N-sulfonylcarboximidamide apoptosis promoters

Abstract

Compounds having the formula are apoptosis promoters. Also disclosed are 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
 A is a five-, six-, or seven-membered aromatic or non-aromatic ring wherein from zero to three carbon atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur; 
 R 1  is selected from the group consisting of alkyl, cyano, halo, haloalkyl, nitro, and —NR 5 R 6 ; 
 R 2 , and R 3  are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkylcarbonyloxy, alkylsulfanyl, alkynyl, aryl, arylalkoxy, aryloxy, aryloxyalkoxy, arylsulfanyl, arylsulfanylalkoxy, cycloalkylalkoxy, cycloalkyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclyloxy, hydroxy, nitro, and —NR 5 R 6 ; 
 R 4  is selected from the group consisting of aryl, arylalkenyl, arylalkoxy, cycloalkenyl, cycloalkyl, heterocyclyl, and heterocyclylalkoxy; 
 R 5  and R 6  are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, arylalkyl, arylalkylsulfanylalkyl, aryloxyalkyl, arylsulfanylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, carboxyalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylsulfanylalkyl, hydroxyalkyl, and a nitrogen protecting group; or 
 R 5  and R 6 , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of imidazolyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl, thiomorpholinyl, and thiomorpholinyl dioxide; and 
 R 15  is selected from the group consisting of hydrogen, alkoxy, alkyl, and halo. 
 
   
   
       2 . The compound of  claim 1  wherein R 3  and R 15  are hydrogen. 
   
   
       3 . The compound of  claim 2  wherein R 2  is —NR 5 R 6 . 
   
   
       4 . The compound of  claim 3  wherein one of R 5  and R 6  is hydrogen and the other is arylsulfanylalkyl. 
   
   
       5 . The compound of  claim 4  wherein A is piperazinyl. 
   
   
       6 . The compound of  claim 5  selected from the group consisting of
 4-(4-benzyl-4-methoxycyclohexyl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-1-piperazinecarboximidamide;   N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-phenyl-1-piperazinecarboximidamide;   N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-methoxy-4-(2-methylbenzyl)cyclohexyl)-1-piperazinecarboximidamide;   4-(4-(2-chlorobenzyl)-4-methoxycyclohexyl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-1-piperazinecarboximidamide;   N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(2-fluorobenzyl)-4-methoxycyclohexyl)-1-piperazinecarboximidamide; and   4-(4-(2-bromobenzyl)-4-methoxycyclohexyl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-1-piperazinecarboximidamide.   
   
   
       7 . The compound of  claim 4  wherein A is phenyl. 
   
   
       8 . The compound of  claim 7  wherein R 4  is piperidinyl. 
   
   
       9 . The compound of  claim 8  selected from the group consisting of
 N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(2-fluorobenzyl)-4-methoxy-1-piperidinyl)benzenecarboximidamide;   N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4,4-dimethyl-1-piperidinyl)benzenecarboximidamide;   N-((4-(((1R)-5-(dimethylamino)-1-((phenylsulfanyl)methyl)pentyl)amino)-3-nitrophenyl)sulfonyl)-4-(4,4-dimethyl-1-piperidinyl)benzenecarboximidamide;   4-(4,4-dimethyl-1-piperidinyl)-N-((3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)phenyl) sulfonyl)benzenecarboximidamide;   4-(4-benzyl-4-methoxy-1-piperidinyl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   4-(4-(cyclohexylmethyl)-4-methoxy-1-piperidinyl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   4-(4-(2,4-difluorobenzyl)-4-methoxy-1-piperidinyl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-methoxy-4-(2-methylbenzyl)-1-piperidinyl)benzenecarboximidamide;   N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(4-fluorobenzylidene)-1-piperidinyl)benzenecarboximidamide;   N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(2-(trifluoromethyl)benzylidene)-1-piperidinyl)benzenecarboximidamide;   N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(3-thienylmethylene)-1-piperidinyl)benzenecarboximidamide;   4-(4-methoxy-4-(2-methylbenzyl)-1-piperidinyl)-N-((3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)phenyl) sulfonyl)benzenecarboximidamide;   N-((4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-methoxy-4-(2-methylbenzyl)-1-piperidinyl)benzenecarboximidamide;   4-(4-methoxy-4-(2-methylbenzyl)-1-piperidinyl)-N-((4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   4-(4-(1,1′-biphenyl-2-ylmethyl)-4-methoxy-1-piperidinyl)-N-((3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)phenyl) sulfonyl)benzenecarboximidamide;   4-(4-(1,1′-biphenyl-2-ylmethyl)-4-methoxy-1-piperidinyl)-N-((4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   4-(4-(1,1′-biphenyl-2-ylmethyl)-4-methoxy-1-piperidinyl)-N-((4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   4-(4-(1,1′-biphenyl-2-ylmethylene)-1-piperidinyl)-N′-((3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)phenyl) sulfonyl)benzenecarboximidamide;   4-(4-(1,1′-biphenyl-2-ylmethylene)-1-piperidinyl)-N′-((4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   4-(4-(1,1′-biphenyl-2-ylmethylene)-1-piperidinyl)-N′-((4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   N′-((3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)phenyl) sulfonyl)-4-(4-(2-(trifluoromethyl)benzylidene)-1-piperidinyl)benzenecarboximidamide;   N′-((4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(2-(trifluoromethyl)benzylidene)-1-piperidinyl)benzenecarboximidamide; and   N′-((4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(2-(trifluoromethyl)benzylidene)-1-piperidinyl)benzenecarboximidamide.   
   
   
       10 . The compound of  claim 7  wherein R 4  is piperazinyl. 
   
   
       11 . The compound of  claim 10  selected from the group consisting of
 N-((4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(3,3-diphenyl-2-propenyl)-1-piperazinyl)benzenecarboximidamide;   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)-1-piperazinyl)-N-((3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)phenyl) sulfonyl)benzenecarboximidamide;   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)-1-piperazinyl)-N-((4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)-1-piperazinyl)-N-((4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide;   4-(4-(3,3-diphenyl-2-propenyl)-1-piperazinyl)-N′-((3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)phenyl) sulfonyl)benzenecarboximidamide;   N′-((4-((1,1-dimethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-(3,3-diphenyl-2-propenyl)-1-piperazinyl)benzenecarboximidamide; and   4-(4-(3,3-diphenyl-2-propenyl)-1-piperazinyl)-N′-((4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzenecarboximidamide.   
   
   
       12 . A pharmaceutical composition comprising a compound of  claim 1  or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier. 
   
   
       13 . A method of promoting apoptosis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of  claim 1 , or a therapeutically acceptable salt thereof.