Fused tricyclic heterocyclic compounds as HIV integrase inhibitors

1. A compound having the formula:

or a pharmaceutically acceptable salts thereof,

wherein:

A is C 1 -C 4 alkylene, C 2 -C 4 alkenylene, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 7-membered heterocycloalkyl, arylene, —O—, —NH—C(O)—, —C(O)NH— or —C(O)—;

the group —X—Y— is selected from —O—C(R 2 ) 2 —, —O—C(R 2 ) 2 —C(R 2 ) 2 —, —C(R 2 ) 2 —O—, —N(R 4 )—C(R 2 ) 2 —, —N(R 4 )—C(R 2 ) 2 —C(R 2 ) 2 — and —C(R 2 ) 2 —N(R 4 )—;

m is 1 or 2;

each occurrence of n is independently 0 or 1;

R a is H or C 1 -C 6 alkyl;

R b is H or C 1 -C 6 alkyl;

R 1 is H or C 1 -C 6 alkyl, which is optionally substituted with up to three R 3 groups;

each occurrence of R 2 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, halo, C 1 -C 6 haloalkyl, —C(O)R 6 , —C(O)N(R 6 ) 2 and —NHC(O)R 6 ;

each occurrence of R 3 is independently selected from C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocycloalkyl, C 6 -C 10 aryl, halo, C 1 -C 6 haloalkyl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)N(R 6 ) 2 , —NHC(O)R 6 and —SR 6 , wherein said C 3 -C 7 cycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group, said 4 to 6-membered monocyclic heterocycloalkyl group and said C 6 -C 10 aryl group can each be optionally and independently substituted with one or more groups, each independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocycloalkyl, C 6 -C 10 aryl, halo, C 1 -C 6 haloalkyl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —NHC(O)R 6 and —SR 6 ;

R 4 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 6 -C 10 aryl, wherein said C 3 -C 7 cycloalkyl group and said C 6 -C 10 aryl group can be optionally substituted with one or more groups, each independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, halo, C 1 -C 6 haloalkyl, —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —NHC(O)R 6 and —S(O) 2 R 6 ;

R 5 is selected from C 1 -C 6 alkyl, —(C 1 -C 3 alkylene) n -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) n -(5 or 6-membered monocyclic heteroaryl), —(C 1 -C 3 alkylene) n -(4 to 6-membered monocyclic heterocycloalkyl) and —(C 1 -C 3 alkylene) n -(C 6 -C 10 aryl), wherein said C 3 -C 7 cycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group, said 4 to 6-membered monocyclic heterocycloalkyl group and said C 6 -C 10 aryl group can each be optionally and independently substituted with one or more groups, each independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocycloalkyl, C 6 -C 10 aryl, halo, C 1 -C 6 haloalkyl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)N(R 6 ) 2 , —NHC(O)R 6 , —S(O) 2 R 6 and —SR 6 ; and

each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl and benzyl.

2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl or (C 1 -C 3 alkylene)-O—(C 1 -C 6 alkyl), or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 5 is —(C 1 -C 3 alkylene) n -(C 6 -C 10 aryl), and wherein the C 6 -C 10 aryl moiety of said —(C 1 -C 3 alkylene) n (C 6 -C 10 aryl) group can be can be optionally and independently substituted with up to 3 groups, each independently selected from C 1 -C 6 alkyl and halo, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the group —X—Y— is selected from —O—CH 2 —, —O—CH 2 —CH 2 — and —CH 2 —O—, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein A is 5 or 6-membered monocyclic heteroaryl or —NH—C(O)—, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein each occurrence of R 2 is H, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , having the formula (Ia):

or a pharmaceutically acceptable salts thereof,

wherein:

A is —NH—C(O)— or 5-membered heteroaryl;

the group —X—Y— is selected from —O—CH 2 —, —O—CH 2 —CH 2 — and —CH 2 —O—;

m is 1 or 2;

R 1 is H, C 1 -C 6 alkyl or —(C 1 -C 3 alkylene)-O—(C 1 -C 6 alkyl);

R 7 represents up to 2 phenyl group substituents, each independently selected from halo; and

R c is H or C 1 -C 6 alkyl.

8. The compound of claim 7 , wherein m is 1 and the group —X—Y— is —O—CH 2 —, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 7 , wherein R 1 is H, ethyl, isopropyl, n-propyl or —CH 2 CH 2 OCH 3 , or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein A is —NHC(O)—, thiadiazolyl or trizolyl, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 7 , wherein each occurrence of R 7 is F, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 7 , wherein R 7 represents two F substitutents, located at the ortho and para positions on the phenyl group to which they are attached, or a pharmaceutically acceptable salt thereof.

13. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

14. 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.

15. 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.

16. A method for the treatment of infection by HIV or for the treatment, or delay in the onset or progression 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.

17. The pharmaceutical composition of claim 14 , further comprising one or more additional therapeutic agents selected from lamivudine, abacavir, darunavir, ritonavir, azanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.

18. A method for the treatment of infection by HIV or for the treatment, or delay in the onset or progression 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, and one or more additional therapeutic agents selected from: lamivudine, darunavir, abacavir, ritonavir, azanavir, emtricitabine, tenofovir, rilpivirine 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, prevent or delay the onset or progression of AIDS.