Inhibitors of histone deacetylase

1. A compound having structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is an optionally substituted carbocyclyl or optionally substituted aryl;

X, if present, is selected from oxazol-diyl, —C(═O)—, —CH(OH)—, and C(═NOH);

Y is selected from —O— and —S—;

Z is selected from N and C(R 7 ), wherein R 7 is selected from hydrogen, halogen, C 1 -C 4 alkyl and —O—C 1 -C 4 alkyl, wherein the alkyl portion of R 7 is optionally substituted;

each of R 1 , R 2 and R 3 is independently selected from hydrogen, halo, optionally substituted heterocyclyl, —N(R 6 ) 2 , —C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—NH 2 , —S(O) 2 —N—(C 1 -C 4 alkyl) 2 , —S(O) 2 —NH—(C 1 -C 4 alkyl), —S(O) 2 —NH 2 , —S(O) 2 —(C 1 -C 4 alkyl), —C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, and —O—C 1 -C 4 haloalkyl, wherein:

each R 6 is independently selected from hydrogen, —C 1 -C 4 alkyl, —C(O)—C 1 -C 4 alkyl, —C(O)-carbocyclyl, —C(O)-heterocyclyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)—O—C 1 -C 4 alkyl, —C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—NH 2 , and —S(O) 2 —C 1 -C 4 alkyl, or

two R 6 bound are taken together with the nitrogen atom to which they are bound to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and

any alkyl portion of R 1 , R 2 , R 3 or R 6 is optionally substituted, or

any two of R 1 , R 2 and R 3 are taken together to form an optionally substituted heterocyclyl, heteroaryl, carbocyclyl or aryl ring;

R 4 is selected from hydrogen, —CH(R′)(R″), optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted carbocyclyl, wherein:

each of R′ and R″ is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or alkynyl, —(C 0 -C 6 alkylene)-(optionally substituted carbocyclyl), —(C 0 -C 6 alkylene)-(optionally substituted aryl), —(C 0 -C 6 alkylene)-(optionally substituted heterocyclyl), and —(C 0 -C 6 alkylene)-(optionally substituted heteroaryl), —(C 2 -C 6 alkenylene or alkynylene)-(optionally substituted carbocyclyl), —(C 2 -C 6 alkenylene or alkynylene)-(optionally substituted aryl), —(C 2 -C 6 alkenylene or alkynylene)-(optionally substituted heterocyclyl), and —(C 2 -C 6 alkenylene or alkynylene)-(optionally substituted heteroaryl);

each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene portion of R′ and R″ is optionally substituted; and

one or more methylene units of each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene portion of R′ and R″ are optionally and independently replaced with —O—, —S—, —S(O)—, —S(O) 2 , or —N(R 6 )—;

R 5 is selected from —OH, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, and —O—C(O)-(optionally substituted C 1 -C 4 alkyl),

wherein:

when X is absent, Y is S; Z is N and R 2 is halo or hydrogen, ring A is other than unsubstituted phenyl unsubstituted cyclohexyl, or unsubstituted cyclopentyl;

when X is —C(O)—, Y is S; Z is N and R 2 is halo, methoxy, methyl or hydrogen, ring A is other than unsubstituted phenyl; and

the compound is other than

2. The compound of claim 1 , wherein:

R 1 is hydrogen;

R 2 is selected from hydrogen, fluoro, chloro, methyl, methoxy, amino, methylcarbonylamino, methylcarbonyl-N-methylamino, dimethylamino, t-butoxycarbonylamino, 2-oxopyrrolidin-1-yl, trifluoromethylcarbonylamino, isopropylcarbonylamino, and phenylcarbonylamino; and

R 3 is selected from hydrogen, fluoro, chloro and methyl, or

R 2 and R 3 are taken together to form 1H-benzo[d]imidazol-5-yl.

3. The compound of claim 1 , wherein X is C(O).

4. The compound of claim 1 , wherein Y is S.

5. The compound of claim 1 , wherein R 4 is selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, and phenyl.

6. The compound of claim 5 , wherein R 4 is selected from hydrogen, methyl, ethyl, isopropyl, 1-propenyl, cyclopropyl, cyclopentyl and phenyl.

7. The compound of claim 1 , wherein R 5 is selected from hydrogen, hydroxy, methyl and ethyl.

8. The compound of claim 1 , wherein Z is N.

9. The compound of claim 1 , wherein ring A is phenyl or cyclopentyl.

10. A pharmaceutical composition comprising:

(a) a compound having structural formula II:

or a pharmaceutically acceptable salt thereof,

wherein:

X, if present, is selected from oxazol-diyl, —C(═O)—, —CH(OH)—, and C(═NOH);

Y is selected from —O— and —S—;

Z is selected from N and C(R 7 ), wherein R 7 is selected from hydrogen, halogen, C 1 -C 4 alkyl and —O—C 1 -C 4 alkyl, wherein the alkyl portion of R 7 is optionally substituted;

each of R 1 , R 2 and R 3 is independently selected from hydrogen, halo, optionally substituted heterocyclyl, —N(R 6 ) 2 , —C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—NH 2 , —S(O) 2 —N—(C 1 -C 4 alkyl) 2 , —S(O) 2 —NH—(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 —NH 2 , —C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, and —O—C 1 -C 4 haloalkyl, wherein:

each R 6 is independently selected from hydrogen, —C 1 -C 4 alkyl, —C(O)—C 1 -C 4 alkyl, —C(O)-carbocyclyl, —C(O)-heterocyclyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)—O—C 1 -C 4 alkyl, —C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—NH 2 , and —S(O) 2 —C 1 -C 4 alkyl, or

two R 6 bound are taken together with the nitrogen atom to which they are bound to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

any alkyl portion of R 1 , R 2 , R 3 or R 6 is optionally substituted; and

at least one of R 1 , R 2 or R 3 is other than hydrogen, or

any two of R 1 , R 2 and R 3 are taken together to form an optionally substituted heterocyclyl, heteroaryl, carbocyclyl or aryl ring; and

R 4 is selected from methyl, ethyl, isopropyl and C 2 -C 3 alkenyl,

wherein the compound is other than:

and

(b) a pharmaceutically acceptable carrier.

11. A compound of structural formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

X, if present, is selected from oxazol-diyl, —C(═O)—, —CH(OH)—, and C(═NOH);

Y is selected from —O— and —S—;

Z is selected from N and C(R 7 ), wherein R 7 is selected from hydrogen, halogen, C 1 -C 4 alkyl and —O—C 1 -C 4 alkyl, wherein the alkyl portion of R 7 is optionally substituted;

each of R 1 , R 2 and R 3 is independently selected from hydrogen, halo, optionally substituted heterocyclyl, —N(R 6 ) 2 , —C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—NH 2 , —S(O) 2 —N—(C 1 -C 4 alkyl) 2 , —S(O) 2 —NH—(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 —NH 2 , —C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, and —O—C 1 -C 4 haloalkyl, wherein:

each R 6 is independently selected from hydrogen, —C 1 -C 4 alkyl, —C(O)—C 1 -C 4 alkyl, —C(O)-carbocyclyl, —C(O)-heterocyclyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)—O—C 1 -C 4 alkyl, —C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—NH 2 , and —S(O) 2 —C 1 -C 4 alkyl, or

two R 6 bound are taken together with the nitrogen atom to which they are bound to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and

any alkyl portion of R 1 , R 2 , R 3 or R 6 is optionally substituted, or

any two of R 1 , R 2 and R 3 are taken together to form an optionally substituted heterocyclyl, heteroaryl, carbocyclyl or aryl ring;

R 4 is selected from —C 1 -C 4 alkyl and —C 2 -C 4 alkenyl;

R 8 , if present, is selected from halogen, optionally substituted —C1-C4-alkyl, optionally substituted —O—C 1 -C 4 alkyl, or any two R 8 are taken together with the atoms to which they are bound to form an optionally substituted heterocyclyl or optionally substituted heteroaryl; and

n is 0, 1, 2, 3, 4, or 5,

wherein the compound is other than: