Substituted quinolizine derivatives useful as HIV integrase inhibitors
View Patent ↗The present invention relates to Substituted Quinolizine Derivatives of Formula (I): and pharmaceutically acceptable salts or prodrug thereof, wherein X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 and R 10 are as defined herein. The present invention also relates to compositions comprising at least one Substituted Quinolizine Derivative, and methods of using the Substituted Quinolizine Derivatives for treating or preventing HIV infection in a subject.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
X is selected from a 5-membered monocyclic heteroaryl and —N(R 6 )C(O)—;
Y is C 1 -C 3 alkylene;
R 1 is selected from phenyl, 5 or 6-membered monocyclic heteroaryl and 9-membered bicyclic heteroaryl, wherein said phenyl group, said 5 or 6-membered monocyclic heteroaryl group and said 9-membered bicyclic heteroaryl group can each be optionally substituted with up to three R 8 groups;
R 2 is H, methyl, or —OR 7 or R 2 and R 4 , together with the carbon atoms to which they are attached, can join to form a 5 to 7-membered monocyclic cycloalkyl group, 5 to 7-membered monocyclic heterocycloalkyl group, or a 5 to 7-membered monocyclic heterocycloalkenyl group, wherein said 5 to 7-membered monocyclic cycloalkyl group, said 5 to 7-membered monocyclic heterocycloalkyl group, and said 5 to 7-membered monocyclic heterocycloalkenyl group can be optionally substituted with up to three R 8 groups, which can be the same or different;
R 3 is H, methyl, or —OR 7 ;
R 4 is selected from methyl, ethyl, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), and —OR 7 ;
R 5 is selected from methyl, ethyl, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), and —OR 7 ;
each occurrence of R 6 is independently H or C 1 -C 6 alkyl;
each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl) and C 3 -C 7 cycloalkyl;
each occurrence of R 8 is independently selected from C 1 -C 6 alkyl, halo and —OR 6 ;
R 9 is H; and
R 10 is H.
2. The compound of claim 1 , wherein X is —NHC(O)—, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein X is 5-membered monocyclic heteroaryl, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein Y is CH 2 , or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein R 1 is phenyl or 9-membered bicyclic heteroaryl, wherein said phenyl and said 9-membered bicyclic heteroaryl groups can each be optionally substituted with up to three R 8 groups, or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , wherein R 1 is phenyl, which is substituted by 1 to 3 halo groups, which can be the same or different, or a pharmaceutically acceptable salt thereof.
7. The compound of claim 5 , wherein R 1 is 2,4-difluorophenyl or 3-chloro-2-fluorophenyl, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein R 2 and R 3 are each independently selected from H, —OH and —O—(C 1 -C 6 alkyl), or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein one of R 2 is H and R 3 is —OH or —O—(C 1 -C 6 alkyl), or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein R 4 and R 5 are each independently selected from methyl, ethyl, and —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , wherein R 4 and R 5 are each independently selected from methyl and —CH 2 CH 2 OCH 3 , or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein R 2 and R 4 , together with the carbon atoms to which they are attached, join to form a 5 to 7-membered monocyclic heterocycloalkyl group, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , wherein R 5 is methyl, or a pharmaceutically acceptable salt thereof.
14. The compound of claim 5 wherein R 3 is H; R 5 is methyl; and R 2 and R 4 , together with the carbon atoms to which they are attached, join to form a group selected from:
pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein R 2 and R 4 , together with the carbon atoms to which they are attached, join to form:
or a pharmaceutically acceptable salt thereof.
16. A compound selected from
or a pharmaceutically acceptable salt thereof.
17. A compound of the formula
or a pharmaceutically acceptable salt thereof.
18. A compound of the formula
or a pharmaceutically acceptable salt thereof.
19. A compound of the formula
or a pharmaceutically acceptable salt thereof.
20. A compund of the formula
21. A compound of the formula
22. A compound of formula
23. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of claim 23 , further comprising one or more additional therapeutic agents selected from, lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.
25. A method for the inhibition of HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
26. A method for the treatment of infection by HIV or for the treatment of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
27. The method of claim 26 , further comprising administering to the subject one or more additional therapeutic agents selected from, abacavir, lamivudine, ritonavir and lopinavir, wherein the amounts administered of the compound of claim 1 and the one or more additional therapeutic agents, are together effective to treat infection by HIV or to treat the progression of AIDS.