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;
E is selected from the group consisting of NR a R b , C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, and C 1 -C 3 alkylene-(5- to 10-membered heteroaryl), wherein the C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;
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 O;
Z is (CR 12 R 13 ) m ;
each R is, independently, selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;
p is 0, 1, 2, 3, or 4;
R a and R b are each, independently, H or unsubstituted C 1 -C 3 alkyl;
m is 1;
and further wherein:
R 1 , R 2 , R 4 , and R 5 are each, independently, selected from the group consisting of H, hydroxyl, 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, hydroxyl, halogen, and deuterium;
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 hydroxyl or one or more halogen; and
R 14 , R 15 , and R 16 are each, independently, selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted with one or more halogen; and
each R 17 and R 18 is, independently, selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted with one or more halogen;
with the proviso that one or more of (a)-(f) is present:
(a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;
(b) E is NR a R b , C 1 -C 3 alkylene-NR a R b , C 2 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl), wherein the C 1 -C 3 alkylene-NR a R b , C 2 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;
(c) E is C 1 alkyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;
(d) at least one of R 14 , R 15 , R 16 , R 17 , and R 18 is unsubstituted C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted with one or more halogen;
(e) at least one of R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and Ru is hydroxyl; or
(f) at least one of R 12 and R 13 is C 1 -C 3 alkyl substituted with hydroxyl.
2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. 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, or a composition according to claim 2 .
4. 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, or a composition according to claim 2 .
5. The compound of claim 1 , wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
6. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 1 , wherein the compound is:
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:
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 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
91. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
92. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
93. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
94. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
95. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
96. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
97. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
98. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
99. A pharmaceutical composition comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
100. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 5 or a pharmaceutically acceptable salt thereof, or a composition according to claim 99 .
101. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 5 or a pharmaceutically acceptable salt thereof, or a composition according to claim 99 .
102. The compound of claim 1 , wherein n is 1.
103. The compound of claim 1 , wherein n is 2.
104. The compound of claim 1 , wherein ring A is phenyl.
105. The compound of claim 1 , wherein ring A is pyridinyl.
106. The compound of claim 1 , wherein T is CR 1 R 2 .
107. The compound of claim 1 , wherein T is O.
108. The compound of claim 1 , wherein W is CR 4 R 5 .
109. The compound of claim 1 , wherein W is O.
110. The compound of claim 1 , wherein V is CR 3 .
111. The compound of claim 1 , wherein T is CR 1 R 2 , W is CR 4 R 5 , and V is CR 3 .
112. The compound of claim 103 , wherein ring A is phenyl, T is CR 1 R 2 , W is CR 4 R 5 , and V is CR 3 .
113. The compound of claim 103 , wherein ring A is pyridinyl, T is CR 1 R 2 , W is CR 4 R 5 , and V is CR 3 .