Fused tricyclic heterocyclic compounds as HIV integrase inhibitors

1. A compound having the formula:

and pharmaceutically acceptable salts thereof,

wherein:

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

X is O, —N(C 1 -C 6 alkyl)- or —C(R 10 )(R 11 ), such that when X═O or —N(C 1 -C 6 alkyl)-, then R 4 , R 5 , R 6 and R 7 are each other than —OR 9 , —N(R 9 ) 2 or halo;

each occurrence of m is independently 0 or 1;

n is 0 or 1, such that when n is 0, then R 4 and R 5 are not present;

R 1 is C 1 -C 6 alkyl, which is optionally substituted with up to 3 groups, each 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 9 , —N(R 9 ) 2 , —C(O)R 9 , —C(O)N(R 9 ) 2 , —NHC(O)R 9 and —SR 9 , 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 9 , —N(R 9 ) 2 , —C(O)R 9 , —C(O)N(R 9 ) 2 , —NHC(O)R 9 and —SR 9 ;

R 2 , R 5 , R 6 , R 7 , R 10 and R 11 are each independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, halo, C 1 -C 6 haloalkyl, —OR 9 , —N(R 9 ) 2 , —C(O)R 9 , —C(O)N(R 9 ) 2 and —NHC(O)R 9 , wherein said C 1 -C 6 alkyl group can be optionally substituted with one or more groups, each independently selected from halo, —OH, —O(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SH or —S(C 1 -C 6 alkyl);

R 3 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, —C(O)R 9 , —C(O)N(R 9 ) 2 and —NHC(O)R 9 , wherein said C 1 -C 6 alkyl group can be optionally substituted with one or more groups, each independently selected from halo, —OH, —O(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SH or —S(C 1 -C 6 alkyl);

R 4 is H, or R 4 and R 5 and the common carbon atom to which they are attached, join to form an endocyclic —C(O)— group;

R 8 is selected from C 1 -C 6 alkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(5 or 6-membered monocyclic heteroaryl), —(C 1 -C 3 alkylene) m -(4 to 6-membered monocyclic heterocycloalkyl) and —(C 1 -C 3 alkylene) m -(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 up to 5 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 9 , —N(R 9 ) 2 , —C(O)R 9 , —C(O)N(R 9 ) 2 , —NHC(O)R 9 and —SR 9 ; and

each occurrence of R 9 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 having the formula:

and pharmaceutically acceptable salts thereof,

wherein:

A is 5 or 6-membered monocyclic heteroaryl or —NH—C(O)—;

X is O, —N(C 1 -C 6 alkyl)- or —C(R 10 )(R 11 ), such that when X═O or —N(C 1 -C 6 alkyl)-, then R 4 , R 5 , R 6 and R 7 are each other than —OR 9 , —N(R 9 ) 2 or halo;

n is 0 or 1, such that when n is 0, then R 4 and R 5 are not present;

R 1 is C 1 -C 6 alkyl, which is optionally substituted with a group selected from phenyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl and —OR 9 , wherein said phenyl group and said 5 or 6-membered monocyclic heteroaryl group can each be optionally and independently substituted with up to two 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 9 , —N(R 9 ) 2 , —C(O)R 9 , —C(O)N(R 9 ) 2 , —NHC(O)R 9 and —SR 9 ;

R 4 is H, or R 4 and R 5 and the common carbon atom to which they are attached, join to form an endocyclic —C(O)— group;

R 5 , R 10 and R 11 are each independently selected from H, C 1 -C 6 alkyl and —OR 9 ;

R 7 is selected from H, C 1 -C 6 alkyl, —OR 9 and —OH;

R 8 is selected from C 1 -C 6 alkyl or benzyl, wherein the phenyl moiety of said benzyl group can be optionally and independently substituted with up to 3 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 9 , —N(R 9 ) 2 , —C(O)R 9 , —C(O)N(R 9 ) 2 , —NHC(O)R 9 and —SR 9 ; and

each occurrence of R 9 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl and benzyl.

3. The compound of claim 1 having the formula (Ib):

and pharmaceutically acceptable salts and prodrugs thereof,

wherein:

A is pyrazolyl, thiadiazolyl, triazolyl, thiazolyl, oxazolyl, oxadiazaolyl or —NHC(O)—;

X is O, —N(C 1 -C 6 alkyl)- or —C(R 10 )(R 11 ), such that when X═O or —N(C 1 -C 6 alkyl)-, then R 4 , R 5 , R 6 and R 7 are each other than —OR 9 , —N(R 9 ) 2 or halo;

n is 0 or 1, such that when n is 0, then R 4 and R 5 are not present;

R 1 is C 1 -C 6 alkyl, which is optionally substituted with a group selected from phenyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl and —O—(C 1 -C 6 alkyl), wherein said phenyl group and said 5 or 6-membered monocyclic heteroaryl group can each be optionally and independently substituted with up to two groups, each independently selected from C 1 -C 6 alkyl, halo and —O—(C 1 -C 6 alkyl);

R 4 is H, or R 4 and R 5 and the common carbon atom to which they are attached, join to form an endocyclic —C(O)— group;

R 5 , R 10 and R 11 are each independently selected from H, C 1 -C 6 alkyl and —O—(C 1 -C 6 alkyl);

R 7 is selected from H, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl) and —OH;

R 8 is selected from C 1 -C 6 alkyl or benzyl, wherein the phenyl moiety of said benzyl group can be optionally and independently substituted with up to 3 groups, each independently selected from C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl) and halo; and

each occurrence of R 9 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl and benzyl.

4. The compound of claim 1 , wherein A is —NHC(O)—.

5. The compound of claim 1 , wherein X is —O—; n is 1; and R 4 , R 5 and R 7 are each H.

6. The compound of claim 1 , wherein X is —CH 2 —; n is 0; and R 7 is H or —OH.

7. The compound of claim 1 , wherein R 8 is benzyl, wherein the phenyl moiety of said benzyl group can be optionally and independently substituted with up to 3 groups, each independently selected from F, Cl, and methyl.

8. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl, which is optionally substituted with a group selected from phenyl, 5 or 6-membered monocyclic heteroaryl, C 3 -C 7 cycloalkyl and methoxy, wherein said phenyl group and said 5 or 6-membered monocyclic heteroaryl group can each be optionally and independently substituted with up to two groups, each independently selected from methoxy, C 1 -C 6 alkyl and fluoro.

9. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

10. 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.

11. 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 or prodrug thereof.

12. 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 or prodrug thereof.

13. The pharmaceutical composition of claim 10 , further comprising one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine and lopinavir.

14. The method of claim 12 , further comprising administering to the subject one or more additional therapeutic agents selected from raltegravir, dolutegravir, 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 or delay the onset or progression of AIDS.