Histone deacetylase inhibitors

1. A compound of the formula (I):

wherein n=0;

Z is R 1 —V-Cy-U—Ar′/Het′;

Ar′/Het′ is:

(i) phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with from 1-3 R p ; provided that the point of connection on said phenyl, pyridyl, or pyrimidinyl to U and the point of connection on said phenyl, pyridyl, or pyrimidinyl to the amide carbonyl do not result in 1,2-relation to one another on said phenyl, pyridyl, or pyrimidinyl; wherein R p at each occurrence is, independently, selected from H, F, chloro, CH 3 , CF 3 , OCH 3 , OCF 3 , and OCHF 2 ;

(ii) a 5-membered heteroaryl selected from pyrazolyl, pyrrolyl, thiazolyl, thienyl, furanyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, and isothiazolyl, each of which is optionally substituted with from 1-3 R p ; provided that the point of connection on said 5-membered heteroaryl to U and the point of connection on said 5-membered heteroaryl to the amide carbonyl do not result in 1,2-relation to one another on said 5-membered heteroaryl;

(iii) a 8-, 9- or 10-membered bicyclic heteroaryl selected from benzothienyl, benzofuranyl, benzothioazolyl, benzoxazolyl, indolyl, isoindolonyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, quinolinyl, and naphthyridinyl; each of which is optionally substituted with from 1-3 R p ;

R 1 is:

(i) hydrogen; or

(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R q ; or

(iii) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 R q ; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R q , and S; or

(iv) heterocyclyl including from 4-10 ring atoms, which is optionally substituted with from 1-3 R q ; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R q , and S; and

each occurrence of R q is independently selected from the group consisting of:

halogen;

C1-C6 alkyl; fluoro(C1-C6)alkyl;

hydroxyl;

hydroxy(C 1 -C 4 )alkyl;

C1-C6 alkoxy; fluoro(C1-C6)alkoxy;

(C1-C6 alkyl)C(O)—;

(C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—;

—N*(R q′ ) 2 , wherein R q ′—N*—R q ′ together form a saturated ring having 5 or 6 ring atoms, wherein 1 or 2 ring atoms in addition to the N* ring atom is/are optionally a heteroatom independently selected from NH, N(alkyl), O, or;

formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl;

benzyl; benzyloxy;

heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present, said alkyl portion serves as the point of attachment to R 1 ; otherwise in the case of C0 alkyl, a heterocyclyl carbon ring atom serves as the point of attachment of the heterocyclyl to R 1 ;

phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R q″ , and S, each of which is optionally substituted with from 1-3 R q″ ;

SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and

nitro;

each occurrence of R q″ is independently selected from the group consisting of:

halogen;

C1-C6 alkyl; fluoro(C1-C6)alkyl;

hydroxyl;

hydroxy(C 1 -C 4 )alkyl;

C1-C6 alkoxy; fluoro(C1-C6)alkoxy;

(C1-C6 alkyl)C(O)—;

(C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—;

-formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl;

benzyl; benzyloxy;

heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present, said alkyl portion serves as the point of attachment to R 1 ; otherwise in the case of C0 alkyl, a heterocyclyl carbon ring atom serves as the point of attachment of the heterocyclyl to R 1 ;

phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—(C1-C6 alkyl), and S;

SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and

nitro;

U is:

(i) ═CR r , wherein the carbon atom in ═CR r is doubly bonded to a ring atom of Cy, thereby forming an exocyclic double bond; or

(ii) —U′—C(R s ) 2 — or —C(R s ) 2 —U′—;

wherein:

R r is hydrogen, F, C1-C6 alkyl, fluoro(C1-C6)alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano;

each occurrence of R s is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano; or

R s —C—R s together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O) m , wherein m is 0-2 and NR u ;

each occurrence of R u is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R v , C(═O)O(C1-C6 alkyl), C(═O)N(R w ) 2 , and SO 2 —R v , wherein R v is selected from C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl; and each occurrence of R w is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl, wherein the aryl and heteroaryl portion in R v and R w can be optionally substituted with one or more independently selected substituents selected from F, C1-C6 alkyl, fluoro(C1-C6)alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;

U′ is a bond; P; NR u ; S(O) m ; CH 2 ; or U″—CH 2 —; wherein U″ is O; NR u ; or S(O) m and m is 0-2;

Cy is C4-C10 cycloalkyl or saturated heterocyclyl including 4-10 ring atoms, wherein from 1-3 heteroatoms are independently selected from), N—H, NR x′ , and S(O) m ; m is 0-2; R x′ is defined as R q″ ; and Cy is optionally substituted with from 1-3 R x′ ; and each occurrence of R x is independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6)alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano; and wherein when the heterocyclyl contains a secondary amine as part of its structure, then:

(i) V is linked through the nitrogen of the secondary amine portion of the heterocyclyl; and

(ii) U is linked to Cy via a Cy ring carbon atom; wherein the bond between U and the Cy ring carbon is a single or double bond; and

(iii) the Cy ring carbon atom that is attached to U is not adjacent to Cy ring nitrogen atom that is attached to V;

V is:

(i) —V′—C(R y ) 2 — or —C(R y ) 2 —V′—; or

(ii) O, NR z , or S(O) m , wherein m is 0-2; or

(iii) —CH═CH—, C═O, C(R y ) 2 —C(═O), —C(═O)—C(R y ) 2 —, —SO 2 NR z , NR z SO 2 , —C(═O)NR z , or NR z C(═O); wherein:

each occurrence of R y is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano; or

R y —C—R y together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O) m and NR aa , and m is 0-2;

each occurrence of R z and R aa is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R v , C(═O)O(C1-C6 alkyl), C(═O)N(R w ) 2 , and SO 2 —R v , wherein R v is selected from C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl; and each occurrence of R w is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl;

V′ is a bond; O; NR u ; S(O) m ; —C(O)—O—(CR y 2 ) 0-2 —, —(CR y 2 ) 0-2 —O—C(O)—, C(R y ) 2 , C(R y ) 2 —C(R y ) 2 ; —(R y ) 2 —V″; or V″—C(R y ) 2 —; wherein V″ is O; NR z ; or S(O) m , and m is 0-2; wherein each occurrence of R u is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R v , C(═O)O(C1-C6 alkyl), C(═O)N(R w ) 2 and SO 2 —R v , wherein R v is selected from C1-C6 alkyl, CH 2 -(heteroaryl including 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl, and each occurrence of R y is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano;

R 2 is selected from H, F, Cl, CF 3 , CF 2 CF 3 , CH 2 CF 3 , OCF 3 , OCHF 2 , phenyl; phenyl substituted with from 1-3 substituents independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6) alkyl C3-C6 cycloalkyl, NH 2 , C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; thienyl; thiazolyl; and pyrazol-1-yl; and

R 3 is H, F, or Cl;

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , wherein Ar′/Het′ is a 5-membered heteroaryl selected from pyrazolyl, pyrrolyl, thiazolyl, thienyl, furanyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, and isothiazolyl, each of which is optionally substituted with from 1-3 R p ; provided that the point of connection on said 5-membered heteroaryl to U and the point of connection on said 5-membered heteroaryl to the amide carbonyl do not result in 1,2-relation to one another on said 5-membered heteroaryl.

3. The compound or salt of claim 1 , wherein Ar′/Het′ is a 8-, 9- or 10-membered bicyclic heteroaryl selected from benzothienyl, benzofuranyl, benzothioazolyl, benzoxazolyl, indolyl, isoindolonyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, quinolinyl, and naphthyridinyl; each of which is optionally substituted with from 1-3 R p .

4. The compound or salt of claim 3 , wherein Ar′/Het′ is a 8-, 9- or 10-membered bicyclic heteroaryl selected from indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, and imidazooxazolyl; each of which is optionally substituted with from 1-3 R p .

5. The compound or salt of claim 1 , wherein R 1 is monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 R q ; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R q , and S.

6. The compound or salt of claim 1 , wherein R 1 is heterocyclyl including from 4-10 ring atoms, which is optionally substituted with from 1-3 R q ; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R q , and S.

7. The compound or salt of claim 1 , wherein one of the following applies: (i) R 2 is a substituent other than hydrogen, and R 3 is hydrogen; or (ii) R 2 is hydrogen, and R 3 is a substituent other than hydrogen.

8. The compound or salt of claim 1 , wherein each of R 2 and R 3 is hydrogen.

9. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, of claim 1 and a pharmaceutically acceptable carrier.

11. A method of selectively inhibiting HDAC3 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 .

12. A method of selectively inhibiting HDAC1 or HDAC2 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 .

13. A method of selectively inhibiting HDAC1, HDAC2, and HDAC3 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 .