WO1998027108A2 - New amide compounds and their use as nitric oxide synthase inhibitors - Google Patents

New amide compounds and their use as nitric oxide synthase inhibitors Download PDF

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Publication number
WO1998027108A2
WO1998027108A2 PCT/JP1997/004243 JP9704243W WO9827108A2 WO 1998027108 A2 WO1998027108 A2 WO 1998027108A2 JP 9704243 W JP9704243 W JP 9704243W WO 9827108 A2 WO9827108 A2 WO 9827108A2
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Prior art keywords
preparation
group
phenyl
alkyl
nmr
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PCT/JP1997/004243
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French (fr)
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WO1998027108A3 (en
Inventor
Yoshikuni Itoh
Takayuki Inoue
Hitoshi Hamashima
Ichiro Shima
Kazuhiko Ohne
Kousei Yoshihara
Teruo Oku
Takumi Yatabe
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
YATABE, Yoshiko
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Priority claimed from AUPO4219A external-priority patent/AUPO421996A0/en
Priority claimed from AUPO5929A external-priority patent/AUPO592997A0/en
Priority claimed from AUPO9030A external-priority patent/AUPO903097A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd., YATABE, Yoshiko filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP52752898A priority Critical patent/JP2001505585A/en
Priority to EP97912529A priority patent/EP0946587A2/en
Priority to AU49680/97A priority patent/AU4968097A/en
Publication of WO1998027108A2 publication Critical patent/WO1998027108A2/en
Publication of WO1998027108A3 publication Critical patent/WO1998027108A3/en

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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • TECHNICAL FIELD This invention relates to new amide compounds and pharmaceutically acceptable salts thereof which are useful as medicament.
  • This invention relates to new amide compounds.
  • One object of this invention is to provide the new and useful amide compounds and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of nitric oxide (NO).
  • Another object of this invention is to provide a process for the preparation of the amide compounds and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said amide compound or a pharmaceutically acceptable salt thereof.
  • Still further object of this invention is to provide a use of said amide compounds or pharmaceutically acceptable salts thereof as a medicament for prophylactic and therapeutic treatment of NO-mediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock (e.g., septic shock, etc.), diabetes (e.g., insulin-dependent diabetes mellitus, etc.), diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.), cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, derma
  • R 1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbaoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
  • R 2 is hydrogen or phenyl(lower)alkyl
  • R* is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, quinolyl or 3,4-methylenedioxyphenyl;
  • R 5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
  • R 7 and R 8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
  • Y is a group of the formula
  • R 3 is hydrogen or a group of the formula -(CH 2 ) consult-R 6 in which R 6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
  • R 11 is phenyl, phenoxy or phenyl(lower)alkoxy; or R 2 and R 3 in combination form a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof, provided that the compound shown below is excluded: a compound of the formula
  • R 1 ' is indolyl or benzofuranyl
  • R 2 ' is hydrogen, lower alkylthio(lower)alkyl or a group of the formula
  • R 5 ' is hydrogen, lower alkoxy or halogen
  • R 3 ' is hydrogen, quinolyl or phenyl which may have a suitable substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen
  • R*' is hydrogen or optionally esterified carboxy
  • X' is S or NR 6 ' in which R 6 ' is hydrogen, lower alkyl or a group of the formula - CH2 - ⁇ JT
  • R 7 ' is lower alkyl or lower alkoxy, and a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an inorganic acid addition salt e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g., arginine, aspartic acid, gultamic acid, etc.
  • lower is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
  • Suitable "lower alkoxy” and “lower alkoxy moiety" in the terms “lower alkoxy(lower)alkoxy” and “phenyl(lower) lkoxy” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy and hexyloxy, in which more preferred one is Ci-C* alkoxy.
  • Suitable "halogen” includes, for example, fluorine, bromine, chlorine and iodine.
  • Optionally esterified carboxy includes carboxy and esterified carboxy. Suitable examples of said ester include lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1 -methoxyethyl ester, 1 -ethoxyethyl ester, etc.); mono(or
  • Suitable "trihalomethyl” includes, for example, trifluoromethyl, trichloromethyl and tribromomethyl, in which preferred one is trifluoromethyl.
  • Suitable “amino protective group” includes, for example, acyl and conventional protective group such as mono(or di or tri)aryl(lower)- alkyl, for example, mono(or di or tri)phenyl(lower)alkyl (e.g., benzyl, trityl, etc.).
  • acyl and “acyl moiety” in the terms “acylamino”, “diacylamino” and “acylamino(lower)alkyl” include, for example, carbamoyl which may be substituted by suitable substituent(s), aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl.
  • acyl which may be substituted by suitable substituent(s)
  • substituent(s) includes a group of the formula
  • R 12 and R 13 are the same or different and each is hydrogen, lower alkyl, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, phenyl(lower)- alkyl, pyridyl, pyridyl(lower)alkyl or 3,4-methylenedioxyphenyl; aliphatic acyl such as lower alkanoyl which may be substituted by one to three halogen atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, trichloroacetyl, trifluoroacetyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert- pentyl
  • naphthyl(lower)alkanoyl e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.
  • aryl(lower)alkoxycarbonyl e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.
  • aryloxycarbonyl e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.
  • aryloxy(lower)alkanoyl e.g., phenoxyacetyl, phenoxypropionyl, etc.
  • arylsulfonyl e.g., phenylsulfonyl, p-tolylsufonyl, etc.
  • heterocyclic acyl such as indolylcarbonyl (e.g., indolylcarbon
  • Optionally protected hydroxy includes hydroxy and protected hydroxy.
  • Suitable examples of "hydroxy protective group" in the term “protected hydroxy” include acyl (e.g., acetyl, trichloroacetyl, etc.), mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
  • acyl e.g., acetyl, trichloroacetyl, etc.
  • mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (
  • Suitable "protected carboxy” is carboxy group protected by conventional protective group such as lower alkoxycarbonyl [e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.], optionally substituted phenyl(lower)- alkoxycarbonyl for example, mono- or di- or triphenyl(lower)- alkoxycarbonyl which may be substituted by nitro [e.g., benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, etc.] and the like.
  • lower alkoxycarbonyl e.g., methoxycarbonyl,
  • Suitable "cyclo(lower)alkyl” includes cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in which more preferred ones are cyclopropyl and cyclobutyl.
  • morpholinyl includes 2-morpholinyl, 3-morpholinyl and 4-morpholinyl (i.e. morpholino).
  • piperidyl includes 1 -piperidyl (i.e. piperidino), 2- piperidyl, 3-piperidyl and 4-piperidyl.
  • the object compound (I) of the present invention can be prepared by the following processes.
  • R 1 , R 2 , R ft , R 5 , R 7 , R 8 , R 9 , X, Y, m and n are each as l 7 defined above,
  • R 1 * is amino protective group
  • R 15 is hydrogen or lower alkyl
  • R 16 is acyl
  • R 1 is acylamino or diacylamino
  • R 18 is carboxy or lower alkoxycarbonyl
  • R 19 is esterified carboxy
  • R 20 is acylamino or diacylamino
  • R 21 is carbamoyl which may be substituted by suitable substituent(s)
  • R 22 is hydroxy protective group
  • R 23 is acyl
  • R 2 * is lower alkyl
  • R 25 is protected carboxy
  • R 26 is esterified carboxy
  • R 27 is carbamoyl which may be substituted by suitable substituent(s)
  • R 28 is acylamino or diacylamino
  • R 29 is acyl
  • R 30 is esterified carboxy.
  • the starting compounds can be prepared by the method of Preparation mentioned below or by a process known in the art for preparing their structually analogous compounds.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group, or a salt thereof with the compound (III) or its reactive derivative at the
  • Suitable reactive derivative of the compound (II) includes Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,0- bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene.
  • Suitable reactive derivative of the compound (III) includes an acid halide, an acid anhydride and an activated ester.
  • the suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'- dicyclohexylcarbodiimide; N-cyclohexyl-N' -morpholinoethylcarbodiimide; N-cyclohexyl-N' -(4-diethylaminocyclohexyl)carbodiimide; N,N' - diisopropylcarbodiimide; N-ethyl-N' -(3-dimethylaminopropyl)- carbodiimide; N,N-carbonyl-bis-(2-methylimidazole) ; pentamethylene- ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 -alkoxy-1 -chloroethylene; trialkyl pho
  • the reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine, or the like.
  • an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (I)-1 or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (IV).
  • the reaction can be carried out in the same manner as in or a manner similar to Example 27.
  • the compound (I)-2 or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to elimination reaction of the amino protective group.
  • Suitable method of this elimination reaction includes conventional one such as hydrolysis, reduction and the like, (i) For hydrolysis :
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base includes an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1 ,5-diazabicyclo[ .3.0]non-5-one, or the like.
  • an alkali metal e.g., sodium, potassium, etc.
  • an alkaline earth metal e.g., magnesium, calcium, etc.
  • trialkylamine e.g., trimethylamine, triethylamine, etc.
  • picoline 1 ,5-diazabicyclo[ .3.0]non-5-one, or the like.
  • Suitable acid includes an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
  • organic acid e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
  • Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid, trifluoroacetic acid, etc.], or the like is preferably carried out in the presence of cation trapping agents [e.g., anisole, phenol, etc.]. This reaction is usually carried out without solvent.
  • the reaction may be carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • reaction temperature is not critical and the reaction is usually carried out under cooling to warming, (ii) For reduction :
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.), or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
  • a metal e.g., tin, zinc, iron, etc.
  • metallic compound e.g., chromium chloride, chromium acetate, etc.
  • organic acid or inorganic acid e.g., formic acid, acetic acid, propionic acid,
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.
  • platinum catalysts e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.
  • nickel catalysts e.g., reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalysts e.g., reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g., reduced iron, Raney iron, Ullman iron, etc.
  • the reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • alcohol e.g., methanol, ethanol, isopropyl alcohol, etc.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (I)-4 or a salt thereof can be prepared by reacting the compound (I) ⁇ 3 or its reactive derivative at the amino group, or a salt thereof with the compound (VI) or its reactive derivative at the carboxy group, or a salt thereof.
  • This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (1 ) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process ⁇ .
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (I)-6 or a salt thereof can be prepared by subjecting the compound (I)-5 or a salt thereof to reduction.
  • the reduction can be carried out in the same manner as in or a manner similar to Example 60.
  • the compound (I)-7 or a salt thereof can be prepared by subjecting the compound (I)-6 or a salt thereof to acylation.
  • the acylation can be carried out in the same manner as in or a manner similar to Example 61.
  • the compound (I)-9 or a salt thereof can be prepared by subjecting the compound (I)-8 or a salt thereof to reduction.
  • the reduction can be carried out in the same manner as in or a manner similar to Example 111.
  • the compound (I)-10 or a salt thereof can be prepared by subjecting the compound (I)-9 or a salt thereof to oxidation.
  • the oxidation can be carried out in the same manner as in or a manner similar to Example 112.
  • the compound (I)-12 or a salt thereof can be prepared by subjecting the compound (I)-11 or a salt thereof to hydrolysis.
  • the hydrolysis can be carried out in the same manner as in or a manner similar to Example 113.
  • the compound (I)-14 or a salt thereof can be prepared by subjecting the compound (I)-13 or a salt thereof to reduction.
  • the reduction can be carried out in the same manner as in or a manner similar to Example 123.
  • the compound (I)-15 or a salt thereof can be prepared by subjecting the compound (I)-14 or a salt thereof to acylation.
  • the acylation can be carried out in the same manner as in or a manner similar to Example 124.
  • the compound (I)-16 or a salt thereof can be prepared by subjecting the compound (I)-12 or a salt thereof to amidation.
  • the compound (I)-18 or a salt thereof can be prepared by subjecting the compound (I)-17 or a salt thereof to elimination reaction of the hydroxy protective group.
  • This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc. ) can be referred to those of the Process (3).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (I)-19 or a salt thereof can be prepared by subjecting the compound (I)-18 or a salt thereof to esterification.
  • the esterification can be carried out in the same manner as in or a manner similar to Example 133.
  • the compound (I)-20 or a salt thereof can be prepared by subjecting the compound (I)-18 or a salt thereof to 0-alkylation.
  • the 0-alkylation can be carried out in the same manner as in or a manner similar to Example 135.
  • the compound (I)-22 or a salt thereof can be prepared by subjecting the compound (I)-21 or a salt thereof to elimination reaction of the carboxy protective group.
  • This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (I)-23 or a salt thereof can be prepared by subjecting the compound (I)-22 or a salt thereof to esterification.
  • the esterification can be carried out in the same manner as in or a manner similar to Example 74.
  • the compound (I)-24 or a salt thereof can be prepared by subjecting the compound (I)-22 or a salt thereof to amidation.
  • the amidation can be carried out in the same manner as in or a manner similar to Example 95.
  • the compound (I)-26 or a salt thereof can be prepared by subjecting the compound (I)-25 or a salt thereof to reduction.
  • the reduction can be carried out in the same manner as in or a manner similar to Example 119.
  • the compound (I)-27 or a salt thereof can be prepared by subjecting the compound (I)-26 or a salt thereof to acylation.
  • the acylation can be carried out in the same manner as in or a manner similar to Example 120.
  • the compound (I)-29 or a salt thereof can be prepared by subjecting the compound (I)-28 or a salt thereof to esterification.
  • the esterification can be carried out in the same manner as in or a manner similar to Example 138.
  • the compound (I)-31 or a salt thereof can be prepared by subjecting the compound (I)-30 or a salt thereof to hydrolysis.
  • the hydrolysis can be carried out in the same manner as in or a manner similar to Example 168.
  • the compound (I)-32 or a salt thereof can be prepared by reacting the compound (I)-31 or its reactive derivative at the carboxy group, or a salt thereof with the compound (VII) or its reactive derivative at the amino group, or a salt thereof.
  • This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (1 ) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process
  • the compound (I)-33 can be prepared by reacting the compound (VIII) with the compound (IX) in the presence of an acid.
  • This reaction can be carried out in the same manner as in or a manner similar to Example 178.
  • Suitable salts of the starting compounds and their reactive derivatives in Process (1) can be referred to the ones as exemplified for the compound (I).
  • the compounds obtained by the above process can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the compound (I) and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.
  • the object compounds (I) and pharmaceutically acceptable salts thereof include solvates [e.g., enclosure compounds (e.g., hydrate, etc.)].
  • the object compounds (I) and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO).
  • the object compounds (I) and pharmaceutically acceptable salts thereof are expected to possess a nitric oxide synthase (NOS)-inhibitory activity or a NOS-production inhibitory activity.
  • NOS nitric oxide synthase
  • NO-mediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock (e.g., septic shock, etc.), diabetes (e.g., insulin-dependent diabetes mellitus, etc.), diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.), cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, dermatitis, hepatitis, liver cirrhosis, multiple sclerosis, pancrea
  • test Compounds In order to illustrate the usefulness of the object compound (I) , the pharmacological test result of the representative compound of the compound (I) is shown in the following. Test Compounds :
  • RAW264.7 American Type Culture Collection, No. TTB71
  • DMEM Dulbecco's modified Eagle's medium
  • penicillin, streptomycin and 10$ heat-inactivated fetal bovine serum were removed from culture flasks by rubber cell scraper and were centrifuged and resuspended in DMEM without phenol red. They were plated in 96-well microtiter plates (10 5 cells per well) and allowed to adhere over 2 hours.
  • test samples were added and the cells were preincubated for 1 hour. Thereafter the cells were activated with both of lipopolysaccharide (LPS) (1/zg/ml) and interferon ⁇ (INF ) (3 u/ml) for 18-24 hours.
  • LPS lipopolysaccharide
  • INF interferon ⁇
  • An equal volume of Griess reagent ( ] % sulfanilamide/0.1/ ⁇ N-naphthylethylenediamine dihydrochloride/2.5% H3PO1*) was added and the cells were incubated at room temperature for 10 minutes. The absorbance was read at 570 nm using microplate reader and NO ⁇ " was measured using NaNO ⁇ as a standard.
  • the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are used in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • the pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee, suppository or ointment, or in a liquid form such as solution, suspension or emulsion for injection, intravenous drip, ingestion, eye drop, etc.
  • auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered in a unit dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, body weight and conditions of the patient or administering method.
  • R 1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two
  • R 2 is hydrogen or phenyl(lower)alkyl
  • R* is phenyl or pyridyl, each of which has suitable substituent(s) selected from the group consisting of trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazoly1, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, or 3, -methylenedioxyphenyl;
  • R 5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
  • R 7 and R 8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
  • Y is a group of the formula
  • R 6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower) lkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
  • R 1 ' is phenyl, phenoxy or phenyl(lower)alkoxy; or R 2 and R 3 in combination form a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
  • R 1 is indolyl which has a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
  • R 2 is hydrogen or phenyl(lower)alkyl
  • R ft is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen or quinolyl;
  • R 5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
  • R 7 and R 8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
  • Y is a group of the formula
  • R 6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
  • R 1 ' is phenyl, phenoxy or phenyl(lower)alkoxy; or R 2 and R 3 in combination form a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
  • R 1 is indolyl or benzofuranyl
  • R 2 is hydrogen or phenyl(lower) lkyl
  • R* is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen or quinolyl;
  • R 5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
  • R 7 and R 8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
  • Y is a group of the formula
  • R 3 is a group of the formula in which R 6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, phenyl which has a suitable substituent selected from the group consisting of amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
  • R 11 is phenyl, phenoxy or phenyl(lower)alkoxy; or R 2 and R 3 in combination form a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
  • R 1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro or benzofuranyl;
  • R 2 is hydrogen
  • R" is phenyl which may have suitable substituent(s) selected from the group consisting of trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy;
  • R 5 is hydrogen
  • Y is a group of the formula
  • R 6 is pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, and n is an integer of 0 to 3; m is 0 or 1 ; and X is NR 9 in which R 9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
  • R 1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
  • the starting compound (430 mg) was dissolved in trifluoroacetic acid (1.5 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, made basic with 1N sodium hydroxide solution and extracted three times with chloroform. The organic layer was dried over magnesium sulfate and filtered. Evaporation of the solvent gave the object compound as an oil (314 mg).
  • the starting compound (600 mg) was heated at 40°C for 2 hours in methyl iodide (10 ml). The reaction mixture was evaporated, and the residue was suspended in an aqueous sodium carbonate solution. The mixture was extracted with chloroform. The organic layer was washed successively with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a chloroform-methanol (20:1) as eluent to give the object compound as a pale yellow oily solid (376.5 mg). mp : 116-119°C MASS (ESI) (m/z) : 302 (M+H) +
  • the object compound was obtained according to a similar manner to that of Preparation 3 except that a mixutre of trifluoroacetic acid and dichloromethane was used instead of trifluoroacetic acid.
  • MASS 322 (M+1)
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • a solution of potassium tert-butoxide (4.2 g) in anhydrous tetrahydrofuran (70 ml) was cooled under nitrogen atmosphere to -70°C, and a solution of the starting compound (10 g) in anhydrous tetrahydrofuran (35 ml) was added while maintaining the reaction temperature at -70°C. After 30 minutes, this solution was added dropwise to a solution of 4-bromobenzoyl chloride (8.21 g) in anhydrous tetrahydrofuran (24 ml) with stirring while cooling at -70°C on a cooling bath. The reaction mixture was stirred at -70°C for 1 hour and quenched with 3N-hydrochloric acid (100 ml).
  • the cooling bath was removed and the reaction mixture was concentrated to dryness under reduced pressure.
  • the residue was dissolved in water (15 ml) and extracted with diethyl ether (twice).
  • the aqueous layer was concentrated in vaciio , and the residue was dissolved in anhydrous methanol.
  • the precipitated white solid (KCl) was removed by filtration.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 91.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5.
  • the object compound was obtained according to a similar manner to that of Preparation 2.
  • the object compound was obtained according to a similar manner to that of Preparation 5 except that a mixture of dichloromethane and dimethylformamide was used instead of dichloromethane.

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Abstract

A compound of formula (I) wherein each symbol is as defined in the specification, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO), and are useful for prevention and/or treatment of NO-mediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock, diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease, cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, dermatitis, hepatitis, liver cirrhosis, multiple sclerosis, pancreatitis, atherosclerosis, and the like in human being and animals.

Description

DESCRIPTION NEW AMIDE COMPOUNDS
TECHNICAL FIELD This invention relates to new amide compounds and pharmaceutically acceptable salts thereof which are useful as medicament.
BACKGROUND ART Some peptide compounds have been known as described, for example, in EP 0394 989 A2.
DISCLOSURE OF INVENTION
This invention relates to new amide compounds.
One object of this invention is to provide the new and useful amide compounds and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of nitric oxide (NO).
Another object of this invention is to provide a process for the preparation of the amide compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said amide compound or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said amide compounds or pharmaceutically acceptable salts thereof as a medicament for prophylactic and therapeutic treatment of NO-mediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock (e.g., septic shock, etc.), diabetes (e.g., insulin-dependent diabetes mellitus, etc.), diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.), cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, dermatitis, hepatitis, liver cirrhosis, multiple sclerosis, pancreatitis, atherosclerosis, and the like in human being and animals.
The object amide compounds of the present invention are novel and can be represented by the following general formula (I)
Figure imgf000004_0001
wherein
R1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbaoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
R2 is hydrogen or phenyl(lower)alkyl;
R* is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, quinolyl or 3,4-methylenedioxyphenyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
.R7 -C0-N
in which R7 and R8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
Ru and R5 in combination form a group of the formula -CH=CH-CH=CH-
Y is a group of the formula
R3
I
-CH- in which R3 is hydrogen or a group of the formula -(CH2)„-R6 in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
Figure imgf000005_0001
in which R11 is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000006_0001
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000006_0002
in which R1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof, provided that the compound shown below is excluded: a compound of the formula
Figure imgf000006_0003
wherein
R1 ' is indolyl or benzofuranyl;
R2' is hydrogen, lower alkylthio(lower)alkyl or a group of the formula
Figure imgf000006_0004
in which R5' is hydrogen, lower alkoxy or halogen; R3' is hydrogen, quinolyl or phenyl which may have a suitable substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen; R*' is hydrogen or optionally esterified carboxy; and X' is S or NR6' in which R6' is hydrogen, lower alkyl or a group of the formula -CH2-^JT
in which R7' is lower alkyl or lower alkoxy, and a pharmaceutically acceptable salt thereof.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc. ) ; an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, gultamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term "lower" is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
Suitable "lower alkyl" and "lower alkyl moiety" in the terms "lower alkylthio", "lower alkylthio(lower)alkyl", "N-(lower)- alkylindolyl" , "lower alkylamino", "di(lower)alkylamino", "phenyl(lower)alkyl" , "amino(lower)alkyl" , "acylamino(lower)alkyl", "hydroxy(lower)alkyl" and "lower alkylpiperazinyl" include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl, in which more preferred one is Ci-C alkyl.
Suitable "lower alkoxy" and "lower alkoxy moiety" in the terms "lower alkoxy(lower)alkoxy" and "phenyl(lower) lkoxy" include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy and hexyloxy, in which more preferred one is Ci-C* alkoxy.
Suitable "halogen" includes, for example, fluorine, bromine, chlorine and iodine.
"Optionally esterified carboxy" includes carboxy and esterified carboxy. Suitable examples of said ester include lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1 -methoxyethyl ester, 1 -ethoxyethyl ester, etc.); mono(or di or tri)- aryl(lower)alkyl ester, for example, mono(or di or tri)phenyl(lower)- alkyl ester which may have one or more suitable substituent(s) [e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.] ; and aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.).
Suitable "trihalomethyl" includes, for example, trifluoromethyl, trichloromethyl and tribromomethyl, in which preferred one is trifluoromethyl.
Suitable "amino protective group" includes, for example, acyl and conventional protective group such as mono(or di or tri)aryl(lower)- alkyl, for example, mono(or di or tri)phenyl(lower)alkyl (e.g., benzyl, trityl, etc.).
Suitable "acyl" and "acyl moiety" in the terms "acylamino", "diacylamino" and "acylamino(lower)alkyl" include, for example, carbamoyl which may be substituted by suitable substituent(s), aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable examples of said acyl are illustrated as follows: "carbamoyl which may be substituted by suitable substituent(s)" includes a group of the formula
Figure imgf000009_0001
wherein R12 and R13are the same or different and each is hydrogen, lower alkyl, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, phenyl(lower)- alkyl, pyridyl, pyridyl(lower)alkyl or 3,4-methylenedioxyphenyl; aliphatic acyl such as lower alkanoyl which may be substituted by one to three halogen atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, trichloroacetyl, trifluoroacetyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert- pentyloxycarbonyl, etc.), lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), lower alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.), cyclo(lower)alkylcarbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), and the like; aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.), aryl(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, etc. ) , naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.], aryl(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.], aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), arylsulfonyl (e.g., phenylsulfonyl, p-tolylsufonyl, etc.), and the like; heterocyclic acyl such as indolylcarbonyl (e.g., indolyl-2-ylcarbonyl, etc.), benzofuranylcarbonyl (e.g., benzofuran-2-ylcarbonyl) , quinoxalinylcarbonyl, quinolylcarbonyl, pyrrolylcarbonyl, benzimidazolylcarbonyl, benzothienylcarbonyl, benzothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, morpholinylcarbonyl (e.g., morpholinocarbonyl) and the like.
"Optionally protected hydroxy" includes hydroxy and protected hydroxy. Suitable examples of "hydroxy protective group" in the term "protected hydroxy" include acyl (e.g., acetyl, trichloroacetyl, etc.), mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
Suitable "protected carboxy" is carboxy group protected by conventional protective group such as lower alkoxycarbonyl [e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.], optionally substituted phenyl(lower)- alkoxycarbonyl for exemple, mono- or di- or triphenyl(lower)- alkoxycarbonyl which may be substituted by nitro [e.g., benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, etc.] and the like.
Suitable "cyclo(lower)alkyl" includes cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in which more preferred ones are cyclopropyl and cyclobutyl.
The term "morpholinyl" includes 2-morpholinyl, 3-morpholinyl and 4-morpholinyl (i.e. morpholino).
The term "piperidyl" includes 1 -piperidyl (i.e. piperidino), 2- piperidyl, 3-piperidyl and 4-piperidyl.
The object compound (I) of the present invention can be prepared by the following processes.
Process (1 )
R1 -COOH
ive
Figure imgf000011_0001
(ID or its reactive derivative at the amino group, or a salt thereof
Figure imgf000011_0002
(I) or a salt thereof
Process (2)
Figure imgf000012_0001
(ID or a salt thereof
Figure imgf000012_0002
(D-l or a salt thereof
Process (3)
R15
Figure imgf000012_0003
or a salt thereof
Elimination reaction of the amino protective group
R15
Figure imgf000012_0004
(I)-2 or a salt thereof
l o Process (4)
Figure imgf000013_0001
or its reactive derivative at the amino group, or a salt thereof
Figure imgf000013_0002
(D-4 or a salt thereof
Process (5)
reduction
Figure imgf000013_0003
or a salt thereof
Figure imgf000013_0004
or a salt thereof
Process (6)
acylation
Figure imgf000013_0005
or a salt thereof
Figure imgf000013_0006
or a salt thereof Process (7)
reduction
Figure imgf000014_0001
or a salt thereof
Figure imgf000014_0002
or a salt thereof
Process (8)
oxidation
Figure imgf000014_0003
or a salt thereof
Figure imgf000014_0004
or a salt thereof
Process (9)
hydrolysis
Figure imgf000014_0005
or a salt thereof
Figure imgf000014_0006
or a salt thereof
l 2 Process (10)
reduction
Figure imgf000015_0001
or a salt thereof
CH2 2NiHn2
Figure imgf000015_0002
or a salt thereof
Process (11)
acylation
Figure imgf000015_0003
or a salt thereof
Figure imgf000015_0004
or a salt thereof
Process (12)
amidation
Figure imgf000015_0005
or a salt thereof
Figure imgf000015_0006
or a salt thereof Process (13)
Elimination reaction of the hydroxy protective group
Figure imgf000016_0001
or a salt thereof
Figure imgf000016_0002
or a salt thereof
Process (14)
esterification
Figure imgf000016_0003
or a salt thereof
Figure imgf000016_0004
or a salt thereof
Process (15)
0-alkylation
Figure imgf000016_0005
or a salt thereof
Figure imgf000016_0006
or a salt thereof Process (16)
Elimination reaction of the carboxy protective group
Figure imgf000017_0001
or a
Figure imgf000017_0002
(D-22 or a salt thereof
Process (17)
esterification
Figure imgf000017_0003
or a
Figure imgf000017_0004
(I)-23 or a salt thereof
Process (18)
amidation
Figure imgf000017_0005
or a
Figure imgf000017_0006
(I)-24 or a salt thereof
l 5 Process (19)
R'
Figure imgf000018_0001
(I)-26 or a salt thereof
Process (20)
R1
Figure imgf000018_0002
(D-27 or a salt thereof
Process (21)
esterification
Figure imgf000018_0003
or a
Figure imgf000018_0004
(D-29 or a salt thereof Process (22)
hydrolysis
Figure imgf000019_0001
(D-30 or a salt thereof
Figure imgf000019_0002
(D-31 or a salt thereof
Process (23)
Figure imgf000019_0003
R2 N COOH (VII) R1-C0N-(Y); or its reactive derivative
X at the amino group, or a salt thereof (D-31 or its reactive derivative at the carboxy group, or a salt thereof
Figure imgf000019_0004
(I)-32 or a salt thereof
Process (24)
R2 R9-NH2
I H R1 -CON - (Y)m-C0N-CH-C0-R» (IX) acid
Figure imgf000019_0005
R* (D-33
wherein R1 , R2, Rft, R5, R7, R8, R9, X, Y, m and n are each as l 7 defined above,
R1 * is amino protective group,
R15 is hydrogen or lower alkyl,
R16 is acyl,
R1 is acylamino or diacylamino,
R18 is carboxy or lower alkoxycarbonyl,
R19 is esterified carboxy,
R20 is acylamino or diacylamino,
R21 is carbamoyl which may be substituted by suitable substituent(s) , R22 is hydroxy protective group, R23 is acyl, R2* is lower alkyl, R25 is protected carboxy, R26 is esterified carboxy, R27 is carbamoyl which may be substituted by suitable substituent(s), R28 is acylamino or diacylamino, R29 is acyl, and R30 is esterified carboxy.
The starting compounds can be prepared by the method of Preparation mentioned below or by a process known in the art for preparing their structually analogous compounds.
The processes for preparing the object compound are explained in detail in the following.
Process (1)
The compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group, or a salt thereof with the compound (III) or its reactive derivative at the
l 8 carboxy group, or a salt thereof.
Suitable reactive derivative of the compound (II) includes Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,0- bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene.
Suitable reactive derivative of the compound (III) includes an acid halide, an acid anhydride and an activated ester. The suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl
Figure imgf000021_0001
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p- cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.); or an ester with an N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2- (IH)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N- hydroxyphthalimide, 1 -hydroxy-6-chloro-1H-benzotriazole, etc. ) .
l 9 These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'- dicyclohexylcarbodiimide; N-cyclohexyl-N' -morpholinoethylcarbodiimide; N-cyclohexyl-N' -(4-diethylaminocyclohexyl)carbodiimide; N,N' - diisopropylcarbodiimide; N-ethyl-N' -(3-dimethylaminopropyl)- carbodiimide; N,N-carbonyl-bis-(2-methylimidazole) ; pentamethylene- ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 -alkoxy-1 -chloroethylene; trialkyl phosphite; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide intramolecular salt; 1-(p- chlorobenzenesulfonyloxy)-6-chloro-1 H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc, ; or the like.
The reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
Process (2)
2 o The compound (I)-1 or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (IV).
The reaction can be carried out in the same manner as in or a manner similar to Example 27.
Process (3)
The compound (I)-2 or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to elimination reaction of the amino protective group.
Suitable method of this elimination reaction includes conventional one such as hydrolysis, reduction and the like, (i) For hydrolysis :
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base includes an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1 ,5-diazabicyclo[ .3.0]non-5-one, or the like.
Suitable acid includes an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
The elimination using Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid, trifluoroacetic acid, etc.], or the like is preferably carried out in the presence of cation trapping agents [e.g., anisole, phenol, etc.]. This reaction is usually carried out without solvent.
The reaction may be carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming, (ii) For reduction :
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.), or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc. ) , nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, Ullman iron, etc.), and the like.
The reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in a liquid state, they can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
Process (4)
The compound (I)-4 or a salt thereof can be prepared by reacting the compound (I)~3 or its reactive derivative at the amino group, or a salt thereof with the compound (VI) or its reactive derivative at the carboxy group, or a salt thereof.
This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (1 ) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process ω.
Process (5)
The compound (I)-6 or a salt thereof can be prepared by subjecting the compound (I)-5 or a salt thereof to reduction.
The reduction can be carried out in the same manner as in or a manner similar to Example 60.
Process (6)
The compound (I)-7 or a salt thereof can be prepared by subjecting the compound (I)-6 or a salt thereof to acylation.
The acylation can be carried out in the same manner as in or a manner similar to Example 61.
Process (7)
The compound (I)-9 or a salt thereof can be prepared by subjecting the compound (I)-8 or a salt thereof to reduction. The reduction can be carried out in the same manner as in or a manner similar to Example 111.
Process (8)
The compound (I)-10 or a salt thereof can be prepared by subjecting the compound (I)-9 or a salt thereof to oxidation.
The oxidation can be carried out in the same manner as in or a manner similar to Example 112.
Process (9)
The compound (I)-12 or a salt thereof can be prepared by subjecting the compound (I)-11 or a salt thereof to hydrolysis.
The hydrolysis can be carried out in the same manner as in or a manner similar to Example 113.
Process (10)
The compound (I)-14 or a salt thereof can be prepared by subjecting the compound (I)-13 or a salt thereof to reduction.
The reduction can be carried out in the same manner as in or a manner similar to Example 123.
Process (11)
The compound (I)-15 or a salt thereof can be prepared by subjecting the compound (I)-14 or a salt thereof to acylation.
The acylation can be carried out in the same manner as in or a manner similar to Example 124.
Process (12)
The compound (I)-16 or a salt thereof can be prepared by subjecting the compound (I)-12 or a salt thereof to amidation.
The amidation can be carried out in the same manner as in or a manner similar to Example 127. Process (13)
The compound (I)-18 or a salt thereof can be prepared by subjecting the compound (I)-17 or a salt thereof to elimination reaction of the hydroxy protective group.
This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc. ) can be referred to those of the Process (3).
Process (14)
The compound (I)-19 or a salt thereof can be prepared by subjecting the compound (I)-18 or a salt thereof to esterification.
The esterification can be carried out in the same manner as in or a manner similar to Example 133.
Process (15)
The compound (I)-20 or a salt thereof can be prepared by subjecting the compound (I)-18 or a salt thereof to 0-alkylation.
The 0-alkylation can be carried out in the same manner as in or a manner similar to Example 135.
Process (16)
The compound (I)-22 or a salt thereof can be prepared by subjecting the compound (I)-21 or a salt thereof to elimination reaction of the carboxy protective group.
This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3). Process (17)
The compound (I)-23 or a salt thereof can be prepared by subjecting the compound (I)-22 or a salt thereof to esterification.
The esterification can be carried out in the same manner as in or a manner similar to Example 74.
Process (18)
The compound (I)-24 or a salt thereof can be prepared by subjecting the compound (I)-22 or a salt thereof to amidation.
The amidation can be carried out in the same manner as in or a manner similar to Example 95.
Process (19)
The compound (I)-26 or a salt thereof can be prepared by subjecting the compound (I)-25 or a salt thereof to reduction.
The reduction can be carried out in the same manner as in or a manner similar to Example 119.
Process (20)
The compound (I)-27 or a salt thereof can be prepared by subjecting the compound (I)-26 or a salt thereof to acylation.
The acylation can be carried out in the same manner as in or a manner similar to Example 120.
Process (21)
The compound (I)-29 or a salt thereof can be prepared by subjecting the compound (I)-28 or a salt thereof to esterification.
The esterification can be carried out in the same manner as in or a manner similar to Example 138.
Process (22) The compound (I)-31 or a salt thereof can be prepared by subjecting the compound (I)-30 or a salt thereof to hydrolysis.
The hydrolysis can be carried out in the same manner as in or a manner similar to Example 168.
Process (23)
The compound (I)-32 or a salt thereof can be prepared by reacting the compound (I)-31 or its reactive derivative at the carboxy group, or a salt thereof with the compound (VII) or its reactive derivative at the amino group, or a salt thereof.
This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (1 ) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process
HI-
Process (24)
The compound (I)-33 can be prepared by reacting the compound (VIII) with the compound (IX) in the presence of an acid.
This reaction can be carried out in the same manner as in or a manner similar to Example 178.
Suitable salts of the starting compounds and their reactive derivatives in Process (1) can be referred to the ones as exemplified for the compound (I).
The compounds obtained by the above process can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
It is to be noted that the compound (I) and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.
The object compounds (I) and pharmaceutically acceptable salts thereof include solvates [e.g., enclosure compounds (e.g., hydrate, etc.)].
The object compounds (I) and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO).
Accordingly, the object compounds (I) and pharmaceutically acceptable salts thereof are expected to possess a nitric oxide synthase (NOS)-inhibitory activity or a NOS-production inhibitory activity.
Accordingly, they are useful for prevention and/or treatment of NO-mediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock (e.g., septic shock, etc.), diabetes (e.g., insulin-dependent diabetes mellitus, etc.), diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.), cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, dermatitis, hepatitis, liver cirrhosis, multiple sclerosis, pancreatitis, atherosclerosis, and the like.
In order to illustrate the usefulness of the object compound (I) , the pharmacological test result of the representative compound of the compound (I) is shown in the following. Test Compounds :
Figure imgf000031_0001
Figure imgf000032_0001
Test : Assay for inhibitory activity on the production of nitric oxide The murine macrophage cell line RAW264.7 (American Type Culture Collection, No. TTB71 ) was used in this study. RAW264.7 cells were grown on F75 plastic culture flasks at 37°C, 5% in Dulbecco's modified Eagle's medium (DMEM) supplemented with L-glutamine, penicillin, streptomycin and 10$ heat-inactivated fetal bovine serum. They were removed from culture flasks by rubber cell scraper and were centrifuged and resuspended in DMEM without phenol red. They were plated in 96-well microtiter plates (105 cells per well) and allowed to adhere over 2 hours.. The test samples were added and the cells were preincubated for 1 hour. Thereafter the cells were activated with both of lipopolysaccharide (LPS) (1/zg/ml) and interferon γ (INF ) (3 u/ml) for 18-24 hours. An equal volume of Griess reagent ( ] % sulfanilamide/0.1/δ N-naphthylethylenediamine dihydrochloride/2.5% H3PO1*) was added and the cells were incubated at room temperature for 10 minutes. The absorbance was read at 570 nm using microplate reader and NO∑" was measured using NaNO∑ as a standard.
Test result :
Figure imgf000033_0001
For therapeutic administration, the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are used in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee, suppository or ointment, or in a liquid form such as solution, suspension or emulsion for injection, intravenous drip, ingestion, eye drop, etc. If needed, there may be included in the above preparation auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
The effective ingredient may usually be administered in a unit dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, body weight and conditions of the patient or administering method.
The preferred embodiments of the amide compounds of the present invention represented by the general formula (I) are as follows. R1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two
3 l suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrol l, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
R2 is hydrogen or phenyl(lower)alkyl;
R* is phenyl or pyridyl, each of which has suitable substituent(s) selected from the group consisting of trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazoly1, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, or 3, -methylenedioxyphenyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
Figure imgf000034_0001
in which R7 and R8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
R" and R5 in combination form a group of the formula -CH=CH-CH=CH-
Y is a group of the formula
R3
I
-CH- in which R3 is hydrogen or a group of the formula
-(CH2)„-R6 in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower) lkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
R
^& in which R1 ' is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000035_0001
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000035_0002
in which R1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
Another preferred embodiments of the amide compounds of the present invention represented by the general formula (I) are as follows. R1 is indolyl which has a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
R2 is hydrogen or phenyl(lower)alkyl;
Rft is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen or quinolyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
Figure imgf000036_0001
in which R7 and R8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
R* and R5 in combination form a group of the formula -CH=CH-CH=CH-
Y is a group of the formula
R3
I
-CH- in which R3 is hydrogen or a group of the formula
-(CH2)n-R6 in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
Figure imgf000037_0001
in which R1 ' is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000037_0002
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000037_0003
in which R1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
Another preferred embodiments of the amide compounds of the present invention represented by the general formula (I) are as follows.
R1 is indolyl or benzofuranyl;
R2 is hydrogen or phenyl(lower) lkyl;
R* is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen or quinolyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
.R7 -C0-N
in which R7 and R8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
Ru and R5 in combination form a group of the formula -CH=CH-CH=CH-
Y is a group of the formula
R3
I
-CH- in which R3 is a group of the formula
Figure imgf000038_0001
in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, phenyl which has a suitable substituent selected from the group consisting of amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
R11
in which R11 is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000038_0002
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000039_0001
in which R1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
The most preferred embodiments of the amide compounds of the present invention represented by the general formula (I) are as follows.
R1 is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro or benzofuranyl;
R2 is hydrogen;
R" is phenyl which may have suitable substituent(s) selected from the group consisting of trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy;
R5 is hydrogen;
Y is a group of the formula
R3
I
-CH- in which R3 is hydrogen or a group of the formula
-(CH2)n-R6 in which R6 is pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, and n is an integer of 0 to 3; m is 0 or 1 ; and X is NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000040_0001
in which R1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
The following Preparations and Examples are given for the purpose of illustrating the present invention in detail.
In the following Examples and Preparations, there are employed the other abbreviations in addition to the abbreviations adopted by the IUPAC-IUB (Commission on Biological Nomenclature).
The abbreviations used are as follows.
Boc tert-butoxycarbonyl
Me methyl
Et ethyl
Pr propyl i-Pr isopropyl
Bu butyl
Ph phenyl
Ts p-toluenesulfonyl
Ac acetyl
Bn benzyl
Cbz benzlyoxycarbonyl
Tf trifluoromethanesulfonyl
The starting compounds used and the object compounds obtained in the following Preparations and Examples are given in the Tables as below, in which the formulae of the starting compounds are in the upper and the formulae of the object compounds are in the lower, respectively. Table
Preparation No. Formula
H BocN COOH
0
H BocN Ph
0
0
H BocN Ph
0
Figure imgf000041_0001
H Me BocN N /
«'
Ph
Figure imgf000041_0002
Table
Preparation No. Formula
Figure imgf000042_0001
Figure imgf000042_0002
4 o Table
Figure imgf000043_0001
Table
Figure imgf000044_0001
Table
Figure imgf000045_0001
Table
Figure imgf000046_0001
Table
Figure imgf000047_0001
Table
Figure imgf000048_0001
Table
Figure imgf000049_0001
Table
Figure imgf000050_0001
Table
Figure imgf000051_0001
Table
Figure imgf000052_0001
Table
Figure imgf000053_0001
Table
Figure imgf000054_0001
Table
Figure imgf000055_0001
Table
Figure imgf000056_0001
Table
Figure imgf000057_0001
Table
Figure imgf000058_0001
Table
Figure imgf000059_0001
Table
Figure imgf000060_0001
Table
Figure imgf000061_0001
Table
Figure imgf000062_0001
Table
Figure imgf000063_0001
Table
Figure imgf000064_0001
Table
Figure imgf000065_0001
Table
Figure imgf000066_0001
Table
Figure imgf000067_0001
Table
Figure imgf000068_0001
Table
Figure imgf000069_0001
Table
Figure imgf000070_0001
Table
Figure imgf000071_0001
Table
Figure imgf000072_0001
7 o Table
Figure imgf000073_0001
Table
Figure imgf000074_0001
Table
Figure imgf000075_0001
Table
Figure imgf000076_0001
Table
Figure imgf000077_0001
Table
Figure imgf000078_0001
Table
Figure imgf000079_0001
Table
Figure imgf000080_0001
Table
Figure imgf000081_0001
Table
Figure imgf000082_0001
Table
Figure imgf000083_0001
Table
Figure imgf000084_0001
Table
Figure imgf000085_0001
Table
Figure imgf000086_0001
Table
Figure imgf000087_0001
Table
Figure imgf000088_0001
Table
Figure imgf000089_0001
Table
Figure imgf000090_0001
Table
Figure imgf000091_0001
Table
Figure imgf000092_0001
Table
Figure imgf000093_0001
Table
Figure imgf000094_0001
Table
Figure imgf000095_0001
Table
Figure imgf000096_0001
Table
Figure imgf000097_0001
Table
Figure imgf000098_0001
Table
Figure imgf000099_0001
Table
Figure imgf000100_0001
Table
Figure imgf000101_0001
Table
Figure imgf000102_0001
l o o Table
Figure imgf000103_0001
Table
Figure imgf000104_0001
Table
Figure imgf000105_0001
Table
Figure imgf000106_0001
Table
Figure imgf000107_0001
Table
Figure imgf000108_0001
Table
Figure imgf000109_0001
l o 7 Table
Figure imgf000110_0001
Table
Figure imgf000111_0001
Table
Figure imgf000112_0001
l l o Table
Figure imgf000113_0001
Table
Figure imgf000114_0001
Table
Figure imgf000115_0001
Table
Figure imgf000116_0001
Table
Figure imgf000117_0001
Table
Figure imgf000118_0001
Table
Figure imgf000119_0001
Table
Figure imgf000120_0001
l l Table
Figure imgf000121_0001
l l 9 Table
Figure imgf000122_0001
Table
Figure imgf000123_0001
Table
Figure imgf000124_0001
Table
Figure imgf000125_0001
Table
Figure imgf000126_0001
Table
Figure imgf000127_0001
Table
Figure imgf000128_0001
Table
Figure imgf000129_0001
Table
Figure imgf000130_0001
Table
Figure imgf000131_0001
Table
Figure imgf000132_0001
Table
Figure imgf000133_0001
Table
Figure imgf000134_0001
Table
Figure imgf000135_0001
Table
Figure imgf000136_0001
l 3 4 Table
Figure imgf000137_0001
Table
Figure imgf000138_0001
Table
Figure imgf000139_0001
Table
Figure imgf000140_0001
Table
Figure imgf000141_0001
Table
Figure imgf000142_0001
Table
Figure imgf000143_0001
Table
Figure imgf000144_0001
Table
Figure imgf000145_0001
Table
Figure imgf000146_0001
Table
Figure imgf000147_0001
Table
Figure imgf000148_0001
Table
Figure imgf000149_0001
Table
Figure imgf000150_0001
Table
Figure imgf000151_0001
1 4 Table
Figure imgf000152_0001
Table
Figure imgf000153_0001
l 5 l Table
Figure imgf000154_0001
Table
Figure imgf000155_0001
Table
Figure imgf000156_0001
Table
Figure imgf000157_0001
Table
Figure imgf000158_0001
Table
Figure imgf000159_0001
Table
Figure imgf000160_0001
Table
Figure imgf000161_0001
Table
Figure imgf000162_0001
Table
Figure imgf000163_0001
Table
Figure imgf000164_0001
Table
Figure imgf000165_0001
Table
Figure imgf000166_0001
Table
Figure imgf000167_0001
Table
Figure imgf000168_0001
Table
Figure imgf000169_0001
Table
Figure imgf000170_0001
Table
Figure imgf000171_0001
l 6 g Table
Figure imgf000172_0001
Table
Figure imgf000173_0001
Table
Figure imgf000174_0001
Table
Figure imgf000175_0001
Table
Figure imgf000176_0001
Table
Figure imgf000177_0001
Table
Figure imgf000178_0001
Table
Figure imgf000179_0001
Table
Figure imgf000180_0001
1 7 Table
Figure imgf000181_0001
Table
Figure imgf000182_0001
Table
Figure imgf000183_0001
Table
Figure imgf000184_0001
Table
Figure imgf000185_0001
Table
Figure imgf000186_0001
Table
Figure imgf000187_0001
Table
Figure imgf000188_0001
Table
Figure imgf000189_0001
Table
Figure imgf000190_0001
Table
Figure imgf000191_0001
Table
Figure imgf000192_0001
Table
Figure imgf000193_0001
Table
Figure imgf000194_0001
l 9 2 Table
Figure imgf000195_0001
Table
Figure imgf000196_0001
Table
Figure imgf000197_0001
Table
Figure imgf000198_0001
Table
Figure imgf000199_0001
Table
Figure imgf000200_0001
Table
Figure imgf000201_0001
Table
Figure imgf000202_0001
Table
Figure imgf000203_0001
Table
Figure imgf000204_0001
Table
Figure imgf000205_0001
Table
Figure imgf000206_0001
Table
Figure imgf000207_0001
Table
Figure imgf000208_0001
Table
Figure imgf000209_0001
2 o 7 Table
Figure imgf000210_0001
Table
Figure imgf000211_0001
Table
Figure imgf000212_0001
Table
Figure imgf000213_0001
Table
Figure imgf000214_0001
Table
Figure imgf000215_0001
Table
Figure imgf000216_0001
Table
Figure imgf000217_0001
Table
Figure imgf000218_0001
Table
Figure imgf000219_0001
Table
Figure imgf000220_0001
Table
Figure imgf000221_0001
Table
Figure imgf000222_0001
Table
Example No. Formula
Figure imgf000223_0001
Figure imgf000223_0002
Table
Example No. Formula
Figure imgf000224_0001
Figure imgf000224_0002
Figure imgf000224_0003
Table
Figure imgf000225_0001
Table
Figure imgf000226_0001
Table
Figure imgf000227_0001
Table
Figure imgf000228_0001
Table
Figure imgf000229_0001
Table
Figure imgf000230_0001
Table
Figure imgf000231_0001
Table
Figure imgf000232_0001
2 3 o Table
Figure imgf000233_0001
2 3 l Table
Figure imgf000234_0001
Table
Figure imgf000235_0001
Table
Figure imgf000236_0001
Table
Figure imgf000237_0001
Table
Figure imgf000238_0001
Table
Figure imgf000239_0001
Table
Figure imgf000240_0001
Table
Figure imgf000241_0001
Table
Figure imgf000242_0001
Table
Figure imgf000243_0001
Table
Figure imgf000244_0001
Table
Figure imgf000245_0001
Table
Figure imgf000246_0001
Table
Figure imgf000247_0001
Table
Figure imgf000248_0001
Table
Figure imgf000249_0001
Table
Figure imgf000250_0001
Table
Figure imgf000251_0001
Table
Example No. Formula
NOz
60
Figure imgf000252_0001
Figure imgf000252_0002
61
Figure imgf000252_0003
N(SOzMe);
Figure imgf000252_0004
Table
Figure imgf000253_0001
Table
Figure imgf000254_0001
Table
Figure imgf000255_0001
Table
Figure imgf000256_0001
Table
Figure imgf000257_0001
Table
Figure imgf000258_0001
Table
Figure imgf000259_0001
Table
Figure imgf000260_0001
Table
Figure imgf000261_0001
Table
Figure imgf000262_0001
Table
Figure imgf000263_0001
Table
Figure imgf000264_0001
Table
Figure imgf000265_0001
Table
Figure imgf000266_0001
Table
Figure imgf000267_0001
Table
Figure imgf000268_0001
Table
Figure imgf000269_0001
Table
Figure imgf000270_0001
Table
Figure imgf000271_0001
Table
Figure imgf000272_0001
Table
Figure imgf000273_0001
Table
Figure imgf000274_0001
Table
Figure imgf000275_0001
Table
Figure imgf000276_0001
Table
Figure imgf000277_0001
Table
Figure imgf000278_0001
Table
Figure imgf000279_0001
Table
Figure imgf000280_0001
Table
Figure imgf000281_0001
Table
Figure imgf000282_0001
Table
Figure imgf000283_0001
Table
Figure imgf000284_0001
Table
Figure imgf000285_0001
Table
Figure imgf000286_0001
Table
Figure imgf000287_0001
Table
Figure imgf000288_0001
Table
Figure imgf000289_0001
Table
Figure imgf000290_0001
Table
Figure imgf000291_0001
Table
Figure imgf000292_0001
Table
Figure imgf000293_0001
Table
Figure imgf000294_0001
Table
Figure imgf000295_0001
Table
Figure imgf000296_0001
Table
Figure imgf000297_0001
Table
Figure imgf000298_0001
Table
Figure imgf000299_0001
Table
Figure imgf000300_0001
Table
Figure imgf000301_0001
Table
Figure imgf000302_0001
Table
Figure imgf000303_0001
Table
Figure imgf000304_0001
Table
Figure imgf000305_0001
Table
Figure imgf000306_0001
Table
Figure imgf000307_0001
Table
Figure imgf000308_0001
Table
Figure imgf000309_0001
Table
Figure imgf000310_0001
Table
Figure imgf000311_0001
Table
Figure imgf000312_0001
Table
3 l l Table
Figure imgf000314_0001
Table
Table
Figure imgf000316_0001
3 l 4 Table
Figure imgf000317_0001
Table
Figure imgf000318_0001
Table
Figure imgf000319_0001
Table
Figure imgf000320_0001
Table
Figure imgf000321_0001
Table
Figure imgf000322_0001
Table
Figure imgf000323_0001
Table
Figure imgf000324_0001
Table
Figure imgf000325_0001
Table
Figure imgf000326_0001
Table
Figure imgf000327_0001
Table
Figure imgf000328_0001
Table
Figure imgf000329_0001
Table
Figure imgf000330_0001
Table
Figure imgf000331_0001
Table
Figure imgf000332_0001
3 3 o Table
Figure imgf000333_0001
Table
Figure imgf000334_0001
Preparation 1
To an ice-cooled mixture of N-(tert-butoxycarbonyl)glycine (1.40 g) and 2-aminoacetophenone hydrochloride (1.61 g) in dichloromethane (14 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.49 g). The mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and then the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methanol= 40/1 ) to give the object compound as white powder (689 mg) .
MASS (ESI) (m/z) : 293 (M+H)+
'H-NMR (CDC13,300MHz) δ : 1.47(9H,s), 3.92(2H,d,J=5Hz) ,
4.78(2H,s), 5.13(1H,br s), 7.05(1H,br s) , 7.45-7.70(3H,m) , 7.92-8.04(2H,m) Preparation 2
A solution of the starting compound (669 mg) and 40% methylamine (0.7 ml) in a mixture of acetic acid (0.7 ml) and xylene (7 ml) was refluxed for 4 hours in a flask equipped with a Dean-Stark trap. The mixture was concentrated, neutralized with 1N sodium hydroxide solution, and extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methanol=50/1 ) to give the object compound as an oil (445 mg).
MASS (ESI) (m/z) : 288 (M+H)+ 1H-NMR (CDCl3,300MHz)(5 : 1.46(9H,s), 3.60(3H,s),
4.48(2H,d,J=5Hz), 5.33(1H,br s) , 6.99(1H,s), 7.30-7.52(5H,m) Preparation 3
The starting compound (430 mg) was dissolved in trifluoroacetic acid (1.5 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, made basic with 1N sodium hydroxide solution and extracted three times with chloroform. The organic layer was dried over magnesium sulfate and filtered. Evaporation of the solvent gave the object compound as an oil (314 mg).
MASS (ESI) (m/z) : 188 (M+H)+ 1H-NMR (CDCls,300MHz) δ : 3.57(3H,s), 3.98(2H,s), 6.98(1H,s), 7.26-7.50(5H,m) Preparation 4
To a solution of the starting compound (3.10 g) in methanol (15 ml) was added concentrated hydrochloric acid (3 ml) , and the mixture was heated to 50°C for 2 hours. The mixture was concentrated, made basic with a IN sodium hydroxide solution, and extracted three times with chloroform. The organic layer was dried over magnesium sulfate, and filtered. Evaporation of the solvent gave the object compound(2.35 g).
MASS (ESI) (m/z) : 308 (M+H)+ 1H-NMR (CDCl3,300MHz)<5 : 3.02-3.22(2H,m) , 3.21 (3H,s), 3.78(3H,s), 4.11(1H,t,J=7Hz), 6.81 (2H,d,J=8Hz) , 6.99(2H,d,J=8Hz), 7.04(1H,s), 7.21-7.48(5H,m) Preparation 5
To an ice-cooled mixture of the starting compound (599 mg) , 2- aminoacetophenone hydrochloride (362 mg) and 1 -hydroxybenzotriazole
(270 mg) in dichloromethane (6 ml) was added 1-(3-dimethylamino- propyl)-3-ethylcarbodiimide (349 mg). The mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and then the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methanol=70/1 ) to give the object compound (823 mg).
MASS (ESI) (m/z) : 417 (M+H)+ 1H-NMR (CDCl3,300MHz)5 : 1.41 (9H,s), 2.96-3.20(2H,m) , 4.47(1H,m), 4.70(2H,AB of ABX,JAB=15Hz) , 5.01(1H,br s) , 6.92(1H,br s) , 7.13(2H,d,J=8Hz) , 7.24(2H,d,J=8Hz) , 7.41-7.68(3H,m), 7.88-8.00(2H,m) Preparation 6
The starting compound (1.1 g) and glyoxal trimeric dihydrate (930 mg) were stirred in methanol (7 ml) at -10°C. Ammonia was bubbled through the solution for 5 minutes and the mixture was stirred at -10°C for 1 hour. The mixture was allowed to warm to room temperature over 18 hours, then poured into water, and extracted twice with dichloromethane. The combined extracts was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a dichloromethane-methanol gradient (20:1 and 10:1) as eluent to give the object compound as an off-white solid (698.6 mg). mp : 180.5-184oC
MASS : 288 (M+H)+ H-NMR (CDC13) δ 1.40(9H,s), 3.29(2H,d,J=7.5Hz) , 4.90(1H,q,J=7.5Hz), 5.25(1H,bd,J=7.5Hz) , 6.89(1H,bs), 6.99(1H,bs), 7.12(2H,d,J=7.5Hz), 7.18-7.30(3H,m), 9.78(1H,bs) Preparation 7
The starting compound (600 mg) was heated at 40°C for 2 hours in methyl iodide (10 ml). The reaction mixture was evaporated, and the residue was suspended in an aqueous sodium carbonate solution. The mixture was extracted with chloroform. The organic layer was washed successively with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a chloroform-methanol (20:1) as eluent to give the object compound as a pale yellow oily solid (376.5 mg). mp : 116-119°C MASS (ESI) (m/z) : 302 (M+H)+
'H-NMR (CDCls, δ ) 1.40(9H,s), 3.05(3H,s),
3.10(1H,dd,J=14.5, 9.0Hz), 3.29(1H,dd,J=14.5, 4.5Hz), 4.93(1H,m), 5.50(1H,br d,J=7.5Hz), 6.63(1H,s), 6.95-7.02(3H,m), 7.15-7.24(3H,m) Preparation 8
The object compound was obtained according to a similar manner to that of Preparation 3 except that a mixutre of trifluoroacetic acid and dichloromethane was used instead of trifluoroacetic acid. MASS : 322 (M+1)
1H-NMR (CDC13) δ 1.43(3H,t,J=8Hz), 3.09-3.27(2H,m) , 3.12(3H,s), 4.07(2H,q,J=8Hz), 4.13(1H,t,J=8Hz) , 6.91 (2H,d,J=8Hz) , 7.00(1H,s), 7.10(2H,d,J=7Hz), 7.19(2H,d,J=8Hz) , 7.21-7.31 (3H,m) Preparation 9
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS(m/z) : 428 (M+1) H-NMR (CDC13) δ 1.43(3H,t,J=7Hz), 1.46(9H,s),
3.25(1H,dd,J=5 and 15Hz), 3.37(1H,m), 4.09(2H,q,J=7Hz), 4.62(2H,d,J=3Hz), 4.67(1H,m), 6.40(1H,m), 6.91 (2H,d,J=8Hz) , 7.15(lH,dd,J=5 and 7Hz) , 7.21 (1H,d,J=8Hz) , 7.58(1H,dd,J=7 and 8Hz), 7.89(2H,d,J=8Hz) , 8.53(1H,d,J=5Hz) Preparation 10
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS(m/z) : 423 (M+1)
'H-NMR (CDC13) δ 1.43(9H,s), 1 ,43(3H,t,J=7Hz), 3.38(3H,s), 3.42(2H,d,J=7Hz), 4.04(2H,q,J=7Hz) , 5.40(1H,m), 6.91(2H,d,J=8Hz), 6.92(1H,s), 7.11(2H,m), 7.20(2H,d,J=8Hz) , 7.54(1H,m), 8.53(1H,d,J=5Hz) Preparation 11 The object compound was obtained according to a similar manner to that of Preparation 3.
MASS(m/z) : 323 (M+1) Preparation 12
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS(m/z) : 452 (M+1)
1H-NMR (CDCls) δ 1.48(9H,s), 3.25(1H,dd,J=5 and 15Hz), 3.35(1H,m), 4.69(1H,m), 4.70(2H,d,J=3Hz), 6.44(1H,m), 7.17(1H,dd,J=5 and 7Hz), 7.22(1H,d,J=8Hz), 7i62(1H,dd,J=7 and 8Hz), 7.74(2H,d,J=8Hz) , 8.04(2H,d,J=8Hz), 8.55(1H,d,J=5Hz) Preparation 13
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS(m/z) : 447 (M+1)
1H-NMR (CDC13) δ 1.48(9H,s), 3.46(2H,d,J=7Hz) , 3.49(3H,s), 5.44(1H,m), 7.07(1H,s), 7.13(2H,m), 7.42(2H,d,J=8Hz) , 7.57(1H,m), 7.68(2H,d,J=8Hz), 8.54(1H,d,J=5Hz) Preparation 1
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS(m/z) : 347 (M+1) Preparation 15
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS(m/z) : 428 (M+1)
'H-NMR (CDCI3) δ 1.41 (9H,s), 1.43(3H,t,J=7Hz) , 3.03(1H,m), 3.22(1H,dd,J=7 and 14Hz), 4.10(2H,q,J=7Hz), 4.57(1H,m), 4.65(2H,m), 5.01 (1H,m), 6.94(2H,d,J=8Hz), 7.16(2H,d,J=6Hz), 7.90(2H,d,J=8Hz), 8.51 (2H,d,J=6Hz) Preparation 16 The object compound was obtained according to a similar manner to that of Preparation 2.
MASS(m/z) : 423 (M+1)
1H-NMR (CDC13) δ 1.42(9H,s), 1.44(3H,t,J=7Hz) , 3.18(3H,s), 3.29(2H,m), 4.06(2H,q,J=7Hz) , 5.41 (1H,m), 6.93(2H,d,J=8Hz) , 6.97(1H,s), 7.06(2H,d,J=6Hz), 7.17(2H,d,J=8Hz), 8.47(2H,d,J=6Hz) Preparation 17
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS(m/z) : 323 (M+1) Preparation 18
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS(m/z) : 415 (M+1)
1H-NMR (CDC13) δ 1.47(9H,s), 4.77(2H,m), 5.42(1H,d,J=5Hz) , 6.51 (1H,m), 7.25(1H,m), 7.53(1H,d,J=8Hz), 7.73(1H,t,J=8Hz) , 8.08(2H,d,J=8Hz), 8.32(2H,d,J=8Hz) , 8.57(1H,d,J=5Hz) Preparation 19
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS(m/z) : 410 (M+1)
1H-NMR (CDCI3) δ 1.46(9H,s), 3.78(3H,s), 4.44(1H,d,J=5Hz), 7.17(1H,s), 7.23(1H,m), 7.47(1H,d,J=8Hz), 7.52(2H,d,J=8Hz), 7.70(1H,m), 8.28(2H,d,J=8Hz), 8.55(1H,d,J=5Hz) Preparation 20
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS(m/z) : 310 (M+1)
1H-NMR (CDC13) δ 3.65(3H,s), 5.48(1H,s), 7.21 (1H,s), 7.23(1H,m), 7.40(1H,d,J=8Hz), 7.52(2H,d,J=8Hz) , 7.71 (1H,t,J=8Hz) , 8.28(2H,d,J=8Hz), 8.57(1H,d,J=5Hz) Preparation 21
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS : 481 (M+1)
1H-NMR (CDCls) δ 1.41 (9H,s), 3.04(2H,d,J=7Hz) , 3.78(3H,s), 4.40(1H,br s), 4.52-4.73(2H,m) , 5.00(1H,br s) , 6.81(2H,d,J=8Hz), 6.82(1H,s), 7.11 (2H,d,J=8Hz), 7.59(1H,d,J=8Hz), 7.78(1H,dd,J=8 and 2Hz) , 8.02(1H,d,J=2Hz) Preparation 22
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 476 (M+1)
1H-NMR (CDCI3) δ 1.40(9H,s), 3.01 (3H,s), 3.02-3.15(1H,m) , 3.20-3.31 (1H,m), 3.76(3H,s), 4.90-5.00(1H,m), 5.62(1H,d,J=8Hz), 6.77(2H,d,J=8Hz) , 6.92(2H,d,J=8Hz) , 7.00-7.10(1H,m), 7.03(1H,s), 7.30(1H,d,J=2Hz) , 7.48(1H,d,J=8Hz) Preparation 23
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 376 (M+1)
'H-NMR (CDCI3) δ 3.11(2H,d,J=8Hz), 3.20(3H,s), 3.78(3H,s), 4.12(1H,t,J=8Hz), 6.80(2H,d,J=8Hz), 6.99(2H,d,J=8Hz), 7.07(1H,s), 7.10(1H,dd,J=8 and 2Hz) , 7.37(1H,s), 7.48(1H,d,J=8Hz) Preparation 24
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 174-176°C MASS : 495 (M+1)
'H-NMR (CDCI3) δ 1.40(9H,s), 3.09-3.22(2H,m) , 4.30-4.58(1H,m) , 4.60-4.80(2H,m), 4.92-5.12(1H,m) , 6.88(1H,br s) , 7.15-7.34(5H,m), 7.80(2H,d,J=8Hz) , 8.02(2H,d,J=8Hz) Preparation 25
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 403 (M+1)
1H-NMR (CDC13) δ 1.46(9H,s), 2.98(3H,s), 3.12(1H,t,J=8Hz) , 3.30-3. 0(1H,m), 5.01 (1H,q,J=8Hz) , 5.58(1H,d,J=8Hz) , 7.00-7.10(2H,m), 7.19-7.30(4H,m), 7.31 (2H,d,J=8Hz), 7.69(2H,d,J=8Hz) Preparation 26
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 303 (M+1)
'H-NMR (CDC13) δ 3.10-3.28(2H,m), 3.22(3H,s), 4.18(1H,t,J=8Hz) , 7.03-7.11(2H,m), 7.16(1H,s), 7.20-7.32(3H,m), 7.39(2H,d,J=8Hz), 7.70(2H,d,J=8Hz) Preparation 27
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 90-95°C MASS : 481 (M+1)
'H-NMR (CDC13) δ 1.41 (9H,s), 3.08(2H,d,J=8Hz) , 3.78(3H,s), 4.41(1H,br s), 4.61-4.80(2H,m) , 5.01(1H,s), 6.81 (2H,d,J=8Hz) , 6.89(1H,br s), 7.11 (2H,d,J=8Hz), 7.76(2H,d,J=8Hz) , 8.06(2H,d,J=8Hz) Preparation 28
The object compound was obtained according to a similar manner to that of Preparation 2. mp : 155-159°C MASS : 476 (M+1)
1H-NMR (CDCls) δ 1.46(9H,s), 3.00-3.18(1H,m) , 3.02(3H,s), 3.22-3.32(1H,m), 3.72(3H,s), 4.98(1H,q,J=8Hz), 5.56(1H,d,J=8Hz), 6.78(2H,d,J=8Hz) , 6.93(2H,d,J=8Hz), 7.11(1H,s), 7.37(2H,d,J=8Hz), 7.67(2H,d,J=8Hz) Preparation 29
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 376 (M+1)
'H-NMR (CDC13) δ 3.01-3.20(2H,m), 3.22(3H,s), 3.73(3H,s), 4.11(1H,t,J=8Hz), 6.81(2H,d,J=8Hz), 7.00(2H,d,J=8Hz) , 7.10(1H,s), 7.40(2H,d,J=8Hz), 7.68(2H,d,J=8Hz) Preparation 30
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 153-155°C MASS : 438 (M+1)
1H-NMR (CDC13) δ 1.42(9H,s), 3.08(2H,d,J=8Hz) , 3.78(3H,s), 4.41(1H,br s), 4.60-4.80(2H,m) , 4.99(1H,br s) , 6.82(2H,d,J=8Hz), 6.83(1H,br s), 7.12(2H,d,J=8Hz), 7.80(2H,d,J=8Hz), 8.05(2H,d,J=8Hz) Preparation 31
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 433 (M+1)
'H-NMR (CDCI3) δ 1.41 (9H,s), 3.01-3.11 (1H,m), 3.05(3H,s), 3.20-3.31 (1H,m), 3.78(3H,s), 4.90-5.03(1H,m), 5.52(1H,d,J=8Hz), 6.78(2H,d,J=8Hz), 6.92(2H,d,J=8Hz) , 7.12(1H,s), 7.33(2H,d,J=8Hz), 7.69(2H,d,J=8Hz) Preparation 32
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 333 (M+1)
1H-NMR (CDC13) δ 3.05-3.20(2H,m), 3.30(3H,s), 3.80(3H,s), 4.13(1H,t,J=8Hz), 6.81(2H,d,J=8Hz), 7.00(2H,d,J=8Hz), 7.14(1H,s), 7.40(2H,d,J=8Hz), 7.70(2H,d,J=8Hz) Preparation 33
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 123-125°C MASS : 511 (M+1)
'H-NMR (CDC13) δ 1.41 (9H,s), 3.20-3.38(2H,m) , 4.50-4.78(3H,m) , 5.03(1H,br s), 6.90(1H,br s), 7.35(1H,d,J=8Hz), 7.40-7.50(2H,m), 7.59-7.69(3H,m) , 7.70-7.81 (5H,m) Preparation 34
The object compound was obtained according to a similar manner to that of Preparation 2. mp : 204-206°C MASS : 506 (M+1)
1H-NMR (CDC13) δ 1.40(9H,s), 2.82(3H,s), 3.22-3.38(1H,m), 3.43-3.58(1H,m), 5.01-5.12(1H,m) , 5.60(1H,d,J=8Hz), 6.98(2H,d,J=8Hz), 7.05(1H,s), 7.18(1H,d,J=8Hz) , 7.40-7.52(5H,m), 7.68-7.72(2H,m) , 7.75-7.81 (1H,m) Preparation 35
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 406 (M+1) 1H-NMR (CDC13) δ 3.10(3H,s), 3.22-3.41 (2H,m) , 4.23(1H,t,J=8Hz), 7.02(1H,s), 7,04-7.11(2H,m), 7.21 (1H,d,J=8Hz). 7.40-7.57(5H,m), 7.70-7.88(3H,m) Preparation 36
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS : 428 (M+1)
1H-NMR (CDCls) δ 1.38(9H,s), 1.42(3H,t,J=8Hz) , 2.93-3.11 (!H,m) , 3.l2-3.28(1H,m), 4.10(2H,q,J=8Hz) , 4.47-4.58(1H,m) , 4.58-4.76(2H,m), 5.11 (1H,d,J=8Hz), 6.93(2H,d,J=8Hz), 7.01 (1H,s), 7.19-7.30(lH,m), 7.59(1H,d,J=8Hz) , 7.90(2H,d,J=8Hz), 8.40-8.59(2H,m) Preparation 37
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 423 (M+1)
^-NMR (CDC13) δ 1.39(9H,s), 1.41 (3H,t,J=8Hz) , 3.18(3H,s), 3.21-3.32(2H,m), 4.08(2H,q,J=8Hz) , 5.01 (1H,q,J=8Hz), 5.44(1H,d,J=8Hz), 6.91 (2H,d,J=8Hz) , 6.98(1H,s), 7.19(2H,d,J=8Hz), 7.40(1H,d,J=8Hz) , 8.38(1H,s), 8.40-8.50(2H,m) Preparation 38
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 323 (M+1)
1H-NMR (CDC13) c5 1.41 (3H,t, =8Hz) , 3.10-3.20(1H,m) , 3.21-3.30(1H,m), 3.28(3H,s), 4.05(2H,q,J=8Hz), 4.13(1H,t,J=8Hz), 6.91(2H,d,J=8Hz), 6.99(1H,s), 7.19(2H,d,J=8Hz), 7.21 (1H,t,J=6Hz) , 7.40(1H,d,J=8Hz) , 8.41 (1H,s), 8.49(1H,d,J=6Hz) Preparation 39
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS : 429 (M+1)
'H-MR (CDC13) δ 1.40(9H,s), 2.90-3.12(1H,m) , 3.18-3.28(1H,m), 4.59(1H,br s), 4.66-4.88(2H,m), 5.10(1H,d,J=8Hz), 7.10(1H,br s), 7.20(2H,d,J=4Hz) , 8.12(2H,d,J=8Hz) , 8.37(2H,d,J=8Hz), 8.52(2H,d,J=8Hz) Preparation 40
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 424 (M+1)
'H-NMR (CDCI3) δ 1.39(9H,s), 3.30(2H,d,J=8Hz) , 3.31 (3H,s), 5.12(1H,q,J=8Hz), 5.38(1H,d,J=8Hz) , 7.09(2H,d,J=4Hz) , 7.19(1H,s), 7.44(2H,d,J=8Hz), 8.29(2H,d,J=8Hz), 8.49(2H,d,J=4Hz) Preparation 41
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 324 (M+1)
1H-NMR (CDCI3) δ 3.11-3.21 (1H,m), 3.28-3.38(1H,m), 3.42(3H,s), 4.2l(1H,t,J=8Hz), 7.09(2H,d,J=6Hz), 7.20(1H,s), 7.49(2H,d,J=8Hz), 8.29(2H,d,J=8Hz), 8.52(2H,d,J=7Hz) Preparation 42
The object compound was obtained according to a similar manner to that of Preparation 1.
MASS (ESI) (m/z) : 491,493 (M+H)+ 1H-NMR (CDCI3,300MHz) <5 : 1.41(9H,s), 3.04(2H,d,J=6Hz) ,
3.75(3H,s), 4.42(1H,br s), 4.54-4.77(2H,m), 5.00(1H,br s), 6.81(2H,d,J=8Hz), 6.85(1H,br s) , 7.12(2H,d,J=8Hz) , 7.63(2H,d,J=7Hz), 7.80(2H,d,J=7Hz) Preparation 43
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 486,488 (M+H)+ 'H-NMR (CDCl3,300MHz)<5 : 1.41 (9H,s), 3.00(3H,s), 3.01-3.32(2H,m), 3.76(3H,s), 4.88-5.02(1H,m), 5.57(1H,d,J=8Hz), 6.76(2H,d,J=8Hz) , 6.88-7.18(5H,m), 7.51(2H,d,J=8Hz) Preparation 44
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 386,388 (M+H)+ 1H-NMR (CDC13,300MHz) <5 : 3.02-3.18(2H,m) , 3.20(3H,s), 3.78(3H,s), 4.12(1H,t,J=7Hz), 6.81 (2H,d,J=8Hz), 6.98(2H,d,J=8Hz), 7.03(1H,s), 7.15(2H,d,J=8Hz), 7.52(2H,d,J=8Hz) Preparation 45
The object compound was obtained according to a similar manner to that of Preparation 1. amorphous solid MASS : 461 (M+1) H-NMR (CDC13) δ : 1.39(9H,s), 3.00-3.20(2H,m) ,
4.40-4.78(3H,m), 5.03(1H,bs), 6.89(1H,bs), 7.19-7.38(5H,m), 7.63(2H,d,J=8Hz), 7.82(2H,d,J=8Hz) Preparation 46
The object compound was obtained according to a similar manner to that of Preparation 2. mp : 162-164°C MASS : 456 (M+1) 'H-NMR (CDC13) δ : 1.41 (9H,s), 2.97(3H,s), 3.11(1 x 1/3H,d,J=8Hz), 3.15(1 x 2/3H,d,J=8Hz) , 3.31(1 x 2/3H,d,J=8Hz), 3.35(1 x 1/3H,d,J=8Hz), 4.9l-5.08(1H,m), 5.59(1H,d,J=8Hz) , 6.99-7.07(3H,m) , 7.09(2H,d,J=8Hz), 7.18-7.23(3H,m) , 7.51 (2H,d,J=8Hz) Preparation 47
The object compound was obtained according to a similar manner to that of Preparation 3. oil
MASS : 356 (M+1)
'H-NMR (CDC13) δ : 3.10-3.25(2H,m) , 3.20(3H,s), 4.17(1H,t,J=8Hz), 7.05(1H,s), 7.10(2H,d,J=8Hz) , 7.l4(2H,d,J=8Hz), 7.20-7.32(3H,m) , 7.53(2H,d,J=8Hz) Preparation 48
A solution of potassium tert-butoxide (4.2 g) in anhydrous tetrahydrofuran (70 ml) was cooled under nitrogen atmosphere to -70°C, and a solution of the starting compound (10 g) in anhydrous tetrahydrofuran (35 ml) was added while maintaining the reaction temperature at -70°C. After 30 minutes, this solution was added dropwise to a solution of 4-bromobenzoyl chloride (8.21 g) in anhydrous tetrahydrofuran (24 ml) with stirring while cooling at -70°C on a cooling bath. The reaction mixture was stirred at -70°C for 1 hour and quenched with 3N-hydrochloric acid (100 ml). The cooling bath was removed and the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (15 ml) and extracted with diethyl ether (twice). The aqueous layer was concentrated in vaciio , and the residue was dissolved in anhydrous methanol. The precipitated white solid (KCl) was removed by filtration. The filtrate was concentrated in vacuo and the residue was crystallized from tetrahydrofuran/diethyl ether to give the object compound as an off-white solid, mp : 183-188°C MASS : 286 (M+H)+ 1 H-NMR (DMSO-de, d) 1.03(3H,t,J=7.0Hz), 4.13(2H,q,J=7.0Hz), 6.24(1H,s), 7.86(2H,d,J=7.5Hz), 8.09(2H,d,J=7.5Hz), 9.10(2H,br s), Preparation 49
The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow amorphous solid
MASS : 531 (M-H)+ 1H-NMR (CDC13, δ ) 1.14(3H,t,J=7.0Hz), 1.40(9H,s),
2.97-3.18(2H,m), 4.16(2H,q,J=7.0Hz) , 4.49(lH,m), 4.96(1H,m), 6.03(1Hx3/7,d,J=7.0Hz), 6.06(1 Hx 4/7,d,J=7.0Hz) , 7.14-7.31 (6H,m), 7.64(2H,d,J=7.5Hz) , 7.95(2Hx3/7,d,J=7.5Hz) , 7.97(2Hx4/7,d,J=7.5Hz) Preparation 50
The object compound was obtained according to a similar manner to that of Preparation 2. pale yellow amorphous solid MASS : 528 (M+H)+ 1H-NMR (CDC13, δ ) 1.18(3H,t,J=7.0Hz), 1.41 (9H,s), 2.69(3H,s), 3.17(1H,dd,J=13.5 and 9.0Hz), 3.37(1H,dd,J=13.5 and 7.0Hz), 4.23(2H,q,J=7.0Hz), 4.98(1H,m), 5.74(1H,d,J=7.5Hz) , 6.97-7.08(4H,m), 7.19-7.27(3H,m) , 7.55(2H,d,J=7.5Hz) Preparation 51
To a solution of the starting compound (2.0 g) in ethanol (20 ml) was added 1N-sodium hydroxide solution (4.16 ml) with stirring at room temperature. The reaction mixture was stirred at 60°C for 6.5 hours and concentrated in vacuo. Water was added to the residue, and the aqueous solution was washed with ethyl acetate (twice). The aqueous layer was acidified to pH 3 with 1N-hydrochloric acid, and extracted with chloroform (twice). The combined extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the object compound (2.13 g) as a pale yellow amorphous solid. MASS : 498 (M-H)+ 1 H-NMR (DMSO-dβ, δ ) 1.27(9Hx 1/5,s) , 1.30(9Hx4/5,s) , 3.01 (3Hx 1/5,s), 3.07(3Hx4/5,s), 3.13-3.21 (2H,m) , 5.09(1H,m), 6.98-7.31 (7H,m), 7.58(2H,d,J=7.5Hz) , 8.03(1H,d,J=7.5Hz) Preparation 52
The object compound was obtained according to a similar manner to that of Preparation 5. off-white amorphous solid
MASS : 513 (M+H)+ 1H-NMR (CDC13, δ ) 1.42(9Hxl/5,s), 1.46(9Hx4/5,s), 2.70(3Hx1/5,s), 2.76(3Hx4/5,s), 2.92(3H,d,J=6.0Hz) , 3.09(1H,dd,J=13.5 and 9.0Hz), 3.34(1H,dd,J=13.5 and 6.0Hz), 4.97(1H,m), 5.47(1H,d,J=7.5Hz) , 6.97-7.06(3H,m) , 7.12(2H,d,J=7.5Hz), 7.19-7.25(3H,m) , 7.53(2H,d,J=7.5Hz) Preparation 53
The object compound was obtained according to a similar manner to that of Preparation 3. pale brown oil
MASS : 413 (M+H)+ H-NMR (CDCls, δ ) 2.91(3H,d,J=4.5Hz), 2.97(3H,s),
3.13(2H,d,J=7.5Hz), 4.17(1H,t,J=7.5Hz) , 7.03-7.31 (6H,m), 7.19(2H,d,J=7.5Hz), 7.56(2H,d,J=7.5Hz) Preparation 54
The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow amorphous solid
MASS : 543 (M+H)+ 1 H-NMR (CDC13, δ ) 1.42(9H,s), 2.85(3H,s), 3.15(1H,dd,J=13.5 and 9.0Hz), 3.30(3H,s), 3.34(1H,dd,J=13.5 and 6.0Hz), 3.74(3H,s), 5.00(1H,m), 5.51(1H,d,J=7.5Hz), 6.99-7.06(2H,m) , 7.09(2H,d,J=7.5Hz), 7.19-7.27(3H,m), 7.53(2H,d,J=7.5Hz) Preparation 55
The object compound was obtained according to a similar manner to that of Preparation 3. pale yellow oil MASS : 443 (M+H)+ 1H-NMR (CDCI3, δ ) 3.03(3H,s), 3.12-3.25(2H,m), 3.30(3H,s), 3.77(3H,s), 4.17(1H,t,J=7.0Hz), 7.04-7.11 (2H,m) , 7.16(2H,d,J=7.5Hz), 7.22-7.32(3H,m) , 7.54(2H,d,J=7.5Hz) Preparation 56
The object compound was obtained according to a similar manner to that of Preparation 5. colorless amorphous solid MASS : 527 (M+H)+ 1H-NMR (CDCI3, δ ) 1.42(9H,s), 2.88(3H,s), 2.99(3H,s), 3.03(3H,s), 3.13(1H,dd,J=13.5 and 7.5Hz), 3.33(1H,dd,J=13.5 and 6.0Hz), 5.00(1H,m), 5.52(1H,d,J=7.5Hz), 7.00-7.09(2H,m), 7.11 (2H,d,J=7.5Hz) , 7.20-7.26(3H,m) , 7.52(2H,d,J=7.5Hz) Preparation 57
The object compound was obtained according to a similar manner to that of Preparation 3. colorless oil MASS : 427 (M+H)+ 1 H-NMR (CDC13, c5) 2.98(3H,s), 3.06(3H,s), 3.07(3H,s), 3.18(2H,d,J=7.5Hz), 4.18(1H,t,J=7.5Hz), 7.04-7.13(2H,m), 7.17(2H,d,J=7.5Hz), 7.22-7.31 (3H,m) , 7.53(2H,d,J=7.5Hz) Preparation 58
The object compound was obtained according to a similar manner to that of Preparation 5. off-white amorphous solid MASS : 575 (M+H)+ 1 H-NMR (CDCI3, δ ) 1.42(9Hx1/5,s), 1.49(9Hx4/5,s) , 2.70(3Hx1/5,s), 2.80(3Hx4/5,s),
3.15(1H,dd,J=13.5 and 9.0Hz), 3.39(1H,dd,J=13.5 and 7.0Hz), 5.01 (1H,m), 5.51(1Hx4/5,d,J=7.5Hz), 5.76(1Hx 1/5,d,J=7.5Hz) , 6.99-7.10(4H,m), 7.17(2H,d,J=7.5Hz) , 7.19-7.28(4H,m) , 7.31(2H,t,J=7.5Hz), 7.56(2H,d,J=7.5Hz) , 9.11(1H,s) Preparation 59
The object compound was obtained according to a similar manner to that of Preparation 3. pale yellow oil MASS : 475 (M+H)+ 1H-NMR (CDCI3, δ ) 3.01 (3H,s), 3.16-3.24(2H,m) , 4.16-4.26(1H,m) , 7.03-7.14(4H,m), 7.22(2H,d,J=7.5Hz) , 7.24-7.34(6H,m) , 7.58(2H,d,J=7.5Hz), 9.19(1H,s) Preparation 60
To a solution of the starting compound (2.65 g) and triethylamine (1.5 ml) in tetrahydrofuran (10 ml) was added isobutyl chloroformate (1.3 ml) at -10°C, and the mixture was stirred at -10°C for 10 minutes. To the solution was added dropwise a solution of o- phenylenediamine (1.15 g) in tetrahydrofuran (10 ml) at -5°C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was concentrated, then the residue was poured into a saturated sodium hydrogencarbonate solution and extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. Evaporation of the solvent gave the object compound as an oil (4.11 g). MASS (ESI) (m/z) : 356 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.40(9Hx 1/3,s) , 1.42(9Hx2/3,s), 3.03-3.28(2H,m), 4.38-4.52(lH,m) , 5.05-5.26(1H,br s) , 6.65-7.42(10H,m) Preparation 61
A solution of the starting compound (3.55 g) in acetic acid (1 ml) and ethanol (10 ml) was refluxed for 4 hours. The mixture was concentrated, neutralized with 1N sodium hydroxide solution, and extracted three times with chloroform. The organic layer was washed successively with 1N hydrochloric acid, a saturated sodium hydrogencarbonate solution and brine, then dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methanol=50/1 ) to give the object compound as a white powder (2.69 g). MASS (ESI) (m/z) : 338 (M+H)+ 'H-NMR (CDCI3,300MHz) δ 1.36(9Hx 1/2,s) , 1.39(9Hx 1/2,s) ,
2.95-3.46(2H,m), 4.41-4.55(1Hx 1/2,m), 5.06-5.22(1Hx1/2,m), 5.30(1Hx1/2,br s), 5.73(1Hx 1/2,d,J=8Hz) , 7.02-7.38(9H,m), 7.68(1Hx1/2,br s) , 8.46(1Hx 1/2,br s) Preparation 62
To a suspension of the starting compound (500 mg) and potassium carbonate (614 mg) in N,N-dimethylformamide (5 ml) was added methyl iodide (0.28 ml) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 30°C for 3 hours. After being cooled to room temperature, the mixture was diluted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo . The residue was purified by flash column chromatography over silica gel with chloroform-methanol (30:1) as eluent to give the object compound (264 mg) as a colorless solid, mp : 186-189°C MASS : 352 (M+H)+ 1 H-NMR (DMSO-de, δ ) 1.12(9Hx 1/8,s) , 1.28(9Hx7/8,s) , 3.14-3.30(2H,m), 3.60(3Hx 1/8,s), 3.62(3Hx7/8,s), 5.11 (1H,m), 7.11-7.29(7H,m), 7.47(1H,d,J=7.5Hz), 7.54(1H,d,J=7.5Hz) , 7.61 (1H,d,J=7.5Hz) Preparation 63
The object compound was obtained according to a similar manner to that of Preparation 3. pale yellow oil MASS : 252 (M+H)+ 1H-NMR (CDC13, δ ) 3.19(1H,dd,J=13.5 and 7.5Hz),
3.27(1H,dd,J=13.5 and 7.5Hz), 3.46(3H,s), 4.35(1H,t,J=7.5Hz) , 7.06-7.12(2H,m), 7.19"7.30(6H,m), 7.77(1H,m) Preparation 64
The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow solid mp : 153-155°C MASS : 447 (M+H)+ 1H-NMR (CDCI3, δ ) 1.41(9H,s), 4.63(1H,dd,J=19.5 and 5.5Hz), 4.77(1H,dd,J=19.5 and 5.5Hz), 5.24(1H,m), 5.71(1H,br d,J=5.5Hz), 6.79(1H,m), 7.29"7.44(5H,m), 7.63(2H,d,J=7.5Hz), 7.80(2H,d,J=7.5Hz) Preparation 65
The object compound was obtained according to a similar manner to that of Preparation 2. pale yellow amorphous solid MASS : 442 (M+H)+ 1H-NMR (CDCI3, δ ) 1.43(9H,s), 3.40(3H,s), 5.96(1H,d,J=7.5Hz), 6.20(1H,d,J=7.5Hz), 7.06(1H,s), 7.20(2H,d,J=7.5Hz), 7.27-7.37(5H,m), 7.53(2H,d,J=7.5Hz) Preparation 66
The object compound was obtained according to a similar manner to that of Preparation 3. brown oil MASS : 342 (M+H)+ 1H-NMR (CDC13, δ ) 3.35(3H,s), 5.21 (1H,s), 7.08(1H,s), 7.20(2H,d,J=7.5Hz), 7.23-7.40(5H,m) , 7.53(2H,d,J=7.5Hz) Preparation 67 The object compound was obtained according to a similar manner to that of Preparation 1. amorphous solid MASS : 417 (M+1) 'H-NMR (CDCls) δ : 1.40(9H,s), 3.11 (2H,d,J=8Hz) ,
4.40-4.60(1H,m), 4.60-4.78(2H,m), 5.00(1H,bs), 6.84(1H,bs), 7.17-7.36(5H,m), 7.49(2H,d,J=8Hz) , 7.90(2H,d,J=8Hz) Preparation 68
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 412 (M+1)
1 H-NMR (CDCI3) δ : 1.41 (9H,s), 2.92(3H,s), 3.00-3.20(lH,m) , 3.24-3. 0(1H,m), 5.00(1H,q,J=8Hz) , 5.59(1H,d,J=8Hz) , 7.00-7.10(3H,m), 7.14(2H,d,J=8Hz) , 7.18-7.30(3H,m) , 7.37(2H,d,J=8Hz) Preparation 69
The object compound was obtained according to a similar manner to that of Preparation 3. oil
MASS : 312 (M+1)
1 H-NMR (CDC13) δ : 3.10-3.28(2H,m), 3.18(3H,s), 4.10-4.24(1H,m), 7.08(2H,d,J=8Hz) , 7.11 (1H,s), 7.21(2H,d,J=8Hz), 7.22-7.33(3H,m) , 7.39(2H,d,J=8Hz) Preparation 70
The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow oil MASS : 395 (M+H)+ 1 H-NMR (CDC13, δ ) 1.49(9H,s), 3.03-3.47(2H,m) , 4.49"4.77(4H,m), 5.03(1H,m), 6.87(1H,m), 7.03-7.27(4H,m) , 7.46(2H,t,J=7.5Hz) , 7.60(1H,t,J=7.5Hz), 7.90(2H,d,J=7.5Hz) Preparation 71
The object compound was obtained according to a similar manner to that of Preparation 2. pale brown oil MASS : 390 (M+H)+ 1 H-NMR (CDCI3, δ ) 1.46(9H,s), 3.31 (1H,dd,J=16.0 and 7.0Hz) , 3.52(1H,dd,J=16.0 and 2.5Hz), 3.60(3H,s), 4.01 (1H,d,J=16.0Hz) , 4.51-5.93(2H,m), 6.91 (1H,s), 7.05(1H,d,J=7.5Hz), 7.11-7.49(8H,m) Preparation 72
The object compound was obtained according to a similar manner to that of Preparation 3. pale brown solid mp : 162-165°C MASS : 290 (M+H)+ 'H-NMR (CDCI3, δ ) 3.10(lH,dd,J=16.0 and 3.0Hz),
3.55(1H,dd,J=16.0 and 11.5Hz), 3.72(3H,s), 4.05-4.28(3H,m), 7.03(1H,s), 7.08(1H,m), 7.12-7.21 (3H,m) , 7.32-7.49(5H,m) Preparation 73
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 436 (M+H)+
'H-NMR (CDCI3,300MHz) δ 1.42(9H,s), 3.12-3.45(2H,m), 3.73(3H,s), 4.44-4.61 (1H,m), 4.62(2H,d,J=2Hz), 5.18(1H,br d,J=8Hz) , 6.82(1H,br t,J=2Hz), 6.94(1H,s), 7.01-7.30(3H,m), 7.41-7.66(4H,m), 7.90(2H,d,J=8Hz) Preparation 74
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 431 (M+H)+
'H-NMR (CDCI3,300MHz) δ 1.41 (9H,s), 2.87(3H,s), 3.18-3.58(2H,m) , 3.70(3H,s), 5.00-5.13(1H,m), 5.70(1H,br d,J=8Hz) , 6.80(1H,s), 6.91-7.40(10H,m) Preparation 75
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 331 (M+H)+
'H-NMR (CDC13,300MHz) <5 3.22-3. 3(2H,m) , 3.25(3H,s), 3.74(3H,s), 4.25(1H,t,J=7Hz), 6.87(1H,s), 7.00-7.48(10H,m) Preparation 76
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 506, 508 (M+H)+ H-NMR (CDCls,300MHz) δ 1.39(9H,s), 3.13(1H,dd,J=13 and 8Hz) , 3.29(1H,dd,J=13 and 6Hz), 4.46-4.78(3H,m) , 5.10(1H,br d,J=8Hz), 6.98(1H,br s), 7.39(2H,d,J=8Hz), 7.64(2H,d,J=8Hz), 7.80(2H,d,J=8Hz) , 8.16(2H,d,J=8Hz) Preparation 77
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 501, 503 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.39(9H,s), 3.28(3H,s), 3.32-3.50(2H,m) , 5.03-5.17(1H,m), 5.33(1H,br d,J=8Hz) , 7.02(1H,s), 7.13(2H,d,J=8Hz), 7.32(2H,d,J=8Hz) , 7.56(2H,d,J=8Hz), 8.11(2H,d,J=8Hz) Preparation 78
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 401, 403 (M+H)+ 1 H-NMR (CDCI3,300MHz) <5 3.25(1H,dd,J=13 and 7Hz), 3.36(3H,s), 3.41(1H,dd,J=13 and 7Hz), 4.20(1H,t,J=7Hz) , 7.03(1H,s), 7.17(2H,d,J=8Hz), 7.31 (2H,d,J=8Hz) , 7.55(2H,d,J=8Hz) , 8.15(2H,d,J=8Hz) Preparation 79 The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 458 (M+H)+ 1 H-NMR (CDC13,300MHz) c5 1.42(9H,s), 2.93-3.15(2H,m) , 3.77(3H,s), 4.34-4.51 (1H,m), 4.62-4.86(2H,m), 5.00(1H,br d,J=8Hz) , 6.82(2H,d,J=8Hz), 6.88(1H,br s) , 7.13(2H,d,J=8Hz), 8.11(2H,d,J=8Hz), 8.35(2H,d,J=8Hz) Preparation 80
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 453 (M+H)+
' H-NMR (CDCI3,300MHz) δ 1.42(9H,s), 3.02-3.33(2H,m) , 3.08(3H,s), 3.76(3H,s), 4.90-5.05(1H,m), 5.55(1H,br d,J=8Hz), 6.77(2H,d,J=8Hz), 6.94(2H,d,J=8Hz) , 7.19(1H,s), 7.41(2H,d,J=8Hz), 8.26(2H,d,J=8Hz) Preparation 81
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 353 (M+H)+ 1 H-NMR (CDC13,300MHz) c5 3.02-3.21 (2H,m) , 3.29(3H,s), 3.78(3H,s), 4.14(1H,t,J=7Hz), 6.82(2H,d,J=8Hz), 7.00(2H,d,J=8Hz) , 7.20(1H,s), 7.46(2H,d,J=8Hz), 8.28(2H,d,J=8Hz) Preparation 82
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 477, 479 (M+H)+
' H-NMR (CDCl3,300MHz)<5 1.41 (9H,s), 3.78(3H,s), 4.56-4.82(2H,m) , 5.19(1H,br s), 5.66(1H,br d,J=8Hz), 6.80(1H,br s), 6.89(2H,d,J=8Hz), 7.32(2H,d,J=8Hz) , 7.63(2H,d,J=8Hz), 7.89(2H,d,J=8Hz) Preparation 83
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 472, 474 (M+H)+
'H-NMR (CDCI3,300MHz) δ 1.41 (9H,s), 3.37(3H,s), 3.78(3H,s), 5.91(1H,br d,J=8Hz), 6.18(1H,br d,J=8Hz) , 6.86(2H,d,J=8Hz) , 7.06(1H,s), 7.19(2H,d,J=8Hz), 7.25(2H,d,J=8Hz) , 7.53(2H,d,J=8Hz) Preparation 84
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 372, 374 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 3.33(3H,s), 3.78(3H,s), 5.15(1H,s), 6.87(2H,d,J=8Hz), 7.05(lH,s), 7.19(2H,d,J=8Hz) , 7.23(2H,d,J=8Hz), 7.52(2H,d,J=8Hz) Preparation 85
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 479, 481 (M-H)" ' H-NMR (CDCI3,300MHz) δ 1.41 (9H,s), 4.55-4.82(2H,m) , 5.24(1H,br s), 5.76(1H,br d,J=8Hz) , 6.81 (1H,br s), 7.28-7.41 (4H,m), 7.63(2H,d,J=8Hz) , 7.79(2H,d,J=8Hz) , Preparation 86
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 476, 478 (M+H)+
' H-NMR (CDC13,300MHz) δ 1.41 (9H,s), 3.40(3H,s),
5.91(1H,br d,J=8Hz), 6.25(1H,br d,J=8Hz), 7.04(1H,s), 7.18(2H,d,J=8Hz), 7.23"7.36(4H,m) , 7.55(2H,d,J=8Hz) Preparation 87
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 376, 378 (M+H)+ 1 H-NMR (CDC13,300MHz) δ 3.35(3H,s), 5.20(1H,s), 7.05(1H,s), 7.19(2H,d,J=8Hz), 7.22-7.38(4H,m) , 7.54(2H,d,J=8Hz) Preparation 88
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 471 (M-H)" 1 H-NMR (CDCI3,300MHz) δ 1.41 (9H,s), 3.09~3.39(2H,m) , 4.48-4.62(1H,m), 4.65-4.88(2H,m) , 5.04(1H,br d,J=8Hz) , 6.97(1H,br s), 7.41 (2H,d,J=8Hz), 8.12(2H,d,J=8Hz) , 8.17(2H,d,J=8Hz), 8.35(2H,d,J=8Hz) Preparation 89
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 468 (M+H)+
'H-NMR (CDCI3,300MHz) δ 1.39(9H,s), 3.31-3.51 (2H,m) , 3.39(3H,s), 5.09-5.22(1H,m), 5.33(1H,br d,J=8Hz) , 7.18(1H,s), 7.33(2H,d,J=8Hz), 7.45(2H,d,J=8Hz) , 8.11 (2H,d,J=8Hz) , 8.28(2H,d,J=8Hz) Preparation 90
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 368 (M+H)+
'H-NMR (CDCI3,300MHz) δ 3.26(1H,dd,J=13 and 7Hz),
3.45(1H,dd,J=13 and 7Hz), 3.50(3H,s), 4.25(1H,t,J=7Hz), 7.20(1H,s), 7.35(2H,d,J=8Hz), 7.49(2H,d,J=8Hz) , 8.15(2H,d,J=8Hz), 8.29(2H,d,J=8Hz) Preparation 91
To an ice-cooled solution of the starting compound (5.32 g) and N,N-diisopropylethylamine (9.6 ml) in N,N-dimethylformamide (27 ml) was added diphenylphosphoryl azide (6.04 g). After 5 minutes, 2- amino-4'-nitroacetophenone hydrochloride (4.53 g) was added portionwise to the above solution, and the resulting deep-colored mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and then the mixture was extracted three times with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=l/1) to give the object compound as a deep-red oil (5.96 g). MASS (ESI) (m/z) : 429 (M+H)+
' H-NMR (CDCI3,300MHz) δ 1.46(9H,s), 3.20-3.43(2H,m) , 4.62-4.78(3H,m), 6.43(1H,br d,J=8Hz), 7.12-7.27(2H,m), 7.56-7.67(1H,m), 8.04(1H,br s) , 8.10(2H,d,J=8Hz) , 8.32(2H,d,J=8Hz), 8.54(1H,d,J=5Hz) Preparation 92
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 424 (M+H)+
'H-NMR (CDC13,300MHZ)(5 1.38(9H,s), 3.38-3.50(2H,m) , 3.53(3H,s), 5.37-5.51 (1H,m), 5.54(1H,br d,J=8Hz) , 7.05-7.20(3H,m) , 7.46(2H,d,J=8Hz), 7.55(1H,t,J=8Hz) , 8.27(2H,d,J=8Hz) , 8.52(1H,d,J=5Hz) Preparation 93
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 324 (M+H)+
' H-NMR (CDCI3,300MHz) δ 3.27-3.50(2H,m), 3.61 (3H,s),
4.62(1H,dd,J=8 and 6Hz), 7.11-7.22(3H,m), 7.50(2H,d,J=8Hz), 7.61(1H,t,J=7Hz), 8.29(2H,d,J=8Hz), 8.58(1H,d,J=5Hz) Preparation 94
The object compound was obtained according to a similar manner to that of Preparation 91.
MASS (ESI) (m/z) : 429 (M+H)+
' H-NMR (CDCl3,300MHz) <5 1.45(9H,s), 3.18-3.42(2H,m) , 4.6l-4.78(3H,m), 6.43(1H,br d,J=8Hz) , 7.10-7.29(2H,m), 7.55-7.67(1H,m), 8.05(1H,br s) , 8.09(2H,d,J=8Hz) , 8.32(2H,d,J=8Hz), 8.54(1H,d,J=5Hz) Preparation 95
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 424 (M+H)+
'H-NMR (CDCl3,300MHz) 5 1.36(9H,s), 3.38-3.50(2H,m), 3.53(3H,s), 5.36-5.54(2H,m), 7.06-7.18(3H,m), 7.46(2H,d,J=8Hz), 7.56(1H,t,J=8Hz), 8.27(2H,d,J=8Hz), 8.52(1H,d,J=5Hz) Preparation 96
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 324 (M+H)+ 1H-NMR (CDCl3,300MHz)<5 3.28-3.51 (2H,m) , 3.62(3H,s),
4.62(1H,dd,J=8 and 6Hz) , 7.11-7.22(3H,m), 7.50(2H,d,J=8Hz), 7.60(1H,t,J=7Hz), 8.29(2H,d,J=8Hz), 8.58(1H,d,J=5Hz) Preparation 97
The object compound was obtained according to a similar manner to that of Preparation 91. oil
MASS : 399 (M+1)
1 H-NMR (CDC13) c5 1.45(9H,s), 2.62(3H,s), 3.20-3.30(1H,m) , 3.31-3.42(1H,m), 4.68(2H,d,J=4Hz), 4.62-4.73(lH,m), 6.43(1H,br s), 7.11-7.30(3H,m), 7.60(1H,t,J=8Hz), 7.99(1H,br s), 8.09(1H,d,J=8Hz) , 8.57(1H,d,J=4Hz), 9.02(1H,s) Preparation 98
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS : 394 (M+1)
' H-NMR (CDC13) δ 1.33(9H,s), 2.60(3H,s), 3.40(3H,s), 3.42(2H,d,J=8Hz), 5.40(1H,q,J=8Hz) , 5.49(lH,d,J=8Hz) , 7.01 (1H,s), 7.07-7.19(2H,m), 7.20(1H,d,J=8Hz), 7.49-7.59(2H,m), 8.42(1H,d,J=2Hz) , 8.52(lH,d,J=2Hz) Preparation 99
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 294 (M+1)
'H-NMR (CDCI3) δ 2.59(3H,s), 3.29-3.50(2H,m) , 3.51 (3H,s), 4.60(1H,t,J=8Hz), 7.02(1H,s), 7.10-7.22(3H,m) , 7.50-7.63(2H,m), 8.48(1H,s), 8.58(1H,d,J=4Hz) Preparation 100
The object compound was obtained according to a similar manner to that of Preparation 91. oil
MASS : 385 (M+1)
'H-NMR (CDCI3) δ 1.41(9H,s), 3.21-3.41 (2H,m), 4.68(1H,br s), 4.70(2H,d,J=6Hz), 6.42(1H,br s), 7.11-7.23(2H,m), 7.42(1H,dd,J=8 and 6Hz) , 7.61 (1H,t,J=8Hz) , 8.02(1H,br s) , 8.20(1H,dd,J=8 and 2Hz), 8.54(1H,d,J=2Hz) , 8.81 (1H,d,J=2Hz) , 9.16(1H,d,J=2Hz) Preparation 101
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 380 (M+1)
' H-NMR (CDCI3) δ 1.38(9H,s), 3.40-3.50(2H,m), 3.43(3H,s), 5.41(1H,q,J=8Hz), 5.50(1H,d,J=8Hz) , 7.07(1H,s), 7.11(2H,t,J=8Hz), 7.35(1H,dd,J=8 and 6Hz) , 7.55(1H,t,J=8Hz), 7.61(1H,d,J=8Hz), 8.49~8.62(3H,m) Preparation 102
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 280 (M+1)
1 H-NMR (CDCI3) δ 3.30-3.39(1H,m), 3.40-3.49(1H,m) , 3.52(3H,s), 4.60(1H,dd,J=8 and 6Hz) , 7.09(1H,s), 7.10-7.19(2H,m), 7.37(1H,dd,J=8 and 6Hz), 7.59(1H,d,J=8Hz), 7.63(1H,dd,J=8 and 2Hz) , 8.53-8.62(3H,m) Preparation 103
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 469 (M-H)"
' H-NMR (CDCl3,300MHz)<5 1.42(9H,s), 1.45(3H,t,J=7Hz) , 3.01(2H,d,J=7Hz), 4.11 (2H,q,J=7Hz) , 4.29-4.52(1H,m) , 4.53-4.74(2H,m), 4.94-5.12(1H,m), 5.90(2H,s), 6.59-6.78(3H,m), 6.93(1H,br s), 6.94(2H,d,J=8Hz) , 7.92(2H,d,J=8Hz) Preparation 104
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 466 (M+H)+ 1 H-NMR (CDC13,300MHz) c5 1.41 (9H,s), 1.42(3H,t,J=7Hz) , 3.01-3.28(2H,m), 3.08(3H,s), 4.05(2H,q,J=7Hz), 4.87-5.01 (1H,m), 5.56(1H,br d,J=8Hz) , 5.90(2H,s), 6.51(1H,d,J=8Hz), 6.52(1H,s), 6.68(1H,d,J=8Hz), 6.91(2H,d,J=8Hz), 6.96(1H,s), 7.17(2H,d,J=8Hz) Preparation 105
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 366 (M+H)+
' H-NMR (CDCl3,300MHz)<5 1.44(3H,t,J=7Hz) , 2.98-3.20(2H,m) , 3.25(3H,s), 4.07(2H,q,J=7Hz), 4.09(1H,t,J=7Hz) , 5.91 (2H,s), 6.55(1H,d,J=8Hz), 6.58(1H,s), 6.72(1H,d,J=8Hz) , 6.92(2H,d,J=8Hz), 6.97(1H,s), 7.19(2H,d,J=8Hz) Preparation 106 The object compound was obtained according to a similar manner to that of Preparation 2 except that ethylamine was used instead of methylamine.
MASS (ESI) (m/z) : 438 (M+H)+
' H-NMR (CDCl3,300MHz)5 1.14(3H,t,J=7Hz) , 1.36(9H,s), 3.35-3.57(2H,m), 3.92-4.18(2H,m), 5.32-5.52(2H,m), 7.05-7.18(3H,m), 7.49(2H,d,J=8Hz), 7.50-7.60(1H,m) , 8.28(2H,d,J=8Hz), 8.53(1H,d,J=5Hz) Preparation 107
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 338 (M+H)+ 1 H-NMR (CDC13,300MHz) δ 1.20(3H,t,J=7Hz) , 3.29~3.52(2H,m) , 3.94-4.20(2H,m), 4.62(1H,t,J=7Hz) , 7.09-7.20(3H,m) , 7.51(2H,d,J=8Hz), 7.53-7.63(1H,m) , 8.28(2H,d,J=8Hz), 8.58(1H,d,J=5Hz) Preparation 108
To a solution of the starting compound (50.25 g) in acetic acid (400 ml) was added 30 hydrogen bromide/acetic acid (d 1.35, 80 ml). Bromine (40.9 g) was added dropwise to the mixture for 20 minutes while the temperature of the reaction mixture was maintained between 20-25°C. After the addition was complete, the mixture was heated at 50°C for 1 hour and allowed to cool to room temperature. The mixture was diluted with diisopropyl ether (400 ml) and the product was filtered and washed with diisopropyl ether. Recrystallization from methanol (750 ml) gave the object compounhd as a white powder (68.83 g).
MASS (ESI) (m/z) : 265, 267 (free, M+H)+ ' H-NMR (DMS0-d_, 300MHz) δ : 5.01 (2H,s), 7.94(1H,s), 8.02(2H,d,J=8Hz), 8.24(2H,d,J=8Hz), 8.41 (1H,s), 9.89(1H,s) Preparation 109 To a suspension of the starting compound (48.7 g) in N,N- dimethylformamide (500 ml) was added sodium azide (9.15 g) at 5 °C. The mixture was stirred at the same temperature for 30 minutes, then at room temperature for 1 hour. The mixture was poured into diluted sodium hydrogencarbonate solution (1.6 L) and extracted three times with ethyl acetate. The extract was washed twice with brine and dried over magnesium sulfate. Evaporation of the solvent gave the object compound as a white solid (18.9g).
MASS (ESI) (m/z) : 228 (M+H)+
'H-NMR (DMS0-d6, 300MHz) δ : 4.92(2H,s), 7.16(1H,s), 7.88(2H,d,J=8Hz), 7.92(1H,s), 8.07(2H,d,J=8Hz) , 8.46(1H,s) Preparation 110
A solution of the starting compound (18.9 g) in a mixture of 2N hydrochloric acid (90 ml) and methanol (90 ml) was hydrogenated (3 atm) over 10% palladium on carbon (1.9 g) at room temperature for 3 hours. After the catalyst was filtered off, the filtrate was concentrated to give a white powder. The white powder was collected by filtration, washed with methanol and dried in vacuo to give the object compound (16.0 g).
MASS (ESI) (m/z) : 202 (free, M+H)+
'H-NMR (DMS0-d6, 300MHz) δ : 4.67(2H,q,J=5Hz) , 7.89(1H,s), 8.08(2H,d,J=8Hz), 8.27(2H,d,J=8Hz) , 8.41 (lH,s), 8.52(3H,br s), 9.78(lH,s) Preparation 111
The object compound was obtained according to a similar manner to that of Preparation 5. oil
MASS : 450 (M+1)
' H-NMR (CDCls) δ 1.42(9H,s), 3.20-3.30(1H,m) , 3.31-3.42(1H,m), 4.62-4.73(1H,m), 4.70(2H,d,J=6Hz) , 6.42(1H,br s) , 7.15(1H,t,J=6Hz), 7.21(1H,d,J=6Hz), 7.23(1H,s), 7.33(1H,s), 7.50(2H,d,J=8Hz), 7.60(1H,t,J=8Hz) , 7.97(1H,s), 8.00(1H,br s), 8.08(2H,d,J=8Hz), 8.57(1H,d,J=8Hz) Preparation 112
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 445 (M+1) ' H-NMR (CDCls) δ 1.38(9H,s), 3.39-3.52(2H,m) , 3.49(3H,s),
5.38-5.52(1H,m), 5.49(1H,br s), 7.01(1H,s), 7.12(2H,d,J=8Hz), 7.22(2H,d,J=8Hz), 7.30(1H,s), 7.38-7.50(3H,m), 7.57(1H,t,J=8Hz), 7.90(1H,s), 8.53(1H,d,J=2Hz) Preparation 113
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 345 (M+1)
'H-NMR (CDCI3) δ 3.29-3.39(1H,m), 3.40-3.50(1H,m) , 3.55(3H,s), 4.58-4.65(1H,m), 7.09(1H,s), 7.15(2H,d,J=8Hz) , 7.23(2H,d,J=8Hz), 7.31 (1H,s), 7.4l-7.48(3H,m), 7.61(1H,t,J=8Hz), 7.90(1H,s), 8.59(1H,d,J=2Hz) Preparation 114
The object compound was obtained according to a similar manner to that of Preparation 5 except that a mixture of dichloromethane and dimethylformamide was used instead of dichloromethane. MASS (ESI) (m/z) : 430 (M+H)+ 'H-NMR (CDCI3,300MHz) δ 1.40(9H,s), 2.52(3H,s),
2.98-3.28(2H,m), 4.48-4.79(3H,m), 5.06(1H,br d,J=8Hz), 7.04(1H,br s), 7.16(2H,d,J=5Hz), 7.28(2H,d,J=8Hz) 7.85 (2H,d,J=8Hz), 8.51 (2H,d,J=5Hz) Preparation 115
The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 425 (M+H)+
'H-NMR (CDCl3,300MHz)(5 1.39 (9H,s), 2.50(3H, s) , 3.21 (3H, s) 3.23-3.34(2H,m), 5.01-5.15(1H,m) , 5.40(1H,br d,J=8Hz) 7.00(1H,s), 7.06(2H,d,J=6Hz), 7 7(2H,d,J=8Hz) 7.28(2H,d,J=8Hz), 8.47(2H,d,J=6Hz) Preparation 116
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 325 (M+H)+ 1 H-NMR (CDCl3,300MHz)(5 2.50(3H,s), 3.09~3.35(2H,m), 3.31 (3H,s) 4.19(1H,d,J=7Hz), 7.02(1H,s), 7.06(2H,d,J=6Hz), 7.13-7.33(4H,m), 8.50(2H,d,J=6Hz) Preparation 117
To an ice-cooled solution of the starting compound (172 mg) in acetic acid (0.8 ml)- water (0,8 ml) was added potassium permanganate (69 mg) , and the mixture was stirred under ice-cooling for 30 minutes. 2-Propanol was added to the mixture and the mixture was stirred for 5 minutes. The mixture was diluted with ethyl acetate and neutralized with IN sodium hydroxide solution. After the precipitate formed was filtered off, the filtrate was extracted three times with ethyl acetate.
The organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave the object compound as a white powder (214 mg).
MASS (ESI) (m/z) : 457 (M+H)+ 'H-NMR (CDC13,300MHz)5 1.39(9H,s), 3.08(3H,s), 3.22-3.38(2H,m), 3.37(3H,s), 5.09-5.25(1H,m) 6.35(1H, brd,J=8Hz), 7.03-7.22(3H, broad), 7.46(2H,d,J=8Hz), 8.00(2H,d,J=8Hz) 8.38-8.61 (2H, broad) Preparation 118
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 357 (M+H)+ ' H-NMR (CDCI3,300MHz) δ 3.09(3H,s), 3.12-3.38(2H,m)
3.40(3H,s), 4.28(1H,t,J=7Hz), 7.08(2H,d,J=6Hz) , 7.15(1H,s) 7.50(2H,d,J=8Hz), 7.99(2H,d,J=8Hz) , 8.50(2H,d,J=6Hz) Preparation 119
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 427 (M+H)+
'H-NMR (CDCl3,300MHz) δ 1.43(9H,s), 3.04(6H,s),
3.18-3.43(2H,m), 4.56(2H,d,J=5Hz) , 4.6l-4.74(1H,m), 6.36(1H,br d,J=8Hz), 6.62 (2H,d,J=8Hz), 7 1(1H,dd,J=8 and 5Hz), 7.20(1H,d,J=8Hz) 7.58(1H,t,J=8Hz), 7.80(1H,br d,J=8Hz) , 7.81 (2H,d,J=8Hz) , 8.54(1H,d,J=5Hz) Preparation 120
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 422 (M+H)+
' H-NMR (CDCl3,300MHz) δ 1.35(9H,s), 2.98(6H,s), 3.37(3H,s), 3.38-3.48(2H,m), 5.28-5.42(1H,m), 5.46(1H,br d,J=8Hz), 6.72(2H,d,J=8Hz), 6.89(1H,s), 7.03-7.11 (2H,m) , 7.13(2H,d,J=8Hz), 7.52(1H,t,J=8Hz) , 8.52(1H,d,J=5Hz) Preparation 121
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 322 (M+H)+ 1 H-NMR (CDCl3,300MHz)(5 2.98(6H,s), 3.23~3.43(2H,m) , 3.44(3H,s), 4.55(1H,dd,J=8 and 5Hz), 6.74(2H,d,J=8Hz), 6.91 (1H,s), 7.07-7.16(2H,m), 7.18(2H,d,J=8Hz) , 7.58(1H,t,J=8Hz), 8.57(1H,d,J=5Hz) Preparation 122
The object compound was obtained according to a similar manner to that of Preparation 91. MASS (ESI) (m/z) : 429 (M+H)+ 1 H-NMR (CDCl3,300MHz) δ 1.45(9H,s), 3.18-3.42(2H,m),
4.60-4.77(1H,m), 4.72(2H,d,J=5Hz) , 6.42(1H,br d,J=8Hz) , 7.16(1H,dd,J=8 and 5Hz), 7.21 (1H,d,J=8Hz), 7.60(1H,t,J=8Hz), 7.70(1H,t,J=8Hz), 8.04(1H,br s) , 8.24(1H,dd,J=8 and 2Hz) , 8.45(1H,dd,J=8 and 2Hz), 8.54(1H,d,J=5Hz), 8.76(1H,t,J=2Hz) Preparation 123
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 424 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.38(9H,s), 3.38-3.51 (2H,m), 3.50(3H,s), 5.36-5.50(1H,m), 5.52(1H,br d,J=8Hz), 7.09(1H,s), 7.10-7.19(2H,m), 7.50-7.68(3H,m) , 8.11-8.23(2H,m) , 8.53(1H,d,J=5Hz) Preparation 124
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 324 (M+H)+ 1 H-NMR (CDCl3,300MHz) δ 3.30-3.51 (2H,m) , 3.58(3H,s), 4.68(1H,dd,J=8 and 5Hz) , 7.04-7.21 (2H,m) , 7.12(1H,s), 7.52-7.72(3H,m), 8.l1-8.25(2H,m), 8.57(1H,d,J=5Hz) Preparation 125
To a solution of the starting compound (1.92 g) in carbon tetrachloride (19 ml) were added N-bromosuccinimide (3.34 g) and 2,2'- azobis(2,4-dimethyl-4-methoxyvaleronitrile) (Wako V-70, 153 mg), and the mixture was heated at 50°C for 15 minutes. After the precipitate formed was filtered off, the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/1) to give the object compound as a red oil (806 mg). MASS (ESI) (m/z) : 202,204 (M+H)+ ' H-NMR (CDCl3,300MHz) δ 3.89(3H,s), 4.61 (2H,s), 7.28(1H,dd,J=8 and 2Hz) , 7.43(1H,d,J=8Hz) , 8.26(1H,d,J=2Hz) Preparation 126
In a nitrogen atmosphere, an ice-cooled solution of diethyl acetamidomalonate (758 mg) in N,N-dimethylformamide (3.5 ml) was added potassium tert-butoxide (437 mg) , and the mixture was stirred under ice- cooling for 1.5 hours. To the mixture was added the starting compound (726 mg) , and the mixture was heated at 60 °C for 1 hour. A saturated sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/2) to give the object compound as white crystals (362 mg).
MASS (ESI) (m/z) : 339 (M+H)+
' H-NMR (CDCl3,300MHz) δ 1.28(6H,t,J=7Hz), 1.95(3H,s), 3.75(2H,s), 3.81 (3H,s), 4.28(4H,q,J=7Hz), 6.78(1H,br s) , 6.99(1H,d,J=8Hz) , 7.08(1H,dd,J=8 and 2Hz), 8.13(1H,d,J=2Hz) Preparation 127
A mixture of the starting compound (345 mg) and 6N hydrochloric acid (1.7 ml) was heated under reflux for 2 hours. The solvent was evaporated to give the object compound as a pale yellow powder (285 mg).
MASS (ESI) (m/z) : 197 (free, M+H)+ 1 H-NMR (DzO,300MHz) δ 3.63(2H,d,J=7Hz) , 4.01 (3H,s),
4.46(1H,t,J=7Hz), 7.96(1H,d,J=8Hz), 8.15(1H,dd,J=8 and 2Hz), 8.45(1H,d,J=2Hz) Preparation 128
To an ice-cooled solution of the starting compound (238 mg) in 1N sodium hydroxide solution (3.0 ml) - 1,4-dioxane (0.6 ml) was added di- tert-butyl dicarbonate (263 mg), and the mixture was stirred at room temperature for 12 hours. After the mixture was concentrated, citric acid monohydrate (93 mg) was slowly added to the mixture. The mixture was extracted three times with chloroform. The organic layer was dried over magnesium sulfate. Evaporation of the solvent gave the object compound as a white powder (194 mg). MASS (ESI) (m/z) : 297 (M+H)+
' H-NMR (CHC13, 300MHz) δ 1.44(9H,s), 3.19-3.41 (2H,m) , 3.87(3H,s), 4.34-4.48(1H,m), 5.86(1H,br d, J=8Hz), 7.32(2H,s), 8.17(1H,s) Preparation 129
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 459 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.49(9H,s), 3.12-3.37(2H,m), 3.82(3H,s), 4.56-4.69(1H,m), 4.72(2H,d,J=5Hz) , 6.38(1H,br d,J=8Hz), 7.40-7.52(2H,m) , 7.88(1H,br s) , 8.09(2H,d,J=8Hz), 8.22(1H,d,J=2Hz) , 8.31 (2H,d,J=8Hz) Preparation 130
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 454 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.38(9H,s), 3.29~3.46(2H,m) , 3.53(3H,s), 3.82(3H,s), 5.31-5.45(1H,m), 5.52(1H,br d,J=8Hz) , 6.98-7.12(2H,m), 7.13(1H,s), 7.47(2H,d,J=8Hz) , 8.12(1H,d,J=2Hz), 8.28(2H,d,J=8Hz) Preparation 131
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 354 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 3.21-3.43(2H,m) , 3.62(3H,s), 3.84(3H,s), 4.53-4.63(1H,m), 7.03-7.16(2H,m) , 7.18(1H,s), 7.51(2H,d,J=8Hz), 8.26(1H,d,J=2Hz), 8.28(2H,d,J=8Hz) Preparation 132
A mixture of the starting compound (5.92 g), dichlorobis(tri- phenylphosphine)palladium(II) (843 mg) , triethylamine (20 ml), and methanol (20 ml) was heated at 110°C under a carbon monoxide (10 atm) atmosphere for 11 hours. After being allowed to cool to room temperature, the mixture was dissolved in chloroform and evaporated. Water was added to the residue and the mixture was extracted three times with ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 4/1) to give the object compound as a white powder (5.48 g).
MASS (ESI) (m/z) : 172 (M+H)+ 1 H-NMR (CDC13,300MHz) δ 4.00(3H,s), 7.82(1H,dd,J=8 and 2Hz) , 8.10(1H,d,J=8Hz), 8.69(1H,d,J=2Hz) Preparation 133
In a nitrogen atmosphere, to a suspention of lithium aluminum hydride (873 mg) in tetrahydrofuran (52 ml) was added the starting compound (5.24 g) in tetrahydrofuran (26 ml) dropwise at a temperature below -30°C for 10 minutes. The mixture was stirred at -30°C for 30 minutes. After the mixture was diluted with ether (60 ml), water (0.9 ml), 15% sodium hydroxide solution (0.9 ml), and water (2.7 ml) were successively added dropwise to the mixture with vigorous stirring. After the precipitate was filtered off, the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/1) to give the object compound as an oil (801 mg).
MASS (ESI) (m/z) : 144 (M+H)+
'H-NMR (CDCl3,300MHz) δ 3.35(1H,br t,J=5Hz), 4.74(2H,d,J=5Hz), 7.23(1H,d,J=8Hz), 7.67(1H,dd,J=8 and 2Hz) , 8.52(1H,d,J=2Hz) Preparation 134
To an ice-cooled solution of the starting compound (742 mg) in dichloromethane (2.5 ml) was added thionyl chloride (681 mg) in dichloromethane (1 ml) dropwise for 5 minutes, and the mixture was stirred under ice-cooling for 30 minutes. After the solvent was evaporated, the residue was dissolved in 1N sodium hydroxide solution with ice-cooling, and the product was extracted three times with chloroform. The organic layer was dried over magnesium sulfate. Evaporation of the solvent gave the object compound as an oil (927 mg).
MASS (ESI) (m/z) : 162 (M+H)+ 1 H-NMR (CDC13,300MHz) δ 4.76(2H,s), 7.58(1H,d,J=8Hz) , 7.85(1H,dd,J=8 and 2Hz), 8.57(1H,d,J=2Hz) Preparation 135
The object compound was obtained according to a similar manner to that of Preparation 126.
MASS (ESI) (m/z) : 343 (M+H)+
' H-NMR (CDCl3,300MHz) <5 1.28(6H,t,J=7Hz) , 1.94(3H,s), 3.83(2H,s), 4.28(4H,q,J=7Hz), 6.71 (1H,br s) , 7.03(1H,d,J=8Hz) , 7.54(1H,dd,J=8 and 2Hz), 8.39(1H,d,J=2Hz) Preparation 136
The object compound was obtained according to a similar manner to that of Preparation 127.
MASS (ESI) (m/z) : 201 (free, M+H)+
'H-NMR (DzO,300MHz) δ 3.59(2H,d,J=7Hz) , 4.50(1H,t,J=7Hz), 7.75(1H,d,J=8Hz), 8.28(1H,dd,J=8 and 2Hz) , 8.72(1H,d,J=2Hz) Preparation 137
The object compound was obtained according to a similar manner to that of Preparation 128
MASS (ESI) (m/z) : 301 (M+H)+
'H-NMR (CHCl3,300MHz)£ 1.42(9H,s), 3.35(2H,br s), 4.50(1H,br s), 5.74(1H,br s) , 7.27(1H,br s), 7.69(1H,br s) , 8.48(1H,br s) Preparation 138
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 463 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.48(9H,s), 3.16-3.43(2H,m),
4.61-4.82(3H,m), 6.26(1H,br d,J=8Hz) , 7.19(1H,d,J=8Hz), 7.59(1H,dd,J=8 and 2 Hz) , 7.74(1H,br s) , 8.10(2H,d,J=8Hz) 8.33(2H,d,J=8Hz), 8.50(1H,d,J=2Hz) Preparation 139
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 458 (M+H)+
' H-NMR (CDC13,300MHz) <5 1.39(9H,s), 3.33~3.57(2H,m) , 3.61 (3H,s), 5.33-5.52(2H,m), 7.11 (1H,d,J=8Hz), 7.12(1H,s), 7.49(2H,d,J=8Hz), 7.53(1H,dd,J=8 and 2Hz), 8.29(2H,d,J=8Hz), 8.48(1H,d,J=2Hz) Preparation 140
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 358 (M+H)+
'H-NMR (CDCI3,300MHz) δ 3.23-3.52(2H,m), 3.67(3H,s), 4.59(1H,t,J=7Hz), 7.13(1H,d,J=8Hz) , 7.15(lH,s), 7.51(2H,d,J=8Hz), 7.58(1H,dd,J=8 and 2Hz), 8.29(2H,d,J=8Hz), 8.51(1H,d,J=2Hz) Preparation 141
The object compound was obtained according to a similar manner to that of Preparation 126.
MASS (ESI) (m/z) : 310 (M+H)+
' H-NMR (CDCl3,300MHz)c5 1.28(6H,t,J=7Hz), 1.95(3H,s), 3.90(2H,s), 4.29(4H,q,J=7Hz), 6.65(1H,br s), 8.36(1H,s), 8.41(2H,s) Preparation 142
The object compound was obtained according to a similar manner to that of Preparation 127.
MASS (ESI) (m/z) : 168 (free, M+H)+ 1 H-NMR (DzO,300MHz) <5 3.49"3.69(2H,m), 4.59(1H,t,J=7Hz), 8.57(1H,d,J=2Hz), 8.62(1H,s), 8.67(1H,d,J=2Hz) Preparation 1 3
The object compound was obtained according to a similar manner to that of Preparation 1 8.
MASS (ESI) (m/z) : 266 (M-H)" 1 H-NMR (CDCI3,300MHz) δ 1.43(9H,s), 3.32-3.51 (2H,m) , 4.56-4.70(1H,m), 5.73(1H,br d, J=8Hz) , 8.50(1H,s), 8.58(1H,s), 8.62(1H,s) Preparation 1 4
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 428 (M-H)"
'H-NMR (CDCI3,300MHz) δ 1.45(9H,s), 3.21-3.48(2H,m) , 4.62-4.83(3H,m), 6.10(1H,br d,J=8Hz) , 7.59(1H,br s), 8.10(2H,d,J=8Hz), 8.32(2H,d,J=8Hz) , 8.42-8.55(3H,m) Preparation 1 5
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 425 (M+H)+
' H-NMR(CDCI3,300MHz) δ 1.38(9H,s) , 3.38-3.62(2H,m) ,
3.63(3H,s), 5.41-5.60(2H,m) 7.12(1H,s), 7.50(2H,d,J=8Hz), 8.28(2H,d,J=8Hz), 8.38-8.53(3H,m) Preparation 146
The object compound was obtained according to a similar manner tothat of Preparation 4.
MASS (ESI) (m/z) : 325 (M+H)+ 1 H-NMR (CDCl3,300MHz) δ 3.29-3.60(2H,m) , 3.66(3H,s), 4.61(1H,t,J=7Hz), 7.16(1H,s), 7.51 (2H,d,J=8Hz), 8.29(2H,d,J=8Hz), 8.39-8.55(3H,m) Preparation 147
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 500 (M+H)+
'H-NMR (CDCl3,300MHz)c5 1.44(9H,s), 1.91-2.31 (2H,m), 2.42-2.68(2H,m), 4.22-4.40(1H,m) , 4.68-4.86(2H,m) , 5.13(2H,s), 5.30(1H,br d,J=8Hz), 7.14(1H,brs) 7.27-7.41 (5H,m), 8.12(2H,d,J=8Hz) , 8.34(2H,d,J=8Hz) Preparation 148
The object compound was obtained according to a similar manner tothat of Preparation 2.
MASS (ESI) (m/z) : 495 (M+H)+
' H-NMR (CDCI3,300MHz) δ 1.43(9H,s), 2.08-2.39(2H,m), 2.40-2.65(2H,m), 3.16(3H,s), 4.98-5.11 (1H,m), 5.11(2H,s), 5.39(1H,br d,J=8Hz), 7.12(1H,s), 7.28-7.41 (5H,m), 7.52(2H,d,J=8Hz) , 8.30(2H,d,J=8Hz) Preparation 149
The object compound was obtained according to a similar manner tothat of Preparation 3.
MASS (ESI) (m/z) : 395 (M+H)+ 1 H-NMR (CDCl3,300MHz) δ 2.38-2.82(4H,m) , 3.71 (3H,s), 5.07(2H,ABq,Δ=0.08, J=13Hz), 5.17(1H,t,J=7Hz), 7.23-7.38(6H,m), 7.55(2H,d,J=8Hz), 8.39(2H,d,J=8Hz) Preparation 150
To an ice-cooled solution of the starting compound (1.17 g) in 1N soduim hydroxide solution (17.5 ml) - 1,4-dioxane (3.5 ml) was added acetic anhydride (0.75 ml). The mixture was stirred under ice-cooling for 1 hour, then at room temperature for 3 hours. The mixture was concentrated, made acidic (pH=3) with 6N hydrochloric acid, extracted three times with chloroform, and dried over magnesium sulfate. Evaporation of the solvent gave the object compound as a colorless oil (1.03 g).
MASS (ESI) (m/z) : 273 (M-H)"
' H-NMR (CDCI3,300MHz) δ 1.43(9H,s), 1.51-1.97(4H,m), 2.00(3H,s), 3.17-3.42(2H,m), 4.25-4.42(1H,m), 5.29(1H,br d,J=8Hz), 6.19(lH,br t,J=8Hz) Preparation 151
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 437 (M+H)+
'H-NMR (CDCl3,300MHz)(5 1.43(9H,s), 1.52-2.00(4H,m), 2.00(3H,s), 3.11-3.28(1H,m), 3.42-3.60(1H,m), 4.31-4.49(1H,m), 4.60-4.97(2H,m) , 5.35(1H,br d,J=8Hz) , 5.99(1H,br t,J=8Hz), 7.46(1H,br t,J=8Hz), 8.12(2H,d,J=8Hz), 8.33(2H,d,J=8Hz) Preparation 152
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 432 (M+H)+
' H-NMR (CDC13,300MHz) δ 1.43(9H,s), 1.48-2.16(4H,m) , 1.98(3H,s), 3.18-3.40(2H,m), 3.68(3H,s), 4.88-5.02(1H,m), 5.19(1H,br d,J=9Hz), 6.05(1H,br t,J=8Hz), 7.12(1H,s), 7.54(2H,d,J=8Hz), 8.30(2H,d,J=8Hz) Preparation 153
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 332 (M+H)+
' H-NMR (CDCI3,300MHz) δ 1.49-2.15(4H,m) , 1.98(3H,s), 3.28(2H,q,J=7Hz), 3.72(3H,s), 4.04(1H,t,J=7Hz), 6.20(1H,br s), 7.15(1H,s), 7.56(2H,d,J=8Hz) , 8.30(2H,d,J=8Hz) Preparation 154
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 399 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.41(9H,s), 2.85-3.15(2H,m) , 4.55-4.68(1H,m), 5.19(2H,ABq, Δ=0.05,J=13Hz) , 5.79(1H,br d,J=8Hz), 7.04-7.53(11H,m) Preparation 155
To a solution of the starting compound (1.04 g) in a mixture of methanol (21 ml) and 1,4-dioxane (21 ml) was added palladium-carbon (10%, 104 mg). The resultig mixture was stirred under hydrogen at 25°C for 8 hours. The catalyst was filtered off and the filtrate was concentrated to give an oil. The oil was purified by column chromatography (silica gel, chloroform/methanol=10/1 ) to give the object compound as an amorphous solid (915 mg). MASS (ESI) (m/z) : 307 (M-H)~
' H-NMR (CDCl3,300MHz) <5 1.45(9H,s), 2.84-3.20(2H,m) , 4.45-4.59(1H,m), 5.95(1H,br d.J=8Hz) , 7.10-7.53(5H,m), 8.05(1H,br s) Preparation 156
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 470 (M+H)+
' H-NMR (CDCl3,300MHz) δ 1.43(3H,t,J=7Hz) , 1.48(9H,s), 2.72-3.22(2H,m), 4.09(2H,q,J=7Hz) , 4.54-4.74(3H,m) , 6.22(1H,br d,J=8Hz), 6.89(2H,d,J=8Hz) , 6.98-7.52(5H,m) , 7.72(1H,br s), 7.88(2H,d,J=8Hz) , 8.27(1H,br s) Preparation 157
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 465 (M+H)+
' H-NMR (CDCl3,300MHz) c 1.42(9H,s), 1.47(3H,t,J=7Hz) , 3.05-3.26(2H,m), 3.59(3H,s), 4.07(2H,q,J=7Hz), 5.32-5.49(1H,m), 5.53(1H,br d,J=8Hz), 6.91(1H,s), 6.94(2H,d,J=8Hz), 6.98-7.55(7H,m) , 9.62(1H,br s) Preparation 158
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 365 (M+H)+
' H-NMR (CDCl3,300MHz) δ 1.41 (3H,t,J=7Hz) , 3.68-4.22(2H,m) , 3.88(3H,s), 3.99(2H,q,J=7Hz), 5.33-5.53(lH,m) , 6.67-7.58(11H,m) Preparation 159
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 418 (M+H)+
' H-NMR (CDC13,300MHz) δ 1.45(9H,s), 3.06-3.27(2H,m) , 4.43-4.62(1H,m), 4.65-4.87(2H,m) , 5.18(1H,br d,J=8Hz), 6.13(lH,t,J=2Hz), 6.29(1H,d,J=2Hz), 7.05(1H,br s) , 7.34(1H,d,J=2Hz), 8.12(2H,d,J=8Hz), 8.35(2H,d,J=8Hz) Preparation 160
The object compound was obtained .according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 413 (M+H)+
' H-NMR (CDCl3,300MHz) δ 1.42(9H,s), 3.16-3.41 (2H,m) , 3.43(3H,s), 5.13-5.28(1H,m), 5.47(1H,br d,J=8Hz), 6.01(1H,d,J=2Hz), 6.27(1H,t,J=2Hz) , 7.17(1H,s), 7.32(1H,d,J=2Hz), 7.49(2H,d,J=8Hz) , 8.29(2H,d,J=8Hz) Preparation 161
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 313 (M+H)+
' H-NMR (CDCl3,300MHz) δ 3.13"3.33(2H,m) , 3.56(3H,s), 4.32(1H,t,J=7Hz), 6.07(1H,d,J=2Hz), 6.31 (1H,t,J=2Hz), 7.18(1H,s), 7.35(1H,d,J=2Hz), 7.51 (2H,d,J=8Hz), 8.29(2H,d,J=8Hz) Preparation 162
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 500 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.41 (9H,s), 3.29-3.56(2H,m), 4.20(2H,s), 4.97-5.11(1H,m), 6.16(lH,br d,J=8Hz), 7.00-7.91 (11H,J=4Hz), 8.22(2H,d,J=8Hz) , 8.28(1H,d,J=2Hz) Preparation 163 The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 400 (M+H)+
' H-NMR (CDCI3,300MHz) δ 3.16-3.48(2H,m) , 4.21 (2H,s), 4.52(1H,J=7Hz), 7.10-7.68(9H,m), 7.79(2H,d,J=8Hz) , 8.22(2H,d,J=8Hz), 8.29(1H,d,J=2Hz) Preparation 164
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (ESI) (m/z) : 472 (M+H)+
'H-NMR (CDCI3,300MHz) δ 1.42(9H,s), 2.91-3.10(2H,m) , 4.32-4.51 (1H,m), 4.67-4.80(2H,m) , 5.05(1H,br d,J=8Hz) , 5.90(2H,d,J=1Hz), 6.59-6.76(3H,m) , 6.95(1H,br s) , 8.11(2H,d,J=8Hz), 8.33(2H,d,J=8Hz) Preparation 165
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 467 (M+H)+
' H-NMR (CDCI3,300MHz) <5 1.41 (9H,s), 3.01-3.29(2H,m) , 3.20(3H,s), 4.89-5.06(1H,m), 5.49(1H,br d,J=8Hz), 5.90(2H,s), 6.46-6.73(3H,m), 7.18(1H,s), 7.43(2H,d,J=8Hz) , 8.27(1H,d,J=8Hz) Preparation 166
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 367 (M+H)+
' H-NMR (CDCI3,300MHz) 2.98-3.22(2H,m) , 3.39(3H,s),
4.13(1H,t,J=7Hz), 5.92(2H,s), 6.51-6.78(3H,m) , 7.19(1H,s), 7.48(2H,d,J=8Hz), 8.28(2H,d,J=8Hz) Preparation 167
The object compound was obtained according to a similar manner to that of Preparation 91. MASS (ESI) (m/z) : 462, 464 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ 1.44(9H,s), 3.18-3.43(2H,m) ,
4.58-4.75(1H,m), 4.64(2H,d,J=5Hz) , 6.42(1H,br d,J=8Hz) , 7.10-7.23(2H,m), 7.53-7.65(1H,m) , 7.61 (2H,d,J=8Hz) , 7.79(2H,d,J=8Hz), 7.92(1H,br s), 8.53(1H,d,J=5Hz) Preparation 168
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 457, 459 (M+H)+
'H-NMR (CDCI3,300MHz) δ 1.37(9H,s), 3.33~3.52(2H,m),
3.42(3H,s), 5.31-5.52(2H,m), 6.99(1H,s), 7.05-7.15(2H,m) , 7.18(2H,d,J=8Hz), 7.48-7.61 (1H,m) , 7.53(2H,d,J=8Hz), 8.53(1H,d,J=5Hz) Preparation 169
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 357, 359 (M+H)+ ' H-NMR (CDCl3,300MHz) δ 3.23"3.47(2H,m) , 3.49(3H,s), 4.59(1H,t,J=7Hz), 7.01 (1H,s), 7.05-7.22(4H,m), 7.54(2H,d,J=8Hz), 7.55-7.64(1H,m) , 8.57(1H,d,J=5Hz) Preparation 1 0
A mixture of acetic anhydride (3.7 ml) and formic acid (1.8 ml) was heated at 50°C for 1.5 hours. After the mixture was allowed to cool to room temperature, sodium formate (896 mg) was suspended in the mixture and stirred for 10 minutes. The starting compound (2.15 g) was added and stirring at room temperature was continued for 3 hours. The reaction mixture was poured into water (30 ml) and the product was extracted three times with chloroform. The organic layer was dried over potassium carbonate. Evaporation of the solvent gave the object compound as a white powder (1.59 g). MASS (ESI) (m/z) : 208 (M+H)+ ' H-NMR (CDCI3,300MHz) δ 1.45(3H,t,J=7Hz) , 4.12(2H,q,J=7Hz), 4.74(2H,d,J=2Hz), 6.78(1H,br s) , 6.96(2H,d,J=8Hz) 7.96(2H,d,J=8Hz), 8.34(1H,s) Preparation 171
In a nitrogen atmosphere, the starting compound (1.56 g) in N,N- dimethylformamide (12.5 ml) was added to a stirred and ice-cooled suspension of sodium hydride (70%, 285 mg) in N,N-dimethylformamide (25 ml). After 30 minutes, benzyl bromide (1.65 g) was added dropwise at 0°C and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into water and the product was extracted three times with ethyl acetate. The organic layer was washed three times with water, once with brine, and dried over magnesium sulfate. Evaporation of the solvent gave the object compound as an oil (2.53 g).
MASS (ESI) (m/z) : 298 (M+H)+
'H-NMR (CDCl3,300MHz) δ 1.44(3H,t,J=7Hz) , 3.01-3.38(2H,m) , 4.11(2H,q,J=7Hz), 5.8l-5.92(1H,m) , 6.51 (1H,br d,J=8Hz) 6.93(2H,d,J=8Hz), 6.95-7.25(5H,m), 7.92(2H,d,J=8Hz), 8.22(1H,s) Preparation 172
A solution of the starting compound (2.15 g) in concentrated hydrochloric acid (2 ml)-ethanol (10 ml) was heated at 50°C for 1.5 hours. The object compound began to precipitate. After cooling, the mixture was diluted with diisopropyl ether (3 ml) and filtration gave the object compound as a white powder (1.20 g) . MASS (ESI) (m/z) : 270 (free, M+H)+
'H-NMR (DMSO-d6,300MHz) δ 1.35(3H,t,J=7Hz) , 3.03-3.23(2H,m) , 4.13(2H,q,J=7Hz), 5.33(1H,t,J=6Hz) , 7.02(2H,d,J=8Hz) 7.08-7.31 (5H,m), 7.95(2H,d,J=8Hz), 8.41(3H,brs) Preparation 173
The object compound was obtained according to a similar manner to that of Preparation 91.
MASS (ESI) (m/z) : 518 (M+H)+
3 8 l ' H-NMR (CDCI3,300MHz) δ 1.42(9H,s), 1.44(3H,t,J=7Hz), 2.85-3.40(4H,m), 4.01-4.18(2H,m) , 4.49~4.72(1H,m) , 4.61-4.75(1H,m), 6.29(1H,br s) , 6.98-7.23(9H,m), 7.42-7.62(1H,m), 7.71~7.93(3H,m), 8.39-8.51 (1H,m) Preparation 174
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 513 (M+H)+
'H-NMR (CDCI3,300MHz) δ 1.37(9H,s), 1.42(3H,t,J=7Hz) ,
3.24(3H,s), 3.32-3.48(2H,m), 3.81 (2H,s), 4.04(2H,q,J=7Hz), 5.25-5.42(1H,m), 5.50(1H,br d,J=8Hz) , 6.82-7.55(12H,m), 8.52(1H,d,J=5Hz) Preparation 175
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 413 (M+H)+
'H-NMR (CDCl3,300MHz) δ 1.42(3H,t,J=7Hz) , 3.33(3H,s), 3.35-3.50(2H,m), 3.84(2H,s), 4.05(2H,q,J=7Hz), 4.68(1H,t,J=7Hz), 6.81-7.25(11H,m), 7.46-7.59(1H,m) , 8.51(1H,d,J=5Hz) Preparation 176
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 452 (M+H)+
'H-NMR (CDCl3,300MHz) δ 0.93(3H,t,J=7Hz) , 1.36(9H,s), 1.43-1.61 (2H,m), 3.35-3.58(2H,m) , 3.82-4.06(2H,m), 5.34(1H,br d,J=8Hz), 5.36-5.53(1H,m), 7.06-7.18(3H,m), 7.48(2H,d,J=8Hz), 7.50-7.63(1H,m), 8.28(2H,d,J=8Hz), 8.54(1H,d,J=5Hz) Preparation 177
The object compound was obtained according to a similar manner to that of Preparation 4. MASS (ESI) (m/z) : 352 (M+H)+
'H-NMR (CDCl3,300MHz) <5 0.92(3H,t,J=7Hz) , 1.41-1.60(2H,m) , 3.28-3.52(2H,m), 3.82-4.08(2H,m) , 4.60(1H,t,J=7Hz), 7.07-7.20(3H,m), 7.48(2H,d,J=8Hz) , 7.51-7.65(1H,m) , 8.28(2H,d,J=8Hz), 8.58(1H,d,J=5Hz) Preparation 178
A mixture of the starting compound (6.88 g), pyrazole (10.20 g), and powdered potassium carbonate (6.91 g) in N,N-dimethylformamide (35 ml) was heated at 140°C for 8 hours. After cooling, the mixture was poured into water and the product was extracted three times with ethyl acetate. The organic layer was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=2/1 ) to give the object compound as a pale yellow powder (4.71 g).
MASS (ESI) (m/z) : 187 (M+H)+ 1 H-NMR (CDCl3,300MHz)£ 2.61 (3H,s), 6.51 (1H,d,J=2Hz) , 7.78(lH,d,J=2Hz), 7.82(2H,d,J=8Hz) , 8.01 (1H,t,J=2Hz) , 8.06(2H,d,J=8Hz) Preparation 179
To a solution of the starting compound (4.66 g) in 5% hydrogen bromide/acetic acid (54 ml) was added bromine (4.34 g) dropwise at room temperature for 10 minutes. A white precipitate was formed. The mixture was heated at 50°C for 20 minutes. After cooling, the precipitate was collected by filtration and purified by recrystallization from methanol-diisopropyl ether to give the object compound (2.61 g).
' H-NMR (DMSO-dδ,300MHz) δ 4.95(2H,s), 6.62(1H,t,J=2Hz), 7.83(1H,d,J=2Hz), 8.03(2H,d,J=8Hz), 8.13(2H,d,J=8Hz), 8.68(1H,d,J=2Hz) Preparation 180
2-Bromo-4'-(pyrazol-1-yl)acetophenone hydrobromide (3.04 g) was dissolved in 1N sodium hydroxide solution. The free acetophenone compound was extracted three times with chloroform, dried over magnesium sulfate. After the solvent was evaporated, the residue was redissolved in chloroform (20 ml) and added all at once to a suspension of hexamethylenetetramine (1.35 g) in chloroform (4.4 ml) at room temperature. The mixture was heated at 50°C for 2 hours. After cooling, the mixture was diluted with chloroform (20 ml) and the white precipitate was collected by filtration. The precipitate was washed twice with ethanol and dried in vacuo to give the object compound (3.75 g). Preparation 181
To a suspension of the starting compound (3.50 g) in ethanol (17.6 ml) was added concentrated hydrochloric acid (4.4 ml) at room temperature and the mixture was stirred at room temperature for 4 hours. The mixture was cooled with ice, and the precipitate was collected by filtration and washed with cold ethanol. The crude product was suspended in water (4.4 ml) and stirred at room temperature for 10 minutes. The suspension was cooled in an ice bath and ethanol (2.2 ml) was added thereto. The precipitate was collected by filtration, washed with cold ethanol, and dried in vacuo to give the object compound (2.00 g).
MASS (ESI) (m/z) : 202 (free, M+H)+
'H-NMR (DMS0-d6,300MHz) <5 4.62(2H,q,J=2Hz),
6.64(1H,t,J=2Hz), 7.87(1H,d,J=2Hz), 8.09(2H,d,J=8Hz) , 8.17(2H,d,J=8Hz), 8.44(3H,br s) , 8.73(1H,d,J=2Hz) Preparation 182
The object compound was obtained according to a similar manner to that of Preparation 91.
MASS (ESI) (m/z) : 450 (M+H)+
' H-NMR (CDC13 , 300MHz) <5 1 .43(9H,s) , 3.27-3.49(2H,m) ,
4.60-4.81 (3H,m) , 6.37( 1 H,br d,J=8Hz) , 6.52(1 H,t,J=2Hz) , 7.18-7.33(2H,m) , 7.62-7.73( l H,m) , 7.78( 1 H,d,J=2Hz) , 7.83(2H,d,J=8Hz), 8.01 (1H,d,J=2Hz) , 8.05(2H,d,J=8Hz) , 8.05(1H,br d,J=8Hz), 8,58(1H,d,J=5Hz) Preparation 183
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 445 (M+H)+
'H-NMR (CDCI3,300MHz) δ 1.37(9H,s), 3.36-3.60(2H,m), 3.48(3H,s), 5.35-5.51 (1H,m), 5.58(1H,br d,J=8Hz) , 6.49(1H,t,J=2Hz), 7.03(1H,s), 7.06-7.18(2H,m) , 7.38(2H,d,J=8Hz), 7.48-7.62(1H,m), 7.74(1H,d,J=2Hz) , 7.76(2H,d,J=8Hz), 7.95(1H,d,J=2Hz), 8.53(1H,d,J=5Hz) Preparation 184
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 345 (M+H)+ 1 H-NMR (CDCl3,300MHz) 5 2.25(2H,br s) , 3.28-3.51 (2H,m) , 3.55(3H,s), 4.64(1H,t,J=7Hz), 6.49(1H,t,J=2Hz) , 7.06(1H,s), 7.10-7.21 (2H,m), 7.41 (2H,d,J=8Hz) , 7.52-7.67(1H,m), 7.73(lH,d,J=2Hz) , 7.75(2H,d,J=8Hz) , 7.95(1H,d,J=2Hz), 8.58(1H,d,J=5Hz) Preparation 185
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 459 (M+H)+
' H-NMR (CDCI3,300MHz) δ 1.10(3H,t,J=7Hz) , 1.36(9H,s), 3.37-3.62(2H,m), 3.85-4.10(2H,m), 5.29-5.60(2H,m), 6.49(1H,t,J=2Hz), 7.01 (1H,s), 7.05-7.21 (2H,m) , 7.39(2H,d,J=8Hz), 7.48-7.61 (1H,m), 7.73(1H,d,J=2Hz), 7.76(2H,d,J=8Hz), 7.96(1H,d,J=2Hz), 8.53(1H,d,J=5Hz) Preparation 186
The object compound was obtained according to a similar manner to that of Preparation 4. MASS (ESI) (m/z) : 359 (M+H)+
' H-NMR (CDCI3,300MHz) δ 1.14(3H,t,J=7Hz), 2.26(2H,br s,NH2), 3.31-3.52(2H,m), 3.87-4.13(2H,m) , 4.62(1H,t,J=7Hz) , 6.49(1H,t,J=2Hz), 7.03(1H,s), 7.07-7.21 (2H,m), 7.40(2H,d,J=8Hz), 7.52-7.65(lH,m), 7.73(1H,d,J=2Hz) , 7.75(2H,d,J=8Hz), 7.95(1H,d,J=2Hz), 8.57(1H,d,J=5Hz) Preparation 187
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (m/z) : 430 (M+1)
' H-NMR (CDCI3) <5 1.46(9H,s), 2.52(3H,s),
3.25(1H,d,J=4,15Hz), 3.37(1H,m), 4.63(2H,d,J=4Hz) , 4.68(1H,m), 6.40(1H,m), 7.13"7.27(4H,m) , 7.59(1H,m), 7.83(2H,d,J=8Hz), 7.87(1H,m), 8.54(1H,d,J=5Hz) Preparation 188
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (m/z) : 425 (M+1)
' H-NMR (CDCI3) δ 1.36(9H,s), 2.51 (3H,s), 3.42(3H,s),
3.43(2H,d,J=7Hz), 5.42(1H,m), 6.96(1H,s), 7.07-7.30(6H,m), 7.53(1H,m), 8.53(1H,d,J=5Hz) Preparation 189
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS (m/z) : 325 (M+1)
1H-NMR (DMS0-d6) δ : 2.51(3H,s), 3.32(1H,dd,J=7 and 14Hz),
3.43(1H,dd,J=5 and 14Hz), 3.50(3H,s), 4.59(1H,dd,J=5 and 7Hz), 6.96(1H,s), 7.02(1H,s), 7.13-7.32(6H,m), 7.59(1H,m), 8.56(1H,d,J=5Hz) Preparation 190
The object compound was obtained according to a similar manner to that of Example 1 6 from the starting compound and 2-bromoethyl methyl ether.
MASS (m/z) : 195 (M+1)
' H-NMR (CDCI3) δ : 2.55(3H,s), 3.46(3H,s), 3.76(2H,m), 4.19(2H,m), 6.96(2H,d,J=8Hz), 7.92(2H,d,J=8Hz) Preparation 191
The object compound was obtained according to a similar manner to that of Preparation 179.
1H-NMR (CDCI3) δ : 3.47(3H,s), 3.78(2H,m), 4.20(2H,m), 4.40(2H,s), 6.99(2H,d,J=8Hz), 7.97(2H,d,J=8Hz) Preparation 192
The object compound was obtained according to a similar manner to that of Preparation 180. Preparation 193
The object compound was obtained according to a similar manner to that of Preparation 181.
MASS (m/z) : 210 (M+1)
'H-NMR (DMS0-d6) δ : 3.37(3H,s), 3.68(2H,t,J=5Hz) , 4.23(2H,t,J=5Hz), 4.51 (2H,s), 7.12(2H,d,J=8Hz), 7.99(2H,d,J=8Hz), 8.40(2H,s) Preparation 194
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (m/z) : 458 (M+1)
'H-NMR (Coda) δ : 1.44(9H,s), 3.24(1H,dd,J=7 and 15Hz), 3.37(1H,m), 3.45(3H,s), 3.76(2H,t,J=5Hz), 4.18(2H,t,J=5Hz), 4.62(2H,d,J=4Hz), 4.68(1H,m), 6.41 (1H,m), 6.96(2H,d,J=8Hz), 7.13(1H,m), 7.20(1H,d,J=8Hz), 7.58(1H,m), 7.86(1H,m) 7.90(2H,d,J=8Hz), 8,54(1H,d,J=5Hz) Preparation 195
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (m/z) : 453 (M+1) ' H-NMR (CDCI3) <5 : 1.35(9H,s), 3.39(3H,s), 3.43(2H,m), 3.46(3H,s), 3.78(2H,t,J=5Hz), 4.15(2H,m), 6.93(1H,s), 6.97(2H,d,J=8Hz), 7.12(2H,m), 7.21 (2H,d,J=8Hz), 7.54(1H,m), 8.53(1H,d,J=5Hz) Preparation 196
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS (m/z) : 353 (M+1)
' H-NMR (CDCI3) δ : 3.32(1H,dd,J=7 and 15Hz),
3.42(1H,dd,J=5 and 15Hz), 3.46(6H,s), 3.77(2H,t,J=5Hz), 4.15(2H,t,J=5Hz), 4.57(1H,dd,J=5 and 7Hz) , 6.95(1H,s), 6.98(2H,d,J=8Hz), 7.12-7.17(2H,m), 7.22(2H,d,J=8Hz) , 7.58(1H,m), 8.57(1H,d,J=5Hz) Preparation 197
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (m/z) : 486 (M+1)
'H-NMR (CDCI3) δ : 1.48(9H,s), 2.78(1H,dd,J=7 and 15Hz), 3.14(1H,dd,J=5 and 15Hz), 4.65(1H,m), 4.75(2H,t,J=4Hz) , 5.13(1H,d,J=13Hz), 5.19(1H,d,J=13Hz) , 5.71 (1H,m), 7.28-7.40(5H,m), 8.13(2H,d,J=8Hz) , 8.35(2H,d,J=8Hz) Preparation 198
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (m/z) : 481 (M+1)
'H-NMR (CDCI3) δ : 1.43(9H,s), 3.07(1H,dd,J=5 and 15Hz), 3.23(1H,dd,J=7 and 15Hz), 3.67(3H,s), 5.05(1H,d,J=13Hz), 5.l5(1H,d,J=13Hz), 5.33(2H,m), 7.11 (1H,s), 7.29-7.37(5H,m), 7.52(2H,d,J=8Hz) , 8.30(2H,d,J=8Hz) Preparation 199
The object compound was obtained according to a similar manner to that of Preparation 3. MASS (m/z) : 381 (M+1)
' H-NMR (CDCl3) δ : 3.02(1H,dd,J=7 and 15Hz),
3.20(1H,dd,J=5 and 15Hz), 3.73(3H,s), 4.50(1H,dd,J=5 and 7Hz), 5.15(1H,d,J=13Hz), 5.20(1H,d,J=13Hz) , 7.15(1H,s), 7.32-7.38(5H,m), 7.53(2H,d,J=8Hz) , 8.31 (2H,d,J=8Hz) Preparation 200
A mixture of the starting compound (4.6 g) and 40% methylamine solution (5 ml) in acetic acid (4,6 ml) and xylene (46 ml) was refluxed in a flask equipped with a Dean-Stark trap for 2 hours. The mixture was concentrated, neutralized with 1N sodium hydroxide solution, and extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methanol) to give the object compound (1.55 g).
MASS (m/z) : 404 (M+1)
' H-NMR (CDCl3) c5 : 1.44(9H,s), 2.75(3H,d,J=6Hz) ,
2.93(1H,dd,J=5 and 15Hz), 3.02(1H,dd,J=7 and 15Hz),
3.75(3H,s), 5.39(1H,m), 5.76(1H,m), 6.43(1H,m),
7.12(1H,s), 7.53(2H,d,J=8Hz), 8.29(2H,d,J=8Hz)
Preparation 201
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS (m/z) : 304 (M+1)
' H-NMR (CDCI3) δ : 2.77(1H,dd,J=5 and 15Hz), 2.81 (3H,d,J=6Hz),
2.90(1H,dd,J=7 and 15Hz), 3.73(3H,s), 4.48(1H,dd,J=5 and 7Hz) ,
7.13(1H,s), 7.54(2H,d,J=8Hz), 8.30(2H,d,J=8Hz)
Preparation 202
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (m/z) : 591 (M+1)
'H-NMR (CDCI3) δ : 1.34(9H,s), 3.12(3H,s), 3.55-3.64(2H,m) , 3.61 (3H,s), 5.93(1H,m), 7.11-7.17(4H,m) , 7.40(1H,dd,J=2 and 8Hz) , 7.47~7.52(3H,m) , 7.59(lH,t,J=8Hz), 8.30(2H,d,J=8Hz), 8.56(1H,d,J=4Hz) Preparation 203
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (m/z) : 587 (M+1)
'H-NMR (CDC13) c5 : 1.37(9H,s), 3.09(3H,s), 3.57(2H,m),
3.62(3H,s), 5.97(1H,m), 6.95-7.17(5H,m), 7.47(2H,d,J=8Hz), 7.57(2H,t,J=8Hz), 8.27(2H,d,J=8Hz) , 8.53(1H,d,J=5Hz) Preparation 204
The object compound was obtained according to a similar manner to that of Preparation 5.
MASS (m/z) : 557 (M+1)
'H-NMR (CDCI3) δ : 1.34(9H,s), 3.13(3H,s), 3.57(2H,d,J=7Hz) ,. 3.61 (3H,s), 5.96(1H,d,J=7Hz), 7.13-7.17(4H,m), 7.31(1H,d,J=8Hz), 7.40-7.59(5H,m) , 8.27(2H,d,J=8Hz) , 8.53(1H,d,J=5Hz) Preparation 205
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 90-94°C MASS (m/z) : 429 (M+1) ' H-NMR (CDCI3) δ : 1.42(9H,s), 3.00-3.12(1H,m) ,
3.17-3.25(1H,m), 4.51 (1H,q,J=8Hz) , 4.66-4.89(2H,m), 5.09(1H,d,J=8Hz), 7.01 (lH,br s) , 7.20-7.29(1H,m) , 7.60(1H,d,J=8Hz), 8.12(2H,d,J=8Hz) , 8.35(2H,d,J=8Hz) , 8.48(1H,s), 8.49-8.58(1H,m) Preparation 206
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS (m/z) : 424 (M+1)
'H-NMR (CDCI3) δ : 1.40(9H,s), 3.25"3.35(2H,m) , 3.30(3H,s) 5.09(1H,q,J=8Hz), 5.41 (lH,d,J=8Hz) , 7.19(1H,s), 7.20(1H,t,J=8Hz), 7.45(2H,d,J=8Hz), 7.46(1H,d,J=8Hz) , 8.29(2H,d,J=8Hz), 8.32(1H,s), 8.49(1H,d,J=2Hz) Preparation 207
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 324 (M+1)
1 H-NMR (CDCI3) δ : 3.11-3.21 (1H,m), 3.22-3.33(1H,m),
3.39(3H,s), 4.20(lH,t,J=8Hz), 7.16-7.23(1H,m),
7.20(1H,s), 7.43(1H,t,J=8Hz), 7.48(2H,d,J=8Hz),
8.29(2H,d,J=8Hz), 8.42(1H,s), 8.50(1H,d,J=6Hz)
Preparation 208
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 138-141 °C MASS (m/z) : 455 (M+1)
' H-NMR (CDCI3) δ : 1.40(9H,s), 1.41 (3H,t,J=8Hz) , 2.98-3.10(1H,m), 3.18-3.28(1H,m), 4.41 (2H,q,J=8Hz) , 4.59(1H,br s), 4.63-4.83(2H,m), 5.22(1H,d,J=8Hz), 7.09(1H,br s), 7.19(2H,d,J=7Hz), 8.00(2H,d,J=8Hz), 8.17(2H,d,J=8Hz), 8.52(2H,d,J=7Hz) Preparation 209
The object compound was obtained according to a similar manner to that of Preparation 2. mp : 165-167°C MASS (m/z) : 451 (M+1)
' H-NMR (CDCI3) c5 : 1.39(3H,t,J=8Hz) , 1.40(9H,s) 3.30(3H,s), 3.31(2H,d,J=8Hz), 4.40(2H,q,J=8Hz), 5.11(1H,q,J=8Hz), 5.41 (1H,d,J=8Hz) , 7.09(2H,d,6Hz) , 7.10(1H,s), 7.34(2H,d,J=8Hz), 8.09(2H,d,J=8Hz), 8.49(2H,d,J=6Hz) Preparation 210
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 351 (M+1)
'H-NMR (CDCls) δ : 1.42(3H,t,J=8Hz), 3.11-3.22(1H,m) , 3.23-3.38(lH,m), 3.40(3H,s), 4.22(1H,t,J=8Hz), 4.40(2H,q,J=8Hz), 7.09(2H,d,J=6Hz) , 7.11 (1H,s), 7.39(2H,d,J=8Hz), 8.10(2H,d,J=8Hz), 8.51 (2H,d,J=6Hz) Preparation 211
The object compound was obtained according to a similar manner to that of Preparation 91. oil
MASS (m/z) : 456 (M+1)
' H-NMR (CDCI3) c5 : 1.40(3H,t,J=8Hz) , 1.42(9H,s), 3.20-3.30(1H,m), 3.30-3.40(1H,m), 4.40(2H,q,J=8Hz), 4.68(1H,br s), 4.70(2H,d,J=4Hz) , 6.41 (1H,d,J=6Hz) , 7.12-7.22(2H,m), 7.60(1H,t,J=8Hz) , 7.95(1H,br s) 7.99(2H,d,J=8Hz), 8.12(2H,d,J=8Hz) , 8.55(1H,d,J=4Hz) Preparation 21
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 451 (M+1)
'H-NMR (CDC13) δ : 1.38(9H,s), 1.40(3H,t,J=8Hz) , 3.43(2H,t,J=7Hz), 3.49(3H,s), 4.40(2H,q,J=8Hz), 5.33-5.50(2H,m), 7.08(1H,s), 7.09"7.20(2H,m), 7.38(2H,d,J=8Hz), 7.57(lH,t,J=8Hz), 8.09(2H,d,J=8Hz) , 8.52(1H,d,J=6Hz) Preparation 213 The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 351 (M+1)
' H-NMR (CDC13) δ : 1.41 (3H,t,J=8Hz) , 3.27-3.39(lH,m), 3.39-3.49(1H,m), 3.51 (3H,s), 4.40(2H,q,J=8Hz), 4.57-4.67(1H,m), 7.lO(1H,s), 7.10-7.20(2H,m), 7.40(2H,d,J=8Hz), 7.60(1H,t,J=8Hz) , 8.09(2H,d,J=8Hz) , 8.59(1H,d,J=4Hz) Preparation 214
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 157-160°C MASS (m/z) : 443 (M+1) ' H-NMR (CDCI3) δ : 1.43(9H,s), 2.62(3H,s),
3.10-3.21 (1H,m), 3.25-3.35(1H,m) , 4.56(1H,br s) , 4.61-4.80(2H,m), 5.07(1H,br s) , 6.93(1H,t,J=8Hz) , 7.30(1H,d,J=8Hz), 7.40(2H,d,J=8Hz) , 8.11 (1H,dd,J=8 and 2Hz) , 8.18(2H,d,J=8Hz), 9.03(1H,d,J=2Hz) Preparation 215
The object compound was obtained according to a similar manner to that of Preparation 2. mp : 194-196°C MASS (m/z) : 438 (M+1)
' H-NMR (CDCI3) c5 : 1.40(9H,s), 2.59(3H,s), 3.29(3H,s), 3.32-3.52(2H,m), 5.11 (lH,q,J=8Hz) , 5.38(1H,d,J=8Hz) , 7.06(1H,s), 7.21(1H,d,J=8Hz), 7.31 (2H,d,J=8Hz), 7.49(1H,dd,J=8 and 2Hz), 8.11 (2H,d,J=8Hz), 8.42(1H,d,J=2Hz) Preparation 216
The object compound was obtained according to a similar manner to that of Preparation 8. oil MASS (m/z) : 338 (M+1)
' H-NMR (CDCI3) δ : 2.61 (3H,s), 3.20-3.31 (1H,m) , 3.40(3H,s), 3.41-3.50(1H,m), 4.21 (1H,t,J=8Hz) , 7.09(1H,s) 7.23(1H,d,J=8Hz), 7.34(2H,d,J=8Hz), 7.51 (lH,d,J=8Hz), 8.18(2H,d,J=8Hz), 8.49(1H,d,J=2Hz) Preparation 217
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS (m/z) : 409 (M+1)
' H-NMR (CDCI3) δ : 1.41 (9H,s), 3.20-3.42(2H,m) , 4.60-4.72(1H,m), 4.70(2H,d,J=4Hz) , 6.41 (1H,br s) , 7.11-7.26(2H,m), 7.60(1H,t,J=8Hz), 7,78(2H,d,J=8Hz) , 8.00(1H,s), 8.01(2H,d,J=8Hz), 8.53(1H,d,J=2Hz) Preparation 218
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS (m/z) : 404 (M+1)
' H-NMR (CDCI3) δ : 1.40(9H,s), 3.43(2H,d,J=2Hz) , 3.50(3H,s), 5.46(2H,br s), 7.10(1H,s), 7.1 (2H,d,J=8Hz) , 7.41 (2H,d,J=8Hz) , 7.57(1H,t,J=8Hz), 7.70(2H,d,J=8Hz) , 8.53(1H,d,J=2Hz) Preparation 219
The object compound was obtained according to a similar manner to that of Preparation 8. amorphous solid MASS (m/z) : 304 (M+1)
' H-NMR (CDCI3) δ : 3.46(2H,d,J=8Hz), 3.60(3H,s), 4.80(1H,t,J=8Hz), 7.11(1H,s), 7.12-7.22(2H,m) , 7.43(2H,d,J=8Hz), 7.61 (lH,t,J=8Hz) , 7.70(2H,d,J=8Hz), 8,58(1H,d,J=2Hz) Preparation 220 The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS (m/z) : 430 (M+1)
' H-NMR (CDCl3) δ : 1.50(9H,s), 3.18-3.28(1H,m) , 3.32-3.47(1H,m), 4.70-4.78(2H,m) , 4.80(1H,br s) , 6.29(1H,br s), 7.27(1H,d,J=6Hz) , 7.71 (lH,br s), 8.10(2H,d,J=8Hz), 8.32(2H,d,J=8Hz) , 8.62(1 H,d,J=6Hz) , 9.14(1H,s) Preparation 221
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS (m/z) : 425 (M+1)
1 H-NMR (CDCI3) <5 : 1.40(9H,s), 3.38-3.48(1H,m) , 3.50-3.60(1H,m), 3.69(3H,s), 5.43(1H,d,J=8Hz) , 5.58(1H,q,J=8Hz), 7.10(1H,s), 7.21 (1H,d,J=4Hz) , 7.50(2H,d,J=8Hz), 8.30(2H,d,J=8Hz) , 8.59(1H,d,J=4Hz) , 9.11 (lH,s) Preparation 222
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 325 (M+1)
1 H-NMR (CDCI3) δ : 3.29-3.39(1H,m), 3.48-3.58(1H,m), 3.73(3H,s), 4.70(1H,t J=8Hz), 7.17(1H,s), 7.29(1H,d,J=6Hz), 7.52(2H,d,J=8Hz) , 8.30(2H,d,J=8Hz) , 8.62(1H,d,J=6Hz), 9.19(1H,s) Preparation 223
The object compound was obtained according to a similar manner to that of Preparation 5. oil MASS (m/z) : 428 (M+1)
1 H-NMR (CDCI3) δ 1.41(3H,t,J=8Hz), 1.43(9H,s), 3.10-3.30(1H,m), 3.31-3.42(1H,m), 4.08(2H,q,J=8Hz) , 4.68(2H,d,J=4Hz) , 4.70(1H,br s), 6.40(1H,br s), 7.09-7.19(2H,m), 7.21(1H,d,J=8Hz), 7.38(1H,t,J=8Hz), 7.41(1H,s), 7.50(1H,d,J=8Hz), 7.60(1H,t,J=8Hz), 7.90(1H,br s), 8.57(1H,d,J=2Hz) Preparation 224
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 423 (M+1)
1H-NMR (CDCI3) δ 1.39(9H,s), 1.44(3H,t,J=8Hz) , 3.33"3.50(2H,m) , 3.43(3H,s), 4.03(2H,q,J=8Hz), 5.30-5.51 (2H,m) , 6.80-6.91 (3H,m), 7.00(1H,s), 7.03-7.18(2H,m), 7.30(1H,t,J=8Hz), 7.53(1H,t,J=6Hz), 8.52(1H,d,J=2Hz) , Preparation 225
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 323 (M+1)
1 H-NMR (CDCI3) <5 1.43(3H,t,J=8Hz), 3.24-3.38(1 H,m), 3.39-3.50(1H,m), 3.50(3H,s), 4.07(2H,q,J=8Hz), 4.52-4.61 (1H,m), 6.80-6.92(3H,m), 7.00(1H,s), 7.10-7.20(2H,m), 7.31(1H,t,J=8Hz), 7.60(lH,t,J=8Hz), 8.59(1H,d,J=2Hz) Preparation 226
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid
MASS (m/z) : 490 (M+1)
1 H-NMR (CDCI3) δ 1.42(9H,s), 3.19-3.30(1H,m) , 3.30-3.41 (1H,m) , 4.61(2H,d,J=4Hz), 4.62-4.73(1H,m) , 5.11(2H,s), 6.41 (1H,br s) , 7.00(2H,d,J=8Hz), 7.12(1H,t,J=8Hz), 7.20(1H,d,J=8Hz), 7.30-7.48(5H,m), 7.59(1H,t,J=8Hz) , 7.84(1H,br s) , 7.91(2H,d,J=8Hz), 8.52(1H,d,J=4Hz) Preparation 227
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 485 (M+1)
' H-NMR (CDC13) δ 1.38(9H,s), 3.38(3H,s), 3.41 (2H,d,J=8Hz), 5.10(2H,s), 5.30-5. 2(1H,m), 5.42-5.50(1H,m) , 6.91 (lH,s), 7.00(2H,d,J=8Hz), 7.10(2H,t,J=8Hz) , 7.20(2H,d,J=8Hz) , 7.30-7.48(5H,m), 7.53(1H,t,J=8Hz) , 8.52(1H,d,J=2Hz) Preparation 228
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 385 (M+1)
1 H-NMR (CDCI3) δ 3.20-3.48(2H,m), 3.48(3H,s), 4.58(1H,t,J=8Hz) , 5.10(2H,s), 6.97(1H,s), 7.00(2H,d,J=8Hz) , 7.13(2H,d,J=8Hz) , 7.21(2H,d,J=8Hz), 7.30-7.50(5H,m) , 7.59(1H,t,J=8Hz) , 8.58(lH,d,J=2Hz) Preparation 229
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS (m/z) : 368 (M+1)
1 H-NMR (CDCI3) δ 1.50(9H,s), 3.18(1H,br s) , 3.70-3.80(1H,m), 4.12(1H,d,J=10Hz), 4.28-4.38(1H,m), 4.71-4.91 (2H,m) , 5.62(1H,d,J=8Hz), 7.53(1H,br s) , 8.13(2H,d,J=8Hz) , 8.33(2H,d,J=8Hz) Preparation 230
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 363 (M+1) 'H-NMR (CDCI3) δ 1.47(9H,s), 3.70(3H,s),
3.91 (1H,dd,J=l5 and 2Hz), 4.22(1H,dd,J=15 and 2Hz) , 4.92-5.01 (1H,m), 5.58(1H,d,J=8Hz), 7.10(1H,s), 7.58(2H,d,J=8Hz), 8.31 (2H,d,J=8Hz) Preparation 231
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 263 (M+1)
1 H-NMR (CDCI3) δ 3.71 (3H,s), 3.81-3.91 (1H,m), 4.00-4.12(2H,m) , 7.10(1H,s), 7.54(2H,d,J=8Hz), 8.30(2H,d,J=8Hz) , Preparation 232
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS (m/z) : 428 (M+1)
'H-NMR (CDCI3) δ 1.48(9H,s), 3.20-3.30(1H,m) , 3.31"3.42(1H,m) , 4.61(2H,d,J=4Hz), 4.63-4.72(1H,m) , 6.09(2H,s), 6.41 (1H,br s) , 6.88(1H,d,J=8Hz), 7.11-7.23(2H,m) , 7.41 (1H,s), 7.50-7.67(2H,m), 7.89(1H,br s), 8,58(1H,d,J=2Hz) Preparation 233
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 423 (M+1)
'H-NMR (CDCI3) δ 1.38(9H,s), 3.40(3H,s), 3.42(2H,d,J=8Hz), 5.30-5.50(2H,m), 5.99(2H,s), 6.70-6.77(2H,m), 6.82(1H,d,J=8Hz), 6.90(1H,s), 7.10(2H,t,J=8Hz) , 7.52(1H,t,J=8Hz), 8.52(1H,d,J=8Hz) Preparation 234
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 323 (M+1)
' H-NMR (CDC13) δ 3.27-3.37(1H,m), 3.38-3.47(1H,m) , 3.50(3H,s), 4.52-4.60(1H,m), 6.00(2H,s), 6.72-6.80(2H,m) , 6.85(1H,d,J=8Hz), 6.93(1H,s), 7.10-7.20(2H,m) , 7.60(1H,t,J=8Hz), 8.59(1H,d,J=2Hz) Preparation 235
The object compound was obtained according to a similar manner to that of Preparation 5. oil
MASS (m/z) : 380 (M-1 ) 1 H-NMR (CDCI3) δ 1.49(9H,s), 3.40(3H,s),
3.51(1H,dd,J=10 and 7Hz), 3.90(1H,dd,J=8 and 2Hz) , 4.30-4.40(1H,m), 4.70-4.90(2H,m) , 5.42(1H,br s) , 7.43(1H,br s), 8.13(2H,d,J=8Hz), 8.35(2H,d,J=8Hz), Preparation 236
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS (m/z) : 377 (M+1)
' H-NMR (CDCI3) δ 1.46(9H,s), 3.33(3H,s), 3.62-3.72(1H,m), 3.70(3H,s), 3.79-3.88(1 H,m), 5.11 (1H,q,J=8Hz), 5.41(1H,d,J=8Hz), 7.19(1H,s), 7.53(2H,d,J=8Hz), 8.30(2H,d,J=8Hz) Preparation 237
The object compound was obtained according to a similar manner to that of Preparation 8. oil MASS (m/z) : 277 (M+1) ' H-NMR (CDCI3) δ 3.40(3H,s), 3.71 (3H,s), 3.77-3.88(2H,m) ,
4.22(2H,br s), 4.37-4.50(1H,m) , 7 9(1H,s), 7.51 (2H,d,J=8Hz) , 8.30(2H,d,J=8Hz), Preparation 238
The object compound was obtained according to a similar manner to that of Preparation 5. oil
MASS (m/z) : 458 (M+1)
1 H-NMR (CDCI3) δ 1.49(9H,s), 3.59"3.68(1H,m) , 3.90-4.02(1 H,m) , 4.30-4.42(1H,m), 4.50-4.62(2H,m) , 4.78-7.84(2H,m) , 5.43(1H,br s), 7.28-7.39(5H,m) , 7.42(1H,br s), 8.13(2H,d,J=8Hz), 8.37(2H,d,J=8Hz) Preparation 239
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS (m/z) : 453 (M+1)
'H-NMR (CDCI3) δ 1.41 (9H,s), 3.68(3H,s), 3.78(lH,t,J=8Hz) , 3.97(1H,t,J=8Hz), 4.52(2H,s), 5.15(1H,q,J=8Hz) , 5.45(1H,d,J=8Hz), 7.19(1H,s), 7.20-7.38(5H,m) , 7.51(2H,d,J=8Hz), 8.30(2H,d,J=8Hz) Preparation 240
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 353 (M+1) ' H-NMR (CDCI3) δ 3.70(3H,s), 3.83(2H,d,J=8Hz) ,
4.30(1H,t,J=8Hz), 4.59(2H,s), 7.18(1H,s), 7.20-7.38(5H,m), 7.51(2H,d,J=8Hz), 8.30(2H,d,J=8Hz) Preparation 241
The object compound was obtained according to a similar manner to that of Preparation 5 except that a mixture of dichloromethane and dimethylformamide was used instead of dichloromethane. amorphous solid MASS (m/z) : 416 (M-1 )
' H-NMR (DMSO-dβ) δ 1.31 (9H,s), 2.70-2.98(2H,m) , 4.19-4.30(1H,m), 4.57-4.75(2H,m), 6.79(1H,s), 6.99(1H,d,J=8Hz), 7.53(1H,s), 8.11-8.30(4H,m), 8.33(2H,d,J=8Hz) Preparation 242
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 413 (M+1)
' H-NMR (CDCl3) δ 1.48(9H,s), 3.33(2H,d,J=7Hz) , 3.62(3H,s), 5.09-5.19(1H,m), 5.19-5.30(1H,m) , 6.90(1H,s), 7.19(1H,s), 7.28(1H,s), 7.51 (1H,s), 7.58(2H,d,J=8Hz) , 8.31 (2H,d,J=8Hz) Preparation 243
The object compound was obtained according to a similar manner to that of Preparation 8. amorphous solid MASS (m/z) : 313 (M+1)
' H-NMR (CDCI3) δ 3.22(2H,d,J=7Hz), 3.69(3H,s), 4.33(1H,t,J=8Hz) , 6.89(1H,s), 7.19(1H,s), 7.28(1H,s), 7.52(2H,d,J=8Hz) , 7.59(lH,s), 8.30(2H,d,J=8Hz) Preparation 244
The object compound was obtained according to a similar manner to that of Preparation 5, oil
MASS (m/z) : 418 (M+1)
1 H-NMR (CDCI3) δ 1.48(9H,s), 3.20-3.30(1H,m) , 3.32-3.43(1H,m), 4.62-4.72(1H,m), 4.67(2H,d,J=2Hz), 6.42(1H,br s), 7.12-7.23(2H,m), 7.47(2H,d,J=8Hz) , 7.60(1H,t,J=8Hz) , 7.89(2H,d,J=8Hz), 7.93(lH,br s) , 8.53(1H,d,J=2Hz) Preparation 245
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS (m/z) : 413 (M+1)
'H-NMR (CDCI3) δ 1.37(9H,s), 3.38-3.48(2H,m), 3.44(3H,s), 5.33-5.52(2H,m), 6.90(1H,s), 7.10(2H,t,J=8Hz), 7.21(2H,d,J=8Hz), 7.40(2H,d,J=8Hz) , 7.57(1H,t,J=8Hz) 8.52(1H,d,J=2Hz) Preparation 246
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 313 (M+1)
' H-NMR (CDCI3) δ 3.27-3.38(1H,m), 3.39-3.50(1H,m), 3.50(3H,s), 4.53-4.62(1H,m), 7.01 (1H,s), 7.13(1H,d,J=8Hz) , 7.18(1H,t,J=8Hz), 7.25(2H,d,J=8Hz), 7.40(2H,d,J=8Hz) , 7.60(1H,t,J=8Hz), 8.59(lH,d,J=2Hz) Preparation 247
A mixture of 6-acetylquinoline (2.0 g) , hydroxylamine hydrochloride (1.0 g) and sodium carbonate (1.7 g) in ethanol (20 ml) was refluxed for 1 hour. After cooling to room temperature, water was added to the mixture. The precipitate was collected and washed with diethyl ether to give the object compound as a pale yellow solid (1.7 g). mp : 170-173°C
MASS (ESI) (m/z) : 187 (M+H)+
' H-NMR (CDCI3, δ ) 2.43(3H,s), 7.44(lH,dd,J=7.5, 4.5Hz), 8.00(1H,s), 8.16-8.23(3H,m), 8.94(1H,d,J=4.5Hz), 9.46(1H,s) Preparation 248
To a solution of the starting compound (1.50 g) in pyridine (15 ml) cooled to 0°C was added p-toluenesulfonyl chloride (1.84 g) with stirring under an atmosphere of nitrogen, and the mixture was stirred at 0°C for 9 hours. After the reaction mixture was poured into ice- water, the precipitate was collected and washed successively with water and 2-propanol to give the object compound as a pale brown solid (1.62 g). mp : 119.5-121°C
MASS (ESI) (m/z) : 341 (M+H)+
' H-NMR (CDC13, δ ) 2.43(3H,s), 2.48(3H,s),
7.36(2H,d,J=7.5Hz), 7.44(1H,dd,J=7.5, 4.5Hz), 7.92-8.03(4H,m) , 8.07(1H,d,J=7.5Hz), 8.l8(1H,d,J=7.5Hz), 8.95(1H,d,J=4.5Hz) Preparation 249
Potassium (258.4 mg) was added to a suspension of the starting compound (1.5 g) in ethanol (40 ml), and the mixture was stirred at room temperature for 72 hours. The precipitate of potassium p- toluenesulfonate was removed by filtration, and the filtrate was diluted with diethyl ether (400 ml). A further precipitate of the potassium salt was filtered off, and the ethereal solution was extracted twice with 1.5N hydrochloric acid (50 ml). The combined extracts were evaporated in vacuo, and the residue was recrystallized from 2-propanol to give the object compound as an off-white solid (1.31 g). mp : 293.5-296°C
MASS (ESI) (m/z) : 187 (M+H)+ 1 H-NMR (DMSO-ds, δ ) 4.72(1H,d,J=5.5Hz),
4.77(1H,d,J=5.5Hz), 7.83(1H,dd,J=7.5, 5.5Hz), 8.30(1H,d,J=7.5Hz), 8.37(1H,d,J=7.5Hz) , 8.55(2H,br s), 8.81(1H,d,J=7.5Hz), 8.97(1H,s), 9.20(1H,d,J=5.5Hz) Preparation 250
The object compound was obtained according to a similar manner to that of Preparation 5. oil
MASS (m/z) : 435 (M+1) 'H-NMR (CDCI3) δ 1.50(9H,s), 3.20-3.31 (1H,m) , 3.3l-3.48(1H,m) , 4.68-4.80(1H,m), 4.87(2H,d,J=4Hz) , 6.49(1H,br s) , 7.l8(1H,t,J=6Hz), 7.22(1H,d,J=8Hz), 7.51 (1H,dd,J=8 and 2Hz) , 7.61(1H,t,J=8Hz), 8.02(1H,br s), 8.13-8.31 (3H,m) , 8.49(1H,s), 8.58(lH,d,J=2Hz), 9.08(1H,d,J=2Hz) Preparation 251
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS (m/z) : 430 (M+1)
' H-NMR (CDCI3) δ 1.40(9H,s), 3.49(2H,d,J=6Hz) , 3.51 (3H,s), 5.38-5.60(2H,m), 7.10(1H,s), 7.1 l-7.20(2H,m) , 7.43(lH,dd,J=8 and 2Hz), 7.59(1H,t,J=8Hz), 7.63(1H,d,J=8Hz), 7.77(1H,s), 8.17(2H,t,J=8Hz) , 8.56(lH,d,J=2Hz), 8.92(1H,d,J=2Hz) , Preparation 252
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 330 (M+1) 'H-NMR (CDCl3) δ 3.40-3.60(2H,m), 3.65(3H,s),
4.88(1H,t,J=8Hz), 7.10-7.21 (3H,m) , 7.46(lH,dd,J=8 and 2Hz) , 7.58-7.70(2H,m), 7.79(1H,s), 8.10-8.20(2H,m), 8.59(1H,d,J=2Hz), 8.99(1H,d,J=2Hz) Preparation 253
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 495 (M+1) ' H-NMR (CDCI3) δ 1.20(3H,t,J=8Hz), 1.40(9H,s),
3.00-3.10(1H,m), 3.20-3.33(lH,m), 4.12(2H,q,J=8Hz) , 5.13(1H,d,J=lOHz), 5.18(1H,d,J=10Hz) , 5.28(1H,d,J=8Hz) , 5.32-5.45(lH,m), 7.09(1H,s), 7.28-7.40(5H,m), 7.51 (2H,d,J=8Hz), 8.30(2H,d,J=8Hz) , Preparation 254
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 395 (M+1)
'H-NMR (CDCI3) δ 1.25(3H,t,J=8Hz), 3.00-3.10(1 H,m) , 3.18-3.30(lH,m), 4.02-4.30(2H,m) , 4.55(1H,t,J=8Hz) , 5.11(1H,d,J=8Hz), 5.18(lH,d,J=8Hz), 7.10(1H,s), 7.28-7.40(5H,m), 7.51 (2H,d,J=8Hz) , 8.29(2H,d,J=8Hz) Preparation 255
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 459 (M+1) ' H-NMR (CDCI3) δ 1.18(3H,t,J=8Hz), 1.40(9H,s),
3.42-3.52(1H,m), 3.53-3.70(1H,m) , 3.95-4.12(2H,m) , 5.50(1H,q,J=8Hz), 5.70(1H,br s) , 7.08(1H,s), 7.10-7.20(2H,m) , 7.21-7.30(2H,m), 7.31 (1H,s), 7.40-7.51 (3H,m) , 7.58(1H,t,J=8Hz), 7.90(1H,s), 8.52(1H,d,J=2Hz) Preparation 256
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 359 (M+1)
' H-NMR (CDCI3) δ 1.20(3H,t,J=8Hz), 3.35"3.60(2H,m) , 3.90-4.17(2H,m), 4.62-4.72(1H,m) , 7.03(1H,s), 7.18(2H,d,J=8Hz), 7.23(2H,d,J=8Hz), 7.31 (1H,s), 7.40-7.50(2H,m), 7.61 (1H,t,J=8Hz) , 7.89-7.92(2H,m), 8.59(1H,d,J=2Hz) Preparation 257 The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS (m/z) : 437 (M+1) ' H-NMR (CDCI3) δ 1.07(3H,t,J=8Hz), 1.32(9H,s),
1.42(3H,t,J=8Hz), 3.12-3.33(1H,m), 3.40-3.60(1H,m) , 3.80-4.00(1H,m), 4.05(2H,q,J=8Hz), 5.41 (1H,q,J=8Hz) , 5.59(1H,d,J=8Hz), 6.90(1H,s), 6.92(2H,d,J=8Hz) , 7.08-7.19(2H,m), 7.21 (2H,d,J=8Hz) , 7.53(1H,t,J=8Hz) , 8.52(1H,d,J=2Hz), Preparation 258
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 337 (M+1)
' H-NMR (CDCI3) δ 1.12(3H,t,J=8Hz), 1.48(3H,t,J=8Hz) , 3.20-3.31 (1H,m), 3.33-3.50(1H,m), 3.80-4.00(2H,m) , 4.03(2H,q,J=8Hz), 4.56-4.70(1H,m) , 6.90(1H,s), 6.92(2H,d,J=8Hz), 7.13(2H,d,J=8Hz) , 7.19-7.30(2H,m) , 7.60(1H,t,J=8Hz), 8.60(1H,d,J=8Hz), Preparation 259
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS (m/z) : 469 (M+1)
'H-NMR (CDCI3) δ 1.44(9H,s), 3.23-3.42(6H,m) , 3.80-3.90(4H,m), 4.60(2H,d,J=2Hz), 4.63-4.78(1H,m) , 6.39(1H,br s), 6.87(2H,d,J=8Hz), 7.12-7.30(2H,m), 7.62(1H,t,J=8Hz), 7.88(3H,d,J=8Hz), 8.58(1H,d,J=2Hz) Preparation 260
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid
MASS (m/z) : 464 (M+1)
1 H-NMR (CDCl3) δ 1.39(9H,s), 3.10-3.22(4H,m) , 3.28-3.60(2H,m) , 3.42(3H,s), 3.80-3.92(4H,m), 5.40(1H,q,J=8Hz) , 5.60(1H,d,J=6Hz), 6.91 (2H,d,J=8Hz) , 6.92(1H,s), 7.11(2H,d,J=8Hz), 7.20(2H,d,J=8Hz) , 7.52(1H,t,J=8Hz), 8.52(1H,d,J=2Hz) Preparation 261
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 364 (M+1)
'H-NMR (CDCI3) δ 3.10-3.28(4H,m), 3.28-3.50(2H,m), 3.46(3H,s), 3.78-3.91 (4H,m), 4.60(1H,t,J=8Hz) , 6.92(2H,d,J=8Hz), 6.93(1H,s), 7.12(2H,t,J=8Hz), 7.20(2H,d,J=8Hz), 7.59(1H,t,J=8Hz), 8.59(1H,d,J=8Hz), Preparation 262
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 478 (M+H)+
'H-NMR (CDCl3,300MHz) δ : 1.10(3H,t,J=7Hz), 1.34(9H,s), 3.10-3.25(4H,m), 3.38-3.65(2H,m) , 3.76-4.04(6H,m), 5.38-5.52(1H,m), 5.65(1H,br d,J=8Hz), 6.91 (2H,d,J=8Hz), 6.93(1H,s), 7.02-7.30(4H,m), 7.45-7.60(1H,m), 8.51 (1H,d,J=5Hz) Preparation 263
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 378 (M+H)+
' H-NMR (CDCl3,300MHz) δ : 1.15(3H,t,J=7Hz) , 3.11-3.31 (4H,m), 3.36-3.57(2H,m), 3.75-4.10(6H,m), 4.68(1H,t,J=7Hz), 6.93(2H,d,J=8Hz), 6.97(1H,s), 7.08-7.29(4H,m), 7.53-7.66(lH,m), 8.54(1H,d,J=5Hz) Preparation 264
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 473 (M+H)+
' H-NMR (CDCl3,300MHz)(5 : 0.76(3H,t,J=7Hz) , 1.38(9H,s), l.40-1.60(2H,m), 3.48-3.80(2H,m) , 3.88-4.08(2H,m) , 5.40-5.60(2H,m), 7.02-7.65(10H,m) , 7.92(1H,s), 8.52(1H,d,J=5Hz) Preparation 265
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 373 (M+H)+
'H-NMR (CDCl3,300MHz) δ • ' 0.78(3H,t,J=7Hz) , 1.36-1.72(2H,m) , 3.42-3.74(2H,m), 3.85-4.24(2H,m) , 4.81-5.02(1H,m) , 7.08(1H,s), 7.15-7.72(9H,m), 7.93(1H,s), 8.55(lH,d,J=5Hz) Preparation 266
To an ice-cooled suspension of sodium hydride (60%, 2.21 g) in N,N-dimethylformamide (35 ml) was added 1 ,2,4-triazole (3.80 g) portionwisely. After the evolution of hydrogen was ceased, the mixture was heated at 40°C for 20 minutes and allowed to cool to room temperature. To this mixture was added the starting compound (6.91 g) and the mixture was heated at 80°C for 4 hours. The mixture was poured into water and extracted three times with ethyl acetate. The extract was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by recrystallization from ethyl acetate-diisopropyl ether to give the object compound (3.36 g).
MASS (ESI) (m/z) : 188 (M+H)+
'H-NMR (CDCl3,300MHz)(5 : 2.65(3H,s), 7.83(2H,d,J=8Hz) , 8.12(2H,d,J=8Hz), 8.15(1H,s), 8.67(1H,s) Preparation 267
The object compound was obtained according to a similar manner to
4 o 8 that of Preparation 108.
MASS (ESI) (m/z) : 266, 268 (free, M+H)+ 'H-NMR (DMSO-de,300MHz) ( : 4.98(2H,s), 8.08(2H,d,J=8Hz) , 8.20(2H,d,J=8Hz), 8.33(1H,s), 9.51 (1H,s) Preparation 268
The object compound was obtained according to a similar manner to that of Preparation 109.
MASS (ESI) (m/z) : 229 (M+H)+
' H-NMR (CDCl3,300MHz) δ : 4.68(2H,s), 7.86(2H,d,J=8Hz) , 8.08(2H,d,J=8Hz), 8.16(1H,s), 8.68(1H,s) Preparation 269
The object compound was obtained according to a similar manner to that of Preparation 110 except that a mixture of methanol and tetrahydrofuran was used instead of methanol. MASS (ESI) (m/z) : 203 (free, M+H)+
' H-NMR (DMSO-d6,300MHz)<5 : 4.65(2H,q,J=5Hz) , 8.00-8.27(4H,m) , 8.34(1H,s), 8.46(3H,br s), 9.54(1H,s) Preparation 270
The object compound was obtained according to a similar manner to that of Preparation 91.
MASS (ESI) (m/z) : 451 (M+H)+
' H-NMR (CDC13,300MHz) δ : 1.46(9H,s), 3.20~3.44(2H,m) , 4.61-4.78(3H,m), 6.44(1H,br d,J=8Hz) , 7.10-7.25(2H,m), 7.54-7.65(1H,m), 7.84(2H,d,J=8Hz) , 8.00(1H,br s) , 8.09(2H,d,J=8Hz), 8.14(1H,s), 8.55(lH,d,J=5Hz) , 8.68(1H,s) Preparation 271
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 446 (M+H)+
' H-NMR (CDCI3,300MHz)5 : 1.36(9H,s), 3.36-3.50(2H,m) ,
3.49(3H,s), 5.35-5.49(1H,m), 5.53(1H,br d,J=8Hz) , 7.05(1H,s), 7.07-7.18(2H,m), 7.44(2H,d,J=8Hz) , 7.50-7.62(1H,m) , 7.74(2H,d,J=8Hz), 8.12(1H,s), 8.54(1H,d,J=5Hz) , 8.59(1H,s) Preparation 272
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 346 (M+H)+
'H-NMR (CDCI3,300MHz) δ : 3.26-3.51 (2H,m) , 3.56(3H,s), 4.61(1H,t,J=7Hz), 7.09(1H,s), 7.15(2H,d,J=8Hz), 7.48(2H,d,J=8Hz), 7.55-7.65(1H,m), 7.74(2H,d,J=8Hz) , 8.12(1H,s), 8.57(1H,d,J=5Hz), 8.59(1H,s) Preparation 273
The object compound was obtained according to a similar manner to that of Preparation 2.
MASS (ESI) (m/z) : 460 (M+H)+
' H-NMR (CDC13,300MHz) <5 : 1.13(3H,t,J=7Hz) , 1.34(9H,s), 3.34-3.60(2H,m), 3.84-4.13(2H,m), 5.33(1H,br d,J=8Hz) , 5.35-5.51 (1H,m), 7.03(lH,s), 7.06-7.18(2H,m), 7.47(2H,d,J=8Hz), 7.50-7.60(1H,m), 7.74(2H,d,J=8Hz), 8.12(1H,s), 8.53(1H,d,J=5Hz), 8.59(1H,s) Preparation 274
The object compound was obtained according to a similar manner to that of Preparation 4.
MASS (ESI) (m/z) : 360(M+H)+
' H-NMR (CDC13,300MHz) δ : 1.16(3H,t,J=7Hz), 3.29"3.52(2H,m) , 3.89-4.14(2H,m), 4.60(1H,t,J=7Hz) , 7.07(1H,s), 7.10-7.20(2H,m), 7.48(2H,d,J=8Hz), 7.54-7.64(1H,m), 7.75(2H,d,J=8Hz), 8.13(1H,s), 8.58(1H,d,J=5Hz) , 8.60(1H,s) Preparation 275
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS (m/z) : 467 (M+1) 1 H-NMR (CDC13)<5 : 1.48(9H,s), 1.68(6H,s), 3.20-3.42(2H,m) , 3.39(4H,s), 4.57(2H,d,J=2Hz), 4.61-4.72(1H,m) , 6.38(1H,d,J=2Hz), 6.81 (2H,d,J=8Hz) , 7.12(1H,t,J=6Hz), 7.20(1H,d,J=8Hz), 7.60(1H,t,J=8Hz) , 7.80(2H,d,J=8Hz) , 7.81 (1H,s), 8.54(1H,d,J=2Hz) Preparation 276
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS (m/z) : 462 (M+1)
1 H-NMR (CDC13)(5 : 1.39(9H,s), 1.67-1.78(6H,m), 3.17-3.23(4H,m) , 3.38(3H,s), 3.47(2H,t,J=8Hz), 5.40(1H,q,J=8Hz), 5.58(1H,d,J=8Hz), 6.91 (1H,s), 6.93(2H,d,J=8Hz) , 7.06-7.20(2H,m), 7.17(2H,d,J=8Hz) , 7.53(1H,t,J=8Hz) , 8.51(1H,d,J=2Hz) Preparation 277
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS (m/z) : 362 (M+1)
1 H-NMR (CDC13)<5 : 1.53-1.68(2H,m), 1.68-1.80(4H,m) , 3.17-3.28(4H,m), 3.28-3.41 (2H,m) , 3.48(3H,s), 4.60(1H,t,J=8Hz), 6.90-7.00(3H,m), 7.10-7.22(4H,m) , 7.59(1H,t,J=8Hz), 8.59(1H,d,J=2Hz) Preparation 278
The starting compound (3.6 g) was dissolved in tetrahydrofuran (36 ml) under a nitrogen atmosphere and cooled to -30βC. 1M Lithium aluminum hydride solution in tetrahydrofuran (11.7 ml) was added dropwise to the solution at -30°C, and the reaction mixture was stirred at -30°C for 1 hour. Water was added carefully, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate and 1 N-hydrochloric acid were added to the suspension and extracted. The organic layer was washed with water, a saturated
4 l l sodium hydrogencarbonate solution and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the object compound (501.3 mg) as a pale yellow amorphous solid.
MASS (m/z) : 484 (M+H)+
'H-NMR (CDC13)(5 : 1.41 (9H,s), 2.80(3H,s),
3.17(1H,dd,J=12.0 and 9.0Hz), 3.37(1H,dd,J=12.0 and 7.0Hz), 5.01 (1H,m), 5.69(1H,d,J=7.5Hz), 6.99~7.06(2H,m), 7.09(2H,d,J=7.5Hz), 7.19~7.26(3H,m) , 7.61 (2H,d,J=7.5Hz), 9.68(1H,s) Preparation 279
The object compound was obtained according to a similar manner to that of Preparation 6.
MASS (m/z) : 522 (M+H)+ 1 H-NMR (CDC13)<5 : 1.47(9H,s), 2.77(3H,s), 3.14(1H,m), 3.38(1H,dd,J=13.5 and 5.5Hz), 4.99(1H,m), 5.80(1H,m), 6.97-7.12(5H,m), 7.19-7.29(5H,m), 7.56(2H,d,J=7.5Hz) Preparation 280
The object compound was obtained according to a similar manner to that of Preparation 3. yellow amorphous solid MASS (m/z) : 422 (M+H)+
' H-NMR (CDC13)£ : 2.93(3H,s), 3.19(2H,d,J=7.5Hz), 4.21(1H,t,J=7.5Hz), 6.98(1H,s), 7.02-7.09(2H,m), 7.12(1H,d,J=7.5Hz), 7.20-7.31 (5H,m) , 7.56(2H,d,J=7.5Hz) Preparation 281
The object compound was obtained according to a similar manner to that of Preparation 91. brown oil
MASS (m/z) : 463 (M+H)+
'H-NMR (CDC13)<5 : 3.28(1H,dd,J=15.0 and 7.0Hz), 3.40(1H,m), 4.72(2H,br s), 4.76(1H,m), 5.15(2H,s), 6.83(1H,m), 7.13-7.42(7H,m), 7.61 (lH,t,J=7.5Hz) , 8.10(2H,d,J=7.5Hz) , 8.15(1H,m), 8.32(2H,d,J=7.5Hz), 8.53(1H,d,J=5.5Hz) Preparation 282
The starting compound (420 mg) , xylene (6 ml) and acetic acid (1 ml) were mixed, and ammonium acetate (462 mg) was added to the solution at room temperature. The reaction mixture was refluxed for 2.5 hours with azeotropic removal of water and allowed to cool. The mixture was concentrated in vacuo , and the residue was dissolved in ethyl acetate. The organic solution was washed with a saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a chloroform-methanol (20:1) as eluent to give the object compound as a brown amorphous solid. MASS (m/z) : 444 (M+H)+ 1 H-NMR (CDCl3)c5 : 3.45(1H,dd,J=15.0 and 7.0Hz), 3.60(1H,m), 5.13(2H,s), 5.19(1H,m), 6.68(1H,m), 7.18-7.41 (9H,m) , 7.67(1H,t,J=7.5Hz), 7.89(2H,d,J=7.5Hz) , 8.21 (2H,d,J=7.5Hz) , 8.54(1H,d,J=5.5Hz) Preparation 283
The starting compound (340 mg) and 30%-hydrogen bromide solution in acetic acid (3 ml) were mixed at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours and diethyl ether was added to the mixture at 0°C The precipitate was collected to give the object compound (376.4 mg) as a pale brown solid, mp : 178-181 °C MASS (m/z) : 310 (M+H)+ 1 H-NMR (DMS0-d6)c5 : 3.61 (1H,dd,J=15.0 and 7.0Hz),
3.68(1H,dd,J=15.0 and 7.0Hz), 5.01(1H,m), 7.57(1H,d,J=7.5Hz) , 7.61(1H,t,J=7.5Hz), 7.99(1H,s), 8.03(2H,d,J=7.5Hz) , 8.11(1H,t,J=7.5Hz), 8.27(2H,d,J=7.5Hz) , 8.72(lH,d,J=5.5Hz) Preparation 284
4 l 3 The object compound was obtained according to a similar manner to that of Preparation 5. off-white solid mp : 190-191.5°C
MASS (m/z) : 349 (M-H)+
' H-NMR (DMSO-d6)<5 : 1.18(3H,t,J=7.5Hz), 4.21 (2H,q,J=7.5Hz), 6.37(1H,d,J=7.5Hz), 7.03(1H,t,J=7.5Hz) , 7.20(1H,t,J=7.5Hz) , 7.28(1H,d,J=1.0Hz), 7.41 (1H,d,J=7.5Hz) , 7.52-7.63(3H,m), 7.69(1H,t,J=7.5Hz), 8.02(2H,d,J=7.5Hz) , 9.40(1H,d,J=7.5Hz) Preparation 285
The object compound was obtained according to a similar manner to that of Preparation 282. yellow amorphous solid
MASS (m/z) : 332 (M+H)+
' H-NMR (DMSO-de)d : 1.29(3H,t,J=7.5Hz) , 4.21 (2H,q,J=7.5Hz) , 6.92-7.74(7H,m), 7.31 (1H,s), 7.93(2H,d,J=7.5Hz) Preparation 286
The object compound was obtained according to a similar manner to that of Example 73. off-white solid mp : 228-230°C
MASS (m/z) : 302 (M-H) +
' H-NMR (DMS0-d6)<5 : 7.02(1H,t,J=7.5Hz) , 7.10-7.61 (6H,m) , 7.59(1H,d,J=7.5Hz), 7.67-7.79(1H,m) , 7.89-8.04(1H,m) Preparation 287
The object compound was obtained according to a similar manner to that of Preparation 5. orange solid mp : 114-117°C
MASS (m/z) : 541 (M-H) + 1 H-NMR (CDCl3 ) c5 : 1 .12(3H,t,J=7.0Hz) , 1 .48(9H,s) ,
2.76(1 H,dd,J=14.5 and 7.0Hz) , 3.04( 1 H,m) , 4.19(2H,q,J=7.0Hz) , 4.67(lH,m), 6.05(1H,dd,J=8.5 and 7.0Hz), 6.17(1H,m), 7.10(1H,t,J=7.5Hz), 7.21-7.49(4H,m), 7.68-7.79(1H,m) , 8.03-8.32(5H,m) Preparation 288
The object compound was obtained according to a similar manner to that of Preparation 2. yellow amorphous solid MASS (m/z) : 538 (M+H)+ 1 H-NMR (CDC13)(5 : 1.12(3H,t,J=7.0Hz), 1.43(9H,s), 3.19(1H,m), 3.32(lH,m), 3.59(3H,s), 4.20(2H,q,J=7.0Hz) , 5.49(1H,m), 5.71 (1H,m), 7.08(lH,t,J=7.5Hz), 7.23-7.37(2H,m) , 7.47-7.57(2H,m), 7.53(2H,d,J=7.5Hz) , 8.33(2H,d,J=7.5Hz) , 8.96(1H,br s) Preparation 289
The object compound was obtained according to a similar manner to that of Preparation 3. yellow amorphous solid
MASS (m/z) : 438 (M+H)+
'H-NMR (CDC13)<5 : 1.19(3H,t,J=7.0Hz) ,
3.07(1H,dd,J=14.5 and 7.5Hz), 3.17(1H,dd,J=14.5 and 7.5Hz), 3.56(3H,s), 4.22(2H,q,J=7.0Hz), 4.52(1H,t,J=7.5Hz) , 7.08(1H,t,J=7.5Hz), 7.30(2H,t,J=7.5Hz) , 7.52(2H,d,J=7.5Hz) , 7.58(2H,d,J=7.5Hz),8.32(2H,d,J=7.5Hz), 9.45(1H,br s) Preparation 290
The object compound was obtained according to a similar manner to that of Preparation 91. brown oil
MASS (m/z) : 501 (M+H)+ H-NMR (CDC13)<5 : 1.17(3H,t,J=7.0Hz) , 1.47(9H,s),
3.10-3.33(2H,m), 4.17(2H,q,J=7.0Hz) , 4.67(1H,m), 6.07(lH,m), 7.09-7.27(3H,m), 7.51-7.66(2H,m) , 8.16-8.57(3H,m) Preparation 291
4 l 5 The object compound was obtained according to a similar manner to that of Preparation 2. dark brown amorphous solid MASS (m/z) : 496 (M+H)+ 1 H-NMR (CDC13)<5 : 1.19(3H,t,J=7.0Hz) , 1.39(9H,s), 3.32(3H,s), 3.49(2H,m), 4.20(2H,q,J=7.0Hz), 4.39(1H,m), 6.03(1H,m), 7.04-7.18(2H,m), 7.45(2H,d,J=7.5Hz) , 7.55(1H,m), 8.30(2H,d,J=7.5Hz), 8.52(1H,m) Preparation 292
The object compound was obtained according to a similar manner to that of Preparation 3. yellow oil
MASS (m/z) : 396 (M+H)+
' H-NMR (CDC13)5 : 1.20(3H,t,J=7.5Hz), 3.35-3.52(2H,m), 3.43(3H,s), 4.23(2H,q,J=7.5Hz), 4.66(1H,t,J=7.5Hz) , 7.19(2H,d,J=7.5Hz), 7.52(2H,d,J=7.5Hz) , 7.63(1H,t,J=7.5Hz) , 8.35(2H,d,J=7.5Hz), 8.59(lH,d,J=7.5Hz) Preparation 293
The object compound was obtained according to a similar manner to that of Example 73.
MASS (m/z) : 389 (M-1 )
1 H-NMR (CDC13)<5 : 1.45(9H,s), 3.07(1H,dd,J=5 and 15Hz), 3.18(1H,dd,J=7 and 15Hz), 3.73(3H,s), 5.36(1H,m), 5.73(1H,d,J=7Hz), 7.l4(1H,s), 7.55(2H,d,J=8Hz), 8.33(2H,d,J=8Hz) Preparation 294
The object compound was obtained according to a similar manner to that of Preparation 5. yellow amorphous solid
MASS (m/z) : 434 (M+H)+
'H-NMR (CDCl3)c5 : 1.43(9H,s), 3.13(1H,m), 3.15(3H,s),
3.35(1H,m), 3.73(3H,s), 3.79(3H,s), 5.41(2H,m), 7.11(1H,s), 7.53(2H,d,J=8.5Hz), 8.30(2H,d,J=8.5Hz) Preparation 295
The object compound was obtained according to a similar manner to that of Preparation 278. yellow amorphous solid MASS (m/z) : 375 (M+H)+
'H-NMR (CDCl3)c5 : 1.45(9H,s), 3.17(1H,m), 3.40(1H,m), 3.77(3H,s), 5.27(1H,m), 5.41(1H,m), 7.10(1H,s), 7.53(2H,d,J=8.5Hz), 8.30(2H,d,J=8.5Hz) , 9.85(1H,s) Preparation 296
The object compound was obtained according to a similar manner to that of Preparation 6. yellow solid mp : 217-218.5°C MASS (m/z) : 413 (M+H)+
'H-NMR (CDC13+CD30D) <5 : 1.40(9H,s), 3.29(2H,d,J=7.5Hz) , 3.61 (3H,s), 5.22(1H,t,J=7.5Hz), 6.92(2H,s), 7.10(1H,s), 7.53(2H,d,J=8.5Hz) , 8.31 (2H,d,J=8.5Hz) Preparation 297
The starting compound (85 mg) and 4N hydrogen chloride solution in ethyl acetate (2 ml) were mixed at 0 °C. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was washed with diethyl ether to give the object compound (89.4 mg) as a pale yellow solid, mp : 88-91°C MASS (m/z) : 313 (M+H)+
' H-NMR (DMS0-d6)<5 : 3.79(lH,dd,J=15.0 and 7.5Hz), 3.85(3H,s), 3.89(1H,dd,J=15.0 and 7.5Hz), 5.66(1H,t,J=7.5Hz) , 7.42(1H,s), 7.59(2H,s), 7.75(2H,d,J=7.5Hz), 8.33(2H,d,J=7.5Hz) Preparation 298
A mixture of the starting compound (5 g) and phenol (3.03 g) in N,N-dimethylacetamide (50 ml) was stirred until the solids were
4 l 7 dissolved. Then potassium carbonate (4.9 g) was added and the solution was refluxed for 1.5 hours. The cooled reaction mixture was treated with water (100 ml) and CHC13 (60 ml). The organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated in vacuo . The residue was purified by flash column chromatography over silica gel with a n-hexane/ethyl acetate (6:1) as eluent to give the object compound (4.85 g) as an orange solid. mp : 64-66°C
MASS (m/z) : 228 (M-H)+
' H-NMR (CDC13)<5 : 2.33(3H,s), 6.79(1H,s), 6.93~7.07(3H,m), 7.17(1H,t,J=7.5Hz), 7.33~7.42(2H,m) , 7.89(1H,d,J=7.5Hz) Preparation 299
Potassium permanganate (4.1 g) was added portionwise, with stirring, over 1 hour to a mixture of the starting compound (2.0 g) and anhydrous magnesium sulfate (2.1 g) in 2-methyl-2-propanol (30 ml) and water (30 ml) at 90 °C. The reaction mixture was stirred at 90°C for 3 hours, and cooled to room temperature. 2-Propanol was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water (60 ml) was added, and the suspension was filtered through a celite pad. The filtrate was acidified with 1N hydrochloric acid, and the precipitate was collected by filtration to give the object compound (845.5 mg) as a pale yellow solid. mp : 181-186"C
MASS (m/z) : 258 (M-H)+
'H-NMR (DMS0-d.)<5 : 7.19(2H,d,J=7.5Hz), 7.29(1H,t,J=7.5Hz), 7.43-7.53(3H,m), 7.83(1H,d,J=7.5Hz), 8.17(1H,d,J=7.5Hz) Preparation 300
The object compound was obtained according to a similar manner to that of Preparation 5. orange amorphous solid
MASS (m/z) : 455 (M+H)+
' H-NMR (CDCl3)c5 : 4.85(2H,d,J=2.5Hz) , 7.09(2H,d,J=7.5Hz) ,
4 1 7.16(1H,br t,J=2.5Hz), 7.23(1H,m), 7.37-7.48(2H,m) , 7.51 (1H,s), 7.61(1H,d,J=7.5Hz), 7.69(2H,d,J=7.5Hz) , 7.87(2H,d,J=7.5Hz), 8.03(1H,d,J=7.5Hz) Preparation 301
The object compound was obtained according to a similar manner to that of Preparation 2. pale brown solid mp : 134-136°C MASS (m/z) : 450 (M+H)+
'H-NMR (CDC13)<5 : 3.59(3H,s), 7.12(2H,d,J=7.5Hz) , 7.19(1H,s), 7.21-7.28(1H,m), 7.28(2H,d,J=7.5Hz) , 7.33(1H,d,J=1.0Hz) , 7.41(2H,d,J=7.5Hz), 7.53(1H,d,J=7.5Hz) , 7.60(2H,d,J=7.5Hz) , 8.09(1H,d,J=7.5Hz) Preparation 302
The object compound was obtained according to a similar manner to that of Example 60. off-white amorphous solid
MASS (m/z) : 420 (M+H)+
'H-NMR (CDC13)<5 : 3.57(3H,s), 4.03(2H,br s),
6.90(1H,d,J=7.5Hz), 7.02(2H,d,J=7.5Hz) , 7.08(1H,t,J=7.5Hz) , 7.11 (1H,s), 7.18(1H,s), 7.23-7.36(5H,m) , 7.57(2H,d,J=7.5Hz) Preparation 303
The object compound was obtained according to a similar manner to that of Example 1 6 from the starting compound and benzyl bromide, colorless oil
' H-NMR (CDC13)5 : 2.18(3H,s), 3.89(3H,s), 5.19(2H,s), 6.82(1H,dd,J=8.5 and 1.5Hz), 7.27"7.43(4H,m), 7.51(2H,d,J=8.5Hz), 7.70(lH,br s) , 7.83(1H,d,J=8.5Hz) Preparation 304
The object compound was obtained according to a similar manner to that of Example 73. colorless solid mp : 108-1 1 1 βC MASS (m/z) : 284 (M-H) +
'H-NMR (DMSO-d6)<5 : 2.07(3H,s), 5.13(2H,s), 7.19(1H,d,J=7.5Hz), 7.29-7.45(3H,m), 7.52(2H,d,J=7.5Hz) , 7.55(1H,s), 7.69(1H,d,J=7.5Hz) Preparation 305
The object compound was obtained according to a similar manner to that of Preparation 5. off-white solid mp : 194-197°C MASS (m/z) : 481 (M+H)+
' H-NMR (DMSO-de)S : 2.06(3H,s), 4.83(2H,d,J=6.0Hz) , 5.31 (2H,s), 7.20(1H,d,J=8.5Hz), 7.25"7.43(4H,m) , 7.53(2H,d,J=8.5Hz) , 7.66(1H,s), 7.77(2H,d,J=8.5Hz), 7.84(1H,d,J=8.5Hz) , 7.97(2H,d,J=8.5Hz), 8.67(1H,br t,J=6.0Hz) Preparation 306
The object compound was obtained according to a similar manner to that of Preparation 303. colorless oil MASS (m/z) : 288 (M+H)+
' H-NMR (CDC13)(5 : 3.90(3H,s), 5.18(2H,s), 7.31 (1H,t,J=8.5Hz) , 7.34-7.43(3H,m), 7.47-7.51 (2H,m), 7.93(1H,d,J=8.5Hz), 8.07(1H,d,J=8.5Hz) Preparation 307
The object compound was obtained according to a similar manner to that of Example 73. colorless solid mp : 125-128°C MASS (m/z) : 272 (M-H)+ ' H-NMR (DMSO-d6)c5 : 5.10(2H,s), 7.32-7.47(5H,m),
7.45(1H,t,J=8.5Hz), 8.05(1H,d,J=8.5Hz) , 8.09(1H,d,J=8.5Hz) Preparation 308 The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow solid mp : 141.5-143°C MASS (m/z) : 467 (M-H)+ ' H-NMR (DMS0-d6)5 : 4.82(2H,d,J=6.0Hz) , 5.18(2H,s),
7.33-7.42(5H,m), 7.44(1H,t,J=8.5Hz), 7.78(2H,d,J=8.5Hz), 7.83(1H,d,J=8.5Hz), 7.99(2H,d,J=8.5Hz), 8.02(1H,d,J=8.5Hz), 9.01(1H,br t,J=6.0Hz) Preparation 309
The object compound was obtained according to a similar manner to that of Preparation 2. brown amorphous solid MASS (m/z) : 464 (M+H)+
' H-NMR (CDCl3)c5 : 3.30(3H,s), 4.78(2H,s), 7,09-7.69(9H,m) , 7.82(1H,d,J=8.5Hz), 7.98(2H,d,J=8.5Hz) , 8.27(1H,d,J=8.5Hz) Preparation 310
The object compound was obtained according to a similar manner to that of Example 60. brown oil
MASS (m/z) : 434 (M+H)+ 1 H-NMR (CDCl3)5 : 3.41 (3H,s), 4.63(2H,s), 6.90-7.66(1 OH,m) , 7.99(1H,d,J=8.5Hz), 8.34(2H,d,J=8.5Hz) Preparation 311
The object compound was obtained according to a similar manner to that of Preparation 298. pale brown oil
'H-NMR (CDC13)C5 : 2.60(3H,s), 6.83(1H,d,J=7.5Hz) , 6.85(1H,s), 7.08(2H,d,J=7.5Hz), 7.23(1H,t,J=7.5Hz) , 7.42(2H,t,J=7.5Hz) , 8.06(1H,d,J=7.5Hz) Preparation 312
The object compound was obtained according to a similar manner to
4 2 l that of Preparation 299. pale yellow solid mp : 1 2-144°C MASS (m/z) : 258 (M-H)+
' H-NMR (DMSO-d6)(5 : 7.16-7.25(4H,m) , 7.32(lH,t,J=7.5Hz), 7.50(2H,t,J=7.5Hz), 8.08(1H,d,J=7.5Hz) Preparation 313
The object compound was obtained according to a similar manner to that of Preparation 5. off-white solid mp : 160-163.5°C MASS (m/z) : 453 (M-H)+
' H-NMR (DMS0-d6)<5 : 4.76(2H,d,J=6.0Hz) , 7.09(1H,d,J=1.5Hz) , 4.17(1H,dd,J=8.5 and 1.5Hz), 7.22(2H,d,J=8.5Hz) , 7.33(1H,t,J=8.5Hz), 7.53(2H,t,J=8.5Hz) , 7.78(2H,d,J=8.5Hz) , 7.94(2H,d,J=8.5Hz), 8.13(1H,d,J=8.5Hz), 9.07(1H,t,J=6.0Hz) Preparation 314
The object compound was obtained according to a similar manner to that of Preparation 2. yellow amorphous solid MASS (m/z) : 450 (M+H)+
'H-NMR (CDC13)(5 : 3.41 (3H,s), 7.10-7.19(4H,m), 7.21 (1H,s), 7.24-7.33(1H,m), 7.30(2H,d,J=8.5Hz), 7.45(2H,t,J=8.5Hz), 7.60(2H,d,J=8.5Hz), 8.22(1H,d,J=8.5Hz) Preparation 315
The object compound was obtained according to a similar manner to that of Example 60. off-white amorphous solid MASS (m/z) : 420 (M+H)+
' H-NMR (CDC13)<5 : 3.55(3H,s), 6.80(1H,d,J=8.5Hz), 6.91-6.98(4H,m), 7.02(1H,t,J=8.5Hz),7.21 (1H,s), 7.23-7.32(4H,m), 7.59(2H,d,J=8.5Hz) Preparation 316
The object compound was obtained according to a similar manner to that of Preparation 303. pale orange solid mp : 90.5-91.5°C
'H-NMR (CDC13)<5 : 3.96(3H,s), 5.28(2H,s), 7.30-7.49(5H,m), 7.70(1H,d,J=7.5Hz), 7.83(1H,d,J=2.5Hz) , 7.85(lH,d,J=7.5Hz) Preparation 317
The object compound was obtained according to a similar manner to that of Example 73. off-white solid mp : 207-210°C
MASS (m/z) : 272 (M-H)+
'H-NMR (DMSO-d6)c5 : 5.40(2H,s), 7.31-7. 9(5H,m) , 7.65(1H,d,J=8.5Hz), 7.87(1H,s), 7.99(1H,d,J=8.5Hz) Preparation 318
The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow solid mp : 171-174°C
MASS (m/z) : 467 (M-H)+ 1 H-NMR (CDC13)<5 : 4.90(2H,d,J=2.5Hz) , 5.32(2H,s),
7.31-7.51 (6H,m), 7.70(2H,d,J=8.5Hz), 7.72(1H,d,J=1.5Hz), 7.90(2H,d,J=8.5Hz), 7.91 (1H,d,J=8.5Hz) Preparation 319
The object compound was obtained according to a similar manner to that of Preparation 2. pale yellow solid mp : 142-144°C
MASS (m/z) : 464 (M+H)+
' H-NMR (CDC13)<5 : 3.59(3H,s), 5.32(2H,s), 7.23"7.52(9H,m) , 7.56(1H,s), 7.61(2H,d,J=8.5Hz), 7.99(1H,d,J=8.5Hz) Preparation 320
The object compound was obtained according to a similar manner to that of Example 60. pale orange amorphous solid
MASS (m/z) : 434 (M+H)+ 1 H-NMR (CDC13)<5 : 3.56(3H,s), 4.03(2H,br s) , 5.17(2H,s), 6.80(1H,d,J=8.5Hz), 7.08(1H,d,J=8.5Hz), 7.17(1H,s), 7.24-7.48(6H,m), 7.30(2H,d,J=8.5Hz) , 7.57(2H,d,J=8.5Hz) Preparation 321
Trifluoromethanesulfonic anhydride (3.15 g) in dichloromethane (10 ml) was added dropwise, with stirring, over 10 minutes to the starting compound (2.0 g) and 4-dimethylaminopyridine (1.49 g) in dichloromethane (40 ml) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 hours, then washed with 1N hydrochloric acid, water, and a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was washed with diethyl ether to give the object compound (3.11 g) as an off- white solid. mp : 90-93.5°C
MASS (m/z) : 328 (M-H)+ 1 H-NMR (CDCl3) : 4.01 (3H,s), 8.09(1H,s), 8.22(2H,s) Preparation 322
A mixture of the starting compound (1.5 g), phenylboric acid (1.11 g), tetrakis(triphenylphosphine)palladium(0) (158 mg), potassium carbonate (945 mg), and toluene (30 ml) was heated at 80°C for 1 hour under a nitrogen atmosphere. After the mixture was allowed to cool to room temperature, ethyl acetate and water were added to the mixture. The suspension was filtered through a celite pad. The aqueous layer was separated, and the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a n-hexane/ethyl acetate (10:1) as eluent to give the object compound (1.15 g) as a pale yellow wax. mp : 51-53°C
'H-NMR (CDC13)(5 : 3.97(3H,s), 7.31-7.37(2H,m) , 7.43-7.49(3H,m) , 7.86(1H,d,J=8.5Hz), 8.13(1H,d,J=8.5Hz), 8.14(1H,s) Preparation 323
The object compound was obtained according to a similar manner to that of Example 73. pale yellow solid mp : 224-227°C
MASS (m/z) : 242 (M-H)+
'H-NMR (DMS0-d6)(5 : 7.37"7.43(2H,m) , 7.46-7.53(3H,m) , 8.00(1H,s), 8.07-8.17(2H,m) Preparation 324
The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow amorphous solid
MASS (m/z) : 437 (M-H)+ 1 H-NMR (CDCl3)c5 : 4.94(2H,d,J=3.0Hz) , 7.31 (1H,br t,J=3.0Hz) , 7.32-7.39(2H,m), 7.42-7.50(3H,m) , 7.70(2H,d,J=8.5Hz) , 7.89(2H,d,J=8.5Hz), 7.42-7.50(3H,m) Preparation 325
The object compound was obtained according to a similar manner to that of Preparation 2. off-white solid mp : 156-159°C
MASS (m/z) : 434 (M+H)+ 1 H-NMR (CDC13)<5 : 3.73(3H,s), 7.24(1H,s), 7.28-7.47(5H,m) , 7.32(2H,d,J=8.5Hz), 7.61 (2H,d,J=8.5Hz), 7.81 (1H,d,J=8.5Hz), 7.82(1H,s), 8.00(1H,d,J=8.5Hz) Preparation 326
The object compound was obtained according to a similar manner to that of Example 60. pale yellow solid mp : 176-178.5°C
MASS (m/z) : 404 (M+H)+ 1 H-NMR (CDCl3)c5 : 3.67(3H,s), 3.97(2H,br s) ,
6.84(1H,d,J=8.5Hz), 7.l7(1H,s),7.31 (2H,d,J=8.5Hz), 7.31-7.40(1H,m), 7.42-7.52(6H,m) , 7.59(2H,d,J=8.5Hz) Preparation 327
Sodium hydride (60%, 1.92 g) was added portionwise to a solution of the starting compound (4.0 g) in anhydrous N,N-dimethylformamide (40 ml) at 0°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 30 minutes. Then benzyl bromide (5.7 ml) was added dropwise at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo . The residue (6.39 g) , IN sodium hydroxide solution (22.8 ml) and ethyl alcohol (50 ml) were combined. The reaction mixture was stirred at room temperature for 3 hours, and concentrated in vacuo. Water was added to the residue, and the aqueous solution was washed with diethyl ether. The aqueous layer was acidified to pH3.5 with 1N hydrochloric acid, and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the object compound (3.6 g) as a colorless oil.
MASS (m/z) : 264(M-H)+
'H-NMR (CDC13)<5 : 1.47(9H,s),3.81 (1H,s) ,3.96(1H,s) , 4.52(2H,d,J=10.0Hz),7.19-7.41(5H,m) Preparation 328
The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow oil MASS (m/z) : 309 (M+H)+
'H-NMR (CDC13)(5 : 1.46(9H,s), 3.17(3H,s), 3.59(3H x 2/5,s), 3.63(3H x 3/5,s), 3.94(2H x 2/5,s), 4.10(2H x 3/5,s), 4.53(2H x 3/5,s), 4.58(2H x 2/5,s), 7.19-7.39(5H,m) Preparation 329
The object compound was obtained according to a similar manner to that of Preparation 278. colorless oil MASS (m/z) : 248 (M-H)+
' H-NMR (CDC13)<5 : 1.45(9H x 1/2,s), 1.49(9H x 1/2,s), 3.79(1H,s), 3.93(1H,s), 4.50(1H,s), 4.55(1H,s), 7.15-7.40(5H,m), 9.41 (1H x 1/2,s), 9.50(1H x 1/2,s) Preparation 330
The object compound was obtained according to a similar manner to that of Preparation 6. brown oil
MASS (m/z) : 288 (M+H)+
' H-NMR (DMS0-d6)5 : 1.35(9H,s), 4.22-4.47(4H,m) , 6.83(1H,s), 7.03(1H,s), 7.17-7.38(5H,s) Preparation 331
The object compound was obtained according to a similar manner to that of Preparation 7.
MASS (m/z) : 302 (M+H)+
'H-NMR (CDC13)S : 1.48(9H,s), 3.59(3H,s), 4.38(1H,d,J=12.5Hz), 4.42(1H,d,J=12.5Hz), 4.56(2H,s), 6.79(1H,s), 6.94(1H,s), 7.l5-7.37(5H,m) Preparation 332
The object compound was obtained according to a similar manner to that of Preparation 297. off-white solid mp : 230-233°C MASS (m/z) : 202 (M+H)+
'H-NMR (DMS0-d6)5 : 3.94(3H,s), 4.33(2H,s), 4.55(2H,s), 7.38-7.49(4H,m), 7.57-7.65(2H,m) , 7.70-7.75(2H,m) Preparation 333
To a precooled solution of the starting compound (400 mg) in N,N-dimethylformamide (4 ml) was added 85% potassium hydroxide powder (91.9 mg). After the mixture was stirred for 1 hour on an ice bath, benzyl bromide (0.174 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred for 7 hours at room temperature, then poured into water, and extracted with chloroform. The organic layer was washed with water (twice) and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a chloroform-methanol (60:1) as eluent to give the object compound (556.6mg) as a yellow oil.
MASS (m/z) : 378 (M+H)+
'H-NMR (CDCI3U : 1.38(9H,s), 4.38(2H,s), 4.57(2H,s), 5.22(2H,s), 6.83(1H,s), 6.98-7.06(3H,m) , 7.21-7.40(8H,m) Preparation 334
The object compound was obtained according to a similar manner to that of Preparation 297. yellow oil
MASS (m/z) : 278 (M+H)+
' H-NMR (CDCl3)c5 : 3.78(2H,s), 3.80(2H,s), 5.18(2H,s), 6.85(1H,s), 6.98(1H,s), 7.01-7.07(2H,m), 7.20-7.38(9H,m) Preparation 335
The object compound was obtained according to a similar manner to that of Preparation 91. dark brown oil
MASS (m/z) : 352 (M+H)+
'H-NMR (CDC13)5 : 1.37(9H,s), 3.02(1H,dd,J=13.5 and 6.0Hz) , 3.15(3H,s), 3.23(1H,dd,J=13.5 and 6.0Hz), 3.71 (3H,s), 3.93(1H,d,J=17.5Hz), 4.28(1H,d,J=17.5Hz) , 5.11 (1H,m), 5.46(1H,m), 7.12(1H,m), 7.18(1H,d,J=7.5Hz) , 7.59(1H,m), 8.54(1H,d,J=4.0Hz) Preparation 336
The object compound was obtained according to a similar manner to that of Example 73. brown amorphous solid MASS (m/z) : 338 (M+H)+
'H-NMR (CDC13)<5 : 1.19(9H,s), 2.80(1H,dd,J=13.5 and 10.5Hz), 3.08(3H,s), 3.35(1H,dd,J=13.5 and 10.5Hz), 4.01(lH,d,J=17.5Hz), 5.06(1H,m), 5.13(1H,d,J=17.5Hz) , 5.67(1H,d,J=9.0Hz), 7.21-7.38(2H,m) , 7.75(1H,m), 8.66(1H,d,J=5.5Hz) Preparation 337
The starting compound (1.3 g), N-(4-nitrophenylmethylene)benzene- sulfonamide (1.68 g) and toluene (6 ml) were mixed, and then N,N- dicyclohexylcarbodiimide (954 mg) in toluene (4 ml) was added to the mixture. The reaction mixture was stirred at 60°C for 15 hours under a nitrogen atmosphere. The suspension was filtered and the solvent was evaporated in vacuo. The residue was taken up in chloroform, washed with a saturated sodium hydrogencarbonate solution (twice) and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with a chloroform- methanol gradient (30:1 and 20:1) as eluent to give the object compound (919.6 mg) as a brown amorphous solid. MASS (m/z) : 424 (M+H)+
' H-NMR (CDC13)S 1.37(9H,s), 3.41-3.52(2H,m) , 4.06(3H,s), 4.93(1H,m), 7.09-8.33(5H,m), 7.53(2H,d,J=7.5Hz), 7.93(2H,d,J=7.5Hz), 8.52(1H,m) Preparation 338
The object compound was obtained according to a similar manner to that of Preparation 3. brown amorphous solid
MASS (m/z) : 324 (M+H)+
' H-NMR (CDC13)<5 : 3.12(1H,m), 3.42(1H,m), 3.63(3H,s), 5.12(1H,m), 7.11-8.23(8H,m), 8.46-8.59(1H,m) Preparation 339
The object compound was obtained according to a similar manner to that of Preparation 247. colorless solid mp : 160.5-161°C
MASS (m/z) : 137 (M+H)+
' H-NMR (CDC13)5 : 2.28(3H,s), 7.57(2H,d,J=5.5Hz) , 8.65(2H,d,J=5.5Hz), 9.85(1H,s) Preparation 340
The object compound was obtained according to a similar manner to that of Preparation 248. off-white solid mp : 74-76°C
MASS (m/z) : 291 (M+H) +
' H-NMR (CDC13)5 : 2.34(3H,s), 2.46(3H,s), 7.37(2H,d,J=8.5Hz) , 7.46(2H,d,J=6.0Hz), 7.93(2H,d,J=8,5Hz) , 8.64(2H,d,J=6.0Hz) Preparation 341
The object compound was obtained according to a similar manner to that of Preparation 249. pale brown solid mp : 192-194°C
' H-NMR (DMS0-d6)<5 : 4.64(2H,q,J=5.5Hz) , 7.96(2H,d,J=7.0Hz) , 8.50(2H,m), 8.91 (2H,d,J=7.0Hz) Preparation 342
The object compound was obtained according to a similar manner to that of Preparation 91. brown oil MASS (m/z) : 385 (M-H)+
' H-NMR (CDC13)<5 : 1.43(9H,s), 3.36(2H,d,J=5.5Hz) ,
4.70(2H,d,J=5.5Hz), 4.73(1H,m), 6.40(1H,m), 7.19-7.29(1H,m), 7.56(1H,d,J=7.0Hz), 7.68(1H,t,J=7.0Hz), 7.71 (2H,d,J=5.5Hz) , 8.55(1H,t,J=7.0Hz), 8.61 (1H,d,J=7.0Hz) , 8.81 (2H,d,J=5.5Hz) Preparation 343
The object compound was obtained according to a similar manner to that of Preparation 2. brown oil
MASS (m/z) : 380 (M+H)+
' H-NMR (CDC13)£ : 1.37(9H,s), 3.45(1H,dd,J=13.5 and 7.5Hz) , 3.55(1H,dd,J=13.5 and 7.5Hz), 3.59(3H,s), 5.49(1H,m), 5.69(1H,m), 7.09-7.17(2H,m), 7.17(1H,s), 7.22(2H,d,J=5,5Hz) , 7.56(1H,t,J=7.5Hz), 8.51 (1H,m), 8.63(2H,d,J=5.5Hz) Preparation 344
The object compound was obtained according to a similar manner to that of Preparation 3. brown oil
MASS (m/z) : 280 (M+H)+
'H-NMR (CDC13)£ : 3.43(2H,t,J=7.0Hz) , 3.66(3H,s), 4.72(1H,t,J=7.0Hz), 7.12-7.19(2H,m) , 7.19(1H,s), 7.25(2H,d,J=5.5Hz), 7.61 (1H,t,J=7.0Hz), 8.58(1H,d,J=7.0Hz) , 8.63(2H,d,J=5.5Hz) Preparation 345
The starting compound (230 mg) was dissolved in absolute ethanol (11.5 ml) under an atmosphere of nitrogen. Sodium ethoxide (1M solution) in ethanol (1.17 ml) was added to the solution at room temperature. To the mixture was added a solution of ethyl 4-(dimethylamino)-2-oxo-3-butenoate (240.4 mg) in absolute ethanol (1.5 ml). The reaction mixture was then stirred at 50°C for 2 hours. The reaction mixture was refluxed for 30 minutes. After cooling the solution, sodium chloride was filtered off. The filtrate was
4 3 l concentrated in vacuo, and the residue was purified by flash column chromatography over silica gel with a chloroform-methanol (40:1) as eluent to give the object compound (170.7 mg) as a dark blue solid. mp : 95-98°C
MASS (m/z) : 269 (M+H)+
' H-NMR (CDC13)(5 : 1.51 (3H,t,J=7.0Hz) , 4.53(2H,q,J=7.0Hz) , 7.30(1H,t,J=7.5Hz), 7.41 (lH,t,J=7.5Hz) , 7.67(1H,d,J=7.5Hz) , 7.71(1H,d,J=7.5Hz), 7.85(1H,s), 7.88(1H,d,J=5.5Hz) , 9.06(1H,d,J=5.5Hz) Preparation 346
The object compound was obtained according to a similar manner to that of Preparation 51. off-white solid mp : 211-218'C
MASS (m/z) : 239 (M-H)+ 1H-NMR (DMSO-d6)<5 : 7.36(1H,t,J=7.5Hz) , 7.48(1H,t,J=7.5Hz) , 7.78(1H,d,J=7.5Hz), 7.81 (1H,d,J=7.5Hz) , 7.87(1H,s), 7.90(1H,d,J=5.5Hz), 9.13(1H,d,J=5.5Hz) Preparation 347
The object compound was obtained according to a similar manner to that of Preparation 5. pale yellow oil
MASS (m/z) : 425 (M-H)+
' H-NMR (CDC13)(5 : 1.40(9H,s), 2.31 (3H,s), 2.97-3.19(2H,m), 3.63-3.75(1H,m), 3.70(3H,s), 4.37(1H,m), 7.00-7.42(11H,m) Preparation 348
The object compound was obtained according to a similar manner to that of Example 73 except that a mixture of methanol and 1 ,4-dioxane was used instead of 1,4-dioxane. colorless solid mp : 74-78°C
MASS (m/z) : 41 1 (M-H) + 1 H-NMR (DMSO-d6)5 : 1.30(9H,s), 2.67-3.03(5H,m), 4.13-4.35(1H,m), 5.33"5.37(1H,m) , 7.06-7.49(10H,m) Preparation 349
The object compound was obtained according to a similar manner to that of Preparation 337. pale yellow oil MASS (m/z) : 454 (M+H)+ 1 H-NMR (CDC13)5 1.43(9H,s), 2.74(3H,s),
3.20(1H,dd,J=13.5 and 6.0Hz), 3.40(1H,dd,J=13.5 and 6.0Hz), 5.13(1H,m), 5.77(1H,d,J=7.5Hz), 7.03-8.03(15H,m) Preparation 350
The object compound was obtained according to a similar manner to that of Preparation 3. off-white amorphous solid MASS (m/z) : 354 (M+H)+
' H-NMR (CDC13)<5 : 2.99(3H,s), 3.24(lH,dd,J=13.5 and 7.5Hz), 3.46(1H,dd,J=13.5 and 7.5Hz), 5.02(1H,m), 7.05-7.69(15H,m) Preparation 351
The object compound was obtained according to a similar manner to that of Preparation 91. amorphous solid MASS : 482 (M+1)
1 H-NMR (CDCI3) δ : 1.42(9H,s), 2.34(3H,s), 2.53(4H,t,J=4Hz), 3.l9-3.30(1H,m), 3.30-3.42(1H,m) , 3.39(4H,t,J=4Hz) , 4.59(2H,d,J=2Hz), 4.62-4.73(1H,m), 6.39(1H,br s), 6.84(2H,d,J=8Hz), 7.11 (1H,t,J=4Hz) , 7.19(1H,d,J=7Hz) , 7.59(1H,d,J=8Hz), 7.81 (3H,d,J=8Hz) , 8.52(1H,d,J=2Hz) Preparation 352
The object compound was obtained according to a similar manner to that of Preparation 2. oil MASS : 477 (M+1) 1 H-NMR (CDCI3) δ : 1.38(9H,s), 2.38(3H,s), 2.50-2.61 (4H,m), 3.27(3H,t,J=4Hz), 3.32-3.48(2H,m), 3.39(3H,s), 5.32-5.41 (1H,m), 5.42-5.50(1H,m), 6.39(1H,br s) , 6.88(1H,d,J=8Hz), 6.91 (1H,s), 6.93(1H,d,J=8Hz), 7.08-7.20(3H,m), 7.50-7.62(1H,m), 7.83(1H,d,J=8Hz) , 8.52(1H,t,J=4Hz) Preparation 353
The object compound was obtained according to a similar manner to that of Preparation 3. oil
MASS : 377 (M+1)
'H-NMR (CDC13) δ : 2.38(3H,s), 2.59-2.68(4H,m) , 3.20-3.30(4H,m), 3.31-3.52(2H,m), 3.48(3H,s), 4.60(1H,dd,J=12Hz and 7Hz) , 6.88(1H,t,J=8Hz), 6.97(2H,d,J=8Hz), 6.98(1H,s), 7.10-7.20(1H,m), 7.21(2H,d,J=8Hz), 7.59(1H,t,J=8Hz) , 8.59(1H,d,J=4Hz) Preparation 354
The object compound was obtained according to a similar manner to that of Preparation 297. mp : 253-256°C
1 H-NMR (DMSO-d*) δ : 3.80-4.03(2H,m) , 3.88(3H,s), 5.54(1H,t,J=6Hz), 7.65(1H,t,J=5Hz), 7.69"7.85(4H,m) , 7.98-8.08(3H,m), 8.16(1H,t,J=8Hz), 8.40(1H,s), 8.69(1H,d,J=5Hz) Preparation 355
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 182-185°C
MASS : 536 (M+1)
1 H-NMR (DMS0-d6) δ • 1.40(9H,s), 2.51-2.68(1H,m),
2.70-2.81 (1H,m), 4.41-4.52(1H,m) , 4.54-4.77(2H,m) , 5.97(2H,s), 6.81(1H,d,J=8Hz), 6.92(1H,dd,J=8Hz and 2Hz), 7.11 (1H,d,J=8Hz), 7.17(1H,s), 7.30(1H,s), 7.84(2H,d,J=8Hz) , 7.90(1H,s), 8.11(2H,d,J=8Hz), 8.12(1H,s), 8.48(1H,s), 9.82(1H,s) Preparation 356
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS : 529 (M-1 ) 1 H-NMR (DMS0-d6) δ : 1.40(9H,s), 2.70-2.83(1H,m),
3.12-3.25(1H,m), 3.61 (3H,s), 5.19(1H,q,J=8Hz), 5.92(2H,s), 6.81(1H,d,J=8Hz), 6.92(1H,d,J=8Hz) , 7.00(1H,s), 7.11 (1H,s), 7.29(1H,s), 7.48(1H,d,J=8Hz), 7.59(2H,d,J=8Hz), 7.73(2H,d,J=8Hz), 7.80(1H,s), 8.31 (1H,s), 9.93(1H,s) Preparation 357
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 431 (M+1)
'H-NMR (CDC13) δ : 2.91-3.10(2H,m), 3.67(3H,s), 4.51(1H,t,J=8Hz), 5.90(2H,s), 6.70(1H,d,J=8Hz) , 6.83(1H,d,J=8Hz), 7.06(1H,s), 7.26(1H,s), 7.20-7.29(2H,m), 7.40-7.58(4H,m), 7.90(1H,s), 9.72(1H,s) Preparation 358
The object compound was obtained according to a similar manner to that of Preparation 91. mp : 129-132"C MASS : 460 (M+1)
'H-NMR (DMS0-d6) δ : 1.29(9H,s), 2.90-3.11 (1H,m), 3.17-3.23(1H,m), 4.47-4.55(1H,m), 4.56-4.78(2H,m), 7.09(1H,d,J=8Hz), 7.20(1H,t,J=8Hz) , 7.30(1H,d,J=8Hz) , 7.40-7.58(3H,m), 7.70(1H,t,J=8Hz), 7.78(2H,d,J=8Hz), 7.85(2H,d,J=8Hz), 8.09(2H,d,J=8Hz) , 8.21 (1H,t,J=6Hz) , 8.50(1H,d,J=4Hz) Preparation 359
The object compound was obtained according to a similar manner to that of Preparation 2. solid
MASS : 455 (M+1) 1 H-NMR (DMS0-d6) δ : 1.30(9H,s), 3.20-3.30(1H,m),
3.33-3.47(1H,m), 3.59(3H,s), 5.30(1H,q,J=8Hz) , 7.00(1H,s), 7.15-7.30(3H,m), 7.33-7.58(4H,m), 7.61-7.80(4H,m), 7.82(1H,d,J=8Hz), 8.09(1H,d,J=8Hz) , 8.50(1H,d,J=4Hz) Preparation 360
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 355 (M+1) 1 H-NMR (DMS0-d6) δ : 3.10-3.20(1H,m) , 3.28-3.38(1H,m),
3.60(3H,s), 4.48(1H,t,J=8Hz), 6.99(1H,s), 7.18-7.30(2H,m), 7.36-7.59(4H,m), 7.60-7.80(6H,m), 8.51 (1H,d,J=2Hz) Preparation 361
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 180-185°C MASS : 522 (M+1)
' H-NMR (DMSO-ds) δ : 1.40(9H,s), 2.52-2.68(1H,m) , 2.70-2.81 (1H,m), 3.70(3H,s), 4.49(1H,q,J=8Hz), 4.55-4.78(2H,m), 6.86(2H,d,J=8Hz) , 7.11 (1H,d,J=8Hz), 7.18(1H,s), 7.50(2H,d,J=8Hz), 7.87(2H,d,J=8Hz) , 7.91 (lH,s), 8.11(2H,d,J=8Hz), 8.11 (1H,s), 8.45(1H,s), 9.75(1H,s) Preparation 362
The object compound was obtained according to a similar manner to that of Preparation 2. mp : 187-193°C MASS : 517 (M+1) 1 H-NMR (DMS0-d6) δ : 1.41 (9H,s), 2.70-2.81 (!H,m),
3.15-3.28(1H,m), 3.61 (3H,s), 3.69(3H,s), 5.30(1H,q,J=8Hz) , 6.83(2H,d,J=8Hz), 7.00(1H,s), 7.11 (lH,s), 7.48(1H,s), 7.50(2H,d,J=8Hz), 7.58(2H,d,J=8Hz) , 7.73(2H,d,J=8Hz) , 7.81 (1H,s), 8.31 (1H,s), 9.90(1H,s) Preparation 363
The object compound was obtained according to a similar manner to that of Preparation 8. solid
MASS : 415 (M-l )
'H-NMR (DMSO-de) δ : 2.73-2.85(1H,m) , 2.90-3.00(1H,m),
3.71 (3H,s), 3.72(3H,s), 4.41 (1H,t,J=8Hz) , 6.87(2H,d,J=8Hz) , 6.99(1H,s), 7.11(1H,s), 7.50(2H,d,J=8Hz) , 7.58(2H,d,J=8Hz), 7.76(2H,d,J=8Hz), 7.81 (1H,s), 8.31 (1H,s) Preparation 364
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS : 473 (M+1)
1 H-NMR (CDC13) δ : 1.21(3H,d,J=8Hz), 1.28(3H,d,J=8Hz) , 1.37(9H,s), 3.72(2H,q,J=8Hz), 4.70(1H,d,J=2Hz) , 4.11(1H,q,J=8Hz), 5.78(1H,br s) , 7.09(1H,s), 7.11-7.70(8H,m) , 7.93(1H,d,J=8Hz), 8.09(1H,d,J=8Hz), 8.52(1H,dd,J=8Hz and 2Hz) Preparation 365
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 373 (M+1 )
Figure imgf000439_0001
3.32-3.42(1H,m), 3.43-3.53(1H,m), 4.59-4.60(1H,m), 4.72-4.81 (1H,m), 6.99(1H,s), 7.11-7.72(7H,m), 7.83(1H,s), 7.89(1H,s), 7.90(1H,s), 8.58(1H,d,J=2Hz) Preparation 366
The object compound was obtained according to a similar manner to that of Preparation 2. oil
MASS : 487 (M+1)
1 H-NMR (CDCI3) δ : 0.79(3H,t,J=7Hz), 1.08-1.20(2H,m) ,
1.30-1.40(2H,m), 1.40(9H,s), 3.40-3.60(2H,m) , 3.80-4.01 (2H,m) , 5.35-5.50(1H,m), 5.41 (1H,br s), 7.00(1H,s), 7.11 (1H,d,J=7Hz) , 7.13(1H,d,J=7Hz), 7.23(1H,s), 7.32(1H,s), 7.41 (2H,d,J=8Hz) , 7.48(2H,d,J=8Hz), 7.59(lH,t,J=8Hz), 7.90(1H,s), 8.53(1H,d,J=4Hz) Preparation 367
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 387 (M+1)
'H-NMR (CDCI3) δ : 0.79(3H,t,J=8Hz) , 1.09-1.21 (2H,m), 1.31-1.55(2H,m), 3.28-3.40(1H,m) , 3.41-3.51 (1H,m) , 3.80-4.01 (2H,m), 4.58(1H,t,J=8Hz) , 7.03(1H,s), 7.12(2H,d,J=8Hz), 7.22(2H,d,J=8Hz) , 7.31 (1H,s), 7.38-7.50(3H,m), 7.59(1H,t,J=8Hz), 7.90(1H,s), 8.59(1H,d,J=4Hz) Preparation 368
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid
MASS : 501 (M+1)
1 H-NMR (CDCI3) δ : 0.79(3H,t,J=8Hz), 1.00-1.20(4H,m),
1.37(9H,s), 1.43-1.52(2H,m), 3.39-3.58(2H,m) , 3.80-4.00(2H,m), 5.30-5.50(2H,m), 7.00(1H,s), 7.11 (2H,d,J=8Hz), 7.22(1H,s), 7.31 (1H,s), 7.38-7.50(4H,m), 7.50-7.60(1H,m), 7.91 (1H,s), 8.52(1H,d,J=2Hz) Preparation 369
The object compound was obtained according to a similar manner to that of Preparation 8. oil
MASS : 401 (M+1)
' H-NMR (CDC13) δ : 0.77(3H,t,J=8Hz) , 1.01-1.20(4H,m) , 1.38-1.57(2H,m), 3.33~3.53(2H,m) , 3.80-4.09(2H,m), 4.62(1H,t,J=8Hz), 7.02(lH,s), 7.10-7.20(2H,m) , 7.22(1H,s), 7.31 (1H,s), 7.41(2H,d,J=6Hz), 7.49(2H,d,J=8Hz), 7.60(1H,t,J=8Hz), 7.91(lH,s), 8.59(1H,d,J=8Hz) Preparation 370
The object compound was obtained according to a similar manner to that of Preparation 2. MASS : 471 (M+1)
'H-NMR (CDCI3) δ : 1.41 (9H,s), 1.43-1.52(4H,m) , 3.22-3.30(1H,m) , 3.40-3.49(1H,m), 3.43~3.49(1H,m) , 5.55(1H,d,J=8Hz) , 5.72(1H,d,J=8Hz), 7.00(1H,s), 7.07-7.70(8H,m) , 7.98(1H,s), 8.09(1H,d,J=8Hz), 8.59(lH,s) Preparation 371
The object compound was obtained according to a similar manner to that of Preparation 8. MASS : 371 (M+1)
'H-NMR (CDCI3) δ : 0.90-1.lO(4H,m), 3.30-3.45(2H,m) , 3.60(1H,q,J=8Hz), 4.91 (1H,t,J=8Hz) , 7.03(1H,s), 7.09-7.60(9H,m), 7.90(lH,s), 8.60(1H,d,J=2Hz) Preparation 372
To a solution of methyl indole-6-carboxylate (300 mg) in methanol (20 ml) was added 1N aqueous sodium hydroxide solution (6 ml) at 0°C. The solution was stirred at room temperature for 2 hours. After evaporation of solvent, the residue was dissolved in water and acidified with 1 hydrochloric acid. The precipitate was dried to give indole-6-carboxylic acid as colorless crystals (204 mg). mp : 250-255βC MASS : 162 (M+1)
1H-NMR (DMSO-de) <5 : 6.50-6.53(lH,m) , 7.55"7.59(1H,m) , 7.60(2H,s), 8.08(1H,s) Preparation 373
The object compound was obtained according to a similar manner to that of Preparation 2. MASS : 485 (M+1)
1 H-NMR (CDC13) δ : 1.40(9H,s), 1.65-1.89(2H,m), 2.10-2.30(2H,m) , 2.30-2.50(2H,m), 3.22-3.32(1H,m), 3.40-3.43(1H,m), 4.48-4.62(1H,m), 5.43"5.50(2H,m) , 6.93(1H,s), 7.07"7.70(8H,m) , 7.91 (1H,s), 8.09(1H,d,J=8Hz), 8.59(1H,s) Preparation 374
The object compound was obtained according to a similar manner to that of Preparation 8. MASS : 385 (M+1) 'H-NMR (CDCI3) δ : 1.61-1.80(2H,m), 2.20-2.42(4H,m) ,
3.28-3.38(1H,m), 3.41-3.50(1H,m), 4.60-4.73(2H,m), 6.98(1H,s), 7.10-7.20(2H,m), 7.22(1H,s), 7.31 (1H,s), 7.39(2H,d,J=8Hz) , 7.41(2H,d,J=8Hz), 7.60(1H,t,J=8Hz) , 7.90(1H,s), 8.60(1H,d,J=2Hz) Preparation 375
The object compound was obtained according to a similar manner to that of Preparation 91. amorphous solid ESI-MS : 450 (M+1)
'H-NMR (CDCI3) δ : 1.45(9H,s), 3.21-3.44(2H,m) , 4.61-4.79(3H,m) , 6.42(1H,d,J=8Hz), 7.11-7.30(3H,m), 7.34(1H,s), 7.51(2H,d,J=8Hz), 7.55-7.68(1H,m) , 7.96(1H,s), 8.01 (1H,s), 8.07(2H,d,J=8Hz), 8.55(1H,d,J=5Hz) , Preparation 376
The object compound was obtained according to a similar manner to that of Preparation 2. oil
ESI-MS : 445 (M+1)
' H-NMR (CDC13) δ 1.37(9H,s), 3.40-3.52(2H,m) , 3.51 (3H,m), 5.35-5.55(3H,m), 7.05(1H,s), 7.08-7.18(2H,m), 7.22(1H,s), 7.31 (1H,s), 7.33-7.63(5H,m), 7.89(1H,s), 8.53(1H,d,J=5Hz) Preparation 377
The object compound was obtained according to a similar manner to that of Preparation 4. oil
ESI-MS : 345 (M+1)
' H-NMR (CDC13) δ : 1.75-2.10(2H,br s) , 3.28-3.51 (2H,m) , 3.58(3H,s), 4.64(1H,t,J=6Hz), 7.08(1H,s), 7.10-7.21 (2H,m), 7.23(1H,s), 7.31 (1H,s), 7.38-7.51 (4H,m) , 7.54-7.65(1H,m), 7.89(1H,s), 8.58(1H,d,J=5Hz) Preparation 378
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid ESI-MS : 450 (M+1)
' H-NMR (CDC13) δ : 1.42(9H,s), 3.00-3.37(2H,m) , 4.58(1H,br s) , 4.65-4.85(2H,m), 5.08(lH,d,J=6Hz) , 7.07(1H,br s), 7.18(2H,d,J=8Hz), 7.38(1H,s), 7.55(2H,d,J=8Hz), 7.98(1H,s), 8.10(2H,d,J=8Hz), 8.55(2H,d,J=8Hz) Preparation 379
The object compound was obtained according to a similar manner to that of Preparation 2. oil
ESI-MS : 445 (M+1)
1H-NMR (CDCI3) δ : 1.41 (9H,s), 3.29(3H,s), 3.38(2H,d,J=8Hz) , 5.15(1H,q,J=8Hz), 5.62(1H,d,J=8Hz) , 7.10(2H,d,J=8Hz) , 7.12(1H,s), 7.25(1H,s), 7.32(1H,s), 7.39(2H,d,J=8Hz), 7.48(2H,d,J=8Hz), 7.91 (1H,s), 8.50(2H,d,J=8Hz) Preparation 380
The object compound was obtained according to a similar manner to that of Preparation 4. oil
ESI-MS : 345 (M+1) 'H-NMR (CDC13) δ : 3.15-3.40(5H,m), 4.28(1H,t,J=6Hz),
7.05-7.13(3H,m), 7.25(1H,s), 7.32(1H,s), 7.38-7.52(4H,m), 7.90(1H,s), 8.51(2H,d,J=4Hz) Preparation 381
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid ESI-MS : 479 (M+1)
'H-NMR (CDC13) δ : 1.48(9H,s), 3.65(2H,dd,J=6Hz and 10Hz), 4.59(2H,d,J=6Hz), 4.79(2H,d,J=6Hz) , 5.45(1H,br s) , 7.18-7.40(6H,m), 7.48(1H,br s) , 7.55(2H,d,J=8Hz), 8.00(1H,s), 8.12(2H,d,J=8Hz) Preparation 382
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid ESI-MS : 474 (M+1)
'H-NMR (CDC13) δ : 1.45(9H,s), 3.64(3H,s), 3.35-4.03(2H,m) , 4.54(2H,s), 5.22(1H,br s), 7.12(1H,s), 7.20-7.38(8H,m), 7.48(2H,d,J=4Hz), 7.91 (1H,s) Preparation 383
The object compound was obtained according to a similar manner to that of Preparation 4. amorphous solid ESI-MS : 382 (M+1) ' H-NMR (CDC13) δ : 3.66(3H,s), 3.88(2H,d,J=6Hz) , 4.60(2H,s), 7.08(1H,s), 7.18-7.40(8H,m), 7.46(2H,s), 7.90(1H,s) Preparation 384
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid ESI-MS : 433 (M+1)
'H-NMR (CDC13) δ : 1.48(9H,s), 1.90-2.24(2H,m) , 2.14(3H,s), 2.63(2H,t,J=6Hz), 4.42(1H,br s), 4.80(2H,t,J=4Hz) , 5.28(1H,br s), 7.20(1H,s), 7.38(1H,s), 7.55(2H,d,J=8Hz), 7.99(1H,s), 8.12(2H,d,J=8Hz) Preparation 385
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid ESI-MS : 429 (M+1)
'H-NMR (CDC13) δ : 1.47(9H,s), 2.02-2.40(2H,m) , 2.13(3H,s), 2.55-2.80(2H,m), 3.69(3H,s), 4.23(1H,t,J=6Hz) , 7.07(1H,s), 7.25(1H,s), 7.34(1H,s), 7.49(4H,s), 7.91 (1H,s) Preparation 386
The object compound was obtained according to a similar manner to that of Preparation 4.
ESI-MS : 328 (M+1) Preparation 387
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid ESI-MS : 474 (M+1)
'H-NMR (CDC13) δ : 0.75(3H,t,J=6Hz), 1.38(9H,s), 1.40-1.65(2H,m), 3.53~3.83(2H,m), 3.93-4.07(2H,m), 4.72(1H,d,J=6Hz), 5.60(1H,q,J=6Hz) , 7.13(1H,s), 7.24(2H,d,J=8Hz), 7.46(2H,d,J=8Hz) , 7.60(1H,t,J=8Hz) , 7.80(2H,d,J=8Hz), 8.15(1H,s), 8.50-8.54(1H,m) , 8.63(1H,s) Preparation 388
The object compound was obtained according to a similar manner to that of Preparation 4. amorphous solid ESI-MS : 374 (M+1)
' H-NMR (CDCI3) δ : 0.75(3H,t,J=6Hz) , 1.37-1.65(2H,m), 3.48(2H,d,J=6Hz), 3.80-4.10(2H,m) , 4.71 (1H,t,J=6Hz) , 7.08(1H,s), 7.13-7.23(2H,m), 7.48(2H,d,J=8Hz), 7.62(1H,t,J=8Hz), 7.75(2H,d,J=8Hz) , 8.14(1H,s), 8.04-8.60(1H,m), 8.61 (1H,s) Preparation 389
The object compound was obtained according to a similar manner to that of Preparation 91. amorphous solid ESI-MS : 450 (M+1)
' H-NMR (CDCI3) δ : 1.45(9H,s), 3.21-3.44(2H,m) , 4.61-4.79(3H,m) , 6.42(1H,d,J=8Hz), 7.11-7.30(3H,m) , 7.34(1H,s), 7.51(2H,d,J=8Hz), 7.55-7.68(1H,m), 7.96(1H,s), 8.01 (1H,s), 8.07(2H,d,J=8Hz), 8.55(1H,d,J=5Hz) Preparation 390
The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid ESI-MS : 473 (M+1) ' H-NMR (CDC13) δ : 0.70(3H,t,J=6Hz) , 1.36(9H,s),
1.35-1.55(2H,m), 3.37-3.55(2H,m), 3.77-4.00(2H,m), 5.44(1H,s), 7.02(1H,s), 7.07-7.20(2H,m), 7.25(1H,s), 7.34(1H,s), 7.38-7.50(4H,m), 7.58(1H,t,J=8Hz), 7.91 (1H,s), 8.55(1H,d,J=4Hz) Preparation 391
The object compound was obtained according to a similar manner to that of Preparation 297. ESI-MS : 373 (M+1)
' H-NMR (DMSO-dβ) δ : 0.65(3H,t,J=6Hz) , 1.30-1.53(2H,m), 3.70-3.98(2H,m), 4.08-4.35(2H,m), 5.48(1H,t,J=6Hz) , 7.55-7.63(2H,m), 7.69(1H,d,J=8Hz) , 7.75(2H,d,J=8Hz) , 7.99(1H,s), 8.01(2H,d,J=8Hz), 8.12(1H,t,J=8Hz), 8.40(1H,s), 8.63(1H,d,J=4Hz), 9.97(1H,s) Example 1
To an ice-cooled solution of the starting compound (100 mg) , indole-2-carboxylic acid (50 mg) and 1 -hydroxybenzotriazole (41.9 mg) in dichloromethane (10 ml) was added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (71.4 mg). The mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and then the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methanol=70/1 ) to give the object compound as white powder (50 mg).
MASS(m/z) : 466 (M+1)
' H-NMR (CDC13) δ : 1.43(3H,t,J=7Hz) , 3.48(3H,s), 3.60(2H,m), 4.03(2H,q,J=7Hz), 5.97(1H,m), 6.91 (2H,d,J=8Hz) , 6.94(1H,s), 6.99(1H,s), 7.10-7.12(3H,m), 7.17(2H,d,J=8Hz) , 7.37(1H,d,J=8Hz), 7.50(1H,t,J=8Hz), 7.63(1H,d,J=8Hz), 9.41 (1H,s) Example 2
The object compound was obtained according to a similar manner to that of Example 1.
MASS(m/z) : 490 (M+1)
' H-NMR (CDCI3) δ : 3.59(3H,s), 3.63(2H,m), 6.02(1H,m), 7.00(1H,s), 7.08(1H,s), 7.11~7.16(3H,m) , 7.38-7.43(3H,m), 7.52(1H,t,J=8Hz), 7.64-7.68(3H,m) , 7.86(1H,m), 8.54(1H,d,J=5Hz), 9.48(1H,m) Example 3
The object compound was obtained according to a similar manner to that of Example 1.
MASS(m/z) : 466 (M+1)
' H-NMR (CDC13) δ : 1.43(3H,t,J=7Hz), 3.19(3H,s), 3.43(2H,m), 4.04(2H,q,J=7Hz), 5.64(1H,m), 6.91 (2H,d,J=8Hz) , 7.01 (2H,s), 7.05(2H,d,J=6Hz), 7.12-7.16(3H,m) , 7.31 (1H,d,J=8Hz) , 7.41(1H,d,J=8Hz), 7.64(1H,d,J=8Hz), 8.45(2H,d,J=6Hz) Example 4
The object compound was obtained according to a similar manner to that of Example 1.
MASS(m/z) : 453 (M+1)
'H-NMR (CDC13) δ : 3.84(3H,s), 6.65(1H,d,J=7Hz) , 7.17(2H,m), 7.20(lH,s), 7.22(1H,m), 7.31 (1H,d,J=8Hz) , 7.40(1H,d,J=8Hz), 7.51(1H,d,J=8Hz), 7.53(2H,d,J=8Hz) , 7.71 (2H,m), 8.29(2H,d,J=8Hz), 8.41 (1H,d,J=8Hz), 8.61 (1H,d,J=5Hz) , 9.26(1H,s) Example 5
The object compound was obtained according to a similar manner to that of Example 1.
MASS(m/z) : 543 (M+1)
'H-NMR (CDCI3) δ : 1.50(9H,s), 3.55(2H,m), 3.60(3H,s), 5.93(1H,q,J=7Hz), 6.97(1H,t,J=8Hz) , 7.10-7.l7(3H,m), 7.40-7.67(6H,m), 8.27(2H,d,J=8Hz) , 8.34(1H,d,J=8Hz), 8.54(1H,d,J=4Hz) Example 6
The object compound was obtained according to a similar manner to that of Example 1.
MASS(m/z) : 483 (M-1)
'H-NMR (CDCI3) δ : 2.62(3H,s), 3.45(3H,s), 3.60(2H,m), 4.28(1H,m), 7.04-7.17(2H,m) , 7.40-7.59(5H,m) , 7.48(2H,d,J=8Hz), 7.72(1H,m), 8.17(1H,d,J=8Hz), 8.27(2H,d,J=8Hz), 8.45(1H,d,J=5Hz) Example 7
The object compound was obtained according to a similar manner to that of Example 1.
MASS(m/z) : 543 (M+1)
' H-NMR (CDC13) δ : 3.30(2H,m), 3.62(3H,s), 5.89(1H,q,J=7Hz), 6.77(1H,d,J=8Hz), 6.90(1H,d,J=8Hz), 7.07(1H,s), 7.11 (2H,m), 7.29(1H,m), 7.42-7.52(1 OH,m), 8.24(2H,d,J=8Hz) , 8.48(1H,d,J=4Hz), 9.47(lH,s) Example 8
The object compound was obtained according to a similar manner to that of Example 1.
MASS(m/z) : 467 (M+1)
' H-NMR (CDCI3) δ : 3.60(2H,m), 3.63(3H,s), 6.01 (1H,q,J=7Hz) , 6.54(1H,s), 7.08-7.17(4H,m), 7.30(1H,m), 7.48(3H,m), 7.57(1H,t,J=8Hz), 7.73(1H,m), 7.79(1H,d,J=8Hz), 8.26(2H,d,J=8Hz), 8.54(1H,d,4Hz) Example 9
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 519 (M+1)
'H-NMR (CDCI3) δ : 3.09(3H,s), 3.30-3.50(2H,m), 3.72(3H,s), 5.6l(1H,q,J=8Hz), 6.71 (2H,d,J=8Hz) , 6.98(2H,d,J=8Hz) , 6.99-7.13(4H,m), 7.17-7.30(2H,m), 7.38(1H,d,J=8Hz), 7.4l(1H,d,J=8Hz), 7.59(1H,d,J=8Hz), 8.49(1H,d,J=8Hz) Example 10
The object compound was obtained according to a similar manner to that of Example 1. mp : 193-195°C MASS : 446 (M+1) 'H-NMR (DMS0-d6) δ : 3.37-3.48(2H,m) , 3.60(3H,s), 5.55(1H,q,J=8Hz), 7.00(1H,t,J=8Hz) , 7.10-7.30(6H,m) , 7.31-7.40(3H,m), 7.60(1H,d,J=8Hz), 7.65(2H,d,J=8Hz) , 7.90(2H,d,J=8Hz), 9.03(1H,d,J=8Hz) Example 11
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 519 (M+1)
1H-NMR (CDC13) δ : 3.13(3H,s), 3.33-3.52(2H,m) , 3.71 (3H,s), 5.70(1H,q,J=8Hz), 5.72(2H,d,J=8Hz) , 7.00(2H,d,J=8Hz) , 7.09(1H,t,J=8Hz), 7.14(1H,s), 7.19-7.29(2H,m) , 7.30-7.41 (3H,m), 7.58-7.70(3H,m) , 8.61 (1H,d,J=8Hz) Example 12
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 476 (M+1)
'H-NMR (CDCI3) δ : 3.11(3H,s), 3.27-3.50(2H,m) , 3.73(3H,s), 5.61(1H,q,J=8Hz), 6.71 (2H,d,J=8Hz) , 6.97(2H,d,J=8Hz) , 7.07(1H,s), 7.10(1H,d,J=8Hz), 7.18-7.28(2H,m) , 7.29-7.40(3H,m), 7.59(1H,d,J=8Hz) , 7.67(2H,d,J=8Hz), 8.30(1H,d,J=8Hz) Example 13
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 549 (M+1)
' H-NMR (CDCI3) δ : 2.89(3H,s), 3.31-3.59(2H,m), 5.53"5.67(1H,m), 6.88(2H,d,J=8Hz), 7.00(1H,s), 7.07(1H,t,J=8Hz), 7.10-7.30(2H,m), 7.20(1H,s), 7.30-7.50(6H,m), 7.59~7.80(5H,m) Example 14
The object compound was obtained according to a similar manner to that of Example 1 . mp : 143-1 7°C MASS : 466 (M+1 ) 1 H-NMR (CDC13 ) δ : 1 .43(3H,t,J=8Hz) , 3.20(3H,s) ,
3.32-3.52(2H,m) , 4.07(2H,q,J=8Hz) , 5.61 (1 H,q,J=8Hz) , 5.91 (2H,d,J=8Hz) , 7.00(2H,s) , 7. 10-7.20(3H,m) , 7.30 ( 1 H,t,J=8Hz) , 7.41 (2H,d,J=8Hz) , 7.63(2H,t,J=8Hz) , 8.39(1 H,s) , 8.48(1H,d,J=4Hz) , 9.40(1H,s) Example 15
The object compound was obtained according to a similar manner to that of Example 1. mp : 130-135°C MASS : 467 (M+1)
' H-NMR (CDCI3) δ : 3.29(3H,s), 3.48(2H,d,J=8Hz), 5.70(1H,q,J=8Hz), 7.00(1H,s), 7.08(2H,d,J=6Hz) , 7.15(1H,t,J=8Hz), 7.24(1H,s), 7.30(1H,t,J=8Hz), 7.39-7.49(1H,m), 7.45(2H,d,J=8Hz) Example 16
The object compound was obtained according to a similar manner to that of Example 1. mp : 191-192°C MASS : 543 (M+1)
'H-NMR (CDCI3) δ : 3.06(3H,s), 3.13-3.23(1H,m), 3.37-3.48(1H,m), 3.78(3H,s), 4.01 (3H,s), 5.43-5.52(1H,m) , 6.80(2H,d,J=8Hz), 6.98(1H,s), 7.00(2H,d,J=8Hz), 7.05-7.20(4H,m) , 7.28-7.40(3H,m), 7.52(2H,d,J=8Hz) , 7.63(1H,d,J=8Hz) Example 17
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 542 (M+1) 'H-NMR (CDCI3) δ : 3.11 (3H,s), 3.29"3.40(1H,m) , 3.41-3.50(1H,m), 3.69(3H,s), 5.50-5.61 (1H,m), 6.79(2H,d,J=8Hz) , 7.02(2H,d,J=8Hz), 7.08-7.20(3H,m) , 7.52(2H,d,J=8Hz) , 7.80-7.92(2H,m), 8.12-8.22(2H,m) , 8.89(1H,d,J=8Hz), 9.62(1H,s) Example 18
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 541 (M+1)
' H-NMR (CDC13) δ : 3.17(3H,s), 3.30-3.51 (2H,m), 3.71 (3H,s), 5.49-5.62(lH,m), 6.73(2H,d,J=8Hz), 7.04(2H,d,J=8Hz), 7.09-7.20(3H,m), 7,50(2H,d,J=8Hz) , 7.60(1H,t,J=8Hz) , 7.78(1H,t,J=8Hz), 7.83(1H,d,J=8Hz) , 8.18(1H,d,J=8Hz) , 8.20-8.33(2H,m), 9.08(1H,d,J=8Hz) Example 19
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 479 (M+1)
'H-NMR (CDCI3) δ : 3.11 (3H,s), 3.21-3.40(2H,m) , 3.72(3H,s), 5.52-5.63(1H,m), 6.13-6.21 (1H,m) , 6.72(2H,d,J=8Hz) , 6.89(1H,s), 6.90(1H,s), 6.99(2H,d,J=8Hz) , 7.03(1H,s), 7.08(2H,d,J=8Hz), 7.50(2H,d,J=8Hz) , 8.11 (1H,d,J=8Hz) Example 20
The object compound was obtained according to a similar manner to that of Example 1. mp : 249-251°C MASS : 530 (M+1)
' H-NMR (CDCI3) δ : 3.21-3.40(2H,m), 3.49(3H,s), 3.70(3H,s), 5.48(lH,q,J=8Hz), 6.79(2H,d,J=8Hz) , 7.08(1H,s), 7.13(2H,d,J=8Hz), 7.23~7.32(2H,m) , 7.38(2H,d,J=8Hz), 7.59(1H,br s), 7.63(3H,d,J=8Hz) , 9.04(1H,d,J=8Hz) Example 21 The object compound was obtained according to a similar manner to that of Example 1. mp : 125-128βC MASS : 546 (M+1)
' H-NMR (CDC13) δ : 3.01 (3H,s), 3.17"3.29(1H,m) , 3.40-3.50(1H,m), 3.78(3H,s), 5.41-5.53(1H,m), 6.89(2H,d,J=8Hz), 6.99(2H,d,J=8Hz), 7.03-7.17(3H,m), 7.34-7.48(2H,m), 7.49-7.60(3H,m), 7.79-7.90(3H,m) Example 22
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 547 (M+1)
1H-NMR (CDCI3) δ : 3.09(3H,s), 3.27-3.39(1H,m), 3.40-3.50(1H,m), 3.72(3H,s), 5.40-5.51 (1H,m), 6.78(2H,d,J=8Hz), 7.01(2H,d,J=8Hz), 7.08-7.17(3H,m) , 7.42~7.60(4H,m) , 7.93(1H,d,J=8Hz), 8.10(1H,d,J=8Hz), 8.40(1H,d,J=8Hz) Example 23
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 531 (M+1)
1 H-NMR (CDCI3) δ : 3.10(3H,s), 3.21-3.38(1H,m), 3.39"3.49(1H,m), 3.72(3H,s), 5.42-5.56(1H,m), 6.80(2H,d,J=8Hz), 7.02(2H,d,J=8Hz), 7.10(1H,s), 7.11 (2H,d,J=8Hz), 7.39-7.51 (2H,m), 7.52(2H,d,J=8Hz), 7.62(1H,d,J=8Hz), 7.80(1H,d,J=8Hz), 8.31 (1H,d,J=8Hz) Example 24
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 531 (M+1) 1 H-NMR (CDCI3) δ 2.91-2.96(1 x1/2H,m), 3.00(3x 1/2H,s) , 3.01-3.28(1H,m), 3.17(3x 1/2H,s) , 3.30-3.40(1 x 1/2H,m) , 3.43-3.60(1H,m), 3.73(3x1/2H,s), 3.78(3x 1/2H,s), 4.27-4.50(2H,m), 5.20-5.40(1H,m) , 6.62-6.82(4H,m) , 6.89(1H,d,J=8Hz), 6.95(1H,d,J=8Hz) , 7.00-7.17(5H,m), 7.52(2H,t,J=8Hz), 7.98(1H,d,J=8Hz) Example 25
The object compound was obtained according to a similar manner to that of Example 1. colorless solid mp : 231-234.5°C MASS : 501 (M-H)+
'H-NMR (DMS0-d6) δ : 3.27-3.41 (2H,m) , 3.44(3H,s), 5.32(1H,m), 7.07(1H,s), 7.12(1H,t,J=7.5Hz), 7.16-7.27(6H,m) , 7.31(1H,d,J=7.5Hz), 7.35(1H,t,J=7.5Hz), 7.36(2H,d,J=7.5Hz), 7.64(2H,d,J=7.5Hz), 7.78(2H,d,J=7.5Hz) , 9.27(1H,d,J=7.5Hz) Example 26
The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid MASS : 526 (M+H)+ 1 H-NMR (CDC13) δ : 3.08(3H,s), 3.38-3.51 (2H,m) , 5.51 (1H,m), 7.06-7.16(5H,m), 7.20-7.25(4H,m), 7.29(1H,t,J=7.5Hz), 7.36-7.43(3H,m), 7.52(2H,d,J=7.5Hz) , 7.55(1H,t,J=7.5Hz), 7.80(1H,d,J=7.5Hz), 8.18(1H,d,J=7.5Hz) Example 27
To a solution of the starting compound (88.2 mg) in dichloromethane (1 ml) was added phenyl isocyanate (32.4 mg) under nitrogen atmosphere at 0°C. The reaction mixture was stirred at room temperature for 5 hours and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform-methanol (10:1) as eluent to give the object compound (80.0 mg) as an off-white solid, mp : 172-175°C MASS : 475 (M+H)+
'H-NMR (CDCI3) δ : 3.03(3H,s), 3.21 (1H,dd,J=13.5 and 9.0Hz), 3.42(1H,dd,J=13.5 and 6.0Hz), 5.31(1H,m), 6.91(1H,m), 6.99-7.40(11H,m), 7.06(2H,d,J=7.5Hz), 7.52(2H,d,J=7.5Hz), 7.49-7.58(1H,m) Example 28
The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid
MASS : 556 (M+H)+ 1 H-NMR (CDCI3) δ : 2.85(3H,s), 2.98(3H,d,J=4.5Hz) ,
3.24(lH,dd,J=13.5 and 9.0Hz), 3.48(1H,dd,J=13.5 and 4.5Hz), 5.52(1H,m), 7.01 (1H,d,J=1.0Hz) , 7.03-7.33(8H,m), 7.10(2H,d,J=7.5Hz), 7.42(2H,d,J=7.5Hz) , 7.49(2H,d,J=7.5Hz), 7.45-7.59(1H,m), 7.69(1H,d,J=7.5Hz) , 9.23(1H,br s) Example 29
The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid MASS : 586 (M+H)+
'H-NMR (CDC13) δ : 2.92(3H,s), 3.24-3.35(1H,m), 3.28(3H,s), 3.49(1H,dd,J=13.5 and 4.5Hz), 3.70(3H,s), 5.57(1H,m), 6.98(1H,d,J=1.0Hz), 7.04-7.11 (1H,m), 7.09(2H,d,J=7.5Hz), 7.15(1H,t,J=7.5Hz), 7.20-7.33(5H,m), 7.40-7.55(2H,m) , 7.52(2H,d,J=7.5Hz), 7.67(1H,d,J=7.5Hz), 9.23(1H,br s) Example 30
The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid MASS : 570 (M+H)+ ' H-NMR (CDCI3) δ : 2.96(3H,s), 2.99(6H,s),
3.30(1H,dd,J=13.5 and 8.5Hz), 3.4g(1H,dd,J=13.5 and 6.0Hz), 5.57(1H,m), 6.97(1H,s), 7.07-7.18(5H,m) , 7.20-7.28(3H,m) , 7.29(1H,t,J=7.5Hz), 7.40-7.48(2H,m) , 7.53(2H,d,J=7.5Hz) , 7.67(1H,d,J=7.5Hz), 9.31 (1H,br s) Example 31
The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid
MASS : 618 (M+H)+ 1 H-NMR (CDC13) δ : 2.91 (3H,s), 3.30(1H,dd,J=13.5 and 8.5Hz), 3.49(1H,dd,J=13.5 and 6.0Hz), 5.58(1H,m), 7.03-7.43(13H,m), 7.12(2H,d,J=7.5Hz), 7.50(2H,d,J=7.5Hz) , 7.70(2H,t,J=7.5Hz) , 9.12(1H,s), 9.27(1H,s) Example 32
The object compound was obtained according to a similar manner to that of Example 1. colorless solid mp : 287-291 °C
MASS : 395 (M+H)+
'H-NMR (DMS0-d6) δ : 3.48(2H,d,J=7.5Hz) , 3.77(3H,s),
5.71(1H,q,J=7.5Hz), 7.01 (1H,t,J=7.5Hz) , 7.10-7.30(7H,m), 7.33-7.40(3H,m), 7.51 (1H,d,J=7.5Hz), 7.60(1H,d,J=7.5Hz), 7.66(1H,d,J=7.5Hz), 9.14(1H,d,J=7.5Hz) Example 33
The object compound was obtained according to a similar manner to that of Example 1. pale brown amorphous solid
MASS : 485 (M+H)+ 1 H-NMR (CDCI3) δ : 3.44(3H,s), 6.48(1H,d,J=7.5Hz) , 7.06(2H,s), 7.11(1H,t,J=7.5Hz), 7.20(2H,d,J=7.5Hz), 7.20-7.45(7H,m) , 7.56(2H,d,J=7.5Hz), 7.62(1H,d,J=7.5Hz) , 8.30(1H,d,J=7.5Hz) , 9.26(1H,s) Example 34
The object compound was obtained according to a similar manner to that of Exmaple 1. yellow amorphous solid
MASS : 531 (M+H)+ H-NMR (CDC13, δ ) 1.53(9H,s), 2.98(3H,s),
3.21(1H,dd,J=13.0 and 8.5Hz), 3.46(1H,dd,J=13.0 and 5.5Hz), 5.51 (1H,m), 7.00(1H,t,J=7.5Hz), 7.03-7.09(2H,m) , 7.05(1H,s), 7.15(2H,d,J=7.5Hz), 7.21-7.27(3H,m) , 7.39(2H,d,J=7.5Hz) , 7.40-7.53(3H,m), 7.57(1H,d,J=7.5Hz) , 8.38(1H,d,J=7.5Hz) Example 35
The object compound was obtained according to a similar manner to that of Preparation 3. yellow amorphous solid
MASS : 431 (M+H)+ 1 H-NMR (CDCI3, δ ) 2.97(3H,s), 3.21 (lH,dd,J=13.0 and 8.5Hz) , 3.46(1H,dd,J=13.0 and 7.0Hz), 5.44-5.57(3H,m), 6.66(1H,t,J=7.5Hz), 6.68(1H,d,J=7.5Hz) , 7.05(1H,s), 7.05-7.10(2H,m), 7.16(2H,d,J=7.5Hz) , 7.17-7.27(5H,m) , 7.38(2H,d,J=7.5Hz), 7.43(1H,d,J=7.5Hz) Example 36
The object compound was obtained according to a similar manner to that of Example 1. off-white amorphous solid
MASS : 574 (M+H)+
'H-NMR (CDCI3) <5 : 3.08(3H,s), 3.27(1H,dd,J=13.5 and 8.5Hz), 3.50(lH,dd,J=13.5 and 6.0Hz), 5.60(1H,m), 7.07(1H,s), 7.H(2H,d,J=7.5Hz), 7.12-7.35(10H,m) , 7.37(2H,d,J=7.5Hz), 7.48(1H,d,J=7.5Hz), 7.52(1H,t,J=7.5Hz) , 7.66(2H,d,J=7.5Hz), 7.75(1H,d,J=7.5Hz), 8.74(1H,d,J=7.5Hz), 9.42(1H,br s) Example 37
The object compound was obtained according to a similar manner to that of Example 1. off-white amorphous solid MASS : 575 (M+H)+ 1 H-NMR (CDC13) δ : 3.07(3H,s), 3.25(lH,dd,J=13.5 and 8.5Hz), 3.50(1H,dd,J=13.5 and 5.5Hz), 5.59(1H,m), 7.06(1H,s), 7.07-7.28(9H,m), 7.32(1H,t,J=7.5Hz) , 7.37(2H,d,J=7.5Hz) , 7.45(1H,d,J=7.5Hz), 7.47-7.52(1H,m) , 7.53(1H,d,J=7.5Hz), 7.58(1H,s), 7.64(2H,t,J=7.5Hz), 7.71 (1H,d,J=7.5Hz), 8.78(1H,d,J=7.5Hz) Example 38
The object compound was obtained according to a similar manner to that of Example 1. yellow amorphous solid
MASS : 531 (M+H)+ 1 H-NMR (CDC13, <5) 1.53(9H,s), 3.07(3H,s),
3.37(1H,dd,J=13.5 and 8.5Hz), 3.50(1H,dd,J=13.5 and 7.0Hz), 5.60(1H,m), 7.05(1H,s) 7.07-7.16(2H,m) , 7.13(2H,d,J=7.5Hz) , 7.21-7.85(8H,m), 7.37(2H,d,J=7.5Hz) , 7.50(1H,d,J=7.5Hz) Example 39
The object compound was obtained according to a similar manner to that of Preparation 3. off-white solid mp : 198-201°C MASS : 431 (M+H)+ 1 H-NMR (CDCI3, δ ) 2.97(3H,s), 3.20(1H,dd,J=12.0 and 8.5Hz), 3.47(1H,dd,J=12.0 and 7.0Hz), 3.78(2H,s), 5.50(1H,m), 6.79(1H,dd,J=7.5 and 1.0Hz), 7.03(1H,s), 7.03-7.09(2H,m), 7.12-7.26(8H,m), 7.29(1H,d,J=7.5Hz) , 7.37(2H,d,J=7.5Hz) Example 40
The object compound was obtained according to a similar manner to that of Example 1.
MASS : 574 (M+H)+ 1 H-NMR (CDCl3) δ : 2.91 (3H,s), 3.58-3.75(2H,m) , 5.60(1H,m), 6.78(2H,d,J=7.5Hz), 7.00(1H,s), 7.06-7.19(3H,m) , 7.16(2H,d,J=7.5Hz), 7.20-7.26(4H,m) , 7.31 (2H,t,J=7.5Hz) , 7.43(1H,d,J=7.5Hz), 7.53-7.60(2H,m) , 7.67(1H,d,J=7.5Hz) , 7.84(1H,d,J=7.5Hz), 8.14(1H,m), 9.61(1H,s), 9.84(1H,br s) Example 41
The object compound was obtained according to a similar manner to that of Example 1. off-white amorphous solid MASS : 575 (M+H)+ 1 H-NMR (CDCI3) δ : 2.98(3H,s), 3.27(1H,dd,J=13.0 and 8.5Hz) , 3.50(1H,dd,J=13.0 and 5.5Hz), 5.53(1H,m), 7.03-7.10(2H,m), 7.06(1H,s), 7.13(2H,d,J=7.5Hz), 7.20-7.28(3H,m), 7.30-7.40(3H,m), 7.42-7.51 (2H,m), 7.55-7.69(4H,m), 7.71(1H,d,J=7.5Hz), 7.99(1H,s), 8.07(1H,d,J=7.5Hz) , 8.46(1H,s) Example 42
The object compound was obtained according to a similar manner to that of Example 1. yellow amorphous solid MASS : 433 (M+H)+
'H-NMR (CDCI3) δ : 3.49(1H,dd,J=16.0 and 7.0Hz), 3.61(3H,s), 3.67(1H,dd,J=16.0 and 2.5Hz), 4.60(1H,m), 5.52(1H,d,J=16.0Hz) , 6.29(1H,m), 6.96(2H,s), 7.05(lH,d,J=7.5Hz), 7.15(1H,d,J=7.5Hz), 7.19(1H,d,J=7.5Hz), 7.21-7.47(9H,m), 7.70(1H,d,J=7.5Hz), 9.20(1H,br s) Example 43
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 474 (M+H)+ 1 H-NMR (CDCl3,300MHz) <5 : 2.91 (3H,s), 3.45(1H,dd,J=13 and 9Hz), 3.66(1H,dd,J=13 and 5Hz) , 3.68(3H,s), 5.58-5.70(1H,m) , 6.81(1H,s), 6.95-7.45(14H,m), 7.64(1H,d,J=8Hz) , 7.84(1H,br s) , 9.51(1H,br s) Example 44
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 475 (M+H)+
' H-NMR (CDCI3,300MHz) δ : 2.91 (3H,s), 3.43(1H,dd,J=13 and 9Hz), 3.66(1H,dd,J=13 and 5Hz), 3.72(3H,s), 5.54-5.67(1H,m), 6.85(1H,s), 6.96-7.72(15H,m), 7.83(1H,d,J=8Hz) Example 45
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 544, 546 (M+H)+ ' H-NMR (CDCI3,300MHz) δ ' 3.30(3H,s), 3.44-3.65(2H,m) , 5.61-5.78(1H,m), 6.95-7.70(13H,m) , 8.06(2H,d,J=8Hz), 9.49(1H,br s) Example 46
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 545, 547 (M+H)+ 'H-NMR (CDCl3,300MHz) δ : 3.31 (3H,s), 3.47"3.67(2H,m) , 5.60-5.72(1H,m), 7.07-7.71 (13H,m) , 8.11 (2H,d,J=8Hz) Example 47
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 496 (M+H)+
' H-NMR (CDCI3,300MHz) δ : 3.12(3H,s), 3.19~3.49(2H,m), 3.75(3H,s), 5.48-5.62(1H,m), 6.75(2H,d,J=8Hz), 6.97(2H,d,J=8Hz), 7.00(1H,s), 7.07-7.82(8H,m), 8.25(2H,d,J=8Hz), 9.55(1H,br s) Example 48 The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 497 (M+H)+
'H-NMR (CDCl3,300MHz)5 : 3.16(3H,s), 3.20-3.49(2H,m), 3.77(3H,s), 5.45-5.59(1H,m), 6.78(2H,d,J=8Hz), 7.00(2H,d,J=8Hz), 7.21-7.75(9H,m) , 8.26(2H,d,J=8Hz) Example 49
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 515, 517 (M+H)+
' H-NMR (CDCl3,300MHz) δ : 3.41 (3H,s), 3.75(3H,s),
6.43(lH,d,J=8Hz), 6.84(2H,d,J=8Hz) , 6.99-7.38(9H,m) , 7.49-7.67(3H,m), 8.39(1H,d,J=8Hz) , 9.41(1H,brs) Example 50
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 519, 521 (M+H)+ 1 H-NMR (CDCI3,300MHz) δ : 3.42(3H,s), 6.42(1H,d,J=8Hz) , 7.02-7.41 (11H,m), 7.50-7.68(3H,m) , 8.31 (1H,d,J=8Hz) , 9.22(1H,br s) Example 51
The object compound was obtained according to a similar manner to that of Example 1. mp : 157-159°C
MASS (ESI) (m/z) : 511 (M+H)+
'H-NMR (CDC13,300MHZ)(5 : 3.44(3H,s), 3.60-3.68(2H,m) , 5.76(1H,q,J=8Hz), 7.07-7.70(10H,m) , 7.98(1H,br d,J=8Hz) , 8.11(2H,d,J=8Hz), 8.31 (2H,d,J=8Hz), 9.41(1H,brs) Example 52
The object compound was obtained according to a similar manner to that of Example 1. mp : 187-188°C MASS (ESI) (m/z) : 467 (M+H)+
'H-NMR (DMSO-d6,300MHz)5 : 3.43-3.68(2H,m) , 3.73(3H,s), 5.86-5.99(1H,m), 6.96-7.68(9H,m) , 7.73(2H,d,J=8Hz) , 8.26(2H,d,J=8Hz), 8.49(1H,d,J=5Hz) , 9.08(1H,br d,J=8Hz) , 10.50(1H,br s) Example 53
The object compound was obtained according to a similar manner to that of Example 1. mp : 259-260°C
MASS (ESI) (m/z) : 468 (M+H)+
' H-NMR (DMS0-d6,300MHz) 5 : 3.50-3.64(2H,m) , 3.70(3H,s), 5.81-5.95(lH,m), 7.12-7.38(5H,m), 7.44-7.68(2H,m) , 7.72(1H,br d,J=8Hz), 7.73(2H,d,J=8Hz) , 8.27(2H,d,J=8Hz) , 8.50(1H,d,J=5Hz), 9.24(1H,br d,J=8Hz) , 10.50(1H,br s) Example 54
The object compound was obtained according to a similar manner to that of Example 1. mp : 174-175°C
MASS (ESI) (m/z) : 467 (M+H)+
'H-NMR (DMSO-d6,300MHz)(5 : 3.42-3.68(2H,m) , 3.72(3H,s), 5.84-6.00(1H,m), 6.97-7.70(9H,m) , 7.73(2H,d,J=8Hz), 8.27(2H,d,J=8Hz) , 8.49(1H,d,J=5Hz) , 9.09(1H,br d,J=8Hz), 10.50(1H,br s) Example 55
The object compound was obtained according to a similar manner to that of Example 1. mp : 180-184°C
MASS : 437 (M+1)
' H-NMR (CDC13) δ : 2.59(3H,s), 3.49(3H,s), 3.50-3.70(2H,m) , 6.01(1H,q,J=8Hz), 7.01 (lH,s), 7.02(1H,s), 7.08-7.16(3H,m) , 7.16-7.29(2H,m), 7.39(1H,d,J=8Hz) , 7.48(1H,d,J=8Hz) , 7.50(1H,t,J=8Hz), 7.62(1H,d,J=8Hz), 7.99(1H,d,J=8Hz) , 8.41 (1H,s), 8.52(1H,d,J=2Hz), 9.69(1H,s) Example 56
The object compound was obtained according to a similar manner to that of Example 1. mp : 197-199°C MASS : 423 (M+1) ' H-NMR (CDCls) δ : 3.53(3H,s), 3.57"3.70(2H,m),
6.00(lH,q,J=8Hz), 7.00(1H,s), 7.09(1H,s), 7.10-7.18(3H,m) , 7.27(1H,t,J=8Hz), 7.31-7.41 (2H,m) , 7.50-7.70(3H,m) , 7.82(1H,d,J=8Hz), 8.50-8.62(3H,m) , 9.49(1H,s) Example 57
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 509 (M+H)+
' H-NMR (CDCl3,300MHz) δ : 1.42(3H,t,J=7Hz) , 3.13(3H,s), 3.19-3.43(2H,m), 4.04(2H,q,J=7Hz), 5.46-5.62(lH,m) , 5.88(2H,s), 6.54(1H,d,J=8Hz), 6.56(lH,s), 6.64(1H,d,J=8Hz) , 6.89(2H,d,J=8Hz), 7.00(1H,s), 7.02-7.68(7H,m) , 7.95(1H,br d,J=8Hz), 9.74(1H,br s) Example 58
The object compound was obtained according to a similar manner to that of Example 1. mp : 214-215°C
MASS (ESI) (m/z) : 481 (M+H)+
' H-NMR (DMSO-de,300MHz) ( : 1.11 (3H,t,J=7Hz), 3.41-3.68(2H,m) , 4.02-4.42(2H,m), 5.85-6.00(1H,m) , 6.95"7.68(9H,m), 7.72(2H,d,J=8Hz), 8.28(2H,d,J=8Hz) , 8.49(1H,d,J=2Hz), 9.12(1H,br d,J=8Hz), 10.50(1H,br s) Example 59
The object compound was obtained according to a similar manner to that of Example 1. mp : 145-150°C MASS : 488 (M+1)
' H-NMR (DMSO-de) δ : 3.41-3.53(1H,m) , 3.54-3.63(1H,m) ,
3.69(3H,s), 5.91(1H,q,J=8Hz), 7.02(1H,t,J=8Hz) , 7.08(1H,s), 7.10-7.20(3H,m), 7.28(1H,s), 7.32-7.41 (2H,m), 7.52-7.68(4H,m) , 7.72(2H,d,J=8Hz), 7.80(1H,d,J=2Hz) , 8.31 (1H,s), 8.50(1H,d,J=2Hz), 9.07(1H,d,J=8Hz) Example 60
A solution of the starting compound (360 mg) and ammonium chloride (5 mg) in ethanol (14.5 ml) - water (1.5 ml) was heated to 70°C. Powdered iron (440 mg) and one drop of concentrated hydrochloric acid were added. The mixture was stirred at 70°C for 15 minutes then allowed to cool to room temperature. The mixture was filtered, concentrated, made basic with 1N sodium hydroxide solution and extracted three times with chloroform. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, chloroform/ methanol=20/1 ) to give the object compound as a pale yellow powder (291 mg). mp : 145-150'C
MASS (ESI) (m/z) : 437 (M+H)+
' H-NMR (CDCI3,300MHz) 5 : 3.44(3H,s), 3.55-3.71 (2H,m) ,
3.78(2H,br s), 5.98-6.12(1H,m), 6.67(2H,d,J=8Hz), 6.89(1H,s), 6.96-7.66(1OH,m), 8.25(1H,br d,J=8Hz), 8.51 (1H,d,J=5Hz), 10.00(1H,br s) Example 61
To a solution of the starting compound (82 mg) in dichloromethane (4 ml) were added triethylamine (0.5 ml) and methanesulfonyl chloride (0.1 ml) at room temperature and the mixture was stirred for 1.5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and then the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methanol= 20/1 ) to give the object compound as pale yellow crystals (84 mg) . mp : 160-165°C
MASS (ESI) (m/z) : 593 (M+H)+
' H-NMR (DMSO-d6,300MHz) ά : 3.45-3.68(2H,m) , 3.55(6H,s), 3.71 (3H,s), 5.86-5.99(lH,m), 6.98-7.73(13H,m), 8.51(1H,d,J=2Hz), 9.13(1H,br d,J=8Hz) , 10.50(1H,br s) Example 62
To a solution of the starting compound (86 mg) in dichloromethane (1 ml) was added acetic anhydride (30 mg) at room temperature and the mixture was stirred for 1 hour. The mixture was diluted with chloroform (2 ml), and then diisopropyl ether was added. The pale yellow precipitate was collected by filtration, washed with diisopropyl ether, and dried in vacuo to give the object compound (84.5 mg). mp : 226-227°C
MASS (ESI) (m/z) : 479 (M+H)+
' H-NMR (DMSO-d6,300MHz) <5 : 2.04(3H,s), 3.40-3.66(2H,m) , 3.60(3H,s), 5.81-5.94(1H,m), 6.93(1H,s), 6.96-7.70(12H,m) , 8.48(1H,d,J=5Hz), 9.02(1H,br d,J=8Hz) , 10.05(lH,br s) , 11.52(1H,br s) Example 63
To an ice-cooled solution of the starting compound (196 mg) in dichloromethane (4 ml) were added pyridine (0.12 ml) and ethyl chloroformate (0.07 ml). The mixture was stirred under ice-cooling for 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and then the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methano 1=20/1) to give the object compound as a pale yellow powder (216 mg).
MASS (ESI) (m/z) : 509 (M+H)+ ' H-NMR (DMSO-dβ,300MHz) (5 : 1.26(3H,t,J=7Hz), 3.41-3.65(2H,m) , 3.60(3H,s), 4.14(2H,q,J=7Hz), 5.8l-5.95(1H,m), 6.91 (1H,s), 6.95-7.67(12H,m), 8.48(1H,d,J=5Hz) , 9.01 (1H.br d,J=8Hz) , 9.71(1H,br s), 11.48(1H,br s) Example 64
To an ice-cooled solution of the starting compound (84 mg) in dichloromethane (1.7 ml) were added pyridine (0.05 ml) and methanesulfonyl chloride (0.02 ml). The mixture was stirred under ice-cooling for 3 hours. A saturated aqueous sodium hydrogencarbonat e solution was added to the mixture, and then the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated.
The residue was purified by column chromatography (silica gel, chloroform/methanol=20/1 ) to give the object compound as a white powder (69 mg).
MASS (ESI) (m/z) : 513 (M-H)~
' H-NMR (DMSO-d6,300MHz) <5 : 3.01 (3H,s), 3.31-3.62(2H,m) , 3.60(3H,s), 5.81-5.95(1H,m), 6.94(1H,s) ,6.97-7.68(12H,m) , 8.48(1H,d,J=5Hz), 9.02(1H,br d,J=8Hz) , 9.88(1H,br s) , 11.50(1H,br s) Example 65
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 468 (M+H)+ ' H-NMR (CDCl3,300MHz) δ : 2.50(3H,s), 3.22(3H,s), 3.38-3.50(2H,m), 5.59-5.72(1H,m), 6.97-7.78(13H,m) , 8.44(2H,d,J=6Hz), 9.50(1H,br s) Example 66
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 500 (M+H)+
' H-NMR (CDCl3,300MHz) δ : 3.09(3H,s), 3.32(3H,s), 3.38-3. 0(2H,m), 5.62-5.77(1H,m) , 6.96-7.69(11H,m) , 7.99(2H,d,J=8Hz), 8.45(2H,d,J=6Hz), 9.55(1H,br s) Example 67
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) .(m/z) : 465 (M+H) + 'H-NMR (CDCI3,300MHz) δ : 2.97(6H,s), 3.49(3H,s), 3.52-3.65(2H,m), 5.91-6.04(1H,m), 6.71 (2H,d,J=8Hz) , 6.91(1H,s), 6.96-7.68(1 OH,m), 7.97(1H,br d,J=8Hz) , 8.52(1H,d,J=5Hz), 9.51(1H,brs) Example 68
The object compound was obtained according to a similar manner to that of Example 1. mp : 200-201°C
MASS (ESI) (m/z) : 467 (M+H)+
' H-NMR (DMS0-d6,300MHz)(5 : 3.41-3.66(2H,m) , 3.69(3H,s), 5.82-5.98(1H,m), 6.95-7.96(11H,m) , 8.13-8.23(2H,m) , 8.48(1H,d,J=5Hz), 9.05(1H,br d,J=8Hz) , 10.50(1H,br s) Example 69
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 497 (M+H)+ 1 H-NMR (CDCl3,300MHz) δ : 3.47-3.61 (2H,m) , 3.67(3H,s), 3.78(3H,s), 5.92-6.07(1H,m), 6.92-8.15(11H,m) , 8.21(lH,d,J=2Hz), 8.25(2H,d,J=8Hz), 9.62(1H,br s) Example 70
The object compound was obtained according to a similar manner to that of Example 1. mp : 154-155°C
MASS (ESI) (m/z) : 501 (M+H)+
'H-NMR (DMSO-de,300MHz) δ : 3.43"3.68(2H,m) , 3.72(3H,s), 5.83-5.97(1H,m), 6.97"7.63(7H,m) , 7.75(2H,d,J=8Hz) , 7.78(1H,dd,J=8 and 2Hz) , 8.27(2H,d,J=8Hz) , 8.52(1H,d,J=2Hz), 9.07(1H,br d,J=8Hz) , 10.50(1H,br s) Example 71
The object compound was obtained according to a similar manner to that of Example 1. mp : 208-209°C
MASS (ESI) (m/z) : 466 (M-H)" 1 H-NMR (DMSO-d6,300MHz)5 : 3.49-3.72(2H,m) , 3.71 (3H,s), 5.86-6.01 (1H,m), 6.97"7.64(6H,m) , 7.75(2H,d,J=8Hz) , 8.27(2H,d,J=8Hz), 8.42(1H,d,J=2Hz) , 8.55(1H,d,J=2Hz), 8.66(1H,s), 9.11(1H,br d,J=8Hz), 10.50(1H,br s) Example 72
The object compound was obtained according to a similar manner to that of Example 1. mp : 190-192°C
MASS (ESI) (m/z) : 538 (M+H)+
'H-NMR (CDCl3,300MHz) δ 2.29"2.72(4H,m) , 3.69(3H,s), 5.07(2H,s), 5.53-5.67(1H,m), 6.93-7.68(14H,m) , 8.29(2H,d,J=8Hz), 9.31(1H,brs) Example 73
A solution of the starting compound (186 mg) in 1N sodium hydroxide solution (2.7 ml) - 1,4-dioxane (5.4 ml) was stirred at room temperature for 1 hour. After the mixture was concentrated, 1N hydrochloric acid was added to the residue. The yellow precipitate formed was collected by filtration and dried in vacuo to give the object compound (157 mg). mp : 170-175°C
MASS (ESI) (m/z) : 448 (M+H)+
' H-NMR (CDCl3,300MHz) ( : 2.22-2.56(4H,m) , 3.79(3H,s), 5.41-5.55(1H,m), 6.98-7.68(6H,m) , 7.84(2H,d,J=8Hz) , 8.33(2H,d,J=8Hz), 9.14(1H,br d,J=8Hz) , 10.50(1H,br s) Example 74 To a solution of the starting compound (41 mg) in chloroform (0.4 ml) - methanol (0.4 ml) was added trimethylsilyldiazomethane/hexane (2.0 M) at room temperature, and the mixture was stirred for 2 hours. After adding acetic acid (0.1 ml) , the mixture was neutralized with a saturated sodium hydrogencarbonate solution and extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, chloroform/methanol= 20/1) to give the object compound as a pale yellow powder (22 mg). mp : 177-179°C
MASS (ESI) (m/z) : 462 (M+H)+
' H-NMR (CDCl3,300MHz) δ : 2.28-2.68(4H,m) , 3.62(3H,s), 3.74(3H,s), 5.52-5.65(1H,m), 7.04-7.68(8H,m) , 7.88(1H,br d,J=8Hz), 8.28(2H,d,J=8Hz) , 10.50(1H,br s) Example 75
The object compound was obtained according to a similar manner to that of Example 1 except that a mixture of dichloromethane and dimethylformamide was used instead of dichloromethane. mp : 230-231°C
MASS (ESI) (m/z) : 523 (M+H)+
' H-NMR (DMSO-ds,300MHz) δ : 2.22-2.60(4H,m) , 3.75(3H,s), 5.38-5.52(1H,m), 6.94-7.64(11H,m), 7.77(2H,d,J=8Hz), 8.28(2H,d,J=8Hz), 8.94(1H,br d,J=8Hz) , 10.50(2H,br s) Example 76
The object compound was obtained according to a similar manner to that of Example 1. mp : 150-155°C
MASS (ESI) (m/z) : 475 (M+H)+ ' H-NMR (DMSO-d6,300MHz) 5 : 1.41-1.62(2H,m) , 1.78(3H,s),
1.98-2.16(2H,m), 3.01-3.20(2H,m), 3.72(3H,s), 5.31-5.46(1H,m) , 6.96-7.64(6H,m), 7.76(2H,d,J=8Hz), 7.86(1H,br t,J=5Hz) , 8.28(2H,d,J=8Hz), 8.88(1H,br d,J=8Hz) , 10.50(1H,br s) Example 77
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 508 (M+H)+
' H-NMR (CDCl3,300MHz) <5 : 1.41 (3H,t,J=7Hz) , 3.24-3.42(2H,m) , 3.61 (3H,s), 4.02(2H,q,J=7Hz), 5.96-6.11 (1H,m) , 6.81-7.58(15H,m), 8.03(1H,br d,J=8Hz), 9.01 (1H,br s) , 9.76(1H,br s) Example 78
The object compound was obtained according to a similar manner to that of Example 1. mp : 196-197'C
MASS (ESI) (m/z) : 456 (M+H)+
' H-NMR (DMSO-d6,300MHz) <5 : 3.38-3.55(2H,m) , 3.70(3H,s), 5.61-5.77(1H,m), 6.16(1H,d,J=4Hz) , 6.29(1H,d,J=4Hz) , 6.98-7.64(7H,m), 7.77(2H,d,J=8Hz) , 8.28(2H,d,J=8Hz) , 9.02(1H,br d,J=8Hz), 10.50(1H,br s) Example 79
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 543 (M+H)+
' H-NMR (CDCl3,300MHz) δ : 3.42-3.75(2H,m) , 4.18(2H,s), 5.4l-5.54(1H,m), 6.98-7.85(17H,m) , 8.21 (2H,d,J=8Hz) , 8.66(1H,d,J=2Hz), 9.27(1H,br s) Example 80
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 510 (M+H)+
' H-NMR (CDC13,300MHz) δ : 3.16-3.45(2H,m) , 3.23(3H,s),
5.46-5.61 (1H,m), 5.89(2H,s), 6.48-6.72(3H,m) , 6.97(1H,s), 7.07-7.69(8H,m), 8.28(2H,d,J=8Hz), 9.38(1H,br s) Example 81 The object compound was obtained according to a similar manner to that of Example 1. mp : 205-206°C
MASS (ESI) (m/z) : 500, 502 (M+H)+
' H-NMR (DMS0-d6,300MHz) ά : 3.41-3.63(2H,m) , 3.62(3H,s), 5.81-5.97(1H,m), 6.95-7.69(13H,m) , 8.49(1H,d,J=5Hz) , 9.03(1H,br d,J=8Hz), 10.50(1H,br s) Example 82
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 556 (M+H)+
'H-NMR (CDCl3,300MHz) δ : 1.41 (3H,t,J=7Hz) , 3.31 (3H,s), 3.48-3.63(2H,m), 3.81 (2H,s), 4.03(2H,q,J=7Hz), 5.89-6.05(1H,m), 6.80-7.67(17H,m) , 7.80(1H,br d,J=8Hz) , 8.52(1H,d,J=5Hz), 9.79(1H,br s) Example 83
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 495 (M+H)+
' H-NMR (CDCl3,300MHz) δ : 0.70(3H,t,J=7Hz) , 1.36-1.58(2H,m), 3.56-3.68(2H,m), 3.84-4.17(2H,m) , 5.98-6.11 (1H,m), 6.97-7.84(12H,m), 8.25(2H,d,J=8Hz) , 8.54(1H,d,J=5Hz) , 9.67(1H,br s) Example 84
The object compound was obtained according to a similar manner to that of Example 1. mp : 134-135βC
MASS (ESI) (m/z) : 482 (M+H)+ 1 H-NMR (DMS0-d6,300MHz) δ : 1.11 (3H,t,J=7Hz) , 3.50-3.62(2H,m) , 4.05-4.38(2H,m), 5.8l-5.96(1H,m), 7.13-7.38(5H,m) , 7.5l(1H,br d,J=8Hz), 7.58-7.75(2H,m) , 7.72(2H,d,J=8Hz), 8.28(2H,d,J=8Hz), 8.51 (1H,d,J=5Hz) , 9.24(1H,br d,J=8Hz) , 10.50(1H,br s) Example 85
The object compound was obtained according to a similar manner to that of Example 1. mp : 245-246°C
MASS (ESI) (m/z) : 488 (M+H)+
'H-NMR (DMSO-ds,300MHz) δ : 3.42-3.66(2H,m) , 3.66(3H,s), 5.82-5.98(1H,m), 6.56(1H,t,J=2Hz) , 6.95-7.21 (3H,m), 7.06(1H,s), 7.25(1H,s), 7.29~7.42(2H,m), 7.55(2H,d,J=8Hz), 7.56-7.69(2H,m), 7.77(1H,d,J=2Hz), 7.91 (2H,d,J=8Hz) , 8.49(1H,d,J=5Hz), 8.55(1H,d,J=2Hz) , 9.05(1H,br d,J=8Hz) , 10.50dH.br s) Example 86
The object compound was obtained according to a similar manner to that of Example 1. mp : 199-200°C
MASS (ESI) (m/z) : 502 (M+H)+
'H-NMR (DMSO-d6,300MHz)5 : 1.07(3H,t,J=7Hz) , 3.41-3.68(2H,m), 3.96-4.32(2H,m), 5.84-5.99(1H,m) , 6.56(1H,t,J=2Hz) , 6.94-7.22(4H,m), 7.26(1H,s), 7.29"7.42(2H,m), 7.52(2H,d,J=8Hz), 7.54-7.70(2H,m) , 7.77(1H,d,J=2Hz) , 7.92(2H,d,J=8Hz), 8.50(1H,d,J=5Hz) , 8.55(1H,d,J=2Hz), 9.10(1H,br d,J=8Hz), 10.50(1H,br s) Example 87
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 495 (M-1)
' H-NMR (DMSO-de) δ : 3.49(1H,dd,J=7 and 14Hz),
3.61 (1H,dd,J=5 and 14Hz), 3.75(3H,s), 3.76(3H,s), 5.92(1H,m), 6.82(1H,dd,J=2 and 8Hz) , 7.05(1H,s), 7.16(2H,m), 7.27(2H,t,J=5Hz), 7.34(1H,d,J=8Hz) , 7.64(1H,d,J=8Hz) , 7.75(2H,d,J=8Hz), 8.26(2H,d,J=8Hz) , 8.49(1H,d,J=5Hz) ,
4 7 o 9.02(1H,d,J=8Hz) Example 88
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 499 (M-1 )
' H-NMR (DMSO-ds) δ : 3.49(1H,dd,J=7 and 15Hz), 3.62(1H,dd,J=5 and 15Hz), 3.73(3H,s), 5.92(1H,m), 7.13-7.19(2H,m), 7.24(1H,d,J=2Hz) , 7.27(1H,s), 7.34(1H,d,J=8Hz), 7.40(1H,d,J=8Hz), 7.63(1H,m), 7.68(1H,d,J=2Hz), 7.73(2H,d,J=8Hz) , 8.25(2H,d,J=8Hz), 8.49(lH,d,J=5Hz), 9.19(1H,d,J=8Hz) Example 89
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 483 (M-1)
' H-NMR (DMSO-dβ) δ : 3.49(1H,dd,J=7 and 15Hz), 3.61 (1H,dd,J=5 and 15Hz), 3.73(3H,s), 5.92(1H,m), 7.02(1H,dt,J=2 and 8Hz) , 7.18(1H,m), 7.24(1H,d,J=2Hz), 7.27(1H,s), 7.32-7.40(3H,m), 7.63(1H,m), 7.74(2H,d,J=8Hz), 8.26(2H,d,J=8Hz), 8.49(1H,d,J=5Hz) , 9.12(1H,d,J=8Hz) Example 90
The object compound was obtained according to a similar manner to that of Example 1. mp : 245°C
MASS (m/z) : 468 (M+1) ' H-NMR (CDC13) <5 : 2.50(3H,s), 3.32(3H,s),
3.47(1H,dd,J=7 and 14Hz), 3.58(1H,dd,J=5 and 14Hz), 5.88(1H,m), 6.97(1H,s), 7.02(1H,t,J=8Hz), 7.15(2H,m), 7.23(1H,d,J=2Hz), 7.29-7.39(6H,m), 7.59(1H,d,J=8Hz) , 7.62(1H,m), 8.49(1H,d,J=5Hz), 9.02(1H,d,J=8Hz) Example 91
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 496 (M+1)
' H-NMR (CDCls) δ : 3.46(3H,s), 3.49(3H,s), 3.60(2H,m), 3.77(2H,t,J=5Hz), 4.14(2H,t,J=5Hz) , 5.98(1H,m), 6.94-6.99(4H,m), 7.09-7.12(3H,m), 7.20(2H,d,J=8Hz) , 7.35(1H,t,J=8Hz), 7.50(1H,m), 7.65(1H,d,J=8Hz), 7.85(1H,d,J=8Hz), 8.54(1H,d,J=5Hz) , 9.44(1H,br s) Example 92
The object compound was obtained according to a similar manner to that of Example 1. mp : 173°C (from AcOEt-hexane)
MASS (m/z) : 381 (M+1)
'H-NMR (CDC13) δ : 3.23(1H,dd,J=5 and 15Hz),
3.32(1H,dd,J=7 and 15Hz), 3.72(3H,s), 5.10(1H,d,J=13Hz), 5.19(1H,d,J=13Hz), 5.93(1H,m), 6.87(1H,s), 7.12-7.17(1H,m), 7.17(1H,s), 7.26-7.33(5H,m), 7.42(2H,d,J=8Hz) , 7.50(2H,d,J=8Hz), 7.63(1H,d,J=8Hz) , 8.28(2H,d,J=8Hz), 9.25(1H,s) Example 93
The object compound was obtained according to a similar manner to that of Example 73.
MASS (m/z) : 432 (M-1)
' H-NMR (DMSO-ds) δ : 3.23(1H,dd,J=5 and 15Hz), 3.34(1H,dd,J=7 and 15Hz), 3.89(3H,s), 5.72(1H,m), 7.05(1H,t,J=8Hz), 7.20(lH,t,J=8Hz), 7.28(1H,s), 7.43(1H,d,J=8Hz), 7.63(1H,d,J=8Hz) , 7.86(2H,d,J=8Hz), 8.31 (1H,s), 8.36(2H,d,J=8Hz), 9.33(1H,d,J=8Hz) Example 94
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 524 (M+1)
' H-NMR (CDCI3) δ : 3.23(2H,d,J=7Hz) , 3.77(3H,s), 4.47(1H,dd,J=7 and 15Hz), 4.66(1H,dd,J=7 and 15Hz), 5.98(1H,m), 6.96(1H,s), 7.08-7.14(3H,m) , 7.22-7.29(1H,m) , 7.38(1H,d,J=8Hz), 7.48(2H,d,J=8Hz) , 7.58(2H,m), 7.67(1H,m), 8.07(1H,d,J=8Hz), 8.26(2H,d,J=8Hz) , 8.44(1H,d,J=8Hz) , 9.46(1H,s) Example 95
To a solution of the starting compound (30 mg) in N,N- dimethylformamide were added triethylamine (0.01 ml) and pivaloyl chloride (0.01 ml) at -20βC and the mixture was stirred at the same temperature for 30 minutes. Aniline (6 mg) was added to the mixture and stirring at room temperature was continued for 1 hour. The mixture was poured into water and extracted three times with ethyl acetate. The extract was washed with a sodium hydrogencarbonate solution and dried over magnesium sulfate. Evaporation of the solvent followed by column chromatography (silica gel, chloroform/methanol) gave the object compound (13 mg) as a pale yellow powder. MASS (m/z) : 509 (M+1) ' H-NMR (CDC13) δ : 3.32(2H,d,J=7Hz) , 3.77(3H,s),
6.03(1H,m), 6.97(1H,s), 7.07-7.78(13H,m) , 8.28(2H,d,J=8Hz) , 8.39(1H,br s) , 9.36(1H,br s) Example 96
The object compound was obtained according to a similar manner to that of Example 95.
MASS (m/z) : 523 (M+1)
1 H-NMR (CD30D) δ : 3.07(2H,m), 3.86(3H,s), 4.34(2H,s), 5.93(1H,t,J=7Hz), 7.09-7.15(6H,m) , 7.28(1H,t,J=8Hz), 7.46(1H,d,J=8Hz), 7.52-7.66(5H,m) , 8.33(2H,d,J=8Hz) Example 97
The object compound was obtained according to a similar manner to that of Example 95.
MASS (m/z) : 510 (M+1)
1H-NMR (CDCI3) δ : 3.38(1H,m), 3.53(1H,dd,J=7 and 15Hz), 3.82(3H,s), 6.11 (1H,m), 7.01-7.13(4H,m) , 7.37-7.44(3H,m) , 7.58(1H,d,J=8Hz), 8.65(1H,t,J=8Hz), 8.14(1H,m), 8.22-8.27(4H,m), 9.37(1H,br s) , 9.73(1H,br s) Example 98
The object compound was obtained according to a similar manner to that of Example 74.
MASS (m/z) : 448 (M+1)
' H-NMR (CDC13) δ : 3.19(1H,dd,J=5 and 15Hz),
3.28(1H,dd,J=7 and 15Hz), 3.68(3H,s), 3.76(3H,s), 5.95(1H,dd,J=5 and 7Hz), 6.98(1H,s), 7.12-7.15(2H,m) , 7.29(1H,t,J=8Hz), 7.37"7.43(1H,m) , 7.52(2H,d,J=8Hz) , 7.65(1H,d,J=8Hz), 6.71 (1H,m), 8.28(2H,d,J=8Hz) , 9.56(1H,m) Example 99
The object compound was obtained according to a similar manner to that of Example 95.
MASS (m/z) : 433 (M+1)
1 H-NMR (DMS0-d6) δ : 2.73(1H,dd,J=5 and 15Hz),
3.17(1H,dd,J=7 and 15Hz), 3.76(3H,s), 5.74(1H,m), 6.85(1H,s), 7.02(1H,t,J=8Hz), 7.18(1H,t,J=8Hz), 7.25(1H,s), 7.26(1H,s), 7.40(1H,s), 7.44(1H,d,J=8Hz) , 7.60(1H,d,J=8Hz) , 7.76(2H,d,J=8Hz), 8.27(2H,d,J=8Hz) , 8.97(1H,d,J=8Hz) Example 100
The object compound was obtained according to a similar manner to that of Example 95.
MASS (m/z) : 523 (M+1)
1 H-NMR (DMSO-ds) δ : 2.64(lH,dd,J=5 and 15Hz), 3.13(3H,s), 3.25(1H,dd,J=7 and 15Hz), 3.76(3H,s), 5.83(1H,m), 7.00(1H,t,J=8Hz), 7.16(2H,t,J=8Hz), 7.24-7.62(8H,m) , 7.77(2H,d,J=8Hz), 8.27(2H,d,J=8Hz) , 8.90(1H,d,J=8Hz) Example 101
The object compound was obtained according to a similar manner to that of Example 95. MASS (m/z) : 539 (M+1)
'H-NMR (DMSO-ds) δ : 3.07(1H,dd,J=5 and 15Hz),
3.44(1H,dd,J=7 and 15Hz), 3.75(3H,s), 3.82(3H,s), 5.83(1H,m), 6.85(lH,t,J=8Hz), 6.99"7.05(3H,m), 7.19(1H,t,J=8Hz), 7.27(1H,s), 7.31 (1H,s), 7.42(1H,d,J=8Hz) , 7.61 (1H,d,J=8Hz) , 7.78(2H,d,J=8Hz), 7.95(1H,d,J=8Hz) , 8.28(2H,d,J=8Hz) , 9.04(1H,d,J=8Hz), 9.40(1H,s) Example 102
The object compound was obtained according to a similar manner to that of Example 95.
MASS (m/z) : 543 (M+1)
'H-NMR (DMS0-d6) δ : 3.02(1H,dd,J=5 and 15Hz), 3.46(1H,dd,J=7 and 15Hz), 3.76(3H,s), 5.88(1H,m), 7.03(1H,t,J=8Hz), 7.18(1H,t,J=8Hz), 7.23~7.26(2H,m) , 7.32(2H,d,J=8Hz), 7.42(1H,d,J=8Hz) , 7.58-7.62(3H,m) , 7.77(2H,d,J=8Hz), 8.27(2H,d,J=8Hz) , 9.07(1H,d,J=8Hz) Example 103
The object compound was obtained according to a similar manner to that of Example 95.
MASS (m/z) : 539 (M+1)
' H-NMR (DMS0-d6) δ : 2.97(1H,dd,J=5 and 15Hz),
3.42(1H,dd,J=7 and 15Hz), 3.69(3H,s), 3.76(3H,s), 5.88(1H,m), 6.84(2H,d,J=8Hz), 7.03(1 H,t,J=8Hz), 7.18(1H,t,J=8Hz), 7.26(2H,s), 7.42(1H,d,J=8Hz), 7.47(2H,d,J=8Hz), 7.60(1H,d,J=8Hz), 7.76(2H,d,J=8Hz) , 8.27(2H,d,J=8Hz) , 9.06(1H,d,J=8Hz) Example 104
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 447 (M+1) 1 H-NMR (DMSO-de) δ : 2.54(3H,d,J=6Hz) , 2.74(1H,dd,J=5 and 15Hz), 3.17(1H,dd,J=7 and 15Hz), 3.76(3H,s), 5.77(1H,m), 7.02(1H,t,J=8Hz), 7.17(1H,t,J=8Hz), 7.23(1H,s), 7.25(1H,s), 7.42(1H,d,J=8Hz), 7.59(1H,d,J=8Hz) , 7.76(2H,d,J=8Hz) , 7.90(1H,m), 8.27(2H,d,J=8Hz), 8.97(1H,d,J=8Hz) Example 105
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS (m/z) : 491 (M+1)
1 H-NMR (CDC13) δ : 2.83(3H,d,J=5Hz), 3.49-3.62(2H,m), 3.63(3H,s), 5.89(1H,q,J=7Hz), 6.57(1H,d,J=8Hz), 7.11-7.18(3H,m), 7.24(1H,dd,J=2 and 8Hz) , 7.43(1H,m), 7.48(2H,d,J=8Hz), 7.58(1H,t,J=8Hz) , 7.67(1H,m), 8.27(2H,d,J=8Hz), 8.56(1H,d,J=5Hz) Example 106
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS (m/z) : 487 (M+1)
'H-NMR (CDCI3) <5 : 2.81 (3H,s), 3.56(2H,m), 3.64(3H,s), 5.90(1H,q,J=7Hz), 6.62(1H,d,J=8Hz) , 6.90(1H,m), 6.96-7.02(2H,m), 7.12-7.17(3H,m) , 7.43-7.49(3H,m) , 7.57(1H,t,J=8Hz), 8.27(2H,d,J=8Hz) , 8.53(1H,d,J=5Hz) Example 107
The object compound was obtained according to a similar manner to that of Preparation 3.
MASS (m/z) : 457 (M+1)
1 H-NMR (CDCI3) δ : 2.83(3H,d,J=5Hz), 3.56(2H,m), 3.62(3H,s), 5.9l(1H,q,J=7Hz), 6.57(1H,t,J=7Hz) , 6.65(1H,d,J=8Hz) , 7.12-7.17(3H,m), 7.31 (2H,t,J=8Hz), 7.43(2H,d,J=8Hz), 7.47(2H,d,J=8Hz), 7.56(1H,t,J=8Hz) , 8,26(2H,d,J=8Hz) , 8.53(1H,d,J=5Hz) Example 108
The object compound was obtained according to a similar manner to that of Preparation 3. MASS (m/z) : 443 (M+1)
'H-NMR (CDCI3) δ : 3.57(2H,m), 3.62(3H,s), 5.53(2H,br s) , 5.93(1H,q,J=7Hz), 6.65(2H,m), 7.12-7.23(3H,m) , 7.43(2H,t,J=8Hz), 7.48(2H,d,J=8Hz) , 7.57(1H,t,J=8Hz) , 8.27(2H,d,J=8Hz), 8.53(1H,d,J=5Hz) Example 109
The object compound was obtained according to a similar manner to that of Example 1. mp : 95-100°C MASS (m/z) : 467 (M+1)
'H-NMR (CDCI3) δ : 3.29(3H,s), 3.38-3.52(2H,m), 5.68(1H,q,J=8Hz), 7.01 (1H,s), 7.10-7.21 (2H,m), 7.21-7.32(2H,m), 7.38-7.50(2H,m) , 7.42(2H,d,J=8Hz) , 7.62(2H,t,J=8Hz), 8.28(2H,d,J=8Hz) , 8.37(1H,s), 8.48(1H,d,J=2Hz), 9.60(1H,s) Example 110
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (m/z) : 494 (M+1) ' H-NMR (CDCl3) δ : 1.41 (3H,t,J=8Hz), 3.30(3H,s),
3.48(2H,d,J=8Hz), 4.40(2H,q,J=8Hz) , 5.70(1H,q,J=8Hz) , 7.00-7.10(3H,m), 7.10-7.20(2H,m), 7.27-7.37(3H,m) , 7.41(1H,d,J=8Hz), 7.61 (1H,d,J=8Hz) , 7.83(1H,d,J=8Hz), 8.07(2H,d,J=8Hz), 8.45(2H,d,J=8Hz) , 9.71 (1H,s) Example 111
A solution of the starting compound (500 mg) in anhydrous THF (20 ml) was added dropwise with stirring to a solution of 1N LiAlHu in THF (2.02 ml) maintained at -78°C. After the addition was complete, the suspension was stirred at -78°C for 30 minutes and then ethyl acetate (30 ml) was added dropwise. The mixture was allowed to warm to about 5°C and then water (30 ml) was added dropwise. The white solid was filtered and washed with ether, and the filtrate and washing were dried and concentrated to give a yellow oil. The oil was chromatographed on silica gel with chloroform as eluent to give the object compound (360 mg). amorphous solid MASS (m/z) : 452 (M+1) H-NMR (CDCls) δ : 3.20(3H,s), 3.43(2H,d,J=8Hz) , 4.71 (2H,s), 5.69(1H,q,J=8Hz), 6.98(1H,s), 7.09(2H,d,J=6Hz) , 7.10-7.21 (4H,m), 7.29(1H,t,J=8Hz) , 7.38(2H,d,J=8Hz) , 7.40(1H,d,J=8Hz), 7.64(lH,d,J=8Hz) , 8.07(1H,d,J=8Hz) , 8.42(2H,d,J=6Hz), 9.63(1H,s) Example 11
Oxalyl chloride (0.10 ml) in CH2CI2 (20 ml) was placed in a three-necked flask equipped with two addition funnels and a stirrer. Dimethyl sulfoxide (0.12 ml) in CH2C12 (10 ml) was placed in one addition funnel, and the other one contained a solution of the starting compound (310 mg) in CHzClz (10 ml). The content of the flask was cooled to -60 °C and dimethyl sulfoxide was added over a period of 10 minutes. Stirring was continued for 20 minutes, followed by addition of the solution of the starting compound during 10 minutes. After the mixture was stirred at -60°C for 20 minutes, triethylamine (0.53 ml) was added over a period of 10 minutes. The cooling bath was removed and the suspension was allowed to warm to room temperature. Water (30 ml) was added, the yellow organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layer was dried and concentrated to give an orange-yellow liquid. This was chromatographed on silica gel with chloroform as eluent to give the object compound (190 mg). amorphous solid MASS (m/z) : 450 (M+1)
1 H-NMR (DMS0-d6) δ : 3.31 (3H,s), 3.46(2H,d,J=8Hz) , 5.69(1H,q,J=8Hz), 7.00(1H,s), 7.08(2H,d,J=6Hz) , 7.13(1H,t,J=8Hz), 7.19(1H,s), 7.29(1H,t,J=8Hz) , 7.34-7.59(3H,m), 7.63(2H,d,J=8Hz) , 7.91 (2H,d,J=8Hz) , 8.49(2H,d,J=8Hz), 9.58(1H,s), 10.20(1H,s) Example 113
The starting compound (500 mg) was dissolved in methanol (20 ml) to which was added 1N NaOH (10,1 ml) and the mixture was stirred at room temperature for about 6 hours. The solvent was then evaporated and the residue was dissolved in a minimum amount of water. The solution was extracted with chloroform and the aqueous layer was acidified to pH 4 with concentrated HCl to give the object compound as an amorphous solid (320 mg). MASS (m/z) : 466 (M+1) 'H-NMR (DMSO-ds) δ : 3.40-3.53(2H,m) , 3.64(3H,s),
5.70(1H,q,J=8Hz), 7.01 (1H,t,J=8Hz) , 7.17(1H,t,J=8Hz) , 7.19(1H,s), 7.22(1H,s), 7.39(1H,d,J=8Hz) , 7.41 (2H,d,J=6Hz) , 7.60(1H,d,J=8Hz), 7.60(2H,d,J=8Hz) , 8.00(2H,d,J=8Hz) , 8.42(2H,d,J=6Hz), 9.09(1H,d,J=8Hz) Example 114
The object compound was obtained according to a similar manner to that of Example 1. mp : 235-238°C MASS (m/z) : 494 (M+1) ' H-NMR (CDC13) δ : 1.40(3H,t,J=8Hz), 3.59(3H,s),
3.60-3.69(2H,m), 4.39(2H,q,J=8Hz) , 6.04(1H,q,J=8Hz) , 7.02(1H,s), 7.05-7.18(4H,m), 7.22(1H,d,J=8Hz) , 7.30-7.42(3H,m), 7.50(1H,t,J=8Hz) , 7.60(1H,d,J=2Hz), 8.00-8.12(3H,m), 8.52(1H,d,J=4Hz) , 9.78(1H,s) Example 115
The object compound was obtained according to a similar manner to that of Example 111. mp : 124-129°C MASS (m/z) : 452 (M+1) 1 H-NMR (CDCI3) δ : 3.49(3H,s), 3.59-3.67(2H,m) , 4.72(2H,s), 6.00(1H,q,J=8Hz), 6.90(1H,s), 7.02-7.18(4H,m) , 7.18-7.30(3H,m), 7.36(1H,s), 7.38(2H,d,J=8Hz) , 7.51(1H,t,J=8Hz), 7.61(1H,d,J=8Hz), 8.01 (1H,d,J=8Hz) , 8.51(1H,d,J=6Hz), 9.59(1H,s) Example 116
The object compound was obtained according to a similar manner to that of Example 113. amorphous solid
MASS (m/z) : 466 (M+1)
1 H-NMR (CDC13+CD30D) δ : 4.20-4.30(1H,m) , 4.31 (3H,s), 4.37-4.49(1H,m), 6.55(1H,q,J=8Hz) , 7.55(1H,t,J=8Hz) , 7.65-7.73(2H,m), 7.79(1H,s), 7.81 (1H,s), 7.82(1H,d,J=8Hz) , 7.94(2H,d,J=8Hz), 7.94(1H,d,J=8Hz) , 8.10(1H,d,J=8Hz) , 8.15(1H,t,J=8Hz), 8.61(2H,d,J=8Hz), 9.01 (1H,d,J=2Hz) , 9.77(1H,d,J=8Hz), Example 117
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid
MASS (m/z) : 489 (M+1)
'H-NMR (CDCI3) δ : 3.51 (3H,s), 3.68-3.83(2H,m) ,
6.21(1H,q,J=8Hz), 7.00-7.10(2H,m) , 7.14-7.50(10H,m) , 7.59(1H,br s), 7.70(1H,brs), 7.90(1H,s), 8.50(1H,d,J=2Hz), 8.80(1H,d,J=8Hz) Example 118
The object compound was obtained according to a similar manner to that of Example 1. mp : 141-145°C
MASS (m/z) : 481 (M+1)
'H-NMR (CDCI3) δ : 2.60(3H,s), 3.30(3H,s), 3.48-3.65(2H,m) , 5.70(1H,q,J=8Hz), 7.00(1H,s), 7.10(lH,s), 7.11-7.29(4H,m) , 7.30(2H,d,J=8Hz), 7.40(1H,s), 7.46(1H,dd,J=8 and 2Hz), 7.61(1H,t,J=8Hz), 8.08(2H,d,J=8Hz), 8.43(1H,s), 9.67(1H,s) Example 119
A solution of the starting compound (420 mg) in ethanol (20 ml) - water (2 ml) was heated to 70°C. Powdered iron (484 mg) and one drop of concentrated hydrochloric acid were added. The mixture was stirred at 70°C for 1 hour, then allowed to cool to room temperature. The reaction mixture was filtered, concentrated, made basic with 1N sodium hydroxide solution and extracted three times with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1 ) to give the object compound as an amorphous solid (380 mg). MASS (m/z) : 451 (M+1)
' H-NMR (CDC13) δ : 2.59(3H,s), 3.00(3H,s), 3.10-3.20(1H,m), 3.31-3.41 (1H,m), 3.61 (2H,br s), 5.41-5.53(1H,m) , 6.57(2H,d,J=8Hz), 6.81 (2H,d,J=8Hz) , 7.01 (1H,s), 7.09-7.17(2H,m), 7.20(1H,d,J=8Hz) , 7.23(1H,t,J=8Hz) , 7.39(1H,d,J=8Hz), 7.48(1H,d,J=8Hz) , 7.62(1H,d,J=8Hz) , 7.80(1H,d,J=8Hz), 8.40(1H,s), 9.51 (1H,s) Example 120
The object compound was obtained according to a similar manner to that of Example 63. amorphous solid MASS (m/z) : 523 (M+1)
1 H-NMR (CDC13) δ : 1.28(3H,t,J=8Hz), 2.50(3H,s), 3.03(3H,s), 3.28-3.49(2H,m), 4.20(2H,q,J=8Hz) , 5.61 (1H,q,J=8Hz) , 6.99(2H,d,J=8Hz), 7.01-7.30(8H,m), 7.37(1H,d,J=8Hz), 7.41(1H,d,J=8Hz), 7.58(1H,d,J=8Hz) , 8.38(1H,s), 8.39(1H,s) Example 1 1
The object compound was obtained according to a similar manner to that of Example 61. amorphous solid MASS (m/z) : 607 (M+1)
'H-NMR (CDCI3) δ : 2.58(3H,s), 2.98(3H,s), 3.12~3.49(1H,m) , 3.39(6H,s), 3.47-3.60(1H,m), 5.52-5.63(1H,m), 7.03(1H,s), 7.09-7.21 (8H,m), 7.38(1H,d,J=8Hz) , 7.41 (1H,dd,J=8 and 2Hz) , 7.59(1H,d,J=8Hz), 8.30(1H,d,J=8Hz) , 8.40(1H,s) Example 122
The object compound was obtained according to a similar manner to that of Example 1. mp : 147-152°C MASS (m/z) : 447 (M+1)
1 H-NMR (CDCl3) δ : 3.58(3H,s), 3.60-3.70(2H,m) , 6.00-6.18(1H,m), 7.02(1H,s), 7.07-7.18(4H,m), 7.19-7.29(1H,m), 7.38(1H,s), 7.39(2H,d,J=8Hz) , 7.49(1H,t,J=8Hz), 7.62(1H,d,J=8Hz) , 7.68(2H,d,J=8Hz) , 8.11(1H,d,J=8Hz), 8.51 (1H,d,J=2Hz) , 9.85(1H,s) Example 123
A solution of the starting compound (852 mg) in anhydrous THF (40 ml) was added dropwise with stirring to a solution of 1N LiAlHu in THF (4.78 ml) maintained at -78°C. After the addition was complete, the suspension was stirred at -78°C for 30 minutes and then ethyl acetate (60 ml) was added dropwise. The mixture was allowed to warm to about 5°C and then water (60 ml) was added dropwise. The white solid was filtered and washed with ether, and the filtrate and washings were dried and concentrated to give a yellow oil. The oil was chromatographed on silica gel with chloroform as eluent to give the object compound (470 mg). amorphous solid MASS (m/z) : 451 (M+1) 1 H-NMR (CDCI3+CD3OD) δ : 3.38-3.61 (2H,m), 3.54(3H,s),
3.90(2H,s), 5.91(1H,t,J=8Hz), 6.97(1H,s), 7.04-7.20(4H,m) , 7.20-7.30(4H,m), 7.30-7.43(3H,m) , 7.59(1H,t,J=8Hz), 7.62(1H,d,J=8Hz), 8.50(1H,d,J=2Hz) Example 124
The object compound was obtained according to a similar manner to that of Example 63. amorphous solid MASS (m/z) : 523 (M+1)
' H-NMR (CDC13+CD30D) δ : 1.27(3H,t,J=8Hz), 3.43-3.52(2H,m) , 3.51 (3H,s), 4.11(2H,q,J=8Hz), 4.34(2H,s), 5.90(1H,t,J=8Hz) , 6.97(1H,s), 7.07-7.30(7H,m), 7.30-7.43(4H,m), 7.59(1H,t,J=8Hz), 7.63(1H,d,J=8Hz), 8.50(1H,d,J=2Hz) Example 125
The object compound was obtained according to a similar manner to that of Example 61. amorphous solid MASS (m/z) : 529 (M+1)
'H-NMR (CDC13) δ : 2.82(3 x 1/4H,s), 2.96(3 x 3/4H,s), 3.33(3 x 3/4H,s), 3.42(3 x 1/4H,s), 3.48-3.70(2H,m), 4.38(2H,s), 6.00(1H,q,J=8Hz), 6.28(1 x 3/4H,s), 6.40(1 x 1/4H,s), 6.90-7.17(5H,m), 7.17-7.33(5H,m), 7.33-7.57(2H,m), 7.57"7.68(1H,m) , 8.38-8.61 (2H,m) Example 126
The object compound was obtained according to a similar manner to that of Preparation 5. amorphous solid MASS (m/z) : 493 (M+1)
1 H-NMR (CDC13) δ : 3.00(3H,s), 3.12(3H,s), 3.55(3H,s), 3.60-3.72(2H,m), 6.09(1H,q,J=8Hz), 7.01 (1H,s), 7.02-7.13(4H,m), 7.18-7.32(3H,m), 7.38(1H,d,J=8Hz) , 7.40-7.52(3H,m), 7.61 (1H,d,J=8Hz) , 8.30(1H,d,J=8Hz), 8.51(1H,d,J=8Hz) Example 127
To a stirred solution of the starting compound (300 mg) and 1- hydroxybenzotriazole (88 mg) in anhydrous dichloromethane (20 ml) at 5°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg). The mixture was stirred at 5°C for 30 minutes and then NH3 gas was bubbled for 15 minutes. The mixture was warmed to 25°C and stirred overnight. The mixture was poured into a saturated sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with brine, dried, and concentrated. Silica gel column chromatographic purification (chloroform/methanol=30/1 ) gave the object compound (120 mg). mp : 155-160°C MASS (m/z) : 463 (M-1) 'H-NMR (DMS0-d6) δ : 3.42-3.57(1H,m) , 3.57-3.65(1H,m) ,
3.70(3H,s), 5.91(1H,q,J=8Hz), 7.01 (1H,t,J=8Hz), 7.10(1H,s), 7.16(2H,t,J=8Hz), 7.23(1H,s), 7.30-7.48(3H,m), 7.51(2H,d,J=8Hz), 7.60(2H,t,J=8Hz) , 7.92(2H,d,J=8Hz) , 8.02(1H,brs), 8.50(1H,d,J=2Hz) , 9.08(1H,d,J=8Hz) Example 128
The object compound was obtained according to a similar manner to that of Preparation 5. mp : 189-193°C MASS (m/z) : 479 (M+1)
'H-NMR (CDCI3+CD3OD) δ : 2.70(3H,s), 3.30(2H,d,J=8Hz), 3.31 (3H,s), 5.68(1H,t,J=8Hz), 6.80(1H,s), 6.84(1H,t,J=8Hz), 6.90(1H,s), 6.92-7.02(3H,m), 7.10-7.20(3H,m), 7.40(2H,d,J=8Hz) , 7.61 (2H,d,J=8Hz) , 8.22(1H,d,J=2Hz) Example 129
The object compound was obtained according to a similar manner to that of Example 1 except that a mixture of dichloromethane and dimethylformamide was used instead of dichloromethane. mp : 233-235°C MASS (m/z) : 468 (M+1) 'H-NMR (DMS0-d6) δ : 3.48-3.60(1H,m) , 3.61-3.72(1H,m) , 3.77(3H,s), 6.00(1H,q,J=8Hz), 7.01 (1H,t,J=8Hz), 7.18(1H,t,J=8Hz), 7.23(1H,s), 7.28(1H,s), 7.40(1H,d,J=8Hz) , 7.51(1H,d,J=6Hz), 7.59(1H,d,J=8Hz), 7.78(2H,d,J=8Hz) , 8.28(2H,d,J=8Hz), 8.63(lH,d,J=4Hz) , 9.09(1H,s), 9.12(1H,d,J=8Hz) Example 130
The object compound was obtained according to a similar manner to that of Example 1. mp : 235-237°C MASS (m/z) : 466 (M+1)
' H-NMR (CDC13) δ : 1.40(3H,t,J=8Hz), 3.51 (3H,s), 3.58-3.68(2H,m), 3.92-4.08(2H,m), 6.09(1H,q,J=8Hz) , 6.73-6.90(3H,m), 7.00(1H,s), 7.01-7.12(4H,m), 7.18-7.30(2H,m) , • 7.31-7.40(1H,m), 7.45(1H,t,J=8Hz) , 7.60(1H,d,J=8Hz) , 8.29(1H,d,J=8Hz), 8.50(1H,d,J=2Hz) Example 131
The object compound was obtained according to a similar manner to that of Example 1. mp : 255-257°C MASS (m/z) : 528 (M+1)
' H-NMR (DMSO-dβ) δ : 3.40-3.52(1H,m), 3.53-3.63(lH,m), 3.58(3H,s), 5.11 (3H,s), 5.89(1H,q,J=8Hz), 6.90(1H,s), 7.01(1H,t,J=8Hz), 7.09(2H,d,J=8Hz), 7.18(2H,d,J=8Hz) , 7.24(1H,s), 7.30-7.50(9H,m), 7.58-7.68(2H,m), 8.49(1H,d,J=2Hz), 9.01 (1H,d,J=8Hz) Example 132
To a solution of the starting compound (970 mg) and methanol (50 ml) in 70 ml of THF was added Pd/C (10%, 300 mg). The resulting mixture was stirred under hydrogen at 25°C for 16 hours. The catalyst was filtered off, and the filtrate was concentrated to give an oil. The oil was chromatographed on silica gel with chloroform as eluent to give the object compound (780 mg) . amorphous solid MASS (m/z) : 438 (M+1)
' H-NMR (CDCI3+CD3OD) δ : 3.48-3.58(2H,m), 3.50(3H,s), 5.88(1H,t,J=8Hz), 6.88(2H,d,J=8Hz) , 6.90(1H,s), 7.07-7.19(4H,m), 7.19-7.30(3H,m) , 7.41 (1H,d,J=8Hz) , 7.60-7.70(2H,m), 8.49(1H,d,J=4Hz) Example 133
Acetic anhydride (52 mg) was added to a stirred solution of the starting compound (150 mg) and pyridine (81 mg) in methylene chloride/N,N-dimethylformamide (10:1, 22 ml) at 5°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed with brine. The organic layer was dried and concentrated to give a solid. The solid was chromatographed on silica gel with chloroform as eluent to give the object compound (110 mg). mp : 227-230°C MASS (m/z) : 480 (M+1) ' H-NMR (DMSO-dβ) <5 : 2.24(3H,s), 3.41-3.52(1H,m),
3.53-3.63(1H,m), 3.62(3H,s), 5.90(1H,q,J=8Hz) , 7.00(1H,s), 7.00(1H,t,J=8Hz), 7.11-7.28(5H,m), 7.32(1H,d,J=8Hz) , 7.38(1H,d,J=8Hz), 7.47(2H,d,J=8Hz), 7.59(1H,d,J=8Hz) , 7.62(1H,t,J=8Hz), 8.49(1H,d,J=8Hz) , 9.01 (1H,d,J=8Hz) Example 134
The object compound was obtained according to a similar manner to that of Example 133. solid
' H-NMR (CDCl3) δ : 3.46(3H,s), 3.80-4.00(2H,m) , 5.92(1H,t,J=8Hz), 6.80(2H,d,J=8Hz), 6.88(1H,s), 7.12-7.29(4H,m), 7.30-7.50(3H,m) , 7.55(1H,t,J=8Hz), 7.70(1H,t,J=8Hz), 7.77(1H,d,J=8Hz), 7.80(1H,d,J=8Hz) , 8.31(1H,d,J=8Hz), 9.62(1H,s) Example 135
Trimethylsilyldiazomethane (2.0M hexane solution, 0.34 ml) was added to a stirred solution of the starting compound (1 0 mg) and N,N- diisopropylethylamine (87 mg) in methanol-acetonitrile (1:9, 10 ml) at room temperature. The mixture was stirred overnight at room temperature, and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine. The organic layer was dried and concentrated to give a solid. The solid was chromatographed on silica gel with chloroform as eluent to give the object compound (100 mg). mp : 250°C (dec.) MASS (m/z) : 452 (M+1)
' H-NMR (DMSO-ds) δ : 3.41-3.51 (1H,m) , 3.52-3.62(lH,m) , 3.59(3H,s), 3.79(3H,s), 5.89(1H,q,J=8Hz) , 6.90(1H,s), 7.00(2H,d,J=8Hz), 7.02(1H,t,J=8Hz) , 7.18(2H,t,J=8Hz) , 7.22(1H,s), 7.31(2H,d,J=8Hz), 7.32-7.40(2H,m) , 7.58-7.68(2H,m), 8.49(1H,d,J=2Hz) , 9.01 (1H,d,J=8Hz) Example 136
The object compound was obtained according to a similar manner to that of Example 1. mp : 210-215°C MASS (m/z) : 406 (M+1) ' H-NMR (DMSO-de) δ : 3.78(3H,s), 3.90-4.02(lH,m),
5.01(1H,t,J=8Hz), 5.40(1H,q,J=8Hz), 7.02(1H,t,J=8Hz) , 7.19(1H,t,J=8Hz), 7.28(1H,s), 7.29(1H,s), 7.41(1H,d,J=8Hz), 7.60(1H,d,J=8Hz) , 7.80(2H,d,J=8Hz) , 8.29(2H,d,J=8Hz), 8.81 (1H,d,J=8Hz) Example 137
The object compound was obtained according to a similar manner to that of Example 1 except that a mixture of dichloromethane and dimethylformamide was used instead of dichloromethane. mp : 11 -120°C MASS (m/z) : 510 (M+1)
'H-NMR (CDCI3) δ : 3.78(3H,s), 4.74-4.82(1H,m), 4.88-4.95(1H,m), 5.90-6.02(1H,m), 7.02(1H,s), 7.11(1H,t,J=8Hz), 7.28(lH,s), 7.40(3H,t,J=8Hz) , 7.51(2H,d,J=8Hz), 7.53(lH,t,J=8Hz), 7.63(1H,d,J=8Hz) , 7.81(1H,d,J=8Hz), 7.97(2H,d,J=8Hz) , 8.30(2H,d,J=8Hz) , 9.40(1H,s) Example 138
Acetic anhydride (112 mg) was added to a stirred solution of the starting compound (150 mg) and pyridine (75 mg) in methylene chloride/N,N-dimethylformamide (10:1, 22 ml) at 5°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed with brine. The organic layer was dried and concentrated to give a solid. The solid was chromatographed on silica gel with chloroform as eluent to give the object compound (165 mg). mp : 110-115°C MASS (m/z) : 448 (M+1)
'H-NMR (DMS0-d6) δ : 2.00(3H,s), 3.70(3H,s), 4.50-4.60(1H,m) , 4.63-4.72(1H,m), 5.68-5.78(1H,m) , 7.03(1H,t,J=8Hz) , 7.20(1H,t,J=8Hz), 7.28(1H,s), 7.31 (1H,s), 7.42(1H,d,J=8Hz) , 7.60(1H,d,J=8Hz), 7.79(2H,d,J=8Hz) , 8.29(2H,d,J=8Hz), 9.05(1H,d,J=8Hz) Example 139
The object compound was obtained according to a similar manner to that of Example 1. mp : 220-223°C MASS (m/z) : 466 (M+1)
1 H-NMR (CDCI3+CD3OD) δ : 3.40-3.60(2H,m), 3.51 (3H,s), 5.90(1H,t,J=8Hz), 6.00(2H,s), 6.70-6.80(2H,m), 6.88(1H,d,J=8Hz), 6.91 (1H,s), 7.09-7.21 (4H,m), 7.29(1H,t,J=8Hz), 7.41 (1H,d,J=8Hz) , 7.59(1H,t,J=8Hz) , 7.69(1H,d,J=8Hz), 8.50(1H,d,J=2Hz) Example 140
The object compound was obtained according to a similar manner to that of Example 1. mp : 125-130°C MASS (m/z) : 418 (M-1)
1 H-NMR (CDC13) δ : 3.31 (3H,s), 3.78(3H,s), 3.98(2H,d,J=8Hz), 5.61(1H,q,J=8Hz), 7.02(1H,t,J=8Hz) , 7.19(1H,t,J=8Hz) , 7.29(1H,s), 7.42(1H,d,J=8Hz), 7.51 (lH,d,J=8Hz), 7.79(2H,d,J=8Hz), 8.29(2H,d,J=8Hz) , 8.91 (1H,d,J=8Hz) Example 141
The object compound was obtained according to a similar manner to that of Example 1. mp : 115-120°C MASS (m/z) : 496 (M+1) 1 H-NMR (DMSO-dβ) δ : 3.71 (3H,s), 4.08(2H,d,J=8Hz) ,
4.58(1H,d,J=10Hz), 4.62(1 H,d,J=10Hz), 5.70(1H,q,J=8Hz) , 7.02(1H,t,J=8Hz), 7.19(1H,t,J=8Hz), 7.21-7.33(7H,m) , 7.42(1H,d,J=8Hz), 7.60(1H,d,J=8Hz) , 7.79(2H,d,J=8Hz) , 8.29(2H,d,J=8Hz), 8.99(1H,d,J=8Hz) Example 1 2
The object compound was obtained according to a similar manner to that of Example 1. mp : 180°C (dec.) MASS (m/z) : 456 (M+1)
1 H-NMR (CDCI3) δ 3.20-3.42(2H,m) , 3.70(3H,s), 5.62(1H,q,J=8Hz), 6.73(1H,s), 7.01 (1H,t,J=8Hz) , 7.18(1H,t,J=8Hz), 7.28(lH,s), 7.30(1H,s), 7.40(1H,d,J=8Hz) , 7.50(1H,s), 7.60(1H,d,J=8Hz), 7.73(2H,d,J=8Hz) , 8.28(2H,d,J=8Hz), 9.00(1 H,d,J=8Hz) Example 1 3
The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (m/z) : 510 (M+1)
1 H-NMR (DMSO-de) δ : 3.00-3.12(2H,m) , 3.45"3.58(1H,m) , 3.77(3H,s), 5.85-5.98(1H,m), 7.02(1 H,t,J=8Hz), 7.20(1H,t,J=8Hz), 7.30(2H,s), 7.58(2H,d,J=6Hz) , 7.60(1H,d,J=8Hz), 7.78(2H,d,J=8Hz) , 8.29(2H,d,J=8Hz), 8.40(2H,d,J=6Hz), 9.10(1H,d,J=8Hz) Example 1 4
The object compound was obtained according to a similar manner to that of Example 1. mp : 145-150°C MASS (m/z) : 501 (M-1)
1 H-NMR (DMS0-d6) δ : 2.90-3.00(1 H,m) , 3.23"3.40(1H,m) , 3.42-3.70(8H,m), 3.80(3H,s), 5.78-5.88(1H,m), 7.01(1H,t,J=8Hz), 7.19(1H,t,J=8Hz), 7.22(1H,s), 7.25(1H,s), 7.41(1H,d,J=8Hz), 7.60(1H,d,J=8Hz) , 7.77(2H,d,J=8Hz) , 8.29(2H,d,J=8Hz), 9.00(1H,d,J=8Hz) Example 1 5
The object compound was obtained according to a similar manner to that of Example 1. mp : 245-250°C MASS (m/z) : 456.5 (M+1)
1 H-NMR (CDC13) δ : 3.39-3.51 (1H,m), 3.52-3.61 (1H,m), 3.60(3H,s), 5.90(1H,q,J=8Hz), 7.01 (1H,t,J=8Hz) , 7.03(1H,s), 7.16(2H,t,J=8Hz), 7.26(1H,s), 7.30-7.40(3H,m) , 7.4l-7.53(3H,m), 7.58-7.71 (2H,m), 8.50(1H,d,J=2Hz), 9.03(1H,d,J=8Hz) Example 1 6
Butyl iodide (120 mg) was added to a stirred solution of the starting compound (190 mg) and potassium carbonate (178 mg) in N,N- dimethylformamide (10 ml) at 5°C The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was poured into water and extracted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to give a solid.
The solid was chromatographed on silica gel with chloroform as eluent to give the object compound (110 mg). mp : 236-240°C MASS (m/z) : 494 (M+1)
' H-NMR (CDC13) δ : 0.92(3H,t,J=8Hz), 1.38-1.50(2H,m), 1.62-1.73(2H,m), 3.40-3.52(1H,m), 3.52-3.63(1H,m), 3.60(3H,s), 4.00(2H,t,J=8Hz), 5.89(1H,q,J=8Hz), 6.90(1H,s), 6.93-7.05(3H,m), 7.16(2H,t,J=8Hz) , 7.24(1H,s), 7.19-7.41 (4H,m), 7.57-7.68(2H,m) , 8.50(1H,d,J=2Hz) , 9.01(1H,d,J=2Hz) Example 147
The object compound was obtained according to a similar manner to that of Example 1. mp : 215-220°C MASS (m/z) : 473 (M+1) ' H-NMR (CDCI3) δ : 3.43-3.70(2H,m) , 3.74(3H,s),
5.98(1H,q,J=8Hz), 7.02(1H,t,J=8Hz) , 7.10-7.21 (3H,m) , 7.29(1H,s), 7.39(2H,t,J=8Hz), 7.51-7.71 (3H.ni), 7.83(1H,d,J=8Hz), 8.00-8.10(2H,m), 8.39(1H,d,J=8Hz) , 8.50(1H,d,J=8Hz), 8.90(1H,d,J=2Hz) , 9.10(1H,d,J=8Hz) Example 148
The object compound was obtained according to a similar manner to that of Example 1 except that dimethylformamide was used instead of dichloromethane. mp : 120-1 5°C MASS (m/z) : 553 (M+1) 1 H-NMR (DMS0-d6) δ : 2.91-3.02(1H,m) , 3.38-3.49(1H,m) ,
3.80(3H,s), 5.89(1H,q,J=8Hz), 5.95(2H,s), 6.81 (1H,d,J=8Hz) , 6.94(1H,d,J=8Hz), 7.02(1H,t,J=8Hz), 7.20(1H,t,J=8Hz) , 7.24(3H,s), 7.41(1H,d,J=8Hz), 7.60(1H,d,J=8Hz) , 7.78(2H,d,J=8Hz), 8.29(2H,d,J=8Hz) , 9.08(1H,d,J=8Hz) Example 149
The object compound was obtained according to a similar manner to that of Example 1. oil
MASS (m/z) : 538 (M+1)
1 H-NMR (CDC13) δ : 1.21(3H,t,J=8Hz), 3.l8-3.28(1H,m), 3.40-3.51 (1H,m), 4.20(2H,q,J=8Hz), 5.07(1H,d,J=15Hz), 5.09(1H,d,J=15Hz), 5.90-6.02(1H,m) , 6.99(1H,s), 7.09-7. 0(2H,m), 7.21-7.45(6H,m) , 7.51 (2H,d,J=8Hz) , 7.6l(1H,d,J=8Hz), 7.80(1H,d,J=8Hz), 8.30(2H,d,J=8Hz) , 9.40(1H,s) Example 150
The object compound was obtained according to a similar manner to that of Example 73. mp : 150-160°C
MASS (m/z) : 448 (M+1)
1 H-NMR (DMSO-ds) <5 : 1 3(3H,t,J=8Hz), 2.88-2.99(1H,m) , 3.30-3.40(1H,m), 4.10-4.28(1H,m) , 4.28-4.41 (1H,m) , 5.79(1H,q,J=8Hz), 7.00(1H,t,J=8Hz) , 7.19(1H,t,J=8Hz) , 7.22(1H,s), 7.27-7.33(1H.m), 7.41 (1H,d,J=8Hz) , 7.60(1H,d,J=8Hz), 7.79(2H,d,J=8Hz), 8.30(2H,d,J=8Hz) , 9.09(1H,d,J=8Hz) Example 151
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 523 (M+1)
'H-NMR (CDCI3) δ : 1.22(3H,t,J=7Hz), 3.33(2H,d,J=7Hz), 4.22(2H,q,J=7Hz), 6.10(1H,q,J=7Hz) , 7.02-7.12(4H,m), 7.21-7.23(2H,m), 7.37-7.45(5H,m) , 7.57(1H,d,J=8Hz) , 8.18(1H,m), 8.23(2H,d,J=8Hz), 8.57(1H,br s), 9.83(1H,br s) Example 152
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 553 (M+1)
' H-NMR (CDCl3) δ : 1.26(3H,t,J=7Hz), 3.29(2H,d,J=7Hz) , 3.73(3H,s), 4.23(2H,q,J=7Hz), 6.05(1H,q,J=7Hz) , 6.77(2H,d,J=8Hz), 7.05-7.12(3H,m) , 7.33-7.41 (5H,m) , 7.58(1H,m), 8.23(2H,d,J=8Hz) , 8.32(1H,m), 8.42(1H,br s), 9.73(1H,br s) Example 153
The object compound was obtained according to a similar manner to that of Example 1.
MASS (m/z) : 567 (M+1)
1 H-NMR (CDCI3) δ : 1.47(3H,t,J=7Hz), 3.53(2H,d,J=7Hz) , 4.46(2H,t,J=7Hz), 6.09(2H,s), 6.29(1H,q,J=7Hz) , 6.85(1H,d,J=8Hz), 6.98(1H,d,J=8Hz), 7.31-7.38(2H,m), 7.49(3H,m), 7.59"7.66(3H,m) , 7.81 (1H,d,J=8Hz) , 8.48(2H,d,J=8Hz), 8.88(1H,br s) Example 154
The object compound was obtained according to a similar manner to that of Example 1. mp : 125-130°C MASS (m/z) : 502 (M+1)
1 H-NMR (DMSO-de) δ : 1.09(3H,t,J=8Hz), 3.42-3.52(1H,m) , 3.54-3.64(1H,m), 4.00-4.11 (IH.m) , 4.20-4.31 (1H,m), 5.91(1H,q,J=8Hz), 7.01 (!H,t,J=8Hz) , 7.03(1H,s), 7.10-7.20(3H,m), 7.28(1H,s), 7.32-7.40(2H,m) , 7.52-7.69(2H,m), 7.53(2H,d,J=8Hz) , 7.73(2H,d,J=8Hz), 7.80(1H,s), 8.31 (1H,s), 8.50(1H,d,J=4Hz) , 9.10(1H,d,J=8Hz) Example 155
The object compound was obtained according to a similar manner to that of Example 1. mp : 140-145°C MASS (m/z) : 480 (M+1)
' H-NMR (DMSO-de) δ : 1.01 (3H,t,J=8Hz), 1.37(3H,t,J=8Hz) , 3.41-3.51 (1H,m), 3.52-3.63(1H,m), 3.89-4.22(2H,m), 4.02(2H,q,J=8Hz), 5.89(1H,q,J=8Hz) , 6.88(1H,s), 6.94-7.00(3H,m), 7.17(2H,t,J=8Hz), 7.22-7.36(4H,m), 7.40(1H,d,J=8Hz), 7.58-7.68(2H,m), 8.50(1H,d,J=2Hz) , 9.08(1H,d,J=8Hz) Example 156
The object compound was obtained according to a similar manner to that of Example 1. mp : 255-260°C MASS (m/z) : 507 (M+1)
' H-NMR (DMSO-de) δ : 3.10-3.18(4H,m) , 3.40-3.51 (1H,m) , 3.52-3.63(1H,m), 3.59(3H,s), 3.69-3.80(4H,m), 5.88(1H,q,J=8Hz), 6.89(1H,s), 6.95-7.07(3H,m) , 7.18(2H,t,J=8Hz), 7.22(1H,s), 7.27(2H,d,J=8Hz), 7.31(1H,d,J=8Hz), 7.39(1H,d,J=8Hz) , 7.59(1H,t,J=8Hz) , 7.61(1H,t,J=8Hz), 8.49(1H,d,J=2Hz), 9.00(1H,d,J=8Hz) Example 157
To a suspension of the starting compound (244 mg) in methanol (10 ml) was added 10% hydrogen chloride/methanol (1 ml). The mixture was evaporated and the residue was dried in vacuo to give the object compound as a pale yellow amorphous powder (275 mg). MASS (ESI) (m/z) : 488 (free, M+H)+ 1 H-NMR (DMSO-d6,30OMHz)(5 : 3.82-4.05(2H,m) , 3.91 (3H,s), 6.04-6.18(1H,m), 6.98-7.10(1H,m), 7.15-7.25(1H,m), 7.32-7.45(2H,m), 7.48-7.74(2H,m) , 7.78-7.85(1H,m) , 7.88(2H,d,J=8Hz), 7.92-8.01 (2H,m) , 8.04(2H,d,J=8Hz) , 8.07-8.18(1H,m), 8.40(1H,s), 8.71 (1H,d,J=5Hz), 9.78(1H,br d,J=8Hz), 9.88(1H,s), 10.50(1H,br s) Example 158 The object compound was obtained according to a similar manner to that of Example 1. mp : 235-236°C
MASS (ESI) (m/z) : 501 (M-H)"
' H-NMR (DMS0-d6,300MHz) δ : 1.08(3H,t,J=7Hz) , 3.51~3.62(2H,m), 3.98-4.30(2H,m), 5.80-5.95(1H,m), 7.03(1H,s), 7.12(1H,s), 7.15-7.37(4H,m), 7.46-7.77(7H,m), 7.81 (1H,s), 8.32(1H,s), 8.51(lH,d,J=5Hz), 9.16(1H,br d,J=8Hz) , 10.50(1H,br s) Example 159
The object compound was obtained according to a similar manner to that of Example 1. mp : 255-260°C (dec.) MASS (ESI) (m/z) : 521 (M+H)+
' H-NMR (DMSO-d6,300MHz) £ : 1.04(3H,t,J=7Hz) , 3.08-3.19(4H,m) , 3.39-3.64(2H,m), 3.67-3.79(4H,m) , 3.87-4.23(2H,m), 5.80-5.95(1H,m), 6.81-7.69(13H,m) , 8.48(1H,d,J=5Hz) , 9.06(1H,br d,J=8Hz), l0.50(1H,br s) Example 160
The object compound was obtained according to a similar manner to that of Example 1.
MASS (ESI) (m/z) : 516 (M+H)+
' H-NMR (DMSO-de,300MHz) (5 : 0.64(3H,t,J=7Hz) , 1.31-1.55(2H,m) , 3.41-3.67(2H,m), 3.90-4.28(2H,m), 5.86-6.00(1H,m), 6.97-7.21 (5H,m), 7.27(1H,s), 7.29"7.42(2H,m) , 7.53(2H,d,J=8Hz), 7.55"7.68(2H,m), 7.73(2H,d,J=8Hz}, 7.81(1H,s), 8.32(1H,s), 8.49(1H,d,J=5Hz) , 9.09(1H,br d,J=8Hz) , 10.50(1H,br s) Example 161
The object compound was obtained according to a similar manner to that of Example 1. mp : 209-210°C (dec.)
MASS (ESI) (m/z) : 489 (M+H)+ 1 H-NMR (DMS0-d6,300MHz) δ : 3.41-3.66(2H,m) , 3.68(3H,s),
5.84-5.99(1H,m), 6.96-7.07(1H,m) , 7.lO(1H,s), 7.11-7.21 (2H,m) , 7.25(1H,s), 7.30-7.42(2H,m), 7.54-7.69(2H,m) , 7.62(2H,d,J=8Hz), 7.93(2H,d,J=8Hz), 8.26(1H,s), 8.49(lH,d,J=5Hz), 9.05(1H,br d,J=8Hz) , 9.34(1H,s), 10.50(1H,br s) Example 162
The object compound was obtained according to a similar manner to that of Example 1. mp : 227-228°C (dec.) MASS (ESI) (m/z) : 503 (M+H)+
'H-NMR (DMSO-de,300MHz) 5 : 1.08(3H,t,J=7Hz) , 3.42-3.67(2H,m) , 3.99-4.35(2H,m), 5.84-6.00(1H,m), 6.95-7.05(1H,m) , 7.05(1H,s), 7.11-7.22(2H,m), 7.26(1H,s), 7.29-7.41 (2H,m) , 7.54-7.70(4H,m) , 7.93(2H,d,J=8Hz), 8.26(1H,s), 8.49(1H,d,J=5Hz), 9.10(lH,br d,J=8Hz), 9.34(1H,s), 10.50(1H,br s) Example 163
The object compound was obtained according to a similar manner to that of Example 1. mp : 240-243°C MASS (m/z) : 505 (M+1)
' H-NMR (DMSO-dδ) δ : 2.49-2.68(6H,m) , 3.13"3.23(4H,m) , 3.42-3.51 (1H,m), 3.52-3.60(1H,m) , 3.58(3H,s), 5.89(1H,q,J=8Hz), 6.85(1H,s), 6.98(2H,d,J=8Hz) , 7.01(1H,t,J=8Hz), 7.11-7.29(5H,m), 7.31 (1H,d,J=8Hz) , 7.39(1H,d,J=8Hz), 7.59(1H,d,J=8Hz), 7.61 (1H,t,J=8Hz) , 8.49(1H,d,J=2Hz), 9.00(1H,d,J=8Hz) Example 164
The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid MASS (m/z) : 565 (M+H)+ 1 H-NMR (CDCI3) δ 2.81 (3H,s), 3.26(1H,dd,J=12.0 and 9.0Hz), 3.46(1H,dd,J=12.0 and 6.0Hz), 5.49(1H,m), 6.97-7.06(4H,m), 7.10(2H,d,J=7.5Hz), 7.13-7.30(6H,m), 7.36(1H,d,J=7.5Hz), 7.50(2H,d,J=7.5Hz), 7.48-7.58(1H,m) , 7.63(1H,d,J=7.5Hz) Example 165
The object compound was obtained according to a similar manner to that of Preparation 5. orange amorphous solid
MASS (m/z) : 453 (M+H)+
'H-NMR (CDCI3-CD3OD) δ : 3.50-3.60(2H,m), 5.68(1H,t,J=7.0Hz) , 7.11 (1H,s), 7.11-7.38(5H,m), 7.40(1H,d,J=7.5Hz) , 7.61-7.70(2H,m), 7.78-7.89(2H,m) , 8.23(2H,d,J=7.5Hz) , 8.50(1H,m) Example 166
The object compound was obtained according to a similar manner to that of Preparation 5. yellow amorphous solid
MASS (m/z) : 609 (M+H)+ 1 H-NMR (CDCI3) δ : 3.53-3.67(2H,m), 3.61 (3H,s), 5.76-5.86(1H,m), 6.93-7.61 (12H,m) , 7.10(1H,s), 7.32(2H,d,J=7.5Hz), 7.77(1H,d,J=7.5Hz) , 7.91 (lH,d,J=7.5Hz), 8.25(2H,d,J=7.5Hz), 8.53(1H,m) Example 167
The object compound was obtained according to a similar manner to that of Example 1. yellow amorphous solid
MASS (m/z) : 581 (M+H)+ 1 H-NMR (CDCI3) δ : 1.09(3H,t,J=7.0Hz),
3.32(1H,dd,J=14.5 and 5.5Hz), 3.45(1H,dd,J=14.5 and 7.5Hz), 3.64(3H,s), 4.16(2H,q,J=7.0Hz), 6.01 (1H,m), 6.81 (1H,s), 7.03-7.12(2H,m), 7.20-7.59(8H,m), 7.51 (2H,d,J=7.5Hz) , 8.30(2H,d,J=7.5Hz), 8.51(1H,s), 9.31 (1H,br s) Example 168
The object compound was obtained according to a similar manner to that of Example 73. off-white solid mp : 189-191 °C
MASS (m/z) : 551 (M-H)+ 1 H-NMR (DMS0-d6) δ : 3.10(1H,dd,J=14.5 and 7.5Hz) , 3.47(1H,dd,J=14.5 and 7.5Hz), 3.57(3H,s), 5.83(1H,q,J=7.5Hz), 6.97"7.07(2H,m) , 7.19(1H,t,J=7.5Hz) , 7.25-7.30(3H,m), 7.41 (!H,d,J=7.5Hz) , 7.59(2H,d,J=7.5Hz), 7.61(1H,d,J=7.5Hz), 7.71 (2H,d,J=7.5Hz) , 8.30(2H,d,J=7.5Hz) , 9.15(1H,d,J=7.5Hz) Example 169
The object compound was obtained according to a similar manner to that of Example 1. pale yellow solid mp : 189-192°C
MASS (m/z) : 656 (M+H)+ 1 H-NMR (DMS0-d5) δ : 2.78(3H x 4/9,s) , 2.86(3H x 5/9,s) , 3.00(1H,dd,J=15.0 and 5.5Hz), 3.42(1H,m), 3.58(3H x 4/9,s), 3.61 (3H x 5/9,s), 4.32(1H x 4/9,d,J=15.0Hz) , 4.43(1H x 5/9,d,J=l 5.0Hz), 4.58(1H x 5/9,d,J=15.0Hz), 4.97(1H x 4/9,d,J=15.0Hz), 5.90(1H,m), 6.82(1H,m), 6.95-7.04(1H,m), 7.03(1H,t,J=7.5Hz) , 7.09-7.35(8H,m), 7.42(1H,d,J=7.5Hz), 7.50~7.63(4H,m) , 7.68(1H,d,J=7.5Hz) , 8.26(2H,d,J=7.5Hz), 9.10(1H,d,J=7.5Hz) Example 170
The object compound was obtained according to a similar manner to that of Example 1. pale yellow solid mp : 290-291.5°C MASS (m/z) : 642 (M+H)+
' H-NMR (DMSO-ds) δ : 2.99(1H,dd,J=14.5 and 5.5Hz), 3.49(3H,s), 3.49(1H,m), 4.41 (2H,d,J=7.0Hz) , 5.84(1H,m), 7.01(1H,t,J=7.5Hz), 7.03(1H,t,J=7.5Hz) , 7.15-7.32(9H,m) , 7.42(1H,d,J=7.5Hz), 7.53(2H,d,J=7.5Hz) , 7.60(1H,d,J=7.5Hz) , 7.75(2H,d,J=7.5Hz), 8.29(2H,d,J=7.5Hz) , 8.51 (1H,t,J=7.0Hz), 9.10(1H,d,J=7.5Hz) Example 171
The object compound was obtained according to a similar manner to that of Example 1. pale yellow solid mp : 208-212°C
MASS (m/z) : 539 (M+H)+ 1 H-NMR (CDCl3) δ : 1.13(3H,t,J=7.0Hz) , 3.48(3H,s),
3.68(2H,d,J=7.5Hz), 4.21 (2H,q,J=7.0Hz) , 6.03(1H,q,J=7.5Hz) , 6.98(1H,s), 7.11(2H,d,J=7.5Hz), 7.15(1H,d,J=7.5Hz) , 7.27(1H,t,J=7.5Hz), 7.37(1H,d,J=7.5Hz) , 7.49(2H,d,J=7.5Hz), 7.53(1H,t,J=7.5Hz), 7.62-7.69(2H,m) , 7.30(2H,d,J=7.5Hz) , 7.52(1H,m), 9.22(1H,br s) Example 172
The object compound was obtained according to a similar manner to that of Example 73. off-white solid mp : 177-181 °C
MASS (m/z) : 509 (M-H)+ 1 H-NMR (DMSO-de) δ : 3.50(3H,s), 3.52-3.62(2H,m), 5.76(lH,m), 7.01(1H,t,J=7.5Hz), 7.12-7.21 (2H,m), 7.24(1H,s), 7.38(2H,d,J=7.5Hz), 7.60(1H,d,J=7.5Hz) , 7.67(1H,t,J=7.5Hz), 7.68(2H,d,J=7.5Hz), 8.29(2H,d,J=7.5Hz), 8.49(1H,d,J=5.5Hz), 9.17(1H,d,J=7.5Hz) Example 173
The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid MASS (m/z) : 586 (M+H)+ 1 H-NMR (CDC13) δ : 3.53(3H,s), 3.62(2H,d,J=7.5Hz), 5.96(lH,q,J=7.5Hz), 7.05(1H,s), 7.08(1H,t,J=7.5Hz), 7.12-7.35(6H,m), 7.41 (1H,d,J=7.5Hz) , 7.53-7.61 (4H,m) , 7.68(1H,t,J=7.5Hz), 7.69(1H,d,J=7.5Hz) , 8.20(1H,d,J=7.5Hz) , 8.28(2H,d,J=7.5Hz), 8.62(1H,m), 8.90(1H,s), 9.21(1H,brs) Example 174
The object compound was obtained according to a similar manner to that of Example 1. yellow amorphous solid
MASS (m/z) : 456 (M+H)+
'H-NMR (CDCI3-CD3OD) δ : 3.43(1H,dd,J=14.5 and 7.5Hz),
3.51(1H,dd,J=14.5 and 7.5Hz), 3.64(3H,s), 5.80(1H,t,J=7.5Hz), 6.90(2H,s), 7.07-7.19(3H,m), 7.27(1H,t,J=7.5Hz), 7.42(1H,d,J=7.5Hz), 7.51 (2H,d,J=7.5Hz) , 7.65(1H,d,J=7.5Hz) , 8.30(2H,d,J=7.5Hz) Example 175
The object compound was obtained according to a similar manner to that of Example 1. yellow amorphous solid
MASS (m/z) : 512 (M+H)+ 1 H-NMR (CDC13) δ : 3.63(1H,dd,J=14.5 and 7.5Hz),
3.70(1H,dd,J=14.5 and 7.5Hz), 3.77(3H,s), 6.07(1H,m), 7.01-7.22(5H,m), 7.44-7.58(1H,m) , 7.51 (2H,d,J=7.5Hz), 7.90(1H,d,J=7.5Hz), 8.19(1H,dd,J=7.5 and 1.5Hz), 8.30(2H,d,J=7.5Hz), 8.57(1H,d,J=1.5Hz) , 9.12(1H,m) Example 1 6
The object compound was obtained according to a similar manner to that of Example 1. yellow solid mp : 195-196.5°C
MASS (m/z) : 473 (M+H)+ 1 H-NMR (DMSO-de) δ : 3.44(1H,dd,J=14.5 and 7.5Hz),
3.62(1H,dd,J=14.5 and 7.5Hz), 3.77(3H,s), 5.88(1H,q,J=7.5Hz) , 7.21(1H,dd,J=7.5 and 4.5Hz), 7.28(1H,s), 7.37(1H,d,J=7.5Hz) , 7.47(1H,d,J=7.5Hz), 7.63"7.80(3H,m) , 7.77(2H,d,J=7.5Hz) , 8.00(1H,d,J=7.5Hz), 8.31 (2H,d,J=7.5Hz) , 8.52(1H,d,J=4.5Hz) , 9.37(1H,d,J=7.5Hz) Example 177
The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 243-245.5°C
MASS (m/z) : 563 (M+H)+ 1 H-NMR (DMSO-de) δ : 3.66(3H,s), 7.05(1H,t,J=7.5Hz) , 7.11-7.19(4H,m), 7.21 (1H,t,J=7.5Hz) , 7.29"7.33(2H,m) , 7.37-7.47(3H,m), 7.49(2H,d,J=7.5Hz) , 7.57(1H,d,J=7.5Hz), 7.64(1H,d,J=7.5Hz), 7.69(2H,d,J=7.5Hz) , 8.01 (1H,d,J=7.5Hz) , 9.90(1H,s) Example 178
The object compound was obtained according to a similar manner to that of Preparation 2. pale yellow amorphous solid
MASS (m/z) : 476 (M-H)+ 1 H-NMR (CDCI3) δ : 2.26(3H,s), 2.36(3H,s), 5.02(2H,s), 7.03(1H,d,J=8.5Hz), 7.15-7.36(9H,m), 7.57(2H,d,J=8.5Hz) , 7.71 (1H,s) Example 179
The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 311-319°C MASS (m/z) : 577 (M+H)+
' H-NMR (DMSO-de) δ : 3.43(3H,s), 4.63(2H,s), 7.05-7.13(3H,m),
7.18-7.29(5H,m), 7.31 (1H,s), 7.32-7.49(4H,m),
7.43(2H,d,J=8.5Hz), 7.67(1H,d,J=8.5Hz) , 7.70(2H,d,J=8.5Hz) ,
7.98(1H,dd,J=8.5 and 1.5Hz), 9.75(1H,s) Example 180
The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 232-234°C MASS (m/z) : 563 (M+H)+ 1 H-NMR (DMSO-de) δ : 3.67(3H,s), 7.06-7.27(7H,m) ,
7.39-7.49(4H,m), 7.51-7.58(3H,m) , 7.69(2H,d,J=8.5Hz) ,
7.72(1H,d,J=8.5Hz), 8.54(1H,d,J=8.5Hz) Example 181
The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 251-252.5°C MASS (m/z) : 575 (M-H)+ 1 H-NMR (DMS0-d6) δ : 3.61 (3H,s), 5.35(2H,s), 7.08(1H,t,J=7.5Hz) ,
7.22(1H,s), 7.23(1H,t,J=7.5Hz), 7.28-7.42(5H,m) ,
7.45-7.53(4H,m), 7.58(2H,d,J=7.5Hz) , 7.65-7.73(3H,m),
8.00(1H,d,J=7.5Hz), 9.59(1H,s) Example 182
The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 253-255°C MASS (m/z) : 547 (M+H)+ 1 H-NMR (CDC13-CD30D) δ : 3.70(3H,s), 6.48(1H,s),
7.12(1H,t,J=7.5Hz), 7.18(1H,s), 7.26-7.35(1H,m) , 7.33(2H,d,J=7.5Hz), 7.46(1H,d,J=7.5Hz) , 7.50-7.63(8H,m) , 7.67-7.73(2H,m), 8.61 (1H,d,J=7.5Hz) Example 183
The object compound was obtained according to a similar manner to that of Preparation 5. off-white amorphous solid
MASS (m/z) : 345 (M+H)+ 1 H-NMR (CDCls) δ • 3.7K3H,br s), 4.77(2H,br s), 5.20(2H,br s), 6.80(1H,s), 7.01 (1H,m), 7.09(1 H,t,J=7.5Hz) , 7.21-7.68(9H,m), 9.28(1H,br s) Example 184
The object compound was obtained according to a similar manner to that of Example 1. off-white amorphous solid
MASS (m/z) : 421 (M+H)+
'H-NMR (CDCl3) δ : 4.77(2H,br s) , 5.11(2H,brs), 5.42(2H,br s) , 6.91(1H,s), 6.91-7.18(3H,m), 7.21-7.60(13H,m), 9.07(1H,br s) Example 185
The object compound was obtained according to a similar manner to that of Preparation 5 except that dimethylformamide was used instead of dichloromethane. off-white solid mp : 198-200°C
MASS (m/z) : 241 (M+H)+
' H-NMR (DMSO-ds) δ : 3.57(3H,s), 6.83(1H,s), 6.90-7.22(4H,m), 7.43(1H x 4/7,s), 7.47(1H x 3/7,s), 7.52-7.66(1H,m) Example 186
The object compound was obtained according to a similar manner to that of Example 1. yellowish brown amorphous solid
MASS (m/z) : 467 (M+H)+
'H-NMR (CDCI3-CD3OD) δ : 3.54(2H,t,J=7.0Hz), 3.72(3H,s), 5.90(1H,t,J=7,0Hz), 7.06-7.43(7H,m) , 7.59(1H,t,J=7.5Hz) , 7.66(1H,d,J=7.5Hz), 7.81 (2H,d,J=7.5Hz) , 8,22(2H,d,J=8.5Hz) , 8.50(1H,d,J=4.5Hz) Example 187
The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 130-132°C
MASS (m/z) : 423 (M+H)+
' H-NMR (CDC13) δ : 3.68(2H,d,J=7.5Hz), 3.69(3H,s),
6.07(1H,q,J=7.5Hz), 7.08(1H,d,J=1.0Hz) , 7.10-7.18(4H,m) , 7.21(2H,d,J=5.5Hz), 7.26(1H,t,J=7,5Hz) , 7.40(1H,d,J=7.5Hz) , 7.55(1H,t,J=7.5Hz), 7.65(1H,d,J=7.5Hz) , 8.16(1H,d,J=7.5Hz) , 8.52(1H,d,J=4.5Hz), 8.64(2H,d,J=5.5Hz), 9.62(lH,s) Example 188
The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid
MASS (m/z) : 500 (M+H)+
' H-NMR (CDCI3) δ : 3.09(3H,s), 3.42(1H,dd,J=13.0 and 9.0Hz), 3.53(1H,dd,J=13.0 and 7.0Hz), 5.58(1H,m), 7.11-7.19(2H,m) , 7.22-7.48(9H,m), 7.71 (1H,d,J=7.5Hz) , 7.75(1H,d,J=7.5Hz) , 7.90(1H,s), 7.98(lH,d,J=5.5Hz), 8.99(1H,d,J=7.5Hz), 9.06(1H,d,J=5.5Hz) Example 189
The object compound was obtained according to a similar manner to that of Example 1. colorless solid mp : 224-228°C
MASS (m/z) : 497 (M+H)+
' H-NMR (CDCI3) δ : 2.80(3H,s), 3.33(1H,dd,J=13.5 and 9.0Hz), 3.52(1H,dd,J=13.5 and 6.0Hz), 5.57(1H,m), 7.05(1H,d,J=1.0Hz), 7.10-7.31 (12H,m), 7.37"7.45(4H,m) , 7.50(2H,d,J=7.5Hz) , 7.63(1H,d,J=7.5Hz), 7.69(1H,d,J=7.5Hz) , 9.27(1H,s) Example 190
The object compound was obtained according to a similar manner to that of Example 1. mp : 200-210°C MASS : 520 (M+1) 1 H-NMR (DMS0-d6) δ : 2.21 (3H,s), 2.41-2.49(4H,m),
3.11-3.20(4H,m), 3.40-3.51 (1H,m), 3.52-3.61 (1H,m), 3.59(3H,s), 5.88(1H,q,J=8Hz), 6.83(1H,s), 6.92-7.07(3H,m), 7.13(2H,t,J=8Hz), 7.20(1H,s), 7.21-7.28(2H,m), 7.31(1H,d,J=8Hz), 7.39(1H,d,J=8Hz) , 7.60(1H,t,J=8Hz) , 7.61(1H,t,J=8Hz), 8.49(1H,d,J=4Hz), 9.00(1H,d,J=8Hz) Example 191
The object compound was obtained according to a similar manner to that of Example 1. mp : 145-150°C
MASS : 506 (M+1)
'H-NMR (DMSO-ds) δ : 3.43-3.64(2H,m) , 3.69(3H,s),
5.91(1H,q,J=8Hz), 7.02(1 H,t,J=8Hz), 7.08(1H,s), 7.11 (1H,s), 7.19(1H,t,J=8Hz), 7.26(1H,s), 7.31-7.41 (3H,m), 7.58(2H,d,J=8Hz), 7.63(1H,t,J=8Hz), 7.72(2H,d,J=8Hz) , 7.80(1H,s), 8.31 (1H,s), 8.50(1H,d,J=4Hz) , 9.11 (1H,d,J=8Hz) Example 192
The object compound was obtained according to a similar manner to that of Example 1. mp : 145-152°C
MASS : 518 (M+1)
' H-NMR (DMSO-de) <5 : 3.41-3.52(1H,m) , 3.52-3.63(1H,m) ,
3.63(3H,s), 3.71 (3H,s), 5.90(1H,q,J=8Hz), 6.81 (1H,d,J=8Hz), 7.08(1H,s), 7.09(1H,s), 7.11 (1H,s), 7.12-7.20(2H,m) , 7.29(lH,d,J=8Hz), 7.32(1H,d,J=8Hz) , 7.58(2H,d,J=8Hz) , 7.62(1H,t,J=8Hz), 7.71 (2H,d,J=8Hz) , 7.80(1H,s), 8.31 (1H,s), 8.50(1H,d,J=4Hz), 9.00(lH,d,J=8Hz) Example 193
The object compound was obtained according to a similar manner to that of Example 1. mp : 155-160°C
MASS : 522 (M+1)
'H-NMR (DMSO-ds) δ : 3.43"3.54(1H,m) , 3.56-3.67(1H,m), 3.71 (3H,s), 5.90(1H,q,J=8Hz), 7.08(1H,s), 7.11 (1H,s), 7.14-7.20(2H,m), 7.28(1H,s), 7.35(1H,d,J=8Hz), 7.40(1H,d,J=8Hz), 7.58(2H,d,J=8Hz) , 7.60-7.70(2H,m) , 7.72(2H,d,J=8Hz), 7.80(1H,s), 8.30(1H,s), 8.49(1H,d,J=4Hz) , 9.18(1H,d,J=8Hz) Example 194
The object compound was obtained according to a similar manner to that of Example 1. mp : 175-180βC
MASS : 574 (M+1)
1 H-NMR (DMSO-de) <5 : 2.90-3.00(1 H,m) , 3.37-3.49(1 H,m) ,
3.70(3H,s), 5.82-5.91 (1H,m), 5.93(2H,s), 6.82(1H,d,J=8Hz) , 6.98(1H,d,J=8Hz), 7.01 (1H,t,J=8Hz) , 7.09(1H,s), 7.11 (1H,s), 7.20(1H,t,J=8Hz), 7.29(2H,d,J=4Hz), 7.42(1H,d,J=8Hz) , 7.60(1H,d,J=8Hz), 7.61 (2H,d,J=8Hz) , 7.72(2H,d,J=8Hz) , 7.80(1H,s), 8.31 (1H,s), 9.03(1H,d,J=8Hz) Example 195
The object compound was obtained according to a similar manner to that of Example 1. mp : 225-230°C
MASS : 498 (M+1)
1 H-NMR (DMSO-dβ) δ : 3.43-3.53(1H,m) , 3.56-3.67(1H,m) ,
3.70(3H,s), 5.9K1H,q,J=8Hz), 7.01 (1H,t,J=8Hz) , 7.07(1H,s), 7.11-7.20(2H,m), 7.28(1H,s), 7.30-7.41 (3H,m) , 7.42-7.58(4H,m) , 7.60(2H,t,J=8Hz), 7.64-7.79(4H,m) , 8.50(1H,d,J=2Hz) , 9.07(1H,d,J=8Hz) Example 196
The object compound was obtained according to a similar manner to that of Example 1. mp : 165-170°C MASS : 560 (M+1)
1 H-NMR (DMSO-de) δ : 2.90-3.00(1H,m), 3.31 (3H,s), 3.38-3.49(1H,m), 3.70(3H,s), 5.89(1H,q,J=8Hz), 6.86(2H,d,J=8Hz), 7.01 (1H,t,J=8Hz), 7.06(1H,s), 7.11(1H,s), 7.19(1H,t,J=8Hz), 7.29(1H,s), 7.41 (1H,d,J=8Hz) , 7.49(2H,d,J=8Hz), 7.58-7.62(3H,m) , 7.72(2H,d,J=8Hz) , 7.80(1H,s), 8.31 (1H,s), 9.02(1H,d,J=8Hz) , 11.62(1H,s) Example 197
The object compound was obtained according to a similar manner to that of Example 1. mp : 110-115°C MASS : 500 (M-1)
'H-NMR (DMS0-d6) δ : 2.31 (3H,s), 3.42-3.53(1H,m), 3.54-3.62(1H,m), 3.69(3H,s), 5.90(1H,q,J=8Hz), 7.00(1H,d,J=8Hz), 7.05(1H,s), 7.10-7.20(3H,m) , 7.28(1H,d,J=8Hz), 7.31 (1H,d,J=8Hz), 7.38(1H,s), 7.58(2H,d,J=8Hz), 7.7.62(1H,t,J=8Hz), 7.71 (2H,d,J=8Hz) , 7.79(1H,s), 8.30(1H,s), 8.50(1H,d,J=2Hz), 9.00(1H,d,J=8Hz) Example 198
The object compound was obtained according to a similar manner to that of Example 1. mp : 140-1 5°C MASS : 516 (M+1)
' H-NMR (DMSO-ds) δ : 1.40(3H,d,J=4Hz) , 1.41 (3H,d,J=4Hz) , 3.49(2H,t,J=8Hz), 4.53-4.69(1H,m) , 5.99(1H,q,J=4Hz) , 6.91 (lH,s), 7.01(1H,t,J=8Hz), 7.12(1H,s), 7.16-7.22(2H,m) , 7.30(1H,s), 7.31-7.40(2H,m), 7.49(2H,d,J=8Hz) , 7.56-7.70(2H,m), 7.73(2H,d,J=8Hz) , 7.81 (1H,s), 8.31 (lH,s), 8.51(1H,d,J=8Hz), 9.02(1H,d,J=8Hz) Example 199
The object compound was obtained according to a similar manner to that of Example 1. mp : 135-140°C MASS : 520 (M+1)
1 H-NMR (DMS0-d6) δ : 1.00(3H,t,J=8Hz) , 3.43-3.53(1H,m) , 3.55-3.65(1H,m), 4.00-4.14(1H,m), 4.18-4.31 (1H,m), 5.92(1H,q,J=8Hz), 6.99-7.10(lH,m), 7.05(1H,s), 7.11 (1H,s), 7.13-7.21 (1H,m), 7.27(1H,s), 7.31 (1H,s), 7.32-7.41 (2H,m) , 7.57(2H,d,J=8Hz), 7.65(1H,t,J=8Hz) , 7.73(2H,d,J=8Hz) , 7.81 (1H,s), 8.31 (1H,s), 8.50(1H,d,J=2Hz), 9.19(1H,d,J=8Hz) Example 200
The object compound was obtained according to a similar manner to that of Example 1. mp : 130-135°C MASS : 536 (M+1)
'H-NMR (DMS0-d6) δ : 1.09(3H,t,J=8Hz) , 3.42-3.52(1H,m) , 3.53-3.63(1H,m), 4.00-4.15(1H,m) , 4.18-4.31 (1H,m) , 5.91(lH,q,J=8Hz), 7.02(1H,s), 7.10-7.20(3H,m) , 7.27dH,s), 7.32(1H,d,J=8Hz), 7.40(lH,d,J=8Hz), 7.53(2H,d,J=8Hz), 7.64(1H,t,J=8Hz), 7.69(1H,s), 7.72(2H,d,J=8Hz), 7.80(lH,s), 8.31 (1H,s), 8.50(1H,d,J=4Hz) , 9.21(1H,d,J=8Hz) Example 201
The object compound was obtained according to a similar manner to that of Example 1. mp : 170-1 5°C MASS : 532 (M-1) 'H-NMR (DMSO-dβ) δ : 0.62(3H,t,J=8Hz) , 1.30-1.52(2H,m) ,
5 o 8 3.42-3.53(1H,m), 3.54-3.68(1H,m), 3.91-4.08(1H,m), 4.10-4.28(1H,m), 5.92(1H,q,J=8Hz) , 6.99-7.09(1H,m), 7.01(1H,s), 7.11(1H,s), 7.12-7.20(1H,m), 7.26(1H,s), 7.30-7.41 (3H,m), 7.51 (2H,d,J=8Hz), 7.62(1H,t,J=8Hz), 7.73(2H,d,J=8Hz), 7.81 (1H,s), 8.32(1H,s), 8.50(1H,d,J=2Hz), 9.17(1H,d,J=8Hz) Example 202
The object compound was obtained according to a similar manner to that of Example 1. mp : 136-138°C MASS : 550 (M+1)
' H-NMR (DMSO-ds) δ : 0.60(3H,t,J=8Hz) , 1.32-1.52(2H,m), 3.42-3.52(1H,m), 3.55-3.68(1H,m), 3.90-4.08(1H,m) , 4.11-4.25(1H,m), 5.91 (1H,q,J=8Hz) , 7.01(1H,s), 7.11(1H,s), 7.17(2H,dd,J=8Hz and 2Hz), 7.23(lH,s), 7.31 (1H,d,J=8Hz), 7.40(1H,d,J=8Hz), 7.53(2H,d,J=8Hz), 7.62(1H,t,J=8Hz), 7.70(1H,s), 7.73(2H,d,J=8Hz), 7.80(1H,s), 8.32(1H,s), 8.50(1H,d,J=2Hz), 9.20(1H,d,J=8Hz) Example 203
The object compound was obtained according to a similar manner to that of Example 1. mp : 148-152°C MASS : 550 (M+1)
' H-NMR (DMS0-d6) δ : 1.40(6H,t,J=8Hz) , 3.42-3.52(2H,m), 4.51-4.68(1H,m), 5.99(1H,q,J=8Hz), 6.91 (1H,s), 7.11 (1H,s), 7.19(2H,t,J=8Hz), 7.30(1H,s), 7.31 (1H,d,J=8Hz), 7.39(1H,d,J=8Hz), 7.50(2H,d,J=8Hz) , 7.63(1H,t,J=8Hz), 7.70(1H,s), 7.73(2H,d,J=8Hz), 7.81 (1H,s), 8.31 (1H,s), 8.50(1H,d,J=4Hz), 9.17(1H,d,J=8Hz) Example 204
The object compound was obtained according to a similar manner to that of Example 1. mp : 1 0-145°C
MASS : 534 (M+1)
' H-NMR (DMSO-de) δ : 1.38(6H,t,J=7Hz), 3.43-3.53(2H,m) , 4.52-4.64(1H,m), 5.95(1H,q,J=8Hz), 6.91 (1H,s), 7.01(1H,t,J=8Hz), 7.12(1H,s), 7 7(2H,t,J=6Hz) , 7.20(1H,s), 7.32-7.42(3H,m), 7.47(2H,d,J=8Hz), 7.62(1H,t,J=8Hz), 7.72(2H,d,J=8Hz), 7.81 (1H,s), 8.50(1H,d,J=4Hz), 9.11(1H,d,J=8Hz) Example 205
The object compound was obtained according to a similar manner to that of Example 1. mp : 240-245°C
MASS : 530 (M+1) H-NMR (DMS0-d6) δ : 0.63(3H,t,J=8Hz) , 1.00-1.13(2H,m), 1.30-1.50(2H,m), 3.41-3.51 (1H,m) , 3.58-3.68(1H,m) , 3.91-4.08(lH,m), 4.18-4.30(1H,m), 5.92(1H,q,J=8Hz) , 7.01(1H,t,J=8Hz), 7.03(1H,s), 7.11 (1H,s), 7.12-7.20(2H,m) , 7.27(1H,s), 7.31(1H,d,J=8Hz), 7.39(1H,d,J=8Hz) , 7.52(2H,d,J=8Hz), 7.53"7.69(2H,m), 7.72(2H,d,J=8Hz), 7.80(1H,s), 8.30(1H,s), 8.49(lH,d,J=2Hz) , 9.09(1H,d,J=8Hz) Example 206
The object compound was obtained according to a similar manner to that of Example 1. mp : 235-240°C
MASS : 565 (M+1)
' H-NMR (DMSO-de) δ : 0.63(3H,t,J=8Hz) , 1.00-1.11 (2H,m) , l.30-1.50(2H,m), 3.40-3.56(1H,m), 3.58-3.70(1H,m), 3.91-4.08(1H,m), 4.18-4.30(1H,m) , 5.93(1H,q,J=8Hz) , 7.07(1H,t,J=6Hz), 7.n-7.22(3H,m), 7.28(1H,s), 7.32(1H,d,J=8Hz), 7.40(1H,d,J=8Hz) , 7.58(2H,d,J=8Hz) , 7.67(1H,t,J=8Hz), 7.69(1H,s), 7.74(2H,d,J=8Hz) , 7.82(1H,s), 8.31-8.45(1H,m), 8.50(1H,d,J=2Hz) , 9.21 (1H,d,J=8Hz)
5 l o Example 207
The object compound was obtained according to a similar manner to that of Example 1. mp : 235-240°C MASS : 546 (M-1)
' H-NMR (DMSO-dδ) δ • 0.63(3H,t,J=8Hz) , 0.98-1.11 (2H,m) , 1.30-1.48(2H,m), 3.40-3.51 (1H,m), 3.58-3.69(1H,m), 3.90-4.08(1H,m), 4.17-4.30(1H,m) , 5.92(1H,q,J=8Hz) , 6.98-7.09(1H,m), 7.02(1H,s), 7.11 (1H,s), 7.13-7.20(1H,m), 7.28(1H,s), 7.30-7.42(3H,m), 7.52(2H,d,J=8Hz), 7.62(1H,t,J=8Hz), 7.73(2H,d,J=8Hz) , 7.81 (1H,s), 8.32(1H,s), 8.49(1H,d,J=2Hz), 9.16(1H,d,J=8Hz) Example 208
The object compound was obtained according to a similar manner to that of Example 1. mp : 235-240°C MASS : 544 (M+1)
'H-NMR (DMS0-d6) δ : 0.61 (3H,t,J=8Hz) , 0.97-1.00(4H,m), 1.31-1.50(2H,m), 3.4l-3.52(1H,m) , 3.59-3.70(1H,m), 3.90-4.08(1H,m), 4.18-4.30(lH,m) , 5.93(1H,q,J=8Hz) , 7.00(1H,d,J=8Hz), 7.02(1H,s), 7.10-7.20(3H,m) , 7.28(1H,s), 7.32(lH,d,J=8Hz), 7.40(1H,d,J=8Hz), 7.52(2H,d,J=8Hz), 7.57-7.70(2H,m), 7.72(2H,d,J=8Hz) , 7.81 (1H,s), 8.31 (1H,s), 8.50(1H,d,J=2Hz), 9.00(1H,d,J=8Hz) Example 209
The object compound was obtained according to a similar manner to that of Example 1. mp : 220-225°C MASS : 562 (M+1)
1 H-NMR (DMS0-d6) δ : 0.60(3H,t,J=8Hz) , 0.92-1.10(4H,m), 1.36-1.50(2H,m), 3.40-3.51 (1H,m), 3.58-3.70(1H,m), 3.91-4.08(1H,m), 4.12-4.30(1H,m), 5.92(1H,q,J=8Hz) ,
5 l l 6.99-7.09(1H,m), 7.00(1H,s), 7.10(1H,s), 7.19(1H,t,J=8Hz) , 7.28(1H,s), 7.30-7.40(3H,m), 7.53(2H,d,J=8Hz) , 7.63(1H,t,J=8Hz), 7.73(2H,d,J=8Hz) , 7.82(1H,s), 8.32(1H,s), 8.50(1H,d,J=2Hz), 9.18(1H,d,J=8Hz) Example 210
The object compound was obtained according to a similar manner to that of Example 1. mp : 53-56°C
MASS (m/z) : 500 (M++1 ,bp) ' H-NMR (CDC13) δ : 3.67(3H,s),
3.76(2H,ABX,J=16Hz, 15Hz and 7.5Hz),
6.10(1H,dd,J=7.5Hz and 7.5Hz), 7.10(1H,s), 7.12(1H,t,J=7.5Hz), 7.19-7.22(2H,m), 7.30(1H,s), 7.40-7.48(4H,m) , 7.55(1H,ddd,J=7.5Hz, 7.5Hz and 2Hz) , 7.64(1H,ddd,J=7.5Hz, 7.5Hz and 2Hz),
7.79(1H,ddd,J=7.5Hz, 7.5Hz and 2Hz) , 7.88(1H,d,J=7.5Hz) , 7.90(1H,s), 8.18(1H,d,J=7.5Hz), 8.27(2H,AB,J=8Hz and 7.5Hz), 8.57(1H,d,J=2Hz), 9.08(1H,d,J=7.5Hz) Example 211
The object compound was obtained according to a similar manner to that of Example 1. mp : 100-105°C MASS : 566 (M+1)
'H-NMR (DMS0-d6) δ : 3.42-3.53(1H,m), 3.54-3.61 (1H,m), 3.68(3H,s), 5.90(1H,q,J=8Hz), 7.08(1H,s), 7.11 (1H,s), 7.18(1H,t,J=6Hz), 7.27(1H,s), 7.29(1H,d,J=8Hz), 7.31-7.39(2H,m), 7.55(2H,d,J=8Hz) , 7.63(1H,t,J=8Hz), 7.72(2H,d,J=8Hz), 7.81 (2H,d,J=8Hz) , 8.31 (1H,s), 8.50(1H,d,J=2Hz), 9.19(1H,d,J=8Hz) Example 212
The object compound was obtained according to a similar manner to that of Example 1. mp : 105-110*0
MASS : 594 (M+1)
' H-NMR (DMS0-d6) δ : 0.61 (3H,t,J=8Hz) , 1.32-1.52(2H,m) , 3.41-3.53(1H,m), 3.57-3.63(1H,m), 3.90-4.05(1H,m), 4.12-4.28(1H,m), 5.92(1H,q,J=8Hz) , 7.01 (1H,s), 7.11 (1H,s), 7.18(1H,t,J=6Hz), 7.24-7.40(4H,m), 7.53(2H,d,J=8Hz), 7.62(1H,t,J=8Hz), 7.72(2H,d,J=8Hz), 7.82(2H,d,J=8Hz) , 8.31 (1H,s), 8.50(1H,d,J=2Hz), 9.21 (1H,d,J=8Hz) Example 213
The object compound was obtained according to a similar manner to that of Example 1. mp : 1 5-1 0°C
MASS : 580 (M+1)
' H-NMR (DMS0-d6) δ : 1.05(3H,t,J=8Hz), 3.41~3.52(1H,m) , 3.42-3.63(1H,m), 3.99-4.12(1H,m), 4.15-4.30(1H,m), 5.91(1H,q,J=8Hz), 7.02(1H,s), 7.11 (1H,s), 7.19(1H,t,J=6Hz) , 7.23-7.40(4H,m), 7.55(2H,d,J=8Hz), 7.64(1H,t,J=8Hz) , 7.72(2H,d,J=8Hz), 7.81 (2H,d,J=8Hz) , 8.31 (1H,s), 8.50(1H,d,J=2Hz), 9.21 (1H,d,J=8Hz) Example 214
The object compound was obtained according to a similar manner to that of Example 1. mp : 155-160°C
MASS : 512 (M-1)
' H-NMR (DMS0-d6) δ : 0.97-1.02(4H,m), 3.27-3.40(2H,m), 3.41-3.49(1H,m), 3.50-3.60(1H,m), 6.11 (1H,q,J=8Hz), 6.98-7.09(1H,m), 7.02(1H,s), 7.09"7.23(3H,m) , 7.29(1H,s), 7.31(1H,d,J=8Hz), 7.40(1H,d,J=8Hz) , 7.59-7.78(5H,m), 7.81 (1H,s), 8.32(1H,s), 8.51 (1H,d,J=8Hz), 9.00(1H,d,J=8Hz) Example 215
The object compound was obtained according to a similar manner to that of Example 1.
5 l 3 mp : 208-218°C
MASS : 547 (M-1)
' H-NMR (DMS0-d6) δ : 0.75-0.89(2H,m) , 1.75(2H,d,J=8Hz) , 3.10-3.20(1H,m), 3.38-3.69(2H,m) , 6.00-6.19(2H,m) , 6.25-6.38(1H,m), 7.l1-7.24(3H,m), 7.31 (1H,s), 7.35-7.41 (2H,m) , 7.47(2H,d,J=8Hz), 7.66-7.79(4H,m) , 7.86(1H,s), 8.36(1H,s), 8.52(1H,d,J=4Hz), 9.18(1H,d,J=8Hz) Example 216
The object compound was obtained according to a similar manner to that of Example 1. mp : 100-105°C
MASS : 486 (M-1)
' H-NMR (DMSO-dβ) δ : 3.43"3.63(2H,m) , 3.64(3H,s),
5.88(1H,q,J=8Hz), 6.48(1H,s), 7.02(1H,s), 7.11 (1H,s), 7.18(1H,dd,J=8Hz and 4Hz), 7.33(1H,d,J=8Hz), 7.49(1H,t,J=4Hz), 7.51-7.58(3H,m), 7.58(1H,s), 7.63(lH,t,J=8Hz) , 7.70(1H,s), 7.73(1H,s), 7.80(1H,s), 7.98(1H,s), 8.31(1H,s), 8.50(1H,d,J=4Hz), 8.92(1H,d,J=8Hz) Example 217
The object compound was obtained according to a similar manner to that of Example 1. mp : 115-120°C
MASS : 486 (M-1)
' H-NMR (DMS0-d6) δ : 1.57-1.72(2H,m) , 2.20-2.48(4H,m), 3.40-3.53(2H,m), 5.79-5.91 (1H,m) , 6.00(1H,q,J=8Hz) , 6.91 (1H,s), 7.02(1H,t,J=8Hz), 7.10-7.22(3H,m) , 7.30(1H,s), 7.3U1H,d,J=8Hz), 7.40(1H,d,J=8Hz) , 7.49(2H,d,J=8Hz) , 7.61(2H,d,J=8Hz), 7.72(2H,d,J=8Hz) , 7.81 (1H,s), 8.32(1H,s), 8.52(1H,d,J=4Hz), 9.01 (1H,d,J=8Hz) Example 218
The object compound was obtained according to a similar manner to that of Example 1.
5 l 4 mp : 55-75°C
'H-NMR (DMSO-ds) δ : 3.45-3.65(2H,m) , 3.65(3H,s), 5.89(1H,q,J=6Hz), 7.08(1H,s), 7.14(1H,s), 7.20(1H,dd,J=8Hz and 6Hz) , 7.30-7.38(2H,m), 7.48(1H,t,J=8Hz) , 7.59(2H,d,J=8Hz), 7.61-7.71 (3H,m) 7.75(2H,d,J=8Hz) , 7.78-7.85(2H,m), 8.32(1H,s), 8.51 (1H,d,J=4Hz), 9.28(1H,d,J=8Hz) Example 219
The object compound was obtained according to a similar manner to that of Example 1. mp : 1 6-150°C
ESI-MS(M+1) : 488
' H-NMR (DMS0-d_) δ : 3.42-3.67(2H,m) , 3.68(3H,s), 5.92(1H,q,J=6Hz), 6.97-7.05(1H,m) , 7.08(1H,s), 7.10-7.21 (3H,m), 7.25(lH,s), 7.30-7.42(2H,m), 7.50-7.68(4H,m) , 7.72(2H,d,J=8Hz), 7.80(1H,s) 8.32(1H,s), 8.50(1H,d,J=2Hz) , 9.07(1H,d,J=8Hz) Example 220
The object compound was obtained according to a similar manner to that of Example 1. mp : 96-155°C
ESI-MS(M+1) : 488
' H-NMR (CDCls) δ : 3.30(3H,s), 3.45-3.55(2H,m),
5.72(1H,q,J=6Hz), 7.05-7.50(12H,m) , 7.65(lH,d,J=8Hz), 7.85-7.97(2H,m), 8.48(2H,d,J=8Hz) , 9.61 (1H,s) Example 221
The object compound was obtained according to a similar manner to that of Example 1. mp : 155-207°C
ESI-MS(M+1) : 517
'H-NMR (CDCI3) δ : 3.70(3H,s), 4.00-4.15(2H,m) ,
4.54(2H,d,J=4Hz), 5.80(1H,q,J=6Hz) , 7.10-7.35(10H,m) , 7.38-7.50(5H,m), 7.65(1H,d,J=8Hz) , 7.91 (1H,s), 8.33(1H,d,J=8Hz), 9.77(1H,s) Example 222
The object compound was obtained according to a similar manner to that of Example 1. mp : 199-201"C
' H-NMR (CDC13) δ : 2.15(3H,s), 2.40-2.78(4H,m) , 3.85(3H,s), 5.74(1H,t,J=6Hz), 7.09-7.37(6H,m) , 7.44(1H,d,J=8Hz) , 7.50(4H,s), 7.68(1H,d,J=8Hz), 7.93(1H,s) Example 223
The object compound was obtained according to a similar manner to that of Example 1. mp : 240-242°C ESI-MS(M+1) : 517
' H-NMR (CDC13) δ : 0.70(3H,t,J=6Hz) , 1.40-1.65(2H,m) , 3.70(2H,d,J=6Hz), 3.86-4.12(2H,m) , 6.09(1H,q,J=6Hz) , 7.04(1H,s), 7.08-7.30(5H,m), 7.40(2H,d,J=8Hz) , 7.52(1H,d,J=8Hz), 7.65(lH,d,J=8Hz) , 7.73(2H,d,J=8Hz) , 8.13(1H,s), 8.18(1H,d,J=8Hz), 8.55(1H,d,J=4Hz), 8.59(lH,s), 9.90(1H,s) Example 224
The object compound was obtained according to a similar manner to that of Example 1. mp : 238-241°C
' H-NMR (CDCI3) δ : 0.72(3H,t,J=6Hz) , 1.40-1.62(2H,m) , 3.62(2H,d,J=6Hz), 3.82-4.15(2H,m), 6.04(1H,q,J=6Hz), 7.02(1H,s), 7.04(1H,s), 7.08-7.17(3H,m) , 7.24(1H,s), 7.32(1H,s), 7.39(1H,s), 7.42(4H,d,J=8Hz) , 7.52(1H,t,J=8Hz), 7.65(1H,d,J=8Hz), 7.80-7.89(1H,m) , 7.90(1H,s), 8.55(1H,d,J=4Hz)

Claims

CLAIMS 1. A compound of the formula
Figure imgf000519_0001
wherein
R' is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
R2 is hydrogen or phenyl(lower)alkyl;
R" is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, quinolyl or 3,4-methylenedioxyphenyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
.R7 -C0-N
in which R7 and R8 are the same or different and each is
5 l 7 hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or R" and R5 in combination form a group of the formula
-CH=CH-CH=CH-
Y is a group of the formula
R3
I
-CH- in which R3 is hydrogen or a group of the formula -(CH2)n-R6 in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
Figure imgf000520_0001
in which R" is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000520_0002
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
5 l 8 -CH,-^R'°
in which R' ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof, provided that the compound shown below is excluded: a compound of the formula
Figure imgf000521_0001
wherein
R' ' is indolyl or benzofuranyl; R2' is hydrogen, lower alkylthio(lower)alkyl or a group of the formula
Figure imgf000521_0002
in which R5' is hydrogen, lower alkoxy or halogen; R31 is hydrogen, quinolyl or phenyl which may have a suitable substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen; R"' is hydrogen or optionally esterified carboxy; and X' is S or NR6' in which R6' is hydrogen, lower alkyl or a group of the formula
Figure imgf000521_0003
in which R7' is lower alkyl or lower alkoxy, and a pharmaceutically acceptable salt thereof.
2. A compound of the formula
5 l 9
Figure imgf000522_0001
wherein
R' is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
R2 is hydrogen or phenyl(lower)alkyl;
R* is phenyl or pyridyl, each of which has suitable substituent(s) selected from the group consisting of trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, or 3, 4-methylenedioxyphenyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
.R7 -C0-N
in which R7 and R8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or R" and R5 in combination form a group of the formula -CH=CH-CH=CH-
Y is a group of the formula
R3
I
-CH- in which R3 is hydrogen or a group of the formula -(CH2)n-R6 in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
R"
in which R' ' is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000523_0001
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000523_0002
in which R' ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2, wherein
R' is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro or benzofuranyl;
R2 is hydrogen;
R" is phenyl which may have suitable substituent(s) selected from the group consisting of trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkox (lower) lkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy;
R5 is hydrogen;
Y is a group of the formula
R3
I
-CH- in which R3 is hydrogen or a group of the formula
-(CHz)„-R6 in which R6 is pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, and n is an integer of 0 to 3; m is 0 or 1 ; and
X is NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
-CH^ R'°
in which R' ° is hydrogen, lower alkyl or lower alkoxy.
4. A compound of the formula
Figure imgf000525_0001
wherein
R' is indolyl which has a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
R2 is hydrogen or phenyl(lower)alkyl;
Rft is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen or quinolyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula R1 -C0-N
in which R7 and R8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
Ru and R5 in combination form a group of the formula -CH=CH-CH=CH-
Y is a group of the formula R3
I
-CH- in which R3 is hydrogen or a group of the formula -(CHz)n-R6 in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
R"
in which R' ' is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000526_0001
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000526_0002
in which R' ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
5. A compound of the formula
Figure imgf000527_0001
wherein
R' is indolyl or benzofuranyl;
R2 is hydrogen or phenyl(lower)alkyl;
Ru is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen or quinolyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
-C0-N β *η
in which R7 and R8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
R" and R5 in combination form a group of the formula -CH=CH-CH=CH-
Y is a group of the formula
R3
I
-CH- in which R3 is a group of the formula
-(CHz).-R6 in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, phenyl which has a suitable substituent selected from the group consisting of amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
R"
in which R" is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000528_0001
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000528_0002
in which R1 ° is hydrogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof.
6. A process for preparing a compound of the formula
Figure imgf000528_0003
wherein
R' is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazoly1, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl; .
R2 is hydrogen or phenyl(lower)alkyl;
Rα is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkylamino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, quinolyl or 3,4-methylenedioxyphenyl;
R5 is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)alkyl, optionally esterified carboxy or a group of the formula
Figure imgf000529_0001
in which R7 and R8 are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
R* and R5 in combination form a group of the formula -CH=CH-CH=CH-
Y is a group of the formula
R3
I
-CH- in which R3 is hydrogen or a group of the formula
-(CHz)n-R6 in which R6 is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)- alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3, or a group of the formula
R"
in which R" is phenyl, phenoxy or phenyl(lower)alkoxy; or R2 and R3 in combination form a group of the formula
Figure imgf000530_0001
m is 0 or 1 ; and X is S or NR9 in which R9 is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula
Figure imgf000530_0002
in which R' ° is hydrogen, lower alkyl or lower alkoxy; or a salt thereof, provided that the compound shown below is excluded: a compound of the formula
R
Figure imgf000530_0003
wherein
R" is indolyl or benzofuranyl;
R2' is hydrogen, lower alkylthio(lower)alkyl or a group of the formula
Figure imgf000531_0001
in which R5' is hydrogen, lower alkoxy or halogen; R3' is hydrogen, quinolyl or phenyl which may have a suitable substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio and halogen; Rft' is hydrogen or optionally esterified carboxy; and X' is S or NR6' in which R6' is hydrogen, lower alkyl or a group of the formula
Figure imgf000531_0002
in which R7' is lower alkyl or lower alkoxy, and a salt thereof, which comprises
(1 ) reacting a compound of the formula
Figure imgf000531_0003
wherein R2, R", R5, X, Y and m are each as defined above, or its reactive derivative at the amino group, or a salt thereof, with a compound of the formula
R' -COOH (III)
wherein R' is as defined above, or its reactive derivative at the carboxy group, or a salt thereof to give a compound of the formula
R'-C
Figure imgf000531_0004
wherein R' , R2, Ru, R5, X, Y and m are each as defined above, or a salt thereof, or
(2) reacting a compound of the formula
Figure imgf000532_0001
wherein R2, R*, R5, X, Y and m are each as defined above, or a salt thereof with a compound of the formula
Figure imgf000532_0002
to give a compound of the formula
Figure imgf000532_0003
wherein R2, R", R5, X, Y and m are each as defined above, or a salt thereof, or (3) subjecting a compound of the formula
Figure imgf000532_0004
wherein R2, Ru, R5, X, Y and m are each as defined above, R'* is amino protective group, and R' 5 is hydrogen or lower alkyl, or a salt thereof to elimination reaction of the amino protective group to give a compound of the formula
Figure imgf000532_0005
wherein R2, R*, R5, R' 5, X, Y and m are each as defined above, or a salt thereof, or (4) reacting a compound of the formula
Figure imgf000532_0006
wherein R2, Ru, R5, X, Y and m are each as defined above, or its reactive derivative at the amino group, or a salt thereof, with a compound of the formula
R'6-0H (VI)
wherein R16 is acyl, or its reactive derivative at the carboxy group, or a salt thereof to give a compound of the formula
Figure imgf000533_0001
wherein R2, R", R5, R1 , X, Y and m are each as defined above, or a salt thereof.
7. A pharmaceutical composition comprising the compound of Claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
8. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof as a medicament.
9. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof as a medicament for prophylactic or therapeutic treatment of NO-mediated diseases.
5 3 l
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