Therapeutic furopyrimidines and thienopyrimidines

Abstract

The invention provides compounds of formula I, II, and III as described herein, as well as pharmaceutical compositions comprising the compounds, and synthetic methods and intermediates that are useful for preparing the compounds. The compounds of formula I, II, and III are useful as anti-viral agents and/or as anti-cancer agents.

1 . (canceled) 
     
     
         2 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is O or S; 
 R is OR 3 , SR 3 , NR 3 R 4 , NR 3 NR 4 R 5 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH 2 ) n —CH(NHR 3 )CO 2 R 4 , (CH 2 ) n —S-alkyl, (CH 2 ) n —S-aryl, Cl, F, Br, I, CN, COOR 3 , CONR 3 R 4 , NHC(═NR 3 )NHR 4 , NR 3 OR 4 , NR 3 NO, NHCONHR 3 , NR 3 N═NR 4 , NR 3 N═CHR 4 , NR 3 C(O)NR 4 R 5 , NR 3 C(S)NR 4 R 5 , NR 3 C(O)OR 4 , CH═N—OR 3 , NR 3 C(═NH)NR 4 R 5 , NR 3 C(O)NR 4 NR 5 R 6 , O—C(O)R 3 , OC(O)—OR 3 , ONH—C(O)O-alkyl, ONHC(O)O-aryl, ONR 3 R 4 , SNR 3 R 4 , S(O)NR 3 R 4 , or SO 2 NR 3 R 4 ; 
 n is 0-5; 
 R 1  is H, NR 3 R 4 , Cl, F, OR 3 , SR 3 , NHCOR 3 , NHSO 2 R 3 , NHCONHR 3 , CN, alkyl, aryl, ONR 3 R 4 , or NR 3 C(O)OR 4 ; 
 R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO 2 -alkyl and NO; or R 3  and R 4  together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; or R 4  and R 5  together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; 
 
       
         
           
           
               
               
           
         
         R 7  is F; and R′ 7  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; 
         R 8  is H, OR 14 , N 3 , NH 2 , or F; and R′ 8  is H, F, OH, O alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R 8  and R′ 8  together may be ═CH 2 , or ═CHF; wherein R 8  and R′ 8  are not both OH; and when one of R 8  and R′ 8  is NH 2 , the other is not OH; and when one of R 8  and R′ 8  is N 3 , the other is not OH; 
         R 9  is H, CH 3 , C 2 H 5 , or N 3 ; 
         R′ 9  is CH 2 OR 14 , CH 2 F, CH 2 SH, CHFOH, CF 2 OH, 
       
       
         
           
           
               
               
           
         
         R 10  and R 11  are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl, or (CH 2 ) n′ —O—(CH 2 ) m CH 3 ; 
         R 12  is an N-linked amino acid residue; 
         R 14  is H, phosphate, di-phosphate, or tri-phosphate; 
         n′ is 2-5; and 
         m is 10-20; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound of  claim 2  wherein R 14  is H. 
     
     
         4 . The compound of  claim 2  wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 2  wherein Y is O. 
     
     
         6 . The compound of  claim 2  wherein R is OR 3 , Cl, SR 3 , NR 3 R 4 , or NR 3 NR 4 R 5 . 
     
     
         7 . The compound of  claim 2  wherein R is hydroxy, chloro, methoxy, mercapto, amino, methylamino, isopropylamino, propylamino, ethylamino, dimethylamino, cyclopropylamino, 2-aminoethylamino, 1-(2-hydroxyethyl)hydrazino, hydrazino, 1-methylhydrazino, azetidino, or pyrrolidino. 
     
     
         8 . The compound of  claim 2  wherein R is NR 3 R 4 . 
     
     
         9 . The compound of  claim 2  wherein R is NR 3 R 4 ; R 3  is H; and R 4  is H. 
     
     
         10 . The compound of  claim 2  wherein R 1  is H or NR 3 R 4 . 
     
     
         11 . The compound of  claim 2  wherein R 1  is H. 
     
     
         12 . The compound of  claim 2  wherein R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of H, alkyl, and substituted alkyl; or R 3  and R 4  together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; or R 4  and R 5  together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring. 
     
     
         13 . The compound of  claim 4  wherein Y is O; R is NR 3 R 4 ; and R 1  is H or NR 3 R 4 . 
     
     
         14 . The compound of  claim 2  wherein R′ 9  is CH 2 OR 14 ; and R 14  is phosphate, di-phosphate, or tri-phosphate. 
     
     
         15 . The compound of  claim 14  wherein one or more pendent hydroxyl groups from the phosphate, di-phosphate, or tri-phosphate group has been converted to an alkoxy, substituted alkoxy, aryloxy, or substituted aryloxy group. 
     
     
         16 . The compound of  claim 14  wherein one or more pendent hydroxyl groups from the phosphate, di-phosphate, or tri-phosphate group has been converted to a group R y —O—; wherein each R y  is independently a 1-20 carbon branched or unbranched, saturated or unsaturated chain, wherein one or more of the carbon atoms is optionally replaced with —O— or —S— and wherein one or more of the carbon atoms is optionally substituted with oxo (═O) or thioxo (═S). 
     
     
         17 . The compound of  claim 14  wherein one or more pendent hydroxyl groups from the phosphate, di-phosphate, or tri-phosphate group has been converted to a group R z —N—; wherein each R z  is a residue of an amino acid. 
     
     
         18 . A pharmaceutical composition comprising a compound as described in  claim 2  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         19 . The composition of  claim 18  which further comprises one or more additional anti-viral agents. 
     
     
         20 . The composition of  claim 18  which further comprises one or more additional HCV polymerase inhibitors. 
     
     
         21 . The composition of  claim 18  which further comprises one or more protease inhibitors. 
     
     
         22 . A method for treating a viral infection, comprising administering to an animal in need thereof an effective amount of a compound as described in  claim 2  or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 22  which further comprises administering to the animal an effective amount of one or more additional HCV polymerase inhibitors. 
     
     
         24 . The method of  claim 22  which further comprises administering to the animal an effective amount of one or more protease inhibitors. 
     
     
         25 . The method of  claim 22  which further comprises administering to the animal an effective amount of ribavirin. 
     
     
         26 . The method of  claim 22  which further comprises administering to the animal an effective amount of interferon-α or pegylated interferon-α (peginterferon-α). 
     
     
         27 . A method for treating cancer comprising administering to an animal in need thereof an effective amount of a compound as described in  claim 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A method for inhibiting a viral RNA or DNA polymerase comprising contacting the polymerase in vitro or in vivo with an effective inhibitory amount of a compound as described in  claim 2 , or a pharmaceutically acceptable salt thereof.