Phenylpyrrolidinone formyl peptide 2 receptor agonists

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is aryl substituted with 1-2 R 1a and 1-2 R 1b or monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and substituted with 1-2 R 1a and 1-2 R 1b ;

Ar 2 is aryl substituted with 1-4 R 2a or 6-membered heteroaryl with 1-2 nitrogen atoms, and substituted with 1-4 R 2a ;

Ar 3 is aryl substituted with 1-4 R 3a or monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and substituted with 1-4 R 3a ;

R 1a is hydrogen or halo;

R 1b is halo, haloalkyl, alkoxy, or haloalkoxy;

R 2a is hydrogen, cyano, halo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, or haloalkoxy; alternatively, two adjacent R 2a groups are taken together with the carbon atoms to which they are attached to form a heterocycle with 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur;

R 3a is cyano, halo, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, (R 1 R 2 N)alkyl, R 1 R 2 N, alkylC(O)(R 2 )Nalkyl, (alkyl) 2 (O)P, (alkoxy) 2 (O)P, (alkoxy)(alkyl)(O)P, (alkyl)(O)(NR 1 )S, alkylSO 2 , or alkylSO 2 NH; alternatively, two adjacent R 3a groups are taken together with the carbon atoms to which they are attached to form a heterocycle with 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur;

R 4a or R 4b is independently hydrogen, alkyl, alkoxy, hydroxylalkyl, alkoxyalkyl, or haloalkoxy; alternatively, R 4a and R 4b together with the carbon atom they are both attached to form a C 3-6 cycloalkyl;

R 5a or R 5b is independently hydrogen, alkyl, hydroxylalkyl, alkoxyalkyl or haloalkoxyl;

R 1 is hydrogen or alkyl; and

R 2 is hydrogen or alkyl; or R 1 R 2 N taken together is azetidinyl, oxazolyl pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, and oxo.

2. The compound of claim 1 , having Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is phenyl substituted with 1-2 R 1a and 1-2 R 1b or 6-membered heteroaryl with 1-3 nitrogen atoms and substituted with 1R 1a and 1-2 R 1b ;

Ar 3 is phenyl substituted with 1-3 R 3a or 5- to 6-membered heteroaryl with 1-3 nitrogen atoms and substituted with 1-3 R 3a ;

R 1a is hydrogen or halo;

R 1b is halo, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 2a is hydrogen, halo, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 3a is cyano, halo, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyalkyl, C 1-4 haloalkyl, (R 1 R 2 N)C 1-4 alkyl, R 1 R 2 N, C 1-4 alkylC(O)(R 2 )NC 1-4 alkyl, (C 1-4 alkyl) 2 (O)P, (C 1-4 alkoxy) 2 (O)P, (C 1-4 alkoxy)(C 1-4 alkyl)(O)P, C 1-4 alkylSO 2 , or C 1-4 alkylSO 2 NH;

R 1 R 2 N taken together is oxazolyl or pyrrolidinyl and is substituted with 0-3 substituents selected from halo, alkyl, and oxo;

R 4a or R 4b is independently hydrogen, C 1-4 alkyl, or C 1-4 hydroxylalkyl; alternatively, R 4a and R 4b together with the carbon atom they are both attached to form a C 3-6 cycloalkyl; and

R 5a or R 5b is independently hydrogen, C 1-4 alkyl, C 1-4 hydroxylalkyl, or C 1-4 alkoxyalkyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is phenyl substituted with 1-2 R 1a and 1-2 R 1b , pyridinyl substituted with 1 R 1a and 1-2 R 1b , or pyrazinyl substituted with 1R 1a and 1-2 R 1b ; and

Ar 3 is phenyl substituted with 1-3 R 3a , pyrazolyl substituted with 1-3 R 3a pyridinyl substituted with 1-3 R 3a , or pyrimidinyl substituted with 1-3 R 3a .

4. The compound of claim 2 , having Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is phenyl substituted with 1-2 R 1a and 1-2 R 1b , pyridinyl substituted with 1 R 1a and 1-2 R 1b , or pyrazinyl substituted with 1 R 1a and 1-2 R 1b ;

R 1a is hydrogen or halo;

R 1b is halo, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 2a is hydrogen, halo, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 3a is cyano, halo, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, C 1-3 haloalkyl, R 1 R 2 N, (C 1-3 alkyl) 2 (O)P, (C 1-3 alkoxy) 2 (O)P, (C 1-3 alkoxy)(C 1-3 alkyl)(O)P, C 1-3 alkylSO 2 , or C 1-3 alkylSO 2 NH;

R 4a or R 4b is independently hydrogen, C 1-3 alkyl, or C 1-3 hydroxylalkyl; alternatively, R 4a and R 4b together with the carbon atom they are both attached to form a C 3-6 cycloalkyl; and

R 5a or R 5b is independently hydrogen, C 1-3 alkyl, C 1-3 hydroxylalkyl, or C 1-3 alkoxyalkyl.

5. The compound of claim 4 , having Formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

R 1a is hydrogen or F;

R 1b is halo, C 1-2 haloalkyl, or C 1-2 alkoxy;

R 2a is hydrogen, halo, C 1-3 alkyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl;

R 3a is halo, hydroxyalkyl, alkoxyalkyl, (C 1-2 alkyl) 2 (O)P, (C 1-2 alkoxy) 2 (O)P, (C 1-2 alkoxy)(C 1-2 alkyl)(O)P, C 1-2 alkylSO 2 , or C 1-2 alkylSO 2 NH; and

R 3a′ is halo.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:

R 1a is hydrogen or F;

R 1b is F, Cl, or CF 3 ;

R 2a is hydrogen, F, Cl, isopropyl, CF 3 , or cyclopropyl;

R 3a is (CH 3 ) 2 (O)P, (CH 3 CH 2 ) 2 (O)P, (CH 3 CH 2 O)(CH 3 )(O)P, CH 3 SO 2 , or CH 3 SO 2 NH; and

R 3a′ is F.

7. The compound of claim 4 , having Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

R 1a is hydrogen or halo;

R 1b is halo, C 1-2 haloalkyl, or C 1-2 alkoxy;

R 2a is hydrogen, halo, C 1-3 alkyl, or C 3-6 cycloalkyl;

R 3a is (C 1-2 alkyl) 2 (O)P, (C 1-2 alkoxy) 2 (O)P, (C 1-2 alkoxy)(C 1-2 alkyl)(O)P, C 1-2 alkylSO 2 , or C 1-2 alkylSO 2 NH.

8. The compound of claim 2 , having Formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

Ar 3 is pyrazolyl substituted with 1-3 R 3a , pyridinyl substituted with 1-3 R 3a , or pyrimidinyl substituted with 1-3 R 3a ;

R 1a is hydrogen or halo;

R 1b is halo, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 2a is hydrogen, halo, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 3a is cyano, halo, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyalkyl, (R 1 R 2 N)C 1-4 alkyl, R 1 R 2 N—, (C 1-4 alkyl) 2 (O)P, (C 1-4 alkoxy) 2 (O)P, (C 1-4 alkoxy)(C 1-4 alkyl)(O)P, C 1-4 alkylSO 2 , or C 1-4 alkylSO 2 NH;

R 1 is hydrogen or alkyl;

R 2 is hydrogen or alkyl; or R 1 R 2 N taken together is oxazolyl or pyrrolidinyl, and is substituted with 0-3 substituents selected from halo, alkyl, or oxo;

R 4a or R 4b is independently hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyalkyl, or C 1-4 haloalkoxy; R 4a and R 4b together with the carbon atom they are both attached to form a C 3-6 cycloalkyl; and

R 5a or R 5b is independently hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyalkyl, or C 1-4 haloalkoxy.

9. The compound of claim 8 , having Formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:

R 1a is hydrogen or halo;

R 1b is halo, C 1-2 haloalkyl, or C 1-2 alkoxy;

R 2a is hydrogen, halo, C 1-3 alkyl, or C 3-6 cycloalkyl;

R 3a is (C 1-2 alkyl) 2 (O)P, (C 1-2 alkoxy) 2 (O)P, (C 1-2 alkoxy)(C 1-2 alkyl)(O)P, C 1-2 alkylSO 2 , or C 1-2 alkylSO 2 NH; and

R 5a or R 5b is independently hydrogen or C 1-2 alkyl.

10. The compound of claim 1 , having Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein:

R 1a is hydrogen or halo;

R 1b is halo, C 1-2 haloalkyl, or C 1-2 alkoxy;

R 2a is hydrogen, halo, C 1-2 haloalkyl, C 1-3 alkyl, or C 3-6 cycloalkyl;

Ar 3 is

R 3a is (C 1-2 alkyl) 2 (O)P, (C 1-2 alkoxy)(C 1-2 alkyl)(O)P, or C 1-2 alkylSO 2 NH;

R 3a′ is halo;

R 4a or R 4b is independently hydrogen, C 1-2 alkyl, or C 1-2 hydroxyalkyl; or R 4a and R 4b together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl; and

R 5a or R 5b is independently hydrogen, C 1-2 alkyl, C 1-2 hydroxyalkyl, or C 1-2 alkoxyalkyl.

11. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

R 4a is hydrogen;

R 4b is hydrogen;

R 5a is C 1-2 alkyl, C 1-2 hydroxylalkyl, or C 1-2 alkoxyalkyl; and

R 5b is hydrogen.

12. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

R 4a is C 1-2 alkyl;

R 4b is C 1-2 alkyl;

R 5a is hydrogen; and

R 5b is hydrogen.

13. A compound of Formula (I):

wherein:

Ar 1 is phenyl, pyridinyl, or pyridazinyl and is substituted with 1 halo, haloalkyl or haloalkoxy substituent in the 4-position and 0-2 additional halo or haloalkyl substituents;

Ar 2 is phenyl or pyridinyl and is substituted with 0-2 substituents selected from cyano, fluoro, alkyl, haloalkyl, cycloalkyl, alkoxy, and haloalkoxy;

Ar 3 is phenyl or pyridinyl and is substituted with 0-2 substituents selected from cyano, halo, hydroxyalkyl, alkoxyalkyl, (R 1 R 2 N)alkyl, (alkyl) 2 (O)P, (alkyl)(O)(NR 1 )S, alkylSO 2 , and alkylSO 2 NH;

R 1 is hydrogen or alkyl; and

R 2 is hydrogen or alkyl;

or (R 1 )(R 2 )N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl and is substituted with 0-3 substituents selected from halo and alkyl;

or a pharmaceutically acceptable salt thereof.

14. A compound of claim 13 where Ar 1 is phenyl substituted with 1 halo, haloalkyl or haloalkoxy substituent in the 4-position and 0-2 additional halo or haloalkyl substituents.

15. A compound of claim 13 where Ar 2 is phenyl substituted with 0 substituents, 1 alkyl or cycloalkyl substituent, or 1-2 fluoro substituents.

16. A compound of claim 13 where Ar 3 is phenyl substituted with 1-2 substituents selected from cyano, halo, hydroxyalkyl, alkoxyalkyl, (R 1 R 2 N)alkyl, (alkyl) 2 (O)P, (alkyl)(O)(NR 1 )S, alkylSO 2 , and alkylSO 2 NH.

17. A compound of claim 13 where R 1 is hydrogen and R 2 is hydrogen.

18. A compound of claim 13 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

19. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

20. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

21. A method for treating a heart disease comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

22. The method of claim 21 wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and cardiac iatrogenic damage.

23. The method of claim 22 wherein the heart failure is selected from the group consisting of congestive heart failure, systolic heart failure, diastolic heart failure, heart failure with reduced ejection fraction (HF R EF), heart failure with preserved ejection fraction (HF P EF), acute heart failure, chronic heart failure of ischemic and non-ischemic origin.

24. A compound, which is

25. A pharmaceutically acceptable salt of

26. A composition comprising the compound of claim 24 and a pharmaceutically acceptable carrier, diluent, or excipient.

27. A composition comprising the pharmaceutically acceptable salt of claim 25 and a pharmaceutically acceptable carrier, diluent, or excipient.

28. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 24 .

29. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutically acceptable salt of claim 25 .

30. A compound, which is

31. A pharmaceutically acceptable salt of

32. A composition comprising the compound of claim 30 and a pharmaceutically acceptable carrier, diluent, or excipient.

33. A composition comprising the pharmaceutically acceptable salt of claim 31 and a pharmaceutically acceptable carrier, diluent, or excipient.

34. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 30 .

35. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutically acceptable salt of claim 31 .

36. A compound, which is

37. A pharmaceutically acceptable salt of

38. A composition comprising the compound of claim 36 and a pharmaceutically acceptable carrier, diluent, or excipient.

39. A composition comprising the pharmaceutically acceptable salt of claim 37 and a pharmaceutically acceptable carrier, diluent, or excipient.

40. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 36 .

41. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutically acceptable salt of claim 37 .

42. A compound, which is

43. A pharmaceutically acceptable salt of

44. A composition comprising the compound of claim 42 and a pharmaceutically acceptable carrier, diluent, or excipient.

45. A composition comprising the pharmaceutically acceptable salt of claim 43 and a pharmaceutically acceptable carrier, diluent, or excipient.

46. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 42 .

47. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutically acceptable salt of claim 43 .

48. A compound, which is

49. A pharmaceutically acceptable salt of

50. A composition comprising the compound of claim 48 and a pharmaceutically acceptable carrier, diluent, or excipient.

51. A composition comprising the pharmaceutically acceptable salt of claim 49 and a pharmaceutically acceptable carrier, diluent, or excipient.

52. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 48 .

53. A method for treating heart failure comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutically acceptable salt of claim 49 .