Histone deacetylase inhibitors

Abstract

Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, such as, for example, a hydroxamic acid group or a carboxylic acid group, can inhibit histone deacetylase. Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, genetic disorders, e.g. Huntington's disease and spinal muscular atrophy and genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy.

1 . A method of treating spinal muscular atrophy in a mammal comprising administering to the mammal an effective amount of an inhibitor of histone deacetylase. 
     
     
         2 . The method of  claim 1  wherein the inhibitor is a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 A is a cyclic moiety selected from the group consisting of C 3-14  cycloalkyl, 3-14 membered heterocycloalkyl, C 4-14  cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, or heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; or A is a saturated branched C 3-12  hydrocarbon chain or an unsaturated branched C 3-12  hydrocarbon chain optionally interrupted by —O—, —S—, —N(R a )—, —C(O)—, —N(R a )—SO 2 —, —SO 2 —N(R a )—, —N(R a )—C(O)—O—, —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —O—C(O)—, —C(O)—O—, —O—SO 2 —, —SO 2 —O—, or —O—C(O)—O—, where each of R a  and R b , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; each of the saturated and the unsaturated branched hydrocarbon chain being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
 each of Y 1  and Y 2 , independently, is —CH 2 —, —O—, —S—, —N(R c )—, —N(R c )—C(O)—O—, —O—C(O)—N(R c )—, —N(R c )—C(O)—N(R d )—, —O—C(O)—O—, or a bond; each of R c  and R d , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 L is a straight C 2-12  hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; said hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, amino, nitro, cyano, C 3-5  cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R e )—, —N(R e )—C(O)—O—, —O—C(O)—N(R e )—, —N(R e )—C(O)—N(R f )—, or —O—C(O)—O—; each of R e  and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 X 1  is O or S; and 
 X 2  is —OR 1 , —SR 1 , —NR 3 —OR 1 , —NR 3 —SR 1 , —C(O)—OR 1 , —CHR 4 —OR 1 , —N═N—C(O)—N(R 3 ) 2 , or —O—CHR 4 —O—C(O)—R 5 , where each of R 1  and R 2 , independently, is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group; R 3  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; R 4  is hydrogen, alkyl, hydroxylalkyl, or haloalkyl; R 5  is alkyl, hydroxylalkyl, or haloalkyl; and provided that when L is a C 2-3  hydrocarbon containing no double bonds and X 2  is —OR 1 , Y 1  is not a bond and Y 2  is not a bond; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . The method of  claim 2 , wherein the compound is 5-phenyl-2,4-pentadienoic acid, 3-methyl-5-phenyl-2,4-pentadienoic acid, 4-methyl-5-phenyl-2,4-pentadienoic acid, 4-chloro-5-phenyl-2,4-pentadienoic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoic acid, 5-(2-furyl)-2,4-pentadienoic acid, 5-phenyl-2-en-4-yn-pentanoic acid, 6-phenyl-3,5-hexadienoic acid, 7-phenyl-2,4,6-heptatrienoic acid, 8-phenyl-3,5,7-octatrienoic acid, potassium 2-oxo-6-phenyl-3,5-hexadienoate, potassium 2-oxo-8-phenyl-3,5,7-octatrienoate, cinnamoylhydroxamic acid, methyl-cinnamoylhydroxamic acid, 4-cyclohexanebutyroylhydroxamic acid, benzylthioglycoloylhydroxamic acid, 5-phenylpentanoylhydroxamic acid, 5-phenyl-2,4-pentadienoylhydroxamic acid, N-methyl-5-phenyl-2,4-pentadienoylhydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoylhydroxamic acid, 4-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-chloro-5-phenyl-2,4-pentadienoylhydroxamic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoylhydroxamic acid, 5-phenyl-2-en-4-yn-pentanoylhydroxamic acid, 5-(2-furyl)-2,4-pentadienoylhydroxamic acid, 6-phenylhexanoylhydroxamic acid, 6-phenyl-3,5-hexadienoylhydroxamic acid, N-methyl-6-phenyl-3,5-hexadienoylhydroxamic acid, 7-phenylheptanoylhydroxamic acid, 7-phenyl-2,4,6-hepta-trienoylhydroxamic acid or 8-phenyloctanoylhydroxamic acid. 
     
     
         4 . The method of  claim 2 , wherein the compound is 5-phenyl-2,4-pentadienoic acid, 8-phenyl-3,5,7-octatrienoic acid, potassium 2-oxo-8-phenyl-3,5,7-octatrienoate, benzylthioglycoloylhydroxamic acid, 5-phenyl-2,4-pentadienoylhydroxamic acid, 6-phenylhexanoylhydroxamic acid, 7-phenyl-2,4,6-hepta-trienoylhydroxamic acid, or 8-phenyloctanoylhydroxamic acid. 
     
     
         5 . The method of  claim 1  wherein the inhibitor is a compound of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 A is a cyclic moiety selected from the group consisting of C 3-14  cycloalkyl, 3-14 membered heterocycloalkyl, C 4-14  cycloalkenyl, 3-14 membered heterocycloalkenyl, monocyclic aryl, or monocyclic heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
 each of X 1  and X 2 , independently, is O or S; 
 Y 1  is —CH 2 —, —O—, —S—, —N(R a )—, —N(R a )—C(O)—O—, —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —C(O)—O—, —O—C(O)—O—, or a bond; each of R a  and R b , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 Y 2  is —CH 2 , —O—, —S—, —N(R c ), —N(R c )—C(O)—O—, —O—C(O)—N(R c )—, —N(R c )—C(O)—N(R d )—, —O—C(O)—, or —O—C(O)—O; each of R c  and R d , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 L is 
 (1) a saturated straight C 1-12  hydrocarbon chain substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, halo, carboxyl, amino, nitro, cyano, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl, or at least two hydroxyl; and further optionally interrupted by —O—, —N(R e )—, —N(R e )—C(O)—O—, —O—C(O)—N(R e )—, —N(R e )—C(O)—N(R f )—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; each of R e  and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; or 
 (2) an unsaturated straight C 4-12  hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond; said unsaturated hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R g )—, —N(R g )—C(O)—O—, —O—C(O)—N(R g )—, —N(R g )—C(O)—N(R h )—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; each of R g  and R h , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and 
 R 2  is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         6 . The method of  claim 5 , wherein the compound is benzylthioglycoloylhydroxamic acid, N-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-chloro-5-phenyl-2,4-pentadienoyl hydroxamic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoyl hydroxamic acid, 5-phenyl-2-en-4-yn-pentanoyl hydroxamic acid, 5-(2-furyl)-2,4-pentadienoylhydroxamic acid, N-methyl-6-phenyl-3,5-hexadienoyl hydroxamic acid, or 7-phenyl-2,4,6-hepta-trienoylhydroxamic acid. 
     
     
         7 . The method of  claim 1  wherein the inhibitor is a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       wherein
 A is a cyclic moiety selected from the group consisting of monocyclic aryl or monocyclic heteroaryl; each of said cyclic moieties being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino; 
 each of X 1  and X 2 , independently, is O or S; 
 each of R 1  and R 2 , independently, is hydrogen, alkyl, hydroxylalkyl, or haloalkyl; 
 each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10 , independently, is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, hydroxylC 1-4  alkyl, haloC h4  alkyl, or amino; and 
 each of a, b, c, d, e, and f, independently, is 0 or 1; provided that at least one of b, c, d, and e is not zero; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . The method of  claim 1  wherein the inhibitor is a compound of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 A is a saturated branched C 3-12  hydrocarbon chain or an unsaturated branched C 3-12  hydrocarbon chain optionally interrupted by —O—, —S—, —N(R a )—, —C(O)—, —N(R a )—SO 2 —, —SO 2 —N(R a )—, —N(R a )—C(O)—O—, —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—, where each of R a  and R b , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; each of the saturated and the unsaturated branched hydrocarbon chain being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
 each of X 1  and X 2 , independently, is O or S; 
 each of Y 1  and Y 2 , independently, is —CH 2 —, —O—, —S—, —N(R c ), —N(R c )—C(O)—O—, —O—C(O)—N(R c )—, —N(R c )—C(O)—N(R d )—, —O—C(O)—O—, or a bond; each of R c  and R d , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 L is a saturated straight C 3-12  hydrocarbon or an unsaturated straight C 4-12  hydrocarbon chain, said hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further optionally interrupted by —O—, —N(R e ), —N(R e )—C(O)—O—, —O—C(O)—N(R e )—, —N(R e )—C(O)—N(R f )—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; each of R e  and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and 
 R 2  is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         9 . The method of  claim 1  wherein the inhibitor is a compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein
 A is a cyclic moiety selected from the group consisting of C 3-14  cycloalkyl, 3-14 membered heterocycloalkyl, C 4-14  cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, and heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; or A is a saturated branched C 3-12  hydrocarbon chain or an unsaturated branched C 3-12  hydrocarbon chain optionally interrupted by —O—, —S—, —N(R a )—, —C(O)—, —N(R a )—SO 2 —, —SO 2 —N(R a )—, —N(R a )—C(O)—O—, 
 
       —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —O—C(O)—, —C(O)—O—, —O—SO 2 —, —SO 2 —O—, or —O—C(O)—O—, where each of R a  and R b , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; each of the saturated and the unsaturated branched hydrocarbon chain being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl;
 each of Y 1  and Y 2 , independently, is —CH 2 —, —O—, —S—, —N(R c )—, —N(R c )—C(O)—O—, —N(R c )—C(O)—, —C(O)—N(R c )—, —O—C(O)—N(R c )—, —N(R c )—C(O)—N(R d )—, —O—C(O)—O—, or a bond; each of R c  and R d , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 L is a straight C 3-12  hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; the hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, nitro, cyano, C 3-5  cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R e )—, —N(R e )—C(O)—O—, —O—C(O)—N(R e )—, —N(R e )—C(O)—N(R f )—, or —O—C(O)—O—; each of R e  and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 X 1  is O or S; and 
 X 2  is —OR 1 , —SR 1 , or —SeR 1 , wherein R 1  is hydrogen, alkyl, acyl, aryl or aralkyl; 
 provided that when Y 1  is a bond and L is saturated, the carbon adjacent to Y 1  is not substituted with C 1-4  alkoxy or hydroxyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         10 . The method of  claim 9 , wherein the compound is S-(2-oxo-8-phenyl)-3,5,7-octatrienyl thioacetate or S-(2-oxo-8-phenoxy)-3,5,7-octatrienyl thioacetate. 
     
     
         11 . The method of  claim 1  wherein the inhibitor is a compound of formula (V): 
       
         
           
           
               
               
           
         
       
       wherein
 A is a cyclic moiety selected from the group consisting of C 3-14  cycloalkyl, 3-14 membered heterocycloalkyl, C 4-14  cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, and heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
 L is a straight C 2-12  hydrocarbon chain containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; the hydrocarbon chain being optionally interrupted by —O—, —S—, —N(R a )—, —C(O)—, —N(R a )—SO 2 —, —SO 2 —N(R a )—, —N(R a )—C(O)—O—, —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —O—C(O)—, —C(O)—O—, —O—SO 2 —, —SO 2 —O—, or —O—C(O)—O—, where each of R a  and R b , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; and being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
 X 1  is O or S; and 
 X 2  is —OR 1 , or —SR 1 , wherein R 1  is hydrogen, alkyl, acyl, aryl or aralkyl; 
 provided that when L is a C 2  hydrocarbon chain having at least one double bond, A is not C 3  cycloalkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         12 . The method of  claim 1  wherein the inhibitor is a compound of formula (VI): 
       
         
           
           
               
               
           
         
       
       wherein
 A is a cyclic moiety selected from the group consisting of C 3-14  cycloalkyl, 3-14 membered heterocycloalkyl, C 4-14  cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, and heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; or A is a saturated branched C 3-12  hydrocarbon chain or an unsaturated branched C 3-12  hydrocarbon chain optionally interrupted by —O—, —S—, —N(R a )—, —C(O)—, —N(R a )—SO 2 —, —SO 2 —N(R a )—, —N(R a )—C(O)—O—, —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —O—C(O)—, —C(O)—O—, —O—SO 2 —, —SO 2 —O—, or —O—C(O)—O—, where each of R a  and R b , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; each of the saturated and the unsaturated branched hydrocarbon chain being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
 each of Y 1  and Y 2 , independently, is —O—, —S—, —N(R c )—, —N(R c )—C(O)—O—, —N(R c )—C(O)—, —C(O)—N(R c )—, —O—C(O)—N(R c )—, —N(R c )—C(O)—N(R d )—, —O—C(O)—O—, or a bond; each of R c  and R d , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 L is a straight C 3-12  hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; the hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, nitro, cyano, C 3-5  cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R e )—, —N(R e )—C(O)—O—, —O—C(O)—N(R e )—, —N(R e )—C(O)—N(R f )—, or —O—C(O)—O—; each of R e  and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; and 
 X 1  is O or S; 
 X 2  is a halogen; 
 provided that when Y 1  and Y 2  are each a bond, L is a C 6-12  hydrocarbon chain containing at least one double bond at C1, C2, C3 or C5 of the hydrocarbon chain from C═X 1 , at least one triple bond, or at least one double bond and one triple bond, the hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C h  4 alkoxy, hydroxyl, halo, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, nitro, cyano, C 3-5  cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R e )—, —N(R e )—C(O)—O—, —O—C(O)—N(R e )—, —N(R e )—C(O)—N(R f )—, or —O—C(O)—O—; each of R e  and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         13 . A method of  claim 12 , wherein the compound is 1,1,1-trifluoro-8-phenyl-3,5,7-octatrien-2-one or 1,1,1-trifluoro-8-phenoxy-3,5,7-octatrien-2-one. 
     
     
         14 . The method of  claim 1  wherein the inhibitor is a compound of formula (VII): 
       
         
           
           
               
               
           
         
       
       wherein
 A is a cyclic moiety selected from the group consisting of C 3-14  cycloalkyl, 3-14 membered heterocycloalkyl, C 4-14  cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, and heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; or A is a saturated branched C 3-12  hydrocarbon chain or an unsaturated branched C 3-12  hydrocarbon chain optionally interrupted by —O—, —S—, —N(R a )—, —C(O)—, —N(R a )—SO 2 —, —SO 2 —N(R a )—, —N(R a )—C(O)—O—, —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —O—C(O)—, —C(O)—O—, —O—SO 2 —, —SO 2 —O—, or —O—C(O)—O—, where each of R a  and R b , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; each of the saturated and the unsaturated branched hydrocarbon chain being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
 each of Y 1  and Y 2 , independently, is —CH 2 —, —O—, —S—, —N(R c )—, —N(R c )—C(O)—O—, —N(R c )—C(O)—, —C(O)—N(R c )—, —O—C(O)—N(R c )—, —N(R c )—C(O)—N(R d )—, —C(O)—, —C(NR c )—, —O—C(O)—O—, or a bond; each of R c  and R d , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 L is a straight C 3-12  hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; the hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, nitro, cyano, C 3-5  cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R e )—, —N(R e )—C(O)—O—, —O—C(O)—N(R e )—, —N(R e )—C(O)—N(R f )—, or —O—C(O)—O—; each of R e  and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
 X 1  is O or S; and 
 each of R g , R h , and R i , independently, is hydrogen or C 1-6  alkyl; 
 provided that when each of Y 1  and Y 2 , independently, is a bond or CH 2 , A is unsubstituted phenyl or heterocyclyl, and L is C 4-6 , L has at least one double bond or at least one triple bond; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         15 . A method of  claim 14 , wherein the compound is 1-oxiranyl-8-phenyl-1-octanone, 1-oxiranyl-7-phenyl-2,4,6-heptatrien-1-one, or 1-oxiranyl-7-phenoxy-2,4,6-heptatrien-1-one. 
     
     
         16 . A method of treating spinal muscular atrophy in a mammal comprising administering to the mammal an effective amount of an inhibitor of histone deacetylase selected from the group consisting of: 5-phenyl-2,4-pentadienoic acid, 3-methyl-5-phenyl-2,4-pentadienoic acid, 4-methyl-5-phenyl-2,4-pentadienoic acid, 4-chloro-5-phenyl-2,4-pentadienoic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoic acid, 5-(2-furyl)-2,4-pentadienoic acid, 5-phenyl-2-en-4-yn-pentanoic acid, 6-phenyl-3,5-hexadienoic acid, 7-phenyl-2,4,6-heptatrienoic acid, 8-phenyl-3,5,7-octatrienoic acid, potassium 2-oxo-6-phenyl-3,5-hexadienoate, potassium 2-oxo-8-phenyl-3,5,7-octatrienoate, cinnamoylhydroxamic acid, methyl-cinnamoylhydroxamic acid, 4-cyclohexanebutyroylhydroxamic acid, benzylthioglycoloylhydroxamic acid, 5-phenylpentanoylhydroxamic acid, 5-phenyl-2,4-pentadienoylhydroxamic acid, N-methyl-5-phenyl-2,4-pentadienoylhydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoylhydroxamic acid, 4-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-chloro-5-phenyl-2,4-pentadienoylhydroxamic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoylhydroxamic acid, 5-phenyl-2-en-4-yn-pentanoylhydroxamic acid, 5-(2-furyl)-2,4-pentadienoylhydroxamic acid, 6-phenylhexanoylhydroxamic acid, 6-phenyl-3,5-hexadienoylhydroxamic acid, N-methyl-6-phenyl-3,5-hexadienoylhydroxamic acid, 7-phenylheptanoylhydroxamic acid, 7-phenyl-2,4,6-hepta-trienoylhydroxamic acid, 8-phenyloctanoylhydroxamic acid, benzylthioglycoloylhydroxamic acid, N-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-chloro-5-phenyl-2,4-pentadienoyl hydroxamic acid, S-(2-oxo-8-phenyl)-3,5,7-octatrienyl thioacetate, S-(2-oxo-8-phenoxy)-3,5,7-octatrienyl thioacetate, 1,1,1-trifluoro-8-phenyl-3,5,7-octatrien-2-one or 1,1,1-trifluoro-8-phenoxy-3,5,7-octatrien-2-one, 1-oxiranyl-8-phenyl-1-octanone, 1-oxiranyl-7-phenyl-2,4,6-heptatrien-1-one, and 1-oxiranyl-7-phenoxy-2,4,6-heptatrien-1-one. 
     
     
         17 . A method of treating spinal muscular atrophy in a mammal comprising administering to the mammal an effective amount of 7-phenyl-2,4,6-heptatrienoic acid.