Compounds
A compound of Formula (I) wherein Y 1 , Y 2 , X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are as defined herein; and pharmaceutically acceptable salts and tautomers thereof, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, in the treatment of diseases in which modulation of STING (Stimulator of Interferon Genes) is beneficial, for example inflammation, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes and as vaccine adjuvants.
1. A compound of Formula (IV):
wherein:
X 31 is S;
X 32 is O;
R 31 is OH and R 32 is NH 2 or R 31 is NH 2 and R 32 is H;
R 33 is OH and R 34 is NH 2 or R 33 is NH 2 and R 34 is H;
R 35 is selected from: F, OH, and OC(O)R 37 ;
R 36 is selected from: F, OH, and OC(O)R 37 ;
provided: at least one of R 35 and R 36 is F; and
R 38 and R 39 are independently selected from: H, CH 2 OC(O)R 37 , CH 2 OCO 2 R 37 , CH 2 CH 2 SC(O)R 37 , and CH 2 CH 2 SSCH 2 R 37 ;
where R 37 is selected from: aryl, heteroaryl, heterocycloalkyl, cycloalkyl, C 1-20 alkyl and C 1-20 alkyl substituted with one to 5 substituents independently selected from: aryl, cycloalkyl, hydroxy and F;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 35 is selected from: F and OH; and
R 36 is selected from: F and OH;
provided: at least one of R 35 and R 36 is F.
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 35 is OH; and
R 36 is F.
4. A compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable salt thereof;
a pharmaceutically acceptable salt of
a pharmaceutically acceptable salt of
a pharmaceutically acceptable salt of
or a pharmaceutically acceptable salt thereof; and
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable excipients.
6. A method of treating a disease state selected from: inflammation, allergic diseases, autoimmune diseases, human immunodeficiency virus (HIV), infectious diseases, cancer, and pre-cancerous syndromes, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula IV, or a pharmaceutically acceptable salt thereof, as described in claim 1 .
7. The method of claim 6 wherein the mammal is a human.
8. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and an antigen or antigen composition.
9. A vaccine composition comprising an antigen or antigen composition and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
10. An immugenic composition comprising an antigen or antigen composition and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
11. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more immunostimulatory agents.
12. A method of treating a disease selected from: HBV, HCV, influenza, skin warts, multiple sclerosis, and allergic inflammation, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described in claim 1 .
13. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
14. A compound which is:
15. A pharmaceutically acceptable salt of a compound of claim 13 which is:
16. A compound of claim 13 which is:
or a pharmaceutically acceptable salt thereof.
17. A compound which is:
18. A pharmaceutically acceptable salt of a compound of claim 13 which is:
19. A compound of claim 13 which is:
or a pharmaceutically acceptable salt thereof.
20. A compound of which is:
21. A pharmaceutically acceptable salt of a compound of claim 13 which is:
22. A pharmaceutical composition comprising a compound of claim 13 , or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable excipients.
23. A method of treating a disease state selected from: inflammation, allergic diseases, autoimmune diseases, human immunodeficiency virus (HIV), infectious diseases, cancer, and pre-cancerous syndromes, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, as described in claim 13 .
24. The method of claim 23 wherein the mammal is a human.
25. A composition comprising a compound of claim 13 , or a pharmaceutically acceptable salt thereof, and an antigen or antigen composition.
26. A vaccine composition comprising an antigen or antigen composition and a compound of claim 13 , or a pharmaceutically acceptable salt thereof.
27. An immugenic composition comprising an antigen or antigen composition and a compound of claim 13 , or a pharmaceutically acceptable salt thereof.
28. A composition comprising a compound of claim 13 , or a pharmaceutically acceptable salt thereof, and one or more immunostimulatory agents.
29. A method of treating a disease selected from: HBV, HCV, influenza, skin warts, multiple sclerosis, and allergic inflammation, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described in claim 13 .
30. A compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable salt thereof; and
or a pharmaceutically acceptable salt thereof.
31. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 38 and R 39 are H.