Deacetylase inhibitors

Abstract

The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.

1 . A compound of the formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is H, halo, or a straight chain C 1 -C 6  alkyl;  
 R 2  is selected from H, C 1 -C 10  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, C 4 -C 9  heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH 2 ) n C(O)R 6 , —(CH 2 ) n OC(O)R 6 , amino acyl, HON—C(O)—CH═C(R 1 )-aryl-alkyl- and —(CH 2 ) n R 7 ;  
 R 3  and R 4  are the same or different and independently H, C 1 -C 6  alkyl, acyl or acylamino, or R 3  and R 4  together with the carbon to which they are bound represent C═O, C═S, or C═NR 8 , or R 2  together with the nitrogen to which it is bound and R 3  together with the carbon to which it is bound can form a C 4 -C 9  heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;  
 R 5  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryl and non-aryl polyheterocycle;  
 n, n 1 , n 2  and n 3  are the same or different and independently selected from 0-6, when n, is 1-6, each carbon atom can be optionally and independently substituted with R 3  and/or R 4 ;  
 X and Y are the same or different and independently selected from H, halo, C 1 -C 4  alkyl, NO 2 , C(O)R 1 , OR 9 , SR 9 , CN, and NR 10 R 11 ;  
 R 6  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR 12 , and NR 13 R 14 ;  
 R 7  is selected from OR 15 , SR 15 , S(O)R 16 , SO 2 R 17 , NR 13 R 14 , and NR 12 SO 2 R 6 ;  
 R 8  is selected from H, OR 15 , NR 13 R 14 , C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;  
 R 9  is selected from C 1 -C 4  alkyl and C(O)-alkyl;  
 R 10  and R 11  are the same or different and independently selected from H, C 1 -C 4  alkyl, and —C(O)-alkyl;  
 R 12  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, C 4 -C 6  heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl;  
 R 13  and R 14  are the same or different and independently selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-acyl, or R 13  and R 14  together with the nitrogen to which they are bound are C 4 -C 9  heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle;  
 R 15  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;  
 R 16  is selected from C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;  
 R 17  is selected from C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR 13 R 14 ;  
 m is an integer selected from 0 to 6; and  
 Z is selected from O, NR 13 , S and S(O);  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . A compound of  claim 1  wherein each of R 1 , X, Y, R 3 , and R 4  is H.  
   
   
       3 . A compound of  claim 2  one of n 2  and n 3  is zero and the other is 1.  
   
   
       4 . A compound of  claim 3  wherein R 2  is H or —CH 2 —CH 2 —OH.  
   
   
       5 . A compound of  claim 1  of the formula (Ia)  
     
       
         
         
             
             
         
       
     
     wherein 
 n 4  is 0-3,  
 R 2  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH 2 ) n C(O)R 6 , amino acyl and —(CH 2 ) n R 7 ;  
 R 5 ′ is heteroaryl, heteroarylalkyl, an aromatic polycycle, a non-aromatic polycycle, a mixed aryl and non-aryl polycycle, polyheteroaryl, or a mixed aryl and non-aryl polyheterocycle  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       6 . A compound of  claim 1  of the formula (Ia)  
     
       
         
         
             
             
         
       
     
     wherein 
 n 4  is 0-3,  
 R 2  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH 2 ) n C(O)R 6 , amino acyl and —(CH 2 ) n R 7 ;  
 R 5 ′ is aryl, arylalkyl, an aromatic polycycle, a non-aromatic polycycle or a mixed aryl and non-aryl polycycle,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       7 . A compound of  claim 6  wherein R 5 ′ is aryl or arylalkyl.  
   
   
       8 . A corm pound of  claim 7  wherein R 5 ′ is p-fluorophenyl, p-chlorophenyl, p-O—C 1 -C 4 -alkylphenyl, p-C 1 -C 4 -alkylphenyl, benzyl, ortho, meta or para-fluorobenzyl, ortho, meta or para-chlorobenzyl, or ortho, meta or para- mono, di or tri-O—C 1 -C 4 -alkylbenzyl.  
   
   
       9 . A compound of  claim 1  of formula Ib:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 2 ′ is selected from H, C 1 -C 6  alkyl, C 4 -C 6  cycloalkyl, alkylcycloalkyl, and —(CH 2 ) 2-4 OR 21  where R 21  is H, methyl, ethyl, propyl, or isopropyl, and  
 R 5 ″ is unsubstituted or substituted 1H-indol-3-yl, benzofuran-3-yl or quinolin-3-yl  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       10 . A compound of  claim 9  wherein R 5 ″ is substituted 1H-indol-3-yl or substituted benzofuran-3-yl.  
   
   
       11 . A compound of  claim 1  of formula (Ic)  
     
       
         
         
             
             
         
       
     
     wherein 
 the ring containing Z 1  is aromatic or non-aromatic which non-aromatic rings are saturated or unsaturated,  
 Z 1  is O, S or N—R 20 ;  
 R 18  is H, halo, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl; aryl, or heteroaryl;  
 R 20  is H, C 1 -C 6 alkyl, C 1 -C 6 alkyl-C 3 -C 9 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl;  
 A 1  is 1, 2 or 3 substituents which are independently H, C 1 -C- 6 alkyl, —OR 19 , halo, alkylamino, aminoalkyl, halo, or heteroarylalkyl,  
 R 2  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH 2 ) n C(O)R 6 , amino acyl and —(CH 2 ) n R 7 ;  
 R 19  is selected from H, C 1 -C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;  
 v is 0, 1 or 2,  
 p is 0-3, and  
 q is 1-5 and r is 0 or  
 q is 0 and r is 1-5  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       12 . A compound of  claim 11  wherein Z 1  is N—R 20 .  
   
   
       13 . A compound of  claim 11  wherein R 2  is H or —CH 2 —CH 2 —OH and the sum of q and r is 1.  
   
   
       14 . A compound of  claim 1  of the formula (Id)  
     
       
         
         
             
             
         
       
     
     wherein 
 Z 1  is O, S or N—R 20 ,  
 R18 is H, halo, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, unsubstituted phenyl, substituted phenyl, or heteroaryl,  
 R 20  is H, C 1 -C 6 alkyl, C 1 -C 6 alkyl-C 3 -C 9 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl;  
 A 1  is 1, 2 or 3 substituents which are independently H, C 1-C-   6 alkyl, —OR 19 , or halo,  
 R 19  is selected from H, C 1 -C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and —(CH 2 CH═CH(CH 3 )(CH 2 )) 1-3 H;  
 p is 0-3, and  
 q is 1-5 and r is 0 or  
 q is 0 and r is 1-5,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       15 . A compound of  claim 14  wherein R 2  is H or —CH 2 —CH 2 —OH and the sum of q and r is 1.  
   
   
       16 . A compound of  claim 11  of formula (Ie)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       17 . A compound of  claim 16  wherein R 18  is H, fluoro, chloro, bromo, a C 1 -C 4 alkyl group, a C 3 -C 7 cycloalkyl group, phenyl or a heteroaryl ring.  
   
   
       18 . A compound of  claim 16  wherein R 2  is H, or —(CH 2 ) s CH 2 OH and wherein s is 1-3.  
   
   
       19 . A compound of  claim 18  wherein R 1  is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3.  
   
   
       20 . A compound of  claim 16  wherein R 18  is H, methyl, ethyl, t-butyl, trifluoromethyl, cyclohexyl, phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl, 2-thiophenyl, or 2-, 3- or 4-pyridyl.  
   
   
       21 . A compound of  claim 20  wherein R 2  is H, or —(CH 2 ) s CH 2 OH and wherein s is 1-3.  
   
   
       22 . A compound of  claim 21  wherein p is 1-3  
   
   
       23 . A compound of  claim 22;  wherein R 1  is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3.  
   
   
       24 . A compound of  claim 23  wherein R 2  is H or —CH 2 —CH 2 —OH and the sum of q and r is 1.  
   
   
       25 . A compound of  claim 16  wherein R 20  is H or C 1 -C 6 alkyl.  
   
   
       26 . A compound of  claim 16  selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.  
   
   
       27 . A compound of  claim 1  of the formula (If)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       28 . A compound of  claim 27  wherein R 2  is H or —(CH 2 ) p CH 2 OH and p is 1-3.  
   
   
       29 . A compound of  claim 28  wherein R 1  is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3.  
   
   
       30 . A compound of  claim 29  wherein R 2  is H or —CH 2 —CH 2 —OH and the sum of q and r is 1.  
   
   
       31 . A compound of  claim 27  which is N-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.  
   
   
       32 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is H, halo, or a straight chain C 1 -C 6  alkyl;  
 R 2  is selected from H, C 1 -C 10  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, C 4 -C 9 -heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH 2 ) n C(O)R 6 , —(CH 2 ) n OC(O)R 6 , amino acyl, HON—C(O)—CH═C(R 1 )-aryl-alkyl- and —(CH 2 ) n R 7 ;  
 R 3  and R 4  are the same or different and independently H, C 1 -C 6  alkyl, acyl or acylamino, or R 3  and R 4  together with the carbon to which they are bound represent C═O, C═S, or C═NR 8 , or, R 2  together with the nitrogen to which it is bound and R 3  together with the carbon to which it is bound can form a C 4 -C 9  heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;  
 R 5  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryl and non-aryl polyheterocycle;  
 n, n 1 , n 2  and n 3  are the same or different and independently selected from 0-6, when n, is 1-6, each carbon atom can be optionally and independently substituted with R 3  and/or R 4 ;  
 X and Y are the same or different and independently selected from H, halo, C 1 -C 4  alkyl, NO 2 , C(O)R 1 , OR 9 , SR 9 , CN, and NR 10 R 11 ;  
 R 6  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR 12 , and NR 13 R 14 ;  
 R 7  is selected from OR 15 , SR 15 , S(O)R 16 , SO 2 R 17 , NR 13 R 14 , and NR 12 SO 2 R 6 ;  
 R 8  is selected from H, OR 15 , NR 13 R 14 , C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;  
 R 9  is selected from C 1 -C 4  alkyl and C(O)-alkyl;  
 R 10  and R 11  are the same or different and independently selected from H, C 1 -C 4  alkyl, and —C(O)alkyl;  
 R 12  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, C 4 -C 9  heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl;  
 R 13  and R 14  are the same or different and independently selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R 13  and R 14  together with the nitrogen to which they are bound are C 4 -C 9  heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle;  
 R 15  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;  
 R 16  is selected from C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;  
 R 17  is selected from C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR 13 R 14 ;  
 m is an integer selected from 0 to 6; and  
 Z is selected from O, NR 13 , S and S(O);  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       33 . A pharmaceutical composition of  claim 32  wherein the compound of formula (I) is selected from the group consisting of selected N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.  
   
   
       34 . A pharmaceutical composition of  claim 32  which is N-hydroxy-3-[4-[[[2-(benzofur-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.  
   
   
       35 . A method for treating a proliferative disorder in a mammal which comprises administering to said mammal a compound of the formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is H, halo, or a straight chain C 1 -C 6  alkyl;  
 R 2  is selected from H, C 1 -C 10  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, C 4 -C 9  heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH 2 ) n C(O)R 6 , —(CH 2 ) n OC(O)R 6 , amino acyl, HON—C(O)—CH═C(R 1 )-aryl-alkyl- and —(CH 2 ) n R 7 ;  
 R 3  and R 4  are the same or different and independently H, C 1 -C 6  alkyl, acyl or acylamino, or R 3  and R 4  together with the carbon to which they are bound represent C═O, C═S, or C═NR, or R 2  together with the nitrogen to which it is bound and R 3  together with the carbon to which it is bound can form a C 4 -C 9  heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;  
 R 5  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryl and non-aryl polyheterocycle;  
 n, n 1 , n 2  and n 3  are the same or different and independently selected from 0-6, when n 1  is 1-6, each carbon atom can be optionally and independently substituted with R 3  and/or R 4 ;  
 X and Y are the same or different and independently selected from H, halo, C 1 -C 4  alkyl, NO 2 , C(O)R 1 , OR 9 , SR 9 , CN, and NR 10 R 11 ;  
 R 6  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR 12 , and NR 13 R 14 ;  
 R 7  is selected from OR 15 , SR 15 , S(O)R 16 , SO 2 R 17 , NR 13 R 14 , and NR 12 SO 2 R 6 ;  
 R 8  is selected from H, OR 15 , NR 13 R 14 , C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;  
 R 9  is selected from C 1 -C 4  alkyl and C(O)-alkyl;  
 R 10  and R 11 , are the same or different and independently selected from H, C 1 -C 4  alkyl, and —C(O)-alkyl;  
 R 12  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, C 4 -C 9  heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl;  
 R 13  and R 14  are the same or different and independently selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R 13  and R 14  together with the nitrogen to which they are bound are C 4 -C 9  heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle;  
 R 15  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;  
 R 16  is selected from C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;  
 R 17  is selected from C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR 13 R 14 ;  
 m is an integer selected from 0 to 6; and  
 Z is selected from O, NR 13 , S and S(O);  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       36 . A method of  claim 35  wherein the compound of formula (I) is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.  
   
   
       37 . A method for regulating p21 promoter which comprises introducing a compound of the formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is H, halo, or a straight chain C 1 -C 6  alkyl;  
 R 2  is selected from H, C 1 -C 10  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, C 4 -C 9  heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH 2 ) n C(O)R 6 , —(CH 2 ) n OC(O)RN, amino acyl, HON—C(O)—CH═C(R 1 )-aryl-alkyl- and —(CH 2 ) n R 7 ;  
 R 3  and R 4  are the same or different and independently H, C 1 -C 6  alkyl, acyl or acylamino, or R 3  and R 4  together with the carbon to which they are bound represent C═O, C═S, or C═NR 8 , or R 2  together with the nitrogen to which it is bound and R 3  together with the carbon to which it is bound can form a C 4 -C 9  heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;  
 R 5  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryl and non-aryl polyheterocycle;  
 n, n 1 , n 2  and n 3  are the same or different and independently selected from 0-6, when n 1  is 1-6, each carbon atom can be optionally and independently substituted with R 3  and/or R 4 ;  
 X and Y are the same or different and independently selected from H, halo, C 1 -C 4  alkyl, NO 2 , C(O)R 1 , OR 9 , SR 9 , CN, and NR 10 R 11 ;  
 R 6  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR 12 , and NR 13 R 14 ;  
 R 7  is selected from OR 15 , SR 15 , S(O)R 16 , SO 2 R 17 , NR 13 R 14 , and NR 12 SO 2 R 6 ;  
 R 8  is selected from H, OR 15 , NR 13 R 14 , C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;  
 R 9  is selected from C 1 -C 4  alkyl and C(O)-alkyl;  
 R 10  and R 11  are the same or different and independently selected from H, C 1 -C 4  alkyl, and —C(O)-alkyl;  
 R 12  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, C 4 -C 9  heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl;  
 R 13  and R 14  are the same or different and independently selected from H, C 1 -C 6 , alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R 13  and R 14  together with the nitrogen to which they are bound are C 4 -C 9  heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle;  
 R 15  is selected from H, C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;  
 R 16  is selected from C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;  
 R 17  is selected from C 1 -C 6  alkyl, C 4 -C 9  cycloalkyl, C 4 -C 9  heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR 13 R 14 ;  
 m is an integer selected from 0 to 6; and  
 Z is selected from O, NR 13 , S and S(O);  
 or a pharmaceutically acceptable salt thereof,  
 into the environment of a mammalian cell.  
 
   
   
       38 . A method of  claim 37  wherein the compound of formula (I) is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-r[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.