7-, 8-, and 10-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use
In its many embodiments, the present invention provides certain 7-, 8-, and 10-substituted amino triazolo quinazoline derivatives of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A, R1, R2, and R4 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutic agents), and methods for their preparation and use, alone and in combination with other therapeutic agents, as antagonists of A2a and/or A2b receptors, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor.
1. A compound having a structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from H, F, Cl, Br, CN, OH, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, and O(C 1 -C 6 )haloalkyl;
R 2 is selected from H, F, Cl, Br, CN, OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )alkyl, O(C 1 -C 6 )haloalkyl, (C 3 -C 4 )cycloalkyl, S(O) 2 (C 1 -C 6 )alkyl, S(O) 2 (C 1 -C 6 )haloalkyl, and 4-5 membered monocyclic heterocycloalkyl comprising 1 or 2 ring nitrogen atoms;
R 4 is selected form H, F, Cl, Br, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl,
with the proviso that at least one of R 1 , R 2 , or R 4 is not H; and
ring A is a moiety selected from:
wherein:
R 3 is selected from:
each R 3A is independently selected from H, F, Cl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OH, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkylNH 2 , O(C 1 -C 6 )alkyl, O(C 1 -C 6 )haloalkyl, C(O)(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylC(O)(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylO(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylCH(OH)(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylS(O) 2 (C 1 -C 3 )alkyl, (C 1 -C 6 )alkylC(O)NH(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylC(O)OH, (C 1 -C 6 )alkylC(O)NH(C 3 -C 6 )cycloalkyl,
—(CH 2 ) n (C 3 -C 7 )cycloalkyl, and —(CH 2 ) n 4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from O, N, S, and S(O) 2 ,
wherein said (C 3 -C 7 )cycloalkyl, and said 4-7 membered monocyclic heterocycloalkyl are each unsubstituted or substituted with 1, 2, or 3 groups independently selected from F, Cl, OH, oxo, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and O(C 1 -C 6 )haloalkyl;
n is 0, 1, or 2;
each R 3Aa is independently selected from H, (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, O(C 1 -C 4 )haloalkyl, and (C 3 -C 4 )cycloalkyl;
R A1 is selected from H, and (C 1 -C 4 )alkyl;
each RA 2 is independently selected from H, F, and (C 1 -C 4 )alkyl;
R A3 is selected from H, F, and (C 1 -C 4 )alkyl;
R A4 is selected from H and OH; and
R A5 is selected from H, F, and (C 1 -C 4 )alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.1):
wherein R 1 is selected from F, Cl, Br, CN, OH, CH 3 , CH 2 CH 3 , OCH 3 OCH 2 CH 3 and O(C 1 -C 6 )haloalkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.2):
wherein R 2 is selected from F, Cl, Br, CN, OH, CH 3 , CHF 2 , CF 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OCHF, S(O) 2 CH 3
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.3):
wherein R 4 is selected from F, Cl, Br, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.4):
wherein R 1 is selected from F, Cl, Br, CN, OH, CH 3 , OCH 3 , and CF 3 ; and
R 2 is selected from F, Cl, Br, CN, OH, CH 3 , OCH 3 , and CF 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.5):
wherein R 1 is selected from F, Cl, Br, CN, OH, CH 3 , OCH 3 , and CF 3 ; and
R 4 is selected from F, Cl, Br, CN, OH, CH 3 , OCH 3 , and CF 3 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is a moiety selected from:
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:
14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A method of treating cancer wherein the cancer is mediated by the adenosine A2a receptor and/or the adenosine A2b receptor comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a person in need thereof.
16. The method of claim 15 , wherein said cancer is selected from melanoma, head and 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, prostate cancer, and metastatic castration resistant prostate cancer.
17. The method of claim 16 , wherein said compound, or a pharmaceutically acceptable salt thereof, is administered in combination with another therapeutic agent.
18. The method of claim 17 , wherein said additional therapeutic agent is a PD-1 antagonist.
19. The method of claim 18 , wherein said additional therapeutic agent is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab.
20. The method of claim 18 , wherein said additional therapeutic agent is pembrolizumab.