HYDROXAMIC ACID DERIVATIVES AS INHIBITORS OF HDAC ENZYMATIC ACTIVITY

摘要

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers: wherein Y1 is a bond, -(C-O)-, -S(O2)-, -C(-O)O-, -OC(-O)-, -(C-O)NR3-, -NR3(C-O)-, -S(O2)NR3-, -NR3S(O2)-, or -NR3(C-O)NR5-, wherein R3 and R5 are independently hydrogen or optionally substituted (C1-C6)alkyl, L1 is a divalent radical of formula -(Alk1)m(O)n(Alk2)p- wherein m, n, p, Alk1, Alk2 and Q are as defined in the claims; z is 0 or 1; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system; -[Linker]- represents a divalent linker radical; R is a radical of formula (X) or (Y): wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R4 is hydrogen; or optionally substituted C1-C6 alkyl, C3-C7cycloalkyl, aryl, aryl(C1-C6 alkyl)-, heteroaryl, heteroaryl(C1-C6 alkyl)-, -(C-O)R3, -(C-O)OR3, or -(C-O)NR3 wherein R3 is hydrogen or optionally substituted (C1-C6)alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, heteroaryl, or heteroaryl(C1-C6 alkyl)-; R41 is hydrogen or optionally substituted C1-C6 alkyl; and B is a monocyclic heterocyclic ring of 5 or 6 ring atoms wherein R1 is linked to a ring carbon adjacent the ring nitrogen shown, and ring B is optionally fused to a second carbocyclic or heterocyclic ring of 5 or 6 ring atoms in which case the bond shown intersected by a wavy line may be from a ring atom in said second ring;