Pyrimidinone derivatives and methods of use thereof

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R is absent or R is oxygen, such that when R is oxygen, this is understood to represent the N-oxide form of the nitrogen atom to which R is attached;

R 1 is —H, alkyl, haloalkyl, —N(R 9 ) 2 , —SR 9 , —S(O) q N(R 6 ) 2 , —S(O) p R 7 , —OR 9 , -(alkylene) n -aryl, -(alkylene) n -cycloalkyl, -(alkylene), n , cycloalkenyl, -(alkylene) n -heterocycloalkyl, -(alkylene) n -heteroaryl, -(alkylene) n -heterocycloalkenyl, —C(O)-aryl, —C(O)-alkyl, -alkylene-O-aryl, -alkylene-O-alkyl or -C(O)NH 2 , wherein any aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 substituents, which can be the same or different, and are selected from alkyl, haloalkyl, hydroxyalkyl, aryl, halo, —OH, —O-haloalkyl, —O-alkyl, -alkylene-O-alkyl, —S(O) p R 7 , —CN, —N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , —NHC(O)R 5 , —NHS(O) q R 7 and —S(O) q N(R 6 ) 2 ;

R 2 is alkyl, haloalkyl, -(alkylene) n -aryl, -(alkylene) n -cycloalkyl, -(alkylene) n -cycloalkenyl, -(alkylene) n -heterocycloalkyl, -(alkylene) n -heteroaryl, -(alkylene) n -heterocycloalkenyl, —C(O)-aryl, —C(O)-alkyl, -alkylene-O-haloalkyl, -alkylene-O-aryl, -alkylene-O-alkyl, —C(O)OR 5 , or —C(O)N(R 6 ) 2 , wherein any aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 substituents, which can be the same or different, and are selected from alkyl, haloalkyl, hydroxyalkyl, aryl, halo, —OH, —O-haloalkyl, —O-alkyl, -alkylene-O-alkyl, —S(O) p R 7 , —CN, —N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , —NHC(O)R 5 , —NHS(O) q R 7 and —S(O) q N(R 6 ) 2 , or R 2 and R 3 and the carbon atom to which they are both attached, combine to form an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group, wherein any of these groups is unsubstituted or substituted with up to 3 substituents, which can be the same or different, and which are selected from alkyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , —NHC(O)R 5 , —NHS(O) q R 7 , —S(O) p R 7 and —S(O) q N(R 6 ) 2 ;

R 3 is alkyl, -(alkylene) n -aryl, -(alkylene) n -cycloalkyl, -(alkylene) n -cycloalkenyl, -(alkylene) n -heterocycloalkyl, -(alkylene) n -heteroaryl, -(alkylene) n -heterocycloalkenyl, —C(O)-aryl, —C(O)-alkyl, -alkylene-O-aryl, -alkylene-O-alkyl, —C(O)OR 5 , or —C(O)N(R 6 ) 2 , wherein any aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 substituents, which can be the same or different, and are selected from alkyl, haloalkyl, hydroxyalkyl, aryl, halo, —OH, —O-haloalkyl, —O-alkyl, -alkylene-O-alkyl, —S(O) p R 7 , —CN, —N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , —NHC(O)R 5 , —NHS(O) q R 7 and —S(O) q N(R 6 ) 2 , or R 2 and R 3 and the carbon atom to which they are both attached, combine to form an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group, wherein any of these groups is unsubstituted or substituted with up to 3 substituents, which can be the same or different, and which are selected from alkyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , —NHC(O)R 5 , —NHS(O) q R 7 , —S(O) p R 7 and —S(O) q N(R 6 ) 2 ;

R 4 is H, alkyl, —C(O)R 5 , —S(O) q R 7 , -alkylene-O-alkyl, -alkylene-O-aryl, -alkylene-S-alkyl, -alkylene-S-aryl, -alkylene-NH-alkyl, -alkylene-NH-aryl, -alkylene-NC(O)O-alkyl, —C(O)OR 5 , —C(O)N(R 6 ) 2 , —C(O)NH—OR 8 , -(alkylene) n -aryl, -(alkylene) n -cycloalkyl, -(alkylene) n -cycloalkenyl, -(alkylene) n -heterocycloalkyl, -(alkylene) n -heterocycloalkenyl or -(alkylene) n -heteroaryl, wherein any aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group that is part of an R 4 group can be unsubstituted or substituted with up to 3 substituents, which can be the same or different, and are selected from: alkyl, aryl, heterocycloalkyl, heteroaryl, -alkylene-O-alkylene-Si(alkyl) 3 , —NH 2 , —NH-alkyl, —N(alkyl) 2 , —OH, -hydroxyalkyl, -alkynylene-aryl, —S(O) p R 7 , —O-alkyl, —O-aryl, —C(O)O-alkyl, —C(O)O-haloalkyl, halo, —NO 2 , —CN, heteroaryl, haloalkyl, —O-haloalkyl, —S-haloalkyl, —S(O)-haloalkyl and -(alkynylene) n -aryl, and wherein a cycloalkyl group that is part of an R 4 group can be fused with a benzene ring, and wherein an alkylene group can be optionally substituted with a group selected from: alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl;

R 5 is alkyl, alkenyl, alkynyl, haloalkyl, -alkylene-O-aryl, -alkylene-S-aryl, -alkylene-N(R 8 )C(O)O-alkyl, -(alkylene) n -aryl, -(alkylene) n -cycloalkyl, -(alkylene) n -cycloalkenyl, -(alkylene) n -heterocycloalkyl, -(alkylene) n -heterocycloalkenyl or -(alkylene) n -heteroaryl, wherein any aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be unsubstituted or substituted with up to 4 substituents, which can be the same or different, and are selected from alkyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-aryl, —S-haloalkyl, -alkylene-O-alkyl, —CN, —N(R 9 ) 2 , —C(O)H, —C(O)R 9 , —C(O)OR 9 , —C(O)N(R 9 ) 2 , —NHC(O)R 9 , —NHS(O) q R 9 , —S(O) p R 9 and —S(O) q N(R 9 ) 2 ;

each occurrence of R 6 is independently H, alkyl, -(alkylene) n -aryl, -(alkylene) n -cycloalkyl, -(alkylene) n -cycloalkenyl, -(alkylene) n -heterocycloalkyl, -(alkylene) n -heterocycloalkenyl or -(alkylene) n -heteroaryl, wherein any of the above groups, excluding H, can be unsubstituted or substituted with from 1 to 3 substituents, which can be the same or different, and which are selected from alkyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R 9 ) 2 , —C(O)H, —C(O)R 9 , —C(O)OR 9 , —C(O)N(R 9 ) 2 , —NHC(O)R 9 , —NHS(O) q R 9 , —S(O) p R 9 and —S(O) q N(R 9 ) 2 ;

each occurrence of R 7 is independently alkyl, aryl, heterocycloalkyl, heteroaryl or cycloalkyl, any of which can be unsubstituted or substituted with from 1 to 3 substituents, which can be the same or different, and which are selected from alkyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, -O-aryl, -alkylene-O-alkyl, —CN, —N(R 9 ) 2 , —C(O)H, —C(O)R 9 , —C(O)OR 9 , —C(O)N(R 9 ) 2 , —NHC(O)R 9 , —NHS(O) q R 9 , —S(O) p R 9 and —S(O) q N(R 9 ) 2 ;

each occurrence of R 8 is independently H or alkyl;

each occurrence of R 9 is independently H, alkyl, -(alkylene) n -aryl, heterocycloalkyl, heteroaryl or cycloalkyl;

each occurrence of R 10 is independently H, alkyl, -(alkylene) n -aryl, heterocycloalkyl, heteroaryl or cycloalkyl;

each occurrence of R 11 is independently H, alkyl, -(alkylene) n -aryl, heterocycloalkyl, heteroaryl or cycloalkyl, or any R 10 and R 11 , together with the carbon atoms to which they are attached, can join to form a 3- to 7-membered fused or spirocyclic ring, or a 4- to 7-membered bridged ring;

R 12 is H, alkyl, -(alkylene) n -aryl, heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy or hydroxyalkyl;

each occurrence of n is independently 0 or 1;

each occurrence of p is independently 0, 1 or 2; and

each occurrence of q is independently 1 or 2,

such that the compound of formula (I) is not a compound having the formula (II):

wherein R i and R ii are defined in the above specification.

2. The compound of claim 1 , wherein R 1 is alkyl or —N(R 9 ) 2 .

3. The compound of claim 2 , wherein R 1 is methyl.

4. The compound of claim 2 , wherein R 1 is —NH 2 .

5. The compound of claim 1 , wherein R 2 is aryl, heteroaryl or cycloalkyl and R 3 is aryl, heteroaryl or cycloalkyl.

6. The compound of claim 5 , wherein R 2 is phenyl, 4-fluorophenyl or pyridyl, and R 3 is phenyl, 4-fluorophenyl or pyridyl.

7. The compound of claim 6 , wherein R 2 and R 3 are each phenyl.

8. The compound of claim 6 , wherein R 2 is phenyl and R 3 is pyridyl.

9. The compound of claim 6 , wherein R 2 and R 3 are each 4-fluorophenyl.

10. The compound of claim 6 , wherein R 2 is phenyl and R 3 is 4-fluorophenyl.

11. The compound of claim 5 , wherein R 4 is -alkylene-aryl.

12. The compound of claim 11 , wherein R 4 is —CH 2 -aryl or —CH(CH 3 )—aryl.

13. The compound of claim 12 , wherein R 4 is —CH 2 -phenyl or —CH(CH 3 )-phenyl, wherein the phenyl group can be optionally substituted with up to 3 substituents, which may be the same or different, and are selected from halo, haloalkyl, heteroaryl, —C(O)O-alkyl, —S-haloalkyl or —NO 2 .

14. The compound of claim 13 , wherein R 4 is:

15. The compound of claim 14 , wherein R 2 is phenyl, 4-fluorophenyl or pyridyl and R 3 is phenyl, 4-fluorophenyl or pyridyl.

16. The compound of claim 15 , wherein R is absent and R 1 is methyl.

17. The compound of claim 15 , wherein R is absent and R 1 is —NH 2 .

18. The compound of claim 16 , wherein R 2 and R 3 are each phenyl.

19. The compound of claim 16 , wherein R 2 and R 3 are each 4-fluorophenyl.

20. The compound of claim 16 , wherein R 2 is phenyl and R 3 is pyridyl.

21. The compound of claim 16 , wherein R 2 is phenyl and R 3 is 4-fluorophenyl.

22. The compound of claim 17 , wherein R 2 and R 3 are each phenyl.

23. The compound of claim 17 , wherein R 2 and R 3 are each 4-fluorophenyl.

24. The compound of claim 17 , wherein R 2 is phenyl and R 3 is pyridyl.

25. The compound of claim 17 , wherein R 2 is phenyl and R 3 is 4-fluorophenyl.

26. The compound of claim 5 , wherein R 4 is -alkylene-heteroaryl.

27. The compound of claim 26 , wherein R 4 is —CH 2 -heteroaryl or —CH(CH 3 )-heteroaryl.

28. The compound of claim 27 , wherein the heteroaryl is thienyl or benzthienyl, and wherein the thienyl or benzthienyl group can be optionally substituted with up to 3 substituents, which may be the same or different, and are selected from halo, alkyl or haloalkyl.

29. The compound of claim 28 , wherein R 4 is:

30. The compound of claim 29 , wherein R 2 is phenyl, 4-fluorophenyl or pyridyl and R 3 is phenyl, 4-fluorophenyl or pyridyl.

31. The compound of claim 29 , wherein R 2 and R 3 are each phenyl.

32. The compound of claim 29 , wherein R 2 and R 3 are each 4-fluorophenyl.

33. The compound of claim 29 , wherein R 2 is phenyl and R 3 is pyridyl.

34. The compound of claim 30 , wherein R 2 and R 3 are each phenyl.

35. The compound of claim 30 , wherein R 2 and R 3 are each 4-fluorophenyl.

36. The compound of claim 30 , wherein R 2 is phenyl and R 3 is pyridyl.

37. The compound of claim 30 , wherein R 2 is phenyl and R 3 is 4-fluorophenyl.

38. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising one or more compounds of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

40. The composition of claim 39 , further comprising at least one antidiabetic agent and/or at least one antiobesity agent that is different from the compounds of claim 1 .

41. The composition of claim 40 , comprising at least one antidiabetic agent that is different from the compounds of claim 1 .

42. The composition of claim 40 , comprising at least one antiobesity agent that is different from the compounds of claim 1 .