Enzyme inhibitors

摘要

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein Ris a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; Ris the side chain of a natural or non-natural alpha amino acid; Y is a bond, -C(=O)-, -S(=O)-, -C(=O)O-, -C(O)NR-, -C(=S)-NR , -C(=NH)NR or -S(=O)NR- wherein R is hydrogen or optionally substituted C-C alkyl; L is a divalent radical of formula -(Alk)(Q)(Alk)- wherein m, n and p are independently 0 or 1 , Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula -X-Q- or -Q-X- wherein X is -O-, S- or NR- wherein R is hydrogen or optionally substituted C-C alkyl, and Q is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, AIk and AIk independently represent optionally substituted divalent C-C cycloalkyl radicals, or optionally substituted straight or branched, C-C alkylene, C-C alkenylene ,or C-C alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NR-) link wherein R is hydrogen or optionally substituted C-C alkyl; X represents a bond; -C(=O); or -S(=O)-; -NRC(=O)-, -C(=O)NR-, -NRC(=O)NR- , -NRS(=O)-, or -S(=O)NR-wherein R and R are independently hydrogen or optionally substituted C-C alkyl; z is 0 or 1 ; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals RRNH-Y-L-X-[CH]- and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONHOH, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms.