Spirocyclic heterocycle compounds useful as HIV integrase inhibitors

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

A is —NHC(O)—;

B is C 3 -C 6 cycloalkyl or 3 to 8-membered heterocycloalkyl, which can be optionally substituted with R 5 ;

X is CH 2 ;

R 1 is —N(C 1 -C 6 alkyl) 2 or R 1 and an R 3 group, together with the atoms to which they are attached, combine to form a 4 to 7-membered heterocycloalkyl, which can be optionally substituted with R 5 ;

R 2 represents up to 3 optional substitutents, each independently selected from halo, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl) and C 1 -C 6 haloalkyl;

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

R 4 is H;

R 5 represents one or more groups, each independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3 to 8-membered monocyclic heterocycloalkyl, 6 to 10-membered bicyclic heterocycloalkyl, —O—(C 1 -C 6 alkyl), —O—(C 6 -C 10 aryl), —O—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —NHS(O) 2 —(C 1 -C 6 alkyl), —S(O) 2 NH—(C 1 -C 6 alkyl), —OC(O)—(C 1 -C 6 haloalkyl), —(C 1 -C 6 alkylene) p -C(O)O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) p -C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) p -C(O)N(R 6 ) 2 , C 1 -C 6 hydroxyalkyl, —P(O)(OR 8 ) 2 , and —CN;

each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl and —(C 1 -C 6 alkylene) p -R 7 ;

each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl and 3 to 8-membered monocyclic heterocycloalkyl;

each occurrence of R 8 is independently selected from H and C 1 -C 6 alkyl; and

each occurrence of p is independently 0 or 1.

2. The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

A is —NHC(O)—;

B is C 3 -C 6 cycloalkyl or 3 to 8-membered heterocycloalkyl, each of which can be optionally substituted with R 5 ;

each occurrence of R a is independently C 1 -C 6 alkyl;

R 2 represents up to 3 optional substituents, each independently selected from halo; and

R 3 is H or C 1 -C 6 alkoxy.

3. The compound of claim 2 , wherein R 3 is methoxy, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

A is —NHC(O)—;

B is C 3 -C 6 cycloalkyl or 3 to 8-membered heterocycloalkyl, each of which can be optionally substituted with R 5 ;

Z is 4 to 7-membered monocyclic heterocycloalkyl, which can be optionally substituted with R 5 ; and

R 2 represents up to 3 optional substituents, each independently selected from halo.

5. The compound of claim 4 , wherein Z is a 6-membered heterocycloalkyl-, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein B is C 3 -C 6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , wherein B is cyclopropyl, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R 2 represents up to 3 substituent groups, each independently selected from F and Cl, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein R 2 and the phenyl group to which R 2 is attached is selected from:

or a pharmaceutically acceptable salt thereof.

10. A compound selected from:

or a pharmaceutically acceptable salt thereof.

11. 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.

12. 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.

13. 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.

14. The pharmaceutical composition of claim 11 , further comprising one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine and lopinavir.

15. The method of claim 13 , further comprising administering to the subject one or more additional therapeutic agents selected from raltegravir, 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, prevent or delay the onset or progression of AIDS.