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 (VI):
wherein:
X 51 is O;
X 52 is O;
R 51 is OH and R 52 is NH 2 or R 51 is NH 2 and R 52 is H;
R 53 is OH and R 54 is NH 2 or R 53 is NH 2 and R 54 is H;
R 55 is selected from: F, OH, and OC(O)R 47 ;
R 56 is F;
R 58 and R 59 are independently selected from: H, CH 2 OC(O)R 57 , CH 2 OCO 2 R 57 , CH 2 CH 2 SC(O)R 57 , and CH 2 CH 2 SSCH 2 R 57 ;
where R 57 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;
provided that at least one of R 58 and R 59 is not H,
or a pharmaceutically acceptable salts thereof.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
R 55 is selected from: F and OH.
3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof,
wherein:
R 55 is OH.
4. A compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.
5. A compound of claim 4 which is:
or a pharmaceutically acceptable salt thereof.
6. A compound of claim 4 which is:
or a pharmaceutically acceptable salt thereof.
7. A compound of claim 4 which is:
or a pharmaceutically acceptable salt thereof.
8. A compound of claim 4 which is:
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable excipients.
10. 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 1, or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 wherein the mammal is a human.
12. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and an antigen or antigen composition.
13. A vaccine composition comprising an antigen or antigen composition and compound of claim 1 , or a pharmaceutically acceptable salt thereof.
14. An immugenic composition comprising an antigen or antigen composition and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more immunostimulatory agents.
16. 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 mammal a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described in claim 1 .