Histone deacetylase inhibitors

1. A method of treating Friedreich's ataxia in a subject in need thereof, comprising administering to the subject an effective amount of a compound having a structure of formula (I):

wherein:

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 having 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 independently selected from O, N, N—H, N—R q , and S; or

(iv) heterocyclyl having 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 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 ofhalogen; C1-C6 alkyl; fluoro(C1-C6 alkyl); hydroxyl; hydroxy(C1-C4 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(C1-C6 alkyl), O, and S; formyl; formyl(C1-C4 alkyl); cyano; cyano(C1-C4 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 independently selected from NH, N(C1-C6 alkyl), O, and S; phenyl or heteroaryl having from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—R q″ , and S, wherein the phenyl or heteroaryl are each 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(C1-C4 alkyl); C1-C6 alkoxy; fluoro(C1-C6 alkoxy); (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; formyl; formyl(C1-C4 alkyl); cyano; cyano(C1-C4 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 independently selected from NH, N(C1-C6 alkyl), O, and S; phenyl or heteroaryl having from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are 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 having 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 having 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 having 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 groups independently 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; O; NR u ; or S(O) m , wherein m is 0-2; CH 2 ; or U″—CH 2 —; wherein U″ is O; NR u ; or S(O) m , wherein m is 0-2;

Cy is C4-C10 cycloalkyl or saturated heterocyclyl having 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 having 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 having 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 having 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 —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 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 having 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 method of claim 1 , wherein Ar′/Het′ is 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 results in a 1,4-relation to one another on said phenyl, pyridyl, or pyrimidinyl.

3. The method of claim 2 , wherein Ar′/Het′ is phenyl.

4. The method of claim 1 , wherein U is ═CR r , wherein R r is hydrogen and the carbon atom in ═CR r is doubly bonded to a ring atom of Cy, thereby forming an exocyclic double bond.

5. The method of claim 1 , wherein Cy is a saturated heterocyclyl having 4-10 ring atoms, wherein 1-3 heteroatoms are independently selected from O, N—H, NR x′ and S(O) m ; and Cy is optionally substituted with from 1-3 R x ; wherein 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 R x′ is defined as R q″ ; and m is 0-2; 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.

6. The method of claim 5 , wherein Cy is a saturated heterocyclyl having 4-6 ring atoms where at least one heteroatom is NH to form a secondary amine.

7. The method of claim 5 , wherein Cy is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, isoxazolidinyl, thiazolidinonyl, imidazolidinonyl, pyrrolidinonyl, azabicyclooctyl, azabicycloheptanyl, or azabicyclohexanyl.

8. The method of claim 1 , wherein R 1 is hydrogen.

9. The method of claim 1 , wherein R 1 is C6-C10 aryl, which is optionally substituted with from 1-3 R q .

10. The method of claim 1 , wherein R 1 is monocyclic or bicyclic heteroaryl having 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 independently selected from N, N—H, and N—R q .

11. The method of claim 1 , wherein V is —V′—C(R y ) 2 — or —C(R y ) 2 —V′—, and wherein each occurrence of R y is independently selected from H, F, OH, C1-C6 alkyl, and C3-C6 cycloalkyl, and V′ is a bond; S(O) m , wherein m is 0-2; —C(O)—O—(CR y 2 ) 0-2 —; —(CR y 2 ) 0-2 —O—C(O)—; C(R y ) 2 ; or C(R y ) 2 —C(R y ) 2 .

12. The method of claim 1 , wherein each of R 2 and R 3 is hydrogen.

13. The method 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 F or Cl.

14. A method of treating Friedreich's ataxia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.