16.1Hz), 7.07 (lH, d, J = 9.2Hz), 7.83 (lH, d, J = 7.8Hz), 7.93 (lH, d, J = 7.8Hz), 7.96 (lH, s), 8.41 (lH, d, J = 16.1Hz), 8.51 (lH, d, J = 9.2Hz)
[0429] 実施例 152 [0429] Example 152
Figure imgf000238_0002
Figure imgf000238_0002
Figure imgf000239_0001
Figure imgf000239_0001
z 〜 ssi圏第 [οε ο]
Figure imgf000239_0002
z ~ ssi zone number [οε ο]
Figure imgf000239_0002
T)09"8'(zH9"eT=f'P'HT)62"8'(s'HT)er8'(zH8"Z=f'P'HT)S6"Z'(zH8"Z=rP'HT)06"Z'(zH T) 09 "8 '( z H9" eT = f'P'HT) 62 "8' ( s ' HT) er8 '( z H8" Z = f'P'HT) S6 "Z'(zH8" Z = rP'HT) 06 "Z '(zH
^6=ΓΡ'Ηΐ) ΐ (ζΗ9·3ΐ=ί"'Ρ'Ηΐ)Ζ9·9'(ω'Ηΐ)80·9— 68'S'(s'HS)WT (S'H 09'S'(S'HS ^ 6 = ΓΡ'Ηΐ) ΐ (ζΗ9 · 3ΐ = ί "'Ρ'Ηΐ) Ζ9 · 9'(ω'Ηΐ) 80 · 9— 68'S '(s'HS) WT ( S ' H 09'S '( S ' HS
)3ε·ε'(τιι'ΗΖ)8 ·ε— ' (ra'HS)SS — ΐ6·ΐ'(ω'Η 88·ΐ— 09·ΐ :軍 9 ( P-OS a)H N-HT ) 3ε · ε '(τιι'ΗΖ) 8 · ε—'(ra'HS) SS — ΐ6 · ΐ '(ω'Η 88 · ΐ— 09 · ΐ: Military 9 (P-OS a) H NH T
。 98邈 . 98邈
( / -9 -
Figure imgf000239_0003
'ε— ^ ^-£-^ /i-i))- ) -ζ) -8) -ε- (Ή) ω^ ^、つ ¾ ^ / ェ邈 (/ -9-
Figure imgf000239_0003
'ε— ^ ^-£-^ / ii))-) -ζ) -8) -ε- (Ή) ω ^ ^, ¾ ^ /
m i)
Figure imgf000239_0004
辛恩 瀚缀 止 s教
Figure imgf000239_0005
mi)
Figure imgf000239_0004
Sung
Figure imgf000239_0005
1
Figure imgf000239_0006
L Ί][4-2 'ε]、 ίί — Η 1
Figure imgf000239_0006
L Ί] [4-2 'ε], ίί — Η
'ε- ^-ε-βτΰ ι- ))-^) -ζ) -8)— ε— (Ή) = ェ  'ε- ^ -ε-βτΰ ι-))-^) -ζ) -8) — ε— (Ή) =
98S6T0/S00Zdf/X3d し 98S6T0 / S00Zdf / X3d
Figure imgf000240_0001
Figure imgf000240_0001
[0432] [表 11]
Figure imgf000241_0001
[0432] [Table 11]
Figure imgf000241_0001
実施例 。s 実施例 。s 実施例 。s 実施例 Example . s Examples. s Examples. s Example
Figure imgf000241_0002
Figure imgf000241_0002
実施例 153 Example 153
(E) - 3- (8— (2- (4 4 メチルベンジルァミノ）ピぺリジン 1ーィル） 1ーヒ ドロキシェチル） 2—メトキシキノリン一 5—ィル）アクリル酸  (E)-3- (8— (2- (4 4 Methylbenzylamino) piperidine 1-yl) 1-hydroxychetyl) 2-methoxyquinoline 1-yl) acrylic acid
1H-NMR(DMSO-d ) δ値： 1.22— 1.34(2H,m),1.75— 1.84(2H,m),2.04— 2.17(2H,m),2.27(  1H-NMR (DMSO-d) δ value: 1.22— 1.34 (2H, m), 1.75— 1.84 (2H, m), 2.04— 2.17 (2H, m), 2.27 (
6  6
3H,s),2.34-2.43(2H,m),2.66(lH,dd,J=12.6,3.0Hz),2.87(lH,d,J=11.5Hz),3.13(lH,d,J 3H, s), 2.34-2.43 (2H, m), 2.66 (lH, dd, J = 12.6,3.0Hz), 2.87 (lH, d, J = 11.5Hz), 3.13 (lH, d, J
=11.5Hz),3.68(2H,s),3.99(3H,s),5.80(lH,dd,J=8.9,3.0Hz),6.56(lH,d,J=15.6Hz),7.08( lH,d,J=9.2Hz),7.10(2H,d,J=7.8Hz),7.21(2H,d,J=7.8Hz),7.82(lH,d,J=7.8Hz),7.84(lH 邈 (^ （ S—べ ίί,^ρ ^E ー S—( ^エ ^ p 、 —= 11.5Hz), 3.68 (2H, s), 3.99 (3H, s), 5.80 (lH, dd, J = 8.9, 3.0Hz), 6.56 (lH, d, J = 15.6Hz), 7.08 (lH, d , J = 9.2Hz), 7.10 (2H, d, J = 7.8Hz), 7.21 (2H, d, J = 7.8Hz), 7.82 (lH, d, J = 7.8Hz), 7.84 (lH 邈 (^ (S—Be ίί, ^ ρ ^ E ー S— (^ E ^ p, —
I - ( /y- 1
Figure imgf000242_0001
'ε)→) -ζ) -8) ε— (Ή) I-(/ y- 1
Figure imgf000242_0001
'ε) →) -ζ) -8) ε— (Ή)
(zH2"6=rP'HT)Se"8'(zH9"eT=rP'HT)02"8'(zH8"Z=rP'HT)S8"Z'(zH8"Z=f'P'HT)S8"Z '(ZHS"8=f'P'H2)^" '(ZHS"8=rP'H2)Sr '(ZH2"6=rP'HT)80" '(ZH9"ST=rP'HT) e"9'( zH0"S'6"8=rPP'HT)T8"e'(s'HS)66"S'(s'H2)69"S'(zHS-n=rP'HT)SrS'(zHe-n=rP'HT )88 '(ζΗ0·ε'9 ΐ=ΓΡΡ'Ηΐ)99 '(ζΗ9·Ζ=ί "' HS)ZS ' C"'HC — ' C"'HS)8I — 0 ' (ω'Η 38·ΐ— 9Ζ·ΐ'(ω'Η 3ε·ΐ— 8Π'(ζΗ9·Ζ=Π'Ηε)9ΐ·ΐ :軍 9 ( P-OS a)H N-HT 邈 (^ （ — S ベ ίί,^Ρ 、 ^EH ー S ( ^エ ^ pci、
Figure imgf000242_0002
(zH2 "6 = rP'HT) Se" 8 '( z H9 "eT = rP'HT) 02"8' ( z H8 "Z = rP'HT) S8" Z '(zH8 "Z = f'P' HT) S8 "Z '(ZHS" 8 = f'P'H2) ^ "'(ZHS" 8 = rP'H2) Sr '(ZH2 "6 = rP'HT) 80"' (ZH9 "ST = rP ' HT) e "9 '(zH0 "S'6"8 = rPP'HT) T8"e'(s'HS) 66 "S '(s' H2) 69"S' (z HS-n = rP'HT ) SrS '(zHe-n = rP'HT) 88' ( ζ Η0 · ε'9 ΐ = ΓΡΡ'Ηΐ) 99 '( ζ Η9 · Ζ = ί "' HS) ZS 'C"' HC — 'C "'HS) 8I — 0'(ω'Η 38 · ΐ— 9Ζ · ΐ '(ω'Η 3ε · ΐ— 8Π' ( ζ Η9 · Ζ = Π'Ηε) 9ΐ · ΐ: Military 9 (P-OS a ) H NH T邈 (^ (— S Be ίί, ^ Ρ, ^ EH ー S (^ E ^ pci,
Figure imgf000242_0002
(zH2"6=rP'HT)W8'(zH9"eT=rP'HT)S2"8'(zH8"Z=f'P'HT)98"Z'(zH8"Z=f P'HT)^8" '(s'HT)S^- '(ra'HS - -S2- '(zH2-6=f'P'HT)60" '(zH0"n'6" T=rPP'HT)2 Ζ·9'(ζΗ9·3ΐ=ί"'Ρ'Ηΐ)Ζ3·9'(ω'Ηζ^8·3— 8 S'(ZH0'n=l"'P'HI)SS'S'(s'HS)66'S'(s'HS)SZ ·ε'(ζΗ3·ΐΐ=ί"'Ρ'Ηΐ) ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)88 '(ζΗ0·ε'9 I=f'PP'HI)Z9'S'(ra'HS)S S - ε·2'(ω'Η2)6Γ2-30·2'(ω'Η2) 8·ΐ- ·ΐ'(ω'Η2) ε·ΐ-82·ΐ:ΐ!} 9 ( P-OS a)H N-HT 邈 (^ （ — S ベ ίί,^Ρ 、 ^ΕΗ ー S ( ^エ ^ pci、(zH2 "6 = rP'HT) W8 '( z H9" eT = rP'HT) S2 "8' ( z H8" Z = f'P'HT) 98 "Z '(zH8" Z = f P'HT ) ^ 8 "'(s'HT) S ^-'(ra'HS--S2-'(zH2-6 = f'P'HT) 60"' (zH0 "n'6" T = rPP'HT) 2 Ζ · 9 '( ζ Η9 · 3ΐ = ί "'Ρ'Ηΐ) Ζ3 · 9 '(ω'Ηζ ^ 8 · 3— 8 S'(ZH0'n = l"'P'HI)SS'S' (s 'HS) 66'S' ( s 'HS) SZ · ε' ( ζ Η3 · ΐΐ = ί "'Ρ'Ηΐ) ΐε' ( ζ Η3 · π = ί"'Ρ'Ηΐ)88' ( ζ Η0 ε'9 I = f'PP'HI) Z9'S '(ra'HS) SS-ε2'(ω'Η2) 6Γ2-302 '(ω'Η2) 8 · 8- · ΐ' (ω ' Η2) ε · ΐ-82 · ΐ: ΐ!} 9 (P-OS a) H NH T邈 (^ (— S B ίί, ^ Ρ, ^ ΕΗ ー S (^ エ ^ pci,
Ά-ι- ( / - 1
Figure imgf000242_0003
-s) -8) -ε- (Ή) Ά-ι- (/-1
Figure imgf000242_0003
-s) -8) -ε- (Ή)
(zH2"6=rP'HT)W8'(zH9"ST=rP'HT)22"8'(zH8"Z=rP'HT)98"Z'(zH8"Z=f 'P'HT)^8" '(zH2"9'r8=rp HT)SS" '(zHr8=f' H2) r '(zH2"6=rP'HT)80" '(zH8"2' r8=rpVHT)20"Z'(zH9"eT=f'P'HT)8e-9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)^Z •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)Z8 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)„ — ' C"'HS)6rS— 90 ' C"'HS)S8'I— SZ'I'(ra'HS)SS'I— ·ΐ :軍 9 ( P-OS a)H N-HT (zH2 "6 = rP'HT) W8 '( z H9" ST = rP'HT) 22 "8' ( z H8" Z = rP'HT) 98 "Z '(zH8" Z = f'P'HT) ^ 8 "'(zH2"9'r8 = rp HT) SS "' (zHr8 = f 'H2) r'(zH2" 6 = rP'HT) 80 "'(zH8"2' r8 = rpVHT) 20 "Z '(zH9 "eT = f'P'HT) 8e-9' ( z H0"S'6"8 = rPP'HT) T8" S '(s'HS) 66 "S' ( s ' H2) ^ Z S '( z HS'II = f'P'HI) SrS' ( z HS'II = f'P'HI) Z8 '( ζ Η0 · ε'9 I = f'PP'HI) 99'S' (ra 'HS) „—'C"'HS)6rS—90' C "'HS) S8'I—SZ'I'(ra'HS)SS'I— · ΐ: Military 9 (P-OS a) H NH T
-I - ( / - 1
Figure imgf000242_0004
ε) - -2)-8)-ε-(Ή) -I-(/-1
Figure imgf000242_0004
ε)--2) -8) -ε- (Ή)
(zH2"6=f'P'HT)Se"8'(zH9"ST=rP'HT)6r8'(zH8"Z=rP' (zH2 "6 = f'P'HT) Se" 8 '( z H9 "ST = rP'HT) 6r8' ( z H8" Z = rP '
98S6T0/S00Zdf/X3d 0173 ，,,J,，,，,,J，,,J)()()()( HZ7.17lHdd8.53.9HZ7.317.422Hm7.84lHd7.8HZ7.86lHd7.8===l98S6T0 / S00Zdf / X3d 0173 ,,, J ,,,,,, J ,,, J) () () () (HZ7.17lHdd8.53.9HZ7.317.422Hm7.84lHd7.8HZ7.86lHd7.8 === l
,，,，,,J,，,,J，,,J()()()()( 702Hs3.993Hs5.81lHdd8.93.0HZ6.58lHd15.6HZ7.09lHd9.2=== ,,,,,, J ,,,, J ,,, J () () () () (702Hs3.993Hs5.81lHdd8.93.0HZ6.58lHd15.6HZ7.09lHd9.2 ===
,，,,J,，,,J，,,J，()()()() 2.442Hm2.67lHdd12.63.0HZ2.88lHd11.5HZ3.13lHd11.5HZ3.===  ,,,, J ,,,, J ,,, J, () () () () 2.442Hm2.67lHdd12.63.0HZ2.88lHd11.5HZ3.13lHd11.5HZ3. ===
禽,，,，,，( )()()() δ 1HNMRDMSOd： l·26l.342Hml·74l·842Hm2.052.202Hm2·31IIllll  Poultry ,,,,, () () () () δ 1HNMRDMSOd: l · 26l.342Hml · 74l · 842Hm2.052.202Hm2 · 31IIllll
〔〕0440 [] 0440
〔〕0439 [] 0439
Figure imgf000243_0001
Figure imgf000243_0001
禽,，,，,，( )()()() δ HNMRDMSOd： l·27l.342Hml·71l·842Hm2.042·172Hm2·34IIllll一 ltll  Poultry ,,,,, () () () () δ HNMRDMSOd: l · 27l.342Hml · 71l · 842Hm2.042 · 172Hm2 · 34IIllll
璧 〔〕 ¾0438158  〔[] ¾0438158
，,,J )()8.51lHd9.2HZ=  ,,, J) () 8.51lHd9.2HZ =
，,，,,J，,,J，,,J)()()()( 6HZ7.017.114Hm7.80lHd7.8HZ7.82lHd7.8HZ8.11lHd15.6HZ===l ,,,,, J ,,, J ,,, J) () () () (6HZ7.017.114Hm7.80lHd7.8HZ7.82lHd7.8HZ8.11lHd15.6HZ === l
,,J，,，,，,,J,，,,J()()()()( • 13lHd11.5HZ3.652Hs3.993Hs5.80lHdd8.93.0HZ6.55lHd15.=== ,, J ,,,,,,, J ,,,, J () () () () (• 13lHd11.5HZ3.652Hs3.993Hs5.80lHdd8.93.0HZ6.55lHd15. ===
,，,，,，,,J,，,,J，)()()()() 3Hs2.193Hs2.352.432Hm2.66lHdd12.63.0HZ2.87lHd11.5HZ3==l 禽,，,，,，( )()()()( δ 1HNMRDMSOd： 1.28l.342Hm1.76l.842Hm2.042.152Hm2.18IIlll (ΖΗ2·6=ΓΡ'Ηΐ)23·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)Ζΐ •8'(s'H2)S8"Z'(s'HT)02"Z'(zH2-6=rP'HT)80"Z'(zHS-8=rP'HT)S0"Z'(zHS-8=f'P'HT)99" 9'(zH9"eT=rP'HT)9e"9'(zH0"S'6"8=f'PP'HT)T8"S'(zHZ"8=f'VH2)6^^'(s'HS)66"S'(s'H () () () () 3Hs2.193Hs2.352.432Hm2.66lHdd12.63.0HZ2.87lHd11.5HZ3 == l Poultry ,,,,, (, ) () () () (δ 1HNMRDMSOd: 1.28l.342Hm1.76l.842Hm2.042.152Hm2.18IIlll (ΖΗ2 · 6 = ΓΡ'Ηΐ) 23 · 8 '(ζ Η9 · 3ΐ = ΓΡ'Ηΐ) Ζΐ • 8'(s' H2) S8 "Z '(s'HT) 02"Z' (zH2-6 = rP'HT) 80 "Z '(zHS-8 = rP'HT) S0"Z' (zHS-8 = f'P'HT) 99 "9 '( z H9" eT = rP'HT) 9e "9' ( z H0 "S'6" 8 = f'PP'HT) T8 "S '(zHZ" 8 = f'VH2) 6 ^^' ( s ' HS) 66 "S '( s ' H
2)39·ε'(υι'Ηε)Ζΐ·ε— 0ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)88 '(ζΗ0·ε'9 ΐ=ί"'ΡΡ'Ηΐ)99 ' C"'HS)„ 2) 39 · ε '(υι'Ηε) Ζΐ · ε— 0ΐ · ε' ( ζ Η3 · π = ί "'Ρ'Ηΐ) 88' ( ζ Η0 · ε'9 ΐ = ί"'ΡΡ'Ηΐ) 99 'C "' HS)„
— ZS ' C"'HS)6rS— SO ' C"'HS)S8'I— 9Ζ·ΐ'(ω'Η ε·ΐ— 8S'I :軍 9 ( OS ) 顺— Ητ — ZS 'C "' HS) 6rS—SO'C"'HS)S8'I— 9Ζ · ΐ'(ω'Η ε · ΐ— 8S'I: Military 9 (OS) 顺 — Η τ
(,^ ^ ( / — s—ベ έ [q] : ε 'ζ))→) -ζ) -8)— ε— (Ή) (, ^ ^ (/ — S—Be έ [q]: ε 'ζ)) →) -ζ) -8) — ε— (Ή)
ε9ΐί^¾ϊ第 [ε^ο]
Figure imgf000244_0001
ε9ΐί ^ ¾ϊ 第 [ε ^ ο]
Figure imgf000244_0001
'(zH9"eT=rP'HT)22"8'(zH2"6=rP'HT) 6" '(ra'He)68" -28" '(zHS"8=rP'HT)T9" '(zH '(zH9 "eT = rP'HT) 22"8' ( z H2 "6 = rP'HT) 6"'(ra'He) 68 "-28"' (zHS "8 = rP'HT) T9"' (zH
2"6=f'P'HT)80"Z'(zH9"eT=f'P'HT)Ze"9'(zH0"S'6"8=rPP'HT)T8"e'(s'HS)66"S'(s'H2)S8 •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)88 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)„ 2 "6 = f'P'HT) 80" Z '(zH9 "eT = f'P'HT) Ze"9' ( z H0 "S'6" 8 = rPP'HT) T8 "e '(s' HS) 66 "S '(s ' H2) S8 • S' (z HS'II = f'P'HI) SrS '(z HS'II = f'P'HI) 88' (ζ Η0 · ε'9 I = f'PP'HI) 99'S '(ra'HS) „
— ZS ' C"'HS)6rS— 90 ' (ω'Η 8·ΐ— 6Ζ·ΐ'(ω'Η 8ε·ΐ— 6S'I :軍 9 ( OSWd) N— Ητ — ZS 'C "' HS) 6rS— 90 '(ω'Η 8 · ΐ— 6Ζ · ΐ'(ω'Η 8ε · ΐ— 6S'I: Army 9 (OSWd) N— Η τ
( / - 9 - Λ^ ^^^^ ·^ -£'Z'l))→) -Ζ)—8) -£- (Ή)
Figure imgf000244_0002
(/-9-Λ ^ ^^^^ · ^-£ 'Z'l)) →) -Ζ) —8)-£-(Ή)
Figure imgf000244_0002
ZH9"eT=f'P'HT)n"8'('zHS"2=rP'HT)½"Z'(ZH8"Z=f'P'HT)28"Z'(ZH8"Z=f'P'HT)08"Z'(z ZH9 "eT = f'P'HT) n" 8 '(' z HS "2 = rP'HT) ½" Z '(ZH8 "Z = f'P'HT) 28"Z' (ZH8 "Z = f 'P'HT) 08 "Z' (z
H9"T=f'P'HT)09"Z'(zHS"8=rP'HT)0e"Z'(zH9TS"8=rPP'HT)62"Z'(zH2"6=f'P'HT)Z0"Z H9 "T = f'P'HT) 09" Z '(zHS "8 = rP'HT) 0e" Z' (zH9TS "8 = rPP'HT) 62" Z '(zH2 "6 = f'P'HT ) Z0 "Z
'(ZHS =f'P'HI)I6'9'(zH9'SI=f'P'HI) S'9'(zH0'S'6'8=f'PP)08'S'(s'HS)86'S'(s'HS)I8 '(ZHS = f'P'HI) I6'9' ( z H9'SI = f'P'HI) S'9 '( z H0'S'6'8 = f'PP) 08'S'(s'HS)86'S'( s ' HS) I8
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)εΓε'(ΖΗ3·π=ΓΡ'Ηΐ) 8·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)39·2'(ω'Η2)ε^·2· Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) εΓε' (ΖΗ3 · π = ΓΡ'Ηΐ) 8 · 2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 39.2'(ω'Η2) ε ^ · 2
— 9S ' (ω'Η 1 — W S'(ra'HS)06'I— Ο8·ΐ'(ω'Η 6ε·ΐ— 6S'I :軍 9 ( OS ) 顺— Ητ y-l -^fi^ ( ^ ^( ^- - ^Δ/ >-) )→) -2)-8)-ε-(Ή)— 9S '(ω'Η 1 — W S'(ra'HS)06'I— Ο8 · ΐ '(ω'Η 6ε · ΐ— 6S'I: Military 9 (OS) 顺 — Η τ yl-^ fi ^ (^ ^ (^--^ Δ />-)) →) -2) -8) -ε- (Ή)
Figure imgf000244_0003
Figure imgf000244_0003
(zH2"6=f'P'HT)W8'(zH9"ST=rP'HT)^"8'(zH (zH2 "6 = f'P'HT) W8 '( z H9" ST = rP'HT) ^ "8' ( z H
98S6T0/S00Zdf/X3d 邈 (^ （ — S ベ ίί,^Ρ 、 ^EH ー S ( ^エ ^ pci、 98S6T0 / S00Zdf / X3d 邈 (^ (— S Be ίί, ^ Ρ, ^ EH ー S (^ E ^ pci,
( / - 1
Figure imgf000245_0001
→) -Ζ) -2) -£- (Ή.) (/-1
Figure imgf000245_0001
→) -Ζ) -2)-£-(Ή.)
(zH2"6=rP'HT)Se"8'(zH9"ei=rP'HT)02"8'(zH8"Z=rP'HT)98"Z'(zH8"Z=rP'HT)^ (zH2 "6 = rP'HT) Se" 8 '( z H9 "ei = rP'HT) 02"8' ( z H8 "Z = rP'HT) 98" Z '(zH8 "Z = rP'HT) ^
8" '(zH2-6=rP'HT)80" 'WT=rP'HT)½"9'(zHS-8=rP'HT)28"9'Wrs-8=rPP'HT 8 "'(zH2-6 = rP'HT) 80"' WT = rP'HT) ½ "9 '( z HS-8 = rP'HT) 28"9'Wrs-8 = rPP'HT
)6Z"9'(zH9"eT=f'P'HT)8e"9'(s'H2)Z6"e'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)99 ) 6Z "9 '( z H9" eT = f'P'HT) 8e "9' ( s 'H2) Z6"e' (zH0 "S'6" 8 = rPP'HT) T8 "S '(s' HS) 66 "S '(s ' H2) 99
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)εΓε'(ΖΗ3·π=ΓΡ'Ηΐ)88·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)5^·2 — ' C"'HS)OS — SO ' C"'HS)S8'I— ·ΐ'(ω'Η Ζε·ΐ— :軍 9 ( P-OS a)H N-HT · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) εΓε' (ΖΗ3 · π = ΓΡ'Ηΐ) 88.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 9 · 2'(ω'Η2) 5 ^ · 2 — 'C "' HS) OS — SO 'C"' HS) S8'I— · ΐ '(ω'Η Ζε · ΐ—: Army 9 (P-OS a) H NH T
m 。 (/^ ^ ( / s— /— ^^^ [ε Ί] ^>^))-^) -Ζ) 8)— ε (Ή)  m. (/ ^ ^ (/ s— / — ^^^ [ε Ί] ^> ^))-^) -Ζ) 8) — ε (Ή)
991圏第 [9^0] (zH2"6=rP'HT)0e"8'(zH9"ST=rP'HT)9 991 zone [9 ^ 0] (zH2 "6 = rP'HT) 0e" 8 '( z H9 "ST = rP'HT) 9
0"8'(zH8"Z=rP'HT)28"Z'(ZH8"Z=rP'HT)8Z"Z'(ZHS"8=rP'H2)^rZ'(ZH2"6=f'P'HT)Z0"Z 0 "8 '( z H8" Z = rP'HT) 28 "Z'(ZH8" Z = rP'HT) 8Z "Z '(ZHS" 8 = rP'H2) ^ rZ' (ZH2 "6 = f 'P'HT) Z0 "Z
'(zHS"8=rP'H2)99"9'(zH9"eT=rP'HT)Se"9'(zH0"S'2"6=rPP'HT)08"S'(s'HS)66"S'(s'H'(zHS "8 = rP'H2) 99"9' ( z H9 "eT = rP'HT) Se" 9 '( z H0 "S'2" 6 = rPP'HT) 08 "S'(s'HS ) 66 "S '( s ' H
Ζ9·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)εΐ·ε'(ω'ΗΖ)68 8 '(ζΗ0·ε'9 I=f'PP'HI)S9 ' (ω'Η ε Ζ9 · ε '( ζ Η3 · π = ί "'Ρ'Ηΐ) εΐ · ε '(ω'ΗΖ) 68 8' ( ζ Η0 · ε'9 I = f'PP'HI) S9 '(ω'Η ε
— 9S ' C"'HS)9rS— WTS'(ra'HS)S8'I— SZ'I'(ra'HS) TI— :軍 9 ( P-OS a)H N-HT
Figure imgf000245_0002
— 9S 'C "' HS) 9rS— WTS '(ra'HS) S8'I— SZ'I'(ra'HS) TI—: Military 9 (P-OS a) H NH T
Figure imgf000245_0002
s 9 第 [e^o]
Figure imgf000245_0003
s 9 No. [e ^ o]
Figure imgf000245_0003
9"eT=rP'HT)Sr8'(zHS"8=rP'H2)68" '(s'H2)S8" '(zHS"8=rP'H2)8^" '(zH2"6=rP'H 9 "eT = rP'HT) Sr8 '( z HS" 8 = rP'H2) 68 "'(s'H2)S8"'(zHS"8 = rP'H2) 8 ^"' (zH2 "6 = rP 'H
T)80"Z'(zH9"eT=rP'HT)ee"9'(zH0"S'6"8=rPP'HT)08"e'(s'HS)86"S'(s'H2)6Z"S'(zHS"n T) 80 "Z '(zH9" eT = rP'HT) ee "9' ( z H0"S'6"8 = rPP'HT) 08" e '(s'HS) 86 "S' ( s ' H2 ) 6Z "S '(zHS" n
=f'P'HI)SrS'(zHS'n=f'P'HI)98 '(ζΗ0·ε'9 I=f'PP'HI)S9 '(s'HS)9S'S'(ra'HS)S S — IS ' C"'HS)9rS— 66·ΐ'(ω'Η 8·ΐ— SZ'I'(ra'HS) TI— :軍 9 ( P-OS a)H N-HT = f'P'HI) SrS '( z HS'n = f'P'HI) 98' ( ζ Η0 · ε'9 I = f'PP'HI) S9 '( s ' HS) 9S'S '(ra' HS) SS — IS 'C "' HS) 9rS— 66 · ΐ '(ω'Η 8 · ΐ— SZ'I'(ra'HS) TI—: Military 9 (P-OS a) H NH T
-I - ( /y- 1
Figure imgf000245_0004
→) -z) -8) ε— (Ή)-I-(/ y- 1
Figure imgf000245_0004
→) -z) -8) ε— (Ή)
9" [圏第  9 "[Band No.
98S6T0/S00Zdf/X3d ΐ,νζ Η9·3ΐ=ΓΡ'Ηΐ)(^·8'(ω'Η9)06·Ζ—ΐ8·Ζ'(ΖΗ9·ΐ'3·8=ΓΡΡ'Ηΐ)ε3·Ζ'(ω'Η2)03·Ζ— ^·Ζ'(ΖΗ 98S6T0 / S00Zdf / X3d ΐ, νζ Η9 · 3ΐ = ΓΡ'Ηΐ) (^ · 8 '(ω'Η9) 06 · Ζ—ΐ8 · Ζ' (ΖΗ9 · ΐ'3 · 8 = ΓΡΡ'Ηΐ) ε3 · Ζ '(ω'Η2) 03 Ζ— ^ · Ζ '(ΖΗ
2-6=f'P'HT)80"Z'(zH9"eT=f'P'HT)Ze-9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)86"S'(s'H2)06 2-6 = f'P'HT) 80 "Z '(zH9" eT = f'P'HT) Ze-9' ( z H0 "S'6" 8 = rPP'HT) T8 "S '(s' HS) 86 "S '(s ' H2) 06
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)3Γε'(ΖΗ3·π=ΓΡ'Ηΐ)68·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2) ^·2 — ZS ' C"'HS)6rS— 90 ' (ω )06·ΐ— I8'I'(ra'HS»。ε·ΐ :軍 9 ( OS ) Η顺— Ητ · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) 3Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 68.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 9-2'(ω'Η2) ^ · 2 — ZS 'C "' HS) 6rS— 90 '(ω) 06 · ΐ— I8'I'(ra'HS». Ε · ΐ: Army 9 (OS) Η 顺 — Η τ
^y-\- ^(^M^ -^^{^y-z- A^^))→) -z)—8)— ε— (a) ^ y-\-^ (^ M ^-^^ {^ y-z- A ^^)) →) -z) —8) — ε— (a)
o 圏第 [os o] o No. [os o]
(zH2"6=rP'HT)Se"8'(zH9"ei=f'P'HT)T2"8'(zH8"Z=f'P (zH2 "6 = rP'HT) Se" 8 '( z H9 "ei = f'P'HT) T2"8' ( z H8 "Z = f'P
'HT)e8" '(ZH8" =rP'HT)S8" '(ZHS"8=rP'H2)62" '(ZHS"8=rP'H2)02" '(ZH2"6=rP'H  'HT) e8 "' (ZH8" = rP'HT) S8 "'(ZHS" 8 = rP'H2) 62 "' (ZHS" 8 = rP'H2) 02 "'(ZH2" 6 = rP'H
T)80"Z'(zH9"eT=rP'HT)Ze-9'(zH0"S'6"8=rPP'HT)T8"e'(s'HS)66"S'(s'H2)69"S'(zHS-n T) 80 "Z '(zH9 " eT = rP'HT) Ze-9' (z H0 "S'6" 8 = rPP'HT) T8 "e '(s'HS) 66"S'(s' H2 ) 69 "S '( z HS-n
=rP'HT)SrS'(zHe-n=rP'HT)88"2'(zH0"S'9"2T=rPP'HT) 9"2'(s'HS)S^-2'(ra'H2)S^-2 — 9S ' C"'HS)6rS— 90 ' C"'HS)S8'I— ·ΐ'(ω'Η Ζε·ΐ— :軍 9 ( P-OS a)H N-HT y- 1 - ^(. ^αΆ {^Ι.Λ(^ ^Λ(—^^Λ( .Λ(^→)→) -Z)—8) -£- (Ή) = rP'HT) SrS '(zHe-n = rP'HT) 88 "2' ( z H0"S'9"2T = rPP'HT) 9" 2 '( s ' HS) S ^ -2' (ra 'H2) S ^ -2 — 9S' C "'HS) 6rS— 90'C"'HS)S8'I— · ΐ'(ω'Η Ζε · ΐ—: Army 9 (P-OS a) H NH T y- 1-^ (. ^ Α Ά {^ Ι.Λ (^ ^ Λ (— ^^ Λ (.Λ (^ →) →) -Z) —8)-£-(Ή)
691圏第 [6^0]
Figure imgf000246_0001
691 zone [6 ^ 0]
Figure imgf000246_0001
zH9"eT=f'P'HT)6r8'(s'H2)^8" '(ra'H2)^r -0r '(zH2"6=rP'HT)80" '(zHS"8=rP'HT zH9 "eT = f'P'HT) 6r8 '( s ' H2) ^ 8"'(ra'H2) ^ r -0r' (zH2 "6 = rP'HT) 80"'(zHS"8 = rP' HT
)e8"9'(zH9"eT=f'P'HT)Ze"9'(zH0"S'6"8=rPP'HT)T8"e'(s'HS)66"S'(s'HS)SZ"S'(s'H2)99 ) e8 "9 '( z H9" eT = f'P'HT) Ze "9' ( z H0"S'6"8 = rPP'HT) T8" e '(s'HS) 66 "S' ( s 'HS) SZ "S'(s'H2) 99
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)^Γε'(ΖΗ3·π=ΓΡ'Ηΐ)68·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)6^·2 · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) ^ Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 68.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 9-2'(ω'Η2 ) 6 ^ 2
- 8S ' C"'HS)0S - Z0 ' (ω'Η Ζ8·ΐ- 8Ζ·ΐ'(ω'Η 6ε·ΐ- θε·ΐ :軍 9 ( P-OS a)H N-HT -8S 'C "' HS) 0S-Z0 '(ω'Η Ζ8 · ΐ- 8Ζ · ΐ'(ω'Η 6ε · ΐ- θε · ΐ: Army 9 (P-OS a) H NH T
- 1 ~ ^(^α { ^Λ^^ ·^Λ^ -Ζ-^ →)→) -Ζ) -8)— ε— (Ή)-1 ~ ^ (^ α {^ Λ ^^ · ^ Λ ^ -Ζ- ^ →) →) -Ζ) -8) — ε— (Ή)
Figure imgf000246_0002
Figure imgf000246_0002
(zH2"6=rP'HT)Se"8'(zH9"ST=rP'HT)02"8'(zH8"Z (zH2 "6 = rP'HT) Se" 8 '( z H9 "ST = rP'HT) 02"8' ( z H8 "Z
=rP'HT)e8"Z'(ZH8"Z=rP'HT)S8"Z'(ZHZ"8=rP'H2)^"Z'(ZH2"6=f'P'HT)80"Z'(ZHZ"8=f = rP'HT) e8 "Z '(ZH8" Z = rP'HT) S8 "Z' (ZHZ" 8 = rP'H2) ^ "Z '(ZH2" 6 = f'P'HT) 80 "Z' (ZHZ "8 = f
P'HC8'9'(zH9'SI=f'P'HI)ZS'9'(zH0'S'6'8=f'PP'HI)I8'S'(ra'HS)Wr — S6'S'(S'HS)69 P'HC8'9 '( z H9'SI = f'P'HI) ZS'9' ( z H0'S'6'8 = f'PP'HI) I8'S '(ra'HS) Wr — S6'S' ( S ' HS) 69
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)^Γε'(ΖΗ3·π=ΓΡ'Ηΐ)68·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)9^·2 · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) ^ Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 68.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 9-2'(ω'Η2 ) 9 ^ · 2
-8ε·2'(ω'Η2)6Γ2- 0·2'(ω'Η2)98·ΐ-8 ·ΐ'(ω'Η3) ε·ΐ-82·ΐ:ΐ!} 9 ( P-OS a)H N-HT -8ε · 2 '(ω'Η2) 6Γ2- 0 · 2'(ω'Η2) 98 · ΐ-8 · ΐ '(ω'Η3) ε · ΐ-82 · ΐ: ΐ!} 9 (P-OS a) H NH T
98S6T0/S00Zdf/X3d W [圏第 [ s o] 98S6T0 / S00Zdf / X3d W [zone number [so]
(zH2"6=rP'HT)Se"8'(zH9"ST=rP'HT)6r8'(s'HT)S6"Z'(zH8"Z=f 'P'HT)^8"Z'(ZH8"Z=rP'HT)28"Z'(ZHS"8=rP'HT)9Z"Z'(S"8=rP'HT)9S"Z'(ZH2"6=rP'HT (zH2 "6 = rP'HT) Se" 8 '( z H9 "ST = rP'HT) 6r8' ( s 'HT) S6"Z' (zH8 "Z = f 'P'HT) ^ 8"Z' (ZH8 "Z = rP'HT) 28" Z '(ZHS "8 = rP'HT) 9Z"Z' (S "8 = rP'HT) 9S" Z '(ZH2 "6 = rP'HT
)80"Z'(zH9"eT=f'P'HT)9e-9'(zH0"S'6"8=rPP'HT)08"S'(s'HS)82^'(s'HS)86"S'(s'H2)88 ) 80 "Z '(zH9" eT = f'P'HT) 9e-9' ( z H0 "S'6" 8 = rPP'HT) 08 "S '(s'HS) 82 ^' ( s ' HS ) 86 "S '( s ' H2) 88
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)^Γε'(ΖΗ3·π=ΓΡ'Ηΐ) 8·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)39·2'(ω'Η¾ε^·2 · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) ^ Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 8 · 2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 39.2'(ω'Η¾ε ^ · 2
-^ε·2'(ω'Η2)9Γ2-^0·2'(ω'Η¾ 8·ΐ-3 ·ΐ'(ω'Η2) ε·ΐ-82·ΐ:ΐ!} 9 ( P-OS a)H N-HT / — s— /— 、 fH 、ベ:^— ε'Π— m— ^ — Ό)— ） -ζ) -8)— ε— (Ή)
Figure imgf000247_0001
-^ ε · 2 '(ω'Η2) 9Γ2- ^ 0 · 2'(ω'Η¾ 8 · ΐ-3 · ΐ '(ω'Η2) ε · ΐ-82 · ΐ: ΐ!} 9 (P- OS a) H NH T / — s— / —, fH, B: ^ — ε'Π— m— ^ — Ό) —) -ζ) -8) — ε— (Ή)
Figure imgf000247_0001
Ή2)ΐ6·8'(ζΗ2·6=ΓΡ'Ηΐ)ε3·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)6Γ8'(ω'Η2)50·8-20·8'(ωΉε)68· -ΐ8· Z'(zH2"6=rP'HT)80"Z'(zH9"eT=rP'HT)9S"9'(zH0"S'6"8=rPP'HT)T8"e'(ra'HS)00^-Z6 Ή2) ΐ6 ・ 8 '( ζ Η2 ・ 6 = ΓΡ'Ηΐ) ε3 ・ 8' ( ζ Η9 ・ 3ΐ = ΓΡ'Ηΐ) 6Γ8 '(ω'Η2) 50 ・ 8-20 ・ 8' (ωΉε) 68 ・-ΐ8 · Z '(zH2 "6 = rP'HT) 80"Z' (zH9 "eT = rP'HT) 9S" 9 '( z H0 "S'6" 8 = rPP'HT) T8 "e' ( ra'HS) 00 ^ -Z6
·ε'(ζΗ3·ΐΐ=ί"'Ρ'Ηΐ) ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)88 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)„ Ε '( ζ Η3 · ΐΐ = ί "'Ρ'Ηΐ) ΐε '( ζ Η3 · π = ί"'Ρ'Ηΐ) 88 '( ζ Η0 · ε'9 I = f'PP'HI) 99'S '(ra'HS) „
- 9S ' (ra'HS rS- 90 ' (ω'Η 68·ΐ- Ο8·ΐ'(ω'Η 6ε·ΐ- θε·ΐ :軍 9 ( P-OS a)H N-HT y-i
Figure imgf000247_0002
) - v)— — 8)— ε— ） -9S '(ra'HS rS- 90'(ω'Η 68 · ΐ- Ο8 · ΐ '(ω'Η 6ε · ΐ- θε · ΐ: Army 9 (P-OS a) H NH T yi
Figure imgf000247_0002
)-v) — — 8) — ε—)
Wrr^=rPP'HT)^8"8'(zH2-6=rP'HT)2S-8'Wr -8=f'P Wrr ^ = rPP'HT) ^ 8 "8 '( z H2-6 = rP'HT) 2S-8'Wr -8 = f'P
P'HT)2S"8'(zH9"eT=rP'HT)2r8'(zHZ"8=rP'HT)e6"Z'(zWT=f'P'HT)88"Z'(zH8"Z=f'P
Figure imgf000247_0003
P'HT) 2S "8 '( z H9" eT = rP'HT) 2r8' ( z HZ "8 = rP'HT) e6" Z '(zWT = f'P'HT) 88 "Z'(zH8" Z = f'P
Figure imgf000247_0003
2-6=f'P'HT)Z0"Z'(zH9"eT=f'P'HT)½-9'(zH0"S'6"8=rPP'HT)08"S'(s'HS)86"S'(s'H2)26 2-6 = f'P'HT) Z0 "Z '(zH9" eT = f'P'HT) ½-9' ( z H0 "S'6" 8 = rPP'HT) 08 "S '(s' HS) 86 "S '(s ' H2) 26
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)^Γε'(ΖΗ3·π=ΓΡ'Ηΐ)88·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)39·2'(ω'Η2)ε^·2 — ZS ' (ra'HS rS— 90 ' (ω'Η 88·ΐ— ΐ8·ΐ'(ω'Η 8ε·ΐ— ·ΐ :軍 9 ( P-OS a)H N-HT · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) ^ Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 88.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 39.2'(ω'Η2 ) ε ^ · 2 — ZS '(ra'HS rS— 90'(ω'Η 88 · ΐ— ΐ8 · ΐ '(ω'Η 8ε · ΐ— · ΐ: Army 9 (P-OS a) H NH T
邈 (^ （ — S—ベ ίί,^Ρ ^ EH ー S— ( ^エ ^ p 、 — ΐ—  邈 (^ (— S—Be ίί, ^ Ρ ^ EH ー S— (^ エ ^ p, — ΐ—
( / —" [—ベ fi ^ ( — 9—ベ ίί,^))― ） -2)-8)-ε-(Ή)  (/ — "[—Be fi ^ (— 9—Be ίί, ^)) ―) -2) -8) -ε- (Ή)
(zH2"6=f'P'HT)SS"8'(z (zH2 "6 = f'P'HT) SS" 8 '( z
98S6T0/S00Zdf/X3d 173
Figure imgf000248_0001
98S6T0 / S00Zdf / X3d 173
Figure imgf000248_0001
(zHS'6=f'P'HI)½'8'(zH9'SI=f'P'HI)W8'( ZH8"Z=rP'HT)Z8"Z'(ZH8"Z=f'P'HT)^8"Z'(ZH8"Z=f'P'H2)99"Z'(ZH8"Z=rP'H2)ZS"Z'(ZH (zHS'6 = f'P'HI) ½'8 '( z H9'SI = f'P'HI) W8' (ZH8 "Z = rP'HT) Z8" Z '(ZH8 "Z = f'P 'HT) ^ 8 "Z'(ZH8" Z = f'P'H2) 99 "Z '(ZH8" Z = rP'H2) ZS "Z' (ZH
2-6=f'P'HT)60"Z'(zH9"eT=f'P'HT)8e-9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)T8 •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)88 '(ζΗ0·ε'9 I=f'PP'HI)Z9'S'(ra'HS)„ 2-6 = f'P'HT) 60 "Z '(zH9" eT = f'P'HT) 8e-9' ( z H0 "S'6" 8 = rPP'HT) T8 "S '(s' HS) 66 "S '(s ' H2) T8 • S' (z HS'II = f'P'HI) SrS '(z HS'II = f'P'HI) 88' (ζ Η0 · ε'9 I = f'PP'HI) Z9'S '(ra'HS) „
— ' C"'HS)0S — 90 '(ω )98·ΐ— 3Ζ·ΐ'(ω'Η ε·ΐ— :軍 9 (9P— OS ) 顺— Ητ
Figure imgf000248_0002
— 'C "' HS) 0S — 90 '(ω) 98 · ΐ— 3Ζ · ΐ'(ω'Η ε · ΐ—: Army 9 ( 9 P— OS) 顺 — Η τ
Figure imgf000248_0002
9Ζΐ圏第 [9S 0] (zH2"6=f'P'HT)W8'(zH9"eT=f'P'HT)S2"8'(zH8"Z=rP'HT)Z8"Z'(zH8"Z=rP' HT)^8"Z'(s'HT)TZ"Z'(ZH8"Z=rP'HT)^9"Z'(ZH8"Z=rP'HT)ZS"Z'(ZH8"Z=rVHT)Se"Z'(ZH 9th Zone [9S 0] (zH2 "6 = f'P'HT) W8 '( z H9" eT = f'P'HT) S2 "8' ( z H8" Z = rP'HT) Z8 "Z ' (zH8 "Z = rP'HT) ^ 8" Z '(s'HT) TZ "Z'(ZH8" Z = rP'HT) ^ 9 "Z '(ZH8" Z = rP'HT) ZS "Z' (ZH8 "Z = rVHT) Se" Z '(ZH
2-6=f'P'HT)80"Z'(zH9"eT=f'P'HT)8e-9'(zH0"S'6"8=rPP'HT)28"S'(s'HS)66"S'(s'H2)28 2-6 = f'P'HT) 80 "Z '(zH9" eT = f'P'HT) 8e-9' ( z H0 "S'6" 8 = rPP'HT) 28 "S '(s' HS) 66 "S '(s ' H2) 28
·ε'(ζΗ3·ΐΐ=ί"'Ρ'Ηΐ) ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)68 '(ζΗ0·ε'9 I=f'PP'HI)Z9'S'(ra'HS)S S — SW(ui'H2 — 80' C"'HS)98'I— ΐ'(ω'Η ε·ΐ— 6S'I :軍 9 ( OSWd) N— Ητ
Figure imgf000248_0003
Ε '( ζ Η3 · ΐΐ = ί "'Ρ'Ηΐ) ΐε '( ζ Η3 · π = ί"'Ρ'Ηΐ) 68 '( ζ Η0 · ε'9 I = f'PP'HI) Z9'S '(ra'HS) SS — SW (ui'H2 — 80' C "'HS) 98'I— ΐ'(ω'Η ε · ΐ— 6S'I: Military 9 (OSWd) N— Η τ
Figure imgf000248_0003
(ζΗ2·6=ΓΡ'Ηΐ)½·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)^·8'(ζΗ2·6=ΓΡ'Ηΐ)20·8'(ζΗ^· T=rP'HT)66" '(ZH8" =rP'HT) 8" '(ZH8" =rP'HT)^8" '(zwr2"6=rPP'HT)^ " '(ZH (ζΗ2 · 6 = ΓΡ'Ηΐ) ½ · 8 '( ζ Η9 · 3ΐ = ΓΡ'Ηΐ) ^ · 8' ( ζ Η2 · 6 = ΓΡ'Ηΐ) 20 · 8 '( ζ Η ^ · T = rP' HT) 66 "'(ZH8" = rP'HT) 8 "'(ZH8" = rP'HT) ^ 8 "'(zwr2" 6 = rPP'HT) ^ "' (ZH
2-6=f'P'HT)80"Z'(zH9"eT=f'P'HT)8e-9'(zH0"S'6"8=rPP'HT)28"S'(s'HS)86"S'(s'H2)S6 2-6 = f'P'HT) 80 "Z '(zH9" eT = f'P'HT) 8e-9' ( z H0 "S'6" 8 = rPP'HT) 28 "S '(s' HS) 86 "S '(s ' H2) S6
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)3Γε'(ΖΗ3·π=ΓΡ'Ηΐ)68·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)89·2'(ω'Η2)9^·2 — 6S ' C"'HS — 80 '(ω'Η 68·ΐ— ΐ8·ΐ'(ω'Η ΐ ·ΐ— ΐ :軍 9 ( OS ) Η顺— Ητ ^ ^ ( / s— /— 、 ;^ ^ : ε 'ζ Ί))→) -Ζ) -s) -£- (Ή.) · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) 3Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 68.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 89.2'(ω'Η2) 9 ^ · 2 — 6S 'C "' HS — 80 '(ω'Η 68 · ΐ— ΐ8 · ΐ'(ω'Η ΐ · ΐ— ΐ: Army 9 (OS) Η 顺 — Η τ ^ ^ (/ s— / —,; ^ ^: ε 'ζ Ί)) →) -Ζ) -s)-£-(Ή.)
98S6T0/S00Zdf/X3d 9173 — ε ' C"'HS)OS — 90' (ra'HS)98'I— SZ'I'(ra'HS)8S'I— :軍 9 ( OS ) 顺— HT
Figure imgf000249_0001
98S6T0 / S00Zdf / X3d 9173 — Ε 'C "' HS) OS — 90 '(ra'HS) 98'I— SZ'I'(ra'HS)8S'I—: Army 9 (OS) 顺 — H T
Figure imgf000249_0001
(ZH  (ZH
2·6=ΓΡΉΐ)ε3·8'(ζΗ9·3ΐ=Γ'ΡΉΐ)02·8'(ω'Η2) 8· -ΐ8· '(ζΗ2·6=ΓΡ'Ηΐ)80· '(ζΗ8· = 2 · 6 = ΓΡΉΐ) ε3 · 8 '( ζ Η9 · 3ΐ = Γ'ΡΉΐ) 02 · 8'(ω'Η2) 8 · -ΐ8 · '(ζΗ2 · 6 = ΓΡ'Ηΐ) 80 ·' (ζΗ8 =
Γ'ΡΉΐ)^ ·9'(ζΗε·2=Γ'Ρ'Ηΐ)0 ·9'(ζΗε·2'8· =ΓΡΡ'Ηΐ)39·9'(9·3ΐ=ΓΡ'Ηΐ)93·9'(ζΗ0·ε' 6"8=f'PP'HT)T8"e'(ra'H^)S2^-9r^'(s'HS)66"S'(zHS-n=rP'HT)2rS'(zHe-n=rP'HT Γ'ΡΉΐ) ^ · 9 '( ζ ΗεΗ2 = Γ'Ρ'Ηΐ) 009' ( ζ Ηε22'8 · = ΓΡΡ'Ηΐ) 39 · 9 '(9.3 · = ΓΡ'Ηΐ) 93 · 9 '( ζ Η0 · ε' 6 "8 = f'PP'HT) T8" e '(ra'H ^) S2 ^ -9r ^' ( s 'HS) 66 "S' ( z HS-n = rP'HT) 2rS '(zHe-n = rP'HT
) 8"2'(zH9" =rVH2)^ "2'(zH0"S'9"2T=rPP'HT)99"2'(zH9" =f' H2)8S"2'(ra'H2)9^"2 — 9S ' (ω'Η 6ΐ· 0 '(ω'Η ε8·ΐ— ·ΐ'(ω'Η ΐε·ΐ— ·ΐ :軍 9 (9p-OS a)H N-HT ) 8 "2 '( z H9" = rVH2) ^ "2'(zH0"S'9"2T = rPP'HT) 99" 2 '( z H9 "= f' H2) 8S" 2 '(ra'H2 ) 9 ^ "2 — 9S '(ω'Η 6ΐ · 0'(ω'Η ε8 · ΐ— · ΐ '(ω'Η ΐε · ΐ— · ΐ: Army 9 ( 9 p-OS a) H NH T
y-9- ^^ Ί] [q] 、 'z) -z)→) -z) -8)— ε— (Ή) y-9- ^^ Ί] [q], 'z) -z) →) -z) -8) — ε— (Ή)
6Ζΐ圏第 [6SW3]  6th Region [6SW3]
=rP'HT)Se"8'(zH9"eT=rP'HT)8r8'(s'H2)S8"Z'(zH2"6=rP'HT)80"Z'(ra'He)96"9-S8"9' (ZH9'SI=f'P'HI)ZS'9'(zH0'S'6'8=f'PP'HI)I8'S'(ra'H ΐΐ· — SO' (S'HS)66'S'(S'HS)S9 •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)Z8 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)„ = rP'HT) Se "8 '( z H9" eT = rP'HT) 8r8'(s' H2) S8 "Z '(zH2" 6 = rP'HT) 80 "Z'(ra'He)96" 9-S8 "9 '(ZH9'SI = f'P'HI) ZS'9' ( z H0'S'6'8 = f'PP'HI) I8'S '(ra'H — · SO' ( S 'HS ) 66'S '(S' HS ) S9 • S '(z HS'II = f'P'HI) SrS' (z HS'II = f'P'HI) Z8 '(ζ Η0 · ε'9 I = f 'PP'HI) 99'S'(ra'HS) „
— 3ε·2'(τιι'Η )6ΐ — SO ' C"'HS)S8'I— SZ'I'(ra'HS) TI— :軍 9 ( P-OS a)H N-HT — 3ε · 2 '(τιι'Η) 6ΐ — SO' C "'HS) S8'I— SZ'I'(ra'HS) TI—: Army 9 (P-OS a) H NH T
邈 (^ （ ^ー S—べ ίί, 一べ。 ¾^p_^^[g Ί]
Figure imgf000249_0002
'£))→) -Ζ) -S) -£- (Ή.) 邈 (^ (^ ー S—Be ίί, One. ¾ ^ p _ ^^ [g Ί]
Figure imgf000249_0002
'£)) →) -Ζ) -S)-£-(Ή.)
2li m [8SW)] 2li m [8SW)]
(zH2"6=rP'HT)2e"8'(zH9"eT=rP'HT)Zr8'(s'H2)S8"Z'(zH2"6=rP'HT)Z0"Z'(zH8TS"8 (zH2 "6 = rP'HT) 2e" 8 '( z H9 "eT = rP'HT) Zr8' ( s ' H2) S8" Z '(zH2 "6 = rP'HT) Z0"Z' (zH8TS " 8
=f'PP'HI) Z'9'(zH8'I=f'P'HI)89'9'(zHS'8=f'P'HI)S9'9'(zH9'SI=f'P'HI)ZS'9'(zH0'S = f'PP'HI) Z'9 '( z H8'I = f'P'HI) 89'9' ( z HS'8 = f'P'HI) S9'9 '( z H9'SI = f 'P'HI) ZS'9' ( z H0'S
'6·8=ΓΡΡ'Ηΐ)ΐ8·3'(ω'Η ^· 8Γ (s'HS)66'S'(s'HS)S9'S'(ra'HS)6rS- 9ΐ·ε'(ζΗ3·ΐΐ '6 · 8 = ΓΡΡ'Ηΐ) ΐ8 · 3'(ω'Η ^ · 8Γ ( s ' HS) 66'S '( s ' HS) S9'S'(ra'HS) 6rS- 9ΐ · ε '( ζ Η3 · ΐΐ
=ΓΡ'Ηΐ)^Γε'(ζΗ3·π=ΓΡ'Ηΐ)68·2'(8Ήε)6 ·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)8^·2 — 8S ' (ω'Η 6ΐΉ0 ' (ω )98·ΐ— 8Ζ·ΐ'(ω'Η„·ΐ— ΐε·ΐ :軍 9 ( OS ) Η顺— Ητ = ΓΡ'Ηΐ) ^ Γε '(ζΗ3 · π = ΓΡ'Ηΐ) 68 · 2' ( 8 Ήε) 6 · 2 '(ζΗ0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 9 · 2'(ω'Η2 ) 8 ^ · 2 — 8S '(ω'Η 6ΐΉ0' (ω) 98 · ΐ— 8Ζ · ΐ '(ω'Η „· ΐ— ΐε · ΐ: Army 9 (OS) Η 顺 — Η τ
98S6T0/S00Zdf/X3d LVZ P'HT)68"8'(zH2-6=f'P'HT)Se-8'WT=f'P'HT)^-8'(zH9"ST=rP'HT)Zr8'(zH6"9=rP' HT)66"Z'(zH6"9=f'P'HT)e6"Z'(s'H2)S8"Z'(zH6"9=rVHT)0Z"Z'(zH6"9=rVHT)8S"Z'(zH 98S6T0 / S00Zdf / X3d LVZ P'HT) 68 "8 '( z H2-6 = f'P'HT) Se-8'WT = f'P'HT) ^-8' ( z H9" ST = rP'HT) Zr8 '( z H6 "9 = rP'HT) 66" Z '(zH6 "9 = f'P'HT) e6"Z'(s'H2) S8 "Z '(zH6" 9 = rVHT) 0Z "Z'(zH6" 9 = rVHT) 8S "Z '(zH
2-6=f'P'HT)80"Z'(zH9"eT=f'P'HT)9e-9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)86"S'(s'H2)S6 2-6 = f'P'HT) 80 "Z '(zH9" eT = f'P'HT) 9e-9' ( z H0 "S'6" 8 = rPP'HT) T8 "S '(s' HS) 86 "S '(s ' H2) S6
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)^Γε'(ΖΗ3·π=ΓΡ'Ηΐ)68·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)99·2'(ω'Η¾9^·2 — ZS ' C"'HS)6rS— 90 ' (ω )68·ΐ— ΐ8·ΐ'(ω'Η„·ΐ—。ε·ΐ :軍 9 ( OS ) Η顺— Ητ · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) ^ Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 68.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 992'(ω'Η¾9 ^ · 2 — ZS 'C "' HS) 6rS— 90 '(ω) 68 · ΐ— ΐ8 · ΐ'(ω'Η„ · ΐ—.ε · ΐ: Army 9 (OS) Η 顺 — Η τ
(zHS'6=f'P'HI)0S'8'(zH9'S ΐ=ΓΡΉΐ)6Γ8'(ω'Η2)58· -8 · '(ΖΗ6·9=ΓΡΉΐ)ε3· '(ΖΗε·8=ΓΡΉΐ) ^· '(ω'Η2)ε2· (zHS'6 = f'P'HI) 0S'8 '( z H9'S ΐ = ΓΡΉΐ) 6Γ8'(ω'Η2) 58 -8 '' (ΖΗ69 = ΓΡΉΐ) ε3 · '(ΖΗε8 = ΓΡΉΐ) ^ · '(ω'Η2) ε2
-SrZ'(s'HT)89"9'(zH9"eT=f'P'HT)Se"9'(zH0"S'6"8=rPP'HT)ZZ"e'(s'HS)S6"S'(s'H2)S8 -SrZ '(s'HT) 89 "9' ( z H9" eT = f'P'HT) Se "9 '( z H0"S'6"8 = rPP'HT) ZZ"e'(s'HS ) S6 "S '( s ' H2) S8
·2'('ζΗ5·Π=ΓΡ'Ηΐ)0Γε'(ζΗ3·π=ΓΡ'Ηΐ)^8·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)29·2'(ω'Η2)ε^·2 2 '(' ζΗ5 · Π = ΓΡ'Ηΐ) 0Γε '( ζ Η3 · π = ΓΡ'Ηΐ) ^ 8-2' ( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 29.2 '(ω 'Η2) ε ^ · 2
- ε·2'(ω'Η2)^Γ2-ε0·2'(ω'Η2)ε8·ΐ-^ ·ΐ'(ω'Η2)ΐε·ΐ-92·ΐ:ΐ!} 9 ( P-OS a)H N-HT y-ι -^fi^ ( ^ ^( ^-Ζ- ^Δ/ >-) )→) -2)-8)-ε-(Ή) -ε · 2 '(ω'Η2) ^ Γ2-ε0 · 2'(ω'Η2) ε8 · ΐ- ^ ΐ '(ω'Η2) ΐε · ΐ-92 · ΐ: ΐ!} 9 (P- OS a) H NH T y-ι-^ fi ^ (^ ^ (^ -Ζ- ^ Δ />-)) →) -2) -8) -ε- (Ή)
S8Ii^¾?第 [29^0] (zH2-6=f'P'HT)Se-8'(zH9"ST=f'P'HT)6r8'(s 'H2)^8"Z'(zH2-6=rP'HT)80"Z'(s'HT)^0"Z'(zHS-8=f'P'HT)20"Z'(zHS-8=f'P'HT)29"9'(z S8Ii ^ ¾? Th [29 ^ 0] (zH2-6 = f'P'HT) Se-8 '( z H9 "ST = f'P'HT) 6r8' ( s 'H2) ^ 8"Z' ( zH2-6 = rP'HT) 80 "Z '(s'HT) ^ 0"Z' (zHS-8 = f'P'HT) 20 "Z '(zHS-8 = f'P'HT) 29" 9 '( z
H9'SI=f'P'HI)ZS'9'(zH0'S'6'8=f'PP'HI)I8'S'(s'HS)66'S'(s'HS) 9'S'(zHS'n=f'P'HI) 3ΐ·ε'(ζΗ3·ΐΐ=ΓΡ'Ηΐ)68 ' (ω'Ηε)εΖ — S9 ' (ω'Ηζ)^ — ' C"'HS)0S — 80 ' (ω'Η H9'SI = f'P'HI) ZS'9 '(z H0'S'6'8 = f'PP'HI) I8'S'(s'HS)66'S'(s' HS) 9'S' (z HS'n = f'P'HI) 3ΐ · ε '( ζ Η3 · ΐΐ = ΓΡ'Ηΐ) 68'(ω'Ηε) εΖ — S9 '(ω'Ηζ) ^ —' C "'HS) 0S — 80' (ω 'Η
88·ΐ- 6Ζ·ΐ'(ω'Η 9Ζ·ΐ- ΐΖ·ΐ'(ω'Η 0 ·ΐ- 0S'I'(S'H9)SS'I :軍 9 ( P-OS a)H N-HT
Figure imgf000250_0001
88 · ΐ-6Ζ · ΐ '(ω'Η 9Ζ · ΐ- ΐΖ · ΐ'(ω'Η 0 · ΐ- 0S'I '( S ' H9) SS'I: Army 9 (P-OS a) H NH T
Figure imgf000250_0001
I8Ip}¾? [Ϊ9Μ)] (zHS'6=f'P'HI)½'8'(zH9'SI=f'P'HI)W8'( ZH8"Z=rP'HT)Z8"Z'(ZH8"Z=f'P'HT)^8"Z'(ZHS"8=f'P'H2)9^"Z'(ZHS"8=rP'H2)62"Z'(ZH I8Ip} ¾? [Ϊ9Μ)] (zHS'6 = f'P'HI) ½'8 '( z H9'SI = f'P'HI) W8' (ZH8 "Z = rP'HT) Z8" Z ' (ZH8 "Z = f'P'HT) ^ 8" Z '(ZHS "8 = f'P'H2) 9 ^"Z' (ZHS "8 = rP'H2) 62" Z '(ZH
2"6=f'P'HT)60"Z'(zH9"eT=f'P'HT)8e"9'(zH0"S'6"8=rPP'HT)T8"e'(s'HS)66"S'(s'H2)SZ •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)88 '(ζΗ0·ε'9 I=f'PP'HI)Z9'S'(ra'HS)„ 2 "6 = f'P'HT) 60" Z '(zH9 "eT = f'P'HT) 8e"9' ( z H0 "S'6" 8 = rPP'HT) T8 "e '(s' HS) 66 "S '(s ' H2) SZ • S' (z HS'II = f'P'HI) SrS '(z HS'II = f'P'HI) 88' (ζ Η0 · ε'9 I = f'PP'HI) Z9'S '(ra'HS) „
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Figure imgf000251_0001
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Figure imgf000251_0001
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J)1.4HZ= 一べ fi （,^ ^ ( — /— 、 ^ 、ベ:^))— ） -Z) -8) -ε- (Ή)
Figure imgf000252_0001
J) 1.4HZ = All fi (, ^ ^ (— / —, ^, Be: ^)) —) -Z) -8) -ε- (Ή)
Figure imgf000252_0001
3·8'(ζΗ9·3ΐ=ΓΡΉΐ)ΐ2·8'(ωΉε)68· -ΐ8· '(ΖΗε· =ΓΡΉΐ)2 · '(ωΉε)εε· -^· '(ΖΗ 3 · 8 '( ζ Η9 · 3ΐ = ΓΡΉΐ) ΐ2 · 8' (ωΉε) 68 · -ΐ8 · '(ΖΗε · = ΓΡΉΐ) 2 ·' (ωΉε) εε ·-^ · '(ΖΗ
2-6=f'P'HT)80"Z'(zH9"eT=f'P'HT)9e-9'(zH0"S'6"8=rPP'HT)08"S'(s'H2)20^'(s'HS)86 2-6 = f'P'HT) 80 "Z '(zH9" eT = f'P'HT) 9e-9' ( z H0 "S'6" 8 = rPP'HT) 08 "S '(s' H2) 20 ^ '(s' HS) 86
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)εΓε'(ΖΗ3·π=ΓΡ'Ηΐ)88·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)39·2'(ω'Η2)5^·2· Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) εΓε' (ΖΗ3 · π = ΓΡ'Ηΐ) 88.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 39.2'(ω'Η2) 5 ^ · 2
— ZS ' (ω'Η 1 — SO ' (ω'Η 8·ΐ— 8Ζ·ΐ'(ω'Η ε·ΐ— 8S'I :軍 9 ( OS ) 顺— Ητ — ZS '(ω'Η 1 — SO'(ω'Η 8 · ΐ— 8Ζ · ΐ '(ω'Η ε · ΐ— 8S'I: Army 9 (OS) 顺 — Η τ
( ^ ^ {Λ y-z - V\ -) ) - ) -Z) -8) -ε- (a)
Figure imgf000252_0002
(^ ^ (Λ yz-V \-))-) -Z) -8) -ε- (a)
Figure imgf000252_0002
(ζΗ2·6=ΓΡΉΐ)23·8'(ζΗ9·3ΐ=ΓΡΉΐ)2Γ8'(ω'Η2)^8· -6 · '(ζΗ8· =Γ'Ρ (ζΗ2 ・ 6 = ΓΡΉΐ) 23 ・ 8 '( ζ Η9 ・ 3ΐ = ΓΡΉΐ) 2Γ8'(ω'Η2) ^ 8 ・ -6 ・ '(ζΗ8 ・ = Γ'Ρ
'HT)9e"Z'(zH8"Z=rP'HT)0e"Z'(zH8"Z=rVHT)T2"Z'(zH8"Z=f'VHT)erZ'(zH2"6=rP'HT 'HT) 9e "Z' (zH8" Z = rP'HT) 0e "Z '(zH8" Z = rVHT) T2 "Z' (zH8" Z = f'VHT) erZ '(zH2 "6 = rP'HT
)Z0"Z'(zH9"eT=f'P'HT)ee-9'(zH0"S'6"8=rPP'HT)08"S'(s'H2)00^'(s'HS)86"S'(s'HS)T8 ) Z0 "Z '(zH9" eT = f'P'HT) ee-9' ( z H0 "S'6" 8 = rPP'HT) 08 "S '(s'H2) 00 ^' ( s ' HS ) 86 "S '(s' HS) T8
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)εΓε'(ΖΗ3·π=ΓΡ'Ηΐ)98·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)99·2'(ω'Η2)ε^·2 — ZS ' (ra'H 0S'S—Z0 ' (ω'Η 88·ΐ— ΐ'(ω'Η Ζε·ΐ— 6S'I :軍 9 ( OSWd) N— Ητ Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) εΓε' (ΖΗ3 · π = ΓΡ'Ηΐ) 98.2 '( ζ Η0 · ε'9 2 ΐ = ΓΡΡ'Ηΐ) 99.2'(ω'Η2) ε ^ · 2 — ZS '(ra'H 0S'S—Z0'(ω'Η 88 · ΐ— ΐ '(ω'Η Ζε · ΐ— 6S'I: Army 9 (OSWd) N— Η τ
( / -Z- Λ^/^ή^ ^ -HI- - 1 ) ) - -Z)—8) -£- (Ή) (/ -Z- Λ ^ / ^ ή ^ ^ -HI--1))--Z) —8)-£-(Ή)
88ΐ ¾ϊ第 [89 W)] (zHS'6=f'P'HI)IS'8'(s'HI)ZS'8'(zH9'SI=f'P'HI)ir8'(z 88ΐ ¾ϊ [89 W)] (zHS'6 = f'P'HI) IS'8 '( s ' HI) ZS'8 '( z H9'SI = f'P'HI) ir8' ( z
H8"Z=rP'HT)S8"Z'(ZH8"Z=rP'HT)08"Z'(s'HT)89"Z'(ZHZ"8=rP'HT)9S"Z'(ZH2"6=rP'H H8 "Z = rP'HT) S8" Z '(ZH8 "Z = rP'HT) 08" Z' (s'HT) 89 "Z '(ZHZ" 8 = rP'HT) 9S "Z' (ZH2" 6 = rP'H
T)Z0"Z'(zHZ-8=rP'HT)^0"Z'(zH0"S'6"8=rPP'HT)T8"e'(s'HS)66"S'(s'H2)08"S'(zHS-n= f'P'HI) ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)88 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)S S— ' (S'HS T) Z0 "Z '(zHZ-8 = rP'HT) ^ 0"Z' (zH0 "S'6" 8 = rPP'HT) T8 "e '(s'HS) 66"S' ( s ' H2 ) 08 "S '( z HS-n = f'P'HI) ΐ · ε' ( ζ Η3 · π = ί"'Ρ'Ηΐ)88' ( ζ Η0 · ε'9 I = f'PP'HI ) 99'S '(ra'HS) SS—' ( S 'HS
)S2 ' (ω'Η 6ΐΉ0 ' (ω'Η 8·ΐ— 6Ζ·ΐ'(ω'Η 6ε·ΐ— 8S'I :軍 9 ( OS ) Η顺— Ητ ) S2 '(ω'Η 6ΐΉ0'(ω'Η 8 · ΐ— 6Ζ · ΐ '(ω'Η 6ε · ΐ— 8S'I: Army 9 (OS) Η 顺 — Η τ
-Ζ- ^ΛΆ ^-Ζ Ί]Α^ ^-9)) -Ζ) -8) -S- (Ή) -Ζ- ^ ΛΆ ^ -Ζ Ί] Α ^ ^ -9)) -Ζ) -8) -S- (Ή)
98S6T0/S00Zdf/X3d 093 f'P'HI) ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)88 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)S S— O S'(s'HS )0S ' C"'HS)6rS— 90 ' (ω )88·ΐ— 9Ζ·ΐ'(ω )8ε·ΐ—。ε·ΐ :軍 9 ( OS ) Η顺— Ητ 98S6T0 / S00Zdf / X3d 093 f'P'HI) ΐ · ε '( ζ Η3 · π = ί "'Ρ'Ηΐ) 88 '( ζ Η0 · ε'9 I = f'PP'HI) 99'S'(ra'HS) SS— O S '(s' HS) 0S 'C "' HS) 6rS- 90 '(ω) 88 · ΐ- 9Ζ · ΐ' (ω) 8ε · ΐ-. ε · ΐ: Army 9 (OS) Η 顺 — Η τ
(,^ ^ ( / s—べェ ^ [4] >^/^ ー ε))— ） -Ζ) 8)— ε— (a)
Figure imgf000253_0001
(, ^ ^ (/ s—Bee ^ [4]> ^ / ^ ー ε)) —) -Ζ) 8) — ε— (a)
Figure imgf000253_0001
02"8'(zH8" =rP'HT) 8" '(ZH8" =rP'HT)^8" '(ZHS"8=rP'HT)9S" '(ra'H2)2^- -SS" '02 "8 '( z H8" = rP'HT) 8 "'(ZH8" = rP'HT) ^ 8 "'(ZHS" 8 = rP'HT) 9S "'(ra'H2) 2 ^--SS "'
(^'H2)n"Z-^0"Z'(zH9"eT=f'P'HT)Ze"9'(zH0"S'6"8=rPP'HT)28"e'(s'H2)e0^'(s'HS)66 ·ε'(ΖΗ3·π=ΓΡ'Ηΐ)9Γε'(ζΗ3·π=ΓΡ'Ηΐ)ΐ6·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)^·2(^ 'H2) n "Z- ^ 0"Z' (zH9 "eT = f'P'HT) Ze" 9 '( z H0 "S'6" 8 = rPP'HT) 28 "e'(s' H2) e0 ^ '(s' HS) 66 · ε' (ΖΗ3 · π = ΓΡ'Ηΐ) 9Γε '(ζ Η3 · π = ΓΡ'Ηΐ) ΐ6 · 2' (ζ Η0 · ε'9 · 2ΐ = ΓΡΡ 'Ηΐ) 9 · 2'(ω'Η2) ^ · 2
- ε·2'(ω'Η2)6Γ2-80·2'(ω'Η2)26·ΐ-28·ΐ'(ω'Η2)^·ΐ- ε·ΐ:ΐ!} 9 ( P-OS a)H N-HT
Figure imgf000253_0002
-ε · 2 '(ω'Η2) 6Γ2-80 · 2'(ω'Η2) 26 · ΐ-28 · ΐ '(ω'Η2) ^ · ΐ- ε · ΐ: ΐ!} 9 (P-OS a) H NH T
Figure imgf000253_0002
(zH2"6=rP'HT)W8'(zH9"ST=rP'HT)S2"8'(zH8"Z=rP'H T)Z8"Z'(ZH8"Z=f'P'HT)^8"Z'(ZH0"e=f'P'HT)WZ'(ZH0"e=rP'HT)SS"Z'(s'HT)Z2"Z'(ZH 2-6=f'P'HT)80"Z'(zH9"eT=f'P'HT)Ze-9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)86 ·ε'(ΖΗ3·π=ΓΡ'Ηΐ)εΓε'(ΖΗ3·π=ΓΡ'Ηΐ) 8·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)99·2'(ω'Η2)5^·2 — ZS ' C"'HS)6rS— SO ' (ω )98·ΐ— ΐ'(ω )8ε·ΐ— ΐ :軍 9 ( OS ) Η顺— Ητ (zH2 "6 = rP'HT) W8 '( z H9" ST = rP'HT) S2 "8' ( z H8" Z = rP'H T) Z8 "Z '(ZH8" Z = f'P'HT ) ^ 8 "Z '(ZH0" e = f'P'HT) WZ' (ZH0 "e = rP'HT) SS" Z '(s'HT) Z2 "Z' (ZH 2-6 = f'P 'HT) 80 "Z'(zH9" eT = f'P'HT) Ze-9 '( z H0 "S'6" 8 = rPP'HT) T8 "S'(s'HS)66" S '( s ' H2) 86 · ε '(ΖΗ3 · π = ΓΡ'Ηΐ) εΓε' (ΖΗ3 · π = ΓΡ'Ηΐ) 8 · 2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 992'(ω'Η2) 5 ^ · 2 — ZS 'C "' HS) 6rS— SO '(ω) 98 · ΐ— ΐ' (ω) 8ε · ΐ— ΐ: Army 9 (OS) Η 顺 — Η τ
（ ^ ^ ( / —べェ ^ [q—s 'ε] 一 ） -z) -8) -ε- (Ή)
Figure imgf000253_0003
(^ ^ (/ -Bee ^ [q-s' ε] i) -z) -8) -ε- (Ή)
Figure imgf000253_0003
(ΖΗ2·6=ΓΡ'Ηΐ)ε3·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)ΐ2 ·8'(ζΗε·8=ΓΡ'Ηΐ)εθ·8'(ω'Ηε)ΐ6·Ζ—ΐ8 (ζΗε·8=ί"'νΗΐ)9^Ζ'(ζΗε·8=ί"'νΗΐ)8ε (ζΗ S'6=rP'HI)80 (zH9'SI=rP'HI)9S'9'(zH0'S'6'8=rPP'HI)08'S'(s'HS)Sr (S'HS)86 ·ε'(ζΗ3·π=ΓΡ'Ηΐ)^Γε'(ζΗ3·π=ΓΡ'Ηΐ)88·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)99·2'(ω'Η2)ε^·2(ΖΗ2 · 6 = ΓΡ'Ηΐ) ε3 · 8 '( ζ Η9 · 3ΐ = ΓΡ'Ρ) ΐ2 8' ( ζ Ηε · 8 = ΓΡ'Ηΐ) εθ · 8 '(ω'Ηε) ΐ6 · Ζ— ΐ8 ( ζ Ηε · 8 = ί "'νΗΐ) 9 ^ Ζ' (ζΗε · 8 = ί"'νΗΐ) 8ε ( ζ Η S'6 = rP'HI) 80 (zH9'SI = rP'HI) 9S' 9 '( z H0'S'6'8 = rPP'HI) 08'S'(s'HS) Sr ( S 'HS) 86 εε (ζΗ3 · π = ΓΡ'Ηΐ) ^ Γε' (ζΗ3 · π = ΓΡ ' Ηΐ) 88 ・ 2 '( ζ Η0 ・ ε'9 ・ 2ΐ = ΓΡΡ'Ηΐ) 99 ・ 2'(ω'Η2) ε ^ ・ 2
— 9ε ' (ra'Hs)os's-zo ' (ω )88·ΐ— 8ζ·ΐ'(ω )6ε·ΐ— οε·ΐ :軍 9 (9ρ— OS ) Η顺— Ητ — 9ε '(ra'Hs) os's-zo' (ω) 88 · ΐ— 8ζ · ΐ '(ω) 6ε · ΐ—οε · ΐ: Army 9 ( 9 ρ— OS) Η 顺 — Η τ
98S6T0/S00Zdf/X3d 1-93 )60"Z'(s'HT)Z0"Z'(zH9"eT=f'P'HT)8e-9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)88 •S'(zHS'n=f'P'HI)SrS'(zHS'n=f'P'HI)88 '(ζΗ0·ε'9 ΐ=ί"'ΡΡ'Ηΐ)Ζ9 ' (ω'Η8) 98S6T0 / S00Zdf / X3d 1-93 ) 60 "Z '(s'HT) Z0"Z' (zH9 "eT = f'P'HT) 8e-9 '( z H0"S'6"8 = rPP'HT) T8"S'(s' HS) 66 "S '(s ' H2) 88 • S' (z HS'n = f'P'HI) SrS '(z HS'n = f'P'HI) 88' (ζ Η0 · ε'9 ΐ = ί "'ΡΡ'Ηΐ) Ζ9'(ω'Η8)
— SW(ui'HS) S— 80 ' (ω )88·ΐ— 9Ζ·ΐ'(ω )8ε·ΐ— 6S'I :軍 9 ( OS ) 顺— Ητ — S W (ui'HS) S— 80 '(ω) 88 · ΐ— 9Ζ · ΐ' (ω) 8ε · ΐ— 6S'I: Military 9 (OS) 顺 — Η τ
( / —べェ ^ [q—ε
Figure imgf000254_0001
'£))→) -z) -s) -£- (Ή.) (/ -Bee ^ [q—ε
Figure imgf000254_0001
'£)) →) -z) -s)-£-(Ή.)
96ΐ ¾ϊ第 [9^0] (ZH2"6=f'P'HT)½'(ZH9"ST=rP'HT)^"8'(zH8"Z=rP'HT)Z8"Z'(ZH8"Z=rP'H ΐ)^8· '(ΖΗε· =ΓΡ'Ηΐ)8^· '(ω'Ηε)0ε· - Γ '(ΖΗ2·6=ΓΡ'Ηΐ)80· '(ΖΗ9·3ΐ=ΓΡ'Ηΐ)8 e"9'(zH0"S'6"8=rPP'HT)T8"e'(s'HS)66"S'(s'H2)ee"S'(zHS"n=rP'HT)SrS'(zHe"n=f 'Ρ'Ηΐ)88 ' C"'HS)08 — '(ζΗ0·ε'9 ΐ=ΓΡΡ'Ηΐ)89 ' (ra'HS)8 S— 1 ^ ' (ra'HS)S S — ' (ra'HS)SS — 80 '(ω'Η 88·ΐ— 8Ζ·ΐ'(ω'Η 0 ·ΐ— 8S'I :軍 9 ( OSWd) N— Ητ 96ΐ ¾ϊ 第 [9 ^ 0] (ZH2 "6 = f'P'HT) ½ '(ZH9" ST = rP'HT) ^ "8' ( z H8" Z = rP'HT) Z8 "Z '(ZH8 "Z = rP'H ΐ) ^ 8 · '(ΖΗε · = ΓΡ'Ηΐ) 8 ^ ·'(ω'Ηε) 0ε ·-Γ '(ΖΗ2 · 6 = ΓΡ'Ηΐ) 80 ·' (ΖΗ9 · 3ΐ = ΓΡ'Ηΐ) 8 e "9 '( z H0"S'6"8 = rPP'HT) T8"e'(s'HS) 66 "S '( s ' H2) ee"S' (zHS "n = rP'HT) SrS '(zHe "n = f'Ρ'Ηΐ) 88 'C"' HS) 08 — '( ζ Η0 · ε'9 ΐ = ΓΡΡ'Ηΐ) 89'(ra'HS) 8 S — 1 ^ '(ra'HS) SS —'(ra'HS) SS — 80 '(ω'Η 88 · ΐ— 8Ζ · ΐ'(ω'Η 0 · ΐ— 8S'I: Army 9 (OSWd) N— Η τ
( / -Z - Λ^Δ^Λ^ - 'Ζ-ηη^-\)) - ) -Ζ) -8) -£- (Ή)
Figure imgf000254_0002
(/ -Z-Λ ^ Δ ^ Λ ^-'Ζ-ηη ^-\))-) -Ζ) -8)-£-(Ή)
Figure imgf000254_0002
)^"8'(zH8" =rP'HT) 8" '(ZH8" =rP'HT)^8" '(s'HT)n- '(ZH2-6=rP'HT)60" '(s'HT ) ^ "8 '( z H8" = rP'HT) 8 "'(ZH8" = rP'HT) ^ 8 "'(s'HT) n-' (ZH2-6 = rP'HT) 60"'(s'HT
)20"Z'(zH9"eT=f'P'HT)8e-9'(s'H2)^0"9'(zH0"S'6"8=rPP'HT)28"S'(s'HS)66"S'(s'H2)69 ) 20 "Z '(zH9" eT = f'P'HT) 8e-9' ( s ' H2) ^ 0 "9 '( z H0"S'6"8 = rPP'HT) 28"S' (s 'HS) 66 "S' ( s ' H2) 69
·ε'(ζΗ3·ΐΐ=ί"'Ρ'Ηΐ) ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)88 '(ζΗ0·ε'9 I=f'PP'HI)89'S'(ra'HS)S S — ε ' (ra'HS)SS 0rS'C"'HS)S8'I— SZ'I'(ra'HS)0 'I— 8S'I :軍 9 ( OS ) 顺— HT
Figure imgf000254_0003
) - V) -Z) -8) -£- (Ή) Ε '( ζ Η3 · ΐΐ = ί "'Ρ'Ηΐ) ΐε '( ζ Η3 · π = ί"'Ρ'Ηΐ) 88 '( ζ Η0 · ε'9 I = f'PP'HI) 89'S '(ra'HS) SS — ε'(ra'HS) SS 0rS'C "'HS) S8'I— SZ'I'(ra'HS) 0 'I— 8S'I: Army 9 (OS)顺 — H T
Figure imgf000254_0003
)-V) -Z) -8)-£-(Ή)
(ΖΗ2·6=ΓΡ'Ηΐ)ε3·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)8ΐ •8'(^'He)88"Z-T8"Z'(zHS"8=f'P'HT)Z9"Z'(zHS"8=rVHT)eS"Z'(zHS"8=rVHT)82"Z'(zH (ΖΗ2 · 6 = ΓΡ'Ηΐ) ε3 · 8 '( ζ Η9 · 3ΐ = ΓΡ'Ηΐ) 8ΐ • 8' (^ 'He) 88 "Z-T8"Z' (zHS "8 = f'P'HT ) Z9 "Z '(zHS" 8 = rVHT) eS "Z'(zHS" 8 = rVHT) 82 "Z '(zH
2"6=rP'HT)80"Z'(zH9"eT=rP'HT)ee"9'(zH0"S'6"8=rPP'HT)08"e'(s'He)66"S'(zHS"n= 2 "6 = rP'HT) 80" Z '(zH9 "eT = rP'HT) ee"9' ( z H0 "S'6" 8 = rPP'HT) 08 "e '(s'He) 66" S '( z HS "n =
98S6T0/S00Zdf/X3d 393 ) ε·8'(ζΗ9·3ΐ=ΓΡΉΐ)32·8'(ω'Η^)06· -8 · '(ΖΗ8·ΐ' ·8=ΓΡΡΉΐ)ΐ9· '(ΖΗ2·6=ΓΡ'Η T)60"Z'(zH9"eT=rP'HT)8e-9'(zH0"S'6"8=rPP'HT)28"e'(s'HS)66"S'(s'H¾T6"S'(zHS-n =ΓΡ'Ηΐ)9Γε'(ζΗ3·π=Γ'Ρ'Ηΐ)ΐ6·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)89·2'(ω'Η¾ ^·2- ε·2'(ω'Η 0rS'(s'HS)60' C"'HS)I6'I— ε8·ΐ'(ω'Η^ ·ΐ— Γΐ :軍 9 ( OS ) Η顺— Ητ 98S6T0 / S00Zdf / X3d 393 ) ε ・ 8 '( ζ Η9 ・ 3ΐ = ΓΡΉΐ) 32 ・ 8'(ω'Η ^) 06-8 · '(ΖΗ8 · ΐ' 8 = ΓΡΡΉΐ) ΐ9 · '(ΖΗ2 ・ 6 = ΓΡ'Η T) 60 "Z '(zH9 " eT = rP'HT) 8e-9' (z H0 "S'6" 8 = rPP'HT) 28 "e '(s'HS) 66"S'(s' H¾T6 "S '( z HS-n = ΓΡ'Ηΐ) 9Γε' ( ζ Η3 · π = Γ'Ρ'Ηΐ) ΐ6'2 '( ζ Η0 · ε'9 · 2 · = ΓΡΡ'Ηΐ) 892' ( ω'Η¾ ^ · 2- ε · 2 '(ω'Η 0rS' ( s 'HS) 60' C "'HS) I6'I— ε8 · ΐ'(ω'Η ^ · ΐ— Γΐ: Army 9 ( OS) Η 顺 — Η τ
( ^ /^ ( / - S - -^ /^ -9-ηη^-Ζ))→) -Ζ) -S) -£- (Ή.)
Figure imgf000255_0001
(^ / ^ (/-S--^ / ^ -9-ηη ^ -Ζ)) →) -Ζ) -S)-£-(Ή.)
Figure imgf000255_0001
P'HT)9Z"Z'(zH8"Z=rP'HT)89"Z'(zH8"Z=rVHT)WZ'(zH8"Z=f'VHT)2S"Z'(zH2"6=rP'H T)80"Z'(zH9"eT=rP'HT)Ze-9'(zH0"S'6"8=rPP'HT)28"e'(s'HS)66"S'(s'H2)S8"S'(zHS-n =f'P'HI)SrS'(s'H9)S6 '(zHS'II=f'P'HI)06 '(ζΗ0·ε'9 ΐ=ί"'ΡΡ'Ηΐ)Ζ9 ' (ra'HS S — ZS ' (ra'HS) — 60 '(ω'Η ΐ6·ΐ— Ζ8·ΐ'(ω'Η„·ΐ— 6S'I :軍 9 ( OSWd) N— Ητ P'HT) 9Z "Z '(zH8" Z = rP'HT) 89 "Z'(zH8" Z = rVHT) WZ '(zH8 "Z = f'VHT) 2S"Z' (zH2 "6 = rP ' H T) 80 "Z '(zH9" eT = rP'HT) Ze-9' ( z H0 "S'6" 8 = rPP'HT) 28 "e '(s'HS) 66"S' ( s ' H2) S8 "S '(z HS-n = f'P'HI) SrS'(s' H9) S6 '(z HS'II = f'P'HI) 06' (ζ Η0 · ε'9 ΐ = ί "'ΡΡ'Ηΐ) Ζ9'(ra'HS S — ZS '(ra'HS) — 60'(ω'Η ΐ6 · ΐ— Ζ8 · ΐ '(ω'Η„ · ΐ— 6S'I: Military 9 (OSWd) N— Η τ
0
Figure imgf000255_0002
-ζ))→) -ζ) -8)— ε— (Ή) 0
Figure imgf000255_0002
-ζ)) →) -ζ) -8) — ε— (Ή)
(zH2"6=f'P'HT)2e"8'(zH9"ST=rP'HT)Zr8'(zHS"8=rP' HT)86"Z'(s'H2)S8"Z'(zHS"8=f'P'HT)TZ"Z'(zHS"8=rVHT)8^"Z'(zHS"8=rVHT)2^"Z'(zH 2-6=f'P'HT)80"Z'(zH9"eT=f'P'HT)ee-9'(zH0"S'6"8=rPP'HT)08"S'(s'H2)90^'(s'HS)86 ·ε'(ΖΗ3·π=ΓΡ'Ηΐ)εΓε'(ΖΗ3·π=ΓΡ'Ηΐ)88·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)39·2'(ω'Η2)ε^·2 — ' (ω'Η 8ΐΉ0 ' (ω'Η 8·ΐ— ΐ'(ω'Η„·ΐ—。ε·ΐ :軍 9 ( OS ) Η顺— Ητ (zH2 "6 = f'P'HT) 2e" 8 '( z H9 "ST = rP'HT) Zr8' ( z HS" 8 = rP 'HT) 86 "Z'(s'H2)S8" Z ' (zHS "8 = f'P'HT) TZ" Z '(zHS "8 = rVHT) 8 ^"Z' (zHS "8 = rVHT) 2 ^" Z '(zH 2-6 = f'P'HT ) 80 "Z '(zH9" eT = f'P'HT) ee-9' ( z H0 "S'6" 8 = rPP'HT) 08 "S '(s'H2) 90 ^' ( s ' HS ) 86 · ε '(· 3 · π = ΓΡ'Ηΐ) εΓε' (ΖΗ3π = ΓΡ'Ηΐ) 88.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 39.2' (ω ' Η2) ε ^ · 2 — '(ω'Η 8ΐΉ0'(ω'Η 8 · ΐ— ΐ '(ω'Η „· ΐ—.ε · ΐ: Army 9 (OS) Η 顺 — Η τ
( ^^. /^ ( / -Z - [q] . -^ ^ -Z) -8) -£- (Ή) lei m in
Figure imgf000255_0003
(^^. / ^ (/ -Z-[q].-^ ^ -Z) -8)-£-(Ή) lei m in
Figure imgf000255_0003
T)ee"8'(zH9"eT=rP'HT)92"8'(zH8"Z=rP'HT)Z8"Z'(zH8"Z=rP'HT)^8"Z'(zH2"6=rP'HT T) ee "8 '( z H9" eT = rP'HT) 92 "8' ( z H8" Z = rP'HT) Z8 "Z '(zH8" Z = rP'HT) ^ 8 "Z' (zH2 "6 = rP'HT
98S6T0/S00Zdf/X3d 893
Figure imgf000256_0001
98S6T0 / S00Zdf / X3d 893
Figure imgf000256_0001
I)SS'8'(zH9'SI=rP'HI)0S'8'(ra'HS)88 —I8 (s'HI)SrZ'(s'HI)Sl (zHS'6=rP'HI I) SS'8 '( z H9'SI = rP'HI) 0S'8'(ra'HS) 88 —I8 ( s 'HI) SrZ'(s'HI) Sl ( z HS'6 = rP'HI
)80"Z'(zH9"eT=f'P'HT)Ze-9'(s'H2)^0"9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)Z9 •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)Z8 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)„ ) 80 "Z '(zH9" eT = f'P'HT) Ze-9' ( s ' H2) ^ 0 "9 '( z H0"S'6"8 = rPP'HT) T8"S' (s 'HS) 66 "S' ( s ' H2) Z9S '( z HS'II = f'P'HI) SrS' ( z HS'II = f'P'HI) Z8 '( ζ Η0 · ε' 9 I = f'PP'HI) 99'S '(ra'HS) „
— ' (ra'H ISHS'(ra'H S8'I— ·ΐ'(ω'Η Ζε·ΐ— 6S'I :軍 9 (9p-os a)H N-HT
Figure imgf000256_0002
-Z) -8) -£- (Ή) — '(Ra'H ISHS'(ra'HS8'I— · ΐ '(ω'Η Ζε · ΐ— 6S'I: Military 9 ( 9 p-os a) H NH T
Figure imgf000256_0002
-Z) -8)-£-(Ή)
SOSfi ¾?第 [S8W)] (ZH2 SOSfi ¾? 2nd [S8W)] ( Z H2
·6=ΓΡΉΐ)93·8'(ζΗ9·3ΐ=ΓΡΉΐ)82·8'(ω'Η2)26· -ε8· '(ω'Η2)2^· -3ε· '(ω'Η2) Γ ・ 6 = ΓΡΉΐ) 93 ・ 8 '( ζ Η9 ・ 3ΐ = ΓΡΉΐ) 82 ・ 8'(ω'Η2) 26 ・ -ε8 ・ '(ω'Η2) 2 ^ ・ -3ε ・'(ω'Η2) Γ
-80"Z'(zH9"eT=f'P'HT)6e-9'(zH0"S'6"8=rPP'HT)Z8"S'(s'HS)00^'(s'H2)99"S'(s'H2)^9 -80 "Z '(zH9" eT = f'P'HT) 6e-9' ( z H0 "S'6" 8 = rPP'HT) Z8 "S '(s'HS) 00 ^' ( s ' H2 ) 99 "S '( s ' H2) ^ 9
·ε'(ΖΗ3·π=ΓΡ'Ηΐ) Γε'(ΖΗ3·π=ΓΡ'Ηΐ)26·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ)69·2'(ω'Η2)9^·2· Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 26.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 69.2'(ω'Η2) 9 ^ · 2
— ζε ' (ra'Hs)ws— srs'C"'Hs)s6'i— ε8·ΐ'(ω'Η ·ΐ— εε·ΐ :軍 9 ( p-os a)H N-HT ^ ^J ^ -HZ- J ^ -9-nn^- ))→) -Z) -8) -£- (Ή) — Ζε '(ra'Hs) ws— srs'C "' Hs) s6'i— ε8 · ΐ '(ω'Η · Η— εε · ΐ: Army 9 (p-os a) H NH T ^ ^ J ^ -HZ- J ^ -9-nn ^-)) →) -Z) -8)-£-(Ή)
XOSp [I8W)] (zH2"6=rP'HT)ee"8'(s'HT)6S"8'(zH9"ST=rP'H XOSp [I8W)] (zH2 "6 = rP'HT) ee" 8 '( s ' HT) 6S "8' ( z H9" ST = rP'H
I)g2-8'(ui'HS)T6" -T8" '(zH8"2=rP'HT)9^" '(zH8"2'2"6=rPP'HT)0^" '(zH2-6=rP'H  I) g2-8 '(ui'HS) T6 "-T8"' (zH8 "2 = rP'HT) 9 ^" '(zH8 "2'2" 6 = rPP'HT) 0 ^ "' (zH2- 6 = rP'H
T)60"Z'(zH9"eT=f'P'HT)8e-9'(zH0"S'6"8=rPP'HT)S8"S'(s'HS)00^'(s'H2)T6"S'(s'HS)0 T) 60 "Z '(zH9" eT = f'P'HT) 8e-9' ( z H0 "S'6" 8 = rPP'HT) S8 "S '(s'HS) 00 ^' ( s ' H2) T6 "S '(s ' HS) 0
6·ε'(ζΗ3·π=ΓΡ'Ηΐ) Γε'(ζΗ3·π=ΓΡ'Ηΐ)26·2'(ζΗ0·ε'9·2ΐ=ΓΡ'Ηΐ)69·2'(ω'Η2)9^·26 · ε '( ζ Η3 · π = ΓΡ'Ηΐ) Γε' (ζΗ3 · π = ΓΡ'Ηΐ) 26.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡ'Ηΐ) 692' (ω ' Η2) 9 ^ · 2
— ζε ' (ra'Hs)ws— srs'C"'Hs)s6'i— ε8·ΐ'(ω'Η ·ΐ— εε·ΐ :軍 9 ( p-os a)H N-HT — Ζε '(ra'Hs) ws— srs'C "' Hs) s6'i— ε8 · ΐ '(ω'Η · ΐ— εε · ΐ: Military 9 (p-os a) H NH T
邈  邈
( ^ . ^^ -£- d ^^-9- -Z))-P) -Ζ) -8) -£- (Ή) (^. ^^-£-d ^^-9- -Z))-P) -Ζ) -8)-£-(Ή)
OOSfi ¾?第 [08^0]
Figure imgf000256_0003
OOSfi ¾? Th [08 ^ 0]
Figure imgf000256_0003
98S6T0/S00Zdf/X3d ½3 Ηΐ)98 '(ζΗ0·ε'9 ΐ=ί"'ΡΡ'Ηΐ) 9 ' (ra'HS)S S— ε ' (ω'Η ) — SO ' C"'HS)6 ·ΐ— 8
Figure imgf000257_0001
(9ρ— OS ) Η顺— Ητ 98S6T0 / S00Zdf / X3d ½3 Ηΐ) 98 '( ζ Η0 · ε'9 ΐ = ί "'ΡΡ'Ηΐ) 9 '(ra'HS) SS— ε'(ω'Η) — SO 'C"' HS) 6 · ΐ— 8
Figure imgf000257_0001
( 9 ρ- OS) Η 顺-Η τ
I - ( /y- 1I-(/ y- 1
Figure imgf000257_0002
Figure imgf000257_0002
(zH2"6=f'P'HT)2e"8'(zH9"ST=f' ΡΉΐ)9Γ8'(ω'Η2)^8· -28· '(8'Ηΐ) 3· '(ζΗ2·6=ΓΡΉΐ)80· '(ζΗ9·3ΐ=ΓΡΉΐ)33·9'(ω Ήε)9 ·9— εε·9'(ω'Ηΐ)3ΐ·9— 80'9'(zH0'S'6'8=l"'PP'HI)I8'S'(s'HS)00' (ω'Η Ο9·ε— OS ·ε'(ΖΗ3·π=ΓΡ'Ηΐ)εΓε'(ΖΗ3·π=ΓΡ'Ηΐ) 8·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)9^·2 — ' (ω'Η ΐ^—Ζ0 '(ω'Η 98·ΐ— 3Ζ·ΐ'(ω'Η Γΐ— ·ΐ :軍 9 (9p-OS a)H N-HT (zH2 "6 = f'P'HT) 2e" 8 '( z H9 "ST = f' ΡΉΐ) 9Γ8 '(ω'Η2) ^ 8 · -28 ·'(8'Ηΐ) 3 · '(ζΗ2 · 6 = ΓΡΉΐ) 80 · '(ζΗ9 · 3ΐ = ΓΡΉΐ) 33 · 9' (ω Ήε) 9 9- εε9 '(ω'Ηΐ) 3ΐ9- 80'9' ( z H0'S'6'8 = l "'PP'HI) I8'S'(s'HS) 00 '(ω'Η Ο9 · ε— OS · ε' (ΖΗ3 · π = ΓΡ'Ηΐ) εΓε '(ΖΗ3 · π = ΓΡ'Ηΐ) 8 · 2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 9 · 2'(ω'Η2) 9 ^ · 2 — '(ω'Η ΐ ^ —Ζ0'(ω'Η 98 · ΐ— 3Ζ · Ϊ́ '(ω'Η Γΐ— · ΐ: Military 9 ( 9 p-OS a) H NH T
1
Figure imgf000257_0003
-ζ)-2) -ε- (Ή) 1
Figure imgf000257_0003
-ζ) -2) -ε- (Ή)
(zHS'6=f'P'HI)IS'8'(zH9'SI= rP'HT)2r8'(zH8"Z=rP'HT)S8"Z'(ZH8"Z=rP'HT)08"Z'(ZH2"6=rP'HT)Z0"Z'(ZH9"ST=f 'P'HI)SS'9'(zH0'S'6'8=f'PP'HI)08'S'(s'HS)00' (zHS'n=f'P'HI)SrS'(zHS'n=f'P'H ΐ) 8·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η^)8^·2- ε·2'(ω'Η2)6Γ2- 0·2'(ω'Η2)28·ΐ-ε
Figure imgf000257_0004
(9ρ— OS ) 顺— Ητ
Figure imgf000257_0005
( / —" [—ベ fi （,^ ^ →) -Ζ) -8)— ε— (Ή) (zHS'6 = f'P'HI) IS'8 '( z H9'SI = rP'HT) 2r8' ( z H8 "Z = rP'HT) S8" Z '(ZH8 "Z = rP'HT) 08 "Z '(ZH2" 6 = rP'HT) Z0 "Z'(ZH9" ST = f 'P'HI) SS'9' ( z H0'S'6'8 = f'PP'HI) 08'S '(s 'HS) 00' ( z HS'n = f'P'HI) SrS '( z HS'n = f'P'H ΐ) 8'2' ( ζ Η0 · ε'9 2 · = ΓΡΡ'Ηΐ) 9 · 2 '(ω'Η ^) 8 ^ · 2- ε · 2'(ω'Η2) 6Γ2- 0 · 2 '(ω'Η2) 28 · ΐ-ε
Figure imgf000257_0004
( 9 ρ- OS) 顺-Η τ
Figure imgf000257_0005
(/ — "[—Be fi (, ^ ^ →) -Ζ) -8) — ε— (Ή)
(zH2"6=rP'HT)2e"8'(zH9"eT=rP'HT)6r8'(s'H2)S8"Z'(zH2"6=rP'HT)80"Z'(zH9"ST =ΓΡ'Ηΐ)93·9'(ω'ΗΖ)9ΐ·9— 86'S'(m'HI)WS— 8 S'(ra'HS)Z9'S— ½'S'(s'HS)00' C"'HS IS'S'(ra'HI) ΐ·ε— 0ΐ·ε'(ω'Ηΐ)06 — S8 '(ζΗ0·ε'9 ΐ=ί"'ΡΡ'Ηΐ) 9 ' (ra'HS)S S(zH2 "6 = rP'HT) 2e" 8 '( z H9 "eT = rP'HT) 6r8' ( s ' H2) S8" Z '(zH2 "6 = rP'HT) 80"Z' (zH9 " ST = ΓΡ'Ηΐ) 93 · 9 '(ω'ΗΖ) 9ΐ · 9—86'S'(m'HI) WS—8 S '(ra'HS) Z9'S—½'S'(s'HS) 00 'C "' HS IS'S '(ra'HI) ΐ · ε— 0ΐ · ε'(ω'Ηΐ) 06 — S8 '( ζ Η0 · ε'9 ΐ = ί "'ΡΡ'Ηΐ) 9 '(ra'HS) SS
— ζε ' C"'Hs)os — 90·^(ω'Η3)ε8·ΐ— 89·ΐ'(ω )εε·ΐ— ·ΐ :軍 9 (9ρ— OS ) Η顺— Ητ y-l- ^(^αΆ ( ^ /-^4-^ - 'Ζ- {Ή"Ξ))→) -2)-8)-ε-(Ή) — Ζε 'C "' Hs) os — 90 · ^ (ω'Η3) ε8 · ΐ— 89 · ΐ '(ω) εε · ΐ— · ΐ: Army 9 ( 9 ρ— OS) Η 顺 — Η τ yl -^ (^ α Ά (^ /-^ 4- ^-'Ζ- (Ή "Ξ)) →) -2) -8) -ε- (Ή)
98S6T0/S00Zdf/X3d 993 ベ fi （,^ ίί （ ίί S) -£- ^-Ζ- (Ή.))→) -Z) -S) -£- (Ή. 98S6T0 / S00Zdf / X3d 993 Fi (, ^ ίί (ίί S)-£-^ -Ζ- (Ή.)) →) -Z) -S)-£-(Ή.
OISp [06 W)] (ΖΗ2·6=Γ'ΡΉΐ)ΐ3·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)εΓ8'(ζΗ OISp [06 W)] (ΖΗ2 · 6 = Γ'ΡΉΐ) ΐ3 · 8 '( ζ Η9 · 3ΐ = ΓΡ'Ηΐ) εΓ8' ( ζ Η
8"Z=rP'HT)S8"Z'(zH8"Z=f'P'H2)08"Z'(zH9"Z=f'VHT)Z2"Z'(ra'He)T2-Z-^rZ'(zH2"6=f 'P'HT)Z0"Z'(ZH9"eT=rP'HT)W9'(zH0"S'6"8=rPP'HT)08"e'(s'HS)66"S'(zHS"n=rP'H ΐ)^·ε'(ζΗ3·ΐΐ=ί"'Ρ'Ηΐ)88 '(ζΗ0·ε'9 ΐ=ΓΡΡ'Ηΐ)Ζ9 ' (ω'Η )ε9 — WS'WHS) 8 "Z = rP'HT) S8" Z '(zH8 "Z = f'P'H2) 08"Z' (zH9 "Z = f'VHT) Z2" Z '(ra'He) T2-Z- ^ rZ '(zH2 "6 = f'P'HT)Z0" Z '(ZH9 "eT = rP'HT) W9' ( z H0"S'6"8 = rPP'HT) 08" e '(s'HS ) 66 "S '( z HS" n = rP'H ΐ) ^ · ε' ( ζ Η3 · ΐΐ = ί "'Ρ'Ηΐ) 88' ( ζ Η0 · ε'9 ΐ = ΓΡΡ'Ηΐ) Ζ9 '(ω'Η) ε9 — WS'WHS)
— 8S ' C"'HS)0S — 90 '(ω'Η 8·ΐ— 99·ΐ'(ω'Η ε·ΐ— ·ΐ :軍 9 ( OS ) Η顺— Ητ — 8S 'C "' HS) 0S — 90 '(ω'Η 8 · ΐ— 99 · ΐ'(ω'Η ε · ΐ— · ΐ: Army 9 (OS) Η 顺 — Η τ
— ΐ—( / —"[—ベ; ^fi^ （ ^ ェ — ε)→) -Ζ) -8)— ε— (Ή) — Ϊ́— (/ — ”[— Be; ^ fi ^ (^ é — ε) →) -Ζ) -8) — ε— (Ή)
mzu ^, [68 w)] mzu ^, [68 w)]
(zH2-6=rP'HT)2e-8'(zH9"ST=f'P'HT)8r8'(s'H2)S8" (zH2-6 = rP'HT) 2e-8 '(z H9 "ST = f'P'HT) 8r8'(s' H2) S8"
'(zHS" =rP'H2)0^" '(zHS" =r H2)TS" '(zHS" =f' HT)T2" '(zH2"6=rP'HT)80" '(ra '(zHS "= rP'H2) 0 ^"' (zHS "= r H2) TS" '(zHS "= f' HT) T2" '(zH2 "6 = rP'HT) 80"' (ra
'HS)6S'9— 0S'9'C"'HI)SS'9— 6S'9'(zH0'S'6'8=rPP'HI)I8'S'(s'HS)00' (ω'Ηζ) S'S— 'HS) 6S'9— 0S'9'C "' HI) SS'9— 6S'9 '( z H0'S'6'8 = rPP'HI) I8'S'(s'HS) 00 '(ω'Ηζ) S'S—
·ε'(ζΗ3·ΐΐ=ί"'Ρ'Ηΐ) ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)68 '(ζΗ0·ε'9 ΐ=ί"'ΡΡ'Ηΐ)89 ' (ra'HS)8 S — ' (ω'Η — 80 ' (ω'Η 8·ΐ— 8 ·ΐ'(ω'Η Γΐ— 8S'I :軍 9 (9p-OS a)H N-HT · Ε '( ζ Η3 · ΐΐ = ί "'Ρ'Ηΐ) ΐε '( ζ Η3 · π = ί"'Ρ'Ηΐ) 68 '( ζ Η0 · ε'9 ΐ = ί "'ΡΡ'Ηΐ ) 89 '(ra'HS) 8 S —'(ω'Η — 80 '(ω'Η 8 · ΐ— 8 · ΐ'(ω'Η Γΐ— 8S'I: Army 9 ( 9 p-OS a) H NH T
- ( / - 1
Figure imgf000258_0001
-S)-8)-S- (Ή) -(/-1
Figure imgf000258_0001
-S) -8) -S- (Ή)
80Sfi ¾?第 [88W)] (zH2"6=rP'HT)Se"8'(zH9"eT=rP'HT)T2"8'(s'H2)S8" '(ra'HS)2^- -2S" '(zH 2"6=f'P'HT)80"Z'(zH9"eT=f'P'HT)9e"9'(zH0"S'6"8=rPP'HT)28"e'(s'HS)00^'(s'H2)ZS •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)88 '(ζΗ0·ε'9 ΐ=ί"'ΡΡ'Ηΐ)89 ' (ra'HS)S S — SW(ui'HS)SS'S—SI ' C"'HS)S8'I— ΐ'(ω'Η ε·ΐ— ·ΐ :軍 9 ( OS ) Η顺— Ητ 80Sfi ¾? No. [88W)] (zH2 "6 = rP'HT) Se" 8 '(z H9 "eT = rP'HT) T2"8' (s 'H2) S8 "'(ra'HS) 2 ^ --2S "'(zH 2" 6 = f'P'HT) 80 "Z'(zH9" eT = f'P'HT) 9e "9 '( z H0"S'6"8 = rPP'HT) 28 "e '(s'HS) 00 ^' (s 'H2) ZS • S' (z HS'II = f'P'HI) SrS '(z HS'II = f'P'HI) 88' ( ζ Η0 · ε'9 ΐ = ί "'ΡΡ'Ηΐ) 89'(ra'HS) SS — S W (ui'HS) SS'S—SI 'C"' HS) S8'I— ΐ '(ω'Η ε · ΐ— · ΐ: Army 9 (OS) Η 顺 — Η τ
— τ—ベ; ^ίί^ （ ^ - — べ ci / ェ — ε)→) -Ζ) -8)— ε— (Ή)— Τ—Be; ^ ίί ^ (^-— Be ci / é — ε) →) -Ζ) -8) — ε— (Ή)
Figure imgf000258_0002
Figure imgf000258_0002
ε3·8'(ζΗ9·3ΐ=ΓΡΉΐ)ε2·8'(ω'Η2)88· -ΐ8· '(ζΗ2·6=ΓΡΉΐ)80· '(ζΗ9·3ΐ=Γ'ΡΉΐ) 3· 9'(zH0"S'6"8=f'PP'HT)T8"e'(s'HS)00^'(s'H2)0S"S'(zHS-n=rP'HT)2rS'(zHe-n=rP' ε3 ・ 8 '( ζ Η9 ・ 3ΐ = ΓΡΉΐ) ε2 ・ 8'(ω'Η2) 88 ・ -ΐ8 ・ '(ζΗ2 ・ 6 = ΓΡΉΐ) 80 ・' (ζΗ9 ・ 3ΐ = Γ'ΡΉΐ) 3 ( z H0 "S'6" 8 = f'PP'HT) T8 "e '(s'HS) 00 ^' ( s ' H2) 0S" S '( z HS-n = rP'HT) 2rS' ( zHe-n = rP '
98S6T0/S00Zdf/X3d 993 ,,J,，,,J，,,J，,,J ()()()(lHdd12.63.0HZ2.732Ht5.7HZ2.86lHd11.5HZ3.11lHd11.5HZ==== 98S6T0 / S00Zdf / X3d 993 ,, J ,,,, J ,,, J ,,, J () () () (lHdd12.63.0HZ2.732Ht5.7HZ2.86lHd11.5HZ3.11lHd11.5HZ ====
禽,，,，,，,， )()()()() δd： 1.21l.302Hm1.71l.812Hm2.072.202Hm2.372.442Hm2.67 Illll  Chicken ,,,,,,,) () () () () δd: 1.21l.302Hm1.71l.812Hm2.072.202Hm2.372.442Hm2.67 Illll
Ts)嫘¾ Ty入yiT^2 V5// 1HNMDMS〇Y rrHI 11ノIl-  Ts) 嫘 ¾ Ty input yiT ^ 2 V5 // 1HNMDMS〇Y rrHI 11 ll-
Figure imgf000259_0001
Figure imgf000259_0001
，,,J，,,J，,,J，,,J)()()()( 1.8HZ7.80lHd7.8HZ7.83lHd7.8HZ8.14lHd15.6HZ8.51lHd9.==== ,,, J ,,, J ,,, J ,,, J) () () () (1.8HZ7.80lHd7.8HZ7.83lHd7.8HZ8.14lHd15.6HZ8.51lHd9. ====
，,,J,，,,J，,,J，,,J)()()()( HZ6.47lHdd3.21.8HZ6.55lHd15.6HZ7.07lHd9.2HZ7.58lHd====  ,,, J ,,,, J ,,, J ,,, J) () () () (HZ6.47lHdd3.21.8HZ6.55lHd15.6HZ7.07lHd9.2HZ7.58lHd ====
，,，,，,,J,，,，,,J)()()()()( 11.5HZ3.232Hs3.993Hs5.80lHdd8.93.0HZ6.28lHs6.33lHd3.2== ,,,,,,, J ,,,,, J) () () () () (11.5HZ3.232Hs3.993Hs5.80lHdd8.93.0HZ6.28lHs6.33lHd3.2 ==
,，,，,,J,，,,J，,,J)()()()( Hm2.332.442Hm2.68lHdd12.63.0HZ2.87lHd11.5HZ3.12lHd===l 禽,，,，,，( )()()()( δ 1HNMRDMSOd： 1.27l.342Hm1.73l.842Hm1.923Hs 2.072.212IIll1 nz m^ 6^o]() () () (Hm2.332.442Hm2.68lHdd12.63.0HZ2.87lHd11.5HZ3.12lHd === l Poultry ,,,,, () () () () (δ 1HNMRDMSOd: 1.27l.342Hm1.73l.842Hm1.923Hs 2.072.212IIll1 nz m ^ 6 ^ o]
(zH2"6=f'P'HT)Se"8'(zH9"eT=f'P'HT)6r8'(s'H2)^8"Z'(zHS"Z=rP'H2)99"Z' (zHS"Z=f'VH2)0^"Z'(zHS"Z=rVHT)92"Z'(zH2"6=f'P'HT)80"Z'(zH2"S=rP'HT)^8"9'(zH (zH2 "6 = f'P'HT) Se" 8 '( z H9 "eT = f'P'HT) 6r8' ( s 'H2) ^ 8"Z' (zHS "Z = rP'H2) 99" Z '(zHS "Z = f'VH2) 0 ^"Z' (zHS "Z = rVHT) 92" Z '(zH2 "6 = f'P'HT) 80"Z' (zH2 "S = rP'HT ) ^ 8 "9 '( z H
9"eT=f'P'HT)Ze-9'(zH2-S=f'P'HT -9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)ZZ 9 "eT = f'P'HT) Ze-9 '( z H2-S = f'P'HT -9' ( z H0"S'6"8 = rPP'HT) T8" S '(s'HS ) 66 "S '(s' H2) ZZ
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)3Γε'(ΖΗ3·π=ΓΡ'Ηΐ)68·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)9^·2 — ZS ' C"'HS — 80 '(ω'Η 8·ΐ— 8Ζ·ΐ'(ω'Η ε·ΐ— 6S'I :軍 9 ( OS ) 顺— Ητ · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) 3Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 68.2 '( ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 9-2'(ω'Η2) 9 ^ · 2 — ZS 'C "' HS — 80 '(ω'Η 8 · ΐ— 8Ζ · ΐ'(ω'Η ε · ΐ— 6S'I: Military 9 (OS) 顺 — Η τ
邈 (^ （ ^— S—ベ ίί,^Ρ ^E ー {Λ^-^^ ^-Ι - ( / - 1 一べ fi （,^ ^ ( —べ έ -ェ ー9))一 ） -2)-8)-ε-(Ή)  邈 (^ (^ — S—Be ίί, ^ Ρ ^ E ー {Λ ^-^^ ^ -Ι-(/-1 All fi (, ^ ^ (—Be έ-ー 9)) 一)- 2) -8) -ε- (Ή)
9ISfi ¾?第 [96 W)] (zHS'6=f'P'HI)IS'8'(zH9'SI= rP'HT)2r8'(zH8"Z=rP'HT)S8"Z'(ZH8"Z=rP'HT)08"Z'(ZH2"6=rP'HT)Z0"Z'(ZH9"ST=f 'P'HI)SS'9'(zH0'S'6'8=f'PP'HI)08'S'(s'HS)00' (zHS'n=f'P'HI)SrS'(zHS'n=f'P'H ΐ) 8·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η^)8^·2- ε·2'(ω'Η2)6Γ2- 0·2'(ω'Η2)28·ΐ-ε 9ISfi ¾? Th [96 W)] (zHS'6 = f'P'HI) IS'8 '( z H9'SI = rP'HT) 2r8' ( z H8 "Z = rP'HT) S8" Z ' (ZH8 "Z = rP'HT) 08" Z '(ZH2 "6 = rP'HT) Z0"Z' (ZH9 "ST = f 'P'HI) SS'9' ( z H0'S'6'8 = f 'PP'HI) 08'S'(s'HS) 00 '( z HS'n = f'P'HI) SrS' ( z HS'n = f'P'H ΐ) 8'2 '( ζ Η0 '9 · 2ΐ = ΓΡΡ'Ηΐ) 9 · 2'(ω'Η ^) 8 ^ · 2-ε · 2 '(ω'Η2) 6Γ2- 0 · 2'(ω'Η2) 28 · ΐ-ε
·ΐ'(ω'Η ^·ΐ— Ζε·ΐ'(ω'Η9ΐ)ΐε·ΐ— ·ΐ'(ζΗε·Ζ=Π'Ηε)98·0:ϋ 9 ( P-OS a)H N-HT · Ϊ́ '(ω'Η ^ · ΐ— Ζε · ΐ'(ω'Η9ΐ) ΐε · ΐ— · ΐ '( ζ Ηε · Ζ = Π'Ηε) 98.0: ϋ 9 (P-OS a) H NH T
邈 (^ 邈 (^
Figure imgf000260_0001
-2)-8)-ε-(Ή)
Figure imgf000260_0001
-2) -8) -ε- (Ή)
9ISp}¾? [S6W)]
Figure imgf000260_0002
9ISp} ¾? [S6W)]
Figure imgf000260_0002
)T2"8-9r8'(zH8"Z=rP'HT)T6"Z'(s'H2)S8"Z'(ZH8"Z=rP'HT)08"Z'(ra'H^)SS-Z-S^"Z'(ZH ) T2 "8-9r8 '( z H8" Z = rP'HT) T6 "Z'(s'H2)S8" Z '(ZH8 "Z = rP'HT) 08"Z'(ra'H ^) SS -ZS ^ "Z '(ZH
2-6=f'P'HT)60"Z'(zH9"eT=f'P'HT)9e-9'(zH0"S'6"8=rPP'HT)28"S'(s'H2)Zr^'(s'He)00 ν(ΖΗ3·π=ΓΡ'Ηΐ)9Γε'(ζΗ3·π=ΓΡ'Ηΐ)06·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)9^·22-6 = f'P'HT) 60 "Z '(zH9" eT = f'P'HT) 9e-9' ( z H0 "S'6" 8 = rPP'HT) 28 "S '(s' H2) Zr ^ '(s'He) 00 ν (ΖΗ3 · π = ΓΡ'Ηΐ) 9Γε' (ζ Η3 · π = ΓΡ'Ηΐ) 06 · 2 '(ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ ) 9 ・ 2 '(ω'Η2) 9 ^ ・ 2
— ZS ' C"'HS) — ΐΐ ' (ω'Η 6·ΐ— 98·ΐ'(ω'Η ΐ ·ΐ— Γΐ :軍 9 ( P-OS a)H N-HT — ZS 'C "' HS) — ΐΐ '(ω'Η 6 · ΐ— 98 · ΐ'(ω'Η ΐ · ΐ— Γΐ: Military 9 (P-OS a) H NH T
1—ベ fi （,^ ^ 1—ベ ^ ） )→)-Z)-2)-£-CR)
Figure imgf000260_0003
1—Be fi (, ^ ^ 1—Be ^)) →) -Z) -2)-£ -CR)
Figure imgf000260_0003
T)Se"8'(zH9"eT=f'P'HT)02"8'(s'H2)^8"Z'(ra'HS)6S"Z-^"Z'(zH2"6=rP'HT)80"Z'(zH9"S
Figure imgf000260_0004
T) Se "8 '( z H9" eT = f'P'HT) 02 "8' ( s ' H2) ^ 8" Z '(ra'HS) 6S "Z-^"Z' (zH2 "6 = rP'HT) 80 "Z '(zH9" S
Figure imgf000260_0004
98S6T0/S00Zdf/X3d 893 ZSS9^0/900Z OAV ozzu ^, [ooeo] 98S6T0 / S00Zdf / X3d 893 ZSS9 ^ 0 / 900Z OAV ozzu ^, [ooeo]
(ζΗ2·6=ΓΡ'Ηΐ)½·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)^·8'(ω'Ηΐ)ΐ6· -88 •Z'(zH8"Z=rP'HT)Z8"Z'(zH8"Z=rP'HT)^8"Z'(ra'HT)69"Z-S9"Z'(zH2"6=rVHT)8S"Z'(zH (ζΗ2 · 6 = ΓΡ'Ηΐ) ½ · 8 '( ζ Η9 · 3ΐ = ΓΡ'Ηΐ) ^ · 8'(ω'Ηΐ) ΐ6 · -88 • Z '(zH8 "Z = rP'HT) Z8" Z '(zH8 "Z = rP'HT) ^ 8"Z'(ra'HT) 69 "Z-S9" Z '(zH2 "6 = rVHT) 8S"Z' (zH
2-6=f'P'HT)60"Z'(zH9"eT=f'P'HT)8e-9'(zH0"S'6"8=rPP'HT)28"S'(s'HS)66"S'(s'H2)T8 2-6 = f'P'HT) 60 "Z '(zH9" eT = f'P'HT) 8e-9' ( z H0 "S'6" 8 = rPP'HT) 28 "S '(s' HS) 66 "S '(s ' H2) T8
·ε'(ζΗ3·ΐΐ=ί"'Ρ'Ηΐ) ΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)88 '(ζΗ0·ε'9 I=f'PP'HI)Z9'S'(ra'HS)„ Ε '( ζ Η3 · ΐΐ = ί "'Ρ'Ηΐ) ΐε '( ζ Η3 · π = ί"'Ρ'Ηΐ) 88 '( ζ Η0 · ε'9 I = f'PP'HI) Z9'S '(ra'HS) „
— 9S ' C"'HS)0S — 80 ' (ω'Η 98·ΐ— 3Ζ·ΐ'(ω'Η 9ε·ΐ— θε·ΐ :軍 9 ( P-OS a)H N-HT — 9S 'C "' HS) 0S — 80 '(ω'Η 98 · ΐ— 3Ζ · ΐ'(ω'Η 9ε · ΐ— θε · ΐ: Army 9 (P-OS a) H NH T
（ ^ ベ:^ ( ^ ci / fH) -^- J ^ -Z)→)-Ζ)-2)-£-(Ή.) (^ Be: ^ (^ ci / fH)-^-J ^ -Z) →) -Ζ) -2)-£-(Ή.)
eiz W [66 W)] (zH2"6=f'P'HT)Se"8'(zH9"eT=f'P'HT)6r8'(s'H2)^8"Z'(zHS"Z=rP'H2)09"Z' (zHS" =f' H2)6S" '(zH "S=rP'HT)2S" '(zHS" =r HT) 2" '(zH2"6=rP'HT)80" '(zH eiz W [66 W)] (zH2 "6 = f'P'HT) Se" 8 '( z H9 "eT = f'P'HT) 6r8' ( s 'H2) ^ 8"Z' (zHS "Z = rP'H2) 09 "Z '(zHS" = f' H2) 6S "'(zH" S = rP'HT) 2S "'(zHS" = r HT) 2 "'(zH2" 6 = rP'HT ) 80 "'(zH
Z-S=f'P'HT)½"9'(zH9"eT=f'P'HT)Ze-9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)T6 ZS = f'P'HT) ½ "9 '( z H9" eT = f'P'HT) Ze-9' ( z H0 "S'6" 8 = rPP'HT) T8 "S '(s'HS ) 66 "S '(s' H2) T6
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)^Γε'(ΖΗ3·π=ΓΡ'Ηΐ)88·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)9^·2 — 9S'S'C"'H I^S— S0'S'(ra'H 8·ΐ— 8 ·ΐ'(ω'Η ε·ΐ— 6^ΐ：掛 9 ( P-OS a)H N-HT
Figure imgf000261_0001
· Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) ^ Γε' (ΖΗ3 · π = ΓΡ'Ηΐ) 88 · 2 '(ζ Η0 · ε'9 · 2ΐ = ΓΡΡ'Ηΐ) 9 · 2'(ω'Η2 ) 9 ^ · 2 — 9S'S'C "'HI ^ S— S0'S'(ra'H 8 · ΐ— 8 · ΐ '(ω'Η ε · ΐ— 6 ^ ΐ ： Kake 9 (P-OS a) H NH T
Figure imgf000261_0001
8ISfi ¾?第 [86 W)] (ζΗ2·6=ΓΡΉΐ)ε3·8'(ζΗ9·3ΐ=ΓΡ'Ηΐ)ΐ2·8'(ω'Η2) 8· -2 8 ISfi ¾? Th [86 W]] (ζΗ2 · 6 = ΓΡΉΐ) ε3 · 8 '( ζ Η9 · 3ΐ = ΓΡ'Ηΐ) ΐ2 · 8'(ω'Η2) 8 · -2
8"Z'(ZH0"e=rP'HT)08"Z'(ZHZ"S=rP'HT)89"Z'(ZHZ"SO"S=rPP'HT)S2"Z'(ZH2"6=rP'HT 8 "Z '(ZH0" e = rP'HT) 08 "Z' (ZHZ" S = rP'HT) 89 "Z '(ZHZ" SO "S = rPP'HT) S2" Z' (ZH2 "6 = rP'HT
)80"Z'(s'HT)28"9'(zH9"eT=f'P'HT)Ze-9'(zH0"S'6"8=rPP'HT)T8"S'(s'HS)66"S'(s'H2)ZZ ) 80 "Z '(s'HT) 28"9' ( z H9 "eT = f'P'HT) Ze-9 '( z H0"S'6"8 = rPP'HT) T8"S' (s 'HS) 66 "S' ( s ' H2) ZZ
·ε'(ΖΗ3·π=ΓΡ'Ηΐ)εΓε'(ΖΗ3·π=ΓΡ'Ηΐ) 8·2'(ζΗ0·ε'9·2ΐ=ΓΡΡ'Ηΐ) 9·2'(ω'Η2)ε^·2 — 9S ' C"'HS)0S — 80 ' C"'HS)S8'I— WI'(ra'HS) TI— :軍 9 ( P-OS a)H N-HT · Ε '(ΖΗ3 · π = ΓΡ'Ηΐ) εΓε' (ΖΗ3 · π = ΓΡ'Ηΐ) 8'2 '( ζ ε ^ · 2 — 9S 'C "' HS) 0S — 80 'C"' HS) S8'I— WI '(ra'HS) TI—: Army 9 (P-OS a) H NH T
邈 (^ （ S / ε— /— 、 ^ ( / S—べェ ^) -9))→) -Z) -S) -£- (Ή.)  邈 (^ (S / ε— / —, ^ (/ S—Be ^) -9)) →) -Z) -S)-£-(Ή.)
98S6T0/S00Zdf/X3d 693 H-NMR(DMSO-d ) δ値： 1.31— 1.38(2H,m),1.80— 1.88(2H,m),2.07— 2.18(2H,m),2.37— 98S6T0 / S00Zdf / X3d 693 H-NMR (DMSO-d) δ value: 1.31— 1.38 (2H, m), 1.80— 1.88 (2H, m), 2.07— 2.18 (2H, m), 2.37—
6  6
2.45(2H,m),2.66(lH,dd,J=12.6,3.0Hz),2.89(lH,d,J=11.5Hz),3.14(lH,d,J=11.5Hz),3. 80(2H,s),3.89(2H,s),3.99(3H,s),5.81(lH,dd,J=8.9,3.0Hz),6.56(lH,d,J=15.6Hz),7.08( lH,d,J=9.2Hz),7.29(lH,t,J=6.9Hz),7.33-7.38(2H,m),7.54-7.62(2H,m),7.81(lH,d,J=7 .8Hz),7.83(2H,s),7.85(lH,d,J=7.8Hz),8.16(lH,d,J=15.6Hz),8.52(lH,d,J=9.2Hz) [0501] 実施例 221  2.45 (2H, m), 2.66 (lH, dd, J = 12.6,3.0Hz), 2.89 (lH, d, J = 11.5Hz), 3.14 (lH, d, J = 11.5Hz), 3.80 (2H , s), 3.89 (2H, s), 3.99 (3H, s), 5.81 (lH, dd, J = 8.9, 3.0Hz), 6.56 (lH, d, J = 15.6Hz), 7.08 (lH, d, J = 9.2Hz), 7.29 (lH, t, J = 6.9Hz), 7.33-7.38 (2H, m), 7.54-7.62 (2H, m), 7.81 (lH, d, J = 7.8Hz), 7.83 (2H, s), 7.85 (lH, d, J = 7.8Hz), 8.16 (lH, d, J = 15.6Hz), 8.52 (lH, d, J = 9.2Hz) [0501] Example 221
(E) - 3- (8— (2- (4- ( (2, 2，一ビチォフェンー5 ィル)メチルァミノ）ピぺリジン —1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）アクリル酸 'H-NMRCDMSO-d ) δ値： 1.29— 1.34(2H,m),1.77— 1.85(2H,m),2.07— 2.19(2H,m),2.38—  (E)-3- (8— (2- (4- ((2, 2, 1-bithiophene-5-yl) methylamino) piperidine-1-yl) 1-hydroxyethyl) 2-methoxyquinoline 1 5 —Yl) acrylic acid 'H-NMRCDMSO-d) δ value: 1.29— 1.34 (2H, m), 1.77—1.85 (2H, m), 2.07—2.19 (2H, m), 2.38—
6  6
2.46(2H,m),2.67(lH,dd,J=12.6,3.0Hz),2.89(lH,d,J=11.5Hz),3.14(lH,d,J=11.5Hz),3. 89(2H,s),3.99(3H,s),5.81(lH,dd,J=8.9,3.0Hz),6.58(lH,d,J=15.6Hz),6.89(lH,d,J=3.2 Hz),7.05-7.11(3H,m),7.22(lH,d,J=3.2Hz),7.45(lH,d,J=5.0Hz),7.84(lH,d,J=7.8Hz),7 .87(lH,d,J=7.8Hz),8.23(lH,J=15.6Hz),8.54(lH,d,J=9.2Hz)  2.46 (2H, m), 2.67 (lH, dd, J = 12.6,3.0Hz), 2.89 (lH, d, J = 11.5Hz), 3.14 (lH, d, J = 11.5Hz), 3.89 (2H , s), 3.99 (3H, s), 5.81 (lH, dd, J = 8.9, 3.0Hz), 6.58 (lH, d, J = 15.6Hz), 6.89 (lH, d, J = 3.2 Hz), 7.05 -7.11 (3H, m), 7.22 (lH, d, J = 3.2Hz), 7.45 (lH, d, J = 5.0Hz), 7.84 (lH, d, J = 7.8Hz), 7.87 (lH, d, J = 7.8Hz), 8.23 (lH, J = 15.6Hz), 8.54 (lH, d, J = 9.2Hz)
[0502] 実施例 222 [0502] Example 222
(E) - 3- (8— (2- (4一（3—（4—tert ブチルフエ-ル）ー2 メチルプロピルアミ ノ）ピぺリジン一 1—ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）ァ クリル酸  (E)-3- (8— (2- (4 (3- (4-tert-butylphenyl) -2 methylpropylamino) piperidine 1-yl) 1-hydroxyethyl) 2— Methoxyquinoline 1-yl) acrylic acid
'H-NMRCDMSO-d ) δ値： 0.81(3H,d,J=6.9Hz),1.23- 1.31(llH,m),1.71- 1.82(3H,m),2.  'H-NMRCDMSO-d) δ value: 0.81 (3H, d, J = 6.9Hz), 1.23-1.31 (llH, m), 1.71-1.82 (3H, m), 2.
6  6
07-2.19(2H,m),2.24-2.30(lH,m),2.34-2.54(4H,m),2.64-2.70(2H,m),2.88(lH,d,J=ll. 5Hz),3.13(lH,d,J=11.5Hz),4.00(3H,s),5.81(lH,dd,J=9.2,3.0Hz),6.57(lH,d,J=15.6Hz ),7.04-7.11(3H,m),7.28(2H,d,J=8.3Hz),7.80-7.87(2H,m),8.19(lH,d,J=15.6Hz),8.53( lH,d,J=9.2Hz)  07-2.19 (2H, m), 2.24-2.30 (lH, m), 2.34-2.54 (4H, m), 2.64-2.70 (2H, m), 2.88 (lH, d, J = ll.5Hz), 3.13 (lH, d, J = 11.5Hz), 4.00 (3H, s), 5.81 (lH, dd, J = 9.2,3.0Hz), 6.57 (lH, d, J = 15.6Hz), 7.04-7.11 (3H, m), 7.28 (2H, d, J = 8.3Hz), 7.80-7.87 (2H, m), 8.19 (lH, d, J = 15.6Hz), 8.53 (lH, d, J = 9.2Hz)
[0503] 実施例 223 [0503] Example 223
(E) - 3- (8- (2- (4—( (フエナントレン 9 ィル)メチルァミノ）ピぺリジン 1 ィル） 1—ヒドロキシェチル） 2—メトキシキノリン一 5—ィル）アクリル酸  (E)-3- (8- (2- (4- ((Phenanthrene 9-yl) methylamino) piperidine 1-yl) 1-hydroxyethyl) 2-methoxyquinoline 5-yl) acrylic acid
1H-NMR(DMSO-d ) δ値： 1.36— 1.45(2H,m),1.87— 1.99(2H,m),2.08— 2.23(2H,m),2.33—  1H-NMR (DMSO-d) δ value: 1.36— 1.45 (2H, m), 1.87— 1.99 (2H, m), 2.08— 2.23 (2H, m), 2.33—
6  6
2.43(2H,m),2.66(lH,dd,J=12.6,3.0Hz),2.89(lH,d,J=11.5Hz),3.15(lH,d,J=11.5Hz),3. 97(3H,s),4.19(2H,s),5.80(lH,dd,J=8.9,3.0Hz),6.55(lH,d,J=15.6Hz),7.05(lH,d,J=9.2 9·3ΐ=ί"'Ρ'Ηΐ)6Γ8'(ω'Η εΐ·8— 60'8'(s'HS) 8 '(zHS'8=f'P'HI)8S'Z'(zHS'8=f'P'HI) e" '(ra'H2)8^" -^" '(zHS"8=rVHT)8r '(zH2"6=rP'HT) 0" '(zH9"ST=rP'HT) e"9'( zH0"S'6"8=rPP'HT)28"e'(zHS" =rb'H2)S^^'(s'He)66"S'(s'H2)½"S'(zHS"n=rP'HT) Ζΐ·ε'(ζΗ3·π=ί"'Ρ'Ηΐ)ΐ6 '(ζΗ0·ε'9 ΐ=ΓΡΡ'Ηΐ)Ζ9 ' (ω'Η ^ — 9S ' (ω'Η 6ΐ — 8 ο ' (ω'Η 6·ΐ—
Figure imgf000263_0001
:軍 9 ( p-os a)H N-HT ri （ ^ ^ ( ε— /— 、 ^ェー 6))— ） -Ζ) 8)— ε (Ή)2.43 (2H, m), 2.66 (lH, dd, J = 12.6,3.0Hz), 2.89 (lH, d, J = 11.5Hz), 3.15 (lH, d, J = 11.5Hz), 3.97 (3H , s), 4.19 (2H, s), 5.80 (lH, dd, J = 8.9, 3.0Hz), 6.55 (lH, d, J = 15.6Hz), 7.05 (lH, d, J = 9.2) 9 · 3ΐ = ί "'Ρ'Ηΐ) 6Γ8'(ω'Η εΐ · 8— 60'8 '( s ' HS) 8 '( z HS'8 = f'P'HI) 8S'Z' (zHS '8 = f'P'HI) e "'(ra'H2) 8 ^"-^ "'(zHS" 8 = rVHT) 8r' (zH2 "6 = rP'HT) 0"'(zH9"ST = rP'HT) e "9 '(zH0"S'6"8 = rPP'HT) 28"e' (zHS "= rb'H2) S ^^ '(s'He) 66"S' ( s ' H2 ) ½ "S '( z HS" n = rP'HT) Ζΐ · ε' ( ζ Η3 · π = ί "'Ρ'Ηΐ) ΐ6' ( ζ Η0 · ε'9 ΐ = ΓΡΡ'Ηΐ) Ζ9 '( ω'Η ^ — 9S '(ω'Η 6ΐ — 8 ο'(ω'Η 6 · ΐ—
Figure imgf000263_0001
: Military 9 (p-os a) H NH T ri (^ ^ (ε — / —, ^ 6 6)) —) -Ζ) 8) — ε (Ή)
Figure imgf000263_0002
Figure imgf000263_0002
(zH2-6=rP'HT)Se-8'(zH9"ST=rP'HT)6r8'(s'H2) ^8" '(ra'H2)SS- -8^" '(ra'He)S^- -6S" '(ZH "S=f'P'HT)^" '(ZH2"6=rP'HT)80" '(ZH (zH2-6 = rP'HT) Se-8 '( z H9 "ST = rP'HT) 6r8' ( s ' H2) ^ 8"'(ra'H2) SS- -8 ^ "'(ra'He ) S ^--6S "'(ZH" S = f'P'HT) ^ "'(ZH2" 6 = rP'HT) 80 "'(ZH
Ζ·ε=ί"'Ρ'Ηΐ)ε6·9'(ζΗ9·3ΐ=ί>'Ρ'Ηΐ)Ζ3·9'(ζΗ0·ε'6·8=ί"'ΡΡ'Ηΐ)ΐ8·3'(δ'Ηε)00· (S'HS)S6 •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)88 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)„ Ε · ε = ί "'Ρ'Ηΐ) ε6 · 9' ( ζ Η9 · 3ΐ = ί > 'Ρ'Ηΐ) Ζ3 · 9' ( ζ Η0 · ε'6 · 8 = ί"'ΡΡ'Ηΐ) ΐ8 · 3 '(δ'Ηε) 00 · (S' HS) S6 • S '(z HS'II = f'P'HI) SrS' (z HS'II = f'P'HI) 88 '(ζ Η0 · Ε'9 I = f'PP'HI) 99'S '(ra'HS) „
— 9S ' C"'HS)6rS— ' (ω'Η 8·ΐ— SZ'I'(ra'HS) TI— :軍 9 ( P-OS a)H N-HT — 9S 'C "' HS) 6rS— '(ω'Η 8 · ΐ— SZ'I'(ra'HS) TI—: Military 9 (P-OS a) H NH T
邈 (^ ^ ( / S—べェ ^( /-·^エ / ェ ） - ))→) -Ζ) -8) -ε- (Ή) 邈 (^ ^ (/ S—Bee ^ (/-· ^ e / ee)-)) →) -Ζ) -8) -ε- (Ή)
Zz m [eoeo]  Zz m [eoeo]
( zH2"6=rP'HT)2e"8'(zH9"ei=rP'HT)er8'(s'H2)S8" '(zHS" =rP'H2)S^" '(zH9" =rV (zH2 "6 = rP'HT) 2e" 8 '( z H9 "ei = rP'HT) er8' ( s ' H2) S8"'(zHS"=rP'H2) S ^"' (zH9 "= rV
H2)8S" '(ZHS" =rVHT)2S" '(ZH "8=rP'H2)^" '(ZH2"6=rP'HT) 0" '(ZH "8=rP'H2 H2) 8S "'(ZHS" = rVHT) 2S "' (ZH" 8 = rP'H2) ^ "'(ZH2" 6 = rP'HT) 0 "' (ZH" 8 = rP'H2
)½"9'(zH9"eT=f'P'HT)9e-9'(zH0"S'6"8=rPP'HT)08"S'(s'H2)80"e'(s'HS)66"S'(s'H2)99 •S'(zHS'II=f'P'HI)SrS'(zHS'II=f'P'HI)Z8 '(ζΗ0·ε'9 I=f'PP'HI)99'S'(ra'HS)„ ) ½ "9 '( z H9" eT = f'P'HT) 9e-9' ( z H0 "S'6" 8 = rPP'HT) 08 "S '(s'H2) 80"e' (s 'HS) 66 "S' ( s ' H2) 99S '( z HS'II = f'P'HI) SrS' ( z HS'II = f'P'HI) Z8 '( ζ Η0 · ε' 9 I = f'PP'HI) 99'S '(ra'HS) „
— SS'2'(ui'HS)ZrS— SO ' C"'HS)S8'I— SZ'I'(ra'HS) TI— :軍 9 ( P-OS a)H N-HT — SS '2'(ui'HS) ZrS— SO 'C "' HS) S8'I— SZ'I '(ra'HS) TI—: Military 9 (P-OS a) H NH T
Figure imgf000263_0003
Figure imgf000263_0003
(zHS'8=f'P'HI)S8'8'(zHS'8=f'P'HI)9r8'(zHS'6=f'P'HI)IS'8'(zH9'6=f'P'HI) (zHS'8 = f'P'HI) S8'8 '( z HS'8 = f'P'HI) 9r8' ( z HS'6 = f'P'HI) IS'8 '( z H9'6 = f'P'HI)
2"8'(zH9"eT=rP'HT)6r8'(zH8"Z=rP'HT)26"Z'(ra'He)98"Z-8Z"Z'(ra'H^)0Z"Z-eS"Z'(zH 2 "8 '( z H9" eT = rP'HT) 6r8' ( z H8 "Z = rP'HT) 26" Z '(ra'He) 98 "Z-8Z"Z'(ra'H ^) 0Z "Z-eS" Z '(zH
98S6T0/S00Zdf/X3d 1-93 ZH8"8=rP'HT)S0"8'(zHeT " =rPP'HT)S9" '(ra'HT)½- -S^" '(ZH " =r HT)9S" '(z 98S6T0 / S00Zdf / X3d 1-93 ZH8 "8 = rP'HT) S0" 8 '( z HeT "= rPP'HT) S9"'(ra'HT) ½- -S ^ "'(ZH" = r HT) 9S "' (z
Η8·8=ί"'Ρ'Ηΐ)ε6·9'(ω'Ηε) 8·9— 6S'9'(ra'HI)6 S— ZS'S'(s'H )SS ' (s'HS)SO' (ra'HS)S Η8 · 8 = ί "'Ρ'Ηΐ) ε6 · 9'(ω'Ηε) 8 · 9— 6S'9 '(ra'HI) 6 S— ZS'S'(s'H) SS '( s ' HS) SO '(ra'HS) S
6·ε— ΐΖ·ε'(ω'Η Οΐ·ε— 68 ' (ω'Η )98 — ΐ ' (ω'Η9)^ — OS'I :軍 9 (OQDWH-^ 。 ¾¾Sui08 /— ^ェ（ / — 8—ベ ίί,^Ρ ^E ー —"[—( / — —ベ; ^fi  6 · ε— ΐΖ · ε '(ω'Η Οΐ · ε— 68' (ω'Η) 98 — ΐ '(ω'Η9) ^ — OS'I: Army 9 (OQDWH- ^ ¾¾Sui08 / — ^ (/ — 8—Be ίί, ^ Ρ ^ E ー — ”[— (/ — —Be; ^ fi
( ^エ（ / 9一べ ^^^^ [ 'x][q]
Figure imgf000264_0001
(^ E (/ 9 all ^^^^ ['x] [q]
Figure imgf000264_0001
^u ^nm^ [ χ : χ = ^^m - m 、09 ί 、 ¾^¾
Figure imgf000264_0002
。 >n辛 爵¾瀚缀、 止 s教
Figure imgf000264_0003
^ u ^ nm ^ [χ : χ = ^^ m-m, 09 ί, ¾ ^ ¾
Figure imgf000264_0002
. > n
Figure imgf000264_0003
Figure imgf000264_0004
。 _nfflw、 マ 簠氺 q¾
Figure imgf000264_0005
Figure imgf000264_0004
. _nfflw, ma 簠 氺 q¾
Figure imgf000264_0005
fH 峯 峯氺 、^ (H、 TfiT^o'o邈 4S、Su¾9、 ^ ( /y- fH 峯 峯 氺, ^ (H, TfiT ^ o'o 邈 4S, Su ¾9, ^ (/ y-
Figure imgf000264_0006
Figure imgf000264_0006
zz m^ [8oeo] zz m ^ [8oeo]
(ZHS'6= (ZHS'6 =
ΓΡΉΐ)ε3·8'(ζΗ9·3ΐ=Γ'ΡΉΐ)02·8'(ω'Η2)68· -ΐ8· '(ω'Η5)ε · -ΐ3· '(ΖΗ2·6=ΓΡΉΐ) 60 '(zH9'SI=f'P'HI)ZS'9'(zHS'6=f'P'HI)I8'S'(s'HS)00' (ω'Ηΐ)38·ε— OrS'C"'HS)S ΓΡΉΐ) ε3 ・ 8 '( ζ Η9 ・ 3ΐ = Γ'ΡΉΐ) 02 ・ 8'(ω'Η2) 68 ・ -ΐ8 ・ '(ω'Η5) ε ・ -ΐ3 ・' (ΖΗ2 ・ 6 = ΓΡΉΐ) 60 '( z H9'SI = f'P'HI) ZS'9' ( z HS'6 = f'P'HI) I8'S '(s'HS) 00'(ω'Ηΐ) 38 · ε— OrS'C "'HS) S
9·ε— 6 ·ε'(ω'Η )0ε·ε— 8 ' (ω'Ηΐ)ΟΖ — 6S ' C"'HZ)S — 88·ΐ'(ω'Η3)ΐ8·ΐ— 03·ΐ'(ω'Η 9 · ε— 6 · ε '(ω'Η) 0ε · ε— 8' (ω'Ηΐ) ΟΖ — 6S 'C "' HZ) S — 88 · ΐ '(ω'Η3) ΐ8 · ΐ— 03 · ΐ '(ω'Η
9)9 ·ΐ— Ζΐ·ΐ'(δ'Ηε)86·0'(ω'Ηε)ε6·0— 68·0'(ω'Ηε)Ζ8·0— S8'0:m 9 ( P-OS a)H N-HT 9) 9 · ΐ— Ζΐ · ΐ '( δ ' Ηε) 86 · 0 '(ω'Ηε) ε6 · 0—68 · 0'(ω'Ηε) Ζ8 · 0— S8'0: m 9 (P- OS a) H NH T
m m
/ (^ ( ^- - ^^-Ζ- ( ^エ 1—ベ fi （,^ ^  / (^ (^--^^-Ζ- (^ et 1—be fi (, ^ ^
( -z - ^Δ^Λ^^ - Β8 '8 Ί '9 '9 'ε— ( ^ （ /(-z-^ Δ ^ Λ ^^- Β 8 '8 Ί' 9 '9' ε— (^ (/
/ ェ ）） "[— ^ (Η— Β8 '9 '9)) -Z-^ ^-l) -8) -£- (Ή)
Figure imgf000264_0007
/))) "[— ^ (Η— Β 8 '9' 9)) -Z- ^ ^ -l) -8)-£-(Ή)
Figure imgf000264_0007
98S6T0/S00Zdf/X3d 393 〔s051 98S6T0 / S00Zdf / X3d 393 [S051
Figure imgf000265_0001
Figure imgf000265_0001
IwIw
, P ( ( 2223 ^1I1lο
Figure imgf000266_0001
, P ((2223 ^ 1I1lο
Figure imgf000266_0001
(ΖΗ6·8 (ΖΗ6 ・ 8
=rP'HT)66"Z'(s'HT)96"Z-T6"Z'(ra'HT)98"Z-08"Z'(zH9T6"Z=rPP'HT)S9"Z'(zHS"Z'6"Z  = rP'HT) 66 "Z '(s'HT) 96" Z-T6 "Z' (ra'HT) 98" Z-08 "Z '(zH9T6" Z = rPP'HT) S9 "Z' (zHS "Z'6" Z
=rPP'HT)0^"Z'(zH6"Z=rP'HT)S2-Z'(zH6"8=rP'HT)T6"9'(zH9T6"Z=rPP'HT)88"9'(zH = rPP'HT) 0 ^ "Z '(zH6" Z = rP'HT) S2-Z' (zH6 "8 = rP'HT) T6" 9 '( z H9T6 "Z = rPP'HT) 88"9' ( z H
9·ΐ=ί"'Ρ'Ηΐ)69·9'(ζΗ6 ' S'0I=f'PP'HI)9rS'(s'HS)S0' (S'HS)S S'(ZHS'S'S ΐ=ΓΡΡ 9 · ΐ = ί "'Ρ'Ηΐ) 69 · 9' ( ζ Η6 'S'0I = f'PP'HI) 9rS'(s'HS) S0 '( S ' HS) S S '( Z HS'S'S ΐ = ΓΡΡ
'HI)S0'S'C"'H S6 — ' (ω'Η ΐ8 — C"'H6)( — ： 3} 9 ODaD)H N-H.  'HI) S0'S'C "' H S6 — '(ω'Η ΐ8 — C"' H6) (—: 3} 9 ODaD) H N-H.
一"ェ  One "
( / - 1 - ^·^0Ά ( ^エ（ / — 9 - , ム Ί] ,、 -HZ- si^ - 'ε- ^-ε) -Ζ)→) -Ζ- ^ -s- d ^^-z)-i ^ ^mu (/-1-^ · ^ 0 Ά (^ d (/ — 9-, mu Ί] ,, -HZ- si ^-'ε- ^ -ε) -Ζ) →) -Ζ- ^ -s- d ^^-z) -i ^ ^ mu
Figure imgf000267_0001
Figure imgf000267_0001
εεζ圏第 [sieo] s'HT)02"8'(zH0"6=f'P'HT)66"Z'(ra'HT)98"Z-08"Z'(zHeT6"Z=rPP'HT)S9"Z'(zHS"Z'6"Z εεζ range [sieo] s ' HT) 02 "8 '( z H0" 6 = f'P'HT) 66 "Z'(ra'HT)98" Z-08 "Z '(zHeT6" Z = rPP' HT) S9 "Z '(zHS"Z'6"Z
=rPP'HT)0^"Z'(zH0"6=rP'HT)06"9'(zH2-8=rP'HT)68"9'(zH6T2"8=rPP'HT)28"9'(zH = rPP'HT) 0 ^ "Z '(zH0" 6 = rP'HT) 06 "9' ( z H2-8 = rP'HT) 68" 9 '( z H6T2 "8 = rPP'HT) 28" 9 '( z H
6'I=f'P'HI)S9'9'(zH0'S'r0I=f'PP'HI)9rS'(s'HS)6S ' (s'HS)SO' (ζΗε·ε' ΐ=ΓΡΡ 6'I = f'P'HI) S9'9 '( z H0'S'r0I = f'PP'HI) 9rS'(s'HS) 6S '(s'HS) SO' ( ζ Ηε · ε 'ΐ = ΓΡΡ
'Ηΐ)ΐΟ·ε'(ω'Η 96 — Ϊ8 ' C"'HS)08 — 0rS'C"'H6)69 — ：！^ 9 ( !DaD)H N-HT 。 ¾¾Sui9M/— ^ェ ( / - 1 - ^·^0Ά ( / ェ {^y-9- ^^J ''Ηΐ) ΐΟ · ε'(ω'Η 96 — Ϊ8 'C "' HS) 08 — 0rS'C"'H6) 69 —:! ^ 9 (! DaD) H NH T. ¾¾ Sui9M / — ^ e (/-1-^ · ^ 0 Ά (/ é {^ y-9- ^^ J '
X ] ^>^ - HS - - 'ε- ^-ε) -ζ)→) -ζ- マX] ^> ^-HS--'ε- ^ -ε) -ζ) →) -ζ-
Figure imgf000267_0002
ム
Figure imgf000267_0003
Figure imgf000267_0002
Mu
Figure imgf000267_0003
^ ^ ^ ^ ^ ^。 ·η# ^ οε^翻 sエ^つ。 osi  ^^^^^^. · Η # ^ οε ^ translation. osi
98S6T0/S00Zdf/X3d 993 一般式 [1]の化合物またはその塩は、強い抗菌活性と高い安全性を有することから98S6T0 / S00Zdf / X3d 993 The compound of general formula [1] or a salt thereof has strong antibacterial activity and high safety.
、優れた抗菌剤として有用である。 It is useful as an excellent antibacterial agent.

Claims

請求の範囲 一般式 Claim General Formula
[化 1]  [Chemical 1]
Figure imgf000269_0001
Figure imgf000269_0001
「式中、 R1は、ハロゲン原子、シァノ基、保護されていてもよいカルボキシル基または 置換されていてもよいアルキル、アルコキシもしくはァシルォキシ基を; R2、 R3、 R4お よび R5は、同一または異なって水素原子、ハロゲン原子、シァノ基、保護されていて もよいカルボキシル基または置換されていてもよいアルキル、ァルケ-ル、アルコキシ 、シクロアルキル、ァミノもしくは力ルバモイル基を; Z1および Z2は、窒素原子または C R7「式中、 R7は、水素原子、ハロゲン原子、シァノ基、保護されていてもよいカルボキ シル基または置換されていてもよいアルキル、ァルケ-ル、アルコキシ、ァミノもしくは 力ルバモイル基を意味する。」であり、かつ、 Z1および Z2の少なくとも一方が窒素原子 を; X1は、酸素原子、硫黄原子、スルフィエル基、スルホ-ル基、 NR8a「式中、 R8aは、 水素原子または置換されて 、てもよ 、アルキルもしくはァリール基を意味する。」また は CR9R1C>「式中、 R9および R1C>は、同一または異なって水素原子または置換されて いてもよいアルキル、ヒドロキシル、ァミノもしくはメルカプト基を意味する。」を ;x2は、 カルボニル基、 NR8b「式中、 R8bは、水素原子または置換されていてもよいアルキル もしくはァリール基を意味する。」または結合手を; X3は、 C アルキレン基または結 "Wherein R 1 represents a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkoxy or acyloxy group; R 2 , R 3 , R 4 and R 5 are A hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, cycloalkyl, amino or rubamoyl group; Z 1 and Z 2 represents a nitrogen atom or CR 7 wherein R 7 is a hydrogen atom, a halogen atom, a cyan group, an optionally protected carboxy group or an optionally substituted alkyl, alkenyl, alkoxy, An amino group or a rubamoyl group ”, and at least one of Z 1 and Z 2 represents a nitrogen atom; X 1 represents an oxygen atom, a sulfur atom, Fier group, sulfol group, NR 8a [wherein R 8a represents a hydrogen atom or a substituted or optionally alkyl or aryl group] or CR 9 R 1C> “wherein R 9 and R 1C> are the same or different and represent a hydrogen atom or an optionally substituted alkyl, hydroxyl, amino or mercapto group. ”; X 2 represents a carbonyl group, NR 8b , wherein R 8b Represents a hydrogen atom or an optionally substituted alkyl or aryl group, or a bond; X 3 represents a C alkylene group or a bond.
1-4  1-4
合手を; R6は、一般式 The Gote; R 6 has the general formula
[化 2]
Figure imgf000270_0001
[Chemical 2]
Figure imgf000270_0001
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を; Rlla、 Rllbおよび Rlleは、同一または異なって水素原 子、ハロゲン原子、保護されていてもよいヒドロキシルもしくはカルボキシル基または 置換されていてもよいアミ入低級アルキル、アルコキシもしくは力ルバモイル基を; R1 2は、一般式 "Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group; R lla , R llb and R lle are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino-substituted lower alkyl, alkoxy or rubamoyl group; R 1 2 is the general formula
[化 3] 一 X6— X4一 R14 [Chemical 3] One X 6 — X 4 One R 14
、 ,
Figure imgf000270_0002
Figure imgf000270_0002
「式中、 R14は、水素原子、保護されていてもよいカルボキシル基または置換されてい てもよぃシクロアルキル、シクロアルケ-ル、アルアルキル、ァリールもしくは複素環式 基を; X4は、酸素原子、硫黄原子、カルボニル基または結合手を; X5は、置換されて いてもよいアルキレン基または結合手を; X6は、置換されていてもよいアルキレン、ァ ルケ-レンもしくはアルキ-レン基またはスルホ -ル基を; X7は、置換されていてもよ いアルキレン基または結合手を意味する。」で表される基を; R13は、水素原子、ァミノ 基の保護基または置換されていてもよいアルキルもしくはァリール基を意味する。」を 意味する。」で表される含窒素複素環化合物またはその塩。 "Wherein R 14 represents a hydrogen atom, an optionally protected carboxyl group or an optionally substituted cycloalkyl, cycloalkyl, aralkyl, aryl or heterocyclic group; X 4 represents oxygen An atom, a sulfur atom, a carbonyl group or a bond; X 5 is an optionally substituted alkylene group or a bond; X 6 is an optionally substituted alkylene, alkylene or alkylene group. X 7 represents an optionally substituted alkylene group or a bond; and R 13 represents a hydrogen atom, an amino group protecting group or a substituted group; Means an alkyl or aryl group which may be "Means. Or a salt thereof.
[2] Z1および Z2が、窒素原子または CR7「式中、 R7は、水素原子、ハロゲン原子、シァノ 基、保護されていてもよいカルボキシル基または置換されていてもよいアルキル、ァ ルケニル、アルコキシ、ァミノもしくは力ルバモイル基を意味する。」であり、かつ、 Z1 および Z2の少なくとも一方が窒素原子; R6力 一般式 [2] Z 1 and Z 2 are a nitrogen atom or CR 7 wherein R 7 is a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, Means a rukenyl, alkoxy, amino or force rubamoyl group, and at least one of Z 1 and Z 2 is a nitrogen atom; R 6 force general formula
Figure imgf000271_0001
Figure imgf000271_0001
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を; Rlla、 Rllbおよび Rlleは、同一または異なって水素原 子、ハロゲン原子、保護されていてもよいヒドロキシルもしくはカルボキシル基または 置換されていてもよいアミ入低級アルキル、アルコキシもしくは力ルバモイル基を; R1 2aは、一般式 "Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group; R lla , R llb and R lle are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino-substituted lower alkyl, alkoxy or rubamoyl group; R 1 2a is the general formula
[化 5]
Figure imgf000271_0002
[Chemical 5]
Figure imgf000271_0002
、 H または H  , H or H
「式中、 R14aは、置換されていてもよいアルアルキル、単環の複素環式または二環式 の複素環式基を; X4は、酸素原子、硫黄原子、カルボ-ル基または結合手を; X5は、 置換されていてもよいアルキレン基または結合手を; X6aは、アルキレン基を意味する o」で表される基を; R13は、水素原子、ァミノ基の保護基または置換されていてもよい アルキルもしくはァリール基を意味する。」で表される基;ただし、 Z2が CR7の場合、 R6 が、一般式 "Wherein R 14a represents an optionally substituted aralkyl, monocyclic heterocyclic or bicyclic heterocyclic group; X 4 represents an oxygen atom, sulfur atom, carbo group or bond X 5 represents an optionally substituted alkylene group or a bond; X 6a represents an alkylene group; a group represented by “o”; R 13 represents a protecting group for a hydrogen atom or an amino group; Or an optionally substituted alkyl or aryl group. Wherein Z 2 is CR 7 and R 6 is a general formula
[化 6]
Figure imgf000272_0001
[Chemical 6]
Figure imgf000272_0001
-N. . R12a -N.. R 12a
または  Or
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を; Rlla、 Rllbおよび Rlleは、同一または異なって水素原 子、ハロゲン原子、保護されていてもよいヒドロキシルもしくはカルボキシル基または 置換されていてもよいアミ入低級アルキル、アルコキシもしくは力ルバモイル基を; R1 2aは、一般式 "Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group; R lla , R llb and R lle are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino-substituted lower alkyl, alkoxy or rubamoyl group; R 1 2a is the general formula
[化 7]
Figure imgf000272_0002
または H [Chemical 7]
Figure imgf000272_0002
Or H
「式中、 R は、置換されていてもよいアルアルキル、単環の複素環式または二環式 の複素環式基を; X4は、酸素原子、硫黄原子、カルボ-ル基または結合手を; X5は、 置換されていてもよいアルキレン基または結合手を; X6aは、アルキレン基を意味する 。」で表される基を; R13は、水素原子、ァミノ基の保護基、または置換されていてもよ いアルキルもしくはァリール基を意味する。」で表される基である請求項 1記載の含窒 素複素環化合物またはその塩。 “Wherein R represents an optionally substituted aralkyl, monocyclic heterocyclic or bicyclic heterocyclic group; X 4 represents an oxygen atom, a sulfur atom, a carbo group or a bond. X 5 represents an optionally substituted alkylene group or a bond; X 6a represents an alkylene group; a group represented by R 13 represents a hydrogen atom, an amino group protecting group, Or an alkyl or aryl group which may be substituted. The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1, which is a group represented by:
[3] R1が、ハロゲン原子、シァノ基または置換されていてもよいアルキル、アルコキシもし くはァシルォキシ基; R2、 R3、 R4および R5力 同一または異なって水素原子、ハロゲ ン原子、シァノ基、保護されていてもよいカルボキシル基または置換されていてもよい アルキル、ァルケ-ル、アルコキシ、ァミノもしくは力ルバモイル基; Z1および Z2が、窒 素原子または CR7「式中、 R7は、水素原子、ハロゲン原子、シァノ基、保護されてい てもよいカルボキシル基または置換されていてもよいアルキル、ァルケ-ル、アルコキ シ、ァミノもしくは力ルバモイル基を意味する。」であり、かつ、 Z1および Z2の少なくとも 8a 一方が窒素原子; Xが、酸素原子、硫黄原子、スルフィエル基、スルホ-ル基、 NR: 「式中、 R8aは、水素原子または置換されていてもよいアルキルもしくはァリール基を 意味する。」または CR9aR1C>a「式中、 R9aおよび R1C>aは、同一または異なって水素原子 または置換されていてもよいヒドロキシル、ァミノもしくはメルカプト基を意味する。」； R 6が、一般式 [3] R 1 is a halogen atom, a cyano group, or an optionally substituted alkyl, alkoxy or acyloxy group; R 2 , R 3 , R 4 and R 5 force the same or different, a hydrogen atom, a halogen atom , A cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, amino or rubamoyl group; Z 1 and Z 2 are a nitrogen atom or CR 7 R 7 represents a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group, or an optionally substituted alkyl, alkenyl, alkoxy, amino or rubamoyl group. And at least Z 1 and Z 2 8a One is a nitrogen atom; X is an oxygen atom, a sulfur atom, a sulfiel group, a sulfole group, NR : “wherein R 8a means a hydrogen atom or an optionally substituted alkyl or aryl group. "or CR 9a R 1C> in a" wherein, R 9a and R 1C> a are the same or different and each represents a hydrogen atom or an optionally substituted hydroxyl, means Amino or mercapto group ";. R 6 is, General formula
[化 8] [Chemical 8]
Figure imgf000273_0001
Figure imgf000273_0001
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を; Rlla、 Rllbおよび Rlleは、同一または異なって水素原 子、ハロゲン原子、保護されていてもよいヒドロキシルもしくはカルボキシル基または 置換されていてもよいアミ入低級アルキル、アルコキシもしくは力ルバモイル基を; R1 2bは、一般式 "Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group; R lla , R llb and R lle are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino-substituted lower alkyl, alkoxy or rubamoyl group; R 1 2b is the general formula
[化 9]
Figure imgf000273_0002
[Chemical 9]
Figure imgf000273_0002
「式中、 RMbは、置換されていてもよい単環の複素環式または二環式の複素環式基 を; X4aは、酸素原子、硫黄原子または結合手を; mは、 1—4の整数を意味する。」で 表される基を; R13aは、水素原子または置換されて ヽてもよ 、アルキルもしくはァリー ル基を意味する。」で表される基;ただし、 Z2が CR7の場合、 R6が、一般式 "Wherein R Mb represents an optionally substituted monocyclic heterocyclic or bicyclic heterocyclic group; X 4a represents an oxygen atom, a sulfur atom or a bond; m represents 1— R 13a represents a hydrogen atom or an optionally substituted alkyl or aryl group. Wherein Z 2 is CR 7 and R 6 is a general formula
[化 10]
Figure imgf000274_0001
[Chemical 10]
Figure imgf000274_0001
— N R12b — NR 12b
または X R 11 Or X R 11
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を; Rlla、 Rllbおよび Rlleは、同一または異なって水素原 子、ハロゲン原子、保護されていてもよいヒドロキシルもしくはカルボキシル基または 置換されていてもよいアミ入低級アルキル、アルコキシもしくは力ルバモイル基を; R1 2bは、一般式 "Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group; R lla , R llb and R lle are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino-substituted lower alkyl, alkoxy or rubamoyl group; R 1 2b is the general formula
[化 11]
Figure imgf000274_0002
[Chemical 11]
Figure imgf000274_0002
「式中、 RMbは、置換されていてもよい単環の複素環式または二環式の複素環式基 を; X4aは、酸素原子、硫黄原子または結合手を; mは、 1—4の整数を意味する。」で 表される基を; R13aは、水素原子または置換されて 、てもよ 、アルキルもしくはァリー ル基を意味する。」で表される基である請求項 1または 2記載の含窒素複素環化合物 またはその塩。 "Wherein R Mb represents an optionally substituted monocyclic heterocyclic or bicyclic heterocyclic group; X 4a represents an oxygen atom, a sulfur atom or a bond; m represents 1— . which means 4 integer a group represented by "; R 13a is a hydrogen atom or substituted, by also refers to alkyl or Ari Le group. The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1 or 2, wherein the group is a group represented by the formula:
[4] Z1および Z2のいずれか一方力 窒素原子;他方が、 CR7「式中、 R7は、水素原子、ハ ロゲン原子、シァノ基、保護されていてもよいカルボキシル基または置換されていても よいアルキル、ァルケ-ル、アルコキシ、ァミノもしくは力ルバモイル基を意味する。」 である請求項 1〜3記載の含窒素複素環化合物またはその塩。 [4] One of Z 1 and Z 2 is a nitrogen atom; the other is CR 7 "wherein R 7 is a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or a substituted group. Or a salt thereof. 4. The nitrogen-containing heterocyclic compound or a salt thereof according to any one of claims 1 to 3, which may be an alkyl, alkaryl, alkoxy, amino, or rubamoyl group.
[5] R6が、一般式 [5] R 6 is a general formula
[化 12]
Figure imgf000274_0003
または N 1 「式中、 R12bは、一般式 [Chemical 12]
Figure imgf000274_0003
Or N 1 "Wherein R 12b is a general formula
[化 13]
Figure imgf000275_0001
または [Chemical 13]
Figure imgf000275_0001
Or
「式中、 RMbは、置換されていてもよい単環の複素環式または二環式の複素環式基 を; X4aは、酸素原子、硫黄原子または結合手を; mは、 1—4の整数を意味する。」を 意味する。」で表される基である請求項 1〜4記載の含窒素複素環化合物またはその 塩。 "Wherein R Mb represents an optionally substituted monocyclic heterocyclic or bicyclic heterocyclic group; X 4a represents an oxygen atom, a sulfur atom or a bond; m represents 1— Means an integer of 4. " The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1, which is a group represented by the formula:
[6] X1が、 NR8a「式中、 R8aは、水素原子または置換されていてもよいアルキルもしくはァ リール基を意味する。」または CR9aR1C>a「式中、 R9aおよび R1C>aは、同一または異なつ て水素原子または置換されて 、てもよ 、ヒドロキシル、ァミノもしくはメルカプト基を意 味する。」；X2が、カルボ-ル基または結合手; R1が、置換されていてもよいアルコキ シ基; R2、 R3、 R4および R5が、同一または異なって水素原子、保護されていてもよい カルボキシル基または置換されて!、てもよ!/、アルキルもしくはァルケ-ル基である請 求項 1〜5記載の含窒素複素環化合物またはその塩。 [6] X 1 is NR 8a “wherein R 8a means a hydrogen atom or an optionally substituted alkyl or aryl group” or CR 9a R 1C> a “wherein R 9a and R 1C> a is the same or different and represents a hydrogen atom or a substituted, optionally hydroxyl, amino or mercapto group. ”; X 2 is a carbo group or a bond; R 1 is , An optionally substituted alkoxy group; R 2 , R 3 , R 4 and R 5 may be the same or different from each other, a hydrogen atom, an optionally protected carboxyl group, or a substituted! And a nitrogen-containing heterocyclic compound or a salt thereof according to claims 1 to 5, which is an alkyl group or an alkyl group.
[7] R3または R4の少なくとも一方が、ハロゲン原子、保護されて!、てもよ 、カルボキシル 基または置換されていてもよい力ルバモイル、アルキル、ァルケ-ルもしくはシクロア ルキル基; Z1が、窒素原子; Z2が、 CR7「式中、 R7は、水素原子、ハロゲン原子、シァ ノ基、保護されていてもよいカルボキシル基または置換されていてもよいアルキル、ァ ルケ-ル、アルコキシ、ァミノもしくは力ルバモイル基を意味する。」； R6が、一般式 [7] At least one of R 3 and R 4 is a halogen atom, protected !, may be a carboxyl group or an optionally substituted rubamoyl, alkyl, alkenyl, or cycloalkyl group; Z 1 is , A nitrogen atom; Z 2 is CR 7 wherein R 7 is a hydrogen atom, a halogen atom, a cyan group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, Means an alkoxy, an amino or a power rubermoyl group. "; R 6 is of the general formula
[化 14]
Figure imgf000275_0002
[Chemical 14]
Figure imgf000275_0002
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を； R12は、一般式 “Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino-substituted lower alkyl, alkoxy or forceful rubamoyl group; R 12 is a general formula
[化 15] 一 X6— X4— R1 4 [Chemical 15] One X 6 — X 4 — R 1 4
Figure imgf000276_0001
Figure imgf000276_0001
または  Or
「式中、 R14は、水素原子、保護されていてもよいカルボキシル基または置換されてい てもよぃシクロアルキル、シクロアルケ-ル、アルアルキル、ァリールもしくは複素環式 基を; X4は、酸素原子、硫黄原子、カルボニル基または結合手を; X5は、置換されて いてもよいアルキレン基または結合手を; X6は、置換されていてもよいアルキレン、ァ ルケ-レンもしくはアルキ-レン基またはスルホ -ル基を; X7は、置換されていてもよ いアルキレン基または結合手を意味する。」で表される基を; R13は、水素原子、ァミノ 基の保護基または置換されて 、てもよ 、アルキルもしくはァリール基を意味する。」で 表される基である請求項 1記載の含窒素複素環化合物またはその塩。 "Wherein R 14 represents a hydrogen atom, an optionally protected carboxyl group or an optionally substituted cycloalkyl, cycloalkyl, aralkyl, aryl or heterocyclic group; X 4 represents oxygen An atom, a sulfur atom, a carbonyl group or a bond; X 5 is an optionally substituted alkylene group or a bond; X 6 is an optionally substituted alkylene, alkylene or alkylene group. X 7 represents an optionally substituted alkylene group or a bond; and R 13 represents a hydrogen atom, an amino group protecting group or a substituted group; Or may mean an alkyl or aryl group. The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1, which is a group represented by:
[8] R3が、水素原子; R4が、保護されて 、てもよ 、カルボキシル基、保護されて 、てもよ V、カルボキシル基で置換されて!、るアルキル、ァルケ-ルもしくはシクロアルキル基 または置換されて 、てもよ 、力ルバモイル基で置換されて 、るアルキルもしくはアル ケニル基で表される請求項 1または 7記載の含窒素複素環化合物またはその塩。 [8] R 3 is a hydrogen atom; R 4 is protected, may be a carboxyl group, protected, may be V, substituted with a carboxyl group !, alkyl, alkenyl, or cyclo The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1 or 7, wherein the nitrogen-containing heterocyclic compound or a salt thereof is represented by an alkyl group or a substituted or a substituted rubamoyl group and an alkyl or alkenyl group.
[9] R4が、保護されて!、てもよ 、カルボキシル基で置換されて 、るアルケニル基; R6が、 一般式 [9] R 4 is protected !, which may be substituted with a carboxyl group and an alkenyl group; R 6 is a group represented by the general formula:
[化 16]
Figure imgf000276_0002
[Chemical 16]
Figure imgf000276_0002
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を; R12eは、一般式 "Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group; R 12e is the general formula
[化 17]
Figure imgf000277_0001
[Chemical 17]
Figure imgf000277_0001
H または  H or
「式中、 RMeは、置換されていてもよいァリール、単環の複素環式または二環式の複 素環式基を; X4aは、酸素原子、硫黄原子または結合手を; x6bは、置換されていても よいアルキレン、ァルケ-レンまたはアルキ-レン基を意味する。」で表される基を; R 13aは、水素原子または置換されていてもよいアルキルもしくはァリール基を意味する 。」で表される請求項 1、 7または 8記載の含窒素複素環化合物またはその塩。 “Wherein R Me represents an optionally substituted aryl, monocyclic heterocyclic or bicyclic bicyclic group; X 4a represents an oxygen atom, sulfur atom or bond; x 6b Represents an optionally substituted alkylene, alkene or alkylene group. ”R 13a represents a hydrogen atom or an optionally substituted alkyl or aryl group. . The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1, 7 or 8, wherein
が、アルコキシ基; R2および R5力 水素原子; R6が、一般式 Is an alkoxy group; R 2 and R 5 forces hydrogen atom; R 6 is a compound of the general formula
[化 18]
Figure imgf000277_0002
[Chemical 18]
Figure imgf000277_0002
「式中、 R11は、 1つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシ ルもしくはカルボキシル基または置換されていてもよいアミ入低級アルキル、アルコ キシもしくは力ルバモイル基を; R14eは、置換されていてもよいァリール、単環の複素 環式または二環式の複素環式基を; X6eは、置換されていてもよいアルキレン基を意 味する。」で表される基である請求項 1または 7〜9記載の含窒素複素環化合物また はその塩。 "Wherein R 11 represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino-substituted lower alkyl, alkoxy or force rubermoyl group; R 14e represents an optionally substituted aryl, monocyclic heterocyclic or bicyclic heterocyclic group; X 6e represents an optionally substituted alkylene group. The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1 or 7 to 9, which is a group.
請求項 1〜10記載の含窒素複素環化合物を含有する抗菌剤。 An antibacterial agent containing the nitrogen-containing heterocyclic compound according to claim 1.
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