Compounds useful for the treatment of cancer, compositions thereof and methods therewith

Abstract

The present invention generally relates to compounds and compositions useful for the modulation of ligase activity. The invention further relates to Compounds of the Invention, compositions thereof, and methods for treating or preventing cancer, a neoplastic disorder, acute or chronic renal failure, an inflammatory disorder, an immune disorder, a cardiovascular disease, an effect of aging or an infectious disease comprising administering an effective amount of a Compound of the Invention. The invention further relates to the use of a Compound of the Invention as a preservative of a cell, blood, tissue or an organ or as an agent to modulate stem cells.

1 . A method for treating or preventing acute or chronic renal failure, an inflammatory disease, an effect of aging, infectious disease an immune disorder or a cardiovascular disease comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 10  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is C or O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 m is 0-5;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5; and  
 r is 0-5;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . A method for treating or preventing a disease responsive to the modulation of ligase activity comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 10  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is C or O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 m is 0-5;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5; and  
 r is 0-5;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       3 . The method of  claim 2 , wherein the ligase activity is inhibited.  
   
   
       4 . The method of  claim 2 , wherein the ligase activity is activated.  
   
   
       5 . The method of  claim 2 , wherein the ligase is E3 ubiquitin-protein ligase.  
   
   
       6 . The method of  claim 5 , wherein the ligase activity is inhibited.  
   
   
       7 . A method for treating or preventing a disease responsive to the modulation of cellular p27/Kip1 levels comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 10  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is C or O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 m is 0-5;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5; and  
 r is 0-5;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       8 . A method for modulating cell growth comprising administering to a patient in need thereof an effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 10  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is C or O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 m is 0-5;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5; and  
 r is 0-5;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       9 . The method of  claim 8 , wherein the cell growth is inhibited.  
   
   
       10 . The method of  claim 8 , wherein the cell is a non-cancerous cell.  
   
   
       11 . A method for preserving a cell, blood, tissue, an organ or an organism comprising contacting said blood, tissue or organ with an effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 10  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is C or O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 m is 0-5;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5; and  
 r is 0-5;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       12 . The method of  claim 11 , wherein the cell, blood, tissue or organ is cryopreserved.  
   
   
       13 . A method for treating or preventing a side-effect of chemotherapy or radiation therapy comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 0  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is C or O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 m is 0-5;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5; and  
 r is 0-5;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       14 . The method of  claim 13 , wherein the side-effect is alopecia.  
   
   
       15 . The method of  claim 13 , wherein the side-effect is low blood count.  
   
   
       16 . The method of  claim 13 , wherein the side-effect is nausea.  
   
   
       17 . The method of  claim 13 , wherein the side-effect is diarrhea.  
   
   
       18 . The method of  claim 13 , wherein the side-effect is an oral lesion.  
   
   
       19 . A method for regulating or controlling the differentiation or maturation of a mammalian stem cell comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 10  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is C or O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 m is 0-5;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5; and  
 r is 0-5;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       20 . A pharmaceutical composition suitable for treating a disease associated with the modulation of a ligase comprising a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 10  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 m is 0-5;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5; and  
 r is 0-5;  
 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
 
   
   
       21 . A pharmaceutical composition suitable for treating a disease associated with the modulation of a ligase comprising a compound of formula (II):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X, W and U are at each occurrence independently H, halogen, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 X′ is H, hydroxy, carboxy, alkoxy, alkylamino, branched or unbranched C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, haloalkyl, acyloxy, thioalkyl, sulfonyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, —C(═O)OR 1 , —OC(═O)R 1 , —C(═O)NR 1 R 2 , —C(═O)NR 1 OR 2 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , —CN, —NO 2 , —NR 1 R 2 , —NR 1 C(═O)R 2 , —NR 1 C(═O)(CH 2 ) q OR 2 , —NR 1 C(═O)(CH 2 ) q R 2 , NR 1 C(═O)(CH 2 ) q NR 1 R 2 , —O(CH 2 ) q NR 1 R 2 ;  
 R 1  and R 2  are independently H or branched or unbranched C 1 -C 10  alkyl;  
 Y at each occurrence is independently H, branched or unbranched C 1 -C 10  alkyl, or  
 when  
 o is 1, Y can be (═O);  
 Z is C or O;  
 Q is H, branched or unbranched C 1 -C 10  alkyl;  
 n is 0-8;  
 o is 0-2;  
 p is 0-2;  
 q is 0-5;  
 r is 0-5; and  
 wherein one of X, X′, U or W is not H,  
 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.