9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use
In its many embodiments, the present invention provides certain 9-substituted amino triazolo quinazoline compounds of the structural Formula (I): and pharmaceutically acceptable salts thereof, wherein, ring A, R 1 and R 2 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutically active agents), and methods for their preparation and use, alone and in combination with other therapeutic agents, as antagonists of A2 a and/or A2 b receptors, and in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2 a receptor and/or the adenosine A2 b receptor.
1. A method of treating cancer comprising administering an effective amount of a compound having a structural Formula (I.1)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from F, Cl, and OCH 3 ;
R 2 is O(C 1 -C 6 )alkyl;
ring A is
R 3 is selected from pyrazolyl, triazolyl, and pyridinyl, wherein said pyrazolyl and said triazolyl, are substituted with 1 or 2 R 3A groups, and wherein said pyridinyl is substituted with 1, 2, or 3 R 3A groups, wherein:
each R 3A is independently selected from CH 3 ,
R A1 is selected from H, and (C 1 -C 4 )alkyl.
2. The method of claim 1 , wherein said cancer is selected from the group consisting of melanoma, head & neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, salivary cancer, and prostate cancer, and metastatic castration resistant prostate cancer.
3. The method of claim 2 , wherein the cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, head & neck cancer, and cervical cancer.
4. The method of claim 2 , wherein said compound, or pharmaceutically acceptable salt thereof, is administered in combination with an additional therapeutic agent.
5. The method of claim 4 , wherein said additional therapeutic agent is a PD-1 antagonist.
6. The method of claim 5 , wherein said PD-1 antagonist is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab.
7. The method of claim 6 , wherein said PD-1 antagonist is pembrolizumab.
8. A method of treating cancer comprising administering an effective amount of a compound to a person in need thereof, wherein the compound is
9. The method of claim 8 , wherein said cancer is selected from the group consisting of melanoma, head & neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, salivary cancer, and prostate cancer, and metastatic castration resistant prostate cancer.
10. The method of claim 9 , wherein the cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, head & neck cancer, and cervical cancer.
11. The method of claim 9 , wherein said compound is administered in combination with an additional therapeutic agent.
12. The method of claim 11 , wherein said additional therapeutic agent is a PD-1 antagonist.
13. The method of claim 12 , wherein said PD-1 antagonist is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab.
14. The method of claim 13 , wherein said PD-1 antagonist is pembrolizumab.
15. A method of treating cancer comprising administering an effective amount of a pharmaceutically acceptable salt of a compound to a person in need thereof, wherein the compound is
16. The method of claim 15 , wherein said cancer is selected from the group consisting of melanoma, head & neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, salivary cancer, and prostate cancer, and metastatic castration resistant prostate cancer.
17. The method of claim 16 , wherein the cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, head & neck cancer, and cervical cancer.
18. The method of claim 16 , wherein said pharmaceutically acceptable salt of said compound is administered in combination with an additional therapeutic agent.
19. The method of claim 18 , wherein said additional therapeutic agent is a PD-1 antagonist.
20. The method of claim 19 , wherein said PD-1 antagonist is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab.
21. The method of claim 20 , wherein said PD-1 antagonist is pembrolizumab.
22. A method of treating cancer comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof to a person in need thereof, wherein the compound is selected from the group consisting of:
23. The method of claim 22 , wherein said cancer is selected from the group consisting of melanoma, head & neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, salivary cancer, and prostate cancer, and metastatic castration resistant prostate cancer.
24. The method of claim 23 , wherein the cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, head & neck cancer, and cervical cancer.
25. The method of claim 23 , wherein said compound or pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.
26. The method of claim 25 , wherein said additional therapeutic agent is a PD-1 antagonist.
27. The method of claim 26 , wherein said PD-1 antagonist is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab.
28. The method of claim 27 , wherein said PD-1 antagonist is pembrolizumab.