Title of Invention	"A PROCESS FOR THE PREPARATION OF PIPERAZINE DERIVATIVES"
Abstract	A process for the preparation of piperazine derivative of general formula (I) or a pharmaceutically acceptable acid addition salt thereof comprising reacting a compound of the general formula (a) with a -C(=X)- group-providing agent in the presence of organic solvent as herein described to obtain a compound of the general formula (b) and reacting the compound of the general formula (b) with a compound of the general formula (c to obtain the general formula (I) and reacting said compound of general formula (I) is to acids as herein defined to form acid addition salt

Title of Invention

"A PROCESS FOR THE PREPARATION OF PIPERAZINE DERIVATIVES"

Abstract

A process for the preparation of piperazine derivative of general formula (I) or a pharmaceutically acceptable acid addition salt thereof comprising reacting a compound of the general formula (a) with a -C(=X)- group-providing agent in the presence of organic solvent as herein described to obtain a compound of the general formula (b) and reacting the compound of the general formula (b) with a compound of the general formula (c to obtain the general formula (I) and reacting said compound of general formula (I) is to acids as herein defined to form acid addition salt

Full Text	The subject invention relates to the process for the preparation of piperazine derivatives. The present invention relates to new piperazine derivatives of the general formula (1) wherein R1 and R2 are independently hyl)rogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 unsaturated alkyl, ketone, substituted or unsubstituted aryl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted arylhyl)roxy, substituted or unsubstituted amino, C1-C4 lower ester, C1-C4 lower thioester, thiol, substituted or unsubstituted carboxyl, epoxy, substituted or unsubstituted C1-C4 lower thioalkoxy; or R1 and R2 are fused to form C3-C4 saturated or unsaturated chain; R3, R4, R5, Rg and R7 are independently hyl)rogen, halogen, hyl)roxy, nitro, C1-C4 lower ester, C1-C4 lower alkyl, C1-C4 lower thioalkyl, substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted lower arylalkoxy, substituted or unsubstituted lower alkylamino, or lower alkyl substituted or unsubstituted carbamate; or among R3, R4, R5, R6 and R7. two adjacent groups are bonded with each other to form 1,2-phenylene or 2,3-naphthylene; X is oxygen, sulfur, or substituted or unsubstituted imino; Y is bonded at the 3-position or 4-position of the aromatic ring part wherein Y is oxygen or -NRg- (wherein, R8 is the same with the above-mentioned R3); Z is hyl)roxy, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryloxy, C1-C4 lower alkylamino, substituted or unsubstituted cycloamino containing 1-5 nitrogen atoms; A is nitrogen or -CH=; its pharmaceutically acceptable acid addition salts and process for the preparation thereof. In the above definitions, C1-C8 alkyl means straight or branched alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, iso-pentyl, hexyl, heptyl, octyl, 2-methylpentyl or the like. C1-C4 lower alkyl means methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Substituted or unsubstituted C3-C6 cycloalkyl means substituted or unsubstituted cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted cyclopropyl, substituted cyclopentyl, substituted cyclohexyl or the like. C1-C4 lower ester means a carboxyl group esterified by a lower alley 1 group. C1-C4 lower alkoxy means methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, tert-butyloxy group or the like. C1-C4 lower thioalkoxy means methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio group or the like. C1-C4 lower alkylamino means methylamino, ethylamino, propylamino, butylamino group or the like. Aryloxy means phenoxy, substituted phenoxy, naphthyloxy or substituted naphthyloxy or the like. Cycloamino group containing 1-5 nitrogen atoms means pyrrolidinyl, pyiTolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, piperazinyl or the like. The present inventors had studied for a long time to find compounds having intensive antitumor activity. As the results, now we have finally found out the facts that the present compounds of the general formula(I) and acid addition salts thereof have not only prominent antitumor activities but very, low toxicities. Accordingly, the one object of the present invention is to provide the novel compounds of the general formula(I) and acid addition salts thereof having not only prominent antitumor activities but very low toxicities. The other object of the present invention is to provide a process for the preparation of the compounds of general formula(I) and acid addition salts thereof. The compounds of the present invention can be mixed with pharmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and the pharmaceutical compositions can be used to prevent or treat with various kinds of tumors of human beings or nuuiunals. Therefore, another object of the present invention is to provide pharmaceutical compositions containing the compounds of the general formula(I) or acid addition salts thereof as active ingredients. Acids which can be reacted with the compounds of the general formula(I) to form acid addition salts are pharmaceutically acceptable inorganic or organic acids; for example, inorganic acids such as hyl)rochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid; organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid, glycolic acid, lactic acid; amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamic acid, lysine, arginine, tyrosine, proline; sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid; or the like. Vehicles which can be used in the preparation of pharmaceutical compositions containing the compounds of the general formula(I) as active ingredients are sweetening agent, binding agent, dissolving agent, aids for dissolution, wetting agent, emulsifying agent, isotonic agent, adsorbent, degrading agent, antioxident, antiseptics, lubricating agent, filler, perfume or the like", such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, calcium stearate, magnesium aluminum silicate, starch, gelatine, tragacanth gum, glycine, silica, alginic acid, sodium alginate, methyl cellulose, sodium carboxy methyl cellulose, agar, water, ethanol, polyethylenglycol.polyvinyhpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanila aroma or the like. Daily dosage of the compound of the general formula(l) may be varied depending on age, sex of patient and the degree of disease. Daily dosage is l.0mg to 5,000mg may be administered one to several times. Accordingly the present invention relates to a process for the preparation of piperazine derivative of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof comprising reacting a compound of the general formula (a) with a -C(=X)- group-providing agent in the presence of organic solvent as herein described to obtain a compound of the general formula (b) and reacting the compound of the general formula (b) with a compound of the general formula (c) to obtain the general formula (Formula Removed) and reacting said compound of general formula (I) with acids as herein defined to form acid addition salt; whe rein R1 and R2 are independently hyl)rogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 unsaturated alkyl, ketone, substituted or unsubstituted aryl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted arylhyl)roxy, substituted or unsubstituted amino, C1-C4 lower ester, C1-C4 lower thioester, thiol, substituted or unsubstituted carboxyl , epoxy, substituted or unsubstituted C1-C4 lower thioalkoxy; or R1 and R2 are fused to form C3-C4 saturated or unsaturated chain; R3 , R4 , R5 , R6 and R7 are independently hyl)rogen, halogen, hyl)roxy, nitro, C4-C4 lower ester, C1-C4 lower alkyl, C1-C4 lower thioalkyl, substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy,substituted or unsubstituted aryl, substituted or unsubstituted lower arylalkoxy, substituted or unsubstituted lower alkylamino, or lower alkyl substituted or unsubstituted carbamate; or among R3, R4, R5, R6 and R7, two adjacent groups are bonded with each other to form 1,2-phenylene or 2,3-naphthylene; X is oxygen, sulfur, or substituted or unsubstituted imino; Y is bonded at the 3-position or 4-position of the aromatic ring part wherein Y is oxygen or -NRg- (wherein, R8 is the same with the above-mentioned R3) ; Z is hyl)roxy, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryloxy, C1-C4 lower alkylamino, substituted or unsubstituted cycloamino containing 1-5 nitrogen atoms; A is nitrogen or -CH=; and Lie is a leaving group such as halogen atom, sulphonyl and the like. The compounds of the general formula (I) according to the present invention may be prepared by the following scheme I. Scheme I (Scheme Removed) wherein Ri, Rz, R3, R4, R5, Re, R7, A, X, Y and Z are as defined above, and Lie is a leaving group such as halogen atom, sulfonyl or the like. The above process comprises reacting a compound of the general formula(a) with a -C(=X)- group-providing agent in organic solvent to obtain a compound of the general formula(b) and successively reacting the compound of the general formula(b) with a compound of the general formula(c). to give the compound of the general formula(I). The used -C(=X)-group-providing agent preferably be selected from 1,1-carbonyldiimidazole, 1,1-carbonylthiodiirnidazole, phosgene, thiophosgene, carbonyldiphenoxide, phenylchloroformate or the like. The reaction may be carried out in conventional organic solvent such as, for example, tetrahyl)rofuran, dichloromethane, chloroform, acetonitrile. And also the reaction is preferably carried out in the presence of coupling agent such as conventional inorganic or organic base. Such conventional inorganic or organic base used in the reaction mecins sodium hyl)ride, potassium hyl)ride, sodium hyl)roxide, potassium hyl)roxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU or the like, and 1-1.5 equivalent, preferably 1-1.1 equivalent thereof may be used. The reaction may be carried out between 3°C and boiling point of the solvent used, preferably at 50°C-100°C for 5-48 hours, preferably for 10 - 24 hours. -C(=X)-group-providing agent may be used in an amount of 1-1.5 equivalent, preferably 1-1.1 equivalent to the starting compound. A compound of the general formula(I) wherein Y is -NRR- may be prepared by the following scheme II SdiemeJLi (Scheme Removed) wherein, R1, R2, R3, R4, R5, Re, R7, Rs, A, X and Z are as defined above. A compound of the general formula(Ib) above may be prepared effectively by introducing R8 providing agent into a compound of the general formula(Ia). Rs providing agent preferably used in the above reaction is C1-Cx lower alkylhalogen, C1-Ca lower alkyl sulfonate, substituted or unsubstituted C3-C8 cycloalkylhalogen, arylhalogen, substituted or unsubstituted C3-C8 cycloalkyl sulfonate, arylsulfonate, or the like. C1-C8 lower alkylhalogen means methylchloride, methylbromide, methyliodide, ethylchloride, ethylbromide, ethyliodide, propylchloride, propylbromide, propyliodide, butylchloride, butylbromide, butyliodide, pentylchloride, pentylbromide, pentyliodide, ethylbromoacetate, or the like. C1-CH lower alkyl sulfonate means methylsulfonate, ethylsulfonate, propylsulfonate, butylsulfonate, pentylsulfonate, or the like. Substituted or unsubstituted C3-C8 cycloalkylhalogen cyclopropylchloride, cyclopropylbromide, cyclopropyliodide, cyclobutylchloride, cyclobutylbromide, cyclobutyliodide, cyclopentylchloride, cyclopentylbromide, cyclopentyliodide, cyclohexylchloride, cyclohexylbromide, cyclohexyliodide, cyclopropyl methylchloride, cyclopropyl methylbromide, cyclopropyl methyliodide, cyclobutyl methylchloride, cyclobutyl methylbromide, cyclobutyl methyliodide, ryclopcnlyl liiclliylchloi ide, cyclopentyl iiielhylbioniide, cyclouenlyl methyliodide, cyclohexyl methylchloride, cyclohexyl methylbromide, cyclohexyl methyliodide, or the like. Arylhalogen means benzylchloride, benzylbromide, benzyliodide, benzoylchloride, benzoylbromide, benzoyliodide, toluylchloride, toluylbromide, toluyliodide, or the like. Substituted or unsubstituted C3-C8 cycloalkyl sulfonate means cyclopropyl sulfonate, cyclobutyl sulfonate, cyclopentyl sulfonate, cyclohexyl sulfonate, methylcyclopropyl sulfonate, methylcyclobutyl sulfonate, methylcyclopentyl sulfonate, methylcyclohexyl sulfonate, or the like. Arylsulfonate means benzyl sulfonate, benzoyl sulfonate, toluyl sulfonate, or the like. More particularly, a compound of the general formula (la) may be reacted with an alkylating agent or ai-ylating agent in a solvent at the temperature of 25-80oC, for 30 minutes - 20 hours to give the object compound of the general formula(lb). An alkylating agent or arylating agent may be used in amount of 1.0 - 1.5 equivalent. Conventional organic solvent such as for example tetrahyl)rofuran, dichloromethane, acelonilrile, dimethylfonnainide may be used in the above reaction. In the above reactions, if any acid material is formed, any basic material may be preferably added as scavenger in order to eliminate the acid material from the reaction phase. Such basic material may be alkali metal hyl)roxide, alkali earth metal hyl)roxide, alkali metal oxide, alkali earth metal oxide, alkali metal carbonate, alkali earth metal carbonate, alkali metal hyl)rogen carbonate, alkali earth metal hyl)rogen carbonate such as sodium hyl)roxide, potassium hyl)roxide, calcium hyl)roxide, magnesium hyl)roxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like, or organic amines. The compound of the general formula(a) is described in prior art ( J. Med. Chem., 1992, 35, 3784, 3792 ) or may be prepared in a similar method to the art. Hereinafter the present invention will be described in more details with reference to following examples but it is not intended to limit the scope of the invention thereinto. Compounds of the general formula(I) and formula (lb) are prepared in following examples according to the above-mentioned process. (Scheme Removed) wherein Ri, R2, R3, R4, Rs, Re, R7, A, X, Y, Z are the same above. -■- (Table Removed) Example 1 l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methylthio phenyl)piperazine: a) Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate: 3-Amino-5,6-dimethyl-2-methoxypyridine(1.52g, O.Olmol) and phenylchloroformate(1.56g, O.Olmol) were dissolved in dichloromethane and was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate : hexane = 1:6) to obtain the titled compound. yield: 92 % 1H NMR(CDCb) d : 2.18(3H,s), 2.36(3I-I,s), 4.00(3H,s), 7.31(5M,m), 8.07(lH,s) b) l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methyl thiophenyl)piperazine: Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate(136mg, 0.5mmol) and l-(2-methylthiophenyl)piperazine(104mg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(76mg, O.Smmol) was added. The mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove tetrahyl)rofuran. The concentrate was purified by column chromatography(ethylacetate : hexane = 1 : 2) to obtain the titled compound, yield : 59% m.p. : 167-1G9\: 1H NMR(CDCl3) δ : 2.21(311,s), 2.43(GII,s), 3.0(3(4II,t). 3.68(411,0, 4.09(3H,s), 6:89(lH,s), 7.06(lH,m), 7.14(3H,s), 8.26(lH,s) Example 2 l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-isopropeny lphenyl)piperazine : Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and l-(2-isopropenylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield: 62 % m.p. : 139-140 °C lH NMR(CDCl3) δ : 2.20(3H,s), 2.21 (6H,s), 3.10(4H,t), 3.64(4H,t), 3.84(3H,s), 5.07(lH,s), 5.13(lH,s), 6.64(lH,s), 6.98(lH,s), 7.04(3H,dd), 7.18(lII,d), 7.91 (1II.s) Example 3 l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2,3,5,6-tetramethylphenyl)piperazine: Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and l-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 71% m.p. : 190-192 oC lH NMR(CDCl3) δ: 2.21(15II,s), 2.42(3II,s), 3.17(411,1), 3.61(411,0, 4.08(3H,s), 6.84(lH,s), 6.89(lH,s), 8.26(lH,s) Example 4 l-[(5-Ethyl-6-methyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-meth ylthiophenyl)piperazine"- Phenyl N-(5-ethyl-6-methyl-2-methoxypyridin-3-yl)carbamate and l-(2-methylthiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 56% m.p. : 160-161o0 lH NMR(CDCl3) δ: 1.19(3H,t), 2.43(3H,s), 2.50(3H,s), 2.58(2H,q), 3.07(4H,t), 3.69(4H,t), 4.15(3H,s), 6.93(lH,s), 7.06(lll,m), 7.14(3H.m), 8.35(1 H,s) Mass(EI) m/z : Calcd for C21H28N4O2 400.1932, found 400.1925 Example 5 l-[(5-Ethyl-6-methyl-2-methoxypyridin-3-yl)aminocarbonyl]-4- (2-isopropenylphenyl)piperazine-' Phenyl N-(5-ethyl-6-methyl-2-methoxypyridin-3-yl)carbarnate and l-(2-isopropenylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 51% m.p. : 185-187°C 1H NMR(CDCl3) δ: 1.18(3H,t), 2.21 (3H,s), 2.42(3H,s), 2.5G(2H,q), 3.08(4H,t), 3.62(4H,t), 4.03(3H,s), 5.08(lH,s), 5.13QH,s), 6.90(lH,s), 7.02(3H,m), 7.18(lH,d), 8.25(lH,s) Example 6 l-[(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(2,3,5,6-t etramethylphenyl)piperazine: Phenyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 69% m.p. : 176-177 °C rH NMR(CDCl3) δ: 1.19(3H,t), 2.21(12H,s), 2.44(3H,s), 2.57(2H,q), 3.17(41-1,0, 3.62(411,0, 4.06(3H,s), 6.84(lH,s), 6.92(lH,s), 8.30(lH,s) Example 7 l-[(5+Ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3-thiophenyl)piperazine: Phenyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(3-thiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 63% m.p. : 108-110 TC 1H NMR(CDCl3) δ: 1.17(3H,t), 2.37(3H,s), 2.49(2H,q), 3.28(4H,t), 3.60(4H,t), 3.98(3H,s), 6.87(4H,m), 6.98(lH,s), 8.18(lH,s) Example 8 l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine: Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 67% m.p. : 82-84°C lH NMR(CDCL3)δ: 0.94(3H,t), 1.58(2H,m), 2.37(3H,s), 2.49(2H,q), 3.25(4H,t), 3.66(4H,t), 3.78(6H,s), 3.99(3H,s), 6.07(3H,m), 6.88(lH,s), 8.16(lH,s) Mass(EI) m/z : Calcd for C23H32N4O1 428.2423, found 428.2447 Example 9 l-[(2-Melhoxy-G-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethylphenyl)piperazine Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 64% m.p. : 145-146 V, 'll NMlKCDChH: 0.95(3H,t), 1.59(2H,m), 2.29(6H,s), 2.41(3H,s), 2.49(2II,q), 3.24(4H,t), 3.67(4H,t), 3.98(3II,s), 6.59(3H,m). 6.89(lM,s), 8.17(lII,s) Mass(El) m/z : Calcd for C23H32N.4O4 428.2423, found 428.2385 Example 10 l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-(3,5- difluorophenyl)piperazine: Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 57% m.p. : 121-123 V, 1H NMR(CDCl3) δ '. 0.95(31-1,0, 1.59(211,m), 2.38(3H,s), 2.50(2H,q), 3.29(3H,t), 3.66(3H,t), 4.00(3H,s), 6.28(lII,m), 6.36(2H,d), 6.87(lII,s), 8.17UH,s) Example 11 l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-(2- methoxyphenyl)piperazine: Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and l-(2-melhoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 71% m.p. : 109-1KTC lH NMR(CDCl3) δ : 0.95(3H,t), 1.59(2H,m), 2.37(3H,s), 2.49(2H,q), 3.12(4H,t), 3.70(4H,t), 3.89(3H,s), 3.97(3H,s), 6.91(4H,rn), 6.95(lH,s), 8.19UH,s) Example 12 l-[(6-Ethyl-2-methoxy-5-methylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine: Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 65% m.p. : 115-11GTC 1H NMR(CDCl3) δ : 1.21 (3H,t), 2.21(3H,s), 2.65(2H,q), 3.27(4H,t), 3.64(4H,t), 3.79(6H,s), 3.98(3H,s), 6.09(3H,m), 6.86(lH,s), 8.12UH,s) Mass(El) m/z : Calcd for C22H30N4O4 414.2267, found 414.2240 Example 13 l-[(6-Ethyl-2-methoxy-5-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dim ethylphenyl)piperazine: Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 61% m.p. : 135-136°C 1H NMR(CDCl3) δ: 1.22(3H,t), 2.21 (3H,s), 2.29(6H,s), 2.65(2H,q), 3.24(4H,t), 3.66(4H,t), 3.98(3H,s), 6.59(3H,m), 6.87(lH,s), 8.12(lH,s) Mass(EI) m/z : Calcd for C22H30N4O2 382.2368, found 382.2376 Example 14 l-[(6-Ethyl-2-methoxy-5-methylpyridin-3-yl)aminocarbonyl]-4-(3-hyl)ro xyphenyl)piperazine: Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 56% m.p. : 168-170°C 1H NMR(CDCl3) δ: 1.21 (3H,t), 2.20(2H,s), 2.63(2H,t), 3.28(4H,t), 3.68(4H,t), 3.98(3H,s), G.41(lH,d), 6.55(lH,d), C.84(lH,m), 6.87(lII,s), 7.13(111,0, 8.10(lH,s) Mass(El) m/z : Calcd for C20H26N4O3 370.2004, found 370.1992 Example 15 l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine: Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 57% m.p : 121-122nC lH NMR(CDCl3) δ: 0.96(3H,t), 1.67(2H,m), 2.21 (3H,s), 2.58(2H,t), 3.26(411,0, 3.68(4H,t), 3.79(6H,s), 3.97(3H,s), 6.14(3H,m), 6.89(lH,s), 8.11 (lH.s) Mass(EI) m/z : Calcd for C23H32N4O4 428.2423, found 428.2423 Example 16 l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminocarbonyl]-4- (3,5-di methylphenyl)piperazine: Phenyl N-(2-inethoxy-5-methyl-6-propylpyridin-3-yl)caibamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 54% m.p. : 138-139 °C 1H NMR(CDCL3) δ: 0.96(3H,t), 1.72(2H,m), 2.21 (6H,s), 2.30(3H,s), 2.59(2H,t), 3.28(4H,t), 3.76(4H,t), 3.97(3H,s), 6.70(3H,m), 6.87(lH,s), 8.11 (lH,s) Mass(EI) m/z : Calcd for C23II32N4O2 396.2525, found 396.2432 Example 17 l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminocarbonyl]-4-(3-hyl)roxy phenyl )piperazine: Phenyl N-(2-metlioxy-5-methyl-6-propylpyridin-3-yl)carbamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 52% m.p. : 153-155 °C rH NMR(CDCl3) δ: 0.95(3H,t), 1.69(2H,m), 2.19(3H,s), 2.59(2H,t), 3.22(4H,t), 3.68(4H,t), 3.97(3H,s), 6.42(lH,d), 6.52(lH,d), 6.87(lH,s), 7.12(lH,t), 8.09(lH,s) Mass (EI) m/z : Calcd for C21H28N4O3 384.2161, found 384.2153 Example 18 l-[N-(2-Methoxy-6,7-dihydro-5H-cyclopnta[b]pyridin-3-yl) aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: Phenyl N-(2-methoxy~6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 59% m.p. : 143-144oC 1H NMR(CDCl3) δ : 2.10(2H,m), 2.87(4H,m), 3.12(4H,t), 3.70(4H,t), 3.78(6H,s), 4.00(3H,s), 6.08(3H,m), 6.90(lH,s), 8.24(lH,s) Example 19 l-[N-(2-Methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) aminocarbonyl] -4- (3,5-dimethy lpheny Dpiperazine: Phenyl N-(2-methoxy-6J-dihyl)ro-5H~cyclopenta[b]pyriclin-3-yl) cai'bamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 55% ' m.p. : 183-185oC: 1H NMR(CDCl3) δ: 2.08(2H,m), 2.28(6H,s), 2.87(4H,m), 3.22(4H,t), 3.67(4H,t), 4.00(3H,s), 6.57(3H,m), 6.89(lH,s), 8.24(lHfs) Example 20 l-[(2-Methoxy-5,6,7,8-tetrahyl)roquinolin-3-yl)aminocarbonyl]-4-(3,5- dimethoxy phenyl) piperazine : Phenyl N-(2-methoxy-5,6,7,8-tetrahyl)roquinoline-3-yl)carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 54% m.p. : 161-163°C lH NMR(CDCl3) δ: 1.75(2H,m), 1.84(2H,m), 2.67(2H.l). 2.73(2H,t), 3.27(4H,t), 3.71 (4H,t), 3.79(6H,s), 3.97(3H,s), 6.10(3H,m), 6.90(lH,s), 8.07QH,s) Example 21 l-[(2-Methoxy-5,6)7,8-tetrahyl)roquinolin-3-yl)aminocarbonyl]-4-(3,5- dimethyphenyl)piperazine: Phenyl N-(2-methoxy-5,6,7,8-tetrahyl)roquinolin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 51% m.p. : 143-144 oC 1H NMR(CDCl3) δ: 1.75(2H,m), 1.84(2H,m), 2.30(6H,s), 2.68(2H,t), 2.72(2H,t), 3.26(4H,t), 3.67(4H,t), 3.97(3H,s), 6.61 (3H,m), 6.91(lH,s), 8.07(lH,s) Example 22 l-[(5,6-Dimethyl-2-rnethoxypyridin-3-yl)arninothiocarbonyl]-4-(3,5-dimethylphenyl)piperazine: Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate(200mg, 0.7mmol) and l-(3,5-dimethylphenyl)piperazine(154mg, 0.7mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBUU(106mg) was added thereto. The mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography ( ethylacetate : hexane = 1 : 2 ) to obtain the titled compound, yield : 50% m.p. : 192-193 °C 1H NMR(CDCl3) δ : 2.21 (3H,s), 2.29(6H,s), 2.36(3H,s), 3.33(4H,t), 3.9C(3H,s), 4.09(411,0, 6.57(3H,m), 7.33(lH,s), 8.11(lH,s) Mass(EI) m/z : Calcd for C21H28N4O1S1 384.1983, found 384.1992 Example 23 l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl]-4-(3,5-difluorophenyl)piperazine: Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 47% m.p. : 60-621 ]H NMR(CDCl3) δ ■ 2.21(3H,s), 2.36(3H,s), 3.39(4II,t), 3.96(311,), 4.10(3H,t), 6.29(3H,m), 7.33(lH,s), 8.14(lH,s) Example 24 l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl]-4-(3-hyl)roxyphenyl)piperazine: Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 43% m.p. : 185-186OC 1H NMR(CDCl3) δ : 2.14(3H,s), 2.36(3H,s), 3.25(4H,t), 3.89(3H,s), 4.09(4H,t), 6.30(lH,d), 6.36(2H,m), 7.03(lH,t), 7.48(lH,s), 8.56(lH,s) Example 25 l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminothiocarbonyl]-4-(3,5 -dimethoxyphenyl)piperazine: Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)thiocarbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound. yield : 55% m.p. : 143-144 °C lH NMR(CDCl3) δ; 0.93(3H,t),.1.66(2H,m), 2.17(3H,s), 2.65(2H,t), 3.38(4H,t), 3.79(6H,s), 3.98(3H,s), 4.15(4H,t), 6.11(3H,m), 7.43(lH,s). 8.25(lH,s) Example 26 l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminothiocarbonyl]-4-(3,5 -dimethoxyphenyl)piperazine: Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound. yield : 52% m.p. : 183-184 °C 1H NMR(CDCl3) δ: 0.98(3H,t), 1.72(2H,m), 2.17(3H,s), 2.62(2H,t), 3.39(4H,t), 3.79(6H,s), 3.96(3H,s), 4.19(4H,t), 6.15(3H,m), 7.42(lH,s), 8.08(lH,s) Mass(EI) m/z : Calcd for C23H32N4O3S1 444.2195, found 444.2171 Example 27 l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminothiocarbonyl]-4-(3,5 -dimethylphenyl)piperazine-' Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound. yield : 49% m.p. : 195-197 °C 1H NMR(CDCl3) δ: 0.98(3H,t), 1.73(2H,m), 2.18(6H,s), 2.34(3H,s), 2.62(2H,t), 3.47(4H,t), 3.96(3H,s), 4.01(4H,t), 6.59(3H,m), 7.02(lH,s), 7.99(lH,s) Mass(EI) m/z : Calcd for C23H32N4O1S1 412.2296, found 412.2266 Example 28 l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminothiocarbonyl]-4-(3- hyl)roxyphenyl)piperazine: Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound. yield : 48% m.p. : 160-162OC 1H NMR(CDCl3) δ : 0.98(3H,t), 1.72(2H,m), 2.22(3H,s), 2.61 (3H,t), 3.31(4H,t), 3.95(3H,s), 4.10(4H,t), 6.45(3H,m), 7.12(lH,t), 7.41 (lH,s), 8.08(lH,s) Mass(EI) m/z : Calcd for C21H28N4O2S1 400.1932, found 400.1969 Example 29 l_[N-(2-Methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl)aminothiocar bonyl]-4-(3,5-dimethoxyphenyl)piperazine: Phenyl N-(2-methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) thiocarbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 55% m.p. : 169-170 °C 1H NMR(CDCl3) δ: 2.10(2H,m), 2.89(4H,m), 3.30(4H,t), 3.77(6H,s), 3.98(3H,s), 4.20(4H,t), 6.05(3H,m), 7.37(lH,s), 8.25(lH,s) Example 30 l-[N-(2-Methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl)arninothiocar bonyl]-4-(3,5-dimethylphenyl)piperazine: Phenyl N-(2-methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) thiocarbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 53% m.p. : 159-161 oC 1H NMR(CDCl3) δ • 2.09(2H,m), 2.28(6H,s), 2.87(4H,m), 3.67(4H,t), 4.00(3H,s), 4.21(4H,t), 6.57(3H,m), 6.93(lH,s), 8.24(lH,s) Example 31 l-[(2-Methoxy-5,6,7,8_tetrahyl)roquinolin-3-yl)aminothiocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine: Phenyl N-[(2-inethoxy-5,G,7,8~teUahyl)roquinolin-3-yl)thiocarbaniate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound. yield : 56% m.p. : 160-161 °C . lH NMR(CDCl3) δ : 1.77(2H,m), 1.83(2H,m), 2.70(2H,t), 2.76(2H,t), 3.38(4H,t), 3.79(6H,s), 3.96(3H,s), 4.16(4H,t), 6.12(3H,m), 7.45(lH,s), 8.03(lH,s) Example 32 l-[(2-Methoxy-5,6,7,8-tetrahyl)roquinolin-3-yl)aminothiocarbonyl]-4-(3,5- dimethylphenyl)piperazine: Phenyl N-(2-methoxy-5,6,7,8-tetrahyl)roquinolin-3-yl)thiocarb£imate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound. yield : 54% m.p. : 200-201 oC 1H NMR(CDCl3) δ : 1.77(2H,m), 1.84(2H,m), 2.34(6H,s), 2.71 (3H,t), 2.75(3H,t), 3.47(4H,t), 3.97(3H,s), 4.42(4H,t), 6.35(3H,m), 6.91 (lH,s), 7.91(lH,s) Example 33 l-[(5,6-Dimethyl-2-methylaminopyridin-3-yl)aminocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine-' Phenyl N-(5,6-dimethyl-2-methylaminopyridin-3-yl)carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 53% m.p. : 150-1511; 1H NMR(CDCl3) δ: 2.29(3H,s), 2.48(3H,s), 3.29(4H,t), 3.45(3H,s), 3.77(6H,s), 3.79(4H,t), 6.10(3H,m), 7.40(lH,s) Example 34 l-[(5,6-Dimethyl-2-methylaminopyridin-3-yl)aminocai'bonyl]-4-(3,5-dimethylphenyl)piperazine: Phenyl N-(5,6-dimethyl-2-methylaminopyridin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 52% m.p. : 160-162°C 1H NMR(CDCl3) δ ; 2.30(9H,s), 2.48(3H,s), 3.31 (4H,t), 3.46(3H,s), 3.78(4H,t), 6.60(3H,m), 7.41(lH,s) Example 35 l-[(5-Ethyl-6-methyl-2-methylaminopyridin-3-yl)aminocarbonyl]-4-(3,5- dimethylphenyl)piperazine: Phenyl N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 56% m.p. : 143-145°C 1H NMR(CDCl3) δ : 1.22(3H,t), 2.28(6H,s), 2.52(3H,s), 2.72(2H,q), 3.29(4H,t), 3.45(3H,s), 3.78(4H,t), 6.59(3H,m), 7.41(lH,s) Example 36 l-[(2-Methylamino-6,7-dihyl)ro-5H-cycloi3enta[b]pyridin-3-yl) aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: Phenyl N-(2-methylamino-6,7-dihyl)i'o-511-cyclopenta[b]pyridin-3-yl) carbamate and l-(3,5~dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 49% m.p. : 148-15CTC lH NMR(CDCl3) δ: 2.09(2H,m), 2.95(4H,m), 3.30(4H,t), 3.47(3H,s), 3.77(4H,t), 3.80(6H,s), 6.10(3H,m), 7.49(lH,s) Example 37 l-[(2-Methylamino-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine: Phenyl N-(2-methylamino-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 48% m.p. : 185-187 °C ]H NMR(CDCl3) δ '• 2.14(2H,m), 2.29(6H,s), 2.95(4H,m), 3.32(4H,t), 3.47(3H,s), 3.79(4H,t), 6.59(3H,m), 7.48(lH,s) Example 38 l_{[5,6-Dimethyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine: Phenyl N-[5,6-dimethyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 58% m.p. : 74-75°C 1H NMR(CDCl3) δ : 1.46(9H,s), 2.20(3H,s), 2.21 (3H,s), 2.90(4H,t), 3.20(4H,t), 3.55(4H,t), 3.65(4H,t), 3.98(3H,s), 6.02(3H,m), 8.20(lH,s) Example 39 l-{[5,6-Dimethyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine: Phenyl N-[5,6-dimethyl-2-(4'-butoxycarbonylpiperazinyl)pyridin-3-yl] carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 56% m.p. : 155-156 °C 1H NMR(CDCl3) δ: 1.48(9H,s), 2.22(3H,s), 2.29(6H,s), 2.35(3H,s), 2.95(4H,t), 3.25(4H,t), 3.57(4H,t), 3.67(4H,t), 6.59(3H,m), 8.21(lH,s) Example 40 l-{[5-Ethyl-6-methyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-climethoxyphenyl)piperazine: Phenyl N-[5-ethyl-6-methyl-2-(4' -t-butoxycarbonylpiperazinyl) pyridin-3-yl]carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 52% m.p. : 119-120°C 1H NMR(CDCl3) δ: 1.25(3H,t), 1.48(9H,s), 2.38(3H,s), 2.51 (2H,q), 2.96(4H,t), 3.27(4H,t), 3.58(8H,m), 3.78(6H,s), 6.08(3H,m), 8.24(lH,s) Example 41 l-{[5-Ethyl-6-methyl-2-(4'-t-butoxycai-bonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine: Phenyl N-[5-ethyl-6-rnethyl-2-(4' -t-butoxycarbonylpiperazinyl) pyridin-3-yl]carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield : 50% m.p. : 126-128 °C 1NMR(CDCl3) δ : 1.20(3H,t), 1.49(9H,s), 2.29(6H,s), 2.39(3H,s), 2.52(2H,q), 2.98(4H,t), 3.23(4H,t), 3.59(8H,m), 6.59(3H,m), 7.58(lH,s), 8.26(lH,s) Example 42 l-[(5,6-Dimethyl-2-piperazinylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-{[5,6-Dimethyl-2-(4'-t-butoxycarbonylpii3erazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(0.218g, 0.4mmol) was dissolved in dichloromethane : nitromethane = 2 : l(lOml) and anisole(0.2Gg, 2.4mmol) and aluminum chloride(0.3g, 2,4mmol) were added slowly thereto. The mixture was stirred at room temperature for 20min. Distilled water(50ml) was added into the mixture and the mixture was made basic with saturated NaHC03 and extracted with dichloromethane and then concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography (methanol : dichloromethane = 8^1) to obtain the titled compound, yield : 89% m.p. : oil phase lH NMR(CDCl3)a: 2.21 (3H,s), 2.35(3II,s), 3.02(411,0, 3.34(411,0, 3.59(4H,t), 3.62(4H,t), 3.78(6H,s), 6.08(3H,m), 8.18(lH,s) Example 43 l_[(5,6-Dimethyl-2-piperazinylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine: l-{[5,6-Dimetriyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 42 to obtain the titled compound, yield : 85% m.p. : 103-105°C 1H NMR(CDCl3) δ: 2.16(3H,s), 2.24(6H,s), 2.40(3H,s), 3.30(4H,O, 3.44(4H,t), 3.50(4H,t), 3.81 (4H,t), 6.95(3H,m), 7.72(lH,s) Example 44 l-[(5-Ethyl-6-methyl-2-piperazinylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-{[5-Ethyl-6-methyl-2-(4'-t-butoxycarbonylpiperazinyi)pyridin-3-yI] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 42 to obtain the titled compound, yield : 88% m.p. : 68-70 oC lH NMR(CDCl3) δ : 1.20(3H,t), 2.40(3H,s), 2.52(2H,q), 2.75(4H,t), 3.32(4H,t), 3.70(8H,m), 3.78(6H,s), 6.09(3H,m), 7.68(lII,s), 8.23(1I-I,s) Example 45 l-[(5-Ethyl-6-methyl-2-piijerazinylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethylphenyl)piperazine: l-{[5-Ethyl-6-methyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 42 to obtain the titled compound. yield : 85% m.p. : 100-102OC; lH NMR(CDCl3) δ: 1.20(3H,t), 2.28(6H,s), 2.39(3H,s), 2.65(2H,q), 2.76(4H,t), 3.00(4H,t), 3.23(4H,t), 3.70(4H,t), 6.58(3H,m), 7.66(lH,s), 8.24(lH,s) Example 46 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate(200mg, 0.67mmol) and l-(3,5-dimethoxyphenyl)piperazine(150mg, 0.67mmol) were dissolved in anhyl)rous tetrahyl)rofuran(15ml) and DBU(100mg, 0.67mmol) was added. The mixture was stirred at room temperature for 2 hrs and concentrated under the reduced pressure to remove tetrahyl)rofuran. The concentrate was purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound. yield : 83% m.p. : 149-151°C 'H NMRCDCl3) δ: 2.57(3II,s), 2.65(3II,s), 3.28(4H,t,J=4.G5ITz), 3.70(4M,t, J=4.65Hz), 3.79(6H,s), 4.06(3H,s), 6.09(lH,s), 6.14(2H,d),6.94(lH,s), 8.87(lH,s) Example 47 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethylphenyl)piperazine-' Phenyl N-(5-acetyl-2-methoxy-6~methylpyridin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound. yield : 82% m.p. : 66-69°C lH NMR(CDCl3) δ : 2.31(6H,s), 2.57(3H,s), 2.65(3H,s), 3.08(4H,t), 3.30(4H,t), 4.10(3H,s), 6.71(2H,d), 6.94(lH,s), 8.89(lH,s) Example 48 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5- difluorophenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound. yield : 77% m.p. : 180-181°C lH NMR(CDCl3) δ : 2.57(3H,s), 2.65(3H,s), 3.33(4H,tJ=5.0Hz), 3.74(4H,t, J=5.0Hz), 4.07(3H,s), 6.37(lH,s), 6.46(2H,d), 6.93(lH,s), 8.85(lH,s) Example 49 l-[(5-Acetyl-2-meLhoxy-G-melhylpyridin-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound, yield : 81% m.p. : oil phase lH NMR(CDCl3) δ : 2.57(3H,s), 2.65(3H,s), 3.34(4H,t), 3.78(4H,t), 4.04(3H,s), 6.93(311,m), 8.80(lH,s) Example 50 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(2,3_ dimethylphenyl)piperazine: Pheny N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound, yield : 81% m.p. : 173-174°C 1H NMR(CDCl3) δ: 2.29(6H,s), 2.58(3H,s), 2.65(3II,s), 2.98(41-1,0, 3.70(4H,t), 4.06(3H,s), 6.91(lH,d), 6.97(lH,s), 7.10(lH,t), 8.89(lH,s) Example 51 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(2- methoxyphenyl)pipenudne-' Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(2-methoxyphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound. yield : 79% m.p. : 153-154°C lH NMR(CDCl3) δ: 2.58(3H,s), 2.65(3H,s), 3.15(411,0, 3.73(4H,0, 3.90(3H,s), 4.06(3H,s), 6.91(lH,d), 6.96(lH,d), 6.97(lH,s), 7.10(lH,t), 8.89(11-I,s) Example 52 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3-hyl)roxyphenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)cai-bamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound, yield : 76% m.p. : oil phase lH NMR(CDCl3) δ: 2.60(3H,s), 2.72(3H,s), 3.34(4H,t), 3.79(4H,t), 3.98(3H,s), 6.45(3H,m), 6.98(lH,m), 8.97(lH,s) Example 53 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminothiocai-bonyl]-4-(3,5 -dimethoxyphenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 77% m.p. : 167-169 C 1H NMR(CDCl3) δ : 2.58(3H,s), 2.68(3H,s), 3.47(4H,t), 3.81 (6H,s), 4.05(3H,s), 4.36(4H,t), 6.42(3H,m), 7.49(lH,s), 9.05QH,s) Example 54 l-[(5-Acetyl~2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(3,5 -dimethylphenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 75% m.p. : 176-177°C 1H NMR(CDCl3) δ: 2.34(6H,s), 2.58(3H,s)( 2.68(3H,s), 3.48(411,0, 4.06(3H,s), 4.43(4H,t), 7.05(3H,m), 7.52(lH,s), 9.04(lH,s) Example 55 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminothiocai'bonyl]-4-(3- hyl)roxyphenyl)piperazine-' Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thioccirbamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound. yield : 71% m.p. : 114-115°C 1H NMR(CDCl3) δ: 2.56(3H,s), 2.75(3H,s), 3.68(4H,t), 4.05(3H,s), 4.45(4H,t), 7.30(4H,m), 9.03(lH,s) Mass(EI) m/z : Calcd for C23H30N4O4S1 458.1987, found 458.2527 Example 56 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dimethoxyphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5- dirnethoxyphenyl)piperazine(100mg, 0.23mmol) was dissolved in anhyl)rous ethanol(15ml) and NaBH4(8.66mg) was added. The reaction solution was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove ethanol and purified by column chromatography (ethylacetate •' hexane = 2:1) to obtain the titled compound, yield : 97% m.p. : 124-126°C 1H NMR(CDCl3) δ: 1.48(3II,d), 2.42(3H,s), 3.27(4Htt), 3.69(411,0, 3.79(6H,s), 3.99(3H,s), 5.03(lH,q), 6.09(lH,s), 6.15(2H,d), 6.90(lH,s), 8.46(lH,s) Mass(EI) m/z : Calcd for C22H30N4O5 430.2216, found 430.2265 Example 57 l-{[5-(l-IIyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dimethylphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethylphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound. yield : 95% m.p. : 153-154°C 1H NMR(CDCl3) δ: 1.48(3H,d), 2.30(6H,s), 2.42(3H,s), 3.26(4H,t), 3.68(4H,t), 3.99(3H,s), 5.05(lH,q), 6.71 (2H,d), 6.96(lH,s), 8.46(lH,s) Mass(EI) m/z : Calcd for C22H30N4O3 398.2317, found 398.2343 Example 58 l-{ [5- (1 -Hyl)roxy ethyl)-2-methoxy-6-methylpyridin-3-yl]aininocarbonyl} -4-(2,3-dimethylphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl]-4-(2,3- dimethylphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound. yield : 96% m.p. : 100-102°C 1H NMR(CDCl3) δ: 1.47(3II,d), 1.59(3H,s), 2.25(3H,s), 2.28(3H,s), 2.43(3H,s), 2.93(4H,t), 3.66(4H,t), 3.99(3H,s), 5.05(lH,q), 6.93(3H,m), 7.11(lM,m), 8.48(lII,s) Example 59 l-{[5-(l-Hyldroxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-difluorophenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 97% m.p. : 184-18G°C 1H NMR(CDCl3) δ : 1.48(3H,d), 2.50(3H,s), 3.30(4H,t), 3.70(4H,t), 4.11(3H,s), 5.06(lH,q), 6.33(lH,s), 6.42(2H,d), 6.92(lH,s), 8.54(lH,s) Example 60 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dichlorophenyl)piperazine : l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 95% m.p. : 197-200 °C 1H NMR(CDCl3) δ : 1.46(3H,d), 2.41 (3H,s), 3.28(4H,t), 3.66(4H,t), 3.96(3H,s), 5.20(lH,q), 7.02(3H,m), 8.42(lH,s) Example 61 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocai-bonyl} -4-(2-methoxyijhenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(2- methoxyphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound. yield : 97% m.p. : 88-90°C 1H NMR(CDCl3) δ: 1.47(3II,d), 2.42(3H,s), 3.11(41-1,0, 3.70(41-1,0, 3.89(3H,s), 3.99(3H,s), 5.03(lH,q), 6.89(3H,m), 6.94(lH,s), 7.05(lH,m). 8.48(lH,s) Example 62 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4- (3-hyl)roxyphenyl)piperazine: l-[5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocai'bonyl]-4-(3-hyl)ro xyphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 87% m.p. : 194-196°C 1H NMR(CDCl3)δ: 1.47(3H,d), 2.41(3H,s), 3.27(4M,t), 3.79(4H,1), 3.98(3H,s), 5.04(lH,q), 6.57(3I-I,m), 6.90(lH,s), 7.13(11-1,0. 8.41(lII,s) Example 63 l-{[5-(l-riyl)roxyelhyl)-2-methoxy-G-inethylpyridin-3-yl]aininothio carbonyl}-4-(3,5-dimethoxyphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(3,.r3 -dimethoxyphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 89% m.p. : 189-190°C 1H NMR(CDCl3) δ: 1.47(3II,d), 2.43(3II,s), 3.35(411,0, 3.78(6H,s), 3.97(3H,s), 4.09(4H,t), 5.05(lH,q), 6.07(3H,m), 7.35(lH,s), 8.42(lH,s) Example 64 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminothio carbonyl}-4-(3,5-dimethylphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(3,5 -dimethylphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 88% in.p. : 170-172 oC lH NMR(CDCl3) δ: 1.46(3H,d), 2.29(6H,s), 2.43(3H,s), 3.43(4H,t), 3.97(3H,s), 4.10(4H,t), 5.06(lH,q), 6.60(3H,m), 7.37(lH,s), 8.40(lH.s) Example 65 l-([5-(l-Hyl)roxy-l-methylethyl)-2--methoxy-6-methylpyridin-3-yl] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine: l-{(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine(214mg, 0.50mmol) was dissolved in tetrahyl)rofuran(lOml) and CH3MgBr(0.50ml, 1.50mmol) was added slowly. The mixture solution was refluxed for 15 hrs and concentrated under the reduced pressure to remove the solvent and extracted with ethylacetate, dried and filtered. The resultant was purified by column chromatography (ethylacetate : hexane = l: 2) to obtain the titled compound, yield : 84% m.p. : 146-148OC JH NMR(CDCl3) δ: 1.64(6Hts), 2.64(3H,s), 3.25(4H.t), 3.67(4H,t), 3.78(6H,s), 3.99(3H,s), 6.07(3H,m), 6.86(lH,s), 8.47(1 H,s) Example 66 l-([5-(l-Hydroxy-l-methylethyl)-2-methoxy-6-methylpyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 65 to obtain the titled compound, yield : 81% m.p. : oil phase 1H NMR(CDCl3) δ: 1.64(6H,s), 2.29(6H,s), 2.65(3H,s), 3.24(4H,t), 3.67(411,0, 3.99(311,s), 6.59(31I,m), 7.05(111,s), 8.48(111.s) Example 67 l-l[5-(l-Hyl)roxy-l-methylpropyl)-2-methoxy-6-methylpyridin-3-yl] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine; l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(214mg, 0.50mmol) was dissolved in tetrahyl)rofuran(l0ml) and C2H5MgBr(0.50mg, 1.50mmol) was added slowly. The mixture solution was refluxed for 15 hours and concentrated under the reduced pressure to remove the solvent and extracted with ethylacetate, dried and filtered. The resultant was purified by column chromatography (ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 76% m.p. : 127-129°C lH NMR(CDCl3) δ: 0.83(3H,t), 1.63(3H,s), 1.94(2H,m), 2.61 (3H,s), 3.26(4H,t), 3.68(4H,t), 3.79(6H,s), 3.99(3H,s), 6.08(3H,m), 6.86QH,s), 8.44(lH,s) Example 68 l-{[5-(l-Hyldroxy-l-methylpropyl)-2-methoxy-6-methylpyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethylphenyl)piperazine was reacted by the same way with the example 67 to obtain the titled compound. yield : 74% m.p. : 164-165 oC 1H NMR(CDCl3) δ: 0.83(3H,t), 1.60(3H,s), 1.95(2H,m), 2.29(6H,s), 2.61(3H,s), 3.23(4H,t), 3.67(4H,t), 3.99(3H,s), 6.59(3H,m), 6.87(lH,s), 8.45(lH,s) Example 69 l-[5-({[4-(3,5-Dimethoxyphenyl)piperazino]carbonyl}amino)-6-methoxy-2 -methylpyridin-3-yl]ethyl ethanthioate: Triphenylphosphine(262mg, l.0mmol) was dissolved in tetrahyl)rofuran(15ml) and diethyl azodicarboxylate(157µ, l.0mmol) was added and then the mixture was stirred at 0'C for 30min. l-([5-(l-Hyl)i-oxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl) -4-(3,5-dimethoxyphenyl)piperazine(213mg, 0.5mmol) and thioacetic acid(72µl, l.Ommol) were dissolved in tetrahyl)rofuran and was added into the above solution. The mixture solution was stirred at 0OC for lhour and at room temperature for lhour and then was concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 62% m.p. : oil phase 1H NMR(CDCl3) δ: 1.55(3H,d), 2.20(3H,s), 2.39(3H,s), 3.15(4H,t), 3.57(4H,t), 3.69(6H,s), 3.90(3H,s), 4.74(lH,q), 6.01 (3H,m), 6.89(lH,s), 8.33(lH,s) Example 70 1 -[5- ({[4- (3,5-Dimethylphenyl)piperazino]carbony 1 }amino) -6-methoxy-2-methylpyridin-3-yl]ethyl ethanthioate: l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 69 to obtain the titled compound, yield : 60% m.p. : oil phase 1H NMR(CDCl3) δ : 1.60(3H,d), 2.26(6H,s), 2.52(3H,s), 3.20(4H,t), 3.64(4H,t), 3.96(3H,s), 4.80(lH,q), 6.56(3H,m), 6.91 (lH.s), 8.38(lH,s) Example 71 1 - {[2-Methoxy -6-methy 1-5- (1 - sulf any lmethy Djaminocarbony 1} -4 - (3,5-dimethoxyphenyl)piperazine: l-[5-({[4-(3,5-Dimethoxyphenyl)piperazino]carbonyl}amino)-G-methoxy-2 -methylpyridin-3-yl]ethyl ethanthioate(180mg, 0.37mmoi) was dissolved in tetrahyl)rofuran(15ml) and LiAlH4(15mg, 0.4mmol) was added and then the mixture was stirred at 0°C for 20min. 2N-HC1 was added the above solution. The mixture was concentrated under the reduced pressure to remove the solvent and extracted with dichloromethane, dried and filtered. The resultant was concentrated under the reduced pressure and purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 88% m.p. : oil phase 1H NMR(CDCl3) δ: 1.42(3H,d), 2.39(3H,s), 3.25(4H,t), 3.66(4H,t), 3.76(6H,s), 3.96(3H,s), 5.02(lH,q), 6.17(3H,m), 6.87(lH,s), 8.41 (lH.s) Example 72 l-{[2-Methoxy-6-methyl-5-(l-sulfanybnethyl)]aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine: l-[5-({[4-(3,5-Dimethylphenyl)piperazino]carbonyl}amino)-6-methoxy-2-methylpyridin-3-yl]ethyl ethanthioate was reacted by the same way with the example 71 to obtain the titled compound, yield : 87% m.p. : oil phase lH NMR(CDCl3) δ: 1.43(3H,d), 2.28(6H,s), 2.40(3H,s), 3.25(4H,t), 3.72(4H,t), 5.03(lH,q), 6.64(3H,m), 6.88(lH,s), 8.42(lH,s) Exmaple 73 l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-{[5-(l-Hyl)roxyethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl} -4-(3,5-dimethoxyphenyl)piperazine was dissolved in chloroform(15ml) and pyridinum p-toluensulfdnate(60mg, 0.23mmol) was added and then the mixture solution was refluxed 16hours. The above solution was concentrated under the reduced pressure to remove chloroform and purified by column chromatography to obtain the titled compound, yield : 93% m.p. : 140-141°C 1H NMR(CDCl3) δ: 2.43(3H,s), 3.27(4H,t), 3.69(4H,0, 3.79(6H,s), 4.00(3H,s), 5.25(lH,d), 5.65(lH,d), 6.08(lH,s), 6.13(2H,d), 6.82(lH,d), 6.91 UH,s), 8.53(lH,s) Mass(EI) m/z : Calcd for C22H28N4O4 412.2110, found 412.2119 Example 74 l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-(3,5- dimethylphenyl)piperazine: l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 73 to obtain the titled compound. yield : 94% m.p. : 131-132°C 1H NMR(CDCl3) δ : 1.57(3H,s), 2.31 (6H,s), 2.43(lH,s), 3.25(4H,t), 3.68(4H,t), 4.00(3H,s), 5.25(lH,d), 5.65(lH,d) δ.60(3H,m), 6.82(lH,dd), 6.92(lH,s), 8.53(lH,s) Mass(EI) m/z : Calcd for G22H28N4O2 380.2212, found 380.2236 Example 75 l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl)piperazine-l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-difluorophenyl)piperazine was reacted by the same way with the example 73 to obtain the titled compound. yield : 93% m.p. : 160-161°C 1H NMR(CDCl3) δ: 2.44(3H,s), 3.30(4H,t,J=5.5Hz), 3.68(4H,t,J=5.5Hz), 4.01 (3H,s), 5.26QH,d), 5.65(lH,d), 6.30(lH,s), 6.39(2H,d), 6.81(lH,dd), 8.53(lH,s) Mass(EI) m/z : Calcd for C22H28N4O4 412.2110, found 412.2102 Example 76 l-[(5-Isopropenyl-2-methoxy-6-methylpyridin-3-yl)aminocai-bonyl]-4- (3,5-dimethoxyphenyl)piperazine: -{[5-(l-Hyl)roxy-l-methylethyl)-2-methoxy-6-methylpyridin-3-yl) aminocarbonyl]}-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 73 to obtain the titled compound. yield : 96% m.p. : 83-85T, 1H NMR(CDCl3) δ: 2.01 (3H,s), 2.38(3H,s), 3.25(4H,t), 3.66(4H,t), 3.78(6II,s), 3.99(3H,s), 4.86(lH,s), 5.30(111,s), G.ll(3H,m), 6.90(lII,s), 8.18(1H,s) Example 77 l-[(5-lsopropenyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine: l-{[5-(l-Hyl)roxy-l-methylethyl)-2-methoxy-6-methylpyridin-3-yl]amin ocarbonyl}-4-(3,5-dimethylphenyl)pii3erazine was reacted by the same way with example 73 to obtain the titled compound. yield : 93% ' m.p. : 140-142 oC lH NMR(CDCl3) δ: 2.01(3H,s), 2.29(6H,s), 2.28(3H,s), 3.23(4H,t), 3.66(4H,t), 3.99(3H,s), 4.86(lH,s), 5.18(lH,s), 6.59(3H,m), 6.91(lH,s), 8.18(lH,s) Example 78 Ethyl 2-{l-[5-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}amino)-6- methoxy-2-methylpyridin-3-yl]ethoxy}acetate-' l-{[5-(l-Hyl)roxy)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(0.5mmol) was dissolved in dimethylformamide(15ml) and NaH(18.5mg, 0.5mmol) was added and then the mixture solution was stirred at room temperature for 15min. Ethylbromoacetate(83.5mg, 0.5mmol) was added into the above mixture and stirred at room temperature for 3hours. The mixture was concentrated under the reduced pressure to remove the solvent and purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 89% m.p. : oil phase hi NMR(CDCl3) δ: 1.25(3H,t), 1.34(3H,d), 2.42(3H,s), 3.00(4H,t), 3.29(4H,t), 3.74(6H,s), 3.97(3H,s), 4.16(4H,s), 4.53QH,q), 6.03(3H,m), 7.58(lH,s) Example 79 4-{l-[5-({[4-(3,5-Dimethoxyphenyl)piperazinolcarbonyUamino)-6-methox y-2-methylpyridin-3-yl]ethoxy}-4-oxobutanoic acid: l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl) -4-(3,5-dimethoxyphenyl)piperazine(107mg, 0.25mmol) and dimethylaminopyridine(3mg, 0.025mmol) were dissolved in pyridine and anhyl)rous succinic acid(50mg, 0.5mmol) was added. The mixture was stirred at room temperature for 5hrs. Distilled water was added into the above mixture. The above solution was extracted with CH2CI2 and the organic phase washed with 1N-HC1 and then concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography (dichloromethane : methanol - 20:1) to obtain the titled compound, yield : 78% m.p. : 158-160oC lH NMR(CDCl3) δ; 1.42(3H,d),-2.43(3H,s), 2.61 (4H,m), 3.24(4H,t), 3.66(4H,t), 3.76(6H,s), 3.95(3H,s), 5.94(lH,q), 6.04(3H,m), 6.89(lH,s), 8.13(lH,s) Example 80 4-{l-[5-({[4-(3,5-Dimethylphenyl)piperazino]carbonyl}amino)-6-methoxy- 2-methylpyridin-3-yl]ethoxy}-4-oxobutanoic acid: l-{[5-(l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 79 to obtain the titled compound, yield : 76% m.p. : 138-1401C lH NMR(CDCl3) δ: 1.43(3H,d), 2.27(6H,s), 2.55(3H,s), 2.65(4H,m), 3.24(4H,t), 3.69(4H,t), 3.95(3H,s), 5.95(lH,q), 6.60(3H,m), 6.88(lH,s), a.ii(ii-i.s) Example 81 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine: a) Phenyl N-(2-methoxyquinolin-3-yl)carbamate: 3-Amino-2-methoxyquinoline(4g, 23mmol) and phenyl chlorofonnate(4.04g, 25mmol) were dissolved in dichloromethane and stirred at room temperature for 2 hours. The above mixture was concentrated under the reduced pressure to remove dichloromethane and purified by column chromatography (hexane : ether =8:1) to obtain the titled compound. yield : 75% m.p. : oil phase 1H NMR (CDCl3) δ 4.01(3H,s), 7.30(5H,s), 7.41(lH,t), 7.70UH,d), 7.71 (lH d). 8.71(1I-I,s) b) l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine'- Phenyl N-(2-methoxyquinolin-3-yl)carbamate(148mg, 0.5mmol) and l-(3,5-dimethoxyphenyl)piperazine(112mg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added. The solution was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove tetrahyl)rofuran and purified by column chromatography (hexane : ether = 5:1) to obtain the titled compound, yield : 81% m.p. : 200-201°C 1H NMR (CDCl3): δ 3.31(4H,t,J=5.0Hz), 3.74(4H,t), 3.79(6H,s), 4.17(3H,s), 6.09(lH,s), 6.17(2H,s), 7.35(lH,t), 7.49(lH,t), 7.71 (lH,d), 7.78(lH,d), 8.78(111,s) Mass(EI) m/z : Calcd for C23H26N4O4 422.1954, found 422.1952 Example 82 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine: Phenyl N-(2-methoxyciuinolin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 79% m.p. : 143-145°C lH NMR (CDCl3): δ 2.30(6H,s), 3.29(4H,t), 3.80(4H,t), 4.18(3H,s). 6.62(3H,m), 7.36(lH,t), 7.49(lH,t), 7.71(lH,d), 7.78(lH,d), 8.79(lH,s) Mass(EI) m/z : Calcd for C23H26N4O2 390.2055, found 390.20G6 Example 83 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2,3-dimethylphenyl) piperazine: Phenyl N-(2-melhoxyquinolin-3-yl)carbamale and l-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound, yield : 83% m.p. : 174-175T; JH NMR (CDCl3): δ 2.20(3H,s), 2.39(3H,s), 3.28(4H,t), 3.69(4H,t), 3.93(3H,s), 5.98(lH,s), 6.30(lH,t), 6.37(lH,s), 6.39(lH,s), 6.63(lH,s) Example 84 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl) piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 78% m.p. : 158-1591C 1H NMR (CDCl3) δ 3.32(4H,tJ=5.0Hz), 3.72(4H,tJ=5.0Hz), 4.19(3H,s), 6.29(lH,s), 6.39(2H,d), 7.36(lH,t), 7.50(lH,t), 7.71(lH,d), 7.81(lH,d), 8.78(lH,s) Example 85 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl) piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 56% m.p. : 156-158 V. 1H NMR (CDCh): 6.83(lH,d), 6.93(1I-I,t), 7.26(lH,t), 7.38(lH,t), 7.52(lH,t), 7.71 (lH.d), 7.83(1I-I,d) Mass (EI) m/z : Calcd for C21H20N4O2CI1 430.0963, found 430.0977 Example 86 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-fluorophenyl)piperazine-* Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(2-fluorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound, yield : 81% m.p. : 156-158oC 1H NMR (CDCW: Example 87 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-chlorophenyl)piperazine-' Phenyl N-(2-methoxyquinoline-3-yl)carbamate and l-(2-chlorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 78% m.p. : 79-80'C 1H NMR (CDCl3) δ 3.32(4H,t), 3.74(4H,t), 4.20(3H.s), 6.82(2II,q), 6.94(2H,m), 7.34(2H,m), 7.48(lH,d), 7.70(lH,d), 7.78(lH,d) Example 88 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-chlorophenyl)piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(3-chlorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 73% m.p. : 97-98°C 1H NMR (CDCl3): δ 3.31 (4H,t), 3.73(4M,t), 4.18(3H,s), 6.82(lH,d), 6.87(lH,d), 6.92(lH,s), 7.21(lH,t), 7.32(lH,s), 7.37(lH,t), 7.51(11-1,0, 7.70(lH,d), 7.78(lH,d), 8.80(lH,s) Example 89 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-hyl)roxyphenyl) piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 75% m.p. : 190-191 C 1H NMR (CDCl3): δ 3.33(4H,t), 3.80(4H,t), 4.19(3H,s), 6.47UH.s), 6.62(2H,s), 7.16(lH,t), 7.32(lH,s), 7.37(lH,t), 7.51 (lH.t), 7.72(lH,d), 7.78(lH,d), 8.78(1I-I,s) Example 90 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl) piperazine^ Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(2-methoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound, yield : 88% m.p. : 159-161 oC lH NMR (CDCL3): 8 3.28(4H,t), 3.71(4H,t), 3.81(3H,s), 4.18(3H,s), 6.52(2H,s), 6.62(lH,s), 7.23(lH,t), 7.31-7.53(3H,m), 7.72(2H,m), 8.81(lH,s) Example 91 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-methylthiophenyl) piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(2-methylthiophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound, yield : 78% m.p. •• 147-149 oC lH NMR (CDCla): 8 2.44(3H,s), 3.07(4H,t), 3.75(411,0, 4.18(3H,s), 7.13(3H,m), 7.18(lH,d), 7.39(2H,m), 7.70(3H,m), 8.81(lH,s) Example 92 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-isopropoxyphenyl) piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(3-isopropoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 93% m.p. : 111-113CC lH NMR (CDCl3) δ 1.34(6H,d), 3.30(4H,t), 3.74(4H,t), 4.18(3II,s), 4.55(lH,m), 6.49(2H,s), 7.05(lH,s), 7.20(lH,t), 7.32(lH,s), 7.37(lH,t), 7.50(lH,t), 7.70(lH,d), 7.77(lH,d). 8.80(lH,s) Example 93 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-cyclopropylmethoxy phenyl)piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(3-cyclopropylmethoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 90% m.p. : 146-147 °C . 1H NMR (CDCl3): δ 0.36(2H,t), 0.65(2H,m), 1.28(lH,m), 3.31 (4H,t), 3.75(4I-I,t), 3.80(2H,d), 4.18(3H,s), 6.50(lH,s), 6.60(2H,s), 7.19(lH,t), 7.32(lH,s), 7.37(lH,t). 7.50(lH,t), 7.70(lH,d), 7.77(lH,d), 8.79(lII,s) Example 94 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-methoxy-5-methyl phenyl)piperazine-' Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 76% m.p. : 115-116°C 1H NMR (CDCl3): δ 2.30(3H,s), 3.14(4H,t), 3.75(4H,t)( 3.87(3H,s), 4.18(3H,s), 6.79(2H,m), 6.84(lH,d), 7.35(2H,m), 7.50(lH,t), 7.72(lH,d), 7.77(lH,d), 8.82(lH,s) Example 95 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-methoxy-5-phenyl phenyl)piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbarnate and l-(2-methoxy-5-phenylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 77% m.p. : 122-1231C rH NMR (CDCl3): d 3.38(4H,t) 3.86(4H,t), 3.97(3H,s), 4.18(3H,s), 7.05(2H,m), 7.34-7.45(6H,m), 7.50(lH,t), 7.56(2H,d), 7.71(2H,d), 7.78(2H,d), 8.88(lH,s) Example 96 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(5-methoxy-2-methyl phenyl)piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 82% m.p. : 128-130 °C , 1H NMR (CDCl3): δ 2.30(3II,s), 3.37(411,0, 3.84(411,0, 3.78(311,s), 3.97(3H,s), 7.05(2H,m), 7.13(lH,d), 7.38(3H,m), 7.62(lH,d), 7.80(lH,s), 8.88(lH,s) Example 97 l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(l-naphthyl)piperazine: Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(l-naphthyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound. yield : 68% m.p. : 158-16oC 1H NMR (CDCl3): δ 3.22(4H,t), 3.86(4H,t), 4.20(3H,s), 7.13(lH,d), 7.38(2H,m), 7.43(lH,t), 7.53(3H,m), 7.62(lH,d). 7.72(lH,d), 7.80(lH,d), 7.86(lH,d), 8.24(lH,d), 8.84(lH,s) Example 98 l-[N-(2-Methoxyquinolin-3-yl)-N-methylaminocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine-' l-[(2-Methoxyquinolin-3-yl)an"\inocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine(106mg, 0.25mmol) was dissolved in dimethylformamide(15ml) and sodium hyl)ride(6.0mg, 0.25mmol) was added and the solution was stirred at room temperature for 15 min. Iodomethane(35mg, 0.25mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound. yield : 93% m.p. : 88-89°C 1H NMR (CDCl3): δ 2.93(4H,t), 3.17(3Ii,s), 3.34(4H,t), 3.72(6H,s), 4.15(31-1,0, 5.95(2H,s), 5.98(lH,s), 7.40(lH,t), 7.61 (2H,m), 7.73(lH,s), 7.84(lH,d) Mass(EI) m/z : Calcd for C24H28N4O4 436.2110, found 436.2105 Example 99 l-[N-Ethyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethox yphenyl)piperazine: l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine(106mg, 0.25mmol) was dissolved in dimethylformamide(15ml) and was sodium hyl)ride(6.0mg, 0.25inmol) was added and the solution was stirred at room temperature for 15 min. Iodoethane(35mg, 0.25mmol) was added to the above solution. The mixture was stirred at room temperature for 16hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound. yield : 91% m.p. : 118-120X: yH NMR (CDCl3): δ 1.16(3H,t), 2.89(4H,t), 3.30(4H,t), 3.63(2M.m), 3.71(6H,s), 4.13(3II,s), 5.93(2H,s), 5.98(lH,s), 7.41(111,0, 7.(30(111,0, 7.66(lH,d), 7.71(lH,s), 7.84(lH,d) Mass(EI) m/z : Calcd for C25H30N4O4 450.2227, found 450.220(3 Example 100 l-[N-Isopropyl-N-(2-methoxyquinolin-3-yl)aminocai_bonyl]-4-(3,5- dimethoxyphenyl)phenyl: l-[(2-Methoxyciuinolin-3-yl)aminocarbonyl]-4-(3,5-dimelhoxyphenyl) piperazinedOGmg, 0.25mmol) was dissolved in dimethylforrnamide(15ml) and sodium hyl)ride(G.0mg, 0.25mmol) was added and the reaction solution was stirred at room temperature for 15 min. 2-Propyliodide(42mg, 0.25mmol) was added to the above solution. The mixture was stirred at room temperature for IG hours and concentrated under the reduced pressure to remove the dimethylformamide. The concentrate was purified by column chromatography (ethylacetate : hexane = 1:2) to obtain the titled compound. yield : 87% m.p. : 123-125°C 1H NMR (CDCl3) δ 1.21(6H,d), 2.79(4H,t), 3.29(4H,t), 3.70(6H,s), 4.08(3H,s), 4.41(lH,m), 5.90(2H,s), 5.96(lH,s), 7.43(lH,t), 7.63(lH,t), 7.69(lH,d), 7.75(lH,s), 7.83(lH,d) Example 101 l-[N-Cyclopropylmethyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-[(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazined(106, 0.25mmol) was dissolved in dimethylformamide(15ml) and sodium hyl)ride(6.2mg, 0.26mmol) was added and the solution was stirred at room temperature for 15 min. Bromomethylcyclopropane(22mg, 0.26mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 78% .m.p. : 118-120TC 1H NMR (CDCl3): δ 0.41(2H,m)f 0.85(2H,m), 1.28(lM,m), 2.88(41-1,1). 3.24(4H,t), 3.42(2H,d), 3.71 (6H,s), 4.13(3H,s), 5.94(3H,s), 7.44(lH,d), 7.62(lH,d), 7.78(3H,m) Example 102 l-[N-Berizyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5- dimethoxyphenyl)piperazine: l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine(114mg, 0.27mmol) was dissolved in dimethylformamide(15ml) and sodium hyl)ride(6.6mg, 0.27mmol) was added and the solution was stirred at room temperature for 15 min. Benzylbromide(46mg, 0.27mmol) was added to the above solution. The mixture was stiired at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethyl fori namide. The concentrate was purified by column chromatography (ethy lacetate : hexane = 1:2) to obtain the titled compound. yield : 90% m.p. : oil phase 1H NMR (CDCl3): δ 2.92(4H,t), 3.39(4H,t), 3.72(6H,s), 4.13(3H,s), 4.79(2H,s), 6.01(3H,m), 7.21(lH,m), 7.25(2H,m), 7.33(3H,m), 7.51(lH,s), 7.57(2H,m), 7.81 (2H,d) Example 103 l-[N-(2-Methoxyquinolin-3-yl)-N-methylaminocarbonyl]-4-(3,5-dimethyl phenyl) piperazine: l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine was reacted by the same way with the example 98 to obtain the titled compound. yield : 92% m.p : 142-143 oC 1H NMR (CDCl3): δ 2.27(GH,d), 2.90(411,0, 3.17(3H,s), 3.34(41-1,0, 4.15(3H,s), 6.41(2H,s), 6.49(lH,s), 7.40(11-1,0, 7.63(lH,t), 7.65(lH,d), 7.73(1I-I,s), 7.84(lH,d) Mass(EI) m/z :. Calcd for C24H28N4O2 404.2212, found 404.2225 Example 104 l-[N-Ethyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethyl phen y 1) piperazine: l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine was reacted by the same way with the example 99 to obtain the titled compound. yield : 89% m.p. : 84-86°C 1H NMR (CDCl3): δ 1.1G(3II,0, 2.21(GII,s), 2.87(411,0, 3.30(411,0, 3.64(2H,q), 4.13(3H,t), 6.40(2H,s), 6.48(111,s), 7.40(111,0, 7.62(111,0, 7.66(lH,d), 7.71(lH,s), 7.84(lH,d) Example 105 l-[N-Isopropyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5- dimethylphenyl)piperazine: l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine was reacted by the same way with the example 100 to obtain the titled compound. yield : 84% m.p. : 114-1151C 1H NMR (CDCL3): 1.21 (6H,d), 2.20(6H,s), 2.77(4H,t), 3.28(4H,t), 4.08(3H,s), 4.39(lH,m), 6.37(2H,s), 6.46(lH,s), 7.41(lH,t), 7.63(lH,t), 7.69(lH,d), 7.75(lH,s), 7.83(lH,d) Example 106 l-[N-Benzyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine: l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine was reacted by the same way with the example 102 to obtain the titled compound, yield : 90% m.p. : oil phase lH NMR (CDCl3): δ 2.24(6H,s), 2.87(4H,t), 3.31 (4H,t), 4.13(3H,s), 4.80(2H,s), 6.42(3H,s), 7.49(lH,t), 7.62(2H,m), 7.72(2H,m) Example 107 l-[N-(2-Methoxyquinolin-3-yl)-N-methylaminocarbonyl]-4-(3- isopropoxyphenyl)piperazine: l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-isopropoxyphenyl) piperazine was reacted by the same way with the example 98 to obtain the titled compound. yield : 92% m.p. : oil phase 1H NMR (CDCl3): δ 1.28(6H,d), 2.97(411,0, 3.18(3H,s), 3.37(411,1). 4.14(3M,s), 4.49(lII,m), 6.41(3Il,m), 7.13(lH,m), 7.40(111,0, 7.62(11-1,0, 7.GG(lH,d), 7.74(lH,s), 7.84(lH,d) Example 108 l-[N-Ethyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3- isopropoxyphenyl)piperazine: l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-isopropoxyijhenyl) piperazine was reacted by the same way with the example 99 to obtain the titled compound. yield : 87% m.p. ' oil phase lH NMR (CDCl3): δ 1.16(311,0, 1.34(611,d), 2.89(4H,t), 3.30(411,t), 3.63(2H,m), 4.13(3H,s), 4.55(lH,m), 6.49(2H,s), 7.05(lH,s), 7.20(lH,t). 7.32(lll,s), 7.37(111,0, 7.50(111,1), 7.70(lH,d), 7.77(lM,d), 8.80(lH,s) Example 109 l-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3,5-diiriethoxyphenyl) piperazine: Phenyl N-(2-methoxyquinolin-3-yl)ihiocarbainate(56mg, 0.5mmol) and l-(3,5-dimethoxyphenyl)piperazine(lllmg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The above solution was concentrated under the reduced pressure to remove tetrahyl)rofuran and concentrated was purified by column chromatography(Hexane : ether - 5:1) to obtain the titled compound. yield : 76% m.p. : 171-172 °C 1H NMR (CDCl3):δ 3.41(4H,t), 3.81 (6H,s), 4.17(3H,s), 4.21(41-1,0, 6.12(11-I.s), 6.20(lH,d), 7.38(lH,t), 7.54(lH,t), 7.74(lH,d), 7.81 (lH,d), 8.90(lll,s) Example 110 l-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3,5-dimethylphenyl) piperazine-' Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound, yield : 79% m.p. : 170-171 oC 1H NMR (CDCl3):a 2.30(6II,s), 3.38(4H,t), 4.09(311,s), 4.17(411,0, 6.63(3II,m), 7.38(11-1,0, 7.54(1H,0, 7.72(lH,d), 7.81(lII,d), 8.96(lll,s) Example 111 l-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3,5-difluorophenyl) piperazine^ Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound, yield : 78% m.p. : 140-142oC lH NMR (CDCl3): δ 3.44(4H,t), 4.20(4H,t), 4.25(3H,s), 6.33(2II,m), 6.45(111,d), 7.41 (IH.t), 7.56(lH,m), 7.72(lH,m), 7.97(lH,m), 8.96(lH,s) Example 112 l-[(2-Methoxyquinolin-3-yl)aminothiocaibonyl]-4-(3,5-dichlorophenyl) piperazine: Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound. yield : 62% tn.p.: 181-183 oC lH NMR (CDCl3): δ 3.44(4H,t), 4.20(4H,t), 4.26(3H,s), 6.77(lH.s), 6.88(2H,0, 7.41(lH,t), 7.59(lH,t), 7.70(2H,m), 8.01(lH,t), 8.11(lH,s), 8.93(lH,s) Example 113 l-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3-methoxyijhenyl) piperazine: Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and l-(3-methoxyphenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound, yield : 81% m.p. : oil phase 1H NMR (CDCl3): δ 3.17(411,0, 3.89(3II,s), 4.17(41-1,0, G.90(4II.m), 7.34(111,0, 7.48(111,1), 7.70(lH,d), 7.77(lH,d), 8.80(lH.s) Example 114 l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine: a) Phenyl N-(2-methylquinolin-3-yl)carbamate: 3-amino-2-rnethylquinoline(4g, 25mmol) and phenyl chloroformate(4.04g, 25mmol) were dissolved in methylene chloride and then was stirred at room temperature for 2 hrs. The mixture solution was concentrated under the reduced pressure to remove methylene chloride and purified by column chromatography(ethylacetate : hexane = P10) to obtain the titled compound. yield : 88% 1H NMR (CDCl3): δ 2.77(3H,s), 7.30-7.53(9H,m), 8.67(lH,s) b) l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate(140mg, 0.5mmol) and l-(3,5-dimethoxyphenyl)piperazine(112mg, 0.5mmol) were dissolved in tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove letraliyl)rofuran and purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 84% m.p. : 199-200 oC 1H NMR (CDCl3): δ 2.81 (3H,s), 3.30(411,1), 3.7G(4H,t), 3.80(61 -I,s), 6.08(lII,s), 6.12(2H,d), 7.48(lH,t), 7.62(1H,0, 7.71(lH,d), 8.03(lH,d), 8.59(HI,s) Example 115 l-[(2-Methylquinolin-3-yi)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound, yield : 86% m.p. : 230-232oC lH NMR (CDCl3): δ 2.31 (6H,s), 2.82(3H,s), 3.29(411,0, 3.76(4H,t), 6.60(3II,s), 7.49(111,0, 7.63(111,0, 7.73(lll,d), 8.05(lll,d), H.GKlII.s) Exeimple 116 l-[(2-methylquinolin-3-yl)aminocarbonyl]-4-(2,3-dimethylphenyl) piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound. yield : 81% m.p. : 169-170 °C , lH NMR (CDCb): 3 2.28(6II,d), 2.84(3II,s), 3.00(411,0, 3.7(K4H,0, 6.94(2H,m), 7.11(11-1,0, 7.49(111,1), 7.63(11-1,0, 7.72(lH,d), 8.07(lH,d), 8.64(lH,s) Example 117 l-[(2-Methoxyauinolin-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl) piperazine^ Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound. yield : 81% m.p. : 238-2401: 1H NMR (CDCl3):δ 2.81(311,0, 3.34(411,1), 3.77(411,0, (5.32(111,0, 6.39(2H,d), 7.49(1H,0, 7.63(1H,0, 7.72(lH,d), 8.03(lH,d), 8.58(lH,s) Example 118 l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl) piperazine: Phenyl N-(2-inethykiuinolin-3-yl)carbarnate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound, yield : 65% m.p. : 247-249oC 3H NMR (CDCl3): δ 2.79(3H,s), 3.33(4H,t), 3.75(4H,t), 6.78(2H,s), 6.87(lH,s), 7.49(lH,t), 7.63(lH,t), 7.72(lH,d), 8.56(lH,s) Example 119 l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl) piperazine- Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(2-inethoxyphenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound. yield : 83% m.p. : 135-1361C 1H NMR (CDCW'-,d 2.82(3H,s), 3.18(4H,t), 3.79(4H,t), 3.91 (3H,s), 6.88(lH,d), 6.97(2H,s), 7.07(lH,m), 7.48(1H,0, 7.62(lH,t), 7.72(lH,d), 8.04(lH,d), 8.63(lH,s) Example 120 l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-fluorophenyl)piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(2-fluorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound, yield : 84% m.p. : 201-203 °C 1H NMR (CDCl3): δ 2.84(3H,s), 3.20(4H,t), 3.80(4H,t), 6.99(2H,m), 7.07(211,111), 7.49(111,0, 7.62(lH,t), 7.71 UH.d), 8.04(lII,d), 8.62QH,s) Example 121 l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-chlorophenyl)piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(2-chlorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound, yield : 72% m.p. : 180-181 oC lH NMR (CDCL3): d 2.83(3H,s), 3.16(4H,t), 3.80(411,0, 7.04(3M,m), 7.40(lH,d), 7.49(11-1,1), 7.(53(111,0, 7.71(lII,d), 8.05(lH,d), 8.62(lH,s) Example 122 l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-methylthiophenyl) piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(2-methylthiophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound. yield : 76% m.p. : 165-166°C lH NMR (CDCl3): δ 2.45(3H,s), 2.85(3H,s), 3.11(411,0, 3.79(411,0, 7.05(lH,m), 7.15(3H,d), 7.49(1H,0, 7.63(1H,0, 7.69(lH,d), 8.07(lH,d), 8.02(lII,s) Example 123 l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-methoxy-5-methyl phenyl)piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate and l"(2-inetlu)xy-5-methylphenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound. yield : 80% m.p. : oil phase lH NMR (CDCl3): δ 2.30(3H,s), 2.72(3H,s), 3.17(4H,t), 3.70(4M,t), 3.87(3H,s), 6.77(lII,s), 6.82(2II,s), 7.73(4H,m), 8.60(lH,s) Example 124 l-[(2-Methylauinolin-3-yl)aminocarbonyl]-4-(l-naphthyl)piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(l-naphlhyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound. yield : 64% m.p. : 220-222 °C 1H NMR (CDCl3): δ 2.83(3H,s), 3.23(4H,t), 3.80(4H,t), 6.91 (lH,s), 7.12(lH,d), 7.44(lH,d), 7.50(3H,m), 7.61(2II,m), 7.73(lH,d), 7.86(lII,d), 8.05(lH,d), 8.23(lH,d), 8.64(lII,s) Example 125 l-[(2-Methylciuinolin-3-yl)aminothiocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine: a) Phenyl N-(2-methylquinolin-3-yl)thiocarbamate: 3-Amino-2-methylquinoline(4g, 25mmol) and phenyl chlorothionoformate(4.32g, 25mmol) were dissolved in methylene chloride and then was stirred at room temperature for 2hours. The mixture solution was concentrated under reduced pressure to remove methylene chloride and purified by column chromalography(ethylacetate : hexane _ 1 : 2) to obtain the titled compound, yield : 78% TH NMR (CDCl3): d 2.77(3H,s), 7.09-7.90(9H,m), 9.14(lH,s) b) l-[(2-Methylquinolin-3-yl)aminothiocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine^ Phenyl N-(2-methylquinolm-3-yl)thiocarbamate(147mg, 0.5mmol) and l-(3,5-dimethoxyphenyl)piperazine(112mg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahyl)rofuran and purified by column chromatography(ethylacetate : hexane = 1 : 2) to obtain the titled compound, yield : 86% m.p. : 211-2121C 1H NMR (CDCb):^ 2.81 (3H,s), 3.35(4H,0, 3.79(6H,s), 4.14(4H,t), 6.07(3II,s), 7.49(2H,t), 7.68(2H,m), 8.01(lH,s), 8.07(lH,d) Example 126 l-[(2-Methylquinolin-3-yl)aminothiocarbonyl]-4-(3,5-dimethylphenyl) piperazine^ Phenyl N-(2-methylquinolin-3-yl)thiocarbarnate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 125 to obtain the titled compound, yield : 81% m.p. : 196-197 °C 1H NMR (CDCl3): δ 2.27(6H,s), 2.81(3H,s), 3.31(41-1,0, 4.11(411,0, C.53(2II,s), G.58(lII,s), 7.48(211,0, 7.67(21I.m), 7.96(1 ll.s), 8.04(HI,d) Example 127 l-[(2-Melhylquinolin-3-yl)aminothiocarbonyl]-4-(3,5-difluorophenyl) piperazine: Phenyl N-(2-methylquin()lin-3-yl)tliiocarbainate and l-(3,5-dil'luorophenyl)piperazine were reacted by the same way with the example 125 to obtain the titled compound, yield : 74% m.p. : 211 -213OC 1H NMR (CDCl3): δ 2.85(3H,s), 3.43(4H,t), 4.22(4H,t), 6.33(2H,m), 7.49(1H,0, 7.64(lH,d), 7.72(lH,t), 8.16(2H,m) Example 128 l-{[2-(Pyridin-2-yl)quinolin-4-yl]aminocarbonyl}-4-(3,5- dimethoxyphenyl)piperazine: Phenyl N-[2-(pyridin-3-yl)quinolin-4-yl]carbamate(171mg, 0.5mmol) arid l-(3,5-dimethoxyphenyl)piperazine(lllmg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added and then the mixture was stirred at room temperature for 2hrs. The above solution was concentrated under the reduced pressure to remove tetrahyl)rofuran and purified by column chromatography (dichloromethane •' methanol=20:l) to obtain the titled compound, yield : 73% m.p. : 97-98oC 1H NMR (CDCl3) δ 3.34(4H,t), 3.79(6H,s), 3.90(4H,t), 6.07(lH,s), 6.12(2H,s), 7.43(lH,t), 7.50(lH,t), 7.68(lH,t), 7.93(lH,t), 8.26(lH,d), 8.59(lH,d). 8.80(lH,d), 8.98(lH,s) Mass(EI) m/z : Calcd for C31H27N5O3 517.2113, found 517.3244 Excimple 129 l-{[2-(Pyridin-3-yl)quinolin-4-yl]aminocarbonyl}-4-(3,5- dimethoxyphenyl)piperazine: Phenyl N-[2-pyridin-3-yl)quinolin-4-yl]carbamate(171mg, 0.5mmol) and l-(3,5-dimelhoxyphenyl)piperazine(llling, 0.5nnnol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added and then the mixture was stirred at room temperature for 2 hours. The above solution was concentrated under the reduced pressure to remove tetrahyl)rofuran and purified by column chromatography (dichloromethane : methanol = 20:1) to obtain the titled compound. yield : 67% m.p. : 95-96oC, rH NMR (CDCl3): δ 3.36(4H,t), 3.87(6H,s), 3.90(4H,t), 6.08(lH,s), 6.12(2H,s), 7.50(lH,t), 7.71(lH,t), 7.93(lH,t), 8.25(lH,d), 8.53(lH,d), 8.67(lII,s), 8.73(lII,d), 9.35(lII,s) Example 130 l-{[2-Thien-2-yl)quinolin-4-yl]aminocai-bonyl}-4-(3,5-dimethoxyphenyl) piperazine: Phenyl N-[2-(thien-2-yl)quinolin-4-yl]carbamate(173mg, 0.5mmol) and l-(3,5-dimethoxyphenyl)piperazine(lllmg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove tetrahyl)rofuran and purified by column chromatography (ethylaetate : hexane = 1:1) to obtain the titled compound. yield : 61% m.p. : oil phase lH NMR (CDCl3): δ 3.37(4H,t), 3.59(6Hts), 3.97(4H,t), 7.01 (3H,m), 7.49(lH,t), 7.69(lH,t), 7.93(lH,t), 8.20(lH,d), 8.52(lH,d), 8.64(lH,s), 8.71 QH.d), 9.35(lH,s) Example 131 l-{[2-(Pyridin-3-yl)quinolin-4-yl]aminocarbonyl}-4-(3,5-dimethylphenyl) piperazine: Phenyl N-[2-(pyridin-3-yl)quinolin-4-yl]carbamate(171mg, 0.5mmol) and l-(3,5-dimethylphenyl)piperazine(95mg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove tetrahyl)rofuran, and purified by column chromatography (ethylacetate : hexane =1:1) to obtain the titled compound. yield : 64% .m.p. : 211-213TC lU NMR (CDCL3):^ 2.31 (6H,s), 3.32(4H,t), 3.85(4H,t), 6.61 (3H,s), 7.47(lH,t), 7.55(lH,t), 7.72(lH,t), 7.86(lH,t), 8.25(lH,d), 8.53(lH,d), 8.66(lH,s), 8.72(lH,d), 9.37(lH,s) Example 132 l-[N-(5,6-Dimethyl-2-methoxypyridin-3-yl)-N-methylaminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100mg, 0.25mmol) was dissolved in dimethylformamide(15ml) and thereto sodium hyl)ride(6.0mg, 0.25mmol) was added. The resulting mixture was stirred at room temperature for 15 min and thereto iodomethane(35mg, 0.25mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced presssure to remove dimethylfonnainiclc, and purified by column chromatography (ethylacetate : hexane=l:2) to obtain the titled compound. yield : 94% m.p. : oil phase lHNMR(CDCl3): δ : 2.17(3H,s), 2.38(3H,s), 2.92(4H,t), 3.04(3H,s), 3.29(411,0, 3.74(6H,s), 3.96(3H,s), 6.00(3H,m), 7.08(lH,s) Example 133 l-[N-Ethyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100mg, 0.25mmol) was dissolved in dimethylfonnamide(15ml) and thereto sodium hyl)ride(6.0mg, 0.25mmol) was added, followed by stirring at room temperature for 15 min and then iodoethane(39.2mg, 0.25mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure to remove dimethylformamide, and purified by column chromatographyCethylacetate : hexane=l:2) to obtain the titled compound, yield : 86% m.p. '• oil phase lH NMR(CDCl3)tf: 1.08(3H,t), 2.04(3H,s), 2.38(3H,s), 2.90(4H,t), 3.26(41-1,0, 3.52(2H,q), 3.74(6H,s), 5.99(3H,m), 7.06(lH,s) Example 134 l-[N-Isopropyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100mg, 0.25mmol) was dissolved in dimethylformamide(15ml) and thereto sodium hyl)ride(6.0mg, 0.25mmol) was added, followed by stirring at room temperature for 15 min, and then 2-iodopropane(42mg, 0.25mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure,to remove dimethylformamide, purified by column chromatographyCethylacetate : hexane=l:2) to obtain the titled compound, yield : 78% m.p. : oil phase 1H NMR(CDCl3) δ: 1.13(6H,d), 2.19(3H,s), 2.38(3H,s), 2.82(4H,t), 3.26(4H,t), 3.74(6H,s), 3.89(3H,s), 4.27(lH,m), 6.06(lH,s), 6.10(2II,d), 7.07(lH,s), 8.14(lH,s) Mass (EI) m/z : Calcd for C24H34N4O4 442.2580, found 442.2538 Examine 135 l-[N-(5,G-Dimethyl-2-methoxypyridin-3-yl)-N-methylaminocarbonyl]-4- (3,5-dimethylphenyl)piperazine-' l-[(5,G-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3)5-dimethyl phenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 97% m.p. : oil phase 1H NMR(CDCl3): δ: 2.15(6H,s), 2.23(3H,s), 2.37(3H,s), 2.89(41-1,0, 3.04(3I-I,s), 3.30(4H,t), 3.97(3H,s), 6.46(3H,m), 7.08(lH,s) Example 136 l-[N-(5,6-Dimethyl-2-methoxypyridin-3-yl)-N-methylaminocarbonyl]-4- (2-methoxyphenyl)piperazine: l_[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-inethoxyph enyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 94% m.p. : 131-132°C 1H NMR(CDCl3) δ: 2.16(3II,s), 2.38(3H,s), 2.80(4H,t), 3.05(3H,s), 3.35(41-1,0, 3.82(3H,s), 3.97(3H.s), 6.83(4H,m), 7.08(111.s) Examine 137 l-[N-Ethyl-N-(5,G-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4- (2-methoxyphenyl)piperazine: l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyph enyl)piperazine was reacted by the same way with the example 133 to obtain the titled compound. . yield : 87% m.p. : 112-113°C 1H NMR(CDCl3) δ: 1.08(3H,O, 2.16(3H,s), 2.38(3H,s), 2.77(411,0, 3.31(411,0, 3.58(2H,q), 3.81 (3H,s), 3.96(3H,s), 6.88(4H,m), 7.06(lH,s) Example 138 l-[N-Benzyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine: l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine(100mg, 0.27mmol) was dissolved in dimethylforrnarnide(15ml) and thereto sodium hyl)ride(6.5mg, 0.27mmol) was added, followed by stirring at room temperature for lhr, and successively benzyl bromide(46.2mg, 0.27mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure and purified by column chromatography(ethylacetate : hexane = 1: 2) to obtain the titled compound, yield : 93% m.p. : oil phase TI NMR(CDCl3) δ: 2.08(3H,s), 2.35(3H,s), 2.85(4M,t), 3.32(41-1,0. 3.81(311,s), 3.90(311,s), 4.7G(2II,s), 6.96(4II,m), 7.41(5H,m) Example 139 l-[N-Cyclopropylmethyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-methoxy phenyl) piperazine: l-[(5,G-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine(100mg, 0.26mmol) was dissolved in dimethylformamide(15ml) and thereto sodium hyl)ride(6.2mg, 0.26mmol) was added, followed by stirring at room temperature for 15 inin, and successively broinomethylcyclopropane(21.8mg, 0.26minol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure and purified by column chromatography (ethylacetate : hexane = 1: 2) to obtain the titled compound, yield : 78% m.p. : oil phase ]H NMR(CDCl3) δ: 0.34(2H,m), 0.49(2H,m), 1.35(lH,m), 2.85(4H,t), 3.28(4H,t), 3.40(2H,s), 3.89(3H,s), 3.97(3H,s), 6.97(4H,m), 7.11(lH,s) Example 140 l-[N-(5,6-Dimethyl-2-methoxypyridin-3-yl)-N-methylaminoccirbonyl]-4- (5-methoxy-2-methylphenyl)piperazine: l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(5-methoxy- 2-methylphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 74% m.p. : 91-93°C 1H NMR(CDCl3) δ: 2.15(3H,s), 2.18(3H,s), 2.39(3H,s), 2.67(4H,t), 3.05(3H,s), 3.30(4H,t), 3.75(3H,s), 3.97(3H,s), 6.48(3H,m), 7.10(lII,s) Example 141 l-[N-Ethyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4- (5-methoxy-2-methylphenyl)piperazine; l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(5-methoxy- 2-methylphenyl)piperazine was reacted by the same way with the example 133 to obtain the titled compound. yield : 94% m.p. : oil phase ]H NMR(CDCl3) δ: 1.09(3H,t), 2.15(3H,s), 2.18(3H,s), 2.39(3H,s), 2.60(4H,t), 3.27(4H,t), 3.59(2H,q), 3.75(3H,s), 3.96(3H,s), 6.45(3H,m), 7.08(lH,s) Example 142 l-[N-Benzyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4- (5-methoxy-2-methylphenyl)piperazine: l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(5-methoxy- 2-methylphenyl)piperazine was reacted by the same way with the example 138 to obtain the titled compound. yield : 97% m.p. : oil phase 1H NMR(CDCl3) δ: 1.25(3H,t), 2.08(3H,s), 2.14(3H,s), 2.35(3H,s), 2.60(4H,t), 3.32(4H,t), 3.74(3H,s), 3.95(3H,s), 4.66(2H,s), 6.44(4H,m), 6.96(5H,m), 7.12(lH,s) Example 143 l-[N-(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)-N-methylamino carbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-[(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)arninocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound, yield : 87% in.p. : 78-79°C lH NMR(CDCl3) δ : 1.14(3H,t), 2.41(3H,s), 2.52(2H,q), 2.91(411,0, 3.02(3II,s), 3.28(41-1,0, 3.74(6H,s), 3.98(3II,s), 5.98(3H,m), 7.11(lH,s) Mass(EI) in/z : Calcd for C23H32N4O4 428.2423, found 428.2434 Example 144 l_[N-(5-Ethyl-2-metlioxy-6-methylpyridin-3-yl)-N-methylamino carbonyl]-4-(3,5-dimethylphenyl)piperazine'- l-[(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 84% in.p. : 86-87°C 1H NMR(CDCl3) δ: 1.14(3H,t), 2.23(6H,s), 2.45(3H,s), 2.58(2H,q), 2.87(4H,t), 3.05(3H,s), 3.30(411,0, 3.98(3H,s), 6.46(3H,m), 7.11(lII,s) Mass (EI) m/z : Calcd for C23H32N4O2 396.2525, found 396.2575 Example 145 l-[N-Ethyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl] -4-(3,5-dimethylphenyl)piperazine: l-[(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 133 to obtain the titled compound. yield : 86% ' m.p. : 84-85°C 1H NMR(CDCl3) δ: 1.13(6H,m), 2.23(6H,s), 2.41(3H,s), 2.58(2H,q), 2.85(4H,t), 3.26(4H,t), 3.46(2H,q), 3.96(3H,s), 6.45(3H,m), 7.08QH,s) Example 146 l_[N-(2-Methoxy-6-methyl-5-propylpyridin-3-yl)-N-methylamino carbonyl]-4-(3,5-ditnethoxyphenyl)piperazine : l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 89% m.p. : oil phase 1H NMR(CDCl3) δ : 1.01 (3H,t), 1.78(2H,m), 2.21(3H,s), 2.78(2H,t), 3.78(6H,s), 3.86(4H,t), 3.99(3H,s), 4.00(3H,s), 4.22(4H,t), 6.01 (3H,m), 7.02(lH,s) Example 147 l-[N-(6-Ethyl-2-methoxy-5-methylpyridin-3-yl)-N-methylamino carbonyl] -4- (3,5-dimethoxy pheny Dpiperazine^ l-[(G-Etliyl-2-methoxy-5-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 85% m.p. : oil phase ]H NMR(CDCl3) δ : 2.21 (3H,t), 2.21 (3H,s), 2.45(2H,q), 3.21 (4H,t), 3.40(3H,s), 3.67(4H,t), 3.77(6H,s), 4.01 (3H,s), 6.07(3H,m), 6.96(lH,s), 8.07(lH,s) Example 148 l-[N-(2-Methoxy-5-methyl-G-propylpyridin-3-yl)-N-methylamino carbonyl] -4- (3,5-dimethoxy pheny Dpiperazine: l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 86% m.p. : 106-107CC 1H NMR(CDCl3) δ: 0.98(3H,t), 1.73(2H,q), 2.18(3H,s), 2.63(2H,t), 2.92(4H,t), 3.05(3H,s), 3.29(4H,t), 3.74(6H,s), 3.96(3H,s), 6.00(3H,m), 7.11(lH,s) Mass (EI) m/z : Calcd for C24H34N4O4 442.2580, found 442.2543 Example 149 l-[N-(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)-N-methylamino carbonyl] -A- (3,5-dimethoxyphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 89% m.p. : oil phase 1H NMR(CDCl3) δ: 2.50(3H,s), 2.70(3H,s), 2.97(4H,t), 3.09(3H,s), 3.33(4H,t), 3.75(6H,s), 4.06(3H,s), 6.03(3H,m), 7.72(lH,s) Mass (EI) m/z : Calcd for C23H30N4O5 442.2216, 442.2229 Example 150 l-[N-Ethyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl ]-4-(3,5-dimethoxyphenyl)piperazine-' l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 133 to obtain the titled compound. yield : 87% m.p. : oil phase lH NMR(CDCl3) δ: 1.09(3H,t), 2.49(3H,s), 2.70(3H,s), 3.00(4H,t), 3.32(41-1,0, 3.77(6H,s), 4.01(3H,s), 4.09(2H,q), 5.98(3H,m), 7.76(lH,s) Example 151 l-[N-(r)-Acelyl-2-methoxy-G-inethylpyridin~3-yl)-N-inelhylarnino Ccirb(jnyl]-4-(3,5-dimethylphenyl)piixirazine: l-[(5-Acelyl-2-inethoxy-G-ineLhylpyridin-3-yl)aiiiinocarbonylJ-4- (3,5-dimethylphenyl)piperazine was reacted by the same with the example 132 to obtain the titled compound. yield : 88% m.p. : oil phase 1H NMRCDCl3): δ: 2.24(6H,s), 2.50(3H,s), 2.70(3H,s), 2.93(4H,t), 3.09(3H,s), 3.28(4H,t), 4.06(3H,s), 6.46(3H,m), 7.73(lH,s) Example 152 l-{N-[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]-N-methyl aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine: l-[N-(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)-N-methylamino carbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.47mmol) was dissolved in anhyl)rous ethanol(15ml) and thereto sodium borohyl)ride(17.3mg) was added, then followed by stirring at room temperature for 2 hrs. The resulting mixture was concentrated under the reduced pressure to remove ethanol and purified by column chromatography(ethylacetate '• hexane = 2:1) to obtain the titled compound, yield : 97% m.p. : oil phase 1H NMR(CDCl3) δ: 1.14(3H,d), 2.44(3H,s), 2.93(4H,t), 3.06(3H,s), 3.30(4H,t), 3.74(6H,s), 3.98(3H,s), 5.03(lH,q), 6.02(3H,m), 7.50(lH,s) Example 153 l-(N-Ethyl-N-[5-(l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl] aminocarbonyl}-4-(3,5-dirnethoxyphenyl)piperazine; l-[N-Ethyl-N-(5-cetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl] -4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 152 to obtain the titled compound. yield : 96% m.p. ': oil phase 1H NMR(CDCl3) δ: 1.09(3H,t), 1.41(3II,d), 2.44(3II,s), 2.91(41-1,0. 3.27(4H.t), 3.54(lH,q), 3.74(6H,s), 3.96(3Hts), 5.03(lH,q), G.02(3H,m), 8.40(1 Ii,s) Example 154 l-{N-[5-(l-Hyl)roxyethyl)-2-methoxy-6-melhylpyndin-3-yl]-N- methylaminocarbonyl]-4-(3,5-dimethylphenyl)piperazine: l-[N-Methyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)amino carbonyl]-4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 152 to obtain the titled compound. yield : 97% m.p. : oil phase 1H NMR(CDCl3)δ: 1.41(3H,d), 2.24(6H,s), 2.44(3H.s), 2.91 (4H,t), 3.06(3II,s), 3.26(4H,t), 3.99(3H,s), 5.03(lH,q), 6.49(3H,m), 7.50(lII,s) Example 155 l-{N-[5-(l-Hyl)roxy-l-methylethyl)-2-methoxy-6-methylpyridin-3-yl]- N-methylaminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine: l-[N-Melhyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)amino carbonyl]-4-(3,5-dimethoxyphenyl)piperazine(221mg, 0.5mmol) was dissolved in tetrahyl)rofuran(lOml) and thereto methyl magnesium bromide(0.50ml, 1.50mmol). The resulting mixture was refluxed for 15 hrs, concentrated under the reduced pressure to remove used solvent, extracted with ethylacetate, filtered to dryness, and purified by column chromalography(ethylacetate '• hexane =1:2) to obtain the titled compound, yield : 92% m.p. •' oil phase 1H NMR(CDCl3) δ: 1.59(6II,s), 2.66(3II,s), 2.93(411,0, 3.0G(3M,s), 3.30(411,0. 3.74(GII,s), 3.99(3II,s), 0.03(311,m), 7.45(lII,s) Example 156 l-{N-[5-(l-Hyl)roxy-l-methylpropyl)-2-methoxy-6-methylpyridin-3-yl] -N-inethylaminocarbonyl}-4-(3,5-dimethylphenyl)piperazine: l-[N-Methyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)amino carbonyl]-4-(3,5-dimethylphenyl)piperazine(213mg, O.Smmol) was dissolved in tetrahyl)rofuran(lOml) and thereto methyl magnesium bromide(0.50ml, 1.50mmol) was added slowly, then refluxed for 15 hrs. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with ethylacetate, filtered to dryness, and purified by column chromatography (ethylacetate : hexane =1:2) to obtain the titled compound. yield : 88% m.p. : oil phase 1H NMR(CDCl3) δ: 0.79(3H,t), 1.58(3H,s), 1.85(2H,q), 2.61(3H,s), 2.99(4H,t), 3.07(3H,s), 3.30(4H,0, 3.76(6H,s), 6.12(3H,m), 7.47(lH,s) Example 157 l-{N-[2-Methoxy.-5-(l-methoxyethyl)-6-methylpyridin-3-yl]-N-methyl aminocarbonyl)-4-(3,5-dimethoxyphenyl)piperazine: l-(N-[5-(l-Hydroxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino carbonyl}-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. vield : 95% m.p. : 117-119oC 1H NMR(CDCl3) δ: 1.34(3H,t), 2.43(3H,s), 2.94(4H,t), 3.06(3H,s), 3.18(3H,s), 3.30(4H,t), 3.74(6H,s), 3.99(3H,s), 4.44(lH,q), 6.02(3H,m), 7.37(lH,s) Example 158 l-[N-(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)-N-methylamino carbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 94% m.p. : oil phase 1H NMR(CDCl3) δ: 2.46(3H,s), 2.93(411,1), 3.07(3II,s), 3.30(411,1), 3.73(6H,s), 3.99(3H,s), 5.25(lH,d), 5.48(lH,d), 6.01(3H,m), 6.78(lH.s), 7.43(lII,s) Example 159 l-[N-(2-Methoxy-6-methyl-5-viiiylpyridin-3-yl)-N-methylarnino carbonyl] -4- (3,5-dimethylpheny Dpiperazine^ l-[(2-Methoxy-G-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield :. 89% m.p. : oil phase 1H NMR(CDCl3) δ : 2.24(6H,s), 2.43(3H,s), 2.90(4H,t), 3.04(3H,s), 3.27(4M,t), 3.99(3H,s), 5.23(lH,d), 5.45(lII,d), 6.05(3H,m), G.77(lH,s), 7.40(lli,s) Example 160 l-[N-Ethyl-N-(2rmethoxy-6rmethyl-5-vinylpyridin-3-yl)aminocarbonyl] -4-(3,5-dimethoxyphenyl)piperazine: l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 133 to obtain the titled compound. vield : 92% m.p. : oil phase 1H NMRCDCl3): δ: 1.09(3H,t), 2.43(3H,s), 2.94(4H,t), 3.28(4H,t), 3.77(GH,s), 4.01(3H,s), 4.11(2H,q), 5.25(lH,d), 5.49(lH,d), 5.98(3H,m), 6.77(lH,s), 7.44(lII,s) Example 161 l-LN-(5-lsoiJropenyl-2-inethoxy-6-methylpyridin-3-yl)-N-inethylamino carbonyl]-4-(3,5-dimethoxyphenyl)piperazine- l-[(5-Isopropenyl-2-methoxy-6-methylpyridin-3-yl)aminocai'bonyl]-4- (3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 92% m.p. : oil phase VH NMR(CDCl3) δ: 1.98(3H,s), 2.43(3H,s), 2.92(4H,t), 3.06(3H,s), 3.29(41-1,1), 3.74(6H,s), 3.99(3H,s), 4.84(lH,s), 5.30(lH,s), 6.01(3H,m), 7.10(lH,s) Example 162 l-[N-(5-Isopropenyl-2-methoxy-6-methylpyridin-3-yl)-N-methylamino carbonyl] -4- (3,5-dimethylphenyl)piperazine: l-[(5-Isoprophenyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound. yield : 91% m.p. : oil phase 1H NMR(CDCl3) δ: 1.98(3II,s), 2.24(6II,s), 2.43(3II,s), 2.90(411,0, 3.06(3H,s), 3.28(411,0, 4.00(3H,s), 4.84(lH,s), 5.19(HI,s), 6.46(3II,m), 7.10(lH,s) ' Example 163 Ethyl 2-(([4-(3,5-dimethoxyphenyl)piperazino]carbonyl}(5-acetyl-2- methoxy-6-methylpyridin-3-yl)amino)acetate: l_[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine(200mg, 0.5mmol) was dissolved in dimethylformainide(15ml) and thereto sodium hyl)ride(18.5mg, O.Smmol) was added, then followed by stirring at room temperature for 15 min, -^ ■ and ethylbromoacetate(83.5mg, 0.5mmol) was added. The resulting mixture was stirred at room temperature for 3 hrs, concentrated under the reduced pressure to remove the used solvent, and purified by column chromatography(ethylacetate : hexaue =1:2) to obtain the titled compound. yield : 84% m.p. •' oil phase lH NMR(CDCl3) δ : 1.26(3H,t), 2.51 (3H,s), 2.69(3H,s), 3.04(4H,t), 3.43(411,0, 3.75(GH,s), 4.05(3H,s), 4.15(2H,q), 4.19(2H,s), 6.08(3H,s), 7.96(lII,s) Example 164 Ethyl 2-({[4-(3,5-dimethylphenyl)piperazino]carbonyl}(5-acetyl-2- methoxy-6-inethylpyridin-3-yl)amino)acetate: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 163 to obtain the titled compound. yield : 80% m.p. : oil phase 1H NMR(CDCl3) δ: 1.25(3H,t), 2.56(3H,s), 2.69(3H,s), 3.00(4H,t), 3.29(4H,t), 3.78(6H,s), 4.06(3II,s), 4.18(2II,s), 5.99(3II,m), 7.98(lII,s) Example 165 2-({[4-(3,5-Dimethoxyphenyl)piperazino]carbonyl}(5-acetyl-2-methoxy-6-methylpyridin-3-yl)amino)acetic acid: Ethyl ({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}(5-acetyl-2-methoxy -6-methylpyridin-3-yl)amino)acetate(200mg, O.«38mmol) was dissolved in mixed solvent of dioxane : distilled water =41 (15ml), and lithium hyl)roxide hyl)rate(48.1mg, 1.14mmol) was added, then followed by stirring at room temperature for 3 hrs. The resulting mixture was made acidic with 1N-HC1, extracted with ethylacetate, filtered to dryness, concentrated under the reduced pressure and purified by column chromatography (ethylacetate : hexane =1:2) to obtain the titled compound, yield : 94% m.p. : 135-137oC 1H NMR(CDCl3U: 2.52(3H,s), 2.69(3H,s), 3.11(4H,t), 3.49(4H,t), 3.74(6H,s), 4.05(3H,s), 4.24(2H,s), 6.15(3H,m), 7.83(lH,s) Example 1(36 Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}[5- (l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino)acetate^ Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl)(5-acetyl-2- methoxy-6-methylpyridin-3-yl)amino)acetate was reacted by the same way with the example 152 to obtain the titled compound. yield : 97% m.p. : 125-127 oC 1H NMR(CDCl3) δ: 1.26(3H,t), 1.42(3H,d), 2.44(3H,s), 3.04(4H,t), 3.31(4H,t), 3.75(6H,s), 3.97(3H,s), 4.16(2H,q), 4.19(2H,s), 6.15(3H,m), 7.69(lH,s) Example 167 Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}[5- (l-hyl)roxyethyl)-2-methoxy-6-rnethylpyridin-3-yl]amino)acetate: Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}[5- (l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino)acetate was reacted by the same way with the example 164 to obtain the titled compound. yield : 92% m.p. : oil phase 1H NMR(CDCh) δ: 1.41(3II,d), 2.44(3II,s), 2.98(411,0, 3.36(411,0, 3.74(CH,s), 3.98(3H,s), 4.40(2H,s), 5.00(lH,q), 6.08(3H,m), 7.69(lH,s) Example 168 Ethyl 2-({[4-(3,5-dimethylphenyl)piperazino]carbonyl}[5- (l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino)acetate: Ethyl 2-({[4-(3,5-diinethylphenyl)piperazino]carbonyl}(5-acetyl-2- methoxy-6-methylpyridin-3-yl)amino)acetate was reacted by the same way with the example 152 to obtain the titled compound. yield : 94% m.p. : 68-70oC 1H NMR(CDCl3) δ: 1.13(3H,t), 1.47(3II,d), 2.33(6H,s), 2.44(3II,s), 2.95(411,0, 3.30(4H,t), 3.98(3I-I,s), 4.10(2II,ci), 5.01(lII,c\|), G.4G(3II,m), 7.71(lll,s) Example 169 2- ({[4- (3,5-Dimethy lpheny l)piperazino]carbony 1} [5- (1 -hyl)roxy ethyl) -2- methoxy-6-methylpyridin-3-yl]amino)acetic acid-' Ethyl 2-({[4-(3,5-dimethylphenyl)piperazino]carbonyl}[5- (l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino)acetate was reacted by the same way with the example 165 to obtain the titled compound. yield : 92% m.p. : 114-116oC 1H NMR(CDCl3) δ : 1.40(3H,d), 2.23(6H,s), 2.40(3H,s), 2.91 (4H,t), 3.21(4H,t), 3.98(3H,s), 4.06(2H,s), 4.90(lH,q), 6.50(3H,m), 6.51(lH,s) Example 170 l-[(4,5-Dimelhyl-2-methxyphenyl)aminocarbonyl]-4-phenylpiperazine a) 3,4-Dimethyl anisole : To 3,4-dimethylphenol(19.3g, 0.16mol), methanol(150ml) and KOH(9.65g, 0.25mol) were added and then refluxed for 2hrs. Methyl iodide(36.5g, 0.25mol) was added thereto, refluxed for 3 hours and then followed by addition of water(150ml). The resulting mixture was extracted with ethylacetate and purified by column chromatography to obtain the titled compound, yield : 81% 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 3.77(3M,s), 6.71(2II,m), 6.97(111,s) b) 4,5-Dimethyl-2-nitroanisole: Trifluoroacetic acid(250ml) was added into 3,4-dimethylanisole(17.1g, 0.13mol), successively sodium nitrite(16.6g, 0.24mol) was added slowly in water bath, and stirred at room temperature for 14 hrs. After trifluoroacetic acid was removed and water was added thereto, the resulting mixture was extracted with ether, and purified by column chromatography to obtain the titled compound, yield : 55% lH NMR(500MHz, CDCl3): δ 2.25(3H,s), 2.32(3M,s), 3.94(3II,s), 6.85(lH,s), 7.70QH,s) c) 4,5-Dimethyl-2-rnethoxyaniline: Tetrahyl)rofuran(lOOml) and ethanol(40ml) were added into 4,5-dimethyl-2-nitroanisole(7.80g, 0.043mol) and then added 10% Pd/activated carbon(0.57g) slowly, hyl)rogenated for 5 hrs. The reaction was completed by the same way with the above and the resulting product was purified by column chromatography to obtain the titled compound. yield : 82% 1H NMR(500MHz, CDCb)-1 S 2.23(3H,s), 2.27(3H,s), 3.90(3H,s), 6.80(lII,s)f 7.68(lH,s) d) Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate: To 4,5-dimethyl-2-methoxyaniline(4.50g, 0.03mol), methylene chloride( 100ml) was added and phenyl chloroformate(4.80g, 0.03mol) was added slowly. The resulting solution was stirred for 2 hrs and thereto water( 150ml) was added, and extracted with methylene chloride and purified by column chromatography to obtain the titled compound, yield : 98% 1H NMR(500MHz, CDCb): d 2.24(3M,s), 2.27(3H,s), 3.89(3H,s), 6.85QH.S). 7.20(5H,m), 7.90(lH,s) e) l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-phenylpiperazine- Phenyl N-(4,5-dimethyl-2-methoxyphenyl)cai'bamate(5.422g, 0.02mol) and l-phenylpiperazine(3.44g, 0.02mol) were dissolved in tetrahyl)rofuran(lOml). After DBU(3.04g, 0.02mol) was added, the resulting solution was stirred at room temperature for 2 hrs, concentrated and purified by column chromatography to obtain the titled compound. yield : 85% m.p.: 143-144 °C 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 3.25(4H.t), 3.67(4H,t), 3.85(3M,s), 6.64(lH,s), 6.94(3H,m), 6.99(lH,s), 7.29(lH,t), 7.91 (lH.s) Example 171 l~[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4- (3,5~dimethoxyphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 85% m.p. : 119-120 °C JH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 3.27(4H,t), 3.70(4H,t), 3.79(6H,s), 3.85(3H,s), 6.17(2H,m), 6.65(lH,s), 6.98(lH,s), 7.90(lH,s) Mass(El) m/z : Calcd for C22H29N3O4 399.2158, found 399.2168 Example 172 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine: Phenyl N- (4,5-dimethy 1-2-methoxyphenyl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 88% m.p. : 177-178°C 1H NMR(500MHZ, CDCl3): δ 2.20(3H,s), 2.21(3II,s), 2.29(GH,s), 3.23(41-1,0, 3.66(41-1,0, 3.85(3H,s), 6.58(2H,m), 6.65(lH,s), 6.99(lH,s), 7.92(11 l.s) Mass(EI) m/z : Calcd for C22H29N3O2 367.2259, found 367.2290 Example 173 l-[4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2,3-dimethylphenyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 95% m.p. : 140-142°C lH NMR(500MHz, CDCl3): δ 2.21(3H,s), 2.22(3H,s), 2.27(3H,s), 2.29(3I-I,s), 2.95(4H,0, 3.67(4H,0, 3.85(3H,s), 6.G5(lH,s), 7.01 (3H,m), 7.93(lH,s) Example 174 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4- (2,3,5,6-tetramethylphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 93% m.p. : oil phase 1H NMR(500MHz, CDCb): 3.84(3II,s), 6.64(lH,s), 6.84(lH,s), 7.95(lII,s) Example 175 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl) piperazine: Phenyl N-(4,5-dimeUiyl-2-methoxyphenyl)carbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 89% m.p. : 102-103oC 1H NMR(500MHZ, CDCl3): δ 2.20(3H,s), 2.22(3H,s), 3.29(4H,t), 3.68(4H,t), 3.85(3M,s), 6.65(lH,s), 6.97(3H,m), 7.89(lH,s) Example 176 l-[(4,5-Uimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-chlorophenyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)cai'bamate and l-(2-chlorophenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 90% m.p. : 176-177°C 1H NMR(500MHz, CDCl3): δ 2.21(3H,s), 2.22(3H,s), 3.10(4H,t,J=5.0Hz), 3.69(4H,tJ=5.0Hz), 3.85(3H,s), 6.65(lH,s), 7.02(2II,m), 7.24(lH,m), 7.39(lH,d,J=4.0Hz), 7.92(lH,s) Example 177 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3-chlorophenyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(3-chlorophenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 84% rap. : 75-76 oC 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.22(3H,s), 3.27(4H,t,J=5.0I-Iz), 3.68(411,tJ=5.0Hz), 3.85(3H,s), 6.65(lH,s), 6.90(3H,m), 7.21(lH.t), 7.90(1 M,s) Mass (El) m/z : Calcd for C20H24N3O2CI1 373.1557, found 373.1590 Example 178 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-hyl)roxy phenyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(2-hyl)roxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 87% m.p. : 197-199t, 'TI NMR(500MHZ, CDCl3): δ 2.20(3H,s), 2.21(3H,s). 2.98(411.0, 3.72(411,0, 3.84(311,s), 0.65(111,s), 6.89(111,0, 7.00(211,m), 7.13(211.rn), 7.89(1 Il.s) Example 179 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3-hyl)roxyphenyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(3-hyl)roxyphenyl) were reacted by the same way with the example 170 to obtain the titled compound. yield : 88% m.p. : 177-178 oC 1H NMR(500MHz, CDCl3): δ 2.19(3H,s), 2.21 (3H,s), 3.24(4H,t), 3.68(4H,t), 3.85(3I-I,s), 6.41 (3H,m), 6.65(lH,s), 6.98(lH,s), 7.13(lH,t), 7.88(lII,s) Example 180 1-[(4,5-Dimetlhyl-2-methoxyphenyl)aminocarbonyl]-4 (3 thiophenyl)) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(3-thiophenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 79% m.p.: 108-1101C 1H NMR(500MHZ, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 3.26(4H,t), 3.65(4H,t), 3.84(3I-I,s), 6.64(lH,s), 6.97(4H,m), 7.05(lH,s), 7.89(lH,s) Example 181 l-[(4,5-Diinethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-acetoxyphenyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)cai'bamate and l-(2-acetoxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 84% m.p.: 129-131 r, rH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21(3H,s), 2.32(3H,s), 3.05(411,1), 3.63(41-1,0, 3.85(3H,s), 6.64(lH,s), G.99(lH,s), 7.04(lH,m), 7.17(2II,m), 7.22(lH,m), 7.90(lH,s) Example 182 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3-acetoxyphenyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(3-acetoxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 87% m.p.: 154-156oC 1H NMR(500MIIz, CDCl3): δ 2.20(3H,s), 2.21(3H,s), 2.29(3II,s), 3.27(4H,0, 3.68(4H,t), 3.85(3H,s), 6.64(lH,s), 6.66(2H,m), 6.82(lH,m), 6.98(lM,s), 7.90(lH,s) Excimple 183 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-methoxyphenyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(2-methoxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 90% m.p.: 144-145°C 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.22(3H,s), 2.26(3H,s), 2.95(4H,t, J=5.0Hz), 3.65(4H,tJ=5.0Hz), 3.78(3H,s), 3.85(3H,s), 6.59(lH,s), 6.65(lH.s), 7.00(lH,s), 7.11(lli,s), 7.93(lH,s) Example 184 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(5-methoxy-2- methylphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 88% m.p.: 140-141oC 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.22(3H,s), 2.2G(3H,s), 2.95(41-1,1, J=5.0Hz), 3.65(4H,t,J=5.0Hz), 3.78(3H,s), 3.85(3H,s), 6.59(lH,s), 6.65(lH,s), 7.00(1I-I,s), 7.11(lH,s), 7.93(lH,s) Example 185 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-melhoxy-5- methy lpheny 1) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 80% m.p.: 107-108°C lH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 2.29(3H,s), 3.10(4H,t, J=5.0Hz), 3.69(4H,t,J=5.0Hz), 3.85(3H,s), 3.86(3H,s), 6.55(lII,s), G.79(2II,m). 7.01 (ll-l,s), 9.94(lH,s) Example 186 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-methoxy-5- phenylphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(2-methoxy-5-phenylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 91% m.p.: 139-140 oC 1H NMR(500MHz, CDCl3): δ 2.21 (3H,s), 2.22(3H,s), 3.20(4H,t), 3.74(4H,t), 3.85(3H,s), 3.94(3H,s), 6.65(lH,s), 7.02(2H,m), 7.32(2H,m), 7.42(2H,t), 7.55(211.cl), 7.93(1 II.s) Example 187 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-isopropenyl phenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(2-isopropenylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 80% m.p.: 134-135 °C 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (6H,s), 3.10(4H,t), 3.64(4H,t), 3.85(3H,s), 5.08(lH,s), 5.14(lH,s), 6.64(lH,s), 7.05(3H,m). 7.70(lH,m). 7.92(1I-I,s) Example 188 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(l-naphthyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(l-naphthyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 92% m.p.: 1G0-1621C lH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 3.31(4II,t,J-5.0Mz), 3.83(3II,s), 4.04(4H,t), 6.39(2H,m), 6.69(lH,s), 7.13(1H,0, 7.30(lH,s), 7.46(lH,s) Example 189 l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(l-anthranyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and l-(l-anthranyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 94% m.p.: 74-75oC 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.22(3II,s), 3.24(4H,t), 3.70(4H,t), 3.8G(3H,s), 6.70(lH,s), 7.05(3H,m), 7.45(5H,m), 8.00(2H,m) Example 190 l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-methylaminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine: l-[(4,5-dimethyl-2-methoxyphenyl)aminoccirbonyl]-4-(3,5-dimethoxy phenyl)piperazine(0.2g, 0.5mmole) was dissolved in dimethylforrnarnide(15ml), sodium hyl)ride(12mg, 0.5mmole) was added thereto slowly, and then the resulting mixture was stirred at room temperature for 15 min, then followed by addition of iodomethane(71mg, 0.5mmole) and subsequently at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dried, filtered and purified by column chromatography to obtain the titled compound. yield: 92% m.p.: 86-88oC 1H NMR(500MHz, CDCl3): δ 2.21 (3H,s), 2.24(3H,s), 2.92(4H,t), 3.0G(3H,s), 3.31 (4H,t), 3.75(6H,s), 3.83(3H,s), 6.00(3II,m), 6.71 UH,s), 6.83(1 II,s) Mass(El) m/z : Calcd for C23H31N3O4 413.2314, found 413.2293 Example 191 l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-methylaminocarbonyl]-4- (3,5-dimethylphenyl)piperazine: l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethyl phenvDpiperazine was reacted by the same way with the example 190 to obtain the titled compound. yield: 90% m.p.: 137-138 °C 1H NMR(500MHz, CDCl3): δ 2.15(3H,s), 2.24(9H,s), 2.88(4H,t), 3.06(3H,s), 3.29(4H,t), 3.83(3H,s), 6.45(3H,m), 6.71(lH,s), 6.83(lH,s) Mass(EI) m/z : Calcd for C23H29N3O2 381.2416, 381.2436 Example 192 l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-methylaminocarbonyl]-4- (3.5-difluorophenyl)piperazine: l-[(4,5-Dimethyi-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl) piperazine was reacted by the same way with the example 190 to obtain the titled compound. yield: 87% m.p.: 98-100'C lH NMR(500MHz, CDCl3): δ 2.16(3H,s), 2.25(3H,s), 2.92(41-1,0, 3.0G(3II,s), 3.29(4H,t), 3.83(3H,s), 6.23(3H,m), 6.72(lH,s), 6.83(lH,s) Example 193 l-[N-Ethyl-N-(4,5-dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphen yl)piperazine(0.2g, O.Smmole) was dissolved in dimethylformamide(15ml), and thereto sodium hyl)ride(12mg, 0.5mmole) was added slowly. The resulting mixture was stirred at room temperature for 15 min. After iodoelhane(78mg, 0.5mmol) was added, the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dryed, filtered and purified by column chromatography to obtain the titled compound, yield: 89% m.p.: oil phase 1H NMR(500MIIz, CDCb): d 1.09(3H,t), 2.16(3H,s), 2.24(311,s). 2.75(41-1,0, 3.28(41-1,0, 3.52(2H,q), 3.75(6H,s), 3.81(3H,s), 5.98(3H,m), 6.70(lH.s), 6.80(lH,s) Example 194 l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-ethylaminocarbonyl]-4- (3,5-dimethylphenyl)piperazine: l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethyl phenyl)piperazine was reacted by the same way with the example 193 to obtain the titled compound. yield: 93% m.p.: 80-82°C lH NMR(500MHz, CDCl3): δ 1.21 (3H,t), 2.15(3H,s), 2.23(9H,s), 2.90(4H,t), 3.25(4H,t), 3.59(2H,q), 3.81 (3H,s), 6.45(3H,m), 6.69(lH,s), 6.81 (lH.s) Example 195 l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-ethylaminocai-bonyl]-4- (3,5-difluorophenyl)piperazine: l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluoro]jhenyl) piperazine was reacted by the same way with the example 193 to obtain the titled compound. yield: 87% m.p.: oil phase 1H NMR(500MHz, CDCl3): δ 1.09(3H,t), 2.16(3H,s), 2.25(3H,s), 2.90(4H,t), 3.27(4H,t), 3.52(2H,q), 3.81 (3H,s), 6.24(3H,m), 6.70(lH,s), 6.81(lH,s) Example 196 l-[N-Isopropyl-N-(4,5-dimethyl-2-melhoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl)piperazine: l-[(4,5-Dimeth3d-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl) piperazine(0.2g, 0.52mmole) was dissolved in dimethylformamide(15ml) and thereto sodium hyl)ride(12.48mg, 0.52mmole) was slowly added. The resulting mixture was stirred at room temperature for 15 min. After 2-iodopropane(87.88mg, 0.52mmole) was added thereto, the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dryed, filtered and purified by column chromatography to obtain the titled compound, yield: 84% m.p.: oil phase lH NMR(500MHz, CDCl3): δ 1.10(3H,s), 1.26(3H,s), 2.20(3H,s), 2.25(3H,s), 2.86(4H,t), 3.26(4H,t), 3.77(3H,s), 4.25(lH,m), 6.17(3H,m), 6.68(lH,s), 6.82QHfs) Example 197 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-(3,5-dimethoxy phenyl)piperazine: (a) Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate: To 3,4-dimethyl-2-methoxyaniline(4.50g, 0.03mol), methylene chloride(100ml) was added and then phenyl chlorothionoformate(5.16g, 0.03mol) was added slowly. The resulting mixture was stirred for 2 hours, and thereto water(150ml) was added. The resulting mixture was extracted with methylene chloride and purified by column chromatography to obtain the titled compound. yield: 92% 1H NMR(500MHz, CDCl3): δ 2.21(3II,s), 2.25(311,s), 3.85(3H,s), 6.80(lH,s), 6.93(5H,m), 7.31 (lH,s) (b) l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate(0.2g, 0.7mmol) and l-(3,5-dimethoxyphenyl)piperazine(0.16g, 0.7mmol) were dissolved in tetrahyl)rofuran(lOml) and thereto DBU(0.11g, 0.7mmole) was added, followed by stirring at room temperature for 2 hours. The resulting product was concentrated and purified by chromatography to obtain the titled compound, yield: 84% m.p.: 128-129°C lH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 2.32(6H,s), 3.37(41-1,1), 3.83(3H,s), 4.08(4H,t), 6.69(3H,m), 7.39(lH,m), 7.47(lII,s) Mass(EI) m/z : Calcd for C22H29N3O3S1 415.1929, found 415.1912 Example 198 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (3,5-dimethylphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(3,5-dimethylphenyl)perazine were reacted by the same way with the example 197 to obtain the titled compound. yield : 90% m.p.: 1G4~1G5°C ]H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 2.32(CH,s), 3.37(4H,t), 3.83(3H,s), 4.08(4H,t), 6.69(3H,m), 7.39(lH,m), 7.47(lH,s) Mass (EI) m/z : Calcd for C22H29N3O1S1 383.2031, found 383.2086 Example 199 l-[(4,5-Dimelhyl-2-melhoxyphenyl)aminothiocarbonyl]-4- (2,3-dimethylphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 89% m.p.: 151-1520 1H NMR(500MHz, CDCl3): δ 2.21(3H,s), 2.24(3H,s), 2.29(GM,s), 3.03(4H,t), 3.83(3H,s), 4.10(4H,t), 6.69(lH,s), 6.97(2H,m), 7.11(111,0 Example 200 l-[(4,5~Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (3,5-difluoraphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield : 92% m.p.: 1G7-168oC 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 2.27(3H,s), 2.32(3H,s), 3.39(4H,t,J=5.0Hz), 3.83(3H,s), 4.14(4H,t), 6.70(lH,s), 6.80(2II,m), 7.36(lH,s), 7.44(lH,s) Example 201 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (3,5-dichlorophenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocai-bamate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 85% m.p.: 188-1891: , 1H NMR(500MI-IZ, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 3.35(41 l,t,J=5.0I-Iz), 3.83(3H,s), 4.04(4H,t,J=5.0Hz), 6.70(2H,m), 6.83(lH,s), 7.30(lH,s), 7.48(lH,s) Mass(EI) m/z : Calcd for C20H24N3O2CI1 423.0938, 423.095G Example 202 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-(2-fluorophenyl) piperazine- Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(2-fluorophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 87% m.p.: 139-140oC 1H NMR(500MHz, CDCl3): δ 2.21 (3H,s), 2.24(3H,s), 3.40(4H,t), 3.83(3H,s), 4.25(4H,t), 6.70(lH,s), 7.13(3H,m), 7.37(2H,m) Example 203 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl3-4-(2-chlorophenyl )piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(2-chlorophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield'. 85% m.p.: 115-116oC; lH NMR(500MHz, CDCl3): δ 2.21 (3H,s), 2.24(3H,s), 3.18(4H,t), 3.83(3II,s), 4.09(4H,t), 6.69(lHfs), 7.05(2H,m), 7.33(lH,s), 7.41(2H,m) Example 204 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (2-methoxyphenyl)piperazine: Plienyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(2-methoxyphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 90% m.p.: oil phase 1H NMR(500MHZ, CDCl3): δ .2.20(3H,s), 2.23(3H,s), 3.14(4H,t,J=5.0Hz), 3.82(3H,s), 3.88(3H,s), 4.06(4H,t,J=5.0Hz), 6.69(1 H,s), 6.94(311,m), 7.30(lH,s), 7.40(lH,s) Example 205 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (2-methylthiophenyl)piperazine' Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(2-methylthiophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 93% m.p.: 136-137oC 1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.26(3H,s), 2.45(3H,s), 3.33(4H,t), 3.82(3H,s), 4.39(4H,t), 6.74(lH,s), 7.16(3H,m), 7.47(2H,m) Example 206 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (3-hyl)roxyphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 77% m.p.: Decomposed(2(XrC) 1H NMR(500MHZ, CDCl3): δ 2.17(3H,s), 2.23(3H,s), 3.31(411,0, 3.82(3II,s), 4.03(31-1,1), G.37(2H,m), 6.47(lII,d), 6.69(lM,s), 7.13(111,1). 7.45(1I-I,s) Example 207 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (2-phenoxyphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(2-phenoxyphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 86% m.p.: oil phase 1H NMR(500MHZ, CDCl3): δ 2.17(3H,s), 2.24(3H,s), 3.19(4H,t), 3.80(3H,s), 3.85(4H,t), 6.66(lH>s), 6.91 (2H,m), 6.98(lH,m), 7.05(3H.m), 7.13(lH,m), 7.23(1I-I,m), 7.31 (2H,m), 7.3G(lH,s) Example 208 l-[(4,5-Diinethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (2-is(jpropenylphenyl)piperazine: Phenyl N-(4,5-dimeLhyl-2-methoxyphenyi)thiocarbamate and l-(2-isopropenylphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound, yield: 75% m.p.: 157-1580 l¥L NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 2.24(3H,s), 3.19(4H,t), 3.82(3H,s), 4.05(4H,t), 5.07(lH,s), 5.16(lH,s), 6.69(lH,s), 7.11(3H,m), 7.33(lH,s), 7.45(lH,s) Example 209 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4- (2-methoxy-5-methylphenyl)piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 87% m.p.: oil phase 1H NMR(500MHz, CDCb): 3.13(4H,t), 3.83(3H,s), 3.85(3H,s), 4.05(411,0, 6.69(lH,s), 6.83(211,m), 7.30(lH,s), 7.40(lH,s) Example 210 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-(l-naphthyl) piperazine: Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and l-(l-naphthyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 87% m.p.: 139-140t lll NMRSOOMIIz, CDCl3): δ 2.23(3H,s), 2.24(3II,s), 3.21(411,1), 3.84(3H,s), 4.09(4H,t), 6.70(lH,.s), 7.10(lH,d), 7.48(5H,m), 7.85(1 H,m), 8.22(lH,d) Example 211 l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 91% m.p.: 103-105 °C 1H NMR(500MHz, CDCk): S 2.54(3H,s), 2.59(3H,s), 3.27(4H,t), 3.70(4H,O. 3.79(6H,s), 3.94(3H,s), 6.13(3H,m), 6.70(lH,s), 7.05(lH,s), 8.72(11-I,s) Example 212 l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbonyl]-4-(3,5-dimethy -lphenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield : 88% m.p.:. 140-1420 LH NMROOOMHz, CDCl3): δ 2.30(3H,s), 2.54(3H,s), 2.59(3H,s), 3.26(4H,t), 3.70(4H,t), 3.97(3H,s), 6.61(3H,m), 6.70(lH,s), 7.06(lH,s), 8.72(lH,s) Example 213 l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbonyl]-4-(3,5-dichloro- phen y 1) piperazine: Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound. yield: 78% m.p.: 170-172 °C 1H NMR(500MHZ, CDCl3): δ 2.54(3H,s), 2.59(3H,s), 3.32(4H,t), 3.74(4H,t). 3.94(3H,s), 6.69(lH,s), 6.86(3H,m), 7.04(lH,s), 8.69(lH,s) Example 214 l-([5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminocarbonyl}-4- (3,5-dimethoxyphenyl)piperazine: 1 -[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbony 1] -4- (3,5-dimethoxyphenyl)piperazine(0.2g, 0.47mmol) was dissolved in anhyl)rous ethanol (15ml), and sodium borohyl)ride(17mg) was added thereto, and then the resulting mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove ethanol, and purified by column chromatography(ethylacetate:hexane = 1:2) to obtain the titled compound. yield: 96% m.p.: 152-154 r, lR NMR(500MHz, CDCl3): δ 1.41(3H,d), 2.32(3H,s), 3.27(4H,t), 3.71 (4H,t), 3.79(6H,s), 3.87(3H,s), 5.04(lH,q), 6.10(3H,m), 6.63(lH,s), 7.01(lH,s), 8.22(lH,s) Example 215 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminocai-bonyl}-4- (3,5-dimethylphenyl)piperazine: l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 214 to obtain the titled compound. yield: 96% m.p.: 140-142 V, 1H NMR(500MHz, CDCl3): δ 1.48(3H,d), 2.33(3H,s), 3.26(4H,t), 3.68(4H,t), 3.87(3H,s), 5.06UH,q), 6.61 (3H,m), 6.64(lH,s), 7.01(lH,s), 8.22(lH,s) Example 216 l-[(2-Methoxy-4-methyl-5-vinylphenyl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine; l-{[5-(l-Hyl)i"oxyethyl)-2-methoxy-4-methylphenyl]aminocarbonyl}-4- (3,5-dimethoxyphenyl)piperazine(0.2g, 0.47mmol) was dissolved in chloroform(15ml), pyridium p-toluenesulfonate(0.12g, 0.47mmol) was added thereto, and the resulting mixture was refluxed for 16 hours, and concentrated under the reduced pressure to remove chloroform and purified by column chromatography(ethylacetate:hexane= 1:2) to obtain the titled compound. yield: 84% m.p.: 163-165°C 1H NMR(500MHz, CDCl3): δ 2.31(3H,s), 3.23(4H,t), 3.58(4H,t), 3.77(6H,s), 3.87(3H,s), 5.20(lH,d), 5.62(lH,d), 6.59(3H,m), 6.63(lH,s), 6.88(lH,t), 6.99(lH,s), 8.32(lH,s) Example 217 l-[(2-Methoxy-4-methyl-5-vinylphenyl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine: l-{[5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminocarbonyl}-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 216 to obtain the titled compound. yield: 82% m.p.: 201-203°C ]H NMR(500MHz, CDCl3): δ 2.29(6H,s), 2.34(3H,s), 3.24(4H,t), 3.68(4H,t), 3.87(3H,s), 5.22(lH,d), 5.66(lH,d), 6.59(3H,m), G.63(lH,s), 6.86(lH,t), 7.02(lll,s), 8.32(lH,s) Example 218 l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 82% m.p.: 163-165'C 1H NMR(500MIIz, CDCl3): δ 2.1G(3IIts), 2.50(311,s), 3.35(411,1), 3.91(6H,s), 4.03(3H,s), 4.13(4H,t), 6.06(3H,m), 6.73(lH,s), 8.62(lH,s) Example 219 l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocai-bonyl]-4- (3,5-dimethylphenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and l-(3,5-dimethylphenyL)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 79% m.p.: 180-182 °C 1H NMR(500MHz, CDCl3): δ 2.29(6H,s), 2.57(6H,s), 3.32(4H,t), 3.92(3H,s), 4.12(4H,t), 6.56(3H,m), 6.72(lH,s), 7.39(lH,s), 8.63(lH,s) Example 220 l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocarbonyl]-4- (3,5-dichlorophenyl)piperazine: Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound. yield: 79% m.p.: 201-203 oC Hi NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.57(3H,s), 3.4G(4H,t), 3.92(3H,s), 4.25(4H,t), 6.64(lH,s), 6.88(3H,m), 7.72(lH,s), 8.57(lH,s) Example 221 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-4-inethylphenyl]aininolhi(jcarbonyl)-4 -(3,5-dimethoxyphenyl)piperazine: l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocai-bony]-4- (3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 214 to obtain the titled compound. yield: 94% m.p.: 146-148°C 'H NMlKSOOMIIz, CDCla): 8 1.44(311,(1), 2.32(3H,s), 3.35(41-1,0, 3.78(6H,s), 3.84(3H,s), 4.1K4H.O, 5.06(lH,q), 6.13(3H,m), 6.66(lH,s), 7.41 (lH,s), 7.77(lH,s) Example 222 l_{[5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminothiocarbonyl}-4 -(3,5-dimethylphenyl)piperazine: l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocarbony]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 214 to obtain the titled compound. yield: 93% m.p.: 150-152 oC 1H NMR(500MHz, CDCl3): δ 1.44(3H,d), 2.29(6H,s), 2.32(3H,s), 3.30(4H,t), 3.84(3H,s), 4.07(4H,O, 5.06(lH,q), 6.61 (3H,m), 6.66(lH,s), 7.38(1I-I,s), 7.79(1I-I,s) Example 223 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminothiocarbonyl}-4 -(3,5-dichlorophenyl)piperazine: l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocarbony]-4- (3,5-dichlorophenyl)piperazine was reacted by the same way with the example 214 to obtain the titled compound. yield: 77% m.p.: 166-168 °C 1H NMR(500MIiz, CDCla): d 1.45(3H,d), 2.33(3H,s), 3.35(411,0, 3.84(3H,s), 4.03(4H,t), 5.07(lH,q), 6.68(3H,m), 6.83(lH,s), 7.37(lH,s), 7.82QH,s) Example 224 Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}-2-methoxy-4,5-dimethylanilino)acetate : l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxy phenyl)piperazine(0.2g, O.Smmol) was dissolved in dimethylformamide(15ml), sodium hyl)ride(18.5mg, O.Smmol) was added thereto, and the resulting mixture was stirred at room temperature. Then, ethyl bromoacetate(83.5mg, 0.5mmol) was added thereto and the resulting mixture was stirred for 3 hours, concentrated under the reduced pressure to remove the used solvent and purified by column chromatography (ethylacetate:hexane=1:2) to obtain the titled compound, yield: 79% m.p.: oil phase 1H NMR(500MHz, CDCl3): δ 1.36(3H.t), 2.15(3II,s), 2.23(3H,s), 2.91(411,0, 3.22(411,0, 3.82(CII,s), 4.12(31I,s), 4.18(2Il,s), 5.98(311,m), 6.69(lll,s), 7.03(lH,s) Example 225 Ethyl 2-({[4-(3,5-dimethylphenyl)piperazino]carbonyl}-2-methoxy-4,5- dimethylanilino)acetate : l_[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4- (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 224 to obtain the titled compound. yield: 78% m.p.: oil phase 1H NMR(500MHz, CDCl3): δ 1.26(3H,t), 1.56(6H,s), 2.17(3M,s), 2.24(3H,s), 3.32(4H,t), 3.52(4H,t), 3.82(3H,s), 4.15(2M,q), 4.18(2M,s), 6.70(3I-I,m), 6.94(lH,s), 7.46(lM,s) Example 226 2-({[4-(3,5-Dimethoxyphenyl)piperazino]carbonyl}-2-methoxy-4,5- dimethylanilino)acetic acid: Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}-2-methoxy-4,5- dimethylanilino)acetate(200mg, 0.41mmole) was dissolved in dioxane: distilled water(4:l, 15ml), lithium hyl)roxide monohyl)rate(50.7mg, 1.23mmol) was added thereto, and then the resulting mixture was stirred at room temperature for 3 hours, acidified with lN-hyl)rochloric acid, extracted with ethylacetate, filtered to dryness, concentrated under the reduced pressure to remove the used solvent, and purified by column chromatography (ethylacetate: hexane" 1:2) to obtain the titled compound. yield: 80% m.p.: 188-189oC 1H NMR(500MHz, CDCl3): δ 2.14(3H,s), 2.23(3II,s), 2.93(411,0, 3.35(4H,t), 3.75(6H,s), 3.87(3H,s), 4.18(2H,s), 5.96(3H,m), G.71(lH,s). 7.71(lH,s) Example 227 2-({[4-(3,5-Dimethylphenyl)piixirazino]carbonyl}-2-methoxy-4,5- dimethylanilino)acetic acid: Ethyl 2-({[4-(3,5-dimethyiphenyl)piperazino]carbonyl}-2-methoxy-4,5- dimethylanilino)acetate was reacted by the same way with the example 226 to obtain the titled compound. yield: 78% m.p.: 170-171°C lH NMR(500MHz, CDCl3): d 2.13(3II,s), 2.24(9H,s), 2.91(411,1), 3.35(4H,t), 3.83(3H,s), 4.18(2H,s), 6.45(3H,m), 6.70(2II,s), 6.80(lH,s) Example 228 l-[(2-Hyl)i-oxy-4,5-dimethylphenyl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine: (a) 4,5-Dimelhyl-2-nitrophenol: To 3,4-dimethylphenol(12.1g, 0.lmol), trifluoroacetic acid(250ml) was added, and in water bath sodium nitrite(12.4g, 0.18mol) was added slowly. The resulting mixture was stirred at room temperature for 14 hours and concentrated under the reduced pressure to remove trifluoroacetic acid, followed by addition of water(150ml), extracted with ether and purified by column chromatography to obtain the tilled compound. yield: 80% lH NMR(500MHz, CDCl3): δ 2.23(3H,s), 2.29(3H,s), 6.93(lH,s), 7.84(lH,s) (b) 4,5-Dimethyl-2-hyl)roxyaniline: To 4,5-dimethyl-2-nitrophenol(11.7g, 0.07mol), tetrahyl)rofuran( 100ml) and ethanol(40ml) were added, and 10% palladium/activated carbon(0.57g) was added slowly, and then the mixture was hyl)rogenaled for 5 hours. The reaction mixture was concentrated and chromatographed by the same way above to obtain the titled compound, yield : 77% lH NMR(500MHz, CDCl3): δ 2.11(6H,s), 6.56(2H,s) (c) Phenyl N-(4,5-dimethyl-2-hyl)roxyphenyl)carbamate: To 4,5-dimethyl-2-hyl)roxyaniline(6.80g, 0.05mole), methylene chloride( 100ml) was added and then phenyl chloroformate(8.0g, 0.05mole) was added slowly. After stirring for 2 hours; addition of water( 150ml), extraction with methylene chloride and column chromatography gave the titled compound. yield: 92% 1H NMR(500MHz, CDCl3): δ 2.17(6H,s), 6.74(lH,s), 7.15(5H.m), 7.31 (lH,s) (d) Phenyl N-[2-(t-butyldimethylsilyloxy)-4,5-dimethylphenyl]cai-bamate: To a mixture of phenyl N-(4,5-dimethyl-2-hyl)roxyphenyl)carbamate (7.72g, 0.03mol) and imidazole(2.2g, 33mmol), methylene chloride( 100ml) was added, and with stirring t-butyldimethylsilylchloride(5.0g, 33mmole) was added. Then the mixture was stirred for 2 hours, and water(150ml) was added thereto. The resulting mixture was extracted with methylene chloride, dried, concentrated under the reduced pressure and purified by column chromatography to obtain the titled compound. yield: 83% 1H NMR(500MMz, CDCl3): δ 0.27(6H,s), 0.98(9H,s), 2.17(6H,s), 7.12(5I-I,m), 7.30(2H,s) (e) l-[(2-IIyl)ioxy-4,5-dimethylphenyl)aminocarbonyl]-4- (3,5-dimethoxyphenyl)piperazine: Phenyl N-[2-(t-butyldimethyisilyloxy)-4,5-dimethylphenyl]carbamate (0.17g, O.Smmole) and l-(3,5-dimelhoxyphenyl)piperazine(0.13g, O.Gmmole) were dissolved in tetrahyl)rofuran(lOml), and thereto with stirring DBU(0.09g, 0.6mmole) was added, and the resulting mixture was stirred for 2 hours, concentrated and chromatographed to obtain the titled compound. yield: 87% m.p.: 145-146°C 1H NMR(500MI-Iz, CDCb): 5 2.14(3H,s), 2.18(3H,s), 3.26(4H,t), 3.67(4H,t), 3.79(6H,s), 6.07(3H,m), 6.40(3H,m), 6.67(lH,s), 6.82(lH,s), 8.87(lH,s) Example 229 l-[(2-Hyl)roxy-4,5-dimethylphenyl)aminocai'bonyl]-4- (3,5-dimethoxyphenyl)piperazine: Phenyl N-[2-hyl)roxy-4,5-dimethylphenyl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 228 to obtain the tilled compound. yield: 84% m.p.: 160-162'C JH NMR(500MHz, CDCl3): δ 2.13(3H,s), 2.17(3H,s), 2.31 (6H.s), 3.26(4H,t), 3.75(4H,t), 6.73(3H,rn), 6.81(lH,s), 8.86(lH,s) Example 230 l-[(2-Hyl)roxy-4,5-diiriethylphenyl)aminoccU"bonyl]-4-(3,5-difluorophenyl) piperazine: Phenyl N-[2-hyl)roxy-4,5-dimethylphenyl)carbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 228 to obtain the titled compound. yield: 80% m.p.: 152-154oC 1H NMR(500MHz, CDCl3): δ 2.17(3H,s), 2.20(3H,s), 3.30(4H,t), 3.70(4H,t), 6.40(3H,m), 6.70(lH,s), 6.82(lH,s), 6.98(lH,s) Example 231 l-[(2-hyl)roxy-4,5-dimethylphenyl)aminocarbonyl]-4-(3,5-dichlorophenyl) piperazine: Phenyl N-(2-hyl)roxy-4,5-dimethylphenyl)carbarnate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 228 to obtain the titled compound. yield: 77% m.p.: oil phase rH NMR(500MIlz, CDCl3): δ 2.15(3H,s), 2.20(3H,s), 3.32(411,0, 3.69(411,0. 6.29(3Ii,m), 6.69(lH,s), 6.81 (lH.s), 8.65(lH,s) Antitumor activities of compounds of the present invention were tested in vitro against 5 kinds of human tumor cell lines and 2 kinds of leukemia tumor cell lines. The method and result of in vitro tests is as follows. Experimental 1 : In vitro antitumor effect against human tumor cell lines. A. Tumor cell line : A549 (human non-small lung cell) SK.OV-3 (human ovarian) I-ICT-15 (human colon) XF 498 (human CNS) SKMEL-2 (human melanoma) B. SRB Assay Method. a. Human solid tumor cell lines, A549(non-small lung cell), SKMEL-2(melanoma), HCT-15(colon), SKOV-3(ovarian), XF-498(CNS) were cultured at 37°C, in 5% C02 incubators using the RPMI 1640 media containing 10% FBS, while they were transfer-cultured successively once or twice per week. Cell cultures were dissolved in a solution of 0.25% trypsin and 3 mM CDTA PBS(-) and then cells were separated from media which the cells were sticked on. b. 5xi03~2xl04 cells were added into each well of 96-well plate and cultured in 5% CO2 incubator, at 37 oC, for 24 hours. c. Each sample drug was dissolved in a little DMSO and diluted with the used medium to a prescribed concentration for experiments, wherein the final concentration of DMSO was controlled below 0.5%. d. Medium of each well cultured for 24 hours as above b. was removed by aspiration. Each 200//1 of drug samples prepared in c. was added into each well and the wells were cultured for 48 hours. Tz(time zero) plates were collected at the point of time drugs were added. e. According to the SRB assay method, cell fixing with TCA, staining with 0.4% SRB solution, washing with 1% acetic acid and elution of dye with lOmM Tris solution were carried out on Tz plates and culture-ended plates, and then, OD values were measured at 520 nm. C. Calculation of result a. Time zero(Tz) value was determined with measuring the SRB protein value at the point of time drugs were added. b. Control value(C) was determined with the OD value of an well untreated with drug. c. Drug-treated test value(T) was determined with the OD value of drug-treated well. d. Effects of drugs were estimated with growth stimulation, net growth inhibition, net killing etc. calculated from Tz, C and T. e. If T ^ Tz, cellular response function was calculated by lOOx(T-Tz)AC-Tz), and if T are shown in the next table 1. * REFERENCE 1) P. Skehan, R. Strong, D Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, S. Kenny and M. R. Boyl) : Proc. Am. Assoc. Cancer Res., 30, 012(1989) 2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. boyl). ; J. Natl. Cancer Inst, 82, 1113(1990) 3) P. Skehan, R. Strong, D. Scudiero, A. monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, S. Kenny and M. R. Boyl).iJ, Natl. Cancer Ins., 82, 1107(1990) D. Results. It was found that compounds of the present invention have the superior antitumor activities than those of cisplatin, one control, and equal to or higher antitumor activities than those of adriamycin, another control, against human solid cancer cell lines. Table 1. (Table Removed) Experimental 2. In vitro antitumor effects against animal leukemia cells. A. Materials : Tumor cell lines '■ L1210(mouse leukemia cell) P388 (mouse lymphoid neoplasma cell) B. Method : Dye Exclusion Assay. 1) The concentrations of L1210 and P388 cells being cultured in RPMI 1640 media containing 10% FBS were regulated to 1 x 10° cells/ml. 2) Sample drugs of respective concentrations diluted in the ratio of log doses were added into cell media, and cultured at 37 oC, for 48 hours, in 50% CO2 incubator, and then viable cell number was measured by dye exclusion test using trypan blue. 3) The concentration of sample compounds showing 50 % cell growth inhibition(IC * REFERENCE 1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, S. Kenney and M. R. Boyl). '■ Proc. Am. Assoc. Cancer Res., 30, (512(1989). 2) L. V. Rubinstein, R. Ii. Shoemaker, K. D. Paull, R. M. Simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks, J. Natl. Cancer Inst., 82, 1113(1990) 3) P. Skehan, R. Strong, D. Scudiero, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyl). : J. Natl. Cancer Inst., 82, 1107(1990) C. Results As the results of measurement of antitumor activities of compounds of the present invention against L1210 and P388 mouse cancer cells, it was found that the compounds tested have equal to or higher antitumor activities than those of the control drug, mitomycin C. (Table Removed) Experimental 3. * In vivo antitumor effects against mouse leukemia P388 cells. A. Material of experiment BDF1 mice were used. B. Method of experiment 1) Leukemia P388 cells being transfer-cultured successively in DBA/2 mouse, were grafted into each mouse of a group comprising 8 mice of 6 week old BDF1 mouse with the dose of 1 XlO'cells/O.lml. 2) Sample drugs were dissolved in PBS or suspended in 0.5% tween 80, and then injected into abdominal cavity of mouse at each prescribed concentration on days 1, 5, 9, respectively. 3) With observation everyl)ay, survival times of tested mice were measured. Antitumor activities was determined in such a manner that the increasing ratio(T/C%) of average survival days of drug-treated groups compared with the control group was calculated using the mean survival times of each tested groups. The results are shown at the next table 3. (Table Removed) * REFERENCE A. Goldin et al.: Euro. J. Cancer, 17, 129 (1981). C. Result Through in vivo experiments using P388 mouse cancer cells, significant antitumor effect of the compounds of examples were observed. Experimental 4. Acute toxicity test (LD50) : Litchfield-Wilcoxon method. 6 weeks old ICR mice(male 30±2.0g) were fed freely with solid feed and water at room temperature, 23±1*C and at humidity 60 ±5%. Sample drugs were injected into the abdominal cavities of mice, while each group comprises 6 mice. Observed during 14 days, external appearances and life or dead were recorded, and then, visible pathogenies were observed from dead animals by dissection. LD50 value was calculated by Litchfiled-wilcoxon method. The results are shown at the next table 4. (Table Removed) As described above, it was found that the compounds of the present invention are more safer and have superior antitumor activities to cisplatin, and accordingly have solved the problems of drugs by the prior art such as restriction of dosage, toxicity, etc. WE CLAIM: A process for the preparation of piperazine derivative of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof comprising reacting a compound of the general formula (a) with a -C(=X)- group-providing agent in the presence of organic solvent as herein described to obtain a compound of the general formula (b) and reacting the compound of the general formula (b) with a compound of the general formula (c) to obtain the general formula (I) . (Formula Removed) and reacting said compound of general formula (I) with acids as herein defined to form acid addition salt; wherein R1, and R2 are independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 unsaturated alkyl, ketone, substituted or unsubstituted aryl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted arylhydroxy, substituted or unsubstituted amino, C1-C4 lower ester, C1-C4 lower thioester, thiol, substituted or unsubstituted carboxyl, epoxy, substituted or unsubstituted C1-C4 lower thioalkoxy; or R1 and R1 are fused to form C3-C4 saturated or unsaturated chain; R3 , R,, R5, Rg and R7 are independently hydrogen, halogen, hydroxy, nitro, C1-C4 lower ester, C1-C4 lower alkyl, C1-C4 lower thioalkyl, substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted lower arylalkoxy, substituted or unsubstituted lower alkylamino, or lower alkyl substituted or unsubstituted carbamate; or among R3, R4, R5, Rg and R7, two adjacent groups are bonded with each other to form 1,2-phenylene or 2,3-naphthylene; X is oxygen, sulfur, or substituted or unsubstituted imino; Y is bonded at the 3-position or 4-position of the aromatic ring part wherein Y is oxygen or -NRg- (wherein, R8 is the same with the above-mentioned R3) ; Z is hydroxy, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryloxy, C1-C4 lower alkylamino, substituted or unsubstituted cycloamino containing 1-5 nitrogen atoms; A is nitrogen or -CH=; and Lie is a leaving group such as halogen atom, sulphonyl and the like. 2. A process for the preparation of piperazine derivative as claimed in claim 1, wherein said -C(=X)- group providing agents are selected form 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgene, carbonyl-diphenoxide, phenylchloroformate and the like. 3 . A process for the preparation of piperazine derivative of the general formula (I) as claimed in claim l, substantially as hereinbefore described in any one of the Examples.

Full Text

The subject invention relates to the process for the preparation of piperazine derivatives. The present invention relates to new piperazine derivatives of the general formula (1)
wherein R1 and R2 are independently hyl)rogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 unsaturated alkyl, ketone, substituted or unsubstituted aryl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted arylhyl)roxy, substituted or unsubstituted amino, C1-C4 lower ester, C1-C4 lower thioester, thiol, substituted or unsubstituted carboxyl, epoxy, substituted or unsubstituted C1-C4 lower thioalkoxy; or R1 and R2 are fused to form C3-C4 saturated or unsaturated chain; R3, R4, R5, Rg and R7 are independently hyl)rogen, halogen, hyl)roxy, nitro, C1-C4 lower ester, C1-C4 lower alkyl, C1-C4 lower thioalkyl, substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted lower arylalkoxy, substituted or unsubstituted lower alkylamino, or lower alkyl substituted or unsubstituted carbamate; or among R3, R4, R5, R6 and R7. two adjacent groups are bonded with each other to form 1,2-phenylene or 2,3-naphthylene; X is oxygen, sulfur, or substituted or unsubstituted imino; Y is bonded at the 3-position or 4-position of the aromatic ring part wherein Y is oxygen or -NRg- (wherein, R8 is the same with the above-mentioned R3); Z is hyl)roxy, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryloxy, C1-C4 lower alkylamino, substituted or unsubstituted cycloamino containing 1-5 nitrogen atoms; A is nitrogen or -CH=; its pharmaceutically acceptable acid addition
salts and process for the preparation thereof.
In the above definitions, C1-C8 alkyl means straight or branched alkyl
group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
tert-butyl, pentyl, iso-pentyl, hexyl, heptyl, octyl, 2-methylpentyl or the
like.
C1-C4 lower alkyl means methyl, ethyl, propyl, iso-propyl, n-butyl,
iso-butyl or tert-butyl.
Substituted or unsubstituted C3-C6 cycloalkyl means substituted or
unsubstituted cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, substituted cyclopropyl, substituted cyclopentyl, substituted
cyclohexyl or the like.
C1-C4 lower ester means a carboxyl group esterified by a lower alley 1
group.
C1-C4 lower alkoxy means methoxy, ethoxy, propoxy, isopropoxy,
butyloxy, isobutyloxy, tert-butyloxy group or the like.
C1-C4 lower thioalkoxy means methylthio, ethylthio, propylthio,
isopropylthio, butylthio, isobutylthio, tert-butylthio group or the like.
C1-C4 lower alkylamino means methylamino, ethylamino, propylamino,
butylamino group or the like.
Aryloxy means phenoxy, substituted phenoxy, naphthyloxy or
substituted naphthyloxy or the like.
Cycloamino group containing 1-5 nitrogen atoms means pyrrolidinyl,
pyiTolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,
triazolyl, tetrazolyl, piperazinyl or the like.
The present inventors had studied for a long time to find compounds
having intensive antitumor activity. As the results, now we have finally
found out the facts that the present compounds of the general
formula(I) and acid addition salts thereof have not only prominent
antitumor activities but very, low toxicities.
Accordingly, the one object of the present invention is to provide the
novel compounds of the general formula(I) and acid addition salts
thereof having not only prominent antitumor activities but very low
toxicities.
The other object of the present invention is to provide a process for
the preparation of the compounds of general formula(I) and acid addition salts thereof.
The compounds of the present invention can be mixed with pharmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and the pharmaceutical compositions can be used to prevent or treat with various kinds of tumors of human beings or nuuiunals.
Therefore, another object of the present invention is to provide pharmaceutical compositions containing the compounds of the general formula(I) or acid addition salts thereof as active ingredients. Acids which can be reacted with the compounds of the general formula(I) to form acid addition salts are pharmaceutically acceptable inorganic or organic acids; for example, inorganic acids such as hyl)rochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid; organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid, glycolic acid, lactic acid; amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamic acid, lysine, arginine, tyrosine, proline; sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid; or the like. Vehicles which can be used in the preparation of pharmaceutical compositions containing the compounds of the general formula(I) as active ingredients are sweetening agent, binding agent, dissolving agent, aids for dissolution, wetting agent, emulsifying agent, isotonic agent, adsorbent, degrading agent, antioxident, antiseptics, lubricating agent, filler, perfume or the like", such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, calcium stearate, magnesium aluminum silicate, starch, gelatine, tragacanth gum, glycine, silica, alginic acid, sodium alginate, methyl cellulose, sodium carboxy methyl cellulose, agar, water, ethanol, polyethylenglycol.polyvinyhpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanila aroma or the like. Daily dosage of the compound of the general formula(l) may be varied depending on age, sex of patient and the degree of disease. Daily dosage is l.0mg to 5,000mg may be administered one to several times.

Accordingly the present invention relates to a process for the preparation of piperazine derivative of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof comprising reacting a compound of the general formula (a) with a -C(=X)- group-providing agent in the presence of organic solvent as herein described to obtain a compound of the general formula (b) and reacting the compound of the general formula (b) with a compound of the general formula (c) to obtain the general formula
(Formula Removed)
and reacting said compound of general formula (I) with acids as herein defined to form acid addition salt;
whe rein R1 and R2 are independently hyl)rogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 unsaturated alkyl, ketone, substituted or unsubstituted aryl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted arylhyl)roxy, substituted or unsubstituted amino, C1-C4 lower ester, C1-C4 lower thioester, thiol, substituted or unsubstituted carboxyl , epoxy, substituted or unsubstituted C1-C4 lower thioalkoxy; or R1 and R2 are fused to form C3-C4 saturated or unsaturated chain; R3 , R4 , R5 , R6 and R7 are independently hyl)rogen, halogen, hyl)roxy, nitro, C4-C4 lower ester, C1-C4 lower alkyl, C1-C4 lower thioalkyl, substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy,substituted or unsubstituted aryl, substituted or unsubstituted lower arylalkoxy, substituted or unsubstituted lower alkylamino, or lower alkyl substituted or unsubstituted carbamate; or among R3, R4, R5, R6 and R7, two adjacent groups are bonded with each other to form 1,2-phenylene or 2,3-naphthylene; X is oxygen, sulfur, or substituted or unsubstituted imino; Y is bonded at the 3-position or 4-position of the aromatic ring part wherein Y is oxygen or -NRg- (wherein, R8 is the same with the above-mentioned R3) ; Z is hyl)roxy, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryloxy, C1-C4 lower alkylamino, substituted or unsubstituted cycloamino containing 1-5 nitrogen atoms; A is nitrogen or -CH=; and Lie is a leaving group such as halogen atom, sulphonyl and the like.
The compounds of the general formula (I) according to the present invention may be prepared by the following scheme I.
Scheme I
(Scheme Removed)
wherein Ri, Rz, R3, R4, R5, Re, R7, A, X, Y and Z are as defined above, and Lie is a leaving group such as halogen atom, sulfonyl or the like.
The above process comprises reacting a compound of the general formula(a) with a -C(=X)- group-providing agent in organic solvent to obtain a compound of the general formula(b) and successively reacting the compound of the general formula(b) with a compound of the general formula(c). to give the compound of the general formula(I). The used -C(=X)-group-providing agent preferably be selected from 1,1-carbonyldiimidazole, 1,1-carbonylthiodiirnidazole, phosgene, thiophosgene, carbonyldiphenoxide, phenylchloroformate or the like. The reaction may be carried out in conventional organic solvent such as, for example, tetrahyl)rofuran, dichloromethane, chloroform,
acetonitrile.
And also the reaction is preferably carried out in the presence of
coupling agent such as conventional inorganic or organic base. Such
conventional inorganic or organic base used in the reaction mecins
sodium hyl)ride, potassium hyl)ride, sodium hyl)roxide, potassium
hyl)roxide, sodium carbonate, potassium carbonate, cesium carbonate,
sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU
or the like, and 1-1.5 equivalent, preferably 1-1.1 equivalent thereof
may be used.
The reaction may be carried out between 3°C and boiling point of the
solvent used, preferably at 50°C-100°C for 5-48 hours, preferably for
10 - 24 hours.
-C(=X)-group-providing agent may be used in an amount of 1-1.5
equivalent, preferably 1-1.1 equivalent to the starting compound.
A compound of the general formula(I) wherein Y is -NRR- may be prepared by the following scheme II
SdiemeJLi
(Scheme Removed)
wherein, R1, R2, R3, R4, R5, Re, R7, Rs, A, X and Z are as defined above.
A compound of the general formula(Ib) above may be prepared effectively by introducing R8 providing agent into a compound of the general formula(Ia).
Rs providing agent preferably used in the above reaction is C1-Cx lower alkylhalogen, C1-Ca lower alkyl sulfonate, substituted or unsubstituted C3-C8 cycloalkylhalogen, arylhalogen, substituted or unsubstituted C3-C8 cycloalkyl sulfonate, arylsulfonate, or the like.
C1-C8 lower alkylhalogen means methylchloride, methylbromide, methyliodide, ethylchloride, ethylbromide, ethyliodide, propylchloride, propylbromide, propyliodide, butylchloride, butylbromide, butyliodide, pentylchloride, pentylbromide, pentyliodide, ethylbromoacetate, or the like.
C1-CH lower alkyl sulfonate means methylsulfonate, ethylsulfonate, propylsulfonate, butylsulfonate, pentylsulfonate, or the like.
Substituted or unsubstituted C3-C8 cycloalkylhalogen cyclopropylchloride, cyclopropylbromide, cyclopropyliodide, cyclobutylchloride, cyclobutylbromide, cyclobutyliodide, cyclopentylchloride, cyclopentylbromide, cyclopentyliodide, cyclohexylchloride, cyclohexylbromide, cyclohexyliodide, cyclopropyl methylchloride, cyclopropyl methylbromide, cyclopropyl methyliodide, cyclobutyl methylchloride, cyclobutyl methylbromide, cyclobutyl methyliodide, ryclopcnlyl liiclliylchloi ide, cyclopentyl iiielhylbioniide, cyclouenlyl methyliodide, cyclohexyl methylchloride, cyclohexyl methylbromide, cyclohexyl methyliodide, or the like.
Arylhalogen means benzylchloride, benzylbromide, benzyliodide, benzoylchloride, benzoylbromide, benzoyliodide, toluylchloride, toluylbromide, toluyliodide, or the like.
Substituted or unsubstituted C3-C8 cycloalkyl sulfonate means cyclopropyl sulfonate, cyclobutyl sulfonate, cyclopentyl sulfonate,
cyclohexyl sulfonate, methylcyclopropyl sulfonate, methylcyclobutyl sulfonate, methylcyclopentyl sulfonate, methylcyclohexyl sulfonate, or the like.
Arylsulfonate means benzyl sulfonate, benzoyl sulfonate, toluyl sulfonate, or the like.
More particularly, a compound of the general formula (la) may be
reacted with an alkylating agent or ai-ylating agent in a solvent at the
temperature of 25-80oC, for 30 minutes - 20 hours to give the object
compound of the general formula(lb).
An alkylating agent or arylating agent may be used in amount of 1.0 -
1.5 equivalent.
Conventional organic solvent such as for example tetrahyl)rofuran,
dichloromethane, acelonilrile, dimethylfonnainide may be used in the
above reaction.
In the above reactions, if any acid material is formed, any basic material may be preferably added as scavenger in order to eliminate the acid material from the reaction phase. Such basic material may be alkali metal hyl)roxide, alkali earth metal hyl)roxide, alkali metal oxide, alkali earth metal oxide, alkali metal carbonate, alkali earth metal carbonate, alkali metal hyl)rogen carbonate, alkali earth metal hyl)rogen carbonate such as sodium hyl)roxide, potassium hyl)roxide, calcium hyl)roxide, magnesium hyl)roxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like, or organic amines.
The compound of the general formula(a) is described in prior art ( J. Med. Chem., 1992, 35, 3784, 3792 ) or may be prepared in a similar method to the art.
Hereinafter the present invention will be described in more details with reference to following examples but it is not intended to limit the scope
of the invention thereinto.
Compounds of the general formula(I) and formula (lb) are prepared in following examples according to the above-mentioned process.
(Scheme Removed)
wherein Ri, R2, R3, R4, Rs, Re, R7, A, X, Y, Z are the same above.
-*■*-

(Table Removed)
Example 1 l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methylthio
phenyl)piperazine:
a) Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate:
3-Amino-5,6-dimethyl-2-methoxypyridine(1.52g, O.Olmol) and
phenylchloroformate(1.56g, O.Olmol) were dissolved in dichloromethane
and was stirred at room temperature for 2 hours. The mixture was
concentrated under the reduced pressure to remove the solvent. The
concentrate was purified by column chromatography(ethylacetate :
hexane = 1:6) to obtain the titled compound.
yield: 92 %
1H NMR(CDCb) d : 2.18(3H,s), 2.36(3I-I,s), 4.00(3H,s), 7.31(5M,m),
8.07(lH,s)
b) l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methyl
thiophenyl)piperazine:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate(136mg, 0.5mmol) and l-(2-methylthiophenyl)piperazine(104mg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(76mg, O.Smmol) was added. The mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove tetrahyl)rofuran. The concentrate was purified by column chromatography(ethylacetate : hexane = 1 : 2) to obtain the titled compound, yield : 59% m.p. : 167-1G9\:
1H NMR(CDCl3) δ : 2.21(311,s), 2.43(GII,s), 3.0(3(4II,t). 3.68(411,0, 4.09(3H,s), 6:89(lH,s), 7.06(lH,m), 7.14(3H,s), 8.26(lH,s)
Example 2
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-isopropeny
lphenyl)piperazine :
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and
l-(2-isopropenylphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield: 62 %
m.p. : 139-140 °C
lH NMR(CDCl3) δ : 2.20(3H,s), 2.21 (6H,s), 3.10(4H,t), 3.64(4H,t), 3.84(3H,s), 5.07(lH,s), 5.13(lH,s), 6.64(lH,s), 6.98(lH,s), 7.04(3H,dd), 7.18(lII,d), 7.91 (1II.s)
Example 3
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2,3,5,6-tetramethylphenyl)piperazine:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and l-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 71% m.p. : 190-192 oC
lH NMR(CDCl3) δ: 2.21(15II,s), 2.42(3II,s), 3.17(411,1), 3.61(411,0, 4.08(3H,s), 6.84(lH,s), 6.89(lH,s), 8.26(lH,s)
Example 4
l-[(5-Ethyl-6-methyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-meth
ylthiophenyl)piperazine"-
Phenyl N-(5-ethyl-6-methyl-2-methoxypyridin-3-yl)carbamate and
l-(2-methylthiophenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 56%
m.p. : 160-161o0
lH NMR(CDCl3) δ: 1.19(3H,t), 2.43(3H,s), 2.50(3H,s), 2.58(2H,q),
3.07(4H,t), 3.69(4H,t), 4.15(3H,s), 6.93(lH,s), 7.06(lll,m), 7.14(3H.m),
8.35(1 H,s)
Mass(EI) m/z : Calcd for C21H28N4O2 400.1932, found 400.1925
Example 5
l-[(5-Ethyl-6-methyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-
(2-isopropenylphenyl)piperazine-'
Phenyl N-(5-ethyl-6-methyl-2-methoxypyridin-3-yl)carbarnate and
l-(2-isopropenylphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 51%
m.p. : 185-187°C
1H NMR(CDCl3) δ: 1.18(3H,t), 2.21 (3H,s), 2.42(3H,s), 2.5G(2H,q),
3.08(4H,t), 3.62(4H,t), 4.03(3H,s), 5.08(lH,s), 5.13QH,s), 6.90(lH,s),
7.02(3H,m), 7.18(lH,d), 8.25(lH,s)
Example 6
l-[(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(2,3,5,6-t etramethylphenyl)piperazine:
Phenyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 69% m.p. : 176-177 °C
rH NMR(CDCl3) δ: 1.19(3H,t), 2.21(12H,s), 2.44(3H,s), 2.57(2H,q), 3.17(41-1,0, 3.62(411,0, 4.06(3H,s), 6.84(lH,s), 6.92(lH,s), 8.30(lH,s)
Example 7
l-[(5+Ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3-thiophenyl)piperazine:
Phenyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and
l-(3-thiophenyl)piperazine were reacted by the same way with the
example 1 to obtain the titled compound.
yield : 63%
m.p. : 108-110 TC
1H NMR(CDCl3) δ: 1.17(3H,t), 2.37(3H,s), 2.49(2H,q), 3.28(4H,t),
3.60(4H,t), 3.98(3H,s), 6.87(4H,m), 6.98(lH,s), 8.18(lH,s)
Example 8
l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 67%
m.p. : 82-84°C
lH NMR(CDCL3)δ: 0.94(3H,t), 1.58(2H,m), 2.37(3H,s), 2.49(2H,q),
3.25(4H,t), 3.66(4H,t), 3.78(6H,s), 3.99(3H,s), 6.07(3H,m), 6.88(lH,s),
8.16(lH,s)
Mass(EI) m/z : Calcd for C23H32N4O1 428.2423, found 428.2447
Example 9
l-[(2-Melhoxy-G-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethylphenyl)piperazine
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 64%
m.p. : 145-146 V,
'll NMlKCDChH: 0.95(3H,t), 1.59(2H,m), 2.29(6H,s), 2.41(3H,s),
2.49(2II,q), 3.24(4H,t), 3.67(4H,t), 3.98(3II,s), 6.59(3H,m). 6.89(lM,s),
8.17(lII,s)
Mass(El) m/z : Calcd for C23H32N.4O4 428.2423, found 428.2385
Example 10
l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-(3,5-
difluorophenyl)piperazine:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and
l-(3,5-difluorophenyl)piperazine were reacted by the same way with the
example 1 to obtain the titled compound.
yield : 57%
m.p. : 121-123 V,
1H NMR(CDCl3) δ '. 0.95(31-1,0, 1.59(211,m), 2.38(3H,s), 2.50(2H,q),
3.29(3H,t), 3.66(3H,t), 4.00(3H,s), 6.28(lII,m), 6.36(2H,d), 6.87(lII,s),
8.17UH,s)
Example 11
l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-(2-
methoxyphenyl)piperazine:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and
l-(2-melhoxyphenyl)piperazine were reacted by the same way with the
example 1 to obtain the titled compound.
yield : 71%
m.p. : 109-1KTC
lH NMR(CDCl3) δ : 0.95(3H,t), 1.59(2H,m), 2.37(3H,s), 2.49(2H,q), 3.12(4H,t), 3.70(4H,t), 3.89(3H,s), 3.97(3H,s), 6.91(4H,rn), 6.95(lH,s), 8.19UH,s)
Example 12
l-[(6-Ethyl-2-methoxy-5-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 65%
m.p. : 115-11GTC
1H NMR(CDCl3) δ : 1.21 (3H,t), 2.21(3H,s), 2.65(2H,q), 3.27(4H,t), 3.64(4H,t), 3.79(6H,s), 3.98(3H,s), 6.09(3H,m), 6.86(lH,s), 8.12UH,s) Mass(El) m/z : Calcd for C22H30N4O4 414.2267, found 414.2240
Example 13
l-[(6-Ethyl-2-methoxy-5-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dim
ethylphenyl)piperazine:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 61%
m.p. : 135-136°C
1H NMR(CDCl3) δ: 1.22(3H,t), 2.21 (3H,s), 2.29(6H,s), 2.65(2H,q), 3.24(4H,t), 3.66(4H,t), 3.98(3H,s), 6.59(3H,m), 6.87(lH,s), 8.12(lH,s) Mass(EI) m/z : Calcd for C22H30N4O2 382.2368, found 382.2376
Example 14
l-[(6-Ethyl-2-methoxy-5-methylpyridin-3-yl)aminocarbonyl]-4-(3-hyl)ro
xyphenyl)piperazine:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and
l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the
example 1 to obtain the titled compound.
yield : 56%
m.p. : 168-170°C
1H NMR(CDCl3) δ: 1.21 (3H,t), 2.20(2H,s), 2.63(2H,t), 3.28(4H,t), 3.68(4H,t),
3.98(3H,s), G.41(lH,d), 6.55(lH,d), C.84(lH,m), 6.87(lII,s), 7.13(111,0,
8.10(lH,s)
Mass(El) m/z : Calcd for C20H26N4O3 370.2004, found 370.1992
Example 15
l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)carbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 57%
m.p : 121-122nC
lH NMR(CDCl3) δ: 0.96(3H,t), 1.67(2H,m), 2.21 (3H,s), 2.58(2H,t),
3.26(411,0, 3.68(4H,t), 3.79(6H,s), 3.97(3H,s), 6.14(3H,m), 6.89(lH,s),
8.11 (lH.s)
Mass(EI) m/z : Calcd for C23H32N4O4 428.2423, found 428.2423
Example 16
l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminocarbonyl]-4- (3,5-di
methylphenyl)piperazine:
Phenyl N-(2-inethoxy-5-methyl-6-propylpyridin-3-yl)caibamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 54%
m.p. : 138-139 °C
1H NMR(CDCL3) δ: 0.96(3H,t), 1.72(2H,m), 2.21 (6H,s), 2.30(3H,s),
2.59(2H,t), 3.28(4H,t), 3.76(4H,t), 3.97(3H,s), 6.70(3H,m), 6.87(lH,s),
8.11 (lH,s)
Mass(EI) m/z : Calcd for C23II32N4O2 396.2525, found 396.2432
Example 17
l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminocarbonyl]-4-(3-hyl)roxy phenyl )piperazine:
Phenyl N-(2-metlioxy-5-methyl-6-propylpyridin-3-yl)carbamate and
l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the
example 1 to obtain the titled compound.
yield : 52%
m.p. : 153-155 °C
rH NMR(CDCl3) δ: 0.95(3H,t), 1.69(2H,m), 2.19(3H,s), 2.59(2H,t),
3.22(4H,t), 3.68(4H,t), 3.97(3H,s), 6.42(lH,d), 6.52(lH,d), 6.87(lH,s),
7.12(lH,t), 8.09(lH,s)
Mass (EI) m/z : Calcd for C21H28N4O3 384.2161, found 384.2153
Example 18
l-[N-(2-Methoxy-6,7-dihydro-5H-cyclopnta[b]pyridin-3-yl) aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: Phenyl N-(2-methoxy~6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 59% m.p. : 143-144oC
1H NMR(CDCl3) δ : 2.10(2H,m), 2.87(4H,m), 3.12(4H,t), 3.70(4H,t), 3.78(6H,s), 4.00(3H,s), 6.08(3H,m), 6.90(lH,s), 8.24(lH,s)
Example 19
l-[N-(2-Methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) aminocarbonyl] -4- (3,5-dimethy lpheny Dpiperazine: Phenyl N-(2-methoxy-6J-dihyl)ro-5H~cyclopenta[b]pyriclin-3-yl) cai'bamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 55% ' m.p. : 183-185oC:
1H NMR(CDCl3) δ: 2.08(2H,m), 2.28(6H,s), 2.87(4H,m), 3.22(4H,t), 3.67(4H,t), 4.00(3H,s), 6.57(3H,m), 6.89(lH,s), 8.24(lHfs)
Example 20
l-[(2-Methoxy-5,6,7,8-tetrahyl)roquinolin-3-yl)aminocarbonyl]-4-(3,5-
dimethoxy phenyl) piperazine :
Phenyl N-(2-methoxy-5,6,7,8-tetrahyl)roquinoline-3-yl)carbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 54%
m.p. : 161-163°C
lH NMR(CDCl3) δ: 1.75(2H,m), 1.84(2H,m), 2.67(2H.l). 2.73(2H,t),
3.27(4H,t), 3.71 (4H,t), 3.79(6H,s), 3.97(3H,s), 6.10(3H,m), 6.90(lH,s),
8.07QH,s)
Example 21
l-[(2-Methoxy-5,6)7,8-tetrahyl)roquinolin-3-yl)aminocarbonyl]-4-(3,5-
dimethyphenyl)piperazine:
Phenyl N-(2-methoxy-5,6,7,8-tetrahyl)roquinolin-3-yl)carbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 51%
m.p. : 143-144 oC
1H NMR(CDCl3) δ: 1.75(2H,m), 1.84(2H,m), 2.30(6H,s), 2.68(2H,t),
2.72(2H,t), 3.26(4H,t), 3.67(4H,t), 3.97(3H,s), 6.61 (3H,m), 6.91(lH,s),
8.07(lH,s)
Example 22
l-[(5,6-Dimethyl-2-rnethoxypyridin-3-yl)arninothiocarbonyl]-4-(3,5-dimethylphenyl)piperazine:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate(200mg, 0.7mmol) and l-(3,5-dimethylphenyl)piperazine(154mg, 0.7mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBUU(106mg) was added thereto. The mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography ( ethylacetate : hexane = 1 : 2 ) to obtain the titled compound, yield : 50% m.p. : 192-193 °C
1H NMR(CDCl3) δ : 2.21 (3H,s), 2.29(6H,s), 2.36(3H,s), 3.33(4H,t), 3.9C(3H,s), 4.09(411,0, 6.57(3H,m), 7.33(lH,s), 8.11(lH,s) Mass(EI) m/z : Calcd for C21H28N4O1S1 384.1983, found 384.1992
Example 23
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl]-4-(3,5-difluorophenyl)piperazine:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 47% m.p. : 60-621
]H NMR(CDCl3) δ ■ 2.21(3H,s), 2.36(3H,s), 3.39(4II,t), 3.96(311,*), 4.10(3H,t), 6.29(3H,m), 7.33(lH,s), 8.14(lH,s)
Example 24
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl]-4-(3-hyl)roxyphenyl)piperazine:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 43% m.p. : 185-186OC
1H NMR(CDCl3) δ : 2.14(3H,s), 2.36(3H,s), 3.25(4H,t), 3.89(3H,s), 4.09(4H,t), 6.30(lH,d), 6.36(2H,m), 7.03(lH,t), 7.48(lH,s), 8.56(lH,s)
Example 25
l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminothiocarbonyl]-4-(3,5
-dimethoxyphenyl)piperazine:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)thiocarbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 22 to obtain the titled compound.
yield : 55%
m.p. : 143-144 °C
lH NMR(CDCl3) δ; 0.93(3H,t),.1.66(2H,m), 2.17(3H,s), 2.65(2H,t),
3.38(4H,t), 3.79(6H,s), 3.98(3H,s), 4.15(4H,t), 6.11(3H,m), 7.43(lH,s).
8.25(lH,s)
Example 26 l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminothiocarbonyl]-4-(3,5
-dimethoxyphenyl)piperazine:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 22 to obtain the titled compound.
yield : 52%
m.p. : 183-184 °C
1H NMR(CDCl3) δ: 0.98(3H,t), 1.72(2H,m), 2.17(3H,s), 2.62(2H,t),
3.39(4H,t), 3.79(6H,s), 3.96(3H,s), 4.19(4H,t), 6.15(3H,m),
7.42(lH,s), 8.08(lH,s) Mass(EI) m/z : Calcd for C23H32N4O3S1 444.2195, found 444.2171
Example 27
l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminothiocarbonyl]-4-(3,5
-dimethylphenyl)piperazine-'
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 22 to obtain the titled compound.
yield : 49%
m.p. : 195-197 °C
1H NMR(CDCl3) δ: 0.98(3H,t), 1.73(2H,m), 2.18(6H,s), 2.34(3H,s),
2.62(2H,t), 3.47(4H,t), 3.96(3H,s), 4.01(4H,t), 6.59(3H,m), 7.02(lH,s),
7.99(lH,s)
Mass(EI) m/z : Calcd for C23H32N4O1S1 412.2296, found 412.2266
Example 28
l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminothiocarbonyl]-4-(3-
hyl)roxyphenyl)piperazine:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and
l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the
example 22 to obtain the titled compound.
yield : 48%
m.p. : 160-162OC
1H NMR(CDCl3) δ : 0.98(3H,t), 1.72(2H,m), 2.22(3H,s), 2.61 (3H,t),
3.31(4H,t), 3.95(3H,s), 4.10(4H,t), 6.45(3H,m), 7.12(lH,t), 7.41 (lH,s),
8.08(lH,s) Mass(EI) m/z : Calcd for C21H28N4O2S1 400.1932, found 400.1969
Example 29
l_[N-(2-Methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl)aminothiocar bonyl]-4-(3,5-dimethoxyphenyl)piperazine:
Phenyl N-(2-methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) thiocarbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 55% m.p. : 169-170 °C
1H NMR(CDCl3) δ: 2.10(2H,m), 2.89(4H,m), 3.30(4H,t), 3.77(6H,s), 3.98(3H,s), 4.20(4H,t), 6.05(3H,m), 7.37(lH,s), 8.25(lH,s)
Example 30
l-[N-(2-Methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl)arninothiocar bonyl]-4-(3,5-dimethylphenyl)piperazine:
Phenyl N-(2-methoxy-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) thiocarbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 53% m.p. : 159-161 oC
1H NMR(CDCl3) δ • 2.09(2H,m), 2.28(6H,s), 2.87(4H,m), 3.67(4H,t), 4.00(3H,s), 4.21(4H,t), 6.57(3H,m), 6.93(lH,s), 8.24(lH,s)
Example 31
l-[(2-Methoxy-5,6,7,8_tetrahyl)roquinolin-3-yl)aminothiocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine:
Phenyl N-[(2-inethoxy-5,G,7,8~teUahyl)roquinolin-3-yl)thiocarbaniate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 22 to obtain the titled compound.
yield : 56%
m.p. : 160-161 °C .
lH NMR(CDCl3) δ : 1.77(2H,m), 1.83(2H,m), 2.70(2H,t), 2.76(2H,t),
3.38(4H,t), 3.79(6H,s), 3.96(3H,s), 4.16(4H,t), 6.12(3H,m), 7.45(lH,s),
8.03(lH,s)
Example 32
l-[(2-Methoxy-5,6,7,8-tetrahyl)roquinolin-3-yl)aminothiocarbonyl]-4-(3,5-
dimethylphenyl)piperazine:
Phenyl N-(2-methoxy-5,6,7,8-tetrahyl)roquinolin-3-yl)thiocarb£imate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 22 to obtain the titled compound.
yield : 54%
m.p. : 200-201 oC
1H NMR(CDCl3) δ : 1.77(2H,m), 1.84(2H,m), 2.34(6H,s), 2.71 (3H,t),
2.75(3H,t), 3.47(4H,t), 3.97(3H,s), 4.42(4H,t), 6.35(3H,m), 6.91 (lH,s),
7.91(lH,s)
Example 33
l-[(5,6-Dimethyl-2-methylaminopyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine-'
Phenyl N-(5,6-dimethyl-2-methylaminopyridin-3-yl)carbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 1 to obtain the titled compound.
yield : 53%
m.p. : 150-1511;
1H NMR(CDCl3) δ: 2.29(3H,s), 2.48(3H,s), 3.29(4H,t), 3.45(3H,s), 3.77(6H,s), 3.79(4H,t), 6.10(3H,m), 7.40(lH,s)
Example 34
l-[(5,6-Dimethyl-2-methylaminopyridin-3-yl)aminocai'bonyl]-4-(3,5-dimethylphenyl)piperazine:
Phenyl N-(5,6-dimethyl-2-methylaminopyridin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 52% m.p. : 160-162°C
1H NMR(CDCl3) δ ; 2.30(9H,s), 2.48(3H,s), 3.31 (4H,t), 3.46(3H,s), 3.78(4H,t), 6.60(3H,m), 7.41(lH,s)
Example 35
l-[(5-Ethyl-6-methyl-2-methylaminopyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethylphenyl)piperazine:
Phenyl N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 56% m.p. : 143-145°C
1H NMR(CDCl3) δ : 1.22(3H,t), 2.28(6H,s), 2.52(3H,s), 2.72(2H,q), 3.29(4H,t), 3.45(3H,s), 3.78(4H,t), 6.59(3H,m), 7.41(lH,s)
Example 36
l-[(2-Methylamino-6,7-dihyl)ro-5H-cycloi3enta[b]pyridin-3-yl) aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine: Phenyl N-(2-methylamino-6,7-dihyl)i'o-511-cyclopenta[b]pyridin-3-yl) carbamate and l-(3,5~dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 49% m.p. : 148-15CTC
lH NMR(CDCl3) δ: 2.09(2H,m), 2.95(4H,m), 3.30(4H,t), 3.47(3H,s), 3.77(4H,t), 3.80(6H,s), 6.10(3H,m), 7.49(lH,s)
Example 37
l-[(2-Methylamino-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine: Phenyl N-(2-methylamino-6,7-dihyl)ro-5H-cyclopenta[b]pyridin-3-yl) carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 48% m.p. : 185-187 °C
]H NMR(CDCl3) δ '• 2.14(2H,m), 2.29(6H,s), 2.95(4H,m), 3.32(4H,t), 3.47(3H,s), 3.79(4H,t), 6.59(3H,m), 7.48(lH,s)
Example 38
l_{[5,6-Dimethyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl]
aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine:
Phenyl N-[5,6-dimethyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl]
carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the
same way with the example 1 to obtain the titled compound.
yield : 58% m.p. : 74-75°C
1H NMR(CDCl3) δ : 1.46(9H,s), 2.20(3H,s), 2.21 (3H,s), 2.90(4H,t), 3.20(4H,t), 3.55(4H,t), 3.65(4H,t), 3.98(3H,s), 6.02(3H,m), 8.20(lH,s)
Example 39
l-{[5,6-Dimethyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine: Phenyl N-[5,6-dimethyl-2-(4'-butoxycarbonylpiperazinyl)pyridin-3-yl] carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 56% m.p. : 155-156 °C
1H NMR(CDCl3) δ: 1.48(9H,s), 2.22(3H,s), 2.29(6H,s), 2.35(3H,s), 2.95(4H,t), 3.25(4H,t), 3.57(4H,t), 3.67(4H,t), 6.59(3H,m), 8.21(lH,s)
Example 40
l-{[5-Ethyl-6-methyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-climethoxyphenyl)piperazine: Phenyl N-[5-ethyl-6-methyl-2-(4' -t-butoxycarbonylpiperazinyl) pyridin-3-yl]carbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound, yield : 52% m.p. : 119-120°C
1H NMR(CDCl3) δ: 1.25(3H,t), 1.48(9H,s), 2.38(3H,s), 2.51 (2H,q), 2.96(4H,t), 3.27(4H,t), 3.58(8H,m), 3.78(6H,s), 6.08(3H,m), 8.24(lH,s)
Example 41
l-{[5-Ethyl-6-methyl-2-(4'-t-butoxycai-bonylpiperazinyl)pyridin-3-yl]
aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine:
Phenyl N-[5-ethyl-6-rnethyl-2-(4' -t-butoxycarbonylpiperazinyl)
pyridin-3-yl]carbamate and l-(3,5-dimethylphenyl)piperazine were
reacted by the same way with the example 1 to obtain the titled
compound.
yield : 50%
m.p. : 126-128 °C
1NMR(CDCl3) δ : 1.20(3H,t), 1.49(9H,s), 2.29(6H,s), 2.39(3H,s),
2.52(2H,q), 2.98(4H,t), 3.23(4H,t), 3.59(8H,m), 6.59(3H,m), 7.58(lH,s),
8.26(lH,s)
Example 42
l-[(5,6-Dimethyl-2-piperazinylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-{[5,6-Dimethyl-2-(4'-t-butoxycarbonylpii3erazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(0.218g, 0.4mmol) was dissolved in dichloromethane : nitromethane = 2 : l(lOml) and anisole(0.2Gg, 2.4mmol) and aluminum chloride(0.3g, 2,4mmol) were added slowly thereto. The mixture was stirred at room temperature for 20min. Distilled water(50ml) was added into the mixture and the mixture was made basic with saturated NaHC03 and extracted with dichloromethane and then concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography (methanol : dichloromethane = 8^1) to obtain the titled compound, yield : 89% m.p. : oil phase
lH NMR(CDCl3)a: 2.21 (3H,s), 2.35(3II,s), 3.02(411,0, 3.34(411,0, 3.59(4H,t), 3.62(4H,t), 3.78(6H,s), 6.08(3H,m), 8.18(lH,s)
Example 43
l_[(5,6-Dimethyl-2-piperazinylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine:
l-{[5,6-Dimetriyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 42 to obtain the titled compound, yield : 85% m.p. : 103-105°C
1H NMR(CDCl3) δ: 2.16(3H,s), 2.24(6H,s), 2.40(3H,s), 3.30(4H,O, 3.44(4H,t), 3.50(4H,t), 3.81 (4H,t), 6.95(3H,m), 7.72(lH,s)
Example 44
l-[(5-Ethyl-6-methyl-2-piperazinylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-{[5-Ethyl-6-methyl-2-(4'-t-butoxycarbonylpiperazinyi)pyridin-3-yI] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 42 to obtain the titled compound, yield : 88% m.p. : 68-70 oC
lH NMR(CDCl3) δ : 1.20(3H,t), 2.40(3H,s), 2.52(2H,q), 2.75(4H,t), 3.32(4H,t), 3.70(8H,m), 3.78(6H,s), 6.09(3H,m), 7.68(lII,s), 8.23(1I-I,s)
Example 45
l-[(5-Ethyl-6-methyl-2-piijerazinylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethylphenyl)piperazine:
l-{[5-Ethyl-6-methyl-2-(4'-t-butoxycarbonylpiperazinyl)pyridin-3-yl]
aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine was reacted by the
same way with the example 42 to obtain the titled compound.
yield : 85%
m.p. : 100-102OC;
lH NMR(CDCl3) δ: 1.20(3H,t), 2.28(6H,s), 2.39(3H,s), 2.65(2H,q),
2.76(4H,t), 3.00(4H,t), 3.23(4H,t), 3.70(4H,t), 6.58(3H,m), 7.66(lH,s),
8.24(lH,s)
Example 46
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate(200mg,
0.67mmol) and l-(3,5-dimethoxyphenyl)piperazine(150mg, 0.67mmol)
were dissolved in anhyl)rous tetrahyl)rofuran(15ml) and DBU(100mg,
0.67mmol) was added. The mixture was stirred at room temperature for
2 hrs and concentrated under the reduced pressure to remove
tetrahyl)rofuran. The concentrate was purified by column
chromatography(ethylacetate : hexane = 1:2) to obtain the titled
compound.
yield : 83%
m.p. : 149-151°C
'H NMRCDCl3) δ: 2.57(3II,s), 2.65(3II,s), 3.28(4H,t,J=4.G5ITz), 3.70(4M,t,
J=4.65Hz), 3.79(6H,s), 4.06(3H,s), 6.09(lH,s), 6.14(2H,d),6.94(lH,s), 8.87(lH,s)
Example 47
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethylphenyl)piperazine-'
Phenyl N-(5-acetyl-2-methoxy-6~methylpyridin-3-yl)carbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 46 to obtain the titled compound.
yield : 82%
m.p. : 66-69°C
lH NMR(CDCl3) δ : 2.31(6H,s), 2.57(3H,s), 2.65(3H,s), 3.08(4H,t),
3.30(4H,t), 4.10(3H,s), 6.71(2H,d), 6.94(lH,s), 8.89(lH,s)
Example 48
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-
difluorophenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and
l-(3,5-difluorophenyl)piperazine were reacted by the same way with the
example 46 to obtain the titled compound.
yield : 77%
m.p. : 180-181°C
lH NMR(CDCl3) δ : 2.57(3H,s), 2.65(3H,s), 3.33(4H,tJ=5.0Hz), 3.74(4H,t,
J=5.0Hz), 4.07(3H,s), 6.37(lH,s), 6.46(2H,d), 6.93(lH,s), 8.85(lH,s)
Example 49
l-[(5-Acetyl-2-meLhoxy-G-melhylpyridin-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound, yield : 81% m.p. : oil phase
lH NMR(CDCl3) δ : 2.57(3H,s), 2.65(3H,s), 3.34(4H,t), 3.78(4H,t), 4.04(3H,s), 6.93(311,m), 8.80(lH,s)
Example 50
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(2,3_ dimethylphenyl)piperazine:
Pheny N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and l-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound, yield : 81% m.p. : 173-174°C
1H NMR(CDCl3) δ: 2.29(6H,s), 2.58(3H,s), 2.65(3II,s), 2.98(41-1,0, 3.70(4H,t), 4.06(3H,s), 6.91(lH,d), 6.97(lH,s), 7.10(lH,t), 8.89(lH,s)
Example 51
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(2-
methoxyphenyl)pipenudne-'
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and
l-(2-methoxyphenyl)piperazine were reacted by the same way with the
example 46 to obtain the titled compound.
yield : 79%
m.p. : 153-154°C
lH NMR(CDCl3) δ: 2.58(3H,s), 2.65(3H,s), 3.15(411,0, 3.73(4H,0,
3.90(3H,s), 4.06(3H,s), 6.91(lH,d), 6.96(lH,d), 6.97(lH,s), 7.10(lH,t),
8.89(11-I,s)
Example 52
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3-hyl)roxyphenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)cai-bamate and l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound, yield : 76% m.p. : oil phase
lH NMR(CDCl3) δ: 2.60(3H,s), 2.72(3H,s), 3.34(4H,t), 3.79(4H,t), 3.98(3H,s), 6.45(3H,m), 6.98(lH,m), 8.97(lH,s)
Example 53 l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminothiocai-bonyl]-4-(3,5
-dimethoxyphenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 77% m.p. : 167-169 *C
1H NMR(CDCl3) δ : 2.58(3H,s), 2.68(3H,s), 3.47(4H,t), 3.81 (6H,s), 4.05(3H,s), 4.36(4H,t), 6.42(3H,m), 7.49(lH,s), 9.05QH,s)
Example 54
l-[(5-Acetyl~2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(3,5 -dimethylphenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound, yield : 75% m.p. : 176-177°C
1H NMR(CDCl3) δ: 2.34(6H,s), 2.58(3H,s)( 2.68(3H,s), 3.48(411,0, 4.06(3H,s), 4.43(4H,t), 7.05(3H,m), 7.52(lH,s), 9.04(lH,s)
Example 55
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminothiocai'bonyl]-4-(3-
hyl)roxyphenyl)piperazine-'
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thioccirbamate and
l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the
example 22 to obtain the titled compound.
yield : 71%
m.p. : 114-115°C
1H NMR(CDCl3) δ: 2.56(3H,s), 2.75(3H,s), 3.68(4H,t), 4.05(3H,s),
4.45(4H,t), 7.30(4H,m), 9.03(lH,s)
Mass(EI) m/z : Calcd for C23H30N4O4S1 458.1987, found 458.2527
Example 56
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dimethoxyphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dirnethoxyphenyl)piperazine(100mg, 0.23mmol) was dissolved in anhyl)rous ethanol(15ml) and NaBH4(8.66mg) was added. The reaction solution was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove ethanol and purified by column chromatography (ethylacetate •' hexane = 2:1) to obtain the titled compound, yield : 97% m.p. : 124-126°C 1H NMR(CDCl3) δ: 1.48(3II,d), 2.42(3H,s), 3.27(4Htt), 3.69(411,0,
3.79(6H,s), 3.99(3H,s), 5.03(lH,q), 6.09(lH,s), 6.15(2H,d), 6.90(lH,s),
8.46(lH,s) Mass(EI) m/z : Calcd for C22H30N4O5 430.2216, found 430.2265
Example 57
l-{[5-(l-IIyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}
-4-(3,5-dimethylphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethylphenyl)piperazine was reacted by the same way with the
example 56 to obtain the titled compound.
yield : 95%
m.p. : 153-154°C
1H NMR(CDCl3) δ: 1.48(3H,d), 2.30(6H,s), 2.42(3H,s), 3.26(4H,t),
3.68(4H,t), 3.99(3H,s), 5.05(lH,q), 6.71 (2H,d), 6.96(lH,s), 8.46(lH,s)
Mass(EI) m/z : Calcd for C22H30N4O3 398.2317, found 398.2343
Example 58
l-{ [5- (1 -Hyl)roxy ethyl)-2-methoxy-6-methylpyridin-3-yl]aininocarbonyl}
-4-(2,3-dimethylphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl]-4-(2,3-
dimethylphenyl)piperazine was reacted by the same way with the
example 56 to obtain the titled compound.
yield : 96%
m.p. : 100-102°C
1H NMR(CDCl3) δ: 1.47(3II,d), 1.59(3H,s), 2.25(3H,s), 2.28(3H,s),
2.43(3H,s), 2.93(4H,t), 3.66(4H,t), 3.99(3H,s), 5.05(lH,q), 6.93(3H,m),
7.11(lM,m), 8.48(lII,s)
Example 59
l-{[5-(l-Hyldroxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-difluorophenyl)piperazine:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 97% m.p. : 184-18G°C
1H NMR(CDCl3) δ : 1.48(3H,d), 2.50(3H,s), 3.30(4H,t), 3.70(4H,t), 4.11(3H,s), 5.06(lH,q), 6.33(lH,s), 6.42(2H,d), 6.92(lH,s), 8.54(lH,s)
Example 60
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dichlorophenyl)piperazine :
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 95% m.p. : 197-200 °C
1H NMR(CDCl3) δ : 1.46(3H,d), 2.41 (3H,s), 3.28(4H,t), 3.66(4H,t), 3.96(3H,s), 5.20(lH,q), 7.02(3H,m), 8.42(lH,s)
Example 61
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocai-bonyl}
-4-(2-methoxyijhenyl)piperazine:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(2-
methoxyphenyl)piperazine was reacted by the same way with the
example 56 to obtain the titled compound.
yield : 97%
m.p. : 88-90°C
1H NMR(CDCl3) δ: 1.47(3II,d), 2.42(3H,s), 3.11(41-1,0, 3.70(41-1,0,
3.89(3H,s), 3.99(3H,s), 5.03(lH,q), 6.89(3H,m), 6.94(lH,s), 7.05(lH,m).
8.48(lH,s)
Example 62
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4- (3-hyl)roxyphenyl)piperazine:
l-[5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocai'bonyl]-4-(3-hyl)ro xyphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 87% m.p. : 194-196°C
1H NMR(CDCl3)δ: 1.47(3H,d), 2.41(3H,s), 3.27(4M,t), 3.79(4H,1), 3.98(3H,s), 5.04(lH,q), 6.57(3I-I,m), 6.90(lH,s), 7.13(11-1,0. 8.41(lII,s)
Example 63
l-{[5-(l-riyl)roxyelhyl)-2-methoxy-G-inethylpyridin-3-yl]aininothio carbonyl}-4-(3,5-dimethoxyphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(3,.r3 -dimethoxyphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 89% m.p. : 189-190°C
1H NMR(CDCl3) δ: 1.47(3II,d), 2.43(3II,s), 3.35(411,0, 3.78(6H,s), 3.97(3H,s), 4.09(4H,t), 5.05(lH,q), 6.07(3H,m), 7.35(lH,s), 8.42(lH,s)
Example 64
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminothio carbonyl}-4-(3,5-dimethylphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(3,5 -dimethylphenyl)piperazine was reacted by the same way with the example 56 to obtain the titled compound, yield : 88% in.p. : 170-172 oC
lH NMR(CDCl3) δ: 1.46(3H,d), 2.29(6H,s), 2.43(3H,s), 3.43(4H,t), 3.97(3H,s), 4.10(4H,t), 5.06(lH,q), 6.60(3H,m), 7.37(lH,s), 8.40(lH.s)
Example 65
l-([5-(l-Hyl)roxy-l-methylethyl)-2--methoxy-6-methylpyridin-3-yl] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine: l-{(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine(214mg, 0.50mmol) was dissolved in tetrahyl)rofuran(lOml) and CH3MgBr(0.50ml, 1.50mmol) was added slowly. The mixture solution was refluxed for 15 hrs and concentrated under the reduced pressure to remove the solvent and extracted with ethylacetate, dried and filtered. The resultant was purified by column chromatography (ethylacetate : hexane = l: 2) to obtain the titled compound, yield : 84% m.p. : 146-148OC
JH NMR(CDCl3) δ: 1.64(6Hts), 2.64(3H,s), 3.25(4H.t), 3.67(4H,t), 3.78(6H,s), 3.99(3H,s), 6.07(3H,m), 6.86(lH,s), 8.47(1 H,s)
Example 66
l-([5-(l-Hydroxy-l-methylethyl)-2-methoxy-6-methylpyridin-3-yl] aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine: l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 65 to obtain the titled compound, yield : 81% m.p. : oil phase
1H NMR(CDCl3) δ: 1.64(6H,s), 2.29(6H,s), 2.65(3H,s), 3.24(4H,t), 3.67(411,0, 3.99(311,s), 6.59(31I,m), 7.05(111,s), 8.48(111.s)
Example 67
l-l[5-(l-Hyl)roxy-l-methylpropyl)-2-methoxy-6-methylpyridin-3-yl] aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine; l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(214mg, 0.50mmol) was dissolved in tetrahyl)rofuran(l0ml) and C2H5MgBr(0.50mg, 1.50mmol) was added slowly. The mixture solution was refluxed for 15 hours and concentrated under the reduced pressure to remove the solvent and extracted with ethylacetate, dried and filtered. The resultant was purified by column chromatography (ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 76% m.p. : 127-129°C
lH NMR(CDCl3) δ: 0.83(3H,t), 1.63(3H,s), 1.94(2H,m), 2.61 (3H,s), 3.26(4H,t), 3.68(4H,t), 3.79(6H,s), 3.99(3H,s), 6.08(3H,m), 6.86QH,s), 8.44(lH,s)
Example 68
l-{[5-(l-Hyldroxy-l-methylpropyl)-2-methoxy-6-methylpyridin-3-yl]
aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethylphenyl)piperazine was reacted by the same way with the
example 67 to obtain the titled compound.
yield : 74%
m.p. : 164-165 oC
1H NMR(CDCl3) δ: 0.83(3H,t), 1.60(3H,s), 1.95(2H,m), 2.29(6H,s),
2.61(3H,s), 3.23(4H,t), 3.67(4H,t), 3.99(3H,s), 6.59(3H,m), 6.87(lH,s),
8.45(lH,s)
Example 69
l-[5-({[4-(3,5-Dimethoxyphenyl)piperazino]carbonyl}amino)-6-methoxy-2 -methylpyridin-3-yl]ethyl ethanthioate: Triphenylphosphine(262mg, l.0mmol) was dissolved in tetrahyl)rofuran(15ml) and diethyl azodicarboxylate(157µ, l.0mmol) was added and then the mixture was stirred at 0'C for 30min. l-([5-(l-Hyl)i-oxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl) -4-(3,5-dimethoxyphenyl)piperazine(213mg, 0.5mmol) and thioacetic acid(72µl, l.Ommol) were dissolved in tetrahyl)rofuran and was added into the above solution. The mixture solution was stirred at 0OC for lhour and at room temperature for lhour and then was concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 62% m.p. : oil phase 1H NMR(CDCl3) δ: 1.55(3H,d), 2.20(3H,s), 2.39(3H,s), 3.15(4H,t),
3.57(4H,t), 3.69(6H,s), 3.90(3H,s), 4.74(lH,q), 6.01 (3H,m), 6.89(lH,s),
8.33(lH,s)

Example 70
1 -[5- ({[4- (3,5-Dimethylphenyl)piperazino]carbony 1 }amino) -6-methoxy-2-methylpyridin-3-yl]ethyl ethanthioate:
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 69 to obtain the titled compound, yield : 60% m.p. : oil phase
1H NMR(CDCl3) δ : 1.60(3H,d), 2.26(6H,s), 2.52(3H,s), 3.20(4H,t), 3.64(4H,t), 3.96(3H,s), 4.80(lH,q), 6.56(3H,m), 6.91 (lH.s), 8.38(lH,s)
Example 71
1 - {[2-Methoxy -6-methy 1-5- (1 - sulf any lmethy Djaminocarbony 1} -4 - (3,5-dimethoxyphenyl)piperazine:
l-[5-({[4-(3,5-Dimethoxyphenyl)piperazino]carbonyl}amino)-G-methoxy-2 -methylpyridin-3-yl]ethyl ethanthioate(180mg, 0.37mmoi) was dissolved in tetrahyl)rofuran(15ml) and LiAlH4(15mg, 0.4mmol) was added and then the mixture was stirred at 0°C for 20min. 2N-HC1 was added the above solution. The mixture was concentrated under the reduced pressure to remove the solvent and extracted with dichloromethane, dried and filtered. The resultant was concentrated under the reduced pressure and purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 88% m.p. : oil phase
1H NMR(CDCl3) δ: 1.42(3H,d), 2.39(3H,s), 3.25(4H,t), 3.66(4H,t), 3.76(6H,s), 3.96(3H,s), 5.02(lH,q), 6.17(3H,m), 6.87(lH,s), 8.41 (lH.s)
Example 72
l-{[2-Methoxy-6-methyl-5-(l-sulfanybnethyl)]aminocarbonyl}-4-(3,5-dimethylphenyl)piperazine:
l-[5-({[4-(3,5-Dimethylphenyl)piperazino]carbonyl}amino)-6-methoxy-2-methylpyridin-3-yl]ethyl ethanthioate was reacted by the same way with the example 71 to obtain the titled compound, yield : 87% m.p. : oil phase
lH NMR(CDCl3) δ: 1.43(3H,d), 2.28(6H,s), 2.40(3H,s), 3.25(4H,t), 3.72(4H,t), 5.03(lH,q), 6.64(3H,m), 6.88(lH,s), 8.42(lH,s)
Exmaple 73
l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-{[5-(l-Hyl)roxyethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl} -4-(3,5-dimethoxyphenyl)piperazine was dissolved in chloroform(15ml) and pyridinum p-toluensulfdnate(60mg, 0.23mmol) was added and then the mixture solution was refluxed 16hours. The above solution was concentrated under the reduced pressure to remove chloroform and purified by column chromatography to obtain the titled compound, yield : 93% m.p. : 140-141°C 1H NMR(CDCl3) δ: 2.43(3H,s), 3.27(4H,t), 3.69(4H,0, 3.79(6H,s),
4.00(3H,s), 5.25(lH,d), 5.65(lH,d), 6.08(lH,s), 6.13(2H,d), 6.82(lH,d),
6.91 UH,s), 8.53(lH,s) Mass(EI) m/z : Calcd for C22H28N4O4 412.2110, found 412.2119
Example 74
l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-(3,5-
dimethylphenyl)piperazine:
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}
-4-(3,5-dimethylphenyl)piperazine was reacted by the same way with
the example 73 to obtain the titled compound.
yield : 94%
m.p. : 131-132°C
1H NMR(CDCl3) δ : 1.57(3H,s), 2.31 (6H,s), 2.43(lH,s), 3.25(4H,t),
3.68(4H,t), 4.00(3H,s), 5.25(lH,d), 5.65(lH,d) δ.60(3H,m), 6.82(lH,dd),
6.92(lH,s), 8.53(lH,s)
Mass(EI) m/z : Calcd for G22H28N4O2 380.2212, found 380.2236
Example 75
l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl)piperazine-l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}
-4-(3,5-difluorophenyl)piperazine was reacted by the same way with the
example 73 to obtain the titled compound.
yield : 93%
m.p. : 160-161°C
1H NMR(CDCl3) δ: 2.44(3H,s), 3.30(4H,t,J=5.5Hz), 3.68(4H,t,J=5.5Hz),
4.01 (3H,s), 5.26QH,d), 5.65(lH,d), 6.30(lH,s), 6.39(2H,d), 6.81(lH,dd),
8.53(lH,s) Mass(EI) m/z : Calcd for C22H28N4O4 412.2110, found 412.2102
Example 76
l-[(5-Isopropenyl-2-methoxy-6-methylpyridin-3-yl)aminocai-bonyl]-4-
(3,5-dimethoxyphenyl)piperazine:
-{[5-(l-Hyl)roxy-l-methylethyl)-2-methoxy-6-methylpyridin-3-yl)
aminocarbonyl]}-4-(3,5-dimethoxyphenyl)piperazine was reacted by the
same way with the example 73 to obtain the titled compound.
yield : 96%
m.p. : 83-85T,
1H NMR(CDCl3) δ: 2.01 (3H,s), 2.38(3H,s), 3.25(4H,t), 3.66(4H,t),
3.78(6II,s), 3.99(3H,s), 4.86(lH,s), 5.30(111,s), G.ll(3H,m), 6.90(lII,s),
8.18(1H,s)
Example 77
l-[(5-lsopropenyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine:
l-{[5-(l-Hyl)roxy-l-methylethyl)-2-methoxy-6-methylpyridin-3-yl]amin
ocarbonyl}-4-(3,5-dimethylphenyl)pii3erazine was reacted by the same
way with example 73 to obtain the titled compound.
yield : 93% '
m.p. : 140-142 oC
lH NMR(CDCl3) δ: 2.01(3H,s), 2.29(6H,s), 2.28(3H,s), 3.23(4H,t),
3.66(4H,t), 3.99(3H,s), 4.86(lH,s), 5.18(lH,s), 6.59(3H,m), 6.91(lH,s),
8.18(lH,s)
Example 78
Ethyl 2-{l-[5-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}amino)-6-
methoxy-2-methylpyridin-3-yl]ethoxy}acetate-'
l-{[5-(l-Hyl)roxy)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(0.5mmol) was dissolved in dimethylformamide(15ml) and NaH(18.5mg, 0.5mmol) was added and then the mixture solution was stirred at room temperature for 15min. Ethylbromoacetate(83.5mg, 0.5mmol) was added into the above mixture and stirred at room temperature for 3hours. The mixture was concentrated under the reduced pressure to remove the solvent and purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 89% m.p. : oil phase hi NMR(CDCl3) δ: 1.25(3H,t), 1.34(3H,d), 2.42(3H,s), 3.00(4H,t),
3.29(4H,t), 3.74(6H,s), 3.97(3H,s), 4.16(4H,s), 4.53QH,q),
6.03(3H,m), 7.58(lH,s)
Example 79
4-{l-[5-({[4-(3,5-Dimethoxyphenyl)piperazinolcarbonyUamino)-6-methox y-2-methylpyridin-3-yl]ethoxy}-4-oxobutanoic acid: l-{[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl) -4-(3,5-dimethoxyphenyl)piperazine(107mg, 0.25mmol) and dimethylaminopyridine(3mg, 0.025mmol) were dissolved in pyridine and anhyl)rous succinic acid(50mg, 0.5mmol) was added. The mixture was stirred at room temperature for 5hrs. Distilled water was added into the above mixture. The above solution was extracted with CH2CI2 and the organic phase washed with 1N-HC1 and then concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography (dichloromethane : methanol - 20:1) to obtain the titled compound, yield : 78% m.p. : 158-160oC lH NMR(CDCl3) δ; 1.42(3H,d),-2.43(3H,s), 2.61 (4H,m), 3.24(4H,t),
3.66(4H,t), 3.76(6H,s), 3.95(3H,s), 5.94(lH,q), 6.04(3H,m), 6.89(lH,s),
8.13(lH,s)
Example 80 4-{l-[5-({[4-(3,5-Dimethylphenyl)piperazino]carbonyl}amino)-6-methoxy-
2-methylpyridin-3-yl]ethoxy}-4-oxobutanoic acid:
l-{[5-(l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl} -4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 79 to obtain the titled compound, yield : 76% m.p. : 138-1401C
lH NMR(CDCl3) δ: 1.43(3H,d), 2.27(6H,s), 2.55(3H,s), 2.65(4H,m), 3.24(4H,t), 3.69(4H,t), 3.95(3H,s), 5.95(lH,q), 6.60(3H,m), 6.88(lH,s),
a.ii(ii-i.s)
Example 81
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)
piperazine:
a) Phenyl N-(2-methoxyquinolin-3-yl)carbamate:
3-Amino-2-methoxyquinoline(4g, 23mmol) and phenyl
chlorofonnate(4.04g, 25mmol) were dissolved in dichloromethane and
stirred at room temperature for 2 hours. The above mixture was
concentrated under the reduced pressure to remove dichloromethane and
purified by column chromatography (hexane : ether =8:1) to obtain the
titled compound.
yield : 75% m.p. : oil phase
1H NMR (CDCl3) δ 4.01(3H,s), 7.30(5H,s), 7.41(lH,t), 7.70UH,d), 7.71 (lH d). 8.71(1I-I,s)
b) l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)
piperazine'-
Phenyl N-(2-methoxyquinolin-3-yl)carbamate(148mg, 0.5mmol) and l-(3,5-dimethoxyphenyl)piperazine(112mg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added. The solution was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove tetrahyl)rofuran and purified by column chromatography (hexane : ether = 5:1) to obtain the titled compound, yield : 81%
m.p. : 200-201°C
1H NMR (CDCl3): δ 3.31(4H,t,J=5.0Hz), 3.74(4H,t), 3.79(6H,s), 4.17(3H,s),
6.09(lH,s), 6.17(2H,s), 7.35(lH,t), 7.49(lH,t), 7.71 (lH,d), 7.78(lH,d),
8.78(111,s)
Mass(EI) m/z : Calcd for C23H26N4O4 422.1954, found 422.1952
Example 82
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)
piperazine:
Phenyl N-(2-methoxyciuinolin-3-yl)carbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 81 to obtain the titled compound.
yield : 79%
m.p. : 143-145°C
lH NMR (CDCl3): δ 2.30(6H,s), 3.29(4H,t), 3.80(4H,t), 4.18(3H,s). 6.62(3H,m), 7.36(lH,t), 7.49(lH,t), 7.71(lH,d), 7.78(lH,d), 8.79(lH,s) Mass(EI) m/z : Calcd for C23H26N4O2 390.2055, found 390.20G6
Example 83
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2,3-dimethylphenyl) piperazine:
Phenyl N-(2-melhoxyquinolin-3-yl)carbamale and l-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound, yield : 83% m.p. : 174-175T;
JH NMR (CDCl3): δ 2.20(3H,s), 2.39(3H,s), 3.28(4H,t), 3.69(4H,t), 3.93(3H,s), 5.98(lH,s), 6.30(lH,t), 6.37(lH,s), 6.39(lH,s), 6.63(lH,s)
Example 84
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl)
piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(3,5-difluorophenyl)piperazine were reacted by the same way with the
example 81 to obtain the titled compound.
yield : 78%
m.p. : 158-1591C
1H NMR (CDCl3) δ 3.32(4H,tJ=5.0Hz), 3.72(4H,tJ=5.0Hz), 4.19(3H,s),
6.29(lH,s), 6.39(2H,d), 7.36(lH,t), 7.50(lH,t), 7.71(lH,d), 7.81(lH,d),
8.78(lH,s)
Example 85
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl)
piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the
example 81 to obtain the titled compound.
yield : 56%
m.p. : 156-158 V.
1H NMR (CDCh): 6.83(lH,d), 6.93(1I-I,t), 7.26(lH,t), 7.38(lH,t), 7.52(lH,t), 7.71 (lH.d),
7.83(1I-I,d) Mass (EI) m/z : Calcd for C21H20N4O2CI1 430.0963, found 430.0977
Example 86
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-fluorophenyl)piperazine-* Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(2-fluorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound, yield : 81% m.p. : 156-158oC
1H NMR (CDCW: Example 87
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-chlorophenyl)piperazine-'
Phenyl N-(2-methoxyquinoline-3-yl)carbamate and
l-(2-chlorophenyl)piperazine were reacted by the same way with the
example 81 to obtain the titled compound.
yield : 78%
m.p. : 79-80'C
1H NMR (CDCl3) δ 3.32(4H,t), 3.74(4H,t), 4.20(3H.s), 6.82(2II,q),
6.94(2H,m), 7.34(2H,m), 7.48(lH,d), 7.70(lH,d), 7.78(lH,d)
Example 88
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-chlorophenyl)piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(3-chlorophenyl)piperazine were reacted by the same way with the
example 81 to obtain the titled compound.
yield : 73%
m.p. : 97-98°C
1H NMR (CDCl3): δ 3.31 (4H,t), 3.73(4M,t), 4.18(3H,s), 6.82(lH,d),
6.87(lH,d), 6.92(lH,s), 7.21(lH,t), 7.32(lH,s), 7.37(lH,t), 7.51(11-1,0,
7.70(lH,d), 7.78(lH,d), 8.80(lH,s)
Example 89
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-hyl)roxyphenyl)
piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the
example 81 to obtain the titled compound.
yield : 75%
m.p. : 190-191 *C
1H NMR (CDCl3): δ 3.33(4H,t), 3.80(4H,t), 4.19(3H,s), 6.47UH.s),
6.62(2H,s), 7.16(lH,t), 7.32(lH,s), 7.37(lH,t), 7.51 (lH.t), 7.72(lH,d),
7.78(lH,d), 8.78(1I-I,s)
Example 90
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl) piperazine^
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(2-methoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound, yield : 88% m.p. : 159-161 oC
lH NMR (CDCL3): 8 3.28(4H,t), 3.71(4H,t), 3.81(3H,s), 4.18(3H,s), 6.52(2H,s), 6.62(lH,s), 7.23(lH,t), 7.31-7.53(3H,m), 7.72(2H,m), 8.81(lH,s)
Example 91
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-methylthiophenyl) piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and l-(2-methylthiophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound, yield : 78% m.p. •• 147-149 oC
lH NMR (CDCla): 8 2.44(3H,s), 3.07(4H,t), 3.75(411,0, 4.18(3H,s), 7.13(3H,m), 7.18(lH,d), 7.39(2H,m), 7.70(3H,m), 8.81(lH,s)
Example 92
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-isopropoxyphenyl)
piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(3-isopropoxyphenyl)piperazine were reacted by the same way with
the example 81 to obtain the titled compound.
yield : 93%
m.p. : 111-113CC
lH NMR (CDCl3) δ 1.34(6H,d), 3.30(4H,t), 3.74(4H,t), 4.18(3II,s),
4.55(lH,m), 6.49(2H,s), 7.05(lH,s), 7.20(lH,t), 7.32(lH,s), 7.37(lH,t),
7.50(lH,t), 7.70(lH,d), 7.77(lH,d). 8.80(lH,s)
Example 93
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-cyclopropylmethoxy
phenyl)piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(3-cyclopropylmethoxyphenyl)piperazine were reacted by the same
way with the example 81 to obtain the titled compound.
yield : 90%
m.p. : 146-147 °C .
1H NMR (CDCl3): δ 0.36(2H,t), 0.65(2H,m), 1.28(lH,m), 3.31 (4H,t), 3.75(4I-I,t), 3.80(2H,d), 4.18(3H,s), 6.50(lH,s), 6.60(2H,s), 7.19(lH,t), 7.32(lH,s), 7.37(lH,t). 7.50(lH,t), 7.70(lH,d), 7.77(lH,d), 8.79(lII,s)
Example 94

l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-methoxy-5-methyl
phenyl)piperazine-'
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way
with the example 81 to obtain the titled compound.
yield : 76%
m.p. : 115-116°C
1H NMR (CDCl3): δ 2.30(3H,s), 3.14(4H,t), 3.75(4H,t)( 3.87(3H,s),
4.18(3H,s), 6.79(2H,m), 6.84(lH,d), 7.35(2H,m), 7.50(lH,t), 7.72(lH,d),
7.77(lH,d), 8.82(lH,s)
Example 95
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(2-methoxy-5-phenyl
phenyl)piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbarnate and
l-(2-methoxy-5-phenylphenyl)piperazine were reacted by the same way
with the example 81 to obtain the titled compound.
yield : 77%
m.p. : 122-1231C
rH NMR (CDCl3): d 3.38(4H,t) 3.86(4H,t), 3.97(3H,s), 4.18(3H,s),
7.05(2H,m), 7.34-7.45(6H,m), 7.50(lH,t), 7.56(2H,d), 7.71(2H,d),
7.78(2H,d), 8.88(lH,s)
Example 96
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(5-methoxy-2-methyl
phenyl)piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way
with the example 81 to obtain the titled compound.
yield : 82%
m.p. : 128-130 °C ,
1H NMR (CDCl3): δ 2.30(3II,s), 3.37(411,0, 3.84(411,0, 3.78(311,s),
3.97(3H,s), 7.05(2H,m), 7.13(lH,d), 7.38(3H,m), 7.62(lH,d), 7.80(lH,s),
8.88(lH,s)
Example 97
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(l-naphthyl)piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and
l-(l-naphthyl)piperazine were reacted by the same way with the
example 81 to obtain the titled compound.
yield : 68%
m.p. : 158-16oC
1H NMR (CDCl3): δ 3.22(4H,t), 3.86(4H,t), 4.20(3H,s), 7.13(lH,d),
7.38(2H,m), 7.43(lH,t), 7.53(3H,m), 7.62(lH,d). 7.72(lH,d), 7.80(lH,d),
7.86(lH,d), 8.24(lH,d), 8.84(lH,s)
Example 98
l-[N-(2-Methoxyquinolin-3-yl)-N-methylaminocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine-'
l-[(2-Methoxyquinolin-3-yl)an"\inocarbonyl]-4-(3,5-dimethoxyphenyl)
piperazine(106mg, 0.25mmol) was dissolved in dimethylformamide(15ml)
and sodium hyl)ride(6.0mg, 0.25mmol) was added and the solution was
stirred at room temperature for 15 min. Iodomethane(35mg, 0.25mmol)
was added to the above solution. The mixture was stirred at room
temperature for 16 hours and concentrated under the reduced pressure
to remove dimethylformamide. The concentrate was purified by column
chromatography(ethylacetate : hexane = 1:2) to obtain the titled
compound.
yield : 93%
m.p. : 88-89°C
1H NMR (CDCl3): δ 2.93(4H,t), 3.17(3Ii,s), 3.34(4H,t), 3.72(6H,s),
4.15(31-1,0, 5.95(2H,s), 5.98(lH,s), 7.40(lH,t), 7.61 (2H,m), 7.73(lH,s),
7.84(lH,d) Mass(EI) m/z : Calcd for C24H28N4O4 436.2110, found 436.2105
Example 99
l-[N-Ethyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethox yphenyl)piperazine:
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine(106mg, 0.25mmol) was dissolved in dimethylformamide(15ml) and was sodium hyl)ride(6.0mg, 0.25inmol) was added and the solution was stirred at room temperature for 15 min. Iodoethane(35mg,
0.25mmol) was added to the above solution. The mixture was stirred at
room temperature for 16hours and concentrated under the reduced
pressure to remove dimethylformamide. The concentrate was purified by
column chromatography(ethylacetate : hexane = 1:2) to obtain the titled
compound.
yield : 91%
m.p. : 118-120X:
yH NMR (CDCl3): δ 1.16(3H,t), 2.89(4H,t), 3.30(4H,t), 3.63(2M.m),
3.71(6H,s), 4.13(3II,s), 5.93(2H,s), 5.98(lH,s), 7.41(111,0, 7.(30(111,0,
7.66(lH,d), 7.71(lH,s), 7.84(lH,d)
Mass(EI) m/z : Calcd for C25H30N4O4 450.2227, found 450.220(3
Example 100
l-[N-Isopropyl-N-(2-methoxyquinolin-3-yl)aminocai_bonyl]-4-(3,5-
dimethoxyphenyl)phenyl:
l-[(2-Methoxyciuinolin-3-yl)aminocarbonyl]-4-(3,5-dimelhoxyphenyl)
piperazinedOGmg, 0.25mmol) was dissolved in dimethylforrnamide(15ml)
and sodium hyl)ride(G.0mg, 0.25mmol) was added and the reaction
solution was stirred at room temperature for 15 min.
2-Propyliodide(42mg, 0.25mmol) was added to the above solution. The
mixture was stirred at room temperature for IG hours and concentrated
under the reduced pressure to remove the dimethylformamide. The
concentrate was purified by column chromatography (ethylacetate :
hexane = 1:2) to obtain the titled compound.
yield : 87%
m.p. : 123-125°C
1H NMR (CDCl3) δ 1.21(6H,d), 2.79(4H,t), 3.29(4H,t), 3.70(6H,s),
4.08(3H,s), 4.41(lH,m), 5.90(2H,s), 5.96(lH,s), 7.43(lH,t), 7.63(lH,t),
7.69(lH,d), 7.75(lH,s), 7.83(lH,d)
Example 101
l-[N-Cyclopropylmethyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-[(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazined(106, 0.25mmol) was dissolved in dimethylformamide(15ml) and sodium hyl)ride(6.2mg, 0.26mmol) was added and the solution was
stirred at room temperature for 15 min. Bromomethylcyclopropane(22mg, 0.26mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 78% .m.p. : 118-120TC 1H NMR (CDCl3): δ 0.41(2H,m)f 0.85(2H,m), 1.28(lM,m), 2.88(41-1,1).
3.24(4H,t), 3.42(2H,d), 3.71 (6H,s), 4.13(3H,s), 5.94(3H,s), 7.44(lH,d),
7.62(lH,d), 7.78(3H,m)
Example 102
l-[N-Berizyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-
dimethoxyphenyl)piperazine:
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)
piperazine(114mg, 0.27mmol) was dissolved in dimethylformamide(15ml)
and sodium hyl)ride(6.6mg, 0.27mmol) was added and the solution was
stirred at room temperature for 15 min. Benzylbromide(46mg, 0.27mmol)
was added to the above solution. The mixture was stiired at room
temperature for 16 hours and concentrated under the reduced pressure
to remove dimethyl fori namide. The concentrate was purified by column
chromatography (ethy lacetate : hexane = 1:2) to obtain the titled
compound.
yield : 90%
m.p. : oil phase
1H NMR (CDCl3): δ 2.92(4H,t), 3.39(4H,t), 3.72(6H,s), 4.13(3H,s),
4.79(2H,s), 6.01(3H,m), 7.21(lH,m), 7.25(2H,m), 7.33(3H,m), 7.51(lH,s),
7.57(2H,m), 7.81 (2H,d)
Example 103
l-[N-(2-Methoxyquinolin-3-yl)-N-methylaminocarbonyl]-4-(3,5-dimethyl phenyl) piperazine:
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine was reacted by the same way with the example 98 to obtain the titled compound.
yield : 92%
m.p : 142-143 oC
1H NMR (CDCl3): δ 2.27(GH,d), 2.90(411,0, 3.17(3H,s), 3.34(41-1,0,
4.15(3H,s), 6.41(2H,s), 6.49(lH,s), 7.40(11-1,0, 7.63(lH,t), 7.65(lH,d),
7.73(1I-I,s), 7.84(lH,d) Mass(EI) m/z :. Calcd for C24H28N4O2 404.2212, found 404.2225
Example 104
l-[N-Ethyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethyl
phen y 1) piperazine:
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)
piperazine was reacted by the same way with the example 99 to obtain
the titled compound.
yield : 89%
m.p. : 84-86°C
1H NMR (CDCl3): δ 1.1G(3II,0, 2.21(GII,s), 2.87(411,0, 3.30(411,0,
3.64(2H,q), 4.13(3H,t), 6.40(2H,s), 6.48(111,s), 7.40(111,0, 7.62(111,0,
7.66(lH,d), 7.71(lH,s), 7.84(lH,d)
Example 105
l-[N-Isopropyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-
dimethylphenyl)piperazine:
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)
piperazine was reacted by the same way with the example 100 to
obtain the titled compound.
yield : 84%
m.p. : 114-1151C
1H NMR (CDCL3): 1.21 (6H,d), 2.20(6H,s), 2.77(4H,t), 3.28(4H,t),
4.08(3H,s), 4.39(lH,m), 6.37(2H,s), 6.46(lH,s), 7.41(lH,t), 7.63(lH,t),
7.69(lH,d), 7.75(lH,s), 7.83(lH,d)
Example 106
l-[N-Benzyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl)piperazine:
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine was reacted by the same way with the example 102 to
obtain the titled compound, yield : 90% m.p. : oil phase
lH NMR (CDCl3): δ 2.24(6H,s), 2.87(4H,t), 3.31 (4H,t), 4.13(3H,s), 4.80(2H,s), 6.42(3H,s), 7.49(lH,t), 7.62(2H,m), 7.72(2H,m)
Example 107
l-[N-(2-Methoxyquinolin-3-yl)-N-methylaminocarbonyl]-4-(3-
isopropoxyphenyl)piperazine:
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-isopropoxyphenyl)
piperazine was reacted by the same way with the example 98 to obtain
the titled compound.
yield : 92%
m.p. : oil phase
1H NMR (CDCl3): δ 1.28(6H,d), 2.97(411,0, 3.18(3H,s), 3.37(411,1).
4.14(3M,s), 4.49(lII,m), 6.41(3Il,m), 7.13(lH,m), 7.40(111,0, 7.62(11-1,0,
7.GG(lH,d), 7.74(lH,s), 7.84(lH,d)
Example 108
l-[N-Ethyl-N-(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3-
isopropoxyphenyl)piperazine:
l-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3-isopropoxyijhenyl)
piperazine was reacted by the same way with the example 99 to obtain
the titled compound.
yield : 87%
m.p. ' oil phase
lH NMR (CDCl3): δ 1.16(311,0, 1.34(611,d), 2.89(4H,t), 3.30(411,t),
3.63(2H,m), 4.13(3H,s), 4.55(lH,m), 6.49(2H,s), 7.05(lH,s), 7.20(lH,t).
7.32(lll,s), 7.37(111,0, 7.50(111,1), 7.70(lH,d), 7.77(lM,d), 8.80(lH,s)
Example 109
l-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3,5-diiriethoxyphenyl)
piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)ihiocarbainate(56mg, 0.5mmol) and
l-(3,5-dimethoxyphenyl)piperazine(lllmg, 0.5mmol) were dissolved in
anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added. The
reaction solution was stirred at room temperature for 2 hours. The
above solution was concentrated under the reduced pressure to remove
tetrahyl)rofuran and concentrated was purified by column
chromatography(Hexane : ether - 5:1) to obtain the titled compound.
yield : 76%
m.p. : 171-172 °C
1H NMR (CDCl3):δ 3.41(4H,t), 3.81 (6H,s), 4.17(3H,s), 4.21(41-1,0,
6.12(11-I.s), 6.20(lH,d), 7.38(lH,t), 7.54(lH,t), 7.74(lH,d), 7.81 (lH,d),
8.90(lll,s)
Example 110
l-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3,5-dimethylphenyl) piperazine-'
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound, yield : 79% m.p. : 170-171 oC
1H NMR (CDCl3):a 2.30(6II,s), 3.38(4H,t), 4.09(311,s), 4.17(411,0, 6.63(3II,m), 7.38(11-1,0, 7.54(1H,0, 7.72(lH,d), 7.81(lII,d), 8.96(lll,s)
Example 111
l-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3,5-difluorophenyl) piperazine^
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and l-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound, yield : 78% m.p. : 140-142oC
lH NMR (CDCl3): δ 3.44(4H,t), 4.20(4H,t), 4.25(3H,s), 6.33(2II,m), 6.45(111,d), 7.41 (IH.t), 7.56(lH,m), 7.72(lH,m), 7.97(lH,m), 8.96(lH,s)
Example 112
l-[(2-Methoxyquinolin-3-yl)aminothiocaibonyl]-4-(3,5-dichlorophenyl)
piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and
l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the
example 109 to obtain the titled compound.
yield : 62%
tn.p.: 181-183 oC
lH NMR (CDCl3): δ 3.44(4H,t), 4.20(4H,t), 4.26(3H,s), 6.77(lH.s),
6.88(2H,0, 7.41(lH,t), 7.59(lH,t), 7.70(2H,m), 8.01(lH,t), 8.11(lH,s),
8.93(lH,s)
Example 113
l-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3-methoxyijhenyl) piperazine:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and l-(3-methoxyphenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound, yield : 81% m.p. : oil phase
1H NMR (CDCl3): δ 3.17(411,0, 3.89(3II,s), 4.17(41-1,0, G.90(4II.m), 7.34(111,0, 7.48(111,1), 7.70(lH,d), 7.77(lH,d), 8.80(lH.s)
Example 114
l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)
piperazine:
a) Phenyl N-(2-methylquinolin-3-yl)carbamate:
3-amino-2-rnethylquinoline(4g, 25mmol) and phenyl chloroformate(4.04g, 25mmol) were dissolved in methylene chloride and then was stirred at room temperature for 2 hrs. The mixture solution was concentrated under the reduced pressure to remove methylene chloride and purified by column chromatography(ethylacetate : hexane = P10) to obtain the titled compound.
yield : 88%
1H NMR (CDCl3): δ 2.77(3H,s), 7.30-7.53(9H,m), 8.67(lH,s)
b) l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)
piperazine:
Phenyl N-(2-methylquinolin-3-yl)carbamate(140mg, 0.5mmol) and
l-(3,5-dimethoxyphenyl)piperazine(112mg, 0.5mmol) were dissolved in tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove letraliyl)rofuran and purified by column chromatography(ethylacetate : hexane = 1:2) to obtain the titled compound, yield : 84% m.p. : 199-200 oC 1H NMR (CDCl3): δ 2.81 (3H,s), 3.30(411,1), 3.7G(4H,t), 3.80(61 -I,s),
6.08(lII,s), 6.12(2H,d), 7.48(lH,t), 7.62(1H,0, 7.71(lH,d), 8.03(lH,d),
8.59(HI,s)
Example 115
l-[(2-Methylquinolin-3-yi)aminocarbonyl]-4-(3,5-dimethylphenyl) piperazine:
Phenyl N-(2-methylquinolin-3-yl)carbamate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound, yield : 86% m.p. : 230-232oC
lH NMR (CDCl3): δ 2.31 (6H,s), 2.82(3H,s), 3.29(411,0, 3.76(4H,t), 6.60(3II,s), 7.49(111,0, 7.63(111,0, 7.73(lll,d), 8.05(lll,d), H.GKlII.s)
Exeimple 116
l-[(2-methylquinolin-3-yl)aminocarbonyl]-4-(2,3-dimethylphenyl)
piperazine:
Phenyl N-(2-methylquinolin-3-yl)carbamate and
l-(2,3-dimethylphenyl)piperazine were reacted by the same way with
the example 114 to obtain the titled compound.
yield : 81%
m.p. : 169-170 °C ,
lH NMR (CDCb): 3 2.28(6II,d), 2.84(3II,s), 3.00(411,0, 3.7(K4H,0,
6.94(2H,m), 7.11(11-1,0, 7.49(111,1), 7.63(11-1,0, 7.72(lH,d),
8.07(lH,d), 8.64(lH,s)
Example 117
l-[(2-Methoxyauinolin-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl)
piperazine^
Phenyl N-(2-methylquinolin-3-yl)carbamate and
l-(3,5-difluorophenyl)piperazine were reacted by the same way with the
example 114 to obtain the titled compound.
yield : 81%
m.p. : 238-2401:
1H NMR (CDCl3):δ 2.81(311,0, 3.34(411,1), 3.77(411,0, (5.32(111,0,
6.39(2H,d), 7.49(1H,0, 7.63(1H,0, 7.72(lH,d), 8.03(lH,d), 8.58(lH,s)
Example 118
l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl) piperazine:
Phenyl N-(2-inethykiuinolin-3-yl)carbarnate and
l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound, yield : 65% m.p. : 247-249oC
3H NMR (CDCl3): δ 2.79(3H,s), 3.33(4H,t), 3.75(4H,t), 6.78(2H,s), 6.87(lH,s), 7.49(lH,t), 7.63(lH,t), 7.72(lH,d), 8.56(lH,s)
Example 119
l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)
piperazine-
Phenyl N-(2-methylquinolin-3-yl)carbamate and
l-(2-inethoxyphenyl)piperazine were reacted by the same way with the
example 114 to obtain the titled compound.
yield : 83%
m.p. : 135-1361C
1H NMR (CDCW'-,d 2.82(3H,s), 3.18(4H,t), 3.79(4H,t), 3.91 (3H,s),
6.88(lH,d), 6.97(2H,s), 7.07(lH,m), 7.48(1H,0, 7.62(lH,t), 7.72(lH,d),
8.04(lH,d), 8.63(lH,s)
Example 120 l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-fluorophenyl)piperazine:

Phenyl N-(2-methylquinolin-3-yl)carbamate and
l-(2-fluorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound, yield : 84% m.p. : 201-203 °C
1H NMR (CDCl3): δ 2.84(3H,s), 3.20(4H,t), 3.80(4H,t), 6.99(2H,m), 7.07(211,111), 7.49(111,0, 7.62(lH,t), 7.71 UH.d), 8.04(lII,d), 8.62QH,s)
Example 121
l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-chlorophenyl)piperazine: Phenyl N-(2-methylquinolin-3-yl)carbamate and
l-(2-chlorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound, yield : 72% m.p. : 180-181 oC
lH NMR (CDCL3): d 2.83(3H,s), 3.16(4H,t), 3.80(411,0, 7.04(3M,m), 7.40(lH,d), 7.49(11-1,1), 7.(53(111,0, 7.71(lII,d), 8.05(lH,d), 8.62(lH,s)
Example 122
l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-methylthiophenyl)
piperazine:
Phenyl N-(2-methylquinolin-3-yl)carbamate and
l-(2-methylthiophenyl)piperazine were reacted by the same way with
the example 114 to obtain the titled compound.
yield : 76%
m.p. : 165-166°C
lH NMR (CDCl3): δ 2.45(3H,s), 2.85(3H,s), 3.11(411,0, 3.79(411,0,
7.05(lH,m), 7.15(3H,d), 7.49(1H,0, 7.63(1H,0, 7.69(lH,d), 8.07(lH,d),
8.02(lII,s)
Example 123
l-[(2-Methylquinolin-3-yl)aminocarbonyl]-4-(2-methoxy-5-methyl
phenyl)piperazine:
Phenyl N-(2-methylquinolin-3-yl)carbamate and
l"(2-inetlu)xy-5-methylphenyl)piperazine were reacted by the same way
with the example 114 to obtain the titled compound.
yield : 80% m.p. : oil phase
lH NMR (CDCl3): δ 2.30(3H,s), 2.72(3H,s), 3.17(4H,t), 3.70(4M,t), 3.87(3H,s), 6.77(lII,s), 6.82(2II,s), 7.73(4H,m), 8.60(lH,s)
Example 124
l-[(2-Methylauinolin-3-yl)aminocarbonyl]-4-(l-naphthyl)piperazine:
Phenyl N-(2-methylquinolin-3-yl)carbamate and
l-(l-naphlhyl)piperazine were reacted by the same way with the
example 114 to obtain the titled compound.
yield : 64%
m.p. : 220-222 °C
1H NMR (CDCl3): δ 2.83(3H,s), 3.23(4H,t), 3.80(4H,t), 6.91 (lH,s),
7.12(lH,d), 7.44(lH,d), 7.50(3H,m), 7.61(2II,m), 7.73(lH,d), 7.86(lII,d),
8.05(lH,d), 8.23(lH,d), 8.64(lII,s)
Example 125
l-[(2-Methylciuinolin-3-yl)aminothiocarbonyl]-4-(3,5-dimethoxyphenyl)
piperazine:
a) Phenyl N-(2-methylquinolin-3-yl)thiocarbamate: 3-Amino-2-methylquinoline(4g, 25mmol) and phenyl chlorothionoformate(4.32g, 25mmol) were dissolved in methylene chloride and then was stirred at room temperature for 2hours. The mixture solution was concentrated under reduced pressure to remove methylene chloride and purified by column chromalography(ethylacetate : hexane _ 1 : 2) to obtain the titled compound, yield : 78% TH NMR (CDCl3): d 2.77(3H,s), 7.09-7.90(9H,m), 9.14(lH,s)
b)
l-[(2-Methylquinolin-3-yl)aminothiocarbonyl]-4-(3,5-dimethoxyphenyl)
piperazine^
Phenyl N-(2-methylquinolm-3-yl)thiocarbamate(147mg, 0.5mmol) and
l-(3,5-dimethoxyphenyl)piperazine(112mg, 0.5mmol) were dissolved in
anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added and
then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahyl)rofuran and purified by column chromatography(ethylacetate : hexane = 1 : 2) to obtain the titled compound, yield : 86% m.p. : 211-2121C
1H NMR (CDCb):^ 2.81 (3H,s), 3.35(4H,0, 3.79(6H,s), 4.14(4H,t), 6.07(3II,s), 7.49(2H,t), 7.68(2H,m), 8.01(lH,s), 8.07(lH,d)
Example 126
l-[(2-Methylquinolin-3-yl)aminothiocarbonyl]-4-(3,5-dimethylphenyl) piperazine^
Phenyl N-(2-methylquinolin-3-yl)thiocarbarnate and l-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 125 to obtain the titled compound, yield : 81% m.p. : 196-197 °C
1H NMR (CDCl3): δ 2.27(6H,s), 2.81(3H,s), 3.31(41-1,0, 4.11(411,0, C.53(2II,s), G.58(lII,s), 7.48(211,0, 7.67(21I.m), 7.96(1 ll.s), 8.04(HI,d)
Example 127
l-[(2-Melhylquinolin-3-yl)aminothiocarbonyl]-4-(3,5-difluorophenyl) piperazine:
Phenyl N-(2-methylquin()lin-3-yl)tliiocarbainate and
l-(3,5-dil'luorophenyl)piperazine were reacted by the same way with the example 125 to obtain the titled compound, yield : 74% m.p. : 211 -213OC
1H NMR (CDCl3): δ 2.85(3H,s), 3.43(4H,t), 4.22(4H,t), 6.33(2H,m), 7.49(1H,0, 7.64(lH,d), 7.72(lH,t), 8.16(2H,m)
Example 128
l-{[2-(Pyridin-2-yl)quinolin-4-yl]aminocarbonyl}-4-(3,5-
dimethoxyphenyl)piperazine:
Phenyl N-[2-(pyridin-3-yl)quinolin-4-yl]carbamate(171mg, 0.5mmol) arid
l-(3,5-dimethoxyphenyl)piperazine(lllmg, 0.5mmol) were dissolved in
anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added and then the mixture was stirred at room temperature for 2hrs. The above solution was concentrated under the reduced pressure to remove tetrahyl)rofuran and purified by column chromatography (dichloromethane •' methanol=20:l) to obtain the titled compound, yield : 73% m.p. : 97-98oC 1H NMR (CDCl3) δ 3.34(4H,t), 3.79(6H,s), 3.90(4H,t), 6.07(lH,s),
6.12(2H,s), 7.43(lH,t), 7.50(lH,t), 7.68(lH,t), 7.93(lH,t), 8.26(lH,d),
8.59(lH,d). 8.80(lH,d), 8.98(lH,s) Mass(EI) m/z : Calcd for C31H27N5O3 517.2113, found 517.3244
Excimple 129
l-{[2-(Pyridin-3-yl)quinolin-4-yl]aminocarbonyl}-4-(3,5-
dimethoxyphenyl)piperazine:
Phenyl N-[2-pyridin-3-yl)quinolin-4-yl]carbamate(171mg, 0.5mmol) and
l-(3,5-dimelhoxyphenyl)piperazine(llling, 0.5nnnol) were dissolved in
anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added and
then the mixture was stirred at room temperature for 2 hours. The
above solution was concentrated under the reduced pressure to remove
tetrahyl)rofuran and purified by column chromatography
(dichloromethane : methanol = 20:1) to obtain the titled compound.
yield : 67%
m.p. : 95-96oC,
rH NMR (CDCl3): δ 3.36(4H,t), 3.87(6H,s), 3.90(4H,t), 6.08(lH,s),
6.12(2H,s), 7.50(lH,t), 7.71(lH,t), 7.93(lH,t), 8.25(lH,d), 8.53(lH,d),
8.67(lII,s), 8.73(lII,d), 9.35(lII,s)
Example 130
l-{[2-Thien-2-yl)quinolin-4-yl]aminocai-bonyl}-4-(3,5-dimethoxyphenyl) piperazine:
Phenyl N-[2-(thien-2-yl)quinolin-4-yl]carbamate(173mg, 0.5mmol) and l-(3,5-dimethoxyphenyl)piperazine(lllmg, 0.5mmol) were dissolved in anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove tetrahyl)rofuran and
purified by column chromatography (ethylaetate : hexane = 1:1) to
obtain the titled compound.
yield : 61%
m.p. : oil phase
lH NMR (CDCl3): δ 3.37(4H,t), 3.59(6Hts), 3.97(4H,t), 7.01 (3H,m),
7.49(lH,t), 7.69(lH,t), 7.93(lH,t), 8.20(lH,d), 8.52(lH,d), 8.64(lH,s),
8.71 QH.d), 9.35(lH,s)
Example 131
l-{[2-(Pyridin-3-yl)quinolin-4-yl]aminocarbonyl}-4-(3,5-dimethylphenyl)
piperazine:
Phenyl N-[2-(pyridin-3-yl)quinolin-4-yl]carbamate(171mg, 0.5mmol) and
l-(3,5-dimethylphenyl)piperazine(95mg, 0.5mmol) were dissolved in
anhyl)rous tetrahyl)rofuran and DBU(117mg, 0.75mmol) was added. The
resulting mixture was stirred at room temperature for 2 hours,
concentrated under the reduced pressure to remove tetrahyl)rofuran, and
purified by column chromatography (ethylacetate : hexane =1:1) to
obtain the titled compound.
yield : 64%
.m.p. : 211-213TC
lU NMR (CDCL3):^ 2.31 (6H,s), 3.32(4H,t), 3.85(4H,t), 6.61 (3H,s),
7.47(lH,t), 7.55(lH,t), 7.72(lH,t), 7.86(lH,t), 8.25(lH,d), 8.53(lH,d),
8.66(lH,s), 8.72(lH,d), 9.37(lH,s)
Example 132
l-[N-(5,6-Dimethyl-2-methoxypyridin-3-yl)-N-methylaminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100mg, 0.25mmol) was dissolved in dimethylformamide(15ml) and thereto sodium hyl)ride(6.0mg, 0.25mmol) was added. The resulting mixture was stirred at room temperature for 15 min and thereto iodomethane(35mg, 0.25mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced presssure to remove dimethylfonnainiclc, and purified by column chromatography (ethylacetate : hexane=l:2) to obtain the titled compound.
yield : 94%
m.p. : oil phase
lHNMR(CDCl3): δ : 2.17(3H,s), 2.38(3H,s), 2.92(4H,t), 3.04(3H,s),
3.29(411,0, 3.74(6H,s), 3.96(3H,s), 6.00(3H,m), 7.08(lH,s)
Example 133
l-[N-Ethyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100mg, 0.25mmol) was dissolved in dimethylfonnamide(15ml) and thereto sodium hyl)ride(6.0mg, 0.25mmol) was added, followed by stirring at room temperature for 15 min and then iodoethane(39.2mg, 0.25mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure to remove dimethylformamide, and purified by column chromatographyCethylacetate : hexane=l:2) to obtain the titled compound, yield : 86% m.p. '• oil phase
lH NMR(CDCl3)tf: 1.08(3H,t), 2.04(3H,s), 2.38(3H,s), 2.90(4H,t), 3.26(41-1,0, 3.52(2H,q), 3.74(6H,s), 5.99(3H,m), 7.06(lH,s)
Example 134
l-[N-Isopropyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100mg, 0.25mmol) was dissolved in dimethylformamide(15ml) and thereto sodium hyl)ride(6.0mg, 0.25mmol) was added, followed by stirring at room temperature for 15 min, and then 2-iodopropane(42mg, 0.25mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure,to remove dimethylformamide, purified by column chromatographyCethylacetate : hexane=l:2) to obtain the titled compound, yield : 78% m.p. : oil phase
1H NMR(CDCl3) δ: 1.13(6H,d), 2.19(3H,s), 2.38(3H,s), 2.82(4H,t), 3.26(4H,t), 3.74(6H,s), 3.89(3H,s), 4.27(lH,m), 6.06(lH,s), 6.10(2II,d),
7.07(lH,s), 8.14(lH,s)
Mass (EI) m/z : Calcd for C24H34N4O4 442.2580, found 442.2538
Examine 135
l-[N-(5,G-Dimethyl-2-methoxypyridin-3-yl)-N-methylaminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine-'
l-[(5,G-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3)5-dimethyl
phenyl)piperazine was reacted by the same way with the example 132
to obtain the titled compound.
yield : 97%
m.p. : oil phase
1H NMR(CDCl3): δ: 2.15(6H,s), 2.23(3H,s), 2.37(3H,s), 2.89(41-1,0,
3.04(3I-I,s), 3.30(4H,t), 3.97(3H,s), 6.46(3H,m), 7.08(lH,s)
Example 136
l-[N-(5,6-Dimethyl-2-methoxypyridin-3-yl)-N-methylaminocarbonyl]-4-
(2-methoxyphenyl)piperazine:
l_[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-inethoxyph
enyl)piperazine was reacted by the same way with the example 132 to
obtain the titled compound.
yield : 94%
m.p. : 131-132°C
1H NMR(CDCl3) δ: 2.16(3II,s), 2.38(3H,s), 2.80(4H,t), 3.05(3H,s),
3.35(41-1,0, 3.82(3H,s), 3.97(3H.s), 6.83(4H,m), 7.08(111.s)
Examine 137
l-[N-Ethyl-N-(5,G-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-
(2-methoxyphenyl)piperazine:
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyph
enyl)piperazine was reacted by the same way with the example 133 to
obtain the titled compound. .
yield : 87%
m.p. : 112-113°C
1H NMR(CDCl3) δ: 1.08(3H,O, 2.16(3H,s), 2.38(3H,s), 2.77(411,0,
3.31(411,0, 3.58(2H,q), 3.81 (3H,s), 3.96(3H,s), 6.88(4H,m), 7.06(lH,s)
Example 138
l-[N-Benzyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine:
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine(100mg, 0.27mmol) was dissolved in dimethylforrnarnide(15ml) and thereto sodium hyl)ride(6.5mg, 0.27mmol) was added, followed by stirring at room temperature for lhr, and successively benzyl bromide(46.2mg, 0.27mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure and purified by column chromatography(ethylacetate : hexane = 1: 2) to obtain the titled compound, yield : 93% m.p. : oil phase
TI NMR(CDCl3) δ: 2.08(3H,s), 2.35(3H,s), 2.85(4M,t), 3.32(41-1,0. 3.81(311,s), 3.90(311,s), 4.7G(2II,s), 6.96(4II,m), 7.41(5H,m)
Example 139
l-[N-Cyclopropylmethyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-methoxy phenyl) piperazine: l-[(5,G-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine(100mg, 0.26mmol) was dissolved in dimethylformamide(15ml) and thereto sodium hyl)ride(6.2mg, 0.26mmol) was added, followed by stirring at room temperature for 15 inin, and successively broinomethylcyclopropane(21.8mg, 0.26minol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure and purified by column chromatography (ethylacetate : hexane = 1: 2) to obtain the titled compound, yield : 78% m.p. : oil phase
]H NMR(CDCl3) δ: 0.34(2H,m), 0.49(2H,m), 1.35(lH,m), 2.85(4H,t), 3.28(4H,t), 3.40(2H,s), 3.89(3H,s), 3.97(3H,s), 6.97(4H,m), 7.11(lH,s)
Example 140 l-[N-(5,6-Dimethyl-2-methoxypyridin-3-yl)-N-methylaminoccirbonyl]-4-
(5-methoxy-2-methylphenyl)piperazine:
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(5-methoxy-
2-methylphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 74%
m.p. : 91-93°C
1H NMR(CDCl3) δ: 2.15(3H,s), 2.18(3H,s), 2.39(3H,s), 2.67(4H,t),
3.05(3H,s), 3.30(4H,t), 3.75(3H,s), 3.97(3H,s), 6.48(3H,m), 7.10(lII,s)
Example 141
l-[N-Ethyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-
(5-methoxy-2-methylphenyl)piperazine;
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(5-methoxy-
2-methylphenyl)piperazine was reacted by the same way with the
example 133 to obtain the titled compound.
yield : 94%
m.p. : oil phase
]H NMR(CDCl3) δ: 1.09(3H,t), 2.15(3H,s), 2.18(3H,s), 2.39(3H,s),
2.60(4H,t), 3.27(4H,t), 3.59(2H,q), 3.75(3H,s), 3.96(3H,s), 6.45(3H,m),
7.08(lH,s)
Example 142
l-[N-Benzyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-
(5-methoxy-2-methylphenyl)piperazine:
l-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(5-methoxy-
2-methylphenyl)piperazine was reacted by the same way with the
example 138 to obtain the titled compound.
yield : 97%
m.p. : oil phase
1H NMR(CDCl3) δ: 1.25(3H,t), 2.08(3H,s), 2.14(3H,s), 2.35(3H,s),
2.60(4H,t), 3.32(4H,t), 3.74(3H,s), 3.95(3H,s), 4.66(2H,s), 6.44(4H,m),
6.96(5H,m), 7.12(lH,s)
Example 143
l-[N-(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)-N-methylamino
carbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-[(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)arninocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 132 to obtain the titled compound, yield : 87% in.p. : 78-79°C
lH NMR(CDCl3) δ : 1.14(3H,t), 2.41(3H,s), 2.52(2H,q), 2.91(411,0, 3.02(3II,s), 3.28(41-1,0, 3.74(6H,s), 3.98(3II,s), 5.98(3H,m), 7.11(lH,s) Mass(EI) in/z : Calcd for C23H32N4O4 428.2423, found 428.2434
Example 144
l_[N-(5-Ethyl-2-metlioxy-6-methylpyridin-3-yl)-N-methylamino
carbonyl]-4-(3,5-dimethylphenyl)piperazine'-
l-[(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 84%
in.p. : 86-87°C
1H NMR(CDCl3) δ: 1.14(3H,t), 2.23(6H,s), 2.45(3H,s), 2.58(2H,q),
2.87(4H,t), 3.05(3H,s), 3.30(411,0, 3.98(3H,s), 6.46(3H,m), 7.11(lII,s)
Mass (EI) m/z : Calcd for C23H32N4O2 396.2525, found 396.2575
Example 145
l-[N-Ethyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]
-4-(3,5-dimethylphenyl)piperazine:
l-[(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 133 to obtain the titled compound.
yield : 86% '
m.p. : 84-85°C
1H NMR(CDCl3) δ: 1.13(6H,m), 2.23(6H,s), 2.41(3H,s), 2.58(2H,q),
2.85(4H,t), 3.26(4H,t), 3.46(2H,q), 3.96(3H,s), 6.45(3H,m), 7.08QH,s)
Example 146
l_[N-(2-Methoxy-6-methyl-5-propylpyridin-3-yl)-N-methylamino carbonyl]-4-(3,5-ditnethoxyphenyl)piperazine : l-[(2-Methoxy-6-methyl-5-propylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 89%
m.p. : oil phase
1H NMR(CDCl3) δ : 1.01 (3H,t), 1.78(2H,m), 2.21(3H,s), 2.78(2H,t),
3.78(6H,s), 3.86(4H,t), 3.99(3H,s), 4.00(3H,s), 4.22(4H,t), 6.01 (3H,m),
7.02(lH,s)
Example 147
l-[N-(6-Ethyl-2-methoxy-5-methylpyridin-3-yl)-N-methylamino
carbonyl] -4- (3,5-dimethoxy pheny Dpiperazine^
l-[(G-Etliyl-2-methoxy-5-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 85%
m.p. : oil phase
]H NMR(CDCl3) δ : 2.21 (3H,t), 2.21 (3H,s), 2.45(2H,q), 3.21 (4H,t),
3.40(3H,s), 3.67(4H,t), 3.77(6H,s), 4.01 (3H,s), 6.07(3H,m), 6.96(lH,s),
8.07(lH,s)
Example 148
l-[N-(2-Methoxy-5-methyl-G-propylpyridin-3-yl)-N-methylamino
carbonyl] -4- (3,5-dimethoxy pheny Dpiperazine:
l-[(2-Methoxy-5-methyl-6-propylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 86%
m.p. : 106-107CC
1H NMR(CDCl3) δ: 0.98(3H,t), 1.73(2H,q), 2.18(3H,s), 2.63(2H,t),
2.92(4H,t), 3.05(3H,s), 3.29(4H,t), 3.74(6H,s), 3.96(3H,s), 6.00(3H,m),
7.11(lH,s)
Mass (EI) m/z : Calcd for C24H34N4O4 442.2580, found 442.2543
Example 149
l-[N-(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)-N-methylamino carbonyl] -A- (3,5-dimethoxyphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 89%
m.p. : oil phase
1H NMR(CDCl3) δ: 2.50(3H,s), 2.70(3H,s), 2.97(4H,t), 3.09(3H,s),
3.33(4H,t), 3.75(6H,s), 4.06(3H,s), 6.03(3H,m), 7.72(lH,s)
Mass (EI) m/z : Calcd for C23H30N4O5 442.2216, 442.2229
Example 150
l-[N-Ethyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl
]-4-(3,5-dimethoxyphenyl)piperazine-'
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the
example 133 to obtain the titled compound.
yield : 87%
m.p. : oil phase
lH NMR(CDCl3) δ: 1.09(3H,t), 2.49(3H,s), 2.70(3H,s), 3.00(4H,t),
3.32(41-1,0, 3.77(6H,s), 4.01(3H,s), 4.09(2H,q), 5.98(3H,m), 7.76(lH,s)
Example 151
l-[N-(r)-Acelyl-2-methoxy-G-inethylpyridin~3-yl)-N-inelhylarnino
Ccirb(jnyl]-4-(3,5-dimethylphenyl)piixirazine:
l-[(5-Acelyl-2-inethoxy-G-ineLhylpyridin-3-yl)aiiiinocarbonylJ-4-
(3,5-dimethylphenyl)piperazine was reacted by the same with the
example 132 to obtain the titled compound.
yield : 88%
m.p. : oil phase
1H NMRCDCl3): δ: 2.24(6H,s), 2.50(3H,s), 2.70(3H,s), 2.93(4H,t),
3.09(3H,s), 3.28(4H,t), 4.06(3H,s), 6.46(3H,m), 7.73(lH,s)
Example 152
l-{N-[5-(l-Hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]-N-methyl aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine: l-[N-(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)-N-methylamino carbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.47mmol) was dissolved in
anhyl)rous ethanol(15ml) and thereto sodium borohyl)ride(17.3mg) was added, then followed by stirring at room temperature for 2 hrs. The resulting mixture was concentrated under the reduced pressure to remove ethanol and purified by column chromatography(ethylacetate '• hexane = 2:1) to obtain the titled compound, yield : 97% m.p. : oil phase
1H NMR(CDCl3) δ: 1.14(3H,d), 2.44(3H,s), 2.93(4H,t), 3.06(3H,s), 3.30(4H,t), 3.74(6H,s), 3.98(3H,s), 5.03(lH,q), 6.02(3H,m), 7.50(lH,s)
Example 153
l-(N-Ethyl-N-[5-(l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]
aminocarbonyl}-4-(3,5-dirnethoxyphenyl)piperazine;
l-[N-Ethyl-N-(5-cetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]
-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with
the example 152 to obtain the titled compound.
yield : 96%
m.p. ': oil phase
1H NMR(CDCl3) δ: 1.09(3H,t), 1.41(3II,d), 2.44(3II,s), 2.91(41-1,0.
3.27(4H.t), 3.54(lH,q), 3.74(6H,s), 3.96(3Hts), 5.03(lH,q), G.02(3H,m),
8.40(1 Ii,s)
Example 154
l-{N-[5-(l-Hyl)roxyethyl)-2-methoxy-6-melhylpyndin-3-yl]-N-
methylaminocarbonyl]-4-(3,5-dimethylphenyl)piperazine:
l-[N-Methyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)amino
carbonyl]-4-(3,5-dimethylphenyl)piperazine was reacted by the same
way with the example 152 to obtain the titled compound.
yield : 97%
m.p. : oil phase
1H NMR(CDCl3)δ: 1.41(3H,d), 2.24(6H,s), 2.44(3H.s), 2.91 (4H,t),
3.06(3II,s), 3.26(4H,t), 3.99(3H,s), 5.03(lH,q), 6.49(3H,m), 7.50(lII,s)
Example 155
l-{N-[5-(l-Hyl)roxy-l-methylethyl)-2-methoxy-6-methylpyridin-3-yl]-
N-methylaminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine:
l-[N-Melhyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)amino carbonyl]-4-(3,5-dimethoxyphenyl)piperazine(221mg, 0.5mmol) was dissolved in tetrahyl)rofuran(lOml) and thereto methyl magnesium bromide(0.50ml, 1.50mmol). The resulting mixture was refluxed for 15 hrs, concentrated under the reduced pressure to remove used solvent, extracted with ethylacetate, filtered to dryness, and purified by column chromalography(ethylacetate '• hexane =1:2) to obtain the titled compound, yield : 92% m.p. •' oil phase
1H NMR(CDCl3) δ: 1.59(6II,s), 2.66(3II,s), 2.93(411,0, 3.0G(3M,s), 3.30(411,0. 3.74(GII,s), 3.99(3II,s), 0.03(311,m), 7.45(lII,s)
Example 156
l-{N-[5-(l-Hyl)roxy-l-methylpropyl)-2-methoxy-6-methylpyridin-3-yl]
-N-inethylaminocarbonyl}-4-(3,5-dimethylphenyl)piperazine:
l-[N-Methyl-N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)amino
carbonyl]-4-(3,5-dimethylphenyl)piperazine(213mg, O.Smmol) was
dissolved in tetrahyl)rofuran(lOml) and thereto methyl magnesium
bromide(0.50ml, 1.50mmol) was added slowly, then refluxed for 15 hrs.
The resulting mixture was concentrated under the reduced pressure to
remove the used solvent, extracted with ethylacetate, filtered to dryness,
and purified by column chromatography (ethylacetate : hexane =1:2) to
obtain the titled compound.
yield : 88%
m.p. : oil phase
1H NMR(CDCl3) δ: 0.79(3H,t), 1.58(3H,s), 1.85(2H,q), 2.61(3H,s),
2.99(4H,t), 3.07(3H,s), 3.30(4H,0, 3.76(6H,s), 6.12(3H,m), 7.47(lH,s)
Example 157
l-{N-[2-Methoxy.-5-(l-methoxyethyl)-6-methylpyridin-3-yl]-N-methyl
aminocarbonyl)-4-(3,5-dimethoxyphenyl)piperazine:
l-(N-[5-(l-Hydroxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino
carbonyl}-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same
way with the example 132 to obtain the titled compound.
vield : 95%
m.p. : 117-119oC
1H NMR(CDCl3) δ: 1.34(3H,t), 2.43(3H,s), 2.94(4H,t), 3.06(3H,s),
3.18(3H,s), 3.30(4H,t), 3.74(6H,s), 3.99(3H,s), 4.44(lH,q), 6.02(3H,m),
7.37(lH,s)
Example 158
l-[N-(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)-N-methylamino
carbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 94%
m.p. : oil phase
1H NMR(CDCl3) δ: 2.46(3H,s), 2.93(411,1), 3.07(3II,s), 3.30(411,1),
3.73(6H,s), 3.99(3H,s), 5.25(lH,d), 5.48(lH,d), 6.01(3H,m), 6.78(lH.s),
7.43(lII,s)
Example 159
l-[N-(2-Methoxy-6-methyl-5-viiiylpyridin-3-yl)-N-methylarnino
carbonyl] -4- (3,5-dimethylpheny Dpiperazine^
l-[(2-Methoxy-G-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield :. 89%
m.p. : oil phase
1H NMR(CDCl3) δ : 2.24(6H,s), 2.43(3H,s), 2.90(4H,t), 3.04(3H,s),
3.27(4M,t), 3.99(3H,s), 5.23(lH,d), 5.45(lII,d), 6.05(3H,m), G.77(lH,s),
7.40(lli,s)
Example 160
l-[N-Ethyl-N-(2rmethoxy-6rmethyl-5-vinylpyridin-3-yl)aminocarbonyl]
-4-(3,5-dimethoxyphenyl)piperazine:
l-[(2-Methoxy-6-methyl-5-vinylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the
example 133 to obtain the titled compound.
vield : 92%
m.p. : oil phase
1H NMRCDCl3): δ: 1.09(3H,t), 2.43(3H,s), 2.94(4H,t), 3.28(4H,t), 3.77(GH,s), 4.01(3H,s), 4.11(2H,q), 5.25(lH,d), 5.49(lH,d), 5.98(3H,m), 6.77(lH,s), 7.44(lII,s)
Example 161
l-LN-(5-lsoiJropenyl-2-inethoxy-6-methylpyridin-3-yl)-N-inethylamino
carbonyl]-4-(3,5-dimethoxyphenyl)piperazine-
l-[(5-Isopropenyl-2-methoxy-6-methylpyridin-3-yl)aminocai'bonyl]-4-
(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 92%
m.p. : oil phase
VH NMR(CDCl3) δ: 1.98(3H,s), 2.43(3H,s), 2.92(4H,t), 3.06(3H,s),
3.29(41-1,1), 3.74(6H,s), 3.99(3H,s), 4.84(lH,s), 5.30(lH,s), 6.01(3H,m),
7.10(lH,s)
Example 162
l-[N-(5-Isopropenyl-2-methoxy-6-methylpyridin-3-yl)-N-methylamino
carbonyl] -4- (3,5-dimethylphenyl)piperazine:
l-[(5-Isoprophenyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 132 to obtain the titled compound.
yield : 91%
m.p. : oil phase
1H NMR(CDCl3) δ: 1.98(3II,s), 2.24(6II,s), 2.43(3II,s), 2.90(411,0,
3.06(3H,s), 3.28(411,0, 4.00(3H,s), 4.84(lH,s), 5.19(HI,s), 6.46(3II,m),
7.10(lH,s) '
Example 163
Ethyl 2-(([4-(3,5-dimethoxyphenyl)piperazino]carbonyl}(5-acetyl-2-
methoxy-6-methylpyridin-3-yl)amino)acetate:
l_[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine(200mg, 0.5mmol) was dissolved in
dimethylformainide(15ml) and thereto sodium hyl)ride(18.5mg, O.Smmol)
was added, then followed by stirring at room temperature for 15 min,
-^ ■
and ethylbromoacetate(83.5mg, 0.5mmol) was added. The resulting
mixture was stirred at room temperature for 3 hrs, concentrated under
the reduced pressure to remove the used solvent, and purified by
column chromatography(ethylacetate : hexaue =1:2) to obtain the titled
compound.
yield : 84%
m.p. •' oil phase
lH NMR(CDCl3) δ : 1.26(3H,t), 2.51 (3H,s), 2.69(3H,s), 3.04(4H,t),
3.43(411,0, 3.75(GH,s), 4.05(3H,s), 4.15(2H,q), 4.19(2H,s), 6.08(3H,s),
7.96(lII,s)
Example 164
Ethyl 2-({[4-(3,5-dimethylphenyl)piperazino]carbonyl}(5-acetyl-2-
methoxy-6-inethylpyridin-3-yl)amino)acetate:
l-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 163 to obtain the titled compound.
yield : 80%
m.p. : oil phase
1H NMR(CDCl3) δ: 1.25(3H,t), 2.56(3H,s), 2.69(3H,s), 3.00(4H,t),
3.29(4H,t), 3.78(6H,s), 4.06(3II,s), 4.18(2II,s), 5.99(3II,m), 7.98(lII,s)
Example 165
2-({[4-(3,5-Dimethoxyphenyl)piperazino]carbonyl}(5-acetyl-2-methoxy-6-methylpyridin-3-yl)amino)acetic acid:
Ethyl ({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}(5-acetyl-2-methoxy -6-methylpyridin-3-yl)amino)acetate(200mg, O.«38mmol) was dissolved in mixed solvent of dioxane : distilled water =41 (15ml), and lithium hyl)roxide hyl)rate(48.1mg, 1.14mmol) was added, then followed by stirring at room temperature for 3 hrs. The resulting mixture was made acidic with 1N-HC1, extracted with ethylacetate, filtered to dryness, concentrated under the reduced pressure and purified by column chromatography (ethylacetate : hexane =1:2) to obtain the titled compound, yield : 94% m.p. : 135-137oC
1H NMR(CDCl3U: 2.52(3H,s), 2.69(3H,s), 3.11(4H,t), 3.49(4H,t), 3.74(6H,s), 4.05(3H,s), 4.24(2H,s), 6.15(3H,m), 7.83(lH,s)
Example 1(36
Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}[5-
(l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino)acetate^
Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl)(5-acetyl-2-
methoxy-6-methylpyridin-3-yl)amino)acetate was reacted by the same
way with the example 152 to obtain the titled compound.
yield : 97%
m.p. : 125-127 oC
1H NMR(CDCl3) δ: 1.26(3H,t), 1.42(3H,d), 2.44(3H,s), 3.04(4H,t),
3.31(4H,t), 3.75(6H,s), 3.97(3H,s), 4.16(2H,q), 4.19(2H,s), 6.15(3H,m),
7.69(lH,s)
Example 167
Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}[5-
(l-hyl)roxyethyl)-2-methoxy-6-rnethylpyridin-3-yl]amino)acetate:
Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}[5-
(l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino)acetate was
reacted by the same way with the example 164 to obtain the titled
compound.
yield : 92%
m.p. : oil phase
1H NMR(CDCh) δ: 1.41(3II,d), 2.44(3II,s), 2.98(411,0, 3.36(411,0,
3.74(CH,s), 3.98(3H,s), 4.40(2H,s), 5.00(lH,q), 6.08(3H,m), 7.69(lH,s)
Example 168
Ethyl 2-({[4-(3,5-dimethylphenyl)piperazino]carbonyl}[5-
(l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino)acetate:
Ethyl 2-({[4-(3,5-diinethylphenyl)piperazino]carbonyl}(5-acetyl-2-
methoxy-6-methylpyridin-3-yl)amino)acetate was reacted by the same
way with the example 152 to obtain the titled compound.
yield : 94%
m.p. : 68-70oC
1H NMR(CDCl3) δ: 1.13(3H,t), 1.47(3II,d), 2.33(6H,s), 2.44(3II,s),
2.95(411,0, 3.30(4H,t), 3.98(3I-I,s), 4.10(2II,ci), 5.01(lII,c|), G.4G(3II,m), 7.71(lll,s)
Example 169
2- ({[4- (3,5-Dimethy lpheny l)piperazino]carbony 1} [5- (1 -hyl)roxy ethyl) -2-
methoxy-6-methylpyridin-3-yl]amino)acetic acid-'
Ethyl 2-({[4-(3,5-dimethylphenyl)piperazino]carbonyl}[5-
(l-hyl)roxyethyl)-2-methoxy-6-methylpyridin-3-yl]amino)acetate was
reacted by the same way with the example 165 to obtain the titled
compound.
yield : 92%
m.p. : 114-116oC
1H NMR(CDCl3) δ : 1.40(3H,d), 2.23(6H,s), 2.40(3H,s), 2.91 (4H,t),
3.21(4H,t), 3.98(3H,s), 4.06(2H,s), 4.90(lH,q), 6.50(3H,m), 6.51(lH,s)
Example 170 l-[(4,5-Dimelhyl-2-methxyphenyl)aminocarbonyl]-4-phenylpiperazine
a) 3,4-Dimethyl anisole :
To 3,4-dimethylphenol(19.3g, 0.16mol), methanol(150ml) and KOH(9.65g, 0.25mol) were added and then refluxed for 2hrs. Methyl iodide(36.5g, 0.25mol) was added thereto, refluxed for 3 hours and then followed by addition of water(150ml). The resulting mixture was extracted with ethylacetate and purified by column chromatography to obtain the titled compound, yield : 81%
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 3.77(3M,s), 6.71(2II,m), 6.97(111,s)
b) 4,5-Dimethyl-2-nitroanisole:
Trifluoroacetic acid(250ml) was added into 3,4-dimethylanisole(17.1g, 0.13mol), successively sodium nitrite(16.6g, 0.24mol) was added slowly in water bath, and stirred at room temperature for 14 hrs. After trifluoroacetic acid was removed and water was added thereto, the resulting mixture was extracted with ether, and purified by column chromatography to obtain the titled compound, yield : 55% lH NMR(500MHz, CDCl3): δ 2.25(3H,s), 2.32(3M,s), 3.94(3II,s),
6.85(lH,s), 7.70QH,s)
c) 4,5-Dimethyl-2-rnethoxyaniline:
Tetrahyl)rofuran(lOOml) and ethanol(40ml) were added into 4,5-dimethyl-2-nitroanisole(7.80g, 0.043mol) and then added 10% Pd/activated carbon(0.57g) slowly, hyl)rogenated for 5 hrs. The reaction was completed by the same way with the above and the resulting product was purified by column chromatography to obtain the titled compound.
yield : 82%
1H NMR(500MHz, CDCb)-1 S 2.23(3H,s), 2.27(3H,s), 3.90(3H,s),
6.80(lII,s)f 7.68(lH,s)
d) Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate:
To 4,5-dimethyl-2-methoxyaniline(4.50g, 0.03mol), methylene chloride( 100ml) was added and phenyl chloroformate(4.80g, 0.03mol) was added slowly. The resulting solution was stirred for 2 hrs and thereto water( 150ml) was added, and extracted with methylene chloride and purified by column chromatography to obtain the titled compound, yield : 98%
1H NMR(500MHz, CDCb): d 2.24(3M,s), 2.27(3H,s), 3.89(3H,s), 6.85QH.S). 7.20(5H,m), 7.90(lH,s)
e) l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-phenylpiperazine-
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)cai'bamate(5.422g, 0.02mol) and
l-phenylpiperazine(3.44g, 0.02mol) were dissolved in
tetrahyl)rofuran(lOml). After DBU(3.04g, 0.02mol) was added, the
resulting solution was stirred at room temperature for 2 hrs,
concentrated and purified by column chromatography to obtain the
titled compound.
yield : 85%
m.p.: 143-144 °C
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 3.25(4H.t), 3.67(4H,t),
3.85(3M,s), 6.64(lH,s), 6.94(3H,m), 6.99(lH,s), 7.29(lH,t), 7.91 (lH.s)
Example 171
l~[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-
(3,5~dimethoxyphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 170 to obtain the titled compound.
yield : 85%
m.p. : 119-120 °C
JH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 3.27(4H,t), 3.70(4H,t),
3.79(6H,s), 3.85(3H,s), 6.17(2H,m), 6.65(lH,s), 6.98(lH,s), 7.90(lH,s)
Mass(El) m/z : Calcd for C22H29N3O4 399.2158, found 399.2168
Example 172
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine:
Phenyl N- (4,5-dimethy 1-2-methoxyphenyl)carbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 170 to obtain the titled compound.
yield : 88%
m.p. : 177-178°C
1H NMR(500MHZ, CDCl3): δ 2.20(3H,s), 2.21(3II,s), 2.29(GH,s),
3.23(41-1,0, 3.66(41-1,0, 3.85(3H,s), 6.58(2H,m), 6.65(lH,s), 6.99(lH,s),
7.92(11 l.s)
Mass(EI) m/z : Calcd for C22H29N3O2 367.2259, found 367.2290
Example 173
l-[4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2,3-dimethylphenyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(2,3-dimethylphenyl)piperazine were reacted by the same way with
the example 170 to obtain the titled compound.
yield : 95%
m.p. : 140-142°C
lH NMR(500MHz, CDCl3): δ 2.21(3H,s), 2.22(3H,s), 2.27(3H,s),
2.29(3I-I,s), 2.95(4H,0, 3.67(4H,0, 3.85(3H,s), 6.G5(lH,s), 7.01 (3H,m),
7.93(lH,s)
Example 174
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-
(2,3,5,6-tetramethylphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way
with the example 170 to obtain the titled compound.
yield : 93%
m.p. : oil phase
1H NMR(500MHz, CDCb): 3.84(3II,s), 6.64(lH,s), 6.84(lH,s), 7.95(lII,s)
Example 175
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl)
piperazine:
Phenyl N-(4,5-dimeUiyl-2-methoxyphenyl)carbamate and
l-(3,5-difluorophenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield : 89%
m.p. : 102-103oC
1H NMR(500MHZ, CDCl3): δ 2.20(3H,s), 2.22(3H,s), 3.29(4H,t), 3.68(4H,t),
3.85(3M,s), 6.65(lH,s), 6.97(3H,m), 7.89(lH,s)
Example 176
l-[(4,5-Uimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-chlorophenyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)cai'bamate and
l-(2-chlorophenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield : 90%
m.p. : 176-177°C
1H NMR(500MHz, CDCl3): δ 2.21(3H,s), 2.22(3H,s), 3.10(4H,t,J=5.0Hz),
3.69(4H,tJ=5.0Hz), 3.85(3H,s), 6.65(lH,s), 7.02(2II,m), 7.24(lH,m),
7.39(lH,d,J=4.0Hz), 7.92(lH,s)
Example 177
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3-chlorophenyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(3-chlorophenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield : 84%
rap. : 75-76 oC
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.22(3H,s), 3.27(4H,t,J=5.0I-Iz),
3.68(411,tJ=5.0Hz), 3.85(3H,s), 6.65(lH,s), 6.90(3H,m), 7.21(lH.t),
7.90(1 M,s)
Mass (El) m/z : Calcd for C20H24N3O2CI1 373.1557, found 373.1590
Example 178
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-hyl)roxy phenyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(2-hyl)roxyphenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield : 87%
m.p. : 197-199t,
'TI NMR(500MHZ, CDCl3): δ 2.20(3H,s), 2.21(3H,s). 2.98(411.0, 3.72(411,0,
3.84(311,s), 0.65(111,s), 6.89(111,0, 7.00(211,m), 7.13(211.rn), 7.89(1 Il.s)
Example 179
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3-hyl)roxyphenyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(3-hyl)roxyphenyl) were reacted by the same way with the example
170 to obtain the titled compound.
yield : 88%
m.p. : 177-178 oC
1H NMR(500MHz, CDCl3): δ 2.19(3H,s), 2.21 (3H,s), 3.24(4H,t), 3.68(4H,t),
3.85(3I-I,s), 6.41 (3H,m), 6.65(lH,s), 6.98(lH,s), 7.13(lH,t), 7.88(lII,s)
Example 180
1-[(4,5-Dimetlhyl-2-methoxyphenyl)aminocarbonyl]-4 (3 thiophenyl))
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(3-thiophenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield: 79%
m.p.: 108-1101C
1H NMR(500MHZ, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 3.26(4H,t), 3.65(4H,t),
3.84(3I-I,s), 6.64(lH,s), 6.97(4H,m), 7.05(lH,s), 7.89(lH,s)
Example 181
l-[(4,5-Diinethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-acetoxyphenyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)cai'bamate and
l-(2-acetoxyphenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield: 84%
m.p.: 129-131 r,
rH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21(3H,s), 2.32(3H,s),
3.05(411,1), 3.63(41-1,0, 3.85(3H,s), 6.64(lH,s), G.99(lH,s), 7.04(lH,m),
7.17(2II,m), 7.22(lH,m), 7.90(lH,s)
Example 182
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3-acetoxyphenyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(3-acetoxyphenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield: 87%
m.p.: 154-156oC
1H NMR(500MIIz, CDCl3): δ 2.20(3H,s), 2.21(3H,s), 2.29(3II,s),
3.27(4H,0, 3.68(4H,t), 3.85(3H,s), 6.64(lH,s), 6.66(2H,m), 6.82(lH,m),
6.98(lM,s), 7.90(lH,s)
Excimple 183
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-methoxyphenyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(2-methoxyphenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield: 90%
m.p.: 144-145°C
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.22(3H,s), 2.26(3H,s), 2.95(4H,t, J=5.0Hz), 3.65(4H,tJ=5.0Hz), 3.78(3H,s), 3.85(3H,s), 6.59(lH,s), 6.65(lH.s), 7.00(lH,s), 7.11(lli,s), 7.93(lH,s)
Example 184
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(5-methoxy-2-
methylphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way
with the example 170 to obtain the titled compound.
yield: 88%
m.p.: 140-141oC
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.22(3H,s), 2.2G(3H,s), 2.95(41-1,1,
J=5.0Hz), 3.65(4H,t,J=5.0Hz), 3.78(3H,s), 3.85(3H,s), 6.59(lH,s), 6.65(lH,s),
7.00(1I-I,s), 7.11(lH,s), 7.93(lH,s)
Example 185
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-melhoxy-5-
methy lpheny 1) piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way
with the example 170 to obtain the titled compound.
yield: 80%
m.p.: 107-108°C
lH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 2.29(3H,s), 3.10(4H,t,
J=5.0Hz), 3.69(4H,t,J=5.0Hz), 3.85(3H,s), 3.86(3H,s), 6.55(lII,s), G.79(2II,m).
7.01 (ll-l,s), 9.94(lH,s)
Example 186
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-methoxy-5-
phenylphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(2-methoxy-5-phenylphenyl)piperazine were reacted by the same way
with the example 170 to obtain the titled compound.
yield: 91%
m.p.: 139-140 oC
1H NMR(500MHz, CDCl3): δ 2.21 (3H,s), 2.22(3H,s), 3.20(4H,t), 3.74(4H,t), 3.85(3H,s), 3.94(3H,s), 6.65(lH,s), 7.02(2H,m), 7.32(2H,m), 7.42(2H,t), 7.55(211.cl), 7.93(1 II.s)
Example 187
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(2-isopropenyl
phenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(2-isopropenylphenyl)piperazine were reacted by the same way with
the example 170 to obtain the titled compound.
yield: 80%
m.p.: 134-135 °C
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (6H,s), 3.10(4H,t), 3.64(4H,t),
3.85(3H,s), 5.08(lH,s), 5.14(lH,s), 6.64(lH,s), 7.05(3H,m). 7.70(lH,m).
7.92(1I-I,s)
Example 188
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(l-naphthyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(l-naphthyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield: 92%
m.p.: 1G0-1621C
lH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 3.31(4II,t,J-5.0Mz),
3.83(3II,s), 4.04(4H,t), 6.39(2H,m), 6.69(lH,s), 7.13(1H,0, 7.30(lH,s),
7.46(lH,s)
Example 189
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(l-anthranyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and
l-(l-anthranyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield: 94%
m.p.: 74-75oC
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.22(3II,s), 3.24(4H,t), 3.70(4H,t),
3.8G(3H,s), 6.70(lH,s), 7.05(3H,m), 7.45(5H,m), 8.00(2H,m)
Example 190
l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-methylaminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine:
l-[(4,5-dimethyl-2-methoxyphenyl)aminoccirbonyl]-4-(3,5-dimethoxy
phenyl)piperazine(0.2g, 0.5mmole) was dissolved in
dimethylforrnarnide(15ml), sodium hyl)ride(12mg, 0.5mmole) was added
thereto slowly, and then the resulting mixture was stirred at room
temperature for 15 min, then followed by addition of iodomethane(71mg,
0.5mmole) and subsequently at room temperature for 16 hours. The
resulting mixture was concentrated under the reduced pressure to
remove the used solvent, extracted with methylene chloride, dried,
filtered and purified by column chromatography to obtain the titled
compound.
yield: 92%
m.p.: 86-88oC
1H NMR(500MHz, CDCl3): δ 2.21 (3H,s), 2.24(3H,s), 2.92(4H,t),
3.0G(3H,s), 3.31 (4H,t), 3.75(6H,s), 3.83(3H,s), 6.00(3II,m), 6.71 UH,s),
6.83(1 II,s)
Mass(El) m/z : Calcd for C23H31N3O4 413.2314, found 413.2293
Example 191
l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-methylaminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine:
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethyl
phenvDpiperazine was reacted by the same way with the example 190
to obtain the titled compound.
yield: 90%
m.p.: 137-138 °C
1H NMR(500MHz, CDCl3): δ 2.15(3H,s), 2.24(9H,s), 2.88(4H,t),
3.06(3H,s), 3.29(4H,t), 3.83(3H,s), 6.45(3H,m), 6.71(lH,s), 6.83(lH,s)
Mass(EI) m/z : Calcd for C23H29N3O2 381.2416, 381.2436
Example 192
l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-methylaminocarbonyl]-4-
(3.5-difluorophenyl)piperazine:
l-[(4,5-Dimethyi-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl)
piperazine was reacted by the same way with the example 190 to
obtain the titled compound.
yield: 87%
m.p.: 98-100'C
lH NMR(500MHz, CDCl3): δ 2.16(3H,s), 2.25(3H,s), 2.92(41-1,0,
3.0G(3II,s), 3.29(4H,t), 3.83(3H,s), 6.23(3H,m), 6.72(lH,s), 6.83(lH,s)
Example 193
l-[N-Ethyl-N-(4,5-dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine:
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphen yl)piperazine(0.2g, O.Smmole) was dissolved in dimethylformamide(15ml), and thereto sodium hyl)ride(12mg, 0.5mmole) was added slowly. The resulting mixture was stirred at room temperature for 15 min. After iodoelhane(78mg, 0.5mmol) was added, the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dryed, filtered and purified by column chromatography to obtain the titled compound, yield: 89% m.p.: oil phase
1H NMR(500MIIz, CDCb): d 1.09(3H,t), 2.16(3H,s), 2.24(311,s). 2.75(41-1,0, 3.28(41-1,0, 3.52(2H,q), 3.75(6H,s), 3.81(3H,s), 5.98(3H,m), 6.70(lH.s), 6.80(lH,s)
Example 194
l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-ethylaminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine:
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethyl
phenyl)piperazine was reacted by the same way with the example 193
to obtain the titled compound.
yield: 93%
m.p.: 80-82°C
lH NMR(500MHz, CDCl3): δ 1.21 (3H,t), 2.15(3H,s), 2.23(9H,s), 2.90(4H,t),
3.25(4H,t), 3.59(2H,q), 3.81 (3H,s), 6.45(3H,m), 6.69(lH,s), 6.81 (lH.s)
Example 195
l-[N-(4,5-Dimethyl-2-methoxyphenyl)-N-ethylaminocai-bonyl]-4-
(3,5-difluorophenyl)piperazine:
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluoro]jhenyl)
piperazine was reacted by the same way with the example 193 to
obtain the titled compound.
yield: 87%
m.p.: oil phase
1H NMR(500MHz, CDCl3): δ 1.09(3H,t), 2.16(3H,s), 2.25(3H,s), 2.90(4H,t),
3.27(4H,t), 3.52(2H,q), 3.81 (3H,s), 6.24(3H,m), 6.70(lH,s), 6.81(lH,s)
Example 196
l-[N-Isopropyl-N-(4,5-dimethyl-2-melhoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl)piperazine:
l-[(4,5-Dimeth3d-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl) piperazine(0.2g, 0.52mmole) was dissolved in dimethylformamide(15ml) and thereto sodium hyl)ride(12.48mg, 0.52mmole) was slowly added. The resulting mixture was stirred at room temperature for 15 min. After 2-iodopropane(87.88mg, 0.52mmole) was added thereto, the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dryed, filtered and purified by column chromatography to obtain the titled compound, yield: 84% m.p.: oil phase
lH NMR(500MHz, CDCl3): δ 1.10(3H,s), 1.26(3H,s), 2.20(3H,s), 2.25(3H,s), 2.86(4H,t), 3.26(4H,t), 3.77(3H,s), 4.25(lH,m), 6.17(3H,m), 6.68(lH,s), 6.82QHfs)
Example 197
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-(3,5-dimethoxy
phenyl)piperazine:
(a) Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate:
To 3,4-dimethyl-2-methoxyaniline(4.50g, 0.03mol), methylene
chloride(100ml) was added and then phenyl chlorothionoformate(5.16g,
0.03mol) was added slowly. The resulting mixture was stirred for 2
hours, and thereto water(150ml) was added. The resulting mixture was
extracted with methylene chloride and purified by column
chromatography to obtain the titled compound.
yield: 92%
1H NMR(500MHz, CDCl3): δ 2.21(3II,s), 2.25(311,s), 3.85(3H,s),
6.80(lH,s), 6.93(5H,m), 7.31 (lH,s)
(b) l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate(0.2g, 0.7mmol) and l-(3,5-dimethoxyphenyl)piperazine(0.16g, 0.7mmol) were dissolved in tetrahyl)rofuran(lOml) and thereto DBU(0.11g, 0.7mmole) was added, followed by stirring at room temperature for 2 hours. The resulting product was concentrated and purified by chromatography to obtain the titled compound, yield: 84% m.p.: 128-129°C
lH NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 2.32(6H,s), 3.37(41-1,1), 3.83(3H,s), 4.08(4H,t), 6.69(3H,m), 7.39(lH,m), 7.47(lII,s) Mass(EI) m/z : Calcd for C22H29N3O3S1 415.1929, found 415.1912
Example 198
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(3,5-dimethylphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(3,5-dimethylphenyl)perazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield : 90%
m.p.: 1G4~1G5°C
]H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 2.32(CH,s),
3.37(4H,t), 3.83(3H,s), 4.08(4H,t), 6.69(3H,m), 7.39(lH,m), 7.47(lH,s)
Mass (EI) m/z : Calcd for C22H29N3O1S1 383.2031, found 383.2086
Example 199
l-[(4,5-Dimelhyl-2-melhoxyphenyl)aminothiocarbonyl]-4-
(2,3-dimethylphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(2,3-dimethylphenyl)piperazine were reacted by the same way with
the example 197 to obtain the titled compound.
yield: 89%
m.p.: 151-152*0
1H NMR(500MHz, CDCl3): δ 2.21(3H,s), 2.24(3H,s), 2.29(GM,s),
3.03(4H,t), 3.83(3H,s), 4.10(4H,t), 6.69(lH,s), 6.97(2H,m), 7.11(111,0
Example 200
l-[(4,5~Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(3,5-difluoraphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(3,5-difluorophenyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield : 92%
m.p.: 1G7-168oC
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 2.27(3H,s),
2.32(3H,s), 3.39(4H,t,J=5.0Hz), 3.83(3H,s), 4.14(4H,t), 6.70(lH,s),
6.80(2II,m), 7.36(lH,s), 7.44(lH,s)
Example 201
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(3,5-dichlorophenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocai-bamate and
l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield: 85%
m.p.: 188-1891: ,
1H NMR(500MI-IZ, CDCl3): δ 2.20(3H,s), 2.24(3H,s), 3.35(41 l,t,J=5.0I-Iz),
3.83(3H,s), 4.04(4H,t,J=5.0Hz), 6.70(2H,m), 6.83(lH,s), 7.30(lH,s),
7.48(lH,s)
Mass(EI) m/z : Calcd for C20H24N3O2CI1 423.0938, 423.095G
Example 202 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-(2-fluorophenyl)
piperazine-
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(2-fluorophenyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield: 87%
m.p.: 139-140oC
1H NMR(500MHz, CDCl3): δ 2.21 (3H,s), 2.24(3H,s), 3.40(4H,t),
3.83(3H,s), 4.25(4H,t), 6.70(lH,s), 7.13(3H,m), 7.37(2H,m)
Example 203
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl3-4-(2-chlorophenyl
)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(2-chlorophenyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield'. 85%
m.p.: 115-116oC;
lH NMR(500MHz, CDCl3): δ 2.21 (3H,s), 2.24(3H,s), 3.18(4H,t),
3.83(3II,s), 4.09(4H,t), 6.69(lHfs), 7.05(2H,m), 7.33(lH,s), 7.41(2H,m)
Example 204
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(2-methoxyphenyl)piperazine:
Plienyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(2-methoxyphenyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield: 90%
m.p.: oil phase
1H NMR(500MHZ, CDCl3): δ .2.20(3H,s), 2.23(3H,s), 3.14(4H,t,J=5.0Hz),
3.82(3H,s), 3.88(3H,s), 4.06(4H,t,J=5.0Hz), 6.69(1 H,s), 6.94(311,m),
7.30(lH,s), 7.40(lH,s)
Example 205 l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(2-methylthiophenyl)piperazine'
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(2-methylthiophenyl)piperazine were reacted by the same way with
the example 197 to obtain the titled compound.
yield: 93%
m.p.: 136-137oC
1H NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.26(3H,s), 2.45(3H,s),
3.33(4H,t), 3.82(3H,s), 4.39(4H,t), 6.74(lH,s), 7.16(3H,m), 7.47(2H,m)
Example 206
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(3-hyl)roxyphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(3-hyl)roxyphenyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield: 77%
m.p.: Decomposed(2(XrC)
1H NMR(500MHZ, CDCl3): δ 2.17(3H,s), 2.23(3H,s), 3.31(411,0,
3.82(3II,s), 4.03(31-1,1), G.37(2H,m), 6.47(lII,d), 6.69(lM,s), 7.13(111,1).
7.45(1I-I,s)
Example 207
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(2-phenoxyphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(2-phenoxyphenyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield: 86%
m.p.: oil phase
1H NMR(500MHZ, CDCl3): δ 2.17(3H,s), 2.24(3H,s), 3.19(4H,t),
3.80(3H,s), 3.85(4H,t), 6.66(lH>s), 6.91 (2H,m), 6.98(lH,m), 7.05(3H.m),
7.13(lH,m), 7.23(1I-I,m), 7.31 (2H,m), 7.3G(lH,s)
Example 208
l-[(4,5-Diinethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(2-is(jpropenylphenyl)piperazine:
Phenyl N-(4,5-dimeLhyl-2-methoxyphenyi)thiocarbamate and l-(2-isopropenylphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound, yield: 75% m.p.: 157-158*0
l¥L NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.21 (3H,s), 2.24(3H,s), 3.19(4H,t), 3.82(3H,s), 4.05(4H,t), 5.07(lH,s), 5.16(lH,s), 6.69(lH,s), 7.11(3H,m), 7.33(lH,s), 7.45(lH,s)
Example 209
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-
(2-methoxy-5-methylphenyl)piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way
with the example 197 to obtain the titled compound.
yield: 87%
m.p.: oil phase
1H NMR(500MHz, CDCb): 3.13(4H,t), 3.83(3H,s), 3.85(3H,s), 4.05(411,0, 6.69(lH,s), 6.83(211,m),
7.30(lH,s), 7.40(lH,s)
Example 210
l-[(4,5-Dimethyl-2-methoxyphenyl)aminothiocarbonyl]-4-(l-naphthyl)
piperazine:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and
l-(l-naphthyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield: 87%
m.p.: 139-140t
lll NMRSOOMIIz, CDCl3): δ 2.23(3H,s), 2.24(3II,s), 3.21(411,1),
3.84(3H,s), 4.09(4H,t), 6.70(lH,.s), 7.10(lH,d), 7.48(5H,m), 7.85(1 H,m),
8.22(lH,d)
Example 211
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 170 to obtain the titled compound.
yield: 91%
m.p.: 103-105 °C
1H NMR(500MHz, CDCk): S 2.54(3H,s), 2.59(3H,s), 3.27(4H,t), 3.70(4H,O.
3.79(6H,s), 3.94(3H,s), 6.13(3H,m), 6.70(lH,s), 7.05(lH,s), 8.72(11-I,s)
Example 212
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbonyl]-4-(3,5-dimethy
-lphenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 170 to obtain the titled compound.
yield : 88%
m.p.:. 140-142*0
LH NMROOOMHz, CDCl3): δ 2.30(3H,s), 2.54(3H,s), 2.59(3H,s),
3.26(4H,t), 3.70(4H,t), 3.97(3H,s), 6.61(3H,m), 6.70(lH,s), 7.06(lH,s),
8.72(lH,s)
Example 213
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbonyl]-4-(3,5-dichloro-
phen y 1) piperazine:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and
l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the
example 170 to obtain the titled compound.
yield: 78%
m.p.: 170-172 °C
1H NMR(500MHZ, CDCl3): δ 2.54(3H,s), 2.59(3H,s), 3.32(4H,t), 3.74(4H,t).
3.94(3H,s), 6.69(lH,s), 6.86(3H,m), 7.04(lH,s), 8.69(lH,s)
Example 214
l-([5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminocarbonyl}-4-
(3,5-dimethoxyphenyl)piperazine:
1 -[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbony 1] -4-
(3,5-dimethoxyphenyl)piperazine(0.2g, 0.47mmol) was dissolved in
anhyl)rous ethanol (15ml), and sodium borohyl)ride(17mg) was added
thereto, and then the resulting mixture was stirred at room temperature
for 2 hours, concentrated under the reduced pressure to remove ethanol,
and purified by column chromatography(ethylacetate:hexane = 1:2) to
obtain the titled compound.
yield: 96%
m.p.: 152-154 r,
lR NMR(500MHz, CDCl3): δ 1.41(3H,d), 2.32(3H,s), 3.27(4H,t),
3.71 (4H,t), 3.79(6H,s), 3.87(3H,s), 5.04(lH,q), 6.10(3H,m), 6.63(lH,s),
7.01(lH,s), 8.22(lH,s)
Example 215
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminocai-bonyl}-4-
(3,5-dimethylphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 214 to obtain the titled compound.
yield: 96%
m.p.: 140-142 V,
1H NMR(500MHz, CDCl3): δ 1.48(3H,d), 2.33(3H,s), 3.26(4H,t),
3.68(4H,t), 3.87(3H,s), 5.06UH,q), 6.61 (3H,m), 6.64(lH,s), 7.01(lH,s),
8.22(lH,s)
Example 216
l-[(2-Methoxy-4-methyl-5-vinylphenyl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine;
l-{[5-(l-Hyl)i"oxyethyl)-2-methoxy-4-methylphenyl]aminocarbonyl}-4-
(3,5-dimethoxyphenyl)piperazine(0.2g, 0.47mmol) was dissolved in
chloroform(15ml), pyridium p-toluenesulfonate(0.12g, 0.47mmol) was
added thereto, and the resulting mixture was refluxed for 16 hours, and
concentrated under the reduced pressure to remove chloroform and
purified by column chromatography(ethylacetate:hexane= 1:2) to obtain
the titled compound.
yield: 84%
m.p.: 163-165°C
1H NMR(500MHz, CDCl3): δ 2.31(3H,s), 3.23(4H,t), 3.58(4H,t), 3.77(6H,s),
3.87(3H,s), 5.20(lH,d), 5.62(lH,d), 6.59(3H,m), 6.63(lH,s), 6.88(lH,t), 6.99(lH,s), 8.32(lH,s)
Example 217
l-[(2-Methoxy-4-methyl-5-vinylphenyl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine:
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminocarbonyl}-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 216 to obtain the titled compound.
yield: 82%
m.p.: 201-203°C
]H NMR(500MHz, CDCl3): δ 2.29(6H,s), 2.34(3H,s), 3.24(4H,t), 3.68(4H,t),
3.87(3H,s), 5.22(lH,d), 5.66(lH,d), 6.59(3H,m), G.63(lH,s), 6.86(lH,t),
7.02(lll,s), 8.32(lH,s)
Example 218
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and
l-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with
the example 197 to obtain the titled compound.
yield: 82%
m.p.: 163-165'C
1H NMR(500MIIz, CDCl3): δ 2.1G(3IIts), 2.50(311,s), 3.35(411,1),
3.91(6H,s), 4.03(3H,s), 4.13(4H,t), 6.06(3H,m), 6.73(lH,s), 8.62(lH,s)
Example 219
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocai-bonyl]-4-
(3,5-dimethylphenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and
l-(3,5-dimethylphenyL)piperazine were reacted by the same way with
the example 197 to obtain the titled compound.
yield: 79%
m.p.: 180-182 °C
1H NMR(500MHz, CDCl3): δ 2.29(6H,s), 2.57(6H,s), 3.32(4H,t),
3.92(3H,s), 4.12(4H,t), 6.56(3H,m), 6.72(lH,s), 7.39(lH,s), 8.63(lH,s)
Example 220
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocarbonyl]-4-
(3,5-dichlorophenyl)piperazine:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and
l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the
example 197 to obtain the titled compound.
yield: 79%
m.p.: 201-203 oC
Hi NMR(500MHz, CDCl3): δ 2.20(3H,s), 2.57(3H,s), 3.4G(4H,t),
3.92(3H,s), 4.25(4H,t), 6.64(lH,s), 6.88(3H,m), 7.72(lH,s), 8.57(lH,s)
Example 221
l-{[5-(l-Hyl)roxyethyl)-2-methoxy-4-inethylphenyl]aininolhi(jcarbonyl)-4
-(3,5-dimethoxyphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocai-bony]-4-
(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the
example 214 to obtain the titled compound.
yield: 94%
m.p.: 146-148°C
'H NMlKSOOMIIz, CDCla): 8 1.44(311,(1), 2.32(3H,s), 3.35(41-1,0,
3.78(6H,s), 3.84(3H,s), 4.1K4H.O, 5.06(lH,q), 6.13(3H,m), 6.66(lH,s),
7.41 (lH,s), 7.77(lH,s)
Example 222
l_{[5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminothiocarbonyl}-4
-(3,5-dimethylphenyl)piperazine:
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocarbony]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 214 to obtain the titled compound.
yield: 93%
m.p.: 150-152 oC
1H NMR(500MHz, CDCl3): δ 1.44(3H,d), 2.29(6H,s), 2.32(3H,s),
3.30(4H,t), 3.84(3H,s), 4.07(4H,O, 5.06(lH,q), 6.61 (3H,m), 6.66(lH,s),
7.38(1I-I,s), 7.79(1I-I,s)
Example 223 l-{[5-(l-Hyl)roxyethyl)-2-methoxy-4-methylphenyl]aminothiocarbonyl}-4
-(3,5-dichlorophenyl)piperazine:
l-[(5-Acetyl-2-methoxy-4-methylphenyl)aminothiocarbony]-4-
(3,5-dichlorophenyl)piperazine was reacted by the same way with the
example 214 to obtain the titled compound.
yield: 77%
m.p.: 166-168 °C
1H NMR(500MIiz, CDCla): d 1.45(3H,d), 2.33(3H,s), 3.35(411,0,
3.84(3H,s), 4.03(4H,t), 5.07(lH,q), 6.68(3H,m), 6.83(lH,s), 7.37(lH,s),
7.82QH,s)
Example 224
Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}-2-methoxy-4,5-dimethylanilino)acetate :
l-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxy phenyl)piperazine(0.2g, O.Smmol) was dissolved in dimethylformamide(15ml), sodium hyl)ride(18.5mg, O.Smmol) was added thereto, and the resulting mixture was stirred at room temperature. Then, ethyl bromoacetate(83.5mg, 0.5mmol) was added thereto and the resulting mixture was stirred for 3 hours, concentrated under the reduced pressure to remove the used solvent and purified by column chromatography (ethylacetate:hexane=1:2) to obtain the titled compound, yield: 79% m.p.: oil phase
1H NMR(500MHz, CDCl3): δ 1.36(3H.t), 2.15(3II,s), 2.23(3H,s), 2.91(411,0, 3.22(411,0, 3.82(CII,s), 4.12(31I,s), 4.18(2Il,s), 5.98(311,m), 6.69(lll,s), 7.03(lH,s)
Example 225
Ethyl 2-({[4-(3,5-dimethylphenyl)piperazino]carbonyl}-2-methoxy-4,5-
dimethylanilino)acetate :
l_[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-
(3,5-dimethylphenyl)piperazine was reacted by the same way with the
example 224 to obtain the titled compound.
yield: 78%
m.p.: oil phase
1H NMR(500MHz, CDCl3): δ 1.26(3H,t), 1.56(6H,s), 2.17(3M,s), 2.24(3H,s), 3.32(4H,t), 3.52(4H,t), 3.82(3H,s), 4.15(2M,q), 4.18(2M,s), 6.70(3I-I,m), 6.94(lH,s), 7.46(lM,s)
Example 226
2-({[4-(3,5-Dimethoxyphenyl)piperazino]carbonyl}-2-methoxy-4,5-
dimethylanilino)acetic acid:
Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}-2-methoxy-4,5-
dimethylanilino)acetate(200mg, 0.41mmole) was dissolved in
dioxane: distilled water(4:l, 15ml), lithium hyl)roxide monohyl)rate(50.7mg,
1.23mmol) was added thereto, and then the resulting mixture was
stirred at room temperature for 3 hours, acidified with lN-hyl)rochloric
acid, extracted with ethylacetate, filtered to dryness, concentrated under
the reduced pressure to remove the used solvent, and purified by
column chromatography (ethylacetate: hexane" 1:2) to obtain the titled
compound.
yield: 80%
m.p.: 188-189oC
1H NMR(500MHz, CDCl3): δ 2.14(3H,s), 2.23(3II,s), 2.93(411,0, 3.35(4H,t),
3.75(6H,s), 3.87(3H,s), 4.18(2H,s), 5.96(3H,m), G.71(lH,s). 7.71(lH,s)
Example 227
2-({[4-(3,5-Dimethylphenyl)piixirazino]carbonyl}-2-methoxy-4,5-
dimethylanilino)acetic acid:
Ethyl 2-({[4-(3,5-dimethyiphenyl)piperazino]carbonyl}-2-methoxy-4,5-
dimethylanilino)acetate was reacted by the same way with the example
226 to obtain the titled compound.
yield: 78%
m.p.: 170-171°C
lH NMR(500MHz, CDCl3): d 2.13(3II,s), 2.24(9H,s), 2.91(411,1), 3.35(4H,t),
3.83(3H,s), 4.18(2H,s), 6.45(3H,m), 6.70(2II,s), 6.80(lH,s)
Example 228
l-[(2-Hyl)i-oxy-4,5-dimethylphenyl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine:
(a) 4,5-Dimelhyl-2-nitrophenol:
To 3,4-dimethylphenol(12.1g, 0.lmol), trifluoroacetic acid(250ml) was
added, and in water bath sodium nitrite(12.4g, 0.18mol) was added
slowly. The resulting mixture was stirred at room temperature for 14
hours and concentrated under the reduced pressure to remove
trifluoroacetic acid, followed by addition of water(150ml), extracted with
ether and purified by column chromatography to obtain the tilled
compound.
yield: 80%
lH NMR(500MHz, CDCl3): δ 2.23(3H,s), 2.29(3H,s), 6.93(lH,s),
7.84(lH,s)
(b) 4,5-Dimethyl-2-hyl)roxyaniline:
To 4,5-dimethyl-2-nitrophenol(11.7g, 0.07mol), tetrahyl)rofuran( 100ml) and ethanol(40ml) were added, and 10% palladium/activated carbon(0.57g) was added slowly, and then the mixture was hyl)rogenaled for 5 hours. The reaction mixture was concentrated and chromatographed by the same way above to obtain the titled compound, yield : 77% lH NMR(500MHz, CDCl3): δ 2.11(6H,s), 6.56(2H,s)
(c) Phenyl N-(4,5-dimethyl-2-hyl)roxyphenyl)carbamate:
To 4,5-dimethyl-2-hyl)roxyaniline(6.80g, 0.05mole), methylene
chloride( 100ml) was added and then phenyl chloroformate(8.0g, 0.05mole)
was added slowly. After stirring for 2 hours; addition of water( 150ml),
extraction with methylene chloride and column chromatography gave
the titled compound.
yield: 92%
1H NMR(500MHz, CDCl3): δ 2.17(6H,s), 6.74(lH,s), 7.15(5H.m),
7.31 (lH,s)
(d) Phenyl N-[2-(t-butyldimethylsilyloxy)-4,5-dimethylphenyl]cai-bamate:
To a mixture of phenyl N-(4,5-dimethyl-2-hyl)roxyphenyl)carbamate
(7.72g, 0.03mol) and imidazole(2.2g, 33mmol), methylene chloride( 100ml)
was added, and with stirring t-butyldimethylsilylchloride(5.0g, 33mmole)
was added. Then the mixture was stirred for 2 hours, and water(150ml)
was added thereto. The resulting mixture was extracted with methylene
chloride, dried, concentrated under the reduced pressure and purified by
column chromatography to obtain the titled compound.
yield: 83%
1H NMR(500MMz, CDCl3): δ 0.27(6H,s), 0.98(9H,s), 2.17(6H,s),
7.12(5I-I,m), 7.30(2H,s)
(e) l-[(2-IIyl)ioxy-4,5-dimethylphenyl)aminocarbonyl]-4-
(3,5-dimethoxyphenyl)piperazine:
Phenyl N-[2-(t-butyldimethyisilyloxy)-4,5-dimethylphenyl]carbamate
(0.17g, O.Smmole) and l-(3,5-dimelhoxyphenyl)piperazine(0.13g,
O.Gmmole) were dissolved in tetrahyl)rofuran(lOml), and thereto with
stirring DBU(0.09g, 0.6mmole) was added, and the resulting mixture
was stirred for 2 hours, concentrated and chromatographed to obtain
the titled compound.
yield: 87%
m.p.: 145-146°C
1H NMR(500MI-Iz, CDCb): 5 2.14(3H,s), 2.18(3H,s), 3.26(4H,t), 3.67(4H,t),
3.79(6H,s), 6.07(3H,m), 6.40(3H,m), 6.67(lH,s), 6.82(lH,s), 8.87(lH,s)
Example 229
l-[(2-Hyl)roxy-4,5-dimethylphenyl)aminocai'bonyl]-4-
(3,5-dimethoxyphenyl)piperazine:
Phenyl N-[2-hyl)roxy-4,5-dimethylphenyl)carbamate and
l-(3,5-dimethylphenyl)piperazine were reacted by the same way with
the example 228 to obtain the tilled compound.
yield: 84%
m.p.: 160-162'C
JH NMR(500MHz, CDCl3): δ 2.13(3H,s), 2.17(3H,s), 2.31 (6H.s),
3.26(4H,t), 3.75(4H,t), 6.73(3H,rn), 6.81(lH,s), 8.86(lH,s)
Example 230
l-[(2-Hyl)roxy-4,5-diiriethylphenyl)aminoccU"bonyl]-4-(3,5-difluorophenyl)
piperazine:
Phenyl N-[2-hyl)roxy-4,5-dimethylphenyl)carbamate and
l-(3,5-difluorophenyl)piperazine were reacted by the same way with the
example 228 to obtain the titled compound.
yield: 80%
m.p.: 152-154oC
1H NMR(500MHz, CDCl3): δ 2.17(3H,s), 2.20(3H,s), 3.30(4H,t), 3.70(4H,t),
6.40(3H,m), 6.70(lH,s), 6.82(lH,s), 6.98(lH,s)
Example 231
l-[(2-hyl)roxy-4,5-dimethylphenyl)aminocarbonyl]-4-(3,5-dichlorophenyl)
piperazine:
Phenyl N-(2-hyl)roxy-4,5-dimethylphenyl)carbarnate and
l-(3,5-dichlorophenyl)piperazine were reacted by the same way with the
example 228 to obtain the titled compound.
yield: 77%
m.p.: oil phase
rH NMR(500MIlz, CDCl3): δ 2.15(3H,s), 2.20(3H,s), 3.32(411,0, 3.69(411,0.
6.29(3Ii,m), 6.69(lH,s), 6.81 (lH.s), 8.65(lH,s)

Antitumor activities of compounds of the present invention were tested in vitro against 5 kinds of human tumor cell lines and 2 kinds of leukemia tumor cell lines. The method and result of in vitro tests is as follows.
Experimental 1 : In vitro antitumor effect against human tumor cell lines.
A. Tumor cell line : A549 (human non-small lung cell)
SK.OV-3 (human ovarian)
I-ICT-15 (human colon)
XF 498 (human CNS)
SKMEL-2 (human melanoma)
B. SRB Assay Method.
a. Human solid tumor cell lines, A549(non-small lung cell),
SKMEL-2(melanoma), HCT-15(colon), SKOV-3(ovarian),
XF-498(CNS) were cultured at 37°C, in 5% C02 incubators using the
RPMI 1640 media containing 10% FBS, while they were
transfer-cultured successively once or twice per week. Cell cultures
were dissolved in a solution of 0.25% trypsin and 3 mM CDTA
PBS(-) and then cells were separated from media which the cells were
sticked on.
b. 5xi03~2xl04 cells were added into each well of 96-well plate and
cultured in 5% CO2 incubator, at 37 oC, for 24 hours.
c. Each sample drug was dissolved in a little DMSO and diluted with
the used medium to a prescribed concentration for experiments,
wherein the final concentration of DMSO was controlled below 0.5%.
d. Medium of each well cultured for 24 hours as above b. was
removed by aspiration. Each 200//1 of drug samples prepared in c. was
added into each well and the wells were cultured for 48 hours. Tz(time
zero) plates were collected at the point of time drugs were added.
e. According to the SRB assay method, cell fixing with TCA, staining with 0.4% SRB solution, washing with 1% acetic acid and elution of dye with lOmM Tris solution were carried out on Tz plates and culture-ended plates, and then, OD values were measured at 520 nm.
C. Calculation of result
a. Time zero(Tz) value was determined with measuring the SRB
protein value at the point of time drugs were added.
b. Control value(C) was determined with the OD value of an well
untreated with drug.
c. Drug-treated test value(T) was determined with the OD value of
drug-treated well.
d. Effects of drugs were estimated with growth stimulation, net
growth inhibition, net killing etc. calculated from Tz, C and T.
e. If T ^ Tz, cellular response function was calculated by
lOOx(T-Tz)AC-Tz), and if T are shown in the next table 1.
* REFERENCE
1) P. Skehan, R. Strong, D Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, S. Kenny and M. R. Boyl) : Proc. Am. Assoc. Cancer Res., 30, 012(1989)
2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. boyl). ; J. Natl. Cancer Inst, 82, 1113(1990)
3) P. Skehan, R. Strong, D. Scudiero, A. monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, S. Kenny and M. R. Boyl).iJ, Natl. Cancer Ins., 82, 1107(1990)
D. Results.
It was found that compounds of the present invention have the
superior antitumor activities than those of cisplatin, one control, and equal to or higher antitumor activities than those of adriamycin, another control, against human solid cancer cell lines.
Table 1.
(Table Removed)
Experimental 2.
In vitro antitumor effects against animal leukemia cells.
A. Materials :
Tumor cell lines '■ L1210(mouse leukemia cell)
P388 (mouse lymphoid neoplasma cell)
B. Method : Dye Exclusion Assay.
1) The concentrations of L1210 and P388 cells being cultured in RPMI 1640 media containing 10% FBS were regulated to 1 x 10° cells/ml.
2) Sample drugs of respective concentrations diluted in the ratio of log doses were added into cell media, and cultured at 37 oC, for 48 hours, in 50% CO2 incubator, and then viable cell number was measured by dye exclusion test using trypan blue.
3) The concentration of sample compounds showing 50 % cell growth inhibition(IC * REFERENCE
1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, S. Kenney and M. R. Boyl). '■ Proc. Am. Assoc. Cancer Res., 30, (512(1989).
2) L. V. Rubinstein, R. Ii. Shoemaker, K. D. Paull, R. M. Simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks, J. Natl. Cancer Inst., 82, 1113(1990)
3) P. Skehan, R. Strong, D. Scudiero, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyl). : J. Natl. Cancer Inst., 82, 1107(1990)
C. Results
As the results of measurement of antitumor activities of compounds of the present invention against L1210 and P388 mouse cancer cells, it was found that the compounds tested have equal to or higher antitumor activities than those of the control drug, mitomycin C.
(Table Removed)
Experimental 3.
* In vivo antitumor effects against mouse leukemia P388 cells.
A. Material of experiment
BDF1 mice were used.
B. Method of experiment
1) Leukemia P388 cells being transfer-cultured successively in DBA/2 mouse, were grafted into each mouse of a group comprising 8 mice of 6 week old BDF1 mouse with the dose of 1 XlO'cells/O.lml.
2) Sample drugs were dissolved in PBS or suspended in 0.5% tween 80, and then injected into abdominal cavity of mouse at each prescribed concentration on days 1, 5, 9, respectively.
3) With observation everyl)ay, survival times of tested mice were measured. Antitumor activities was determined in such a manner that the increasing ratio(T/C%) of average survival days of drug-treated groups compared with the control group was calculated using the mean survival times of each tested groups.
The results are shown at the next table 3.

(Table Removed)
* REFERENCE
A. Goldin et al.: Euro. J. Cancer, 17, 129 (1981).
C. Result
Through in vivo experiments using P388 mouse cancer cells, significant antitumor effect of the compounds of examples were observed.
Experimental 4.
Acute toxicity test (LD50) : Litchfield-Wilcoxon method.
6 weeks old ICR mice(male 30±2.0g) were fed freely with solid feed and water at room temperature, 23±1*C and at humidity 60 ±5%. Sample drugs were injected into the abdominal cavities of mice, while each group comprises 6 mice. Observed during 14 days, external appearances and life or dead were recorded, and then, visible pathogenies were observed from dead animals by dissection. LD50 value was calculated by Litchfiled-wilcoxon method. The results are shown at the next table 4.
(Table Removed)
As described above, it was found that the compounds of the present invention are more safer and have superior antitumor activities to cisplatin, and accordingly have solved the problems of drugs by the prior art such as restriction of dosage, toxicity, etc.

WE CLAIM:
A process for the preparation of piperazine derivative of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof comprising reacting a compound of the general formula (a) with a -C(=X)- group-providing agent in the presence of organic solvent as herein described to obtain a compound of the general formula (b) and reacting the compound of the general formula (b) with a compound of the general formula (c) to obtain the general formula (I) .
(Formula Removed)
and reacting said compound of general formula (I) with acids as herein defined to form acid addition salt; wherein R1, and R2 are independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C8 unsaturated alkyl, ketone, substituted or unsubstituted aryl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted arylhydroxy, substituted or unsubstituted amino, C1-C4 lower ester, C1-C4 lower thioester, thiol, substituted or unsubstituted carboxyl, epoxy, substituted or unsubstituted C1-C4 lower thioalkoxy; or R1 and R1 are fused to form C3-C4 saturated or unsaturated chain; R3 , R,, R5, Rg and R7 are independently hydrogen, halogen, hydroxy, nitro, C1-C4 lower ester, C1-C4 lower alkyl, C1-C4 lower thioalkyl,
substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted lower arylalkoxy, substituted or unsubstituted lower alkylamino, or lower alkyl substituted or unsubstituted carbamate; or among R3, R4, R5, Rg and R7, two adjacent groups are bonded with each other to form 1,2-phenylene or 2,3-naphthylene; X is oxygen, sulfur, or substituted or unsubstituted imino; Y is bonded at the 3-position or 4-position of the aromatic ring part wherein Y is oxygen or -NRg- (wherein, R8 is the same with the above-mentioned R3) ; Z is hydroxy, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy, substituted or unsubstituted aryloxy, C1-C4 lower alkylamino, substituted or unsubstituted cycloamino containing 1-5 nitrogen atoms; A is nitrogen or -CH=; and Lie is a leaving group such as halogen atom, sulphonyl and the like.
2. A process for the preparation of piperazine derivative as claimed in claim 1, wherein said -C(=X)- group providing agents are selected form 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgene, carbonyl-diphenoxide, phenylchloroformate and the like.
3 . A process for the preparation of piperazine derivative of the general formula (I) as claimed in claim l, substantially as hereinbefore described in any one of the Examples.

Documents:

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2140-del-1997-correspondence-po.pdf

2140-del-1997-description (complete).pdf

2140-del-1997-form-1.pdf

2140-del-1997-form-2.pdf

2140-del-1997-form-4.pdf

2140-del-1997-form-6.pdf

2140-del-1997-gpa.pdf

2140-del-1997-petition-138.pdf

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Patent Number

187298

Indian Patent Application Number

2140/DEL/1997

PG Journal Number

12/2002

Publication Date

23-Mar-2002

Grant Date

04-Oct-2002

Date of Filing

31-Jul-1997

Name of Patentee

SAMJIN PHARMACEUTICAL CO. LTD.,

Applicant Address

338-8, SEOKYO-DONG, MAPO-KU, SEOUL, 121-210, REPUBLIC OF KOREA.

Inventors:

#	Inventor's Name	Inventor's Address
1	KANG, DONG-WOOK	#268-203, JOOKONG APT, 4, WONMOON-DONG, KWACHON, KYUNGKI-DO, 427-030 REPUBLIC OF KOREA.
2	KWON, HO-SEOK	#506-1105,SINDONGA, APT., 1274, KWONSUN-DONG, JWONSUN-KU, SUWEON, KYUNGKI-DO, 441-390, REPUBLIC OF KOREA.
3	LEE, JAE-EUNG	390-3, SINJANG-DONG, HANAM, KYUNGKI-DO, 465-032, REPUBLIC OF KOREA.
4	JOO, JEONG-HO	289-83, JORYANGJIN 2-DONG, DONGJAK-KU, SEOUL, 156052, REPUBLIC OF KOREA.
5	LEE, YOUNG-HEE	866-5, BONO 1-DONG, ANSAN, KYUNGKI-DO, 425-181, REPUBLIC OF KOREA.
6	CHUNG, SUN-GAN	#131-904, MOKHWA APT, 850, KEUMJEONG-DONG, KUNPO, KYUNGKI-DO, 435-050, REPUBLIC OF KOREA.
7	LEE, SUN-HWAN	#105-403, DAELIM APT, DOKKOK-DONG, SONGTAN, PANGTAK, KYUNGKI-DO, 459-100, REPUBLIC OF KOREA.
8	EUI-HWAN CHO	#105-101, HYUNDAI 1ST APT., KAEPO-DONG, KANGNAM-KU, SEOUL, 135-240, REPUBLIC OF KOREA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	97-22984	1997-06-03	Republic of Korea
2	97-23192	1997-06-04	Republic of Korea
3	96-40596	1996-09-18	Republic of Korea
4	97-22985	1997-06-03	Republic of Korea
5	97-23193	1997-06-04	Republic of Korea