Substituted macrocyclic compounds and related methods of treatment
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.
1. A compound of Formula I or a pharmaceutically acceptable salt thereof:
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:
14. A compound of Formula II or a pharmaceutically acceptable salt thereof:
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:
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:
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
38. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
40. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
41. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
42. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
43. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
44. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
45. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
46. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
47. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
48. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
49. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
50. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
51. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
52. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
53. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
54. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
55. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
56. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
57. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
58. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
59. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
60. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
61. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
62. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
63. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
64. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
65. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
66. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
67. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
68. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
69. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
70. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
71. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
72. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
73. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
74. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
75. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
76. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
77. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
78. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
79. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
80. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
81. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
82. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
83. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
84. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
85. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
86. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
87. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
88. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
89. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
90. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
91. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
92. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
93. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
94. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
95. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
96. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
97. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
98. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
99. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
100. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
101. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
102. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
103. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
104. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
105. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
106. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
107. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
108. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
109. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
110. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
111. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
112. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
113. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
114. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
115. The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
116. The compound of claim 14 , wherein the compound is:
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.