MDM2 Inhibitors

A compound of structural formula I:

• wherein, R1 is linear or branched C1-C5 alkyl, C3-C5 cycloalkyl or
• R2 is H or (C1-C6 alkyl), wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl, —C(O)NR9R10, —NR9R10 and methanesulfonyl;
• R3 is a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted by 1 to 3 substituents independently selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, —O—(C1-C6)alkyl, —O—(C3-C6)cycloalkyl, —S—(C1-C6)alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkoxy, —CN, —C(O)NR9R10, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH2NR9R10, —CH2NR9—C(O)R10, methyl-imidazolyl-, —CH2C(O)NR9R10, —CH2C(O)OH, —C(O)OH, —CH2C(O)O—(C1-C4)alkyl, —N(R9)—C(O)—(C1-C4)alkyl, —NR9R10, —C(O)O—(C1-C4)alkyl, —CH2CN, tetrahydropyrrol-1-yl, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH, or with —CH3 and —OH;
• wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl, —C(O)NR9R10, —NR9R10 and methanesulfonyl;
• or
• R3 is selected from:
• R5 is a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted with 1 to 3 substituents independently selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, —O—(C1-C6)alkyl, —O—(C3-C6)cycloalkyl, —S—(C1-C6)alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkoxy, —CN, —C(O)NR9R10, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH2NR9R10, —CH2NR9—C(O)R10, methyl-imidazolyl-, —CH2C(O)NR9R10, —CH2C(O)OH, —C(O)OH, —CH2C(O)O—(C1-C4)alkyl, —N(R9)—C(O)—(C1-C4)alkyl, —NR9R10, —C(O)OCH3, —CH2CN, tetrahydropyrrol-1-yl, azetidin-1-yl, and azetidin-1-yl substituted with one or more —OH, or with —CH3 and —OH;
• wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl, —C(O)NR9R10, —NR9R10 and methanesulfonyl;
• or
• R5 is selected from:
• R6 is selected from halogen, halomethyl, methyl and cyano;
• R7 is selected from H, (C1-C6) alkyl and halogen;
• wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl, —C(O)NR9R10, —NR9R10 and methanesulfonyl;
• wherein:
• R8 is selected from —OH, —OCH3, —NH2, —NHMe, —NMe2, —NHCOMe, —NHCOH and methanesulfonyl;
• R9 is H or alkyl having 1 to 4 carbon atoms;
• R10 is H or (C1-C6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl and methanesulfonyl;
• wherein
• R11 is selected from —OCH3, —CH2CH3, —OH, halomethoxy and H;
• R12 is H or (C1-C6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl, —C(O)NR9R10, —NR9R10 and methanesulfonyl;
• R13 is halogen or alkyl having 1 to 4 carbon atoms;
• R14 is H or (C1-C6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl, —C(O)NR9R10, —NR9R10 and methanesulfonyl;
• R15 is selected from NH2, —C(O)OH, —NH(C(O)—CH3) and —C(O)—NH(CH3);
• R16 is selected from H, (C1-C6) alkyl and halogen;
• wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl, —C(O)NR9R10, —NR9R10 and methanesulfonyl;
• and
• R17 is selected from —C(O)—NR9(R10), (C1-C6)alkyl, —C(O)(C1-C6)alkyl, and —C(O)O(C1-C6)alkyl;
• wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl, —C(O)NR9R10, —NR9R10 and methanesulfonyl;
• and
• X1 is oxygen or sulfur;
• Y, X2, V and W are each independently carbon or nitrogen;
• wherein when Y is carbon, R4 is selected from H, hydroxyl, —O—(C1-C6)alkyl, —CN, halogen, (C1-C6)alkyl, —C(O)OH, —CH2C(O)OH, —CH2C(O)NR9R10, and —C(O)O—(C1-C6)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C1-C4)alkyl and methanesulfonyl;
• or
• a stereoisomer, an enantiomer, a diastereomer, a racemate, a mesomer, a cis/trans isomer, a tautomer, an isotopic variant of the compound of structural formula I, or any combination thereof;
• or a pharmaceutical salt, a solvate, a hydrate, a polymorph or a prodrug of the compound of structural formula I, the stereoisomer, the enantiomer, the diastereomer, the racemate, the mesomer, the cis/trans isomer, the tautomer, the isotopic variant or their combination;
• or a hydrate of the pharmaceutical salt.