Inhibitors of histone deacetylase

A histone deacetylase inhibitor of formula 1(a):

• 1482
• or a pharmaceutically acceptable salt thereof, wherein
• J is C1-C3-hydrocarbyl, —N(R20)—, —N(R20)—CH2—, —O—, or —O—CH2—;
• R20 is —H or —Me;
• X and Y are independently selected from —NH2, cycloalkyl, heterocyclyl, aryl, heteroaryl, and A—(C1-C6-alkyl)n—B—;
• A is H, C1-C6-alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• B is —NH—, —O—, or a direct bond;
• and
• n is 0 (in which case A is directly bonded to B) or 1.

A histone deacetylase inhibitor of formula (2):

• 1542
• or a pharmaceutically acceptable salt thereof, wherein
• Cy2 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted;
• X1 is selected from the group consisting of a covalent bond, M1—L2—M1, and L2—M2—L2 wherein
• L2, at each occurrence, is independently selected from the group consisting of a chemical bond, C1-C4 alkylene, C2-C4 alkenylene, and C2-C4 alkynylene, provided that L2 is not a chemical bond when X1 is M1—L2—M1;
• M1, at each occurrence, is independently selected from the group consisting of —O—, —N(R7)—, —S—, —S(O)—, S(O)2—, —S(O)2N(R7)—, —N(R7)—S(O)2—, —C(O)—, —C(O)—NH—, —NH—C(O)—, —NH—C(O)—O— and —O—C(O)—NH—, wherein R7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl;
• and
• M2 is selected from the group consisting of M1, heteroarylene, and heterocyclylene, either of which rings is optionally substituted;
• Ar2 is arylene or heteroarylene, each of which is optionally substituted;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl;
• q is 1 or 1;
• and
• Ay2 is a 5-6 membered cycloalkyl, heterocyclyl, or heteroaryl substituted with an amino or hydroxy moiety (preferably these groups are ortho to the amide nitrogen to which Ay2 is attached) and further optionally substituted;
• provided that when Cy2 is naphthyl, X1 is —CH2—, Ar2 is phenyl, R5 and R6 are H, and q is 0 or 1, Ay2 is not phenyl or o-hydroxyphenyl.

A histone deacetylase inhibitor of formula (3):

• 1704
• or a pharmaceutically acceptable salt thereof, wherein
• Ar3 is arylene or heteroarylene, either of which is optionally substituted;
• Cy3 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted, and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted;
• provided that when Cy3 is a cyclic moiety having —C(O)—, —C(S)—, —S(O)—, or —S(O)2— in the ring, then Cy3 is not additionally substituted with a group comprising an aryl or heteroaryl ring;
• and
• X2 is selected from the group consisting of a chemical bond, L3, W1—L3, L3—W1, W1—L3—W1, and L3—W1—L3, wherein
• W1, at each occurrence, is S, O, or N(R9), where R9 is selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl;
• and
• L3 is C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene;
• provided that X2 does not comprise a —C(O)—, —C(S)—, —S(O)—, or —S(O)2— group;
• and further provided that when Cy3 is pyridine, then X2 is L3, W1—L3, or L3—W1.