Substituted pyrido[1,2-a]pyrazines as HIV integrase inhibitors

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is a bond or C 1 -C 3 alkylene;

R 1 is C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- to 11-membered bicyclic heteroaryl, wherein said C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- to 11-membered bicyclic heteroaryl is optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —CN, —N(R 4 ) 2 , —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —OC(O)R 7 , —C(O)N(R 4 ) 2 , —NHC(O)R 7 or —C(O)OR 7 ;

R 2 is —C(R 7 )(R 8 )N(R 4 ) 2 , or C 1 -C 6 hydroxyalkyl;

R 3 is C 2 -C 6 alkenyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkenyl or C 3 -C 7 cycloalkyl; or R 2 and R 3 , together with the carbon atoms to which they are attached, optionally form a cyclic group Y;

each occurrence of R 4 is independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkylene)-O—(C 1 -C 6 alkyl) or —C(O)R 10 ;

R 7 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or phenyl;

R 8 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or phenyl; or R 7 and R 8 , together with the carbon atom to which they are attached, form a carbonyl;

R 10 is C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 9- to 11-membered bicyclic heteroaryl, 4- to 8-membered monocyclic heterocycloalkyl, or 8- to 11-membered bicyclic heterocycloalkyl;

Y is selected from the group consisting of:

wherein Y is optionally substituted on one or more ring carbon atoms with one or more C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —OH, —O—(C 1 -C 6 alkyl), —C(O)OR 6 , —C(O)N(R 9 ) 2 , C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- to 11-membered bicyclic heteroaryl, and wherein Y is further optionally substituted on one or more ring nitrogen atoms with C 1 -C 6 alkyl, —C(O)OR 6 , —C(O)N(R 4 ) 2 or —C(O)—(C 1 -C 3 alkylene)-N(R 4 ) 2 , wherein Y does not have the structure:

wherein the * symbols designate the point of attachment of R 2 and R 3 to the rest of the compound;

R 6 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- to 11-membered bicyclic heteroaryl; and

each occurrence of R 9 is independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or —(C 1 -C 3 alkylene)-O—(C 1 -C 6 alkyl).

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

or a pharmaceutically acceptable salt thereof, wherein:

A is C 1 -C 3 alkylene; and

R 5A , R 5B , R 5C , R 5D , and R 5E are each independently H, C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, —N(R 4 ) 2 , —CN, C(O)N(R 4 ) 2 , —O—(C 1 -C 6 alkyl), —C(O)OR 7 or —NHC(O)R 7 .

3. The compound of claim 2 , having the formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R 5B , R 5C , and R 5D , are each independently H, F, or Cl.

4. The compound of claim 3 , wherein:

(a) R 5B is H, R 5C is F, and R 5D is Cl;

(b) R 5B is Cl, R 5C is F, and R 5D is H; or

(c) R 5B is H, R 5C is F, and R 5D is H.

5. The compound of claim 4 , wherein:

R 2 is —C(O)NHCH 2 CH 2 OCH 3 , —CH 2 OH or —CH 2 NH 2 ; and

R 3 is cyclopentenyl, cyclohexenyl, cyclopentyl, isopropyl, —C(CH 3 )═CH 2 , —CH 3 or —CH 2 CH 3 .

6. The compound of claim 4 , wherein R 2 and R 3 , together with the carbon atoms to which they are attached, form a cyclic group Y.

7. The compound of claim 6 , wherein R 2 and R 3 , together with the carbon atoms to which they are attached, form a cyclic group Y having the structure:

wherein the * symbols designate the point of attachment of R 2 and R 3 to the rest of the compound.

8. The compound of claim 2 , wherein up to two of R 5A , R 5B , R 5C , R 5D , and R 5E are independently H or halo.

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

12. A method for the inhibition of human immunodeficiency virus 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.