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 method of treating a mammal in need of treatment or prevention of a disorder or disease that is responsive to inhibition of ubiquitin E1 comprising:
 administering to the subject an effective amount of one or more pyrazolidinyl compounds of Formula (I), or a 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, heteroaralkyl, 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, 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 , or 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 , or C(NR 1 )NR 3 R 4 ; and 
         n is 0-5;
 wherein the disorder or disease that is responsive to inhibition of ubiquitin E1 is unwanted cell proliferation caused by loss of p53 activity or treatment of viral infections. 
 
       
     
     
         2 . The method of  claim 1 , wherein the pyrazolidinyl compound is of Formula (II), or a 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, heteroaralkyl, 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. 
       
     
     
         3 . The method of  claim 1 , wherein the pyrazolidinyl compound is of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof is 
       
         
           
           
               
               
           
         
         wherein, 
         each X is O, 
         Y is NO 2 , 
         n is 1, and 
         Z is halogen or C(O)OR 3 , wherein R 3  is a C 1 -C 12  straight or branched chain alkyl. 
       
     
     
         4 . The method of  claim 1 , wherein the pyrazolidinyl compound is 4-[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid methyl ester. 
     
     
         5 . The method of  claim 1 , wherein the disorder or disease that is responsive to inhibition of ubiquitin E1 is unwanted cell proliferation caused by loss of p53 activity. 
     
     
         6 . The method of  claim 5 , wherein the unwanted cell proliferation caused by loss of p53 activity is myeloma. 
     
     
         7 . The method of  claim 5 , wherein the loss of p53 activity is due to increased Mdm2 activity. 
     
     
         8 . The method of  claim 7 , wherein the unwanted cell proliferation caused by loss of p53 activity is a solid tumor or a disseminated cancer. 
     
     
         9 . The method of  claim 8 , wherein the tumor is a cancer of the lung, prostate, breast, liver, colon, breast, kidney, pancreas, brain, skin, testes or ovaries, leukemia or lymphoma. 
     
     
         10 . The method of  claim 5 , wherein the unwanted cell proliferation caused by loss of p53 activity is melanoma, carcinoma, leukemia, lymphoma, pediatric sarcoma, sarcoma, breast cancer, ovarian cancer, testicular cancer, prostate cancer, brain cancer, head or neck cancer, or lung cancer. 
     
     
         11 . The method of  claim 1 , wherein the disorder or disease that is responsive to inhibition of ubiquitin E1 is a viral infection. 
     
     
         12 . The method of  claim 11 , wherein the viral infection is a retroviral infection. 
     
     
         13 . The method of  claim 12 , wherein the retroviral infection is an HIV infection.