Phospholipid compounds and methods of making and using the same

Abstract

Phospholipid compounds and methods of using the same, singly or in combination with additional agents, and pharmaceutical formulations of said compounds for the treatment of viral infections are disclosed.

Description

The abstract discloses phospholipid compounds and methods of using them alone or in combination with additional agents, as well as pharmaceutical formulations of such compounds for the treatment of viral infections.

Claims

CLAIMS 1. A compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof, wherein: R1is H, C3-10 cycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl containing one, two, or three N; the cycloalkyl, aryl, or heteroaryl of R1is optionally substituted with one, two, or three groups independently selected from R1Aand -NR13AR14A; each R1Ais independently halo, -CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3haloalkoxy, C3-6cycloalkyl, or 5-10 membered heteroaryl containing one, two, or three heteroatoms selected from N and O; each R13Ais independently H or C1-C3 alkyl optionally substituted witheach R14Ais independently H or C1-3alkyl; R2is H or C1-3 alkyl; R3is C1-3haloalkyl; Q is C10-21alkylene or C10-21alkenylene; the alkylene or alkenylene of Q is optionally substituted with 1 to 6 Q1A; each Q1Ais independently halo; L is a bond, -O-, or -O(CR12AR12B)n-; each R12Ais independently H or C1-6alkyl; each R12Bis independently H or C1-6 alkyl; and n is 1 or 2; X is a bond or C1-3alkylene; T is a bond or -O-; and Z is C1-6 alkylene;with the proviso that when X is a bond and T is -O-, then L is a bond.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Ia3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Ib4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R2is H.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Z is -(CH2)r-, r is 1-6.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein Z is -(CH2)r-, r is 1-3.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Z is -(CH2)3-.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Z is -(CH2)2-.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Z is -CH2-.

10. The compound of any one of claims 1-6 and 9, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Ic:

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein L is -O(CR12AR12B)n-; each R12Ais independently H or C1-6alkyl; each R12Bis independently H or C1-6alkyl; and n is 1 or 2.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L is -O(CR12AR12B)-; R12Ais H or C1-6alkyl; and R12Bis H or C1-6alkyl.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein L is -O(CR12AR12B)-; R12Ais H or C1-3 alkyl; and R12Bis H or C1-3 alkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L is -OCH2-.

15. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, whereinR1is C6-10 aryl, or 5-10 membered heteroaryl containing one, two, or three N; the aryl, or heteroaryl of R1is optionally substituted with one, two, or three groups independently selected from R1Aand -NR13AR14A; each R1Ais independently halo, -CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, or 5-10 membered heteroaryl containing one, two, or three heteroatoms selected from N and O; each R13Ais independently H or C1-3 alkyl optionally substituted with NR13A1R14A1; R13A1is H or C1-3 alkyl; R14A1is H or C1-3 alkyl; and each R14Ais independently H or C1-3alkyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1is C6-10 aryl, or 5-10 membered heteroaryl containing one, two, or three N; the aryl or heteroaryl of R1is optionally substituted with one, two, or three groups independently selected from R1A; and each R1Ais independently halo, -CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3haloalkoxy, or 5-10 membered heteroaryl containing one, two, or three heteroatoms selected from N and O.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R1is C6-10aryl, or 5-10 membered heteroaryl containing one or two N; the aryl or heteroaryl of R1is optionally substituted with one, two, or three groups independently selected from R1A; and each R1Ais independently halo, -CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, or 5-10 membered heteroaryl containing one, two, or three heteroatoms selected from N and O.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, whereinR1is phenyl or naphthyl; the phenyl or naphthyl of R1is optionally substituted with one, two, or three groups independently selected from R1A; and each R1Ais independently halo, -CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3 haloalkoxy, or 5-10 membered heteroaryl containing one, two, or three heteroatoms selected from N and O.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl optionally substituted with one, two, or three groups independently selected from R1A; and each R1Ais independently halo, -CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3 haloalkoxy, or 5-10 membered heteroaryl containing one, two, or three heteroatoms selected from N and O.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl optionally substituted with one or two groups independently selected from R1A; and each R1Ais independently halo, -CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3 haloalkoxy, or 5-10 membered heteroaryl containing one, two, or three heteroatoms selected from N and O.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl optionally substituted with one or two groups independently selected from R1A; and each R1Ais independently halo, -CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or 5-10 membered heteroaryl containing one, two, or three N.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, whereinR1is phenyl optionally substituted with one or two groups independently selected from R1A; and each R1Ais independently halo, -CN, C1-3alkoxy, or 5-6 membered heteroaryl containing one, two, or three N.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl optionally substituted with one or two groups independently selected from R1A; and each R1Ais independently halo, C1-3alkoxy, or -CN.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl optionally substituted with one or two groups independently selected from R1A; and each R1Ais independently F, or -CN.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with F and -CN.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with F and -OCH3.

29. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R1is H.

30. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein31. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R1-L- is H.

32. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R1is 5-10 membered heteroaryl containing one or two N; the heteroaryl of R1is optionally substituted with one, two, or three groups independently selected from R1A; and each R1Ais independently halo, -CN, or C1-3 alkoxy.

33. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1is quinolinyl optionally substituted with one or two groups independently selected from R1A; and each R1Ais independently halo, -CN, or C1-3 alkoxy.

34. The compound of any one of claims 1-6, 9, and 10, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Id:

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein X is a bond.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein X is C1-3 alkylene.

37. The compound of any one of claims 1-34 and 36, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-.

38. The compound of any one of claims 1-34 and 36, or a pharmaceutically acceptable salt thereof, wherein X is -C2H4-.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein T is a bond.

40. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein T is -O-.

41. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Ie:

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein Q is C10-21alkylene optionally substituted with 1 to 6 Q1A; each Q1Ais independently halo.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein Q is C10-21alkylene, optionally Q is –(CH2)m-, m is 10-21.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein Q is C13-21 alkylene, optionally Q is –(CH2)m-, m is 13-21.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein Q is C15-20alkylene, optionally Q is –(CH2)m-, m is 15-20.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein Q is -C16H32-, optionally Q is –(CH2)16-.

47. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein Q is -C17H34-, optionally Q is –(CH2)17-.

48. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein Q is -C18H36-, optionally Q is –(CH2)18-.

49. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein Q is -C19H38-, optionally Q is –(CH2)19-.

50. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein Q is -C20H40-, optionally Q is –(CH2)20-.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein R3is C1-3fluoroalkyl.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein R3is -CF3.

53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein R3is – CF2CF3.

54. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein R3is -CHF2.

55. A compound as shown in Table 1, or a pharmaceutically acceptable salt thereof.

56. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

57. The pharmaceutical composition of claim 56, wherein the pharmaceutical composition is for oral administration.

58. A method of treating or preventing a viral infection in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-55, or a therapeutically effective amount of the pharmaceutical composition of claim 56.

59. The method of claim 58, wherein the compound or the pharmaceutical composition is administered to the subject via oral, intravenous, subcutaneous, or inhalation administration.

60. The method of claim 58 or 59, wherein the compound or the pharmaceutical composition is administered to the subject via oral administration.

61. The method of any one of claims 58-60, wherein the method comprises administering to the human at least one additional therapeutic agent or prophylactic agent.

62. The method of claim 61, wherein the at least one additional therapeutic agent comprises an influenza A treatment agent, an influenza B treatment agent, a coronavirus treatment agent, or a COVID-19 treatment agent.

63. The method of any one of claims 58-62, wherein the viral infection is Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, or Orthomyxovirus virus infection.

64. The method of any one of claims 58-63, wherein the viral infection is pneumoviridae virus infection.

65. The method of any one of claims 58-64, wherein the viral infection is human metapneumoavirus (hMPV).

66. The method of any one of claims 58-64, wherein the viral infection is respiratory syncytial virus infection.

67. The method of any one of claims 58-63, wherein the viral infection is picornaviridae.

68. The method of any one of claims 58-63 and 67, wherein the viral infection is Human rhinovirus (HRV).

69. The method of any one of claims 58-63 and 67, wherein the viral infection is enterovirus.

70. Use of a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.

71. The use of claim 70, wherein the medicament is used with at least one additional therapeutic agent.

72. The use of claim 71, wherein the at least one additional therapeutic agent comprises an influenza A treatment agent.

73. The use of claim 71, wherein the at least one additional therapeutic agent comprises an influenza B treatment agent.

74. The use of claim 71, wherein the at least one additional therapeutic agent comprises an agent for the treatment of coronavirus.

75. The use of claim 71, wherein the at least one additional therapeutic agent comprises an agent for the treatment of COVID-19.