| 摘要 |
Compounds of formula (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers:;
wherein Q, V and W independently represent —N═ or —C═; B is a divalent radical selected from (B1), (B2), (B3), (B4), (B5) and (B6).
;
wherein the bond marked * is linked to the ring containing Q, V and W through -[Linker1]- and the bond marked ** is linked to A through -[Linker2]-; A is an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system; -[Linker1]- and -[Linker2]- independently represent a bond, or a divalent linker radical; and R is (a) a radical of formula R1R2CHNH—Y-L1-X1—(CH2)z— or (b) a radical of formula R-L1-Y1—(CH2)z—. |
| 主权项 |
1. A compound of formula (I), or a salt, or N-oxide thereof:wherein
n is 0 or 1; Q, V and W independently represent —N═ or —C═; B is a divalent radical selected from (B1), (B2), (B3), (B4), (B5) and (B6):wherein the bond marked * is linked to the ring containing Q, V and W;
A is an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system; -[Linker]- represents a bond, or a divalent linker radical; Z1 is (a) a radical of formula R1R2CHNH—Y-L1-X1—(CH2)n— or (b) a radical of formula R-L1-Y1—(CH2)z—, wherein:
R is a radical of formula (X) or (Y) R1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group;R6 is hydrogen; or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, aryl or heteroaryl or —(C═O)R3, —(C═O)OR3, or —(C═O)NR3 wherein R3 is hydrogen or optionally substituted (C1-C6)alkyl;R2 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)NR3—, —C(═S)—NR3, —C(═NH)—NR3 or —S(═O)2NR3— wherein R3 is hydrogen or optionally substituted C1-C6 alkyl;Y1 is a bond, —(C═O)—, —S(O2)—, —C(═O)O—, —OC(═O)—, —NR3(C═O)—, —S(O2)NR3—, —NR3S(O2)—, or —NR3(C═O)NR4—, wherein R3 and R4 are independently hydrogen or optionally substituted (C1-C6)alkyl,L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)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 p is 0, a divalent radical of formula -Q′-X2— wherein X2 is —O—, —S— or NRA— wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q′ is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members,Alk1 and Alk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NRA—) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl;X1 is a bond, —C(═O)—; or —S(═O)2—; —NR4C(═O)—, —C(═O)NR4—, —NR4C(═O)—NR5—, —NR4S(═O)2—, or —S(═O)2NR4— wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; andz is 0 or 1. |
