Cyclic dinucleotides as sting agonists

Abstract

Disclosed are compounds, compositions and methods for treating of diseases, syndromes, or disorders that are affected by the modulation of STING. Such compounds are represented by Formula (I) as follows:wherein R, R1B, R1C, R2B, R2C, B1, W, X, Y, Z are defined herein.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R is CH 2 ; 
 R 1B  is hydrogen, hydroxy, or fluoro; 
 R 1C  is hydroxy, thiol, or BH 3   − ; 
 R 2B  is hydrogen, hydroxy, methoxy, or fluoro; 
 R 2C  is hydroxy, thiol, or BH 3   − ; 
 B 1  is rings b1, b2, b3, b4, b5, b6, b7 or b8 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           W is —O— or —NH—; 
           X is —O— or —NH—; 
           Y is —CH 2 —, —O— or —NH—; 
           Z is —CH 2 —, —O— or —NH—; 
           wherein:
 (a) only one of X and Y is NH, and only one of W and Z is NH, in any instance; 
 
           and 
           (b) when B 1  is b6 or b7, then R 2B  is other than fluoro or hydroxy; 
         
         or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein B 1  is b1, b2, b3, b4, b5, b6, or b8 
       
         
           
           
               
               
           
         
       
     
     
         3 - 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein W is NH; and B 1  is b1, b2, b3, b4, b6, or b8 
       
         
           
           
               
               
           
         
       
     
     
         6 - 7 . (canceled) 
     
     
         8 . The compound of claim  7 , wherein W and X are —O—; such that when B 1  is b6, then R 2B  is other than fluoro or hydroxy. 
     
     
         9 . The compound of  claim 22 , wherein B 1  is b1, b2, b3, b4, b5, b6, or b8 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound that is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt form thereof. 
       
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1  and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the composition is a solid oral dosage form. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the composition is a syrup, an elixir or a suspension. 
     
     
         14 . A method of treating a disease, syndrome, or condition modulated by STING or affected by the agonism of STING, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R is CH 2  or O; 
 R 1B  is hydrogen, hydroxy, or fluoro; 
 R 1C  is hydroxy, thiol, or BH 3   − ; 
 R 2B  is hydrogen, hydroxy, methoxy, or fluoro; 
 R 2C  is hydroxy, thiol, or BH 3   − ; 
 B 1  is b1, b2, b3, b4, b5, b6, b7 or b8 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           W is —O— or —NH—, 
           X is —O— or —NH—, 
           Y is —CH 2 —, —O— or —NH—, 
           Z is —CH 2 —, —O— or —NH—, 
         
         wherein:
 (a) wherein only one of X and Y is NH, and only one of W and Z is NH, in any instance; 
 (b) when R is CH 2  and B 1  is b6 or b7, then R 2B  is other than fluoro or hydroxy; and 
 (c) the compound of Formula (I) is other than a compound wherein R, W, X, Y, and Z, are each O; R 1B  and R 2B  are each hydroxy; B 1  is b1; and R 1B  and R 2B  are each hydroxy; 
 
       
       or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof. 
     
     
         15 . 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 . 
     
     
         16 . The method of  claim 15 , wherein said disease, syndrome, or condition is cancer. 
     
     
         17 . The method of  claim 16 , wherein said cancer is melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, or fibrosarcoma. 
     
     
         18 . The method of  claim 15 , wherein said disease, syndrome, or condition is a viral infection. 
     
     
         19 . The method of  claim 18 , wherein the viral infection is hepatitis B. 
     
     
         20 . A method of treating a disease, syndrome, or condition that is a viral infection, melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, or fibrosarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of  claim 8 . 
     
     
         21 . The method of  claim 20 , wherein the viral infection is hepatitis B. 
     
     
         22 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R is O; 
 R 1B  is hydrogen, hydroxy, or fluoro; 
 R 1C  is hydroxy, thiol, or BH 3   − ; 
 R 2B  is hydrogen, hydroxy, methoxy, or fluoro; 
 R 2C  is hydroxy, thiol, or BH 3   − ; 
 B 1  is b1, b2, b3, b4, b5, b6, b7 or b8: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           W is —O— or —NH—; 
           X is —O— or —NH—; 
           Y is —CH 2 —, —O— or —NH—; 
           Z is —CH 2 —, —O— or —NH—; 
           wherein:
 (a) only one of X and Y is NH, and only one of W and Z is NH, in any instance; 
 (b) the compound of Formula (I) is other than a compound wherein W, X, Y, and Z, are each O; R 1B  and R 2B  are each hydroxy; B 1  is b1; and R 1B  and R 2B  are each hydroxy; and 
 (c) the compound of Formula (I) is other than a compound wherein:
 R 1B  is hydrogen, hydroxy, or fluoro; 
 (i) R 1C  and R 2C  are hydroxy; (ii) R 1C  is hydroxy and R 2C  is thiol; or (iii) R 1C  is thiol and R 2C  is hydroxy; 
 R 2B  is hydrogen, hydroxy, methoxy, or fluoro; 
 B 1  is b6: 
 
 
         
       
       
         
           
           
               
               
           
         
         
           
             
               W is —O—; 
               X is —O— or —NH—; 
               Y is —CH 2 —, —O— or —NH—; 
               Z is —CH 2 —, —O— or —NH—; 
               provided that only one of X and Y is NH; 
             
           
           or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.