LPA receptor antagonists and uses thereof

1. A compound of Formula (I),

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3 to 10 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6 to 10 membered aryl, or 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R 1A , which can be the same or different, wherein each R 1A is independently selected from halogen, cyano, nitro, oxo, C 1-4 alkyl, C 3-10 cycloalkyl, 3 to 10 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6 to 10 membered aryl, 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —N(R 1B1 )(R 1B2 ), —O—R 1B1 , —S—R 1B1 , —C(O)N(R 1B1 )(R 1B2 ), —NR 1B1 C(O)R 1B2 , —NR 1B1 C(O)N(R 1B2 )(R 1B3 ), —S(O) 0-2 R 1B1 , —S(O) 2 N(R 1B1 )(R 1B2 ), and —NR 1B1 S(O) 2 R 1B2 , wherein each R 1B1 , R 1B2 , and R 1B3 is independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl,

wherein each R 1A alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with 1 to 4 R 1C , which can be the same or different, and wherein each R 1C is independently C 1-4 alkyl, halogen, cyano, —O—R 1D1 , or —N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 is independently hydrogen or C 1-6 alkyl, and

wherein each R 1B1 , R 1B2 , and R 1B3 alkyl and each R 1B1 , R 1B2 , and R 1B3 cycloalkyl is optionally substituted with 1 to 3 halogens; or

R 1 is —O—R 1D1 or —N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 is independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl, wherein each C 1-6 alkyl, or C 3-6 cycloalkyl is optionally substituted with 1 to 4 R 1E , which can be the same or different, wherein each R 1E is independently selected from halogen, cyano, hydroxy, oxo, C 1-4 alkyl, C 3-10 cycloalkyl, 3 to 10 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6 to 10 membered aryl, 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —O—R 1F1 , —N(R 1F1 )(R 1F2 ), —C(O)N(R 1F1 )(R 1F2 ), —NR 1F1 C(O)R 1F2 , —S(O) 0-2 R 1F1 , —S(O) 2 N(R 1F1 )(R 1F2 ), and —NR 1F1 S(O) 2 R 1F2 , wherein each R 1F1 and R 1F2 is independently hydrogen or C 1-6 alkyl, wherein each R 1E alkyl, cycloalkyl, aryl, and heteroaryl is optionally substituted with 1 to 3 R 1G , which can be the same or different, and wherein each R 1G is independently C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halogen, or cyano;

R 2 is hydrogen or C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from halogen, cyano, C 1-4 alkoxy, and C 3-10 cycloalkyl; or

R 2 is C 3-6 cycloalkyl optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from halogen, cyano, C 1-4 alkoxy, and C 1-4 alkyl;

each R 3 is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, —O—R 2A1 , and —N(R 2A1 )(R 2A2 ), wherein the C 1-6 alkyl is optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from C 1-4 alkoxy and halogen, and wherein each R 2A1 and R 2A2 is independently hydrogen or C 1-3 alkyl optionally substituted with 1 to 3 halogens, which can be the same or different;

n is 0, 1, 2, 3, or 4;

R 4 is C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from halogen, cyano, C 1-4 alkoxy, —C(O)N(R 4A1 ), and —N(R 4A1 )(R 4A2 ), wherein each R 4A1 and R 4A2 is independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl; or

R 4 is C 3-6 cycloalkyl or 3 to 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl or heterocyclyl are optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from halogen, cyano, C 1-4 alkyl, and C 1-4 alkoxy;

each of X 1 , X 2 , X 3 , and X 4 is independently selected from CH and N;

each Y 1 and Y 2 is independently hydrogen, deuterium, or C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from deuterium, halogen, cyano, C 2-3 alkynyl, C 1-4 alkoxy, and —C(O)NH—(C 1-4 H 3-9 ); and

Z is C 1-8 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl are each optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 substituents, which can be the same or different, selected from C 1-4 alkoxy and halogen; or

Y 1 and Z together with the carbon to which they are attached form C 3-6 cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl are each optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from cyano, C 1-4 alkyl, C 1-4 alkoxy, C 6-10 aryl, and halogen, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 aryl is optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from C 1-4 alkyl, C 1-4 alkoxy, and halogen, and Y 2 is hydrogen or deuterium.

2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I is of Formula (IIa):

3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIb):

wherein each R 3 can be the same or different.

4. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIc):

5. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IId):

6. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIe):

7. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIf):

wherein each R 3 can be the same or different.

8. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIg):

wherein each R 3 can be the same or different.

9. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIh):

10. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIi):

11. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIj):

12. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIk):

13. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIl):

14. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIm):

15. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIn):

16. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (I) is of Formula (IIo):

17. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is hydrogen.

18. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is C 1-6 alkyl or C 2-6 alkynyl, each optionally substituted with 1 to 4 R 1A , which can be the same or different, wherein each R 1A is independently selected from halogen, cyano, hydroxy, C 1-4 alkoxy, and C 3-6 cycloalkyl.

19. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is —CH 3 , —CHF 2 , —CF 3 ,

20. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is —O—R 1D1 or —N(R 1D1 )(R 1D2 ), wherein each R 1D and R 1D2 is independently —H, —CH 3 , —C 2 H 5 , or —C(CH 3 ) 3 .

21. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

22. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is cyclopropyl or cyclobutyl, each optionally substituted with 1 to 4 R 1A , which can be the same or different, each independently selected from —F, —Cl, —CN, ═O, —OH, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 —OH, —CH 2 —NH 2 , —OCH 3 , —NH 2 , —NH—CH 2 —CF 3 ,

—NO 2 , cyclopropyl, isoxazyl, phenyl, pyridyl, and —C(O)NH 2 , wherein each isoxazyl or pyridyl is optionally substituted with 1 to 2 —F or —CH 3 .

23. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

24. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the R 1 is bicyclopentanyl or bicyclooctanyl, each optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from —F, —Cl, —OH, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —O—CH 3 , and oxetanyl.

25. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

26. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the R 1 is spiropentanyl, spirohexanyl, spiroheptanyl, or spirodecanyl, each optionally substituted with 1 to 4 R 1A , which can be the same or different, wherein each R 1A is each independently selected from —F, —Cl, —OH, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, and —O—CH 3 .

27. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

28. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is azetidinyl, oxetyl, thietanyl, pyrrolidinyl, dioxolanyl, tetrahydropyranyl, piperidinyl, or morpholinyl, each optionally substituted with 1 to 4 R 1A , which can be the same or different, each independently selected from —F, —Cl, —OH, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —C 2 H 5 , —CH 2 —CF 3 , and —O—CH 3 .

29. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

30. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is an oxabicyclohexanyl optionally substituted with 1 to 4 R 1A , which can be the same or different, wherein each R 1A is independently selected from —F, —Cl, —OH, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , and —O—CH 3 .

31. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

32. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is an oxabicyclohexanyl optionally substituted with 1 to 4 R 1A , which can be the same or different, wherein each R 1A is independently selected from —F, —Cl, —OH, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , and —O—CH 3 .

33. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

34. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is an oxaspiroheptane optionally substituted with 1 to 4 substituents, which can be the same or different, each independently selected from —F, —Cl, —OH, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , and —O—CH 3 .

35. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

36. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is phenyl optionally substituted with 1 to 3 R 1A , which can be the same or different, wherein each R 1A is independently selected from —F, —Cl, —CN, or —CH 3 .

37. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is imidazolyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinonyl, pyrimidinyl, pyridazinyl, benzoisoxazolyl, pyrazolopyridinyl, imidazopyridinyl, or benzoimidazolyl, each optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from —F, —Cl, —CN, —CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —NH 2 , —N(CH 3 ) 2 , —SO 2 —CH 3 ,

38. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is

39. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is —CH 3 or —F.

40. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y 1 is C 1-4 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, and C 1-4 alkoxy, and Y 2 is hydrogen.

41. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y 1 is —CH 3 or —CH 2 F.

42. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is phenyl, optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen and C 1-4 alkyl.

43. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is

44. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is pyridyl, optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from —F, —Cl, —Br, and —CH 3 .

45. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is

46. A pharmaceutical composition comprising a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable excipient.

47. A method of treating, stabilizing, or lessening the severity or progression of an LPAR1 mediated disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.