Novel bis-Benzylidine Piperidone Proteasome Inhibitor with Anticancer Activity

A compound having the structural formula II

• wherein A is one of:
• (i) phenyl, optionally substituted with 1-5 substituents selected from the group consisting of R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF3, and OCF3;
• (ii) naphthyl, optionally substituted with 1-5 substituents selected from the consisting of R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF3, and OCF3;
• (iii) a 5 or 6 membered monocyclic heteroaryl group, having 1-3 heteroatoms selected from the group consisting of 0, N, and S, optionally substituted with 1-3 substituents selected from the group consisting of R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF3, and OCF3;
• and
• (iv) an 8 to 10 membered bicyclic heteroallyl group containing 1-3 heteroatoms selected from the group consisting of O, N, and S;
• and the second ring is fused to the first ring using 3 to 4 carbon atoms, and the bicyclic hetero aryl group is optionally substituted with 1-3 substituents selected from the group consisting of R1, OR1, NR1R2, S(O)qR1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF3, and OCF3;
• wherein X is OR1 or NP, wherein P is selected from the group consisting of R1, C(O)R1, C(O)OR1, C(O)NR1R2, S—N(R1)COOR1, and S—N(R1), wherein R1 and R2 are selected from the group consisting of hydrogen, nitro, hydroxyl, carboxy, amino, halogen, cyano and C1-C14 linear or branched alkyl groups, that are optionally substituted with 1-3 substituents selected from the group consisting of C1-C14 linear or branched alkyl, up to perhalo substituted C1-C14 linear or branched alkyl, C1-C14 alkoxy, hydrogen, nitro, hydroxyl, carboxy, amino, C1-C14 alkylamino, C1-C14 dialkylamino, halogen, and cyano;
• wherein Z is selected from the group consisting of hydrogen;
• C1 to C14 linear, branched, or cyclic alkyls;
• phenyl;
• benzyl, 1-5 substituted benzyl, C1 to C3 alkyl-phenyl, wherein the alkyl moiety is optionally substituted with halogen up to perhalo;
• up to perhalo substituted C1 to C14 linear or branched alkyls;
• —(CH2)q—Y, where Y is a 5 or 6 membered monocyclic heterocyclic ring, containing 1 to 4 atoms selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or an 8 to 10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, wherein said alkyl moiety is optionally substituted with halogen up to perhalo, and wherein the variable q is an integer ranging from 0 to 4;
• wherein r is (i) R1, C(O)R1, C(O)OR1, C(O)NR1R2, S—N(R1)COOR1, S—N(R1)COO(B), S(B);
• and
• wherein each R1-R2, other then per-halo substituted C1-C14 linear or branched alkyl, is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C14 linear or branched alkyl, up to perhalo substituted C1-C14 linear or branched alkyl, C1-C3 alkoxy, hydroxyl, carboxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano.