Preparation of piperazinylnicotinamides and related compounds as histone deacetylase inhibitors for treatment of cancer.

Abstract

Title compds. [I; X1 = CH, N; X2 = CH, N, NO; A = 5-6 membered heteroaryl; R1, R2, R5, R6 = H, alkyl; R1R2 = (CH2)2-3; R1R5, R3R5, R3R6 = (CH2)1-3; R3 = alkyl, [C(R10)2]aR9; R4 = H, alkyl, CO2R7, SO2R7, CONR7R10, COR7; R3R4 = (CH2)3-4; R7 = H, alkyl, [C(R10)2]aR9; R8 = halo, cyano, amide, CO2H, alkyl, alkoxy, alkenyl, alkynyl, (substituted) aryl, heteroaryl; R9 = (substituted) aryl; R10 = H, (substituted) alkyl; R11 = NH2, OR10, SH; a = 0-2; p = 0-4], were prepd. Thus, title compd. benzyl (2S)-4-[5-[[(2-aminophenyl)amino]carbonyl]pyridin-2-yl]-2-methylpiperazine-1-carboxylate was prepd. in 3 steps from tert-Bu 2-aminophenylcarbamate, 6-chloronicotinoyl chloride, and benzyl (2S)-2-methylpiperazine-1-carboxylate. I showed HDAC inhibition with IC50's of <3 μM. [on SciFinder(R)]