Isoindolinone kinase inhibitors

Abstract

Compounds having the formula are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

1 . A compound of formula (I)  
     
       
         
         
             
             
         
       
     
     or a therapeutically acceptable salt thereof, wherein 
 R 1  is selected from the group consisting of hydrogen and alkyl;  
 R 2  is selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, carboxyalkoxy, carboxyalkyl, halo, haloalkyl, heterocyclylalkoxy, hydroxy, nitro, and —NR c R d ; and  
 one of R 3  and R 4  is A—X—R 5  and the other is hydrogen; wherein A—X—R 5  is drawn with its left end attached to the parent molecular moiety;  
 R 5  is selected from the group consisting of aryl, heteroaryl, and heterocyclyl;  
 A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, haloalkoxy, and haloalkyl; and  
 X is selected from the group consisting of O, NR a , N(R a )C(S)N(R b ), (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n , CH 2 C(O)N(R a ), and N(R a )C(O), wherein R a  and R b  are independently selected from the group consisting of hydrogen and alkyl, m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to A and its right end attached to R 5 .  
 
   
   
       2 . The compound of  claim 1  wherein R 3  is A—X—R 5  and R 4  is hydrogen.  
   
   
       3 . The compound of  claim 2  wherein X is selected from the group consisting of O, NR a , N(R a )C(S)N(R b ), CH 2 C(O)N(R a ), and N(R a )C(O).  
   
   
       4 . The compound of  claim 3  selected from the group consisting of 
 4-(4-phenoxyphenyl)-1-isoindolinone;    4-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]-3-fluorophenyl}-1-isoindolinone;    4-(2-anilino-1H-benzimidazol-5-yl)-1-isoindolinone;    N-(3-methylphenyl)-2-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]acetamide;    N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-1,3-thiazole-2-carboxamide;    N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]thiourea;    4-(2,5-dimethoxyphenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-1,3-thiazole-2-carboxamide;    4-(3-bromophenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-1,3-thiazole-2-carboxamide;    4-(4-methoxyphenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-1,3-thiazole-2-carboxamide; and    4-[4-(1H-benzimidazol-2-ylamino)phenyl]-1-isoindolinone.    
   
   
       5 . The compound of  claim 2  wherein X is (CH 2 ) m N(R a )C(O)N(R b )(CH 2 ) n .  
   
   
       6 . The compound of  claim 5  wherein R 2  is other than hydrogen.  
   
   
       7 . The compound of  claim 6  selected from the group consisting of 
 N-(3-methylphenyl)-N′-[4-(7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-(7-amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}acetamide;    N 2 ,N 2 -dimethyl-N 1 -{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}glycinamide;    N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}nicotinamide;    N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-phenylacetamide;    2-(2-methoxyethoxy)-N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}acetamide;    N-{4-[6-(2-methoxyethoxy)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]phenyl}-N′-(3-methylphenyl)urea;    ({7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}oxy)acetic acid;    N-[4-(7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-[4-(7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    ({7-[4-({[(3-methylphenyl)amino]carbonyl }amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetic acid;    N-{4-[7-(2-methoxyethoxy)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]phenyl}-N′-(3-methylphenyl)urea;    benzyl 7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamate;    N-[4-(6-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-(3-methylphenyl)-N′-(4-{7-[3-(4-morpholinyl)propoxy]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}phenyl)urea;    N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}benzamide;    3-(dimethylamino)-N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}benzamide;    N-(3-methylphenyl)-N′-[4-(6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-(6-amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea; and    N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}acetamide.    
   
   
       8 . The compound of  claim 5  wherein R 2  is hydrogen.  
   
   
       9 . The compound of  claim 8  wherein R 5  is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are unsubstituted.  
   
   
       10 . The compound of  claim 9  selected from the group consisting of 
 N-2,3-dihydro-1H-inden-5-yl-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-1,3-benzodioxol-5-yl-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-phenylurea; and    N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-phenylurea.    
   
   
       11 . The compound of  claim 8  wherein R 5  is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are monosubstituted.  
   
   
       12 . The compound of  claim 11  wherein A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are unsubstituted.  
   
   
       13 . The compound of  claim 12  selected from the group consisting of 
 N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(4-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(4-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(4-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(4-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(4-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-(trifluoromethoxy)phenyl]urea;    N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-phenoxyphenyl)urea;    N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-(trifluoromethyl)phenyl]urea;    N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(4-phenoxyphenyl)urea;    N-[3-(benzyloxy)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;    N-(3-ethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-cyanophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    methyl 3-[({[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]amino}carbonyl)amino]benzoate;    N-(3-acetylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-methylphenyl)-N′-[6-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-pyridinyl]urea;    N-(5-methyl-3-pyridinyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-(3-methylphenyl)-N′-[3-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-methyl-N′-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-chlorophenyl)-N-methyl-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-methyl-N′-(3-methylphenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea; and    N-(3-methylphenyl)-N′-[5-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-thienyl]urea.    
   
   
       14 . The compound of  claim 11  wherein A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are monosubstituted.  
   
   
       15 . The compound of  claim 14  selected from the group consisting of 
 N-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-(3-chlorophenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;    N-(4-chlorophenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-bromophenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethoxy)phenyl]urea;    N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethoxy)phenyl]urea;    N-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-(3-chlorophenyl)-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-(3-chlorophenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;    N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-chlorophenyl)urea;    N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-chlorophenyl)urea;    N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;    N-(3-chlorophenyl)-N′-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;    N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea;    N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea;    N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;    N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;    N-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea; and    N-(3-chlorophenyl)-N′-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea.    
   
   
       16 . The compound of  claim 8  wherein R 3  is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are disubstituted.  
   
   
       17 . The compound of  claim 16  wherein A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are unsubstituted.  
   
   
       18 . The compound of  claim 17  selected from the group consisting of 
 N-(2,3-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2,3-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2,4-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2,5-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,4-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,5-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2,3-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(2,5-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,4-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,5-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-chloro-4-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(4-bromo-3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-chloro-4-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3-chloro-4-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[2-fluoro-5-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea; and    N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea.    
   
   
       19 . The compound of  claim 16  wherein A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are monosubstituted.  
   
   
       20 . The compound of  claim 19  selected from the group consisting of 
 N-(3,4-dimethylphenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,4-dimethylphenyl)-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,4-dimethylphenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-(3,5-dimethylphenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea;    N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;    N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea;    N-(3,5-dimethylphenyl)-N′-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;    N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;    N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea;    N-(3,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;    N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;    N-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea; and    N-(3,5-dimethylphenyl)-N′-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea.    
   
   
       21 . A pharmaceutical composition comprising a compound of  claim 1  or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.  
   
   
       22 . A method for inhibiting a protein kinase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of  claim 1 , or a therapeutically acceptable salt thereof.  
   
   
       23 . A method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of  claim 1 , or a therapeutically acceptable salt thereof.