Substituted macrocyclic compounds and related methods of treatment

11542,276

17/104993

November 25, 2020

The present invention provides compounds useful for the treatment of narcolepsy or cataplexy in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.

Alkermes, Inc. (Waltham, MA, US)

Alkermes, Inc. (Waltham, MA, US)

1. A compound of Formula I or a pharmaceutically acceptable salt thereof: [chemical expression included] wherein: ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; T is CR 1 R 2 or O; W is CR 4 R 5 or O; U is CR 6 R 7 ; X is CR 8 R 9 ; V is CR 3 or N; Y is NR 10 , O or absent; Z is (CR 12 R 13) m ; R is halogen or deuterium; and p is 0, 1, 2, 3, or 4; and further wherein: m is 1, 2, 3, or 4; R 1 , R 2 , R 4 , and R 5 are each, independently, selected from the group consisting of H, halogen, and deuterium; or, alternatively, R 2 and R 5 together with the carbon atoms to which they are attached, form a single bond; R 3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or, alternatively, R 3 and R 1 , together with the carbon atoms to which they are attached, form a C 3 -C 5 cycloalkyl; or, alternatively, R 3 and R 4 , together with the carbon atoms to which they are attached, form a C 3 -C 5 cycloalkyl; R 6 , R 7 , R 8 , R 9 , and R 11 are each, independently, selected from the group consisting of H, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen atoms; and each R 12 and R 13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen atoms.

2. The compound of claim 1 , wherein n is 1 or 2.

3. The compound of claim 1 , wherein ring A is phenyl.

4. The compound of claim 1 , wherein ring A is pyridinyl.

5. The compound of claim 1 , wherein Y is O.

6. The compound of claim 1 , wherein Y is absent.

7. The compound of claim 1 , wherein T is CR 1 R 2 .

8. The compound of claim 1 , wherein T is O.

9. The compound of claim 1 , wherein W is CR 4 R 5 .

10. The compound of claim 1 , wherein W is O.

11. The compound of claim 1 , wherein V is CR 3 .

12. The compound of claim 1 , wherein m is 1 or 2.

13. The compound of claim 1 , wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included]

14. A compound of Formula II or a pharmaceutically acceptable salt thereof: [chemical expression included] wherein: ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; T is CR 1 R 2 or O; W is CR 4 R 5 or O; U is CR 6 R 7 ; X is CR 8 R 9 ; V is CR 3 or N; Y is NR 10 , O or absent; Z is (CR 12 R 13) m ; R is halogen or deuterium; and p is 0, 1, 2, 3, or 4; and further wherein: m is 2, 3, 4, or 5 when Y is absent; or m is 1, 2, 3, or 4 when Y is NR 10 or O; R 1 , R 2 , R 4 , and R 5 are each, independently, selected from the group consisting of H, halogen, and deuterium; or, alternatively, R 2 and R 5 together with the carbon atoms to which they are attached, form a single bond; R 3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or, alternatively, R 3 and R 1 , together with the carbon atoms to which they are attached, form a C 3 -C 5 cycloalkyl; or, alternatively, R 3 and R 4 , together with the carbon atoms to which they are attached, form a C 3 -C 5 cycloalkyl; R 6 , R 7 , R 8 , R 9 , and R 11 are each, independently, selected from the group consisting of H, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen atoms; and each R 12 and R 13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen atoms.

15. The compound of claim 14 , wherein n is 1 or 2.

16. The compound of claim 14 , wherein ring A is phenyl.

17. The compound of claim 14 , wherein ring A is pyridinyl.

18. The compound of claim 14 , wherein Y is O.

19. The compound of claim 14 , wherein Y is absent.

20. The compound of claim 14 , wherein T is CR 1 R 2 .

21. The compound of claim 14 , wherein T is O.

22. The compound of claim 14 , wherein W is CR 4 R 5 .

23. The compound of claim 14 , wherein W is O.

24. The compound of claim 14 , wherein V is CR 3 .

25. The compound of claim 14 , wherein m is 1 or 2.

26. The compound of claim 14 , wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included]

27. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.

29. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound of claim 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

31. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 14 or a pharmaceutically acceptable salt thereof.

32. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 14 or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

39. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

41. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

42. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

43. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

44. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

45. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

46. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

50. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

51. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

52. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

53. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

54. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

55. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

56. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

57. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

58. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

59. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

60. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

61. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

62. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

63. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

64. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

65. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

66. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

67. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

68. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

69. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

70. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

71. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

72. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

73. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

74. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

75. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

76. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

77. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

78. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

79. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

80. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

81. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

82. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

83. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

84. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

85. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

86. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

87. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

88. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

89. The compound of claim 1 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

90. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

91. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

92. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

93. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

94. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

95. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

96. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

97. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

98. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

99. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

100. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

101. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

102. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

103. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

104. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

105. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

106. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

107. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

108. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

109. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

110. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

111. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

112. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

113. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

114. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

115. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

116. The compound of claim 14 , wherein the compound is: [chemical expression included] or a pharmaceutically acceptable salt thereof.

117. A pharmaceutical composition comprising a compound of claim 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

118. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 13 or a pharmaceutically acceptable salt thereof.

119. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 13 or a pharmaceutically acceptable salt thereof.

120. A pharmaceutical composition comprising a compound of claim 26 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

121. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 26 or a pharmaceutically acceptable salt thereof.

122. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 26 or a pharmaceutically acceptable salt thereof.

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