Cyclic nucleotide analogs

Abstract

Disclosed herein are cyclic nucleotide analogs, methods of synthesizing cyclic nucleotide analogs and methods of treating diseases and/or conditions such as viral infections, cancer, and/or parasitic diseases with cyclic nucleotide analogs.

What is claimed is: 
     
         1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         B 1  is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; 
         X 1  is O (oxygen) or S (sulfur); 
         R 1  is selected from the group consisting of —Z 1 —R 9 , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; 
         Z 1  is selected from the group consisting of O (oxygen), S (sulfur) and N(R 10 ); 
         R 2  and R 3  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 2-6  alkynyl, an optionally substituted C 1-6  haloalkyl and an optionally substituted aryl(C 1-6  alkyl); or R 2  and R 3  are taken together to form a group selected from the group consisting of an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 3-6  cycloalkenyl, an optionally substituted C 3-6  aryl and an optionally substituted C 3-6  heteroaryl; 
         R 4  is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 2-6  alkynyl and an optionally substituted allenyl; 
         R 5  is hydrogen or an optionally substituted C 1-6  alkyl; 
         R 6  is selected from the group consisting of hydrogen, halogen, azido, amino, cyano, an optionally substituted C 1-6  alkyl, —OR 11  and —OC(═O)R 12 ; 
         R 7  is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted C 1-6  alkyl, —OR 13  and —OC(═O)R 14 ; 
         R 8  is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted C 1-6  alkyl, —OR 15  and —OC(═O)R 16 ; 
         R 9  is selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-6  alkyl), an optionally substituted heteroaryl(C 1-6  alkyl), an optionally substituted heterocyclyl(C 1-6  alkyl) and Formula (II); 
         R 10  is selected from the group consisting of hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-6  alkyl), an optionally substituted heteroaryl(C 1-6  alkyl) and an optionally substituted heterocyclyl(C 1-6  alkyl); 
         R 11 , R 13  and R 15  are independently hydrogen or an optionally substituted C 1-6  alkyl; 
         R 12 , R 14  and R 16  are independently an optionally substituted C 1-6  alkyl or an optionally substituted C 3-6  cycloalkyl; 
         provided that if X 1  is O (oxygen), and R 1  is —O—R 9  or —N(R 10 )—R 9 , then at least one of R 2  and R 3  is selected from the group consisting of an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 2-6  alkynyl, an optionally substituted C 1-6  haloalkyl and an optionally substituted aryl(C 1-6  alkyl), or R 2  and R 3  are taken together to form a group selected from the group consisting of an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 3-6  cycloalkenyl, an optionally substituted C 3-6  aryl and an optionally substituted C 3-6  heteroaryl; 
         wherein Formula (II) is: 
       
       
         
           
           
               
               
           
         
         R 20  and R 21  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24  alkyl and an optionally substituted aryl; 
         R 22  is selected from the group consisting of hydrogen, an optionally substituted C 1-24  alkyl, an optionally substituted aryl, an optionally substituted —O—C 1-24  alkyl and an optionally substituted —O-aryl; and 
         Y 1  is O (oxygen) or S (sulfur); and 
         provided that a compound of Formula (I) cannot be 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein X 1  is O. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is —Z 1 —R 9 . 
     
     
         4 . The compound of  claim 1 , wherein R 2  and R 3  are both hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is an optionally substituted N-linked a-amino acid or an optionally substituted N-linked α-amino acid ester derivative. 
     
     
         6 . The compound of  claim 1 , wherein R 4  is hydrogen or azido. 
     
     
         7 . The compound of  claim 1 , wherein R 5  is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein R 6  is hydrogen, halogen or an optionally substituted C 1-6  alkyl. 
     
     
         9 . The compound of  claim 1 , wherein R 6  is —OR 11  or —OC(═O)R 12 . 
     
     
         10 . The compound of  claim 1 , wherein R 7  is hydrogen, halogen or an optionally substituted C 1-6  alkyl. 
     
     
         11 . The compound of  claim 1 , wherein R 8  is hydrogen or an optionally substituted C 1-6  alkyl. 
     
     
         12 . The compound of  claim 1 , wherein R 1  is —Z 1 —R 9 , Z 1  is O, S or N(R 10 ); and R 9  is selected from the group consisting of an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C 1-6  alkyl) and Formula (II). 
     
     
         13 . The compound of  claim 12 , wherein R 9  is Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein B 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         R A2  is selected from the group consisting of hydrogen, halogen and NHR J2 , wherein R J2  is selected from the group consisting of hydrogen, —C(═O)R K2  and —C(═O)OR L2 ; 
         R B2  is halogen or NHR W2 , wherein R W2  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 3-8  cycloalkyl, —C(═O)R M2  and —C(═O)OR N2 ; 
         R C2  is hydrogen or NHR O2 , wherein R O2  is selected from the group consisting of hydrogen, —C(═O)R P2  and —C(═O)OR Q2 ; 
         R D2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         R E2  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 3-8  cycloalkyl, —C(═O)R R2  and —C(═O)OR S2 ; 
         R F2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         Y 2  is N or CR I2 , wherein R I2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 2-6 -alkenyl and an optionally substituted C 2-6 -alkynyl; 
         R G2  is an optionally substituted C 1-6  alkyl; 
         R H2  is hydrogen or NHR T2 , wherein R T2  is independently selected from the group consisting of hydrogen, —C(═O)R U2  and —C(═O)OR V2 , and 
         R K2 , R L2 , R M2 , R N2 , R P2 , R Q2 , R R2 , R S2 , R U2  and R V2  are independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 3-6  cycloalkenyl, C 3-6  cycloalkynyl, C 6-10  aryl, heteroaryl, heterocyclyl, aryl(C 1-6  alkyl), heteroaryl(C 1-6  alkyl) and heterocyclyl(C 1-6  alkyl). 
       
     
     
         15 . The compound of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutical acceptable salt of the foregoing. 
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. 
     
     
         17 . A method of ameliorating or treating a neoplastic disease comprising administering an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to a subject suffering from the neoplastic disease. 
     
     
         18 . A method of ameliorating or treating a viral infection comprising administering an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to a subject suffering from the viral infection. 
     
     
         19 . A method of ameliorating or treating a viral infection comprising contacting a cell infected with the viral infection with an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a mono-, di- or tri-phosphate thereof, a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt any of the aforementioned compounds.