Cyclic dinucleotides for treating conditions associated with sting activity such as cancer
This disclosure features dinucleotide compounds that modulate Stimulator of Interferon Genes (STING) activity, for use for example in the treatment of cancer. This disclosure also features compositions as well as other methods of using and making the same (Formula (A)). A and B are each independently selected from the group consisting of Formulae (i), (ii), (iii), and (iv).
1. A compound of the formula
wherein
X 1 and X 5 are each independently halo or —OH;
Y 1 and Y 2 are each independently —OH or —SH; and
A and B are each independently
or a stereoisomer or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 which is
or a stereoisomer or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 which is
or a stereoisomer or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 2 which is
or a stereoisomer or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 2 which is
or a stereoisomer or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
7. A combination pharmaceutical product comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents.
8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.
9. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of diseases or conditions that may be alleviated by the induction of an immune response via the STING pathway.
10. A method of treating diseases and conditions in which the modulation of STING is indicated in a subject in need thereof which comprises administering a therapeutically effective amount of compound according to claim 1 or a pharmaceutically acceptable salt thereof.
11. A method of treating cancer comprising administering a therapeutically effective amount of one or more compounds according to claim 1 or a pharmaceutically acceptable salt thereof.
12. The method of claim 11 wherein the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin's lymphoma, bladder cancer, esophageal carcinoma, gastric carcinoma, ovarian carcinoma, cervical carcinoma, pancreatic carcinoma, prostate carcinoma, breast cancers, urinary carcinoma, brain tumors such as glioblastoma, non-Hodgkin's lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, multiple myeloma, gastrointestinal stromal tumors, mesothelioma, and other solid tumors or other hematological cancers.
13. The method of claim 12 wherein the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin's lymphoma or bladder cancer.
14. A method for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound, according to claim 1 , or a pharmaceutically acceptable salt thereof,
in combination with the administration of a therapeutically effective amount of one or more immuno-oncology agents.
15. The method of claim 14 , wherein the immuno-oncology agent is ipilimumab.
16. The method of claim 14 , wherein the immuno-oncology agent is a PD-L1 antagonist.
17. A method for treating a subject afflicted with cancer comprising administering to the subject a therapeutically effective amount of:
a) a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and
b) an anti-cancer agent which is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity.
18. The method of claim 17 , wherein the anti-PD-1 antibody is nivolumab or pembrolizumab.
19. The method of claim 18 , wherein the anti-PD-1 antibody is nivolumab.
20. A compound which is
21. A compound which is
22. A compound which is
or a stereoisomer or a pharmaceutically acceptable salt thereof.
23. A compound which is
24. A compound which is
or a stereoisomer or a pharmaceutically acceptable salt thereof.
25. A compound which is
26. A compound which is
27. A compound which is
28. A compound which is
29. A compound which is
30. A compound selected from
(1S,3R,6S,8R,9R,10S,12R,15S,17R,18R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-17-(6-amino-9H-purin-9-yl)-9,18-dihydroxy-3,12-disulfanyl-4,7,13,16-tetraoxa-2,11-diaza-3lambda5,12 lambda5-diphosphatricyclo[13.3.0.0 6,10 ]octadecane-3,12-dione;
(1S,3S,6S,8R,9R,10S,12R,15S,17R,18R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-17-(6-amino-9H-purin-9-yl)-9,18-dihydroxy-3,12-disulfanyl-4,7,13,16-tetraoxa-2,11-diaza-3lambda5,12 lambda5-diphosphatricyclo[13.3.0.0 6,10 ]octadecane-3,12-dione;
(1S,3S,6S,8R,9R,10S,12S,15S,17R,18R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-17-(6-amino-9H-purin-9-yl)-9,18-dihydroxy-3,12-disulfanyl-4,7,13,16-tetraoxa-2,11-diaza-3lambda5,12 lambda5-diphosphatricyclo[13.3.0.0 6,10 ]octadecane-3,12-dione;
(1S,3R,6S,8R,9R,10S,12S,15S,17R,18R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-17-(6-amino-9H-purin-9-yl)-9,18-dihydroxy-3,12-disulfanyl-4,7,13,16-tetraoxa-2,11-diaza-3lambda5,12 lambda5-diphosphatricyclo[13.3.0.0 6,10 ]octadecane-3,12-dione; or
(1S,6S,8R,9R,10S,15S,17R,18R)-8-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-17-(6-amino-9H-purin-9-yl)-3,9,12,18-tetrahydroxy-4,7,13,16-tetraoxa-2,11-diaza-3lambda5,12lambda5-diphosphatricyclo[13.3.0.0 6,10 ]octadecane-3,12-dione.