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 A2a and/or A2b receptors, and 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 F, Cl, (C 1 -C 6 )alkyl, and O(C 1 -C 6 )alkyl;
R 2 is selected from H, F, Cl, (C 1 -C 6 )alkyl, and O(C 1 -C 6 )alkyl;
ring A is a moiety selected from:
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 (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OH, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )haloalkyl, oxo, (C 1 -C 4 )alkylC(O)(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, —(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 oxygen and nitrogen, 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, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl;
n is 0, 1, or 2;
R A1 is selected from H, and (C 1 -C 4 )alkyl;
R A2 is 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
R 1 is selected from F, Cl, and OCH 3 ; and
R 2 is selected from H, F, Cl, CH 3 , and OCH 3 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is a moiety selected from:
wherein:
R 3 is selected from
wherein:
each R 3A is a moiety selected from
and
each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
ring A is the moiety:
wherein:
R 3 is selected from
wherein:
each R 3A is a moiety selected from:
and
each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R 3 is selected from
wherein:
each R 3A is a moiety selected from:
and
each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R 3 is selected from
wherein:
each R 3A is a moiety selected from:
and
each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R 3 is selected from
wherein:
each R 3A is a moiety selected from:
and
each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R 3 is selected from
wherein:
each R 3A is a moiety selected from:
and each R 3Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R 3 is selected from
wherein:
each R 3A is a moiety selected from:
each R Aa is independently selected from (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, and O(C 1 -C 4 )haloalkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:
11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. 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 selected from H, F, Cl, CH 3 , and OCH 3 ;
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 H R A1 is selected from H, and (C 1 -C 4 )alkyl;
R A2 is H;
R A3 is H; and
R A5 is H.
13. The compound of claim 12 , wherein R 1 is F and R 2 is OCH 3 .
14. The compound of claim 12 , wherein R 3 is pyrazolyl, wherein said pyrazolyl is substituted with
15. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
16. A compound, wherein the compound is:
17. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
18. A compound, wherein the compound is:
19. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
20. A compound, wherein the compound is:
21. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
22. A compound, wherein the compound is:
23. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
24. A compound, wherein the compound is:
25. A pharmaceutical composition comprising a compound of claim 16 and a pharmaceutically acceptable carrier.