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1. WO2020205934 - PYRROLE COMPOUNDS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:


wherein:

R1 is an unsubstituted or a substituted C2 alkenyl, an unsubstituted or a substituted C2 alkynyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted bicyclic heteroaryl or an unsubstituted or a substituted monocyclic heterocyclyl, wherein when the C2 alkenyl, the C2 alkynyl, an unsubstituted Ci-4 haloalkyl and the monocyclic heteroaryl are substituted, the C2 alkenyl, the C2 alkynyl and the monocyclic heteroaryl are independently substituted with one or more substituents selected from the group consisting of halogen, an unsubstituted Ci-4 alkyl, an unsubstituted Ci-4 haloalkyl, an unsubstituted C i-4 hydroxyalkyl, an unsubstituted monocyclic C3-6 cycloalkyl and a hydroxy-substituted monocyclic C3-6 cycloalkyl;

R2 and R3 are independently selected from the group consisting of hydrogen, an unsubstituted or a substituted Ci-4 alkyl, an unsubstituted Ci-4 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, an unsubstituted Ci-4 hydroxyalkyl and an unsubstituted C 1-5 alkoxyalkyl, wherein when the monocyclic C3-6 cycloalkyl and the monocyclic 3-6 heterocyclyl are substituted, the monocyclic C3-6 cycloalkyl and the monocyclic 3-6 heterocyclyl are independently substituted with one or more substituents selected from the group consisting of halogen or hydroxy, and wherein when the Ci-4 alkyl is substituted, the Ci-4 alkyl is substituted with one or more substituents selected from the group consisting of a phosphate, an O-linked a-amino acid and an O-carboxy, and provided that at least one of R2 and R3 is not hydrogen; or

R2 and R3 are taken together along with the carbon to which R2 and R3 are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl or an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, wherein when the C3-6 cycloalkyl and 3-6 membered heterocyclyl are substituted, the C3-6 cycloalkyl and the 3-6 membered heterocyclyl are independently substituted with 1 or 2 substituents selected from the group consisting of halogen and hydroxy;

R4 and R5 are independently hydrogen, halogen, an unsubstituted Ci-4 alkyl, a deuterated Ci-4 alkyl or an unsubstituted C2-4 alkenyl;

R6 is hydrogen, an unsubstituted Ci-4 alkyl, a deuterated Ci-4 alkyl or an unsubstituted C3-4 alkenyl; and

provided that at least one of R4, R5 and R6 is not hydrogen; or

R5 is hydrogen, halogen, an unsubstituted Ci-4 alkyl or an unsubstituted C2-4 alkenyl; and R4 and R6 are taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring;

X s CRA or N;

R7a, R7b, R7C and R7d are independently hydrogen, halogen, an unsubstituted Ci-4 haloalkyl, cyano or an unsubstituted Ci-4 alkoxy;

R8 is hydrogen, -CH20C(=0)-(an unsubstituted Ci-4 alkyl), -CH20C(=0)-0(an unsubstituted Ci-4 alkyl), -CH2-(a-amino acid) or -CTb-phosphate; and

RA is hydrogen, halogen, an unsubstituted Ci-4 haloalkyl or cyano.

2. The compound of Claim 1, wherein R2 and R3 are independently selected from the group consisting of hydrogen, an unsubstituted Ci-4 alkyl, an unsubstituted Ci-4 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, an unsubstituted Ci-4 hydroxyalkyl and an unsubstituted C1-5 alkoxyalkyl, wherein when the monocyclic C3-6 cycloalkyl and the monocyclic 3-6 heterocyclyl are substituted, the monocyclic C3-6 cycloalkyl and the monocyclic 3-6 heterocyclyl are independently substituted with one or more substituents selected from the group consisting of halogen or hydroxy.

3. The compound of Claim 2, wherein R2 and R3 are each an unsubstituted Ci-4 alkyl.

4. The compound of Claim 1, wherein R2 and R3 are independently selected from the group consisting of hydrogen, a substituted Ci-4 alkyl, an unsubstituted Ci-4 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, an unsubstituted Ci-4 hydroxyalkyl and an unsubstituted C 1-5 alkoxyalkyl, wherein the Ci-4 alkyl is substituted with one or more substituents selected from the group consisting of a phosphate, an O-linked a-amino acid and an O-carboxy.

5. The compound of any one of Claims 1-4, wherein one of R2 and R3 is hydrogen.

6. The compound of Claim 5, wherein the other of R2 and R3 is an unsubstituted Ci-4 alkyl.

7. The compound of Claim 5, wherein the other of R2 and R3 is a substituted Ci-4 alkyl, wherein when the Ci-4 alkyl is substituted, the Ci-4 alkyl is substituted with one or more substituents selected from the group consisting of a phosphate, an O-linked a-amino acid and an O-carboxy.

8. The compound of Claim 5, wherein the other of R2 and R3 is an unsubstituted Ci-4 haloalkyl.

9. The compound of Claim 5, wherein the other of R2 and R3 is an unsubstituted monocyclic C3-6 cycloalkyl.

10. The compound of Claim 5, wherein the other of R2 and R3 is a substituted monocyclic C3-6 cycloalkyl.

11. The compound of Claim 5, wherein the other of R2 and R3 is an unsubstituted monocyclic 3-6 membered heterocyclyl.

12. The compound of Claim 5, wherein the other of R2 and R3 is a substituted monocyclic 3-6 membered heterocyclyl.

13. The compound of Claim 5, wherein the other of R2 and R3 is an unsubstituted Ci-4 hydroxyalkyl.

14. The compound of Claim 5, wherein the other of R2 and R3 is an unsubstituted Ci-5 alkoxyalkyl.

15. The compound of Claim 1, wherein R2 and R3 are taken together along with the carbon to which R2 and R3 are attached to form an unsubstituted or a substituted

monocyclic C3-6 cycloalkyl or an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, wherein when the C3-6 cycloalkyl and 3-6 membered heterocyclyl are substituted, the C3-6 cycloalkyl and the 3-6 membered heterocyclyl are independently substituted with 1 or 2 substituents selected from the group consisting of halogen and hydroxy.

16. The compound of Claim 15, wherein R2 and R3 are taken together along with the carbon to which R2 and R3 are attached to form an unsubstituted monocyclic C3-6 cycloalkyl.

17. The compound of Claim 15, wherein R2 and R3 are taken together along with the carbon to which R2 and R3 are attached to form a substituted monocyclic C3-6 cycloalkyl

18. The compound of Claim 55, wherein R2 and R3 are taken together along with the carbon to which R2 and R3 are attached to form an unsubstituted monocyclic 3-6 membered heterocyclyl.

19. The compound of Claim 15, wherein R2 and R3 are taken together along with the carbon to which R2 and R3 are attached to form a substituted monocyclic 3-6 membered heterocyclyl.

20. The compound of Claim 18 or 19, wherein the monocyclic 3-6 membered heterocyclyl is selected from the group consisting of an unsubstituted or substituted oxetane,

an unsubstituted or substituted thietane, an unsubstituted or substituted
an



unsubstituted or substituted O an unsubstituted or substituted an

s/:

unsubstituted or substituted
an unsubstituted or substituted
and an

unsubstituted or substituted
.

21. The compound of any one of Claims 1-20, wherein R4 is hydrogen.

22. The compound of any one of Claims 1-20, wherein R4 is halogen.

23. The compound of any one of Claims 1-20, wherein R4 is an unsubstituted Ci-4 alkyl.

24. The compound of any one of Claims 1-20, wherein R4 is a deuterated Ci-4 alkyl.

25. The compound of any one of Claims 1-24. wherein R5 is hydrogen.

26. The compound of any one of Claims 1-24. wherein R5 is halogen.

27. The compound of any one of Claims 1-24. wherein R5 is an unsubstituted Ci-4 alkyl.

28. The compound of any one of Claims 1-27. wherein R6 is an unsubstituted Ci-4 alkyl.

29. The compound of any one of Claims 1-27, wherein R6 is an unsubstituted C3-4 alkenyl.

30. The compound of any one of Claims 1-20, wherein R5 is hydrogen; and R4 and R6 are taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring.

31. The compound of any one of Claims 1-20, wherein R5 is halogen; and R4 and R6 are taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring.

32. The compound of any one of Claims 1-20, wherein R5 is an unsubstituted Ci-4 alkyl; and R4 and R6 are taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring.

33. The compound of any one of Claims 1-20, wherein R5 is an unsubstituted C2-4 alkenyl; and R4 and R6 are taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring.

34. The compound of any one of Claims 1-33, wherein X1 is N.

35. The compound of any one of Claims 1-33, wherein X1 is CRA.

36. The compound of Claim 35, wherein RA is hydrogen.

37. The compound of Claim 35, wherein RA is halogen.

38. The compound of Claim 35, wherein RA is an unsubstituted Ci-4 haloalkyl.

39. The compound of Claim 35, wherein RA is cyano.

40. The compound of Claim 35, wherein RA is an unsubstituted Ci-4 alkoxy.

41. The compound of any one of Claims 1-40, wherein R7a is hydrogen.

42. The compound of any one of Claims 1-40, wherein R7a is halogen.

43. The compound of any one of Claims 1-40, wherein R7a is an unsubstituted Ci- 4 haloalkyl.

44. The compound of any one of Claims 1-40, wherein R7a is cyano.

45. The compound of any one of Claims 1-40, wherein R7a is an unsubstituted Ci- 4 alkoxy.

46. The compound of any one of Claims 1-45, wherein R7b is hydrogen.

47. The compound of any one of Claims 1-45, wherein R7b is halogen.

48. The compound of any one of Claims 1-45, wherein R b is an unsubstituted Ci- 4 haloalkyl.

49. The compound of any one of Claims 1-45, wherein R7b is cyano.

50. The compound of any one of Claims 1-45, wherein R b is an unsubstituted Ci- 4 alkoxy.

51. The compound of any one of Claims 1-50, wherein R7c is hydrogen.

52. The compound of any one of Claims 1-50, wherein R7c is halogen.

53. The compound of any one of Claims 1-50, wherein R7c is an unsubstituted Ci- 4 haloalkyl.

54. The compound of any one of Claims 1-50, wherein R7c is cyano.

55. The compound of any one of Claims 1-50, wherein R7c is an unsubstituted Ci- 4 alkoxy.

56. The compound of any one of Claims 1-55, wherein R7d is hydrogen.

57. The compound of any one of Claims 1-55, wherein R7d is halogen.

58. The compound of any one of Claims 1-55, wherein R7d is an unsubstituted Ci- 4 haloalkyl.

59. The compound of any one of Claims 1-55, wherein R7d is cyano.

60. The compound of any one of Claims 1-55, wherein R7d is an unsubstituted Ci- 4 alkoxy.

61. The compound of any one of Claims 1-60, wherein R1 is an unsubstituted C2 alkenyl.

62. The compound of any one of Claims 1-60, wherein R1 is a substituted C2 alkenyl.

63. The compound of any one of Claims 1-60, wherein R1 is an unsubstituted C2 alkynyl.

64. The compound of any one of Claims 1-60, wherein R1 is a substituted C2 alkynyl.

65. The compound of any one of Claims 1-60, wherein R1 is an unsubstituted Ci-4 haloalkyl.

66. The compound of any one of Claims 1-60, wherein R1 is an unsubstituted monocyclic heteroaryl.

67. The compound of any one of Claims 1-60, wherein R1 is a substituted monocyclic heteroaryl.

68. The compound of any one of Claims 1-60, wherein R1 is an unsubstituted bicyclic heteroaryl.

69. The compound of any one of Claims 1-60, wherein R1 is a substituted bicyclic heteroaryl.

70. The compound of any one of Claims 1-60, wherein R1 is an unsubstituted monocyclic heterocyclyl.

71. The compound of any one of Claims 1-60, wherein R1 is a substituted monocyclic heterocyclyl.

72. The compound of any one of Claims 1-71, wherein R8 is hydrogen.

73. The compound of any one of Claims 1-71, wherein R8 is -CH20C(=0)-(an unsubstituted Ci-4 alkyl).

74. The compound of any one of Claims 1-71, wherein R8 is -CH20C(=0)-0(an unsubstituted Ci-4 alkyl).

75. The compound of any one of Claims 1-71, wherein R8 is -CH2-(a-amino acid).

76. The compound of any one of Claims 1-71, wherein R8 is -CTh-phosphate.

77. The compound of Claim 1, wherein the compound is selected from the group consisting of :


foregoing.

78. The compound of Claim 1, wherein the compound is selected from the group consisting of :




, or a pharmaceutically acceptable salt of any of the foregoing.

79. The compound of Claim 78 or 79, wherein the compound is selected from the group consisting of :




, or a pharmaceutically acceptable salt of any of the foregoing.

any of the foregoing.

81. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-80, or a pharmaceutically acceptable salt thereof, and excipient.

82. Use of the compound of any one of Claims 1-80 in the preparation of a medicament for the treatment of hepatitis B.

83. Use of the compound of any one of Claims 1-80 in the preparation of a medicament for the treatment of hepatitis D.

84. The use of any one of Claims 82-83, wherein the use further comprises the use of one or more additional agents selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence specific oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator.

85. The use of Claim 84, wherein the one or more additional agents are selected from the group consisting of recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide and tenofovir disoproxil.

86. A compound of any one of Claims 1-80 for use in treating hepatitis B.

87. A compound of any one of Claims 1-80 for use in treating hepatitis D.

88. The compound of any one of Claims 86-87, wherein the compound is used in combination with one or more additional agents selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence specific oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator.

89. The compound of Claim 88, wherein the one or more additional agents are selected from the group consisting of recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide and tenofovir disoproxil.

90. A method for treating hepatitis B in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-80 suffering from hepatitis B.

91. A method for treating hepatitis D in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-80 suffering from hepatitis D.

92. The method of any one of Claims 90-91, further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence specific oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator.

93. The method of Claim 92, wherein the additional agent selected from the group consisting of recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide and tenofovir disoproxil.