NEW INDOLYL AND BENZOFURANYL CARBOXAMIDES AS INHIBITORS OF NITRIC OXIDE PRODUCTION

Abstract: A compound of formula (I) wherein R<1> is indolyl or benzofuranyl; R<2> is hydrogen, lower alkylthio(lower)alkyl or a group of formula (1) in which 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<4> is hydrogen or optionally esterified carboxy; and X is S or NR<6> in which R<6> is hydrogen, lower alkyl or a group of formula (2) in which R<7> is lower alkyl or lower alkoxy, and a pharmaceutically acceptable salt thereof, which 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, and the like.

Description: DESCRIPTION NEW INDOLYL AND BENZOFURANYL CARBOXAMIDES AS INHIBITORS OF NITRIC OXIDE PRODUCTION 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 0 394 989 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 erythematosis, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, 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) : wherein R' is indolyl or benzofuranyl; R 2 is hydrogen, lower alkylthio(lower)alkyl or a group of the formula: in which 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; and X is S or NR 6 in which R 6 is hydrogen, lower alkyl or a group of the formula * . in which R 7 is lower alkyl or lower alkoxy. 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 H, carbon atom(s), unless otherwise provided. Suitable "lower alkyl" and "lower alkyl moiety" in the terms "lower alkylthio" and "lower alkylthio(lower)alkyl" 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, and in which more preferred one is Ci-C* alkyl. Suitable "lower alkoxy" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert- pentyloxy and hexyloxy, and in which more preferred one is Ci-Cn 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, U-chlorophenyl ester, U-methoxyphenyl ester, etc.). The object compound (I) of the present invention can be prepared by the following process. Process (1 ) wherein R' , R 2 , R 3 , R* and X are each as defined above. The starting compounds can be prepared by the method of Preparation mentioned below or by a process known in the art for preparing structually analogous compounds thereto. The process for preparing the object compound is 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 carboxy group, or a salt thereof. Suitable reactive derivative of the compound (II) includes Schiffs 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 [(CfohN^CH-] 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, l-hydroxy-2- (IH)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N- hydroxyphthalimide, 1-hydroxy-6-chloro-lH-benzotriazole, etc. ) . 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 1 -(3-dimethylatninopropyl)- 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-lH-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. 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 erythematosis, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, and the like in human being and animals. 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 Compound : Test : Assay for inhibitory activity on the production of nitric oxide The murine macrophage cell line RAW264.7 (American Type Culture Collection, No. TIB71 ) 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 ] 0% 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 (10 s 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 μg/ml) and interferon γ (INF r ) (3 u/ml) for 18-24 hours. An equal volume of Griess reagent { } % sulfanilamide/0.1# N-naphthylethylenediamine dihydrochloride/2.5% foPOu) was added and the cells were incubated at room temperature for 10 minutes. The absorbance was read at 570 nm using microplate reader and NO2 ' was measured using NaN0 2 as a standard. Test result : 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 or suppository, 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 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 t-butoxycarbonyl Et ethyl Me methyl Ph phenyl Ts p-toluenesulfonyl 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 Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table Table 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 l-(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 (CDCl 3 ,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 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) + 'H-NMR (CDC1 3 ,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) + 'H-NMR (CDCl3,300MHz)f5 : 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 (2.12 g) in tetrahydrofuran (20 ml) was added successively isobutyl chloroformate (1.1 ml) and N-methylmorpholine (0.9 ml) at -25°C, and the mixture was stirred at the temperature for 5 minutes. The above mixture was added to a solution of dl-2-benzoylglycine ethyl ester hydrochloride (2.05 g) and N-methylmorpholine (0.9 ml) in tetrahydrofuran (5 ml) at -20°C, and the mixture was allowed to warm to room temperature for 2 hours. Water was added to the mixture, and 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, hexane/ ethyl acetate=3/1 ) to give the object compound as an oil (2.36 g). MASS (ESI) (m/z) : 455 (M+H) + 'H-NMR (CDC1 3 ,300MHZ) <5 : 1.13(3H,t,J=7Hz) , 1.41 (9H,s), 2.95-3.21 (2H,m), 4.13(2H,q,J=7Hz), 4.38-4.60(1H,m), 4.83-5.05(1H,m), 6.02-6.20(1H,m), 7.10-7.37(6H,m), 7.42-7.71 (3H,m), 8.01-8.18(2H,m) Preparation 5 The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 450 (M+H) + 1 H-NMR (CDCl 3 ,300MHz)<5 : 1.12(3H,t,J=7Hz) , 1.40(9H,s), 2.68(3H,s), 3.08-3.42(2H,m), 4.21 (2H,q,J=7Hz), 4.89-5.05(1H,m), 5.77(1H,br d,J=8Hz), 6.96-7.48(10H,m) Preparation 6 The object compound was obtained according to a similar manner to that of Preparation 3. MASS (ESI) (m/z) : 350 (M+H) + 1 H-NMR (CDC13,300MHz) δ ' 1.08(3H,t,J=7Hz) , 2.80(3H,s), 3.21-3.48(2H,m), 4.15(2H,q,J=7Hz), 4.25-4.72(3H,m), 7.00-7.48(10H,m) Preparation 7 The object compound was obtained according to a similar manner to that of Preparation 1. MASS (ESI) (m/z) : 413 (M+H) + 1 H-NMR (CDC13,300MHz) <5 : 1.41 (9H,s), 3.05(2H,d,J=6Hz) , 3.75(3H,s), 4.43(1H,br s), 4.58-4.81 (2H,m), 5.05(1H,br s), 6.81(2H,d,J=8Hz), 6.91 (1H,br s), 7.12(2H,d,J=8Hz) , 7.42-7.68(3H,m), 7.95(2H,d,J=7Hz) Preparation 8 The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 408 (M+H) + 1 H-NMR (CDC13,300MHz) δ : 1.42(9H,s), 3.00-3.33(2H,m) , 3.02(3H,s), 3.77(3H,s), 4.89-5.04(1H,m) , 5.63(1H,d,J=8Hz), 6.76(2H,d,J=8Hz) , 6.94(2H,d,J=8Hz) , 7.02(1H,s), 7.18-7.45(5H,m) Preparation 9 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) + 1 H-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 10 The object compound was obtained according to a similar manner to that of Preparation 1. MASS (ESI) (m/z) : 491,493 (M+H) + 1 H-NMR (CDCl 3 ,300MHz) f5 : 1.41(9H,s), 3.04(2H,d,J=6Hz) , 3.75(3H,s), 4.42(lH,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 11 The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 486,488 (M+H) + 1 H-NMR (CDCl 3 ,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 12 The object compound was obtained according to a similar manner to that of Preparation 9. MASS (ESI) (m/z) : 386,388 (M+H) + 'H-NMR (CDCl 3 ,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 13 The object compound was obtained according to a similar manner to that of Preparation 1. MASS (ESI) (m/z) : 429 (M+H) + 1 H-NMR (CDC13,300MHz) δ : 1.41 (9H,s), 2.52(3H,s), 2.99-3.21 (2H,m), 4.48(1H,br s) , 4.53-4.79(2H,m) , 5.03(1H,br s), 6.90(1H,br s) , 7.13-7.25(7H,m) , 7.83(2H,d,J=8Hz) Preparation 14 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 (CDCl 3 ,300MHz)0 : 1.40(9H,s), 2.50(3H,s), 2.94(3H,s), 3.00-3.40(2H,m), 4.90-5.10(lH,m), 5.59(1H,br d,J=8Hz), 6.95-7.35(10H,m) Preparation 15 The object compound was obtained according to a similar manner to that of Preparation 9. MASS (ESI) (m/z) : 324 (M+H) + 1 H-NMR (CDCl3,300MHz)<5 : 2.50(3H,s), 3.08-3.27(2H,m) , 3.17(3H,s), 4.16(1H,t,J=7Hz), 7.03(1H,s), 7.05-7.35(9H,m) Preparation 16 The . object compound was obtained according to a similar manner to that of Preparation 1. MASS (ESI) (m/z) : 495, 497 (M+H) + 1 H-NMR (CDC13,300MHz) δ : 1.40(9H,s), 2.98-3.20(2H,m), 4.47(1H,m), 4.55-4.78(2H,m), 5.10(1H,br d,J=8Hz) , 7.01(1H,br s), 7.14(2H,d,J=8Hz), 7.25(2H,d,J=8Hz) , 7.64(2H,d,J=8Hz) , 7.81 (2H,d,J=8Hz) Preparation 17 The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 490, 492 (M+H) + 1 H-NMR (CDCl 3 ,300MHz)<5 : 1.39(9H,s), 3.12(3H,s), 3.13-3.22(2H,m), 4.91-5.08(1H,m), 5.47(1H,br d,J=9Hz) , 6.90-7.30(7H,m), 7.52(2H,d,J=8Hz) Preparation 18 The object compound was obtained according to a similar manner to that of Preparation 9. MASS (ESI) (m/z) : 390, 392 (M+H) + 1 H-NMR (CDCl3,300MHz) (5 : 3.02-3.26(2H,m), 3.27(3H,s), 4.1l(1H,t,J=7Hz), 7.02(2H,d,J=8Hz), 7.03(1H,s), 7.15(2H,d,J=8Hz), 7.22(2H,d,J=8Hz), 7.53(2H,d,J=8Hz) Preparation 19 The object compound was obtained according to a similar manner to that of Preparation 1. amorphous solid MASS : 461 (M+1 ) 'H-NMR (CDC1 3 ) δ : 1.39(9H,s), 3.00-3.20(2H,m) , 4.40-4.78(3H,m), 5.03(1H,bs), 6.89(lH,bs), 7.19-7.38(5H,m) , 7.63(2H,d,J=8Hz), 7.82(2H,d,J=8Hz) Preparation 20 The object compound was obtained according to a similar manner to that of Preparation 2. mp : 162-164°C MASS : 456 (M+1) 1 H-NMR (CDCI3) 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), 4.91-5.08(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 21 The object compound was obtained according to a similar manner to that of Preparation 3. oil MASS : 356 (M+1) 1 H-NMR (CDCI3) 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), 7.14(2H,d,J=8Hz), 7.20-7.32(3H,m) , 7.53(2H,d,J=8Hz) Preparation 22 The object compound was obtained according to a similar manner to that of Preparation 1. amorphous solid MASS : 417 (M+1) 1 H-NMR (CDC1 3 ) 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 23 The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 412 (M+1) 'H-NMR (CDCls) δ ' 1.41 (9H,s), 2.92(3H,s), 3.00-3.20(lH,m) , 3.24-3.40(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 24 The object compound was obtained according to a similar manner to that of Preparation 3. oil MASS : 312 (M+1) 'H-NMR (CDCI3) 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 25 The object compound was obtained according to a similar manner to that of Preparation 1. mp : 135-139°C MASS : 397 (M+1) 1 H-NMR (CDCI3) δ : 1.41 (9H,s), 2.41 (3H,s), 3.00-3.20(2H,m) , 4.50(1H,d,J=5Hz), 4.57-4.78(2H,m), 5.07(1H,d,J=5Hz), 6.91 (1H,s), 7.18-7.33(7H,m), 7.83(2H,d,J=8Hz) Preparation 26 The object compound was obtained according to a similar manner to that of Preparation 2. mp : 131-133°C MASS : 392 (M+1) 'H-NMR (CDC1 3 ) δ : 1.39(9H,s), 2.38(3H,s), 2.97(3H,s), 3.11(1 x 1/3H,d,J=8Hz), 3.17(1 x 2/3H,d,J=8Hz), 3.31(1 x 2/3H,d,J=8Hz), 3.36(1 x 1/3H,d,J=8Hz) , 4.93-5.08(lH,m), 5.59(1H,d,J=8Hz), 7.00(1H,s), 7.01-7.09(2H,m), 7.09-7.16(2H,m), 7.16-7.28(5H,m) Preparation 27 The object compound was obtained according to a similar manner to that of Preparation 3. oil MASS : 292 (M+1) 'H-NMR (CDCI3) δ : 2.37(3H,s), 3.10-3.27(2H,m), 3.19(3H,s), 4.17(1H,t,J=8Hz), 7.01 (1H,s), 7.09(2H,d,J=8Hz) , 7.12-7.33(7H,m) Preparation 28 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) + 'H-NMR (CDC13,300MHz ) δ : 1.41(9H,s), 2.96-3.20(2H,m) , 4.47(1H,m), 4.70(2H,AB of ABX,J AB =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 29 The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 412 (M+H) + 'H-NMR (CDCl 3 ,300MHz)f5 : 1.40(9H,s), 3.13(3H,s), 3.15-3.32(2H,m), 4.92-5.07(1H,m), 5.58(1H,br d,J=8Hz), 6.93-7.55(1OH,m) Preparation 30 The object compound was obtained according to a similar manner to that of Preparation 3. MASS (ESI) (m/z) : 312 (M+H) + 'H-NMR (CDC13,300MHz) δ : 3.06-3.25(2H,m) , 3.24(3H,s), 4.17(1H,t,J=7Hz), 6.98-7.50(1OH,m) Preparation 31 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 : 180.5-184°C MASS : 288 (M+H) + 1 H-NMR (CDCl a ) δ : 1.40(9H,s), 3.29(2H,d,J=7.5Hz) , 4.90(lH,q,J=7.5Hz), 5.25(1H,bd,J=7.5Hz) , 6.89(1H,bs), 6.99(lH,bs), 7.12(2H,d,J=7.5Hz), 7.18-7.30(3H,m), 9.78(1H,bs) Preparation 32 To a precooled solution of the starting compound (500 mg) in N,N- dimethylformamide (5 ml) was added 85% potassium hydroxide powder (115 mg). After the mixture was stirred for 1 hour on an ice bath, α- chloro-p-xylene (230.4 #1) was added dropwise to the reaction mixture. The resulting suspension was stirred at 5°C for 14 hours, then poured into water, and extracted with chloroform. The organic layer was washed twice with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was washed with diethyl ether to give the object compound as a colorless solid (418.3 mg). mp : 157-158.5°C MASS : 392 (M+H) + 'H-NMR (CDCI3) δ : 1.36(9H,s), 2.30(3H,s), 3.l9(2H,m), 4.63(1H,d,J=16.0Hz), 4.71 (1H,d,J=16.0Hz) , 5.01 (1H,m), 5.32(1H,m), 6.63(1H,s), 6.77(2H,d,J=7.5Hz) , 6.98-7.23(8H,m) Preparation 33 The object compound was obtained according to a similar manner to that of Preparation 3. colorless oil MASS : 292 (M+H) + 'H-NMR (CDCI3) δ : 2.31 (3H,s), 3.02(1H,dd,J=13.5 and 7.5Hz), 3.12(1H,dd,J=13.5 and 7.5Hz), 4.06(1H,t,J=7.5Hz) , 4.76(1H,d,J=14.5Hz), 4.83(1H,d,J=14.5Hz) , 6.71 (1H,s), 6.86(2H,d,J=7.5Hz), 6.99-7.04(3H,m) , 7.10(2H,d,J=7.5Hz), 7.20-7.30(3H,m) Preparation 34 The object compound was obtained according to a similar manner to that of Preparation 1. white crystals mp : 134-135°C MASS (ESI) (m/z) : 383 (M+H) + 1 H-NMR (CDCl 3 ,300MHz) δ : 1.41(9H,s), 3.00-3.22(2H,m) , 4.47(1H,m), 4.69(2H,AB of ABX, J AB =19Hz), 5.03(1H,br s), 6.90(1H,br s), 7.16-7.68(8H,m), 7.95(2H,d,J=8Hz) Preparation 35 The object compound was obtained according to a similar manner to that of Preparation 2. white crystals mp : 130-1311: MASS (ESI) (m/z) : 378 (M+H) 4 'H-NMR (CDC13,300MHz) c5 : 1.41(9H,s), 2.96(3H,s), 3.06-3.20(1H,m), 3.28-3.40(1H,m) , 4.92-5.06(1H,m) , 5.57(lH,br d,J=9Hz), 7.00-7.43(11H,m) Preparation 36 The object compound was obtained according to a similar manner to that of Preparation 3. white powder MASS (ESI) (m/z) : 278 (M+H) + 'H-NMR (CDCl 3 ,300MHz)(5 : 3.10-3.28(2H,m) , 3.18(3H,s), 4.16(1H,t,J=7Hz), 7.05(1H,s), 7.07-7.45(10H,m) Preparation 37 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 : 1 16-1 19°C MASS (ESI) (m/z) : 302 (M+H) + ' H-NMR (CDCI3 , 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 38 The object compound was obtained according to a similar manner to that of Preparation 3. yellow oil MASS (ESI) (m/z) : 202 (M+H) + 'H-NMR (CDCI3, δ ) 3.09(1H,dd,J=14.5, 7.5Hz), 3.l3(1H,dd,J=14.5, 7.5Hz), 3.23(3H,s), 4.12(1H,t,J=7.5Hz) , 6.69(1H,s), 6.99(1H,s), 7.03(2H,d,J=7.5Hz), 7.16-7.32(3H,m) Preparation 39 The object compound was obtained according to a similar manner to that of Preparation 3. yellow oil MASS (ESI) (m/z) : 188 (M+H) 4 'H-NMR (CDCI3, δ ) 2.82(1H,dd,J=14.5, 8.5Hz), 3.37(1H,dd,J=14.5, 2.5Hz), 4.35(1H,dd,J=8.5, 2.5Hz), 6.99(2H,s), 7.12(2H,d,J=7.5Hz), 7.20-7.34(4H,m) Preparation 40 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(1H,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 41 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) + 1 H-NMR (CDC1 3 , 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), 8.18(1H,d,J=7.5Hz) , 8.95(1H,d,J=4.5Hz) Preparation 42 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-de, 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(lH,d,J=7.5Hz), 8.97(lH,s), 9.20(1H,d,J=5.5Hz) Preparation 43 The object compound was obtained according to a similar manner to that of Preparation 28. pale yellow solid MASS (ESI) (m/z) : 434 (M+H) + 1 H-NMR (CDC13, δ ) 1.42(9H,s), 3.15(2H,d,J=7.5Hz), 4.50(1H,m), 4.80(1H,dd,J=20.5, 5.5Hz), 4.89(1H,dd,J=20.5, 5.5Hz), 5.03(1H,m), 6.95(1H,m), 7.19-7.35(5H,m), 7.52(lH,dd,J=7.5, 5.5Hz), 8.16-8.27(2H,m), 8.30(1H,d,J=7.5Hz), 8.48(1H,s), 9.07(1H,d,J=5.5Hz) Preparation 44 The object compound was obtained according to a similar manner to that of Preparation 2. pale violet amorphous solid MASS (ESI) (m/z) : 429 (M+H) + 'H-NMR (CDCI3, δ ) 1.42(9H,s), 3.05(3H,s), 3.18(1H,dd,J=13.5, 8.5Hz), 3.37(1H,dd,J=13.5, 6.0Hz), 5.03(1H,m), 5.59(lH,br d,J=7.5Hz), 7.03-7.11 (2H,m), . 7.18(lH,s), 7.20-7.31 (3H,m), 7.44(1H,dd,J=7.5, 5.5Hz), 7.57(1H,d,J=7.5Hz), 7.70(1H,s), 8. l5(2H,t,J=7.5Hz) , 8.95(1H,d,J=5.5Hz) Preparation 45 The object compound was obtained according to a similar manner to that of Preparation 3. pale yellow oil MASS (ESI) (m/z) : 329 (M+H) + 'H-NMR (CDCI3, δ ) 3.13-3.30(2H,m), 3.27(3H,s), 4.20(1H,t,J=7.5Hz), 7.08-7.15(2H,m) , 7.18(1H,s), 7.21-7.34(3H,m) 7.43(1H,dd,J=7.5, 5.5Hz) 7.63(1H,d,J=7.5Hz) , 7.73(1H,s), 8.15(2H,t,J=7.5Hz), 8.93(lH,d,J=5.5Hz) Preparation 46 The object compound was obtained according to a similar manner to that of Preparation 40. off-white solid mp : 205-208°C MASS (ESI) (m/z) : 187 (M+H) + 1 H-NMR (CDCI3-CD3OD, δ ) 2.40(3H,s), 7.59(1H,t,J=7.5Hz), 7.73(lH,t,J=7.5Hz), 7.87(1H,d,J=7.5Hz), 8.l0(1H,d,J=7.5Hz), 8.28(1H,d,J=1.0Hz), 9.46(1H,d,J=1.0Hz) Preparation 47 The object compound was obtained according to a similar manner to that of Preparation 41. pale brown solid mp : 165-174°C MASS (ESI) (m/z) : 341 (M+H) + 1 H-NMR (CDCI3, δ ) 2.44(3H,s), 2.47(3H,s), 7.39(1H,d,J=7.5Hz), 7.60(1H,t,J=7.5Hz), 7.79(lH,t,J=7.5Hz) , 7.85(lH,d,J=7.5Hz) , 7.98(2H,d,J=7.5Hz), 8.11 (1H,d,J=7.5Hz) , 8.28(lH,d,J=l .5Hz), 9.l4(1H,d,J=1.5Hz) Preparation 48 The object compound was obtained according to a similar manner to that of Preparation 42. off-white solid mp : 290-294°C MASS (ESI) (m/z) : 187 (M+H) + 1 H-NMR (DMSO-de, δ ) 4.75(1H,d,J=5.5Hz) , 4.79(1H,d,J=5.5Hz), 7.80(1H,t,J=7.5Hz), 8.02(1H,t,J=7.5Hz) , 8.18(lH,d,J=7.5Hz) , 8.25(1H,d,J=7.5Hz), 8.61 (2H,br s) , 9.27(lH,d,J=1.0Hz) , 9.41(1H,d,J=1.0Hz) Preparation 49 The object compound was obtained according to a similar manner to that of Preparation 28. pale yellow amorphous solid MASS (ESI) (m/z) : 434 (M+H) + 'H-NMR (CDCI3, δ ) 1.43(9H,s), 3.10-3.19(2H,m) , 4.51 (1H,m), 4.79(1H,dd,J=20.5, 4.5Hz), 4.88(1H,dd,J=20.5, 4.5Hz), 5.03(1H,m), 6.93(lH,m), 7.17-7.34(5H,m), 7.69(1H,t,J=7.5Hz), 7.90(1H,t,J=7.5Hz), 7.97(1H,d,J=7.5Hz), 8.18(1H,d,J=7.5Hz) , 8.73(1H,d,J=1.0Hz), 9.40(1H,d,J=l .0Hz) Preparation 50 The object compound was obtained according to a similar manner to that of Preparation 2. pale brown amorphous solid MASS (ESI) (m/z) : 429 (M+H) + 'H-NMR (CDCI3, δ ) 1.45(9H,s), 3.03(3H,s), 3.l7(1H,dd,J=13.0, 9.0Hz), 3.39(1H,dd,J=13.0, 5.5Hz), 5.05(lH,m), 5.63(1H,d,J=7.5Hz), 7.03-7.12(2H,m) , 7.19-7.38(4H,m), 7.60(1H,t,J=7.5Hz) , 7.76(1H,t,J=7.5Hz) , 7.83(1H,d,J=7.5Hz), 8.00(1H,d,J=l .0Hz) , 8.12(1H,d,J=7.5Hz) , 8.80(1H,d,J=1.0Hz) Preparation 51 The object compound was obtained according to a similar manner to that of Preparation 3. pale brown amorphous solid MASS (ESI) (m/z) : 329 (M+H) + 'H-NMR (CDCI3, δ ) 3.18-3.25(2H,m), 3.22(3H,s), 4.21(1H,t,J=7.5Hz), 7.06-7.13(2H,m) , 7.20-7.36(4H,m), 7.60(1H,t,J=7.5Hz), 7.76(1H,t,J=7.5Hz) , 7.83(1H,d,J=7.5Hz) , 8.04(1H,d,J=1.5Hz), 8.12(1H,d,J=7.5Hz) , 8.83(1H,d,J=1.5Hz) Preparation 52 The object compound was obtained according to a similar manner to that of Preparation 1. mp : 1414-146°C MASS : 413 (M+1) 'H-NMR (CDCI3) δ : 1.41 (9H,s), 3.00-3.20(2H,m) , 3.87(3H,s), 4.49(1H,d,J=5Hz), 4.53-4.74(2H,m) , 5.08(lH,d,J=5Hz), 6.95(3H,d,J=8Hz) , 7. l9~7.32(5H,m) , 7.92(2H,d,J=8Hz) Preparation 53 The object compound was obtained according to a similar manner to that of Preparation 2. mp : 125-128°C MASS : 408 (M+1) 'H-NMR (CDC1 3 ) δ : 1.38(9H,s), 2.93(3H,s), 3.11(1 xl/3H,d,J=8Hz), 3.17(1 X2/3H,d,J=8Hz), 3.31(1 x2/3H,d,J=6Hz), 3.37(1 x l/3H,d,J=6Hz), 3.83(3H,s), 4.99(1H,q,J=8Hz), 5.59(1H,d,J=8Hz), 6.92(2H,d,J=8Hz), 6.98(1H,s), 7.00-7.10(2H,m) 7.14(2H,d,J=8Hz), 7.20-7.30(3H,m) Preparation 54 The object compound was obtained according to a similar manner to that of Preparation 3. oil MASS : 308 (M+1) 'H-NMR (CDCI3) δ : 3.08-3.28(2H,m), 3.12(3H,s), 3.81 (3H,s), 4.17(1H,t,J=8Hz), 6.94(2H,d,J=8Hz), 6.99(lH,s), 7.09(2H,d,J=8Hz), 7.11-7.40(5H,m) Preparation 55 The object compound was obtained according to a similar manner to that of Preparation 32. colorless solid mp : 144-150°C MASS (ESI) (m/z) : 408 (M+H) + 'H-NMR (CDCI3, δ ) 1.37(9H,s), 3.20(2H,m), 3.78(3H,s), 4.59(1H,d,J=14.5Hz), 4.70(1H,d,J=14.5Hz), 5.03(1H,m), 5.35(1H,m), 6.61 (1H,s), 6.76(2H,d,J=9.0Hz), 6.81(2H,d,J=9.0Hz), 6.97-7.06(3H,m) , 7.17-7.23(3H,m) Preparation 56 The object compound was obtained according to a similar manner to that of Preparation 3. off-white oil MASS (ESI) (m/z) : 308 (M+H) + 'H-NMR (CDCI3, δ ) 3.03(1H,dd,J=l4.5, 7.5Hz), 3.14(1H,dd,J=14.5, 7.5Hz), 3.77(3H,s), 4.09(1H,t,J=7.5Hz), 4.73(1H,d,J=15.0Hz), 4.81 (1H,d,J=15.0Hz), 6.71 (1H,s), 6.81(2H,d,J=7.5Hz), 6.91 (2H,d,J=7.5Hz), 7.01-7.07(3H,s), 7.19-7.30(3H,m) Preparation 57 The object compound was obtained according to a similar manner to that of Preparation 28. pale yellow oil MASS (ESI) (m/z) : 367 (M+H) + 1 H-NMR (CDCI3, δ ) 1.47(9H,s), 1.98(1H,m), 2.13(3H,s), 2.16(1H,m), 2.61(2H,t,J=7.5Hz), 4.41 (1H,m), 4.77(2H,t,J=4.5Hz), 5.23(1H,m), 7.14(1H,m), 7.50(2H,t,J=7.5Hz), 7.63(1H,t,J=7.5Hz) , 7.98(2H,d,J=7.5Hz) Preparation 58 The object compound was obtained according to a similar manner to that of Preparation 2. pale brown oil MASS (ESI) (m/z) : 362 (M+H) + 'H-NMR (CDCI3, δ ) 1.43(9H,s), 2.12(3H,s), 2.12-2.61 (4H,m) , 3.63(3H,s), 5.05-5.26(2H,m), 7.01 (1H,s), 7.33-7.51 (5H,m) Preparation 59 The object compound was obtained according to a similar manner to that of Preparation 3. pale yellow oil MASS (ESI) (m/z) : 262 (M+H) + 'H-NMR (CDCI3, δ ) 2.08(1H,m), 2.11 (3H,s), 2.25(1H,m), 2.55-2.77(2H,m), 3.61 (3H,s), 4.20(1H,t,J=7.5Hz) , 7.01 (1H,s), 7.33-7.48(5H,m) Preparation 60 To a solution of the starting compound (893 mg) in tetrahydrofuran (4.5 ml) was added 2,4-bis(4-methoxyphenyl)-1 ,3- dithia-2,4-diphosphetane-2,4-disulfide (552 mg). The mixture was stirred at 50°C for 4.5 hours, then allowed to cool to room temperature and concentrated. The crude product was purified by column chromatography (silica gel, chloroform) to give the object compound as pale orange powder (476 mg). MASS (ESI) (m/z) : 489, 491 (M+H) + 'H-NMR (CDCl 3 ,300MHz) <5 : 1.41 (9H,s), 3.12-3.32(2H,m) , 3.76(3H,s), 5.11-5.31 (2H,m), 6.80(2H,d,J=8Hz), 7.02(2H,d,J=8Hz), 7.36(2H,d,J=8Hz) , 7.50(2H,d,J=8Hz) , 7.87(1H,s) Preparation 61 The object compound was obtained according to a similar manner to that of Preparation 9. MASS (ESI) (m/z) : 389,391 (M+H) + 'H-NMR (CDC13,300MHz) δ : 2.84(1H,dd,J=13 and 9Hz) , 3.31(1H,dd,J=13 and 5Hz), 3.78(3H,s), 4.46(1H,dd,J=9 and 5Hz), 6.86(2H,d,J=8Hz) , 7.13(2H,d,J=8Hz), 7.40(2H,d,J=8Hz), 7.51 (2H,d,J=8Hz), 7.88(1H,s) Preparation 62 The object compound was obtained according to a similar manner to that of Preparation 28. mp : 140-143°C MASS : 427 (M+1) 'H-NMR (CDC1 3 ) δ 1.38(9H,s), 1.43(3H,t,J=8Hz), 3.00-3. l9(2H,m) , 4.11(2H,q,J=8Hz), 4.40-4.72(3H,m) , 4.96-5.10(1H,m), 6.90(1H,br s), 6.92(2H,d,J=8Hz), 7.13-7.35(5H,m), 7.91(2H,d,J=8Hz) Preparation 63 The object compound was obtained according to a similar manner to that of Preparation 2. mp : 86-91°C MASS : 422 (M+1) 'H-NMR (CDC1 3 ) δ 1.41 (9H,s), 1.42(3H,t,J=8Hz), 2.92(3H,s), 3.11(1 xi/3H,d,J=10Hz), 3.18(1 x2/3H,d,J=10Hz), 3.31(1 x2/3H,d,J=6Hz), 3.36(1 x 1/3H,d,J=6Hz), 4.05(2H,q,J=8Hz), 5.00(1H,q,J=8Hz), 5.60(1H,d,J=8Hz) , 6.91(2H,d,J=8Hz), 6.99(1H,s), 7.00-7.09(2H,m) , 7.13(2H,d,J=8Hz), 7.l9-7.25(3H,m) Preparation 64 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) 'H-NMR (CDCI3) 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 65 The object compound was obtained according to a similar manner to that of Preparation 28. amorphous solid MASS : 411 (M+1) 'H-NMR (CDCI3) δ 1.29(3H,t,J=8Hz), 1.40(9H,s), 2.71(2H,q,J=8Hz), 3.00-3.20(2H,m) , 4.40-4.53(1H,m), 4.58-4.80(2H,m), 5.00-5.15(1H,m) , 6.94(lH,s), 7.12-7.40(7H,m) , 7.88(2H,d,J=8Hz) Preparation 66 The object compound was obtained according to a similar manner to that of Preparation 2. oil MASS : 406 (M+1) 'H-NMR (CDCI3) δ 1.22(3H,t,J=8Hz), 1.40(9H,s), 2.67(2H,q,J=8Hz) , 2.93(3H,s), 3.08-3.20(1H,m), 3.30-3.40(1H,m), 5.00(1H,q,J=8Hz), 5.69(1H,d,J=8Hz), 7.00(1H,s), 7.01-7.10(2H,m), 7.10-7.18(2H,m), 7.18-7.32(5H,m) Preparation 67 The object compound was obtained according to a similar manner to that of Preparation 64. oil MASS : 306 (M+1) 'H-NMR (CDCI3) δ 1.30(3H,t,J=8Hz), 2.68(2H,q,J=8Hz) , 3.09-3.28(2H,m), 3.18(3H,s), 4.13(1H,t,J=8Hz) , 7.01 (lH,s), 7.04-7.10(2H,m), 7.12-7.30(7H,m) Preparation 68 The object compound was obtained according to a similar manner to that of Preparation 28. oil MASS : 447 (M+1) 'H-NMR (CDCI3) δ 1.40(9H,s), 3.02(2H,d,J=6Hz), 3.76(3H,s), 4.33-4.47(1H,m), 4.50-4.71 (2H,m) , 4.91-5.30(1H,m) , 6.72-6.80(1H,m), 6.81 (2H,d,J=8Hz) , 7.11 (2H,d,J=8Hz), 7.30-7.40(1H,m), 7.4l-7.48(2H,m), 7.51 (1H,d,J=8Hz) Preparation 69 The object compound was obtained according to a similar manner to that of Preparation 2. oil MASS : 442 (M+1) 'H-NMR (CDCI3) δ 1.47(9H,s), 2.86(3H,s), 3.01-3. !2(1H,m), 3.22-3.31 (1H,m), 3.73(3H,s), 4.89-5.00(lH,m), 5.61(1H,d,J=8Hz), 6.73(2H,d,J=8Hz), 6.97(2H,d,J=8Hz), 7.00(1H,s), 7.20-7.39(3H,m), 7.44(lH,d,J=8Hz) Preparation 70 The object compound was obtained according to a similar manner to that of Preparation 64. oil MASS : 342 (M+1) 'H-NMR (CDCls) δ 3.04(3H,s), 3.08-3.17(2H,m), 3.75(3H,s), 4.11(1H,t,J=8Hz), 6.80(2H,d,J=8Hz), 7.00(2H,d,J=8Hz), 7.01 (1H,s), 7.21-7.40(3H,m), 7.47(1H,d,J=7Hz) Preparation 71 The object compound was obtained according to a similar manner to that of Preparation 28. mp : 115-122°C MASS : 427 (M+1) 'H-NMR (CDC1 3 ) δ 1.42(9H,s), 2.42(3H,s), 3.07(2H,d,J=7Hz) , 3.76(3H,s), 4.38-4.50(1H,m), 4.58-4.77(2H,m), 4.98-5.10(1H,m), 6.81(2H,d,J=8Hz), 6.87-6.92(1H,m) , 7.11 (2H,d,J=8Hz) , 7.29(2H,d,J=8Hz), 7.85(2H,d,J=8Hz) Preparation 72 The object compound was obtained according to a similar manner to that of Preparation 2. oil MASS : 422 (M+1) 'H-NMR (CDCI3) δ 1.42(9H,s), 2.38(3H,s), 2.99(3H,s), 3.01-3.18(1H,m), 3.20-3.30(1H,m), 3.71(3H,s), 4.93(1H,q,J=8Hz), 5.58(1H,d,J=8Hz) , 6.73(2H,d,J=8Hz) , 6.93(2H,d,J=8Hz), 7.00(1H,s), 7.11 (2H,d,J=7Hz), 7.20(2H,d,J=7Hz) Preparation 73 The object compound was obtained according to a similar manner to that of Preparation 64. oil MASS : 322 (M+1) 'H-NMR (CDCI3) δ 2.39(3H,s), 3.10(1H,t,J=8Hz) , 3.19(3H,s), 3.80(3H,s), 4.12(lH,t,J=8Hz), 6.81 (2H,d,J=8Hz), 7.00(2H,d,J=8Hz), 7.01 (1H,s), 7.12-7.23(5H,m) Preparation 74 The object compound was obtained according to a similar manner to that of Preparation 28. mp : 105-108°C MASS : 447 (M+1) 'H-NMR (CDC1 3 ) δ 1.40(9H,s), 3.06(2H,d,J=7Hz) , 3.79(3H,s), 4.41(1H,br s), 4.58-4.77(2H,m) , 4.99(lH,br s), 6.81(2H,d,J=8Hz), 6.83(1H,s), 7.12(2H,d,J=8Hz), 7.49(2H,d,J=7Hz), 7.90(2H,d,J=7Hz) Preparation 75 The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid 'H-NMR (CDCI3) δ 1.40(9H,s), 2.98-3.13(1H,m), 3.00(3H,s), 3.21-3.32(1H,m), 3.78(3H,s), 4.90-5.02(1H,m), 5.57(1H,d,J=8Hz), 6.78(2H,d,J=8Hz), 6.93(2H,d,J=8Hz) , 7.02(1H,s), 7.18(2H,d,J=8Hz), 7.38(2H,d,J=8Hz) Preparation 76 The object compound was obtained according to a similar manner to that of Preparation 64. oil 'H-NMR (CDCI3) δ 3.11(2H,t,J=7Hz), 3.19(3H,S), 3.80(3H,s), 4.l1(1H,t,J=8Hz), 6.80(2H,d,J=8Hz), 7.00(2H,d,J=8Hz) , 7.02(1H,s), 7.20(2H,d,J=8Hz), 7.38(2H,d,J=8Hz) Preparation 77 The object compound was obtained according to a similar manner to that of Preparation 28. amorphous solid MASS : 447 (M+1) 'H-NMR (CDCI3) <5 1.40(9H,s), 3.07(2H,d,J=6Hz), 3.73(3H,s), 4.42(1H,br s), 4.58-4.80(2H,m) , 5.01 (1H,br s), 6.81(2H,d,J=8Hz), 6.84(1H,br s), 7.11 (2H,d,J=8Hz), 7.42(1H,t,J=8Hz), 7.59(1H,d,J=8Hz), 7.81 (lH,d,J=8Hz), 7.91 (1H,s) Preparation 78 The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 442 (M+1) 'H-NMR (CDC1 3 ) δ 1.43(9H,s), 3.00(3H,s), 3.11-3.32(2H,m), 3.79(3H,s), 4.9l-5.03(1H,m), 5.88(1H,br s) , 6.78(2H,d,J=8Hz), 6.93(2H,d,J=8Hz), 7.03-7.19(2H,m) , 7.21 (1H,s), 7.30-7.40(2H,m) Preparation 79 The object compound was obtained according to a similar manner to that of Preparation 64. oil MASS : 342 (M+1) 'H-NMR (CDCI3) δ 3.07-3.20(2H,m), 3.18(3H,s), 3.78(3H,s), 4.20(1H,t,J=8Hz), 6.80(2H,d,J=8Hz), 6.99(2H,d,J=8Hz) , 7.09(1H,s), 7.11-7.21 (1H,m), 7.28(1H,s), 7.30-7.40(2H,m) Preparation 80 The object compound was obtained according to a similar manner to that of Preparation 28. mp : 120-123°C MASS : 431 (M+1) 'H-NMR (CDCI3) δ 1.43(9H,s), 3.08(2H,d,J=8Hz), 3.76(3H,s), 4.42(1H,br s), 4.58-4.78(2H,m) , 5.00(1H,br s), 6.82(2H,d,J=8Hz), 6.87(lH,s), 7.10-7.22(4H,m), 8.00(2H,t,J=7Hz) Preparation 81 The object compound was obtained according to a similar manner to that of Preparation 2. amorphous solid MASS : 426 (M+1) 'H-NMR (CDC1 3 ) δ 1.41 (9H,s), 2.99(3H,s), 3.01-3.32(2H,m), 3.74(3H,s), 4.90-5.02(1H,m), 5.70(1H,d,J=7Hz) , 6.76(2H,d,J=8Hz), 6.95(2H,d,J=8Hz), 7.01 (1H,s), 7.03-7.16(2H,m), 7.16-7.23(2H,m) Preparation 82 The object compound was obtained according to a similar manner to that of Preparation 64. oil MASS : 326 (M+1) 'H-NMR (CDCI3) δ 3.08-3.22(2H,m), 3.18(3H,s), 3.80(3H,s), 4.18(1H,t,J=8Hz), 6.80(2H,d,J=8Hz), 6.99(2H,d,J=8Hz), 7.00(lH,s), 7.09(2H,t,J=8Hz), 7.20-7.30(2H,m) Preparation 83 The object compound was obtained according to a similar manner to that of Preparation 28. mp : 131-134°C MASS : 457 (M+1) . 'H-NMR (CDCI3) δ 1.43(9H,s), 1.47(3H,t,J=8Hz) , 3.05(2H,d,J=8Hz), 3.77(3H,s), 4.10(2H,q,J=8Hz), 4.41 (1H.br s) , 4.51-4.73(2H,m), 5.01(1H,br s), 6.80(2H,d,J=8Hz) , 6.90(1H,br s), 6.92(2H,d,J=8Hz), 7.11 (2H,d,J=8Hz) , 7.91 (2H,d,J=8Hz) Preparation 84 The object compound was obtained according to a similar manner to that of Preparation 2. solid MASS : 452 (M+1) 'H-NMR (CDCI3) δ 1.41 (9H,s), 1.44(3H,t,J=8Hz) , 2.99(3H,s), 3.01-3.l3(1H,m), 3.20-3.31 (1H,m) , 3.78(3H,s), 4.03(2H,q,J=8Hz), 4.88-4.98(1H,m) , 5.58(1H,q,J=8Hz), 6.78(2H,d,J=8Hz), 6.88-7.00(5H,m), 7.12(2H,d,J=8Hz) Preparation 85 The object compound was obtained according to a similar manner to that of Preparation 64. oil MASS : 352 (M+1) 'H-NMR (CDC1 3 ) δ 1.43(3H,t,J=8Hz), 3.02-3.17(2H,m), 3.18(3H,s), 3.75(3H,s), 4.00-4. !8(1H,m), 4.05(2H,q,J=8Hz), 6.80(2H,d,J=8Hz), 6.91 (2H,d,J=8Hz), 6.98(lH,s), 7.00(2H,d,J=8Hz), 7.19(2H,d,J=8Hz) Preparation 86 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 vacwo, and the residue was dissolved in anhydrous methanol. The precipitated white solid (KCI) 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) + 'H-NMR (DMSO-de, δ ) 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 87 The object compound was obtained according to a similar manner to that of Preparation 28. pale yellow amorphous solid MASS : 531 (M-H) + 'H-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(1H,m), 4.96(lH,m), 6.03(1Hx3/7,d,J=7.0Hz), 6.06(lHx4/7,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 88 The object compound was obtained according to a similar manner to that of Preparation 2. pale yellow amorphous solid MASS : 528 (M+H) + 'H-NMR (CDCI3, r5) 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(lH,d,J=7.5Hz), 6.97-7.08(4H,m), 7.19-7.27(3H,m), 7.55(2H,d,J=7.5Hz) Preparation 89 The object compound was obtained according to a similar manner to that of Preparation 3. pale yellow oil MASS : 428 (M+H) + 'H-NMR (CDCI3, δ ) 1.20(3H,t,J=7.0Hz), 2.97(3H,s), 3.22(2H,d,J=7.0Hz), 4.19(lH,t,J=7.0Hz), 4.25(2H,q,J=7.0Hz), 7.05-7.15(4H,m), 7.21-7.33(3H,m), 7.57(2H,d,J=7.5Hz) Preparation 90 The object compound was obtained according to a similar manner to that of Preparation 28. pale yellow solid mp : 148-152.5°C MASS : 383 (M+H) + 1 H-NMR (CDCI3, δ ) l.41(9H,s), 3.12(2H,d,J=7.0Hz) , 4.49(1H,m), 4.65(1H,dd,J=20.5 and 5.5Hz), 4.75(1H,dd,J=20.5 and 5.5Hz), 5.03(1H,m), 6.89(1H,m), 7.28-7.32(5H,m), 7.50(2H,t,J=7.5Hz) , 7.62(1H,t,J=7.5Hz), 7.94(2H,d,J=7.5Hz) Preparation 91 The object compound was obtained according to a similar manner to that of Preparation 2. brown amorphous solid MASS : 378 (M+H) + 'H-NMR (CDC13, δ ) 1.42(9H,s), 2.97(3H,s), 3.14(1H,dd,J=13.5 and 9.0Hz), 3.35(1H,dd,J=13.5 and 7.0Hz), 5.01 (1H,m), 5.59(1H,d,J=7.5Hz), 7.01-7.08(2H,m) , 7.03(lH,s), 7.17-7.29(5H,m), 7.32-7.44(3H,m) Preparation 92 The object compound was obtained according to a similar manner to that of Preparation 3. brown oil MASS : 278 (M+H) + 'H-NMR (CDC13, δ ) 3.14(1H,dd,J=13.5 and 7.5Hz), 3.18(3H,s), 3.21(1H,dd,J=13.5 and 7.5Hz), 4.15(1H,t,J=7.5Hz), 7.05(lH,s), 7.09(2H,d,J=7.5Hz), 7. l9-7.44(8H,m) Preparation 93 The object compound was obtained according to a similar manner to that of Preparation 28. MASS (ESI) (m/z) : 503, 505 (M-H) ~ 'H-NMR (CDCl3,300MHz)<5 1.38(3H,t,J=7Hz), 1.41 (9H,s), 3.04(2H,d,J=7Hz), 3.98(2H,q,J=7Hz), 4.32-4.49(lH,m) , 4.53-4.77(2H,m), 4.99(1H,br d,J=8Hz), 6.80(2H,d,J=8Hz), 6.83(1H,br s), 7.10(2H,d,J=8Hz) , 7.62(2H,d,J=8Hz), 7.80(2H,d,J=8Hz) Preparation 94 The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 500, 502 (M+H) + 'H-NMR (CDCl 3 ,300MHz)<5 1.39(3H,t,J=7Hz) , 1.41 (9H,s), 2.99(3H,s), 3.05(1H,dd,J=13 and 9Hz) , 3.25(1H,dd,J=13 and 5Hz) , 3.98(2H,q,J=7Hz), 4.86-5.02(1H,m) , 5.56(1H,br d,J=8Hz), 6.73(2H,d,J=8Hz), 6.91 (2H,d,J=8Hz), 7.01 (1H,s), 7.09(2H,d,J=8Hz), 7.51 (2H,d,J=8Hz) Preparation 95 The object compound was obtained according to a similar manner to that of Preparation 9. MASS (ESI) (m/z) : 400, 402 (M+H) + 'H-NMR (CDC13,300MHz ) δ 1.40(3H,t,J=7Hz) , 3.00-3.18(2H,m), 3.19(3H,S), 4.00(2H,q,J=7Hz), 4.10(1H,t,J=7Hz), 6.80(2H,d,J=8Hz), 6.96(2H,d,J=8Hz) , 7.04(lH,s), 7.15(2H,d,J=8Hz), 7.54(2H,d,J=8Hz) Preparation 96 The object compound was obtained according to a similar manner to that of Preparation 28. MASS (ESI) (m/z) : 491, 493 (M+H) + 'H-NMR (CDCl 3 ,300MHz) δ 1.41 (9H,s), 2.92-3.18(2H,m), 3.87(3H,s), 4.40-4.53(1H,m), 4.53-4.78(2H,m), 5.02(1H,br d,J=8Hz) , 6.95(2H,d,J=8Hz), 6.98(1H,br s) , 7.09(2H,d,J=8Hz), 7.40(2H,d,J=8Hz), 7.93(2H,d,J=8Hz) Preparation 97 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 (CDCl 3 ,300MHz)<5 1.40(9H,s), 3.09(3H,s), 3.10-3.31 (2H,m) , 3.83(3H,s), 4.9l-5.06(1H,m), 5.48(1H,br d,J=8Hz), 6.88-7.01 (5H,m), 7.17(2H,d,J=8Hz), 7.35(2H,d,J=8Hz) Preparation 98 The object compound was obtained according to a similar manner to that of Preparation 9. MASS (ESI) (m/z) : 386, 388 (M+H) + 'H-NMR (CDCl3,300MHz)r5 3.02-3.25(2H,m) , 3.23(3H,s), 3.83(3H,s), 4.12(1H,t,J=7Hz), 6.89-7.02(5H,m), 7.20(2H,d,J=8Hz), 7.38(2H,d,J=8Hz) Preparation 99 The object compound was obtained according to a similar manner to that of Preparation 28. MASS (ESI) (m/z) : 455 (M-H) ~ 'H-NMR (CDCl3,300MHz)<5 1.39(3H,t,J=7Hz), 1.42(9H,s), 2.96-3.12(2H,m), 3.88(3H,s), 3.98(2H,q,J=7Hz) , 4.33-4.51 (IH.m), 4.52-4.79(2H,m) , 4.93-5.11 (1H,m) , 6.81(2H,d,J=8Hz), 6.92(lH,br s), 6.95(2H,d,J=8Hz), 7.10(2H,d,J=8Hz), 7.92(2H,d,J=8Hz) Preparation 100 The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 452 (M+H) + 'H-NMR (CDCl 3 ,300MHz)f5 1.39(3H,t,J=7Hz), 1.41 (9H,s), 2.97(3H,s), 3.00-3.31 (2H,m), 3.81 (3H,s), 3.98(2H,q,J=7Hz) , 4.86-5.01 (1H,m), 5.62(1H,br d,J=8Hz), 6.74(2H,d,J=8Hz) , 6.85-6.95(4H,m), 6.96(1H,s), 7.15(2H,d,J=8Hz) Preparation 101 The object compound was obtained according to a similar manner to that of Preparation 9. MASS (ESI) (m/z) : 352 (M+H) + 'H-NMR (CDCl3,300MHz) δ 1.40(3H,t,J=7Hz), 3.00-3.19(2H,m) , 3.17(3H,s), 3.82(3H,s), 4.00(2H,q,J=7Hz), 4.10(1H,t,J=7Hz) , 6.80(2H,d,J=8Hz), 6.89"7.02(5H,m) , 7.20(2H,d,J=8Hz) Preparation 102 The object compound was obtained according to a similar manner to that of Preparation 28. MASS (ESI) (m/z) : 441 (M-H)- 'H-NMR (CDCl3,300MHz)«5 1.42(9H,s), 3.06(2H,d,J=7Hz) , 3.76(3H,s), 3.88(3H,s), 4.34-4.52(1H,m), 4.54-4.79(2H,m), 4.91-5.l0(1H,m), 6.82(2H,d,J=8Hz), 6.91 (1H,br s) , 6.96(2H,d,J=8Hz) , 7.12(2H,d,J=8Hz), 7.93(2H,d,J=8Hz) Preparation 103 The object compound was obtained according to a similar manner to that of Preparation 2. MASS (ESI) (m/z) : 438 (M+H) + 'H-NMR (CDCl3,300MHz)<5 1.41 (9H,s), 2.98(3H,s), 3.01-3.31 (2H,m), 3.76(3H,s), 3.81(3H,s), 4.88-5.00(1H,m) , 5.59(1H,br d,J=8Hz) , 6.77(2H,d,J=8Hz), 6.87-7.00(5H,m) , 7.14(2H,d,J=8Hz) Preparation 104 The object compound was obtained according to a similar manner to that of Preparation 9. MASS (ESI) (m/z) : 338 (M+H) + 'H-NMR (CDCl 3 ,300MHz) δ 3.01-3.20(2H,m) , 3.18(3H,s), 3.78(3H,s), 3.83(3H,s), 4.10(lH,t,J=7Hz), 6.81 (2H,d,J=8Hz), 6.89-7.05(5H,m), 7.20(2H,d,J=8Hz) Example 1 To an ice-cooled solution of the starting compound (76 mg) , indole-2-carboxylic acid (66 mg) and 1-hydroxybenzotriazole (58 mg) in dichloromethane (1 ml) was added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (96 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 (128 mg). MASS (ESI) (m/z) : 331 (M+H) + 'H-NMR (CDCl 3 ,300MHz) f5 : 3.62(3H,s), 4.80(2H,d,J=5Hz) , 6.98-7.92(12H,m), 9.50(1H,br s) Example 2 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 332 (M+H) + 'H-NMR (CDCl 3 ,300MHz)<5 : 3.64(3H,s), 4.80(2H,d,J=5Hz), 7.05(1H,s), 7.20-7.72(12H,m) Example 3 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 493 (M+H) + 'H-NMR (CDCl3,300MHz)<5 : 1.06(3H,t,J=7Hz) , 2.81 (3H,s), 3.42-3.65(2H,m), 4.17(2H,q,J=7Hz), 5.48-5.64(1H,m), 6.88-7.63(15H,m), 8.41 (1H,br s) , 9.50(1H,br s) Example 4 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 494 (M+H) + 'H-NMR (CDC13,300MHz) δ : 1.12(3H,t f J=7Hz) , 2.81 (3H,s), 3.32-3.56(2H,m), 4.22(2H,q,J=7Hz) , 5.48-5.62(1H,m) , 7.05-7.70(15H,m), 7.82(1H,br d,J=8Hz) Example 5 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 451 (M+H) + 'H-NMR (CDCl 3 ,300MHz) δ : 3.09(3H,s), 3.22-3.50(2H,m), 3.72(3H,s), 5.50-5.64(lH,m), 6.72(2H,d,J=8Hz), 6.96(2H,d,J=8Hz), 7.00-7.65(11H,m) , 8.13(1H,br d,J=8Hz) , !0.50(1H,br s) Example 6 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 452 (M+H) + 'H-NMR (CDCl3,300MHz)<5 : 3.06(3H,s), 3.17-3.48(2H,m), 3.75(3H,s), 5.41-5.56(1H,m), 6.77(2H,d,J=8Hz), 6.98(2H,d,J=8Hz), 7.10(1H,s), 7.18-7.80(l1H,m) Example 7 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 529, 531 (M+H) + 'H-NMR (CDCl3,300MHz) δ ' 3.08(3H,s), 3.22-3.50(2H,m), 3.72(3H,s), 5.50-5.64(1H,m), 6.72(2H,d,J=8Hz), 6.98(2H,d,J=8Hz), 7.00-7.65(10H,m), 8.11 (1H,br d,J=8Hz) , 9.95(1H,br s) Example 8 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 530, 532 (M+H) + 'H-NMR (CDCl 3 ,300MHz) <5 : 3.06(3H,s), 3.15~3.48(2H,m), 3.75(3H,s), 5.40-5.55(1H,m), 6.77(2H,d,J=8Hz) , 6.98(2H,d,J=8Hz), 7.05-7.75(11H,m) Example 9 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 467 (M+H) + 'H-NMR (CDCl 3 ,300MHz) δ : 2.50(3H,s), 3.01 (3H,s), 3.22-3.56(2H,m), 5.51-5.66(1H,m), 6.98-7.68(15H,m), 7.95(1H,br d,J=8Hz), 9.60(1H,br s) Example 10 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 468 (M+H) + 'H-NMR (CDCl 3 ,300MHz)δ : 2.50(3H,s), 3.00(3H,s), 3.22-3.55(2H,m), 5.46-5.60(lH,m) , 7.02-7.80(16H,m) Example 11 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 533, 535 (M+H) + 'H-NMR (CDCl 3 ,300MHz)<5 : 3.18(3H,s), 3.30-3.48(2H,m) , 5.52-5.68(1H,m), 6.93-8.00(15H,m), 9.78(1H,br s) Example 12 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 534, 536 (M+H) + 'H-NMR (CDCl 3 ,300MHz)<5 : 3.18(3H,s), 3.26-3.49(2H,m) , 5.47-5.61 (1H,m), 6.98-7.70(15H,m) Example 13 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (ESI) (m/z) : 499 (M+H) + 'H-NMR (CDCl3+CD 3 OD,300MHz) δ : 2.88(3H,s), 3.00(1 xl/3H,d,J=8Hz), 3.03(1 x2/3H,d,J=8Hz), 3.11(1 x2/3H,d,J=4Hz), 3.16(1 x l/3H,d,J=4Hz) , 5.30(1H,q,J=6Hz), 6.70-6.90(6H,m), 6.90-7.04(5H,m) , 7.10(1H,s), 7.16(1H,d,J=8Hz), 7.26(2H,d,J=8Hz), 7.40(1H,d,J=8Hz) Example 14 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (ESI) (m/z) : 500 (M+H) + 1 H-NMR (CDC1 3 ,300MHz) δ : 2.99(3H,s), 3.30(1 xi/3H,d,J=8Hz), 3.32(1 x2/3H,d,J=8Hz), 3.49(1 X2/3H,d,J=4Hz), 3.51(1 x 1/3H,d,J=4Hz) , 5.49-5.60(1H,m), 7.00-7.19(5H,m), 7.19-7.32(4H,m), 7.40(1H,t,J=8Hz), 7.49(1H,s), 7.52(3H,d,J=8Hz), 7.64(lH,d,J=8Hz), 7.93(lH,d,J=8Hz) Example 15 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (ESI) (m/z) : 455 (M+H) + 1 H-NMR (CDC1 3 ,300MHz) δ : 3.01 (3H,s), 3.32(1 xl/3H,d,J=8Hz), 3.39(1 x2/3H,d,J=8Hz), 3.49(1 x2/3H,d,J=4Hz), 3.52(1 x l/3H,d,J=4Hz) , 5.60(1H,q,J=8Hz), 7.00-7.19(7H,m), 7.19-7.30(4H,m) , 7.30-7.43(3H,m), 7.61 (1H,d,J=8Hz), 8.17(1H,d,J=8Hz), 9.88(lH,s) Example 16 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (ESI) (m/z) : 456 (M+H) + 1 H-NMR (CDC13,300MHz) δ : 2.99(3H,s), 3.29(1 xl/3H,d,J=8Hz), 3.32(1 x2/3H,d,J=8Hz) , 3.49(1 x2/3H,d,J=4Hz), 3.52(1 x 1/3H,d,J=4Hz) , 5.48-5.60(1H,m), 7.03-7.11 (3H,m) , 7.15(2H,d,J=8Hz) , 7.20-7.31 (4H,m), 7.38(2H,d,J=8Hz) , 7.41-7.58(3H,m) , 7.67(1H,d,J=8Hz), 7.80(1H,d,J=8Hz) Example 17 The object compound was obtained according to a similar manner to that of Example 1. mp : 145-150°C MASS (ESI) (m/z) : 435 (M+H) + 'H-NMR (CDCl 3 ,300MHz)<5 : 2.31 (3H,s), 3.02(3H,s), 3.33-3.57(2H,m), 5.60-5.73(1H,m), 7.00-7.12(7H,m), 7.12-7.22(6H,m), 7.36(lH,d,J=8Hz), 7.59(1H,d,J=8Hz), 8.57(1H,d,J=8Hz) Example 18 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (ESI) (m/z) : 436 (M+HV 'H-NMR (CDCl3,300MHz) r5 : 2.38(3H,s), 3.00(3H,s), 3.30(1 xi/3H,d,J=8Hz), 3.38(1 x2/3H,d,J=8Hz), 3.50(1 x2/3H,d,J=4Hz), 3.52(1 X 1/3H,d,J=4Hz) , 5.48-5.62(1H,m), 7.02-7.14(5H,m) , 7.16-7.33(6H,m) , 7.35-7.55(3H,m), 7.65(lH,d,J=8Hz) , 7.91 (1H,d,J=8Hz) Example 19 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (ESI) (m/z) : 455 (M+H) + 'H-NMR (CDCl 3 ,300MHz) c5 : 3.18(3H,s), 3.40-3.50(2H,m), 5.70(1H,q,J=8Hz), 6.98-7.29(10H,m) , 7.30-7.42(4H,m) , 7.59(1H,d,J=8Hz), 8.60(1H,d,J=8Hz) Example 20 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS (ESI) (m/z) : 456 (M+H) + 'H-NMR (CDC13,300MHz ) δ ' 3.19(3H,s), 3.30-3.51 (2H,m), 5.49-5.60(1H,m), 7.04(2H,d,J=8Hz) , 7.10(1H,s), 7.14-7.31 (5H,m), 7.31-7.52(6H,m), 7.64(1H,d,J=8Hz), 7.78(1H,d,J=8Hz) Example 21 The object compound was obtained according to a similar manner to that of Example 1. colorless solid mp : 223-226°C MASS (ESI) (m/z) : 435 (M+H) f 1 H-NMR (CDC13,300MHz) δ : 2.23(3H,s), 3.23"3.40(2H,m) , 4.77(1H,d,J=16.0Hz), 4.83(1H,d,J=16.0HZ) , 5.60(1H,q,J=7.5Hz), 6.70(1H,s), 6.78(2H,d,J=7.5Hz), 6.93(1H,s), 6.97-7.29(10H,m), 7.37(lH,d,J=7.5Hz), 7.58(1H,d,J=7.5Hz), 7.62(1H,d,J=7.5Hz), 9.47(1H,br s) Example 22 The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid MASS (ESI) (m/z) : 421 (M+H) + 'H-NMR (CDCls, δ ) 3.00(3H,s), 3.30(1H,dd,J=12.0, 8.5Hz), 3.49(1H,dd,J=12.0, 5.5Hz), 5.57(1H,m), 6.99-7.43(l5H,m) , .7.63(1H,d,J=7.5Hz), 7.76(1H,d,J=7.5Hz) , 9.41 (1H,s) Example 23 The object compound was obtained according to a similar manner to that of Example 1. colorless solid mp : 234-239°C MASS (ESI) (m/z) : 345 (M+H) + 'H-NMR (CDCI3-CD3OD, δ ) 3.17(3H,s), 3.20(1H,dd,J=13.5, 9.0Hz), 3.34(1H,dd,J=13.5, 5.5Hz), 5.49(1H,dd,J=9.0, 5.5Hz), 6.66(lH,s), 6.97-7.03(3H,m), 7.13(1H,t,J=7.5Hz), 7.18-7.31 (5H,m), 7.41 (1H,d,J=7.5Hz), 7.68(1H,d,J=7.5Hz) Example 24 The object compound was obtained according to a similar manner to that of Example 1. colorless solid mp : 251-256°C MASS (ESI) (m/z) : 331 (M+H) + 'H-NMR (CDCI3-CD3OD, δ ) 3.31(2H,d,J=7.5Hz), 5.39(1H,t,J=7.5Hz), 6.90(2H,s), 7.02-7.31 (8H,m), 7.39(1H,d,J=7.5Hz), 7.64(1H,d,J=7.5Hz) Example 25 The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 202-206°C MASS (ESI) (m/z) : 472 (M+H) + 'H-NMR (CDCI3, δ ) 3.10(3H,s), 3.35(1H,dd,J=13.5, 8.5Hz), 3.53(1H,dd,J=13.5, 5.5Hz), 5.61 (1H,m), 7.03(lH,s), 7.09-7.17(3H,m), 7.20(1H,s), 7.23~7.32(4H,m) , 7.38-7.46(2H,m), 7.56(1H,dd,J=7.5, 2.5Hz), 7.65(1H,d,J=7.5Hz), 7.67(1H,s), 7.75(1H,d,J=7.5Hz) , 8.11(2H,d,J=7.5Hz), 8.93(1H,d,J=5.5Hz) , 9.40(1H,s) Example 26 The object compound was obtained according to a similar manner to that of Example 1. off-white amorphous solid MASS (ESI) (m/z) : 472 (M+H) A 'H-NMR (CDCI3, δ ) 3.07(3H,s), 3.33(1H,dd,J=13.5, 10.0Hz), 3.55(1H,dd,J=13.5, 5.5Hz), 5.62(1H,m), 7.03(1H,s), 7.07-7.18(3H,m), 7.22-7.33(5H,m) , 7.41 (lH,d,J=7.5Hz), 7.60(1H,t,J=7.5Hz), 7.69(2H,t,J=7.5Hz) , 7.77(1H,t,J=7.5Hz) , 7.82(1H,d,J=7.5Hz), 8.02(1H,d,J=1.0Hz), 8.13(lH,d,J=7.5Hz), 8.80(1H,d,J=1.0Hz), 9.37(1H,br s) Example 27 The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid MASS (ESI) (m/z) : 451 (M+H) ¥ 'H-NMR (CDCI3, δ ) 3.08(3H,s), 3.38(lH,dd,J=13.5, 9.0Hz), 3.50(1H,dd,J=13.5, 6.0Hz), 3.82(3H,s), 5.64(1H,m), 6.92(2H,d,J=7.5Hz), 7.03-8.14(14H,m) , 9.63(1H,br s) Example 28 The object compound was obtained according to a similar manner to that of Example 1. colorless solid mp : 221-230.5°C MASS (ESI) (m/z) : 451 (M+H) + 'H-NMR (CDCI3, δ ) 3.32(2H,m), 3.70(3H,s), 4.74(2H,s), 5.62(1H,m), 6.67(1H,s), 6.71 (2H,d,J=7.5Hz), 6.82(2H,d,J=7.5Hz), 6.93(1H,d,J=1.0Hz) , 6.99-7.30(8H,m) , 7.37(lH,d,J=7.5Hz), 7.56-7.65(2H,m) , 9.50(1H,s) Example 29 The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 192.5-198°C MASS (ESI) (m/z) : 405 (M+H) + 'H-NMR (CDCI3, δ ) 2.10(3H,s), 2.30-2.75(4H,m), 3.66(3H,s), 5.71(1H,q,J=7.5Hz), 6.95"7.04(2H,m) , 7.11 (1H,t,J=7.5Hz) , 7.21-7.47(7H,m), 7.58(1H,d,J=7.5Hz) , 7.63(1H,d,J=7.5Hz) , 9.54(lH,s) Example 30 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 532, 534 (M+H) + 1 H-NMR (CDCI3,300MHz) δ : 3.27-3.50(2H,m) , 3.74(3H,s), 5.69-5.83(1H,m), 6.79(2H,d,J=8Hz), 6.88(1H,s), 7.04(2H,d,J=8Hz), 7.08-7.69(9H,m), 7.88(1H,s), 9.46(1H,br s) Example 31 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 533, 535 (M+H) + 'H-NMR (CDCl 3 ,300MHz)f5 : 3.30-3.49(2H,m), 3.75(3H,s), 5.68-5.82(1H,m), 6.79(2H,d,J=8Hz) , 7.09(2H,d,J=8Hz), 7.20-7.80(10H,m), 7.89(1H,s) Example 32 The object compound was obtained according to a similar manner to that of Example 1. mp : 178-182°C MASS : 465 (M+1) 'H-NMR (CDC1 3 ) δ : 1.42(3H,t,J=8Hz) , 3.02(3H,s), 3.36-3.59(2H,m), 4.02(2H,q,J=8Hz), 5.67(1H,q,J=8Hz), 6.89(2H,d,J=8Hz), 7.01 (1H,s), 7.03-7.13(6H,m), 7.17-7.30(4H,m), 7.38(1H,d,J=8Hz) , 7.60(1H,d,J=8Hz) , 8.48(1H,d,J=8Hz) Example 33 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 466 (M+1) 'H-NMR (CDCI3) δ : 1.42(3H,t,J=8Hz), 2.95(3H,s), 3.23-3.37(1H,m), 3.43-3.53(lH,m), 4.02(2H,q,J=8Hz), 5.45-5.58(lH,m), 6.90(2H,d,J=8Hz) , 7.01 (1H,s), 7.03-7.18(4H,m), 7.19-7.31 (4H,m) , 7.40(1H,t,J=8Hz) , 7.43(1H,s), 7.5l(1H,d,J=8Hz), 7.63(1H,d,J=8Hz), 7.81(1H,d,J=8Hz) Example 34 The object compound was obtained according to a similar manner to that of Example 1. mp : 174-178°C MASS : 449 (M+1) 'H-NMR (CDCI3) δ : 1.28(3H,t,J=8Hz), 2.69(2H,q,J=8Hz) , 3.08(3H,s), 3.40-3.60(2H,m), 5.68-5.80(1H,m), 7.02-7.19(7H,m), 7.19-7.30(6H,m), 7.40(1H,d,J=8Hz) , 7.61 (1H,d,J=8Hz), 8.69(1H,d,J=8Hz) Example 35 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 450 (M+1) 'H-NMR (CDCI3) δ : 1.24(3H,t,J=8Hz), 2.69(2H,t,J=8Hz), 3.00(3H,s), 3.25-3.38(1H,m), 3.43-3.57(1H,m), 5.48-5.60(1H,m), 7.00-7.19(5H,m), 7.19-7.32(6H,m), 7.40(1H,t,J=8Hz), 7.45(1H,s), 7.5KlH,d,J=8Hz), 7.63(1H,d,J=8Hz) , 7.81(1H,d,J=8Hz) Example 36 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 485 (M+1) 'H-NMR (CDCI3) δ : 2.93(3H,s), 3.30-3.50(2H,m), 3.70(3H,s), 5.53-5.63(1H,m), 6.71 (2H,d,J=8Hz) , 6.98(2H,d,J=8Hz), 7.00-7.12(3H,m), 7.16-7.40(5H,m), 7.42(1H,d,J=8Hz), 7.60(1H,d,J=8Hz), 8.40(1H,d,J=8Hz) Example 37 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 465 (M+1) 'H-NMR (CDCI3) δ : 2.39(3H,s), 3.10(3H,s), 3.30-3.50(2H,m) , 3.70(3H,s), 5.61(1H,q,J=8Hz), 6.70(2H,d,J=8Hz), 6.99(2H,d,J=8Hz), 7.01-7.28(8H,m) , 7.38(1H,d,J=8Hz) , 7.60(1H,d,J=8Hz), 8.42(1H,d,J=8Hz) Example 38 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 485 (M+1) 1 H-NMR (CDC1 3 ) δ : 3.09(3H,s), 3.30-3.50(2H,m) , 3.70(3H,s), 5.62(1H,q,J=8Hz), 6.70(2H,d,J=8Hz) , 6.99.(2H,d,J=8Hz), 7.01-7.29(6H,m), 7.29-7.40(3H,m), 7.59(1H,d,J=8Hz), 8.51(1H,d,J=8Hz) Example 39 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 485 (M+1) 'H-NMR (CDCls) δ : 3.10(3H,s), 3.31-3.52(2H,m) , 3.70(3H,s), 5.60-5.72(1H,m), 6.73(2H,d,J=8Hz), 7.01 (2H,d,J=8Hz) , 7.07-7.20(4H,m), 7.20-7.30(2H,m) , 7.30-7.50(3H,m), 7.61 (1H,d,J=8Hz), 8.59(1H,d,J=8Hz) Example 40 The object compound was obtained according to a similar manner to that of Example 1. amorphous solid MASS : 469 (M+1) 'H-NMR (CDCI3) <5 : 3.08(3H,s), 3.30-3.40(2H,m) , 3.71 (3H,s), 5.67(1H,q,J=8Hz), 6.71 (2H,d,J=8Hz) , 7.00(2H,d,J=8Hz), 7.03-7.30(8H,m), 7.39(1H,d,J=8Hz), 7.60(1H,d,J=8Hz), 8.60(1H,d,J=8Hz) Example 41 The object compound was obtained according to a similar manner to that of Example 1. mp : 115-118 0 C MASS : 495 (M+1) 'H-NMR (CDCI3) δ : 1.42(3H,t,J=8Hz), 3.03(3H,s), 3.20-3.31 (1H,m), 3.36-3.47(1H,m), 3.70(3H,s), 4.03(2H,q,J=8Hz), 5.48-5.59(1H,m) , 6.73(2H,d,J=8Hz), 6.90(2H,d,J=8Hz), 6.99(2H,d,J=8Hz), 7.00(2H,s), 7.08-7.18(3H,m), 7.23(1H,t,J=8Hz) , 7.39(1H,d,J=8Hz) , 7.61(1H,d,J=8Hz), 7.86(1H,d,J=8Hz) , 9.60(1H,s) Example 42 The object compound was obtained according to a similar manner to that of Example 1. mp : >250°C MASS : 529 (M+1) 'H-NMR (CDCI3) <5 : 3.17-3.40(2H,m), 3.52(3H,s), 3.68(3H,s), 5.49(1H,q,J=8Hz), 6.79(2H,d,J=8Hz), 7.01-7.18(2H,m) , 7.07(1H,s), 7.21(2H,d,J=8Hz), 7.36(2H,d,J=8Hz), 7.39(1H,t,J=8Hz), 7.61 (2H,d,J=8Hz) , 8.09(1H,d,J=8Hz), 8.19(1H,d,J=8Hz), 8.39(1H,d,J=8Hz) Example 43 The object compound was obtained according to a similar manner to that of Example 1. pale yellow amorphous solid MASS : 571 (M+H) + 'H-NMR (CDCI3) δ : 1.16(3H,t,J=7.0Hz), 2.79(3H,s), 3.42(1H,dd,J=12.0 and 10.0Hz), 3.53(1H,dd,J=12.0 and 5.5Hz), 4.22(2H,q,J=7.0Hz), 5.53(1H,m), 6.98(1H,d,J=l .0Hz) , 7.04-7.10(4H,m), 7.11 (1H,t,J=7.5Hz) , 7.20-7.30(4H,m), 7.33(1H,d,J=7.5Hz), 7.56(2H,d,J=7.5Hz), 7.64(1H,d,J=7.5Hz) , 7.91 (1H.br d,J=7.5Hz), 9.21(1H,br s) Example 44 The object compound was obtained according to a similar manner to that of Example 1. off-white solid mp : 258.5-260°C MASS : 421 (M+H) + 'H-NMR (CDCI3) δ : 3.02(3H,s), 3.29(1H,dd,J=13.0 and 8.5Hz), 3.49(1H,dd,J=13.0 and 5.5Hz), 5.58(1H,m), 7.02-7.09(3H,m) , 7.10(1H,s), 7.15(1H,d,J=7.5Hz), 7.20-7.43(10H,m), 7.66(1H,d,J=7.5Hz), 7.73(1H,d,J=7.5Hz) , 9.48(1H,s) Example 45 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 543, 545 (M+H) + 'H-NMR (CDCl 3 ,300MHz) δ : 1.39(3H,t,J=7Hz) , 3.06(3H,s), 3.25(1H,dd,J=13 and 9Hz), 3.41 (1H,dd,J=13 and 5Hz), 3.97(2H,q,J=7Hz), 5.46-5.61 (1H,m), 6.75(2H,d,J=8Hz), 6.95(2H,d,J=8Hz), 7.00-7.70(10H,m), 7.90(1H,br d,J=8Hz) , 9.55(1H,br s) Example 46 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 (CDCl 3 ,300MHz)(5 : 1.40(3H,t,J=7Hz) , 3.04(3H,s), 3.22(1H,dd,J=13 and 9Hz) , 3.41 (1H,dd,J=13 and 5Hz), 3.98(2H,q,J=7Hz), 5.41-5.55(1H,m) , 6.77(2H,d,J=8Hz), 6.98(2H,d,J=8Hz), 7.05-7.75(1 IH.m) Example 47 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 529, 531 (M+H) 4 'H-NMR (CDCl 3 ,300MHz) δ ' 3.15(3H,s), 3.29-3.48(2H,m), 3.81 (3H,s), 5.52-5.66(lH,m), 6.91 (2H,d,J=8Hz) , 6.97(2H,d,J=8Hz), 7.00(1H,s), 7.02-7.68(9H,m), 8.01(1H,br d,J=8Hz), 9.84(1H,br s) Example 48 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 530, 532 (M+H) + 'H-NMR (CDCl3,300MHz)<5 : 3.12(3H,s), 3.25-3.48(2H,m), 3.82(3H,s), 5.45-5.60(1H,m), 6.93(2H,d,J=8Hz), 6.99(2H,d,J=8Hz), 7.03(1H,s), 7.11-7.70(10H,m) Example 49 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 495 (M+H) + 1 H-NMR (CDCl3,300MHz)f5 : 1 ,39(3H,t,J=7Hz), 3.02(3H,s), 3.18-3.48(2H,m), 3.82(3H,s), 3.96(2H,q,J=7Hz) , 5.45-5.59(lH,m), 6.74(2H,d,J=8Hz) , 6.91 (2H,d,J=8Hz), 6.95(2H,d,J=8Hz), 7.01 (1H,s), 7.02-7.68(7H,m), 7.88(1H,br d,J=8Hz), 9.59(1H,br s) Example 50 The object compound was obtained according to a similar manner to that of Example 1. MASS (ESI) (m/z) : 481 (M+H) + 'H-NMR (CDCl 3 ,300MHz) δ : 3.04(3H,s), 3. l9-3.48(2H,m) , 3.74(3H,s), 3.82(3H,s), 5.47-5.61 (1H,m) , 6.74(2H,d,J=8Hz) , 6.91(2H,d,J=8Hz), 6.98(2H,d,J=8Hz) , 7.01 (1H,s), 7.02-7.68(7H,m), 7.92(1H,br d,J=8Hz) , 9.66(1H,br s)

Claims: CLAIMS 1 . A compound of the formula : wherein R' is indolyl or benzofuranyl; R 2 is hydrogen, lower alkylthio(lower)alkyl or a group of the formula: in which 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; and X is S or NR 6 in which R 6 is hydrogen, lower alkyl or a group of the formula: in which R 7 is lower alkyl or lower alkoxy, and a pharmaceutically acceptable salt thereof. 2. A process for preparing a compound of the formula: wherein R' is indolyl or benzofuranyl; R 2 is hydrogen, lower alkylthio(lower)alkyl or a group of the formula: in which 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; and X is S or NR 6 in which R 6 is hydrogen, lower alkyl or a group of the formula: in which R 7 is lower alkyl or lower alkoxy, or a salt thereof, which comprises reacting a compound of the formula: wherein R 2 , R 3 , R" and X are each as defined above, or its reactive derivative, or a salt thereof, with a compound of the formula: R'-COOH wherein R' is as defined above, or its reactive derivative, or a salt thereof. 3. A pharmaceutical composition comprising the compound of Claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier. 4. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof as a medicament. 5. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of NO-mediated diseases.

Inventors: HAMASHIMA HITOSHI, INOUE TAKAYUKI, ITOH YOSHIKUNI, YATABE TAKUMI, HAMASHIMA, HITOSHI, INOUE, TAKAYUKI, ITOH, YOSHIKUNI, YATABE, TAKUMI
Applicants: FUJISAWA PHARMACEUTICAL CO, HAMASHIMA HITOSHI, INOUE TAKAYUKI, ITOH YOSHIKUNI, YATABE TAKUMI, FUJISAWA PHARMACEUTICAL CO., LTD., HAMASHIMA, HITOSHI, INOUE, TAKAYUKI, ITOH, YOSHIKUNI, YATABE, TAKUMI
Application year: 1997
Main classification: C07D403
IPC codes: A61K31, A61P1, A61P3, A61P9, A61P11, A61P19, A61P25, A61P29, A61P37, A61P39, C07D233, C07D401, C07D403, C07D405, C07D409, C07D413, C07D417, C07D521