Inhibitors of nucleotidyl transferases and use in herpes and hepatitis viral infections therefor

Abstract

The present disclosure relates to identification of inhibitors of hepatitis and herpesvirus replication including compounds of the formula: wherein the variables are as defined herein. Also provided are methods of treatment using agents so identified.

What is claimed: 
     
         1 . A method of inhibiting a cellular or herpesvirus nucleic acid metabolism enzyme comprising contacting said enzyme with a compound having the formula: 
       
         
           
           
               
               
           
         
         or a compound of the formula: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 4  is alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 R 5  and R 8  are each independently hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; 
 R 6  is hydrogen, hydroxy, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 7  is aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; or 
 
         a compound of the formula: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 9  is alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 R 10  is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 11  is hydrogen or Y 1 —O—X 1 —OR 12 ; wherein:
 Y 1  is alkanediyl (C≤8)  or substituted alkanediyl (C≤8) ; 
 X 1  is arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups; 
 R 12  is aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         wherein:
 R 4  is alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (c≤12) , or a substituted version of any of these groups; 
 R 5  and R 8  are each independently hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; 
 R 6  is hydrogen, hydroxy, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 7  is aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; or 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         3 . The method of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         wherein:
 R 9  is alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 R 10  is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 11  is hydrogen or Y 1 —O—X 1 —OR 12 ; wherein:
 Y 1  is alkanediyl (C≤8)  or substituted alkanediyl (C≤8) ; 
 X 1  is arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups; 
 R 12  is aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         4 . The method of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         5 . The method of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         6 . The method of  claim 4 , wherein the salt is an ethanolamine salt. 
     
     
         7 . The method of  claim 1 , further comprising contacting said enzyme with a second inhibitor of said enzyme. 
     
     
         8 . The method of  claim 7 , further comprising contacting said enzyme with said compound a second time. 
     
     
         9 . The method of  claim 7 , wherein said enzyme is located in a cell. 
     
     
         10 . The method of  claim 9 , wherein said cell is located in vitro. 
     
     
         11 . The method of  claim 9 , wherein said cell is located in a living subject. 
     
     
         12 . The method of  claim 11 , wherein said subject is a vertebrate infected with a herpesvirus. 
     
     
         13 . The method of  claim 12 , wherein said compound is administered intravenously, intraarterially, orally, buccally, nasally, ocularly, rectally, vaginally, topically, intramuscularly, intradermally, cutaneously or subcutaneously. 
     
     
         14 . The method of  claim 12 , wherein said subject is further administered a second anti-herpesvirus therapy. 
     
     
         15 . The method of  claim 14 , wherein said second anti-herpesvirus therapy is foscarnet or a nucleoside analog. 
     
     
         16 . The method of  claim 15 , wherein said nucleoside analog is acyclovir, famciclovir, valaciclovir, penciclovir, or ganciclovir. 
     
     
         17 . The method of  claim 15 , wherein said second anti-herpesvirus therapy is administered to said subject before or after said compound. 
     
     
         18 . The method of  claim 15 , wherein said second anti-herpesvirus therapy is administered to said subject at the same time as said compound. 
     
     
         19 . The method of  claim 1 , wherein said subject has previously received a first-line anti-herpesvirus therapy. 
     
     
         20 . The method of  claim 19 , wherein said herpesvirus has developed resistance to said first-line anti-herpesvirus therapy. 
     
     
         21 . The method of  claim 1 , wherein said herpevirus is selected from a human alpha herpesvirus, a human beta herpesvirus or a human gamma herpesvirus. 
     
     
         22 . The method of  claim 21 , wherein the human alpha herpesvirus is selected from herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), and Varicella-Zoster virus (VZV). 
     
     
         23 . The method of  claim 21 , wherein the human beta herpesvirus is selected from human cytomegalovirus (HCMV), human herpesvirus 6A (HHV-6A), human herpesvirus 6B (HHV-6B), and human herpesvirus 7 (HHV-7). 
     
     
         24 . The method of  claim 21 , wherein the human gamma herpesvirus is selected from Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV). 
     
     
         25 . The method of  claim 1 , wherein the herpesvirus is a non-human herpesvirus. 
     
     
         26 . The method of  claim 25 , wherein the herpesvirus is Marek's disease virus, equine herpesviruses, Bovine herpeviruses, or pseudorabies virus. 
     
     
         27 . A pharmaceutical composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or tautomer thereof, dispersed in a pharmaceutically acceptable buffer, diluent, excipient or carrier. 
       
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the pharmaceutical composition is formulated for administration: orally, nasally, buccally, corneally, rectally, vaginally, or topically. 
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein the pharmaceutical composition formulated for administration via injection. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the injection is formulated for administration: intradermally, cutaneously, ocularly, subcutaneously, intramuscularly, intraperitoneally, intraarterially, or intravenously. 
     
     
         31 . The pharmaceutical composition of  claim 27 , wherein the pharmaceutically acceptable salt is an ethanolamine salt. 
     
     
         32 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is aryl (C≤12) , aralkyl (C≤8) , heteroaryl (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) , aralkylamino (C≤18) , diaralkylamino (C≤8) , or a substituted version of any of these groups; 
 R 2  is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 3  is hydrogen, amino, carboxyl, cyano, halo, hydroxy, nitro, hydroxysulfonyl, or sulfonylamine; or
 alkyl (C≤8) , aryl (C≤8) , acyl (C≤8) , alkoxy (C≤8) , acyloxy (C≤8) , amido (C≤8) , or substituted version of any of these groups; 
 
 X 2  is hydrogen or —C(O)R a , wherein: R a  is hydroxy, alkoxy (C≤8) , or substituted alkoxy (C≤8) ; or 
 
         a compound of the formula: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 4  is alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 R 5  and R 8  are each independently hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; 
 R 6  is hydrogen, hydroxy, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 7  is aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; or 
 
         a compound of the formula: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 9  is alkyl (C≤12) , aryl(C 12 ), aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 R 10  is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 11  is hydrogen or Y 1 —O—X 1 —OR 12 ; wherein:
 Y 1  is alkanediyl (C≤8)  or substituted alkanediyl (C≤8) ; 
 X 1  is arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups; 
 R 12  is aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . The compound of  claim 32  further defined as: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is aryl (C≤12) , aralkyl (C≤18) , heteroaryl (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) , aralkylamino (C≤18) , diaralkylamino (C≤18) , or a substituted version of any of these groups; 
 R 2  is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 X 2  is hydrogen or —C(O)R a , wherein: R a  is hydroxy, alkoxy (C≤8) , or substituted alkoxy (C≤8) ; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The compound of  claim 32  further defined as: 
       
         
           
           
               
               
           
         
         wherein:
 R 5  is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; 
 R 6  is hydrogen, hydroxy, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 7  is aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 . The compound of  claim 32  further defined as: 
       
         
           
           
               
               
           
         
         wherein:
 R 10  is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and 
 R 11  is hydrogen or Y 1 —O—X 1 —OR 12 ; wherein:
 Y 1  is alkanediyl (C≤8)  or substituted alkanediyl (C≤8) ; 
 X 1  is arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups; 
 R 12  is aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         36 . The compound of  claim 32 , wherein R 2 , R 5 , or R 10  is hydrogen. 
     
     
         37 . The compound of  claim 36 , wherein R 2 , R 5 , and R 10  are hydrogen. 
     
     
         38 . The compound of  claim 33 , wherein R 1  is aralky (C≤18) , aralkylamino (C≤18) , or a substituted version of either group. 
     
     
         39 . The compound of  claim 34 , wherein R 6  is hydroxy. 
     
     
         40 . The compound of  claim 34 , wherein R 7  is aryl (C≤12) . 
     
     
         41 . The compound of  claim 35 , wherein R 11  is Y 1 —O—X 1 —OR 12 ; wherein:
 Y 1  is alkanediyl (C≤8) ; 
 X 1  is arenediyl (C≤12) , or a substituted version of either of these groups; 
 R 12  is aryl (C≤12)  or substituted aryl (C≤12) . 
 
     
     
         42 . The compound according to any one of  claims 32 - 35 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         44 . A pharmaceutical composition comprising:
 (A) a compound according to any one of  claims 32 - 43 ; and   (B) an excipient.   
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein the pharmaceutical composition is formulated for administration: orally, nasally, buccally, corneally, rectally, vaginally, topically, intradermally, cutaneously, ocularly, subcutaneously, intramuscularly, intraperitoneally, intraarterially, or intravenously. 
     
     
         46 . The pharmaceutical composition of  claim 44 , wherein the pharmaceutical composition is formulated as a unit dose. 
     
     
         47 . A method of inhibiting a hepatitis B virus RNaseH comprising administering an effective amount of a compound or composition according to any one of  claims 32 - 46 . 
     
     
         48 . The method of  claim 47 , wherein the method is performed in vitro. 
     
     
         49 . The method of  claim 47 , wherein the method is performed in vivo. 
     
     
         50 . The method of  claim 47 , wherein the method is performed ex vivo. 
     
     
         51 . The method of  claim 47 , wherein the method is sufficient to inhibit viral replication. 
     
     
         52 . A method of inhibiting replication of a hepatitis B virus comprising contacting the virus with an effective amount of a compound or composition according to any one of  claims 32 - 46 . 
     
     
         53 . The method of  claim 52 , wherein the method is performed in vitro. 
     
     
         54 . The method of  claim 52 , wherein the method is performed in vivo. 
     
     
         55 . The method of  claim 52 , wherein the method is performed ex vivo. 
     
     
         56 . The method of  claim 52 , wherein the method is sufficient to treat an infection of a hepatitis B virus. 
     
     
         57 . A method of treating an infection of a hepatitis B virus in a patient comprising administering a therapeutically effective amount of a compound or composition according to any one of  claims 32 - 46 . 
     
     
         58 . The method of  claim 57 , wherein the method further comprises a second antiviral treatment. 
     
     
         59 . The method of  claim 58 , wherein the second antiviral therapy is interferon alfa-2b, lamivudine, adefovir, telbivudine, entercavir, or tenofovir.