Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• Q is a bond or optionally can be selected from O, NR7 or S(O)v, when n* is an integer from 1 to 6;
• Z is S(═O)2;
• Ra at each occurrence is independently selected from H, (C1-C3)alkyl, (halo)(C1-C3)alkyl, (hydroxy)(C1-C3)alkyl, (alkoxy)(C1-C3)alkyl, or cyano;
• Rb is H, halo, (C1-C3)alkyl, (halo)(C1-C3)alkyl, (hydroxy)(C1-C3)alkyl, (alkoxy)(C1-C3)alkyl, or cyano;
• Rc and Rd are independently selected from H, halo, (C1-C3)alkyl, (C1-C3)alkoxy, (halo)(C1-C3)alkyl, (halo)(C1-C3)alkoxy, (alkoxy)(C1-C3)alkyl, or (hydroxy)(C1-C3)alkyl,
• or Rc and Rd may optionally combine to form a spiro-cycloalkyl or heterocyclo ring system;
• Re is
• (a) H or halo;
• or
• (b) (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocyclo, cyano, halogen, hydroxyl, —OR5, NR7R8, or heterocycloalkyl, any of which may be optionally substituted with 1 or more Rx groups as allowed by valence;
• R′ and R″ at each occurrence, respectively, are independently H, halo, (C1-C3)alkyl, (C1-C3)alkoxy, (halo)(C1-C3)alkyl, (halo)(C1-C3)alkoxy, (alkoxy)(C1-C3)alkyl, (hydroxy)(C1-C3)alkyl, —S—(C1-C3)alkyl, C(O)(C1-C3)alkyl, —NR7R8, or hydroxyl, or R′ and R″ bound to the same carbon atom may optionally combine to form ═O;
• R1 is
• (a) —COOH, —C(O)OR10, —C(O)NHOH, —C(O)NH—NH2, —C(O)NHS(O)2R10, —S(O)2NHC(O)R10, —S(O)2NR7R8, —NR7C(O)R10, —NR7C(O)OR5, —C(O)NR7R8, —NR7S(O)2R10, —NR7C(O)NR7R8, —S(O)vR10, hydroxylalkyl, -cyclopropyl-COOH, or CN;
• or
• (b) heteroaryl or heterocyclo, either of which may be optionally independently substituted with one or more Rx groups as allowed by valence;
• R2 is
• (a) —NR7R8, NR7C(O)OR10, NR7C(O)NR7R10, or —C(Ra)R5R6;
• or
• (b) aryl, heteroaryl, cycloalkyl, or heterocyclo, any of which may be optionally independently substituted with one or more Rx groups as allowed by valence;
• R3 and R4 are independently aryl or heteroaryl, either of which may be optionally independently substituted with one or more Rx groups as allowed by valence;
• R5 and R6 at each occurrence, respectively, are independently selected from
• (a) H or CN;
• (b) -(alkylene)t-OH, -(alkylene)t-OR9, -(alkylene)t-SR9, -(alkylene)t-NR10R11, -(alkylene)t-C(O)R9, -(alkylene)t-C(O)OR9, -(alkylene)t-OC(O)R9, -(alkylene)t-S(O)vR9, -(alkylene)t-NHS(O)2R10, -(alkylene)t-N(R11)S(O)2R10, -(alkylene)t-S(O)2NR10R11, -(alkylene)t-N(R11)S(O)2NR10R11, —NR10C(O)R9, —C(O)NR10R11, —NR10S(O)2R9, S(O)2NR10, or NR10C(O)NR10R11;
• or
• (c) haloalkyl, haloalkoxy, C1-6-alkyl, C2-6alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, (C3-8-cycloalkyl)(C1-3alkyl), C4-8-cycloalkenyl, aryl, aryl(C1-3-alkyl), heteroaryl, heteroaryl(C1-3-alkyl), heterocyclo or heterocyclo(C1-3-alkyl), any of which may be optionally independently substituted with one or more Rx groups as allowed by valence;
• R7 and R8 at each occurrence, respectively, are independently selected from H, cyano, —OC1-6-alkyl, C1-6-alkyl, halo(C1-6)-alkyl, cycloalkyl, C2-6-alkenyl, C2-6-alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocyclo(C1-10alkyl), or (C3-8-cycloalkyl)(C1-3alkyl), any of which may be optionally substituted as allowed by valence with one or more Rx, or R7 and R8 may combine to form a C4-C8-heterocyclo ring optionally substituted with one or more Rx;
• R9 is haloalkyl, haloalkoxy, C1-6-alkyl, C2-6alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, (C3-8-cycloalkyl)(C1-3alkyl), C4-8-cycloalkenyl, aryl, heteroaryl, heterocyclo, or heterocycloalkyl, any of which may be optionally independently substituted with one or more Rx groups as allowed by valence;
• R10 and R11 at each occurrence, respectively, are independently selected from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, any of which may be optionally substituted as allowed by valence with one or more Rx, or R10 and R11 may combine to form a heterocyclo ring optionally substituted with one or more Rx;
• Rx at each occurrence is independently, deuterium, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)t-OR*, -(alkylene)t-S(O)vR*, -(alkylene)t-NR+R++, -(alkylene)t-C(═O)R*, -(alkylene)t-C(═S)R*, -(alkylene)t-C(═O)OR*, -(alkylene)t-OC(═O)R*, -(alkylene)t-C(═S)OR*, -(alkylene)t-C(═O)NR+R++, -(alkylene)t-C(═S)NR+R++, -(alkylene)t-N(R+)C(═O)NR+R++, -(alkylene)t-N(R+)C(═S)NR+R++, -(alkylene)t-N(R+)C(═O)R*, -(alkylene)t-N(R+)C(═S)R*, -(alkylene)t-OC(═O)NR+R++, -(alkylene)t-OC(═S)NR+R++, -(alkylene)t-SO2NR+R++, -(alkylene)t-N(R+)SO2R*, -(alkylene)t-N(R+)SO2NR+R++, -(alkylene)t-N(R+)C(═O)OR*, -(alkylene)t-N(R+)C(═S)OR*, or -(alkylene)t-N(R+)SO2R*, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more halo, cyano, oxo, -(alkylene)t-OR*, -(alkylene)t-S(O)vR*, -(alkylene)t-NR+R++, -(alkylene)t-C(═O)R*, -(alkylene)t-C(═S)R*, -(alkylene)t-C(═O)OR*, -(alkylene)t-OC(═O)R*, -(alkylene)t-C(═S)OR*, -(alkylene)t-C(═O)NR+R++, -(alkylene)t-C(═S)NR+R++, -(alkylene)t-N(R+)C(═O)NR+R++, - (alkylene)t-N(R+)C(═S)NR+R++, -(alkylene)t-N(R+)C(═O)R*, -(alkylene)t-N(R+)C(═S)R*, -(alkylene)t-OC(═O)NR+R++, -(alkylene)t-OC(═S)NR+R++, -(alkylene)t-SO2NR+R++, -(alkylene)t-N(R+)SO2R*, -(alkylene)t-N(R+)SO2NR+R++, -(alkylene)t-N(R+)C(═O)OR*, -(alkylene)t-N(R+)C(═S)OR*, or -(alkylene)t-N(R+)SO2R*;
• R* is H, haloalkyl, haloalkoxy, C1-6-alkyl, C2-6alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, aryl, heteroaryl, or heterocyclo;
• R+ and R++ are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, or R+ and R++ bound to the same nitrogen atom may optionally combine to form a heterocyclo ring system;
• n and n* are each independently selected from 0 or an integer from 1 to 6;
• t at each occurrence is independently 0 or an integer from 1 to 6;
• and
• v at each occurrence is independently 0, 1 or 2.