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 R 1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R 2 is the side chain of a natural or non-natural alpha amino acid; Y is a bond, -C(=O)-, -S(=O) 2 -, -C(=O)O-, -C(=O)NR 3 -, -C(=S)-NR 3 , -C(=NH)NR 3 or -S(=O) 2 NR 3 - wherein R 3 is hydrogen or optionally substituted C 1 -C 6 alkyl; L 1 is a divalent radical of formula -(Alk 1 ) m (Q) n (Alk 2 )p- 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 2 -Q 1 - or -Q 1 -X 2 - wherein X 2 is -O-, S- or NR A - wherein R A is hydrogen or optionally substituted C 1 -C 3 alkyl, and Q 1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, Alk 1 and Alk 2 independently represent optionally substituted divalent C 3 -C 7 , cycloalkyl radicals, or optionally substituted straight or branched, C 1 -C 6 alkylene, C 2 -C 6 alkenylene ,or C 2 -C 6 alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NR A -) link wherein R A is hydrogen or optionally substituted C 1 -C 3 alkyl; X 1 represents a bond; -C(=O); or - S(=O) 2 -; -NR 4 C(=O)-, -C(=O)NR 4 -,-NR 4 C(=O)NR 5 -, -NR 4 S(=O) 2 -, or -S(=O) 2 NR 4 - wherein R 4 and R 5 are independently hydrogen or optionally substituted C 1 -C 6 alkyl; z is 0 or 1; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R 1 R 2 NH-Y-L 1 -X 1 -[CH 2 ] z - and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent radical of formula -(CH 2 ) x - L 3 -Ar 1 -L 4 - wherein x is 0 or 1; L 3 is Z or L 2 or Z-L 2 wherein Z is a bond, -NR 3 -, -NR 3 C(=O)-, -C(=O)NR 3 -,-NR 4 C(=O)-NR 3 -, -C(=S)-NR 3 , -C(=N)-NR 3 -NR 3 S(=O) 2 -, or -S(=O) 2 NR 3 - wherein R 3 is hydrogen or C 1 -C 6 alkyl; - C(=O); or -S(=O) 2 -; and L 2 is a bond or an optionally substituted divalent C 1 -C 3 alkylene radical; Ar 1 is a divalent phenyl radical or a divalent mono-, or bi-cyclic heteroaryl radical having 5 to 13 ring members; and L 4 is a bond or optionally substituted -CH 2 - or -CH=CH-.