Amino-substituted (E)-2,6-dialkoxystyryl 4-substituted-benzylsulfones for treating proliferative disorders

A compound of formula I:

• wherein:
• X is selected from the group consisting of (i) and (ii) below:
• X1 is selected from the group consisting of (i), (ii) and (iii) below:
• g is 0 or 1;
• each M is a bivalent connecting group independently selected from the group consisting of —(C1-C6)alkylene-, —(CH2)a—V—(CH2)b—, —(CH2)d—W—(CH2)e— and -Z-;
• each y is independently selected from the group consisting of 0 and 1;
• each V is independently selected from, the group consisting of arylene, heteroarylene, —C(═O)—, —C(═S)—, —S(═O)—, —SO2—, —C(═O)O—;
• —C(═O)(C1-C6)perfluoroalkylene-, —C(═O)NR4—, —C(═S)NR4— and —SO2NR4—;
• each W is independently selected from the group consisting of —NR4—, —O— and —S—;
• each a is independently selected from the group consisting of 0, 1, 2 and 3;
• each b is independently selected from the group consisting of 0, 1, 2 and 3;
• each d is independently selected from the group consisting of 1, 2 and 3;
• each e is independently selected from the group consisting of 0, 1, 2 and 3;
• -Z- is
• wherein the absolute stereochemistry of -Z- is D or L or a mixture of D and L;
• each Ra is independently selected from the group consisting of —H, —(C1-C6)alkyl, —(CH2)3—NH—C(NH2)(═NH), —CH2C(═O)NH2, —CH2COOH, —CH2SH, —(CH2)2C(═O)—NH2, —(CH2)2COOH, —CH2-(2-imidazolyl), —CH(CH3)—CH2—CH3, —CH2CH(CH3)2, —(CH2)4—NH2, —(CH2)2—S—CH3, phenyl, CH2-phenyl, —CH2—OH, —CH(OH)—CH3, —CH2-(3-indolyl), —CH2-(4-hydroxyphenyl), —CH(CH3)2 and —CH2—CH3;
• and includes compounds wherein Ra and R1 combine to form a 5-, 6- or 7-membered heterocyclic ring;
• each R1 is independently selected from the group consisting of unsubstituted aryl, substituted aryl, substituted heterocyclic, unsubstituted heterocyclic, —CO2R5, —C(═O)NR42, —CR4R6R7, —C(═NH)—NR42, —(C1-C6)perfluoroalkyl, —CF2Cl, —P(═O)(OR4)2, —OP(═O)(OR4)2 and a monovalent peptidyl moiety with a molecular weight of less than 1000;
• provided that when y is 0 and R1 is —CO2R5, R5 is not —H;
• each R2 is independently selected from the group consisting of —H, —(C1-C6)alkyl, and aryl(C1-C3)alkyl, wherein —R2 and -(M)y-R1 may optionally be linked covalently to form a 5-, 6- or 7-membered substituted or unsubstituted heterocycle;
• each R3 is independently selected from —(C1-C6)alkyl;
• each R4 is independently selected from the group consisting of —H, and —(C1-C6)alkyl;
• each R5 is independently selected from the group consisting of —H, —(C1-C6)alkyl and —(C1-C6)acyl;
• each R6 is independently selected from the group consisting of —(C1-C6)alkyl, —CO2R5, —C(═O)R7, —OR5, —OC(═O)(CH2)2CO2R5, —SR4, guanidine, —NR42, —NR43+, —N+(CH2CH2OR5)3, phenyl, substituted phenyl, heterocyclic, substituted heterocyclic and halogen;
• each R7 is independently selected from the group consisting of —Ra, halogen, —NR42, and heterocycles containing two nitrogen atoms;
• and
• Q is selected from the group consisting of —H, —(C1-C6)alkoxy, halogen, —(C1-C6)alkyl and —NR42;
• wherein the substituents for the substituted aryl and substituted heterocyclic groups comprising or included within R1, R2, Ra, R6 and R7, are independently selected from the group consisting of halogen, (C1-C6)alkyl, —NO2, —C≡N, —CO2R5, —C(═O)O(C1-C3)alkyl, —OR5, —(C2-C6)alkylene-OH, phosphonato, —NR42, —NHC(═O)(C1-C6)alkyl, sulfamyl, —OC(═O)(C1-C3)alkyl, —O(C2-C6)alkylene-N((C1-C6)alkyl)2 and —CF3;
• provided:
• (1) when R1 is a monovalent peptidyl moiety of molecular weight less than 1000 and V is —C(═O)—, —C(═S)—, —S(═O)— or —SO2—, and b is 0;
• then said peptidyl moiety is coupled to M through the amino terminus of the peptidyl moiety or through a sidechain amino group to form an amide, thioamide, sulfinamide or sulfonamide respectively;
• (2) when R1 is a monovalent peptidyl moiety of molecular weight less than 1000 and V is —C(═O)NR4 or —SO2NR4, and b is 0,
• then said peptidyl moiety is coupled to M through the carboxy terminus of the peptidyl moiety or through a sidechain carboxyl group to form an imide or sulfonimide, respectively;
• and
• (3) when R1 is a monovalent peptidyl moiety of molecular weight less than 1000 and W is —NR4—, —S— or —O—, and e is 0,
• then said peptidyl moiety is coupled to M through the carboxy terminus of the peptidyl moiety or through a sidechain carboxyl group to form a carboxamide, carbothioic acid ester or carboxylic ester respectively;
• or a salt of such a compound.