NOVEL N-SUBSTITUTED-PYRROLIDINES AS INHIBITORS OF MDM2-P-53 INTERACTIONSThere are provided compounds of the formula (I) wherein X, Y, R1, R2, R3, R3, R4, and R5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof which are useful as anticancer agents.A compound of the formula (I)whereinX is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy,Y is one to four group(s) independently selected from the group consisting of H, F, CI, Br,I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, heteroaryl, heterocycle, COOR', OCOR', CONR'R', NR'COR', NR'S02R',S02NR'R' and NR'R' whereinR' and R' are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycleand in the case of R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,one of Ri and R2 is selected from the group consisting of lower alkyl,substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,one of R3 and R4 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen, R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,-CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R', -CH2(CH2)n-CO(CH2)nNR'R', -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R', -(CH2)n-NR'S02R', -COCH2(CH2)n-COOH, -(CH2)n-COOR', -(CH2)n-CONR'R', -CO(CH2)n-OR',-COCH2(CH2)n-SR' , -COCH2(CH2)n-SOR' , -COCH2(CH2)n-S02R' , -COCH2(CH2)n-COR' , -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R', -COCH2(CH2)n-S02NR'R',-COCH2(CH2CH20)m-(CH2)n-R' , -COCH2(CH2CH20)m-(CH2)n-OH,-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R',-COCH2(CH2CH20)m-(CH2)n-NR'COR', -COCH2(CH2CH20)m-(CH2)n-NR'S02R',-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR',-COCH2(CH2CH20)m-(CH2)n-CONR'R', -COCH2(CH2CH20)m-(CH2)n-S02R',-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R',-COCH2(CH2CH20)m-(CH2)n-S02NR'R', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR' ,-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'S02R', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R',-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R', -COCH2-COR', -COCH2-SOR' and-COCH2S02R' wherein R' and R' are as above,m, n, and p are independently 0 to 6,and the pharmaceutically acceptable salts and esters thereof. 2. A compound of claim 1 of the formula (IA)whereinX is selected from the group consisting of F, CI and Br, Y is one to two group(s) independently selected from the group consisting of H, F, CI, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl and lower alkoxy,Ri is hydrogen,one of R2 and R3 is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl and the other is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl,R4 is hydrogen,R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,-CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R', -CH2(CH2)n-CO(CH2)nNR'R', -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R', -(CH2)n-NR'S02R', -COCH2(CH2)n-COOH, -(CH2)n-COOR -(CH2)n-CONR'R', -CO(CH2)n-OR',-COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-S02R', -COCH2(CH2)n-COR', -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R', -COCH2(CH2)n-S02NR'R',-COCH2(CH2CH20)m-(CH2)n-R' , -COCH2(CH2CH20)m-(CH2)n-OH,-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R',-COCH2(CH2CH20)m-(CH2)n-NR'COR', -COCH2(CH2CH20)m-(CH2)n-NR'S02R',-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR' ,-COCH2(CH2CH20)m-(CH2)n-CONR'R', -COCH2(CH2CH20)m-(CH2)n-S02R',-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R',-COCH2(CH2CH20)m-(CH2)n-S02NR'R', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR' ,-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR', -COCH2(CH2)p-(CH2CH20)m-(CH2)...
ＭＤＭ2-Ｐ-53 상호작용 억제제로서의 신규 Ｎ-치환된-피롤리딘본 발명은, 항암제로서 유용한 화학식 I의 화합물, 및 이의 거울상 이성질체, 약학적으로 허용가능한 염 및 에스터에 관한 것이다: [화학식 I] 상기 식에서, X, Y, R1, R2, R3, R3, R4, 및 R5는 본원에 기재된 바와 같다.하기 화학식 I의 화합물, 또는 이의 약학적으로 허용가능한 염 또는 에스터:[화학식 I]상기 식에서,X는 H, F, Cl, Br, I, 시아노, 니트로, 에틴일, 사이클로프로필, 메틸, 에틸, 이소프로필, 비닐 및 메톡시로 이루어진 군으로부터 선택되고,Y는 독립적으로 H, F, Cl, Br, I, CN, OH, 니트로, 저급 알킬, 사이클로알킬, 저급 알콕시, 저급 알켄일, 사이클로알켄일, 저급 알킨일, 아릴, 헤테로아릴, 헤테로사이클, COOR', OCOR', CONR'R", NR'COR", NR"SO2R', SO2NR'R" 및 NR'R"로 이루어진 기로부터 선택된 1 내지 4개의 기이고, 이때,R' 및 R"는 독립적으로 H, 저급 알킬, 치환된 저급 알킬, 저급 사이클로알킬, 치환된 저급 사이클로알킬, 저급 알켄일, 치환된 저급 알켄일, 저급 사이클로알켄일, 치환된 저급 사이클로알켄일, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로사이클, 또는 치환된 헤테로사이클로부터 선택되고,R' 및 R"는 또한, 독립적으로, 연결되어 치환된 또는 비치환된 사이클로알킬, 치환된 또는 비치환된 사이클로알켄일, 치환된 또는 비치환된 헤테로아릴 또는 치환된 또는 비치환된 헤테로사이클로부터 선택된 환형 구조를 형성할 수 있고,R1 및 R2중 하나는 저급 알킬, 치환된 저급 알킬, 저급 알켄일, 치환된 저급 알켄일, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로사이클, 치환된 헤테로사이클, 사이클로알킬, 치환된 사이클로알킬, 사이클로알켄일 및 치환된 사이클로알켄일로 이루어진 군으로부터 선택되고, 다른 하나는 수소이고,R3 및 R4 중 하나는 저급 알킬, 치환된 저급 알킬, 저급 알켄일, 치환된 저급 알켄일, 아릴, 치환된 아릴, 헤테로아릴, 치환된 헤테로아릴, 헤테로사이클, 치환된 헤테로사이클, 사이클로알킬, 치환된 사이클로알킬, 사이클로알켄일, 및 치환된 사이클로알켄일로 이루어진 군으로부터 선택되고, 다른 하나는 수소이고, R5는 저급 알킬, 치환된 저급 알킬, -CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'SO2R", -COCH2(CH2)n-COOH, -(CH2)n-COOR', -(CH2)n-CONR'R", -CO(CH2)n-OR', -COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-SO2R', -COCH2(CH2)n-COR', -COCH2(CH2)n-SO3H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-SO2NR'R", -COCH2(CH2CH2O)m-(CH2)n-R', -COCH2(CH2CH2O)m-(CH2)n-OH, -COCH2(CH2CH2O)m-(CH2)n-OR', -COCH2(CH2CH2O)m-(CH2)n-NR'R", -COCH2(CH2CH2O)m-(CH2)n-NR'COR", -COCH2(CH2CH2O)m-(CH2)n-NR'SO2R", -COCH2(CH2CH2O)m-(CH2)n-COOH, -COCH2(CH2CH2O)m-(CH2)n-COOR', -COCH2(CH2CH2O)m-(CH2)n-CONR'R", -COCH2(CH2CH2O)m-(CH2)n-SO2R', -COCH2(CH2CH2O)m-(CH2)n-COR', -COCH2(CH2CH2O)m-(CH2)n-SONR'R", -COCH2(CH2CH2O)m-(CH2)n-SO2NR'R", -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-R', -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-OR', -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-NR'SO2R", -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-SO2R', -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-COR', -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-SONR'R", -COCH2(CH2)p-(CH2CH2O)m-(CH2)n-SO2NR'R", -COCH2-COR', -COCH2-SOR' 및 -COCH2SO2R'로 이루어진 군으로부터 선택되고, 이때, R' 및 R"은 상기와 같고,m, n, 및 p는 독립적으로 0 내지 6이다.