4-pyridinonetriazine derivatives as HIV integrase inhibitors

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

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

X is C 1 - C 3 alkylene;

Y is O, —C(R 8 ) 2 — or —N(R 4 )—;

R 1 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl);

R 2 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 6 alkylene) p -C(O)OR 6 , —(C 1 -C 6 alkylene) p -C(O)R 6 , —(C 1 -C 6 alkylene) p -C(O)N(R 9 ) 2 , C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), wherein said C 3 -C 7 cycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group and said 5 or 6-membered monocyclic heterocycloalkyl group can be optionally substituted with R 7 ;

R 3 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heterocycloalkyl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), wherein said C 3 -C 7 cycloalkyl group and said 5 or 6-membered monocyclic heterocycloalkyl group can be optionally substituted with one or more groups selected from R 7 , or R 2 and R 3 , together with the common carbon atom to which they are both attached, can optionally join to form a spirocyclic C 3 -C 7 cycloalkyl group or a spirocyclic C 3 -C 7 cycloalkenyl group, wherein said spirocyclic C 3 -C 7 cycloalkyl group and said spirocyclic C 3 -C 7 cycloalkenyl group can be optionally substituted with one or more groups selected from R 7 , and wherein said spirocyclic C 3 -C 7 cycloalkyl group can be fused to another ring, selected from C 3 -C 7 cycloalkyl, 3 to 8-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl, and wherein said spirocyclic C 3 -C 7 cycloalkyl group can form a spirocyclic ring system with a C 3 -C 7 cycloalkyl group or a 3 to 8-membered monocyclic heterocycloalkyl group, or R 1 and R 3 , together with the carbon atoms to which they are attached, can optionally join to form a 3 to 8-membered monocyclic heterocycloalkyl group, which can be optionally substituted with one or more groups selected from R 7 ;

R 4 is selected from H, C 1 -C 6 alkyl, —SO 2 R 6 , —C(O)R 6 , —(C 1 -C 6 alkylene) p -C(O)N(R 9 ) 2 , and —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl);

R 5 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; and

each occurrence of R 6 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, phenyl, 3 to 8-membered monocyclic heterocycloalkyl or 6-membered monocyclic heteroaryl and 8 to 10-membered bicyclic heteroaryl, wherein said C 3 -C 7 cycloalkyl group, said phenyl group, said 5 or 6-membered monocyclic heteroaryl group and said 8 to 10-membered bicyclic heteroaryl group can be optionally substituted with R 7 ;

each occurrence of R 7 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), —OC(O)—(C 1 -C 6 haloalkyl), —(C 1 -C 6 alkylene) p -C(O)OR 6 , —(C 1 -C 6 alkylene) p -C(O)R 6 , —(C 1 -C 6 alkylene) p -C(O)N(R 9 ) 2 , C 1 -C 6 hydroxyalkyl, —P(O)(OR 11 ) 2 , and —CN;

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

each occurrence of R 9 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 6 alkylene)-N(R 9 ) 2 , C 1 -C 6 haloalkyl, —C(O)O(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) p -R 10 and —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl);

each occurrence of R 10 is independently selected from H, 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 1 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 Y is O, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein Y is —CHR 8 — or —N(R 4 )—; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein A is —NH—C(O)—, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein A is 5 or 6-membered monocyclic heteroaryl, or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof,

wherein:

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

Y is selected from O, —NHR 4 , —CH 2 — or —CH(CH 3 )—;

R 1 is C 1 -C 6 alkyl or —CH 2 CH 2 OCH 3 ;

R 2 is selected from H, C 1 -C 6 alkyl, and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl);

R 3 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heterocycloalkyl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), or R 2 and R 3 , together with the common carbon atom to which they are both attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group which can be optionally substituted as set forth in claim 1 , or R 1 and R 3 , together with the atoms o which they are attached, join to form a 3 to 8-membered heterocycloalkyl group, which can be optionally substituted as set forth above for the compounds of formula (I);

R 4 is selected from H, C 1 -C 6 alkyl and —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl);

R 5 represents up to 2 optional substitutents, each independently selected from halo; and

R 11 is H or methyl.

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

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is C 1 -C 6 alkyl;

R 2 is selected from H, C 1 -C 6 alkyl, and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl);

R 3 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heterocycloalkyl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), or R 2 and R 3 , together with the common carbon atom to which they are both attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group which can be optionally substituted as set forth in claim 1 ;

R 4 is selected from H, C 1 -C 6 alkyl and —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl);

R 5 represents up to 2 optional substitutents, each being fluoro; and

R 11 is H or methyl.

8. The compound of claim 1 , wherein R 2 is H, methyl or —CH 2 CH 2 OCH 3 , or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein R 3 is methyl, cyclopropyl, —CH 2 CH 2 OCH 3 or tetrahyrdopyranyl, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein R 2 and R 3 , together with the common carbon atom to which they are both attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group that is optionally substituted as set forth in claim 1 , or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein R 1 and R 3 , together with the atoms to which they are both attached, join to form a 3 to 8-membered monocyclic heterocycloalkyl group that is optionally substituted as set forth in claim 1 , or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein R 4 is methyl or —CH 2 CH 2 OCH 3 , or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein R 5 represents: (i) a single fluoro group in the para position or (ii) two fluoro groups, in the ortho and para positions, or a pharmaceutically acceptable salt thereof.

14. A compound selected from

or a pharmaceutically acceptable salt thereof.

15. 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.

16. The pharmaceutical composition of claim 15 , further comprising one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine and lopinavir.

17. 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.

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.

19. The method of claim 18 , 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, or delay the onset or progression of AIDS.