Inhibitors of ubiquitin E1

Abstract

The present invention features pyrazolidinyl compounds, pharmaceutical compositions of substituted pyrazolidinyl compounds and methods of treating a patient suffering from cancer or viral infection, the method comprising administering to a patient one or more pyrazolidinyl compounds of the invention.

1 . A compound of Formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof: 
     
       
         
         
             
             
         
       
     
     wherein,
 each X is independently O, S or NR 1 ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, is C(O)R, C(O)OR, or C(O)NRR 2 , each optionally substituted with a substituent; 
 each R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, each optionally substituted with a substituent; 
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, each optionally substituted with a substituent; 
 Y is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, nitro, or halogen; 
 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, or heteroaryl groups may be substituted with H, halogen, nitro, cyano, alkoxy, thioalkoxy, NR 3 R 4 , S(O)R 5 , S(O) 2 R 5 ; 
 wherein each of R 3  and R 4  are independently selected from H, alkyl, aralkyl, or aryl; 
 wherein R 5  is OH, OR 3 , NH 2 , or NHR 3 ; 
 Z is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, C(O)R 3 , C(O)OR 3 , C(O)SR 3 , C(O)NR 3 R 4 , C(S)OR 3 , C(NR 1 )OR 3 , C(NR 1 )NR 3 R 4 ; and 
 n is 0-5. 
 
   
   
       2 . The compound of  claim 1 , wherein Y is H, nitro or aryl. 
   
   
       3 . The compound of  claim 2 , wherein aryl is phenyl. 
   
   
       4 . The compound of  claim 3 , wherein the phenyl group is substituted with S(O) 2 R 5 , and R 5  is NH 2 . 
   
   
       5 . The compound of  claim 1 , wherein Z is H, C(O)OR 3 , or halogen. 
   
   
       6 . The compound of  claim 5 , wherein R 3  is alkyl. 
   
   
       7 - 9 . (canceled) 
   
   
       10 . A compound of Formula (II), or pharmaceutically acceptable salt, solvate or hydrate thereof: 
     
       
         
         
             
             
         
       
     
     wherein,
 each X is independently O, S or NR 1 ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, is C(O)R, C(O)OR, or C(O)NRR 2 ; 
 each R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl; 
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl. 
 
   
   
       11 . The compound of  claim 1  or  10  wherein each X is O. 
   
   
       12 - 14 . (canceled) 
   
   
       15 . A pharmaceutical composition comprising (i) one or more compounds of Formula (I) of  claim 1  and (ii) a pharmaceutically acceptable carrier. 
   
   
       16 - 17 . (canceled) 
   
   
       18 . A kit comprising an effective amount of one or more compounds of Formula (I) of  claim 1  in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to a cell proliferative disorder or a retroviral infection. 
   
   
       19 . A method of treating a subject suffering from or susceptible to a cell proliferative disorder or disease comprising:
 administering to the subject an effective amount of one or more pyrazolidinyl compounds.   
   
   
       20 . (canceled) 
   
   
       21 . The method of  claim 19  further comprising identifying a subject in need of such treatment for a cell proliferative disorder or disease and administering the one or more compounds to the identified subject. 
   
   
       22 . The method of  claim 19  wherein the one or more compounds of the following Formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject: 
     
       
         
         
             
             
         
       
     
     wherein,
 each X is independently O, S or NR 1 ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, is C(O)R, C(O)OR, or C(O)NRR 2 , each optionally substituted with a substituent; 
 each R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, each optionally substituted with a substituent; 
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, each optionally substituted with a substituent; 
 Y is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, nitro, or halogen; 
 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, or heteroaryl groups may be substituted with H, halogen, nitro, cyano, alkoxy, thioalkoxy, NR 3 R 4 , S(O)R 5 , S(O) 2 R 5 ; 
 wherein each of R 3  and R 4  are independently selected from H, alkyl, aralkyl, or aryl; 
 wherein R 5  is OH, OR 3 , NH 2 , or NHR 3 ; 
 Z is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, C(O)R 3 , C(O)OR 3 , C(O)SR 3 , C(O)NR 3 R 4 , C(S)OR 3 , C(NR 1 )OR 3 , C(NR 1 )NR 3 R 4 ; and 
 n is an integer of from 0 to 5. 
 
   
   
       23 . The method of  claim 19  wherein the one or more compounds of the following Formula (II), or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject: 
     
       
         
         
             
             
         
       
     
     wherein,
 each X is independently O, S or NR 1 ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, is C(O)R, C(O)OR, or C(O)NRR 2 ; 
 each R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl; 
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl. 
 
   
   
       24 - 25 . (canceled) 
   
   
       26 . A method of treating a virally infected mammalian cells comprising:
 administering to the cells an effective amount of one or more pyrazolidinyl compounds.   
   
   
       27 - 29 . (canceled) 
   
   
       30 . The method of  claim 26  wherein one or more compounds of the following Formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject: 
     
       
         
         
             
             
         
       
     
     wherein,
 each X is independently O, S or NR 1 ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, is C(O)R, C(O)OR, or C(O)NRR 2 , each optionally substituted with a substituent; 
 each R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, each optionally substituted with a substituent; 
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, each optionally substituted with a substituent; 
 Y is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, nitro, or halogen; 
 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, or heteroaryl groups may be substituted with H, halogen, nitro, cyano, alkoxy, thioalkoxy, NR 3 R 4 , S(O)R 5 , S(O) 2 R 5 ; 
 wherein each of R 3  and R 4  are independently selected from H, alkyl, aralkyl, or aryl; 
 wherein R 5  is OH, OR 3 , NH 2 , or NHR 3 ; 
 Z is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, C(O)R 3 , C(O)OR 3 , C(O)SR 3 , C(O)NR 3 R 4 , C(S)OR 3 , C(NR 1 )OR 3 , C(NR 1 )NR 3 R 4 ; and 
 n is n is an integer of from 0 to 5. 
 
   
   
       31 . The method of claim  36  wherein the one or more compounds of the following Formula (II), or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject: 
     
       
         
         
             
             
         
       
     
     wherein,
 each X is independently O, S or NR 1 ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, is C(O)R, C(O)OR, or C(O)NRR 2 ; 
 each R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl; 
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl. 
 
   
   
       32 - 33 . (canceled) 
   
   
       34 . A method of treating a subject suffering from or susceptible to a viral infection comprising:
 administering to the subject an effective amount of one or more pyrazolidinyl compounds.   
   
   
       35 - 37 . (canceled) 
   
   
       38 . The method of  claim 34  wherein one or more compounds of the following Formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject: 
     
       
         
         
             
             
         
       
     
     wherein,
 each X is independently O, S or NR 1 ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, is C(O)R, C(O)OR, or C(O)NRR 2 , each optionally substituted with a substituent; 
 each R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, each optionally substituted with a substituent; 
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, each optionally substituted with a substituent; 
 Y is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, nitro, or halogen; 
 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, or heteroaryl groups may be substituted with H, halogen, nitro, cyano, alkoxy, thioalkoxy, NR 3 R 4 , S(O)R 5 , S(O) 2 R 5 ; 
 wherein each of R 3  and R 4  are independently selected from H, alkyl, aralkyl, or aryl; 
 wherein R 5  is OH, OR 3 , NH 2 , or NHR 3 ; 
 Z is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, C(O)R 3 , C(O)OR 3 , C(O)SR 3 , C(O)NR 3 R 4 , C(S)OR 3 , C(NR 1 )OR 3 , C(NR 1 )NR 3 R 4 ; and 
 n is 0-5. 
 
   
   
       39 . The method of  claim 34  wherein the one or more compounds of the following Formula (II), or pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject: 
     
       
         
         
             
             
         
       
     
     wherein,
 each X is independently O, S or NR 1 ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl, is C(O)R, C(O)OR, or C(O)NRR 2 ; 
 each R 2  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl; 
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteroaralkyl. 
 
   
   
       40 - 41 . (canceled) 
   
   
       42 . A method of treating a subject suffering from or susceptible to a disease or disorder where of where inflammation or an immune response is exhibited, comprising:
 administering to the subject an effective amount of one or more pyrazolidinyl compounds.   
   
   
       43 - 49 . (canceled) 
   
   
       50 . A method of modulating Mdm2 autoubiquitination in a subject, the method comprising the step of administering to the subject one or more compounds of Formula I of  claim 1  in an amount and under conditions sufficient to modulate Mdm2 autoubiquitination. 
   
   
       51 - 63 . (canceled) 
   
   
       54 . A pharmaceutical composition comprising (i) one or more compounds of Formula (II) of  claim 10  and (ii) a pharmaceutically acceptable carrier. 
   
   
       55 . A kit comprising an effective amount of one or more compounds of Formula (II) of  claim 10  in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to a cell proliferative disorder or a retroviral infection.