Cyclic Dinucleotides As Sting Agonists

Abstract

Disclosed are compounds, compositions and methods for treating viral infections, diseases, syndromes, or disorders that are affected by the modulation of STING. Such compounds are represented by Formula (I) as follows: wherein R 1A , R 1B , R 1C , B 1 , R 2A , and R 2B are defined herein.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1A  is hydroxy or fluoro and R 1C  is hydrogen; or, R 1A  is —O— and R 1C  is CH 2  such that R 1A  and R 1C  are taken together with the atoms to which they are attached to form a 5-membered ring; 
 R 1B  is hydroxy or thiol; 
 B 1  is b1 or b2: 
 
       
         
           
           
               
               
           
         
         R 2A  is hydroxy or methoxy; 
         R 2B  is hydroxy or thiol; 
         provided that the compound of Formula (I) is other than (1R,6R,8R,9R,10R,15R,17R,18R)-17-(2-Amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-8-(6-amino-9H-purin-9-yl)-9-fluoro-3,12,18-trihydroxy-2,4,7,11,13,16-hexaoxa-3λ 5 , 12λ 5 -diphosphatricyclo[13.2.1.0 6,10 ]octadecane-3,12-dione, bis-ammonium salt; 
         or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein B 1  is b2 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound that is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt form thereof. 
       
     
     
         4 . A pharmaceutical composition comprising a compound of  claim 1  and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a pharmaceutically acceptable diluent. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the composition is a solid oral dosage form. 
     
     
         6 . The pharmaceutical composition of  claim 4 , wherein the composition is a syrup, an elixir or a suspension. 
     
     
         7 . A pharmaceutical composition comprising a compound of  claim 3  and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a pharmaceutically acceptable diluent. 
     
     
         8 . A method of treating a disease, syndrome, or condition modulated by STING, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
         9 . A method of treating a disease, syndrome, or condition, wherein said disease, syndrome, or condition is affected by the agonism of STING, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
         10 . The method of  claim 9 , wherein said disease, syndrome, or condition is cancer. 
     
     
         11 . The method of  claim 10 , wherein said cancer is melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, or fibrosarcoma. 
     
     
         12 . The method of  claim 9 , wherein said disease, syndrome, or condition is a viral infection. 
     
     
         13 . The method of  claim 12 , wherein the viral infection is hepatitis B.