Spirocyclic heterocyclic 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 a 3 to 8-membered heterocycloalkyl, which can be optionally substituted with one or more groups, each independently selected from R 5 ;

X is C 1 -C 4 alkylene;

R 1 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 4 alkylene)-S—(C 1 -C 6 alkyl), —(C 1 -C 4 alkylene)-SO 2 —(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —(C 1 -C 4 alkylene)-N(C 1 -C 6 alkyl) 2 , —(C 1 -C 4 alkylene)-P(O)(—O—C 1 -C 6 alkyl) 2 , —(C 1 -C 4 alkylene)-P(O)(OH) 2 , phenyl, 3 to 8-membered monocyclic heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl;

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 selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl) and C 1 -C 6 haloalkyl;

each occurrence of R 5 is 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 , wherein X is —CH 2 —, or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof,

wherein:

A is: —NHC(O)—;

B is 4 to 7-membered monocyclic heterocycloalkyl;

R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl);

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

each occurrence of R 3 is independently H or C 1 -C 6 alkoxy.

4. The compound of claim 1 , wherein B is selected from:

or a pharmaceutically acceptable salt thereof.

5. 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.

6. The compound of claim 5 , wherein R 2 and the phenyl group to which R 2 is attached is:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein 1 is selected from methyl, ethyl, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 OCH 3 and —CH 2 CH 2 OCH 2 CH 3 , or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein one occurrence of R 3 is H and the other occurrence of R 3 is H or methoxy, or a pharmaceutically acceptable salt thereof.

9. A compound selected from

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 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.

12. 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.

13. The method of claim 11 , 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 AIDS.