Carboxamides as modulators of sodium channels
Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.
1. A compound of formula (I-B)
or a pharmaceutically acceptable salt thereof, wherein:
L is O, C(R) 2 , or a single bond;
X 1a is N or CH;
X 2a is N, N—O − , or CR 2a ;
X 3a is N or CR 3a ;
X 4a is N or CR 4a ;
X 5 is N or CR 5 ;
X 6 is N or CR 6 ;
X 7 is N or CR 7 ;
X 9 is N or CR 9 ;
X 10 is N or CR 10 ;
X 11 is N or CR 11 ;
each R is independently H or C 1 -C 6 alkyl;
R 2a is H, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 3a is H, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 4a is H, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 5 , R 6 , and R 7 are defined as follows:
(i) R 5 , R 6 , and R 7 are each independently H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, or —W—(CH 2 ) n ,—R W ;
(ii) R 5 is H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, or —W—(CH 2 ) n ,—R W ; and R 6 and R 7 , together with the carbon atoms to which they are attached, forma ring of formula:
or
(iii) R 5 and R 6 , together with the carbon atoms to which they are attached, form a ring of formula:
and
R 7 is H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n ,—R w :
R 8 is H or —O—(CH 2 ) n —R W ;
R 9 , R 10 , and R 11 are each independently H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n —R W ;
R 12 and R 13 are each independently H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n ,—R W ; or R 12 and R 13 , together with the carbon atoms to which they are attached, form a ring of formula:
Y 1 , Y 2 , Z 1 , and Z 2 are each independently O or C(R 14 ) 2 ;
each R 14 is independently H, halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;
each W is independently O or a single bond;
each R W is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
n is 0 or 1;
wherein when R 8 is H, then at least one of X 5 , X 6 , and X 7 is not N or CH;
wherein one or two of X 1a , X 2a , X 3a , and X 4a is N or N + —O − ;
wherein no more than one of X 5 , X 6 , and X 7 is N;
wherein no more than one of X 9 , X 10 , and X 11 is N.
2. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 .
4. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
5. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
6. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
7. The method of claim 6 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutically acceptable salt.
8. The compound of claim 1 , wherein the compound is
4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 .
10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 8 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
11. A pharmaceutical composition comprising the compound of claim 8 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
12. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 8 , or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 , wherein the voltage-gated sodium channel is Nav1.8.
14. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound claim 8 , or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 , where the method comprises treating or lessening the severity in the subject of neuropathic pain.
16. The method of claim 15 , wherein the neuropathic pain comprises post-herpetic neuralgia.
17. The method of claim 15 , wherein the neuropathic pain comprises idiopathic small-fiber neuropathy.
18. The method of claim 14 , wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain.
19. The method of claim 18 , wherein the musculoskeletal pain comprises osteoarthritis pain.
20. The method of claim 14 , wherein the method comprises treating or lessening the severity in the subject of acute pain.
21. The method of claim 20 , wherein the acute pain comprises acute post-operative pain.
22. The method of claim 14 , wherein the method comprises treating or lessening the severity in the subject of postsurgical pain.
23. The method of claim 22 , wherein the postsurgical pain comprises bunionectomy pain.
24. The method of claim 22 , wherein the postsurgical pain comprises abdominoplasty pain.
25. The method of claim 14 , wherein the method comprises treating or lessening the severity in the subject of visceral pain.
26. The method of claim 14 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, or pharmaceutically acceptable salt thereof.
27. The compound of claim 1 , wherein the compound is
4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 27 .
29. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 27 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
30. A pharmaceutical composition comprising the compound of claim 27 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
31. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 27 , or a pharmaceutically acceptable salt thereof.
32. The method of claim 31 , wherein the voltage-gated sodium channel is Nav1.8.
33. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound claim 27 , or a pharmaceutically acceptable salt thereof.
34. The method of claim 33 , where the method comprises treating or lessening the severity in the subject of neuropathic pain.
35. The method of claim 34 , wherein the neuropathic pain comprises post-herpetic neuralgia.
36. The method of claim 34 , wherein the neuropathic pain comprises idiopathic small-fiber neuropathy.
37. The method of claim 33 , wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain.
38. The method of claim 37 , wherein the musculoskeletal pain comprises osteoarthritis pain.
39. The method of claim 33 , wherein the method comprises treating or lessening the severity in the subject of acute pain.
40. The method of claim 39 , wherein the acute pain comprises acute post-operative pain.
41. The method of claim 33 , wherein the method comprises treating or lessening the severity in the subject of postsurgical pain.
42. The method of claim 41 , wherein the postsurgical pain comprises bunionectomy pain.
43. The method of claim 41 , wherein the postsurgical pain comprises abdominoplasty pain.
44. The method of claim 33 , wherein the method comprises treating or lessening the severity in the subject of visceral pain.
45. The method of claim 33 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, or pharmaceutically acceptable salt thereof.
46. The compound of claim 1 , wherein the compound is
4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl[amino[pyridine -2-carboxamide;
or a pharmaceutically acceptable salt thereof.
47. The compound of claim 46 .
48. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 46 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
49. A pharmaceutical composition comprising the compound of claim 46 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
50. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 46 , or a pharmaceutically acceptable salt thereof.
51. The method of claim 50 , wherein the voltage-gated sodium channel is Nav1.8.
52. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound claim 46 , or a pharmaceutically acceptable salt thereof.
53. The method of claim 52 , where the method comprises treating or lessening the severity in the subject of neuropathic pain.
54. The method of claim 53 , wherein the neuropathic pain comprises post-herpetic neuralgia.
55. The method of claim 53 , wherein the neuropathic pain comprises idiopathic small-fiber neuropathy.
56. The method of claim 52 , wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain.
57. The method of claim 56 , wherein the musculoskeletal pain comprises osteoarthritis pain.
58. The method of claim 52 , wherein the method comprises treating or lessening the severity in the subject of acute pain.
59. The method of claim 58 , wherein the acute pain comprises acute post-operative pain.
60. The method of claim 52 , wherein the method comprises treating or lessening the severity in the subject of postsurgical pain.
61. The method of claim 60 , wherein the postsurgical pain comprises bunionectomy pain.
62. The method of claim 60 , wherein the postsurgical pain comprises abdominoplasty pain.
63. The method of claim 52 , wherein the method comprises treating or lessening the severity in the subject of visceral pain.
64. The method of claim 52 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, or pharmaceutically acceptable salt thereof.
65. The compound of claim 1 , wherein the compound is
44-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
66. The compound of claim 65 .
67. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 65 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
68. A pharmaceutical composition comprising the compound of claim 65 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
69. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 65 , or a pharmaceutically acceptable salt thereof.
70. The method of claim 69 , wherein the voltage-gated sodium channel is Nav1.8.
71. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound claim 65 , or a pharmaceutically acceptable salt thereof.
72. The method of claim 71 , where the method comprises treating or lessening the severity in the subject of neuropathic pain.
73. The method of claim 72 , wherein the neuropathic pain comprises post-herpetic neuralgia.
74. The method of claim 72 , wherein the neuropathic pain comprises idiopathic small-fiber neuropathy.
75. The method of claim 71 , wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain.
76. The method of claim 75 , wherein the musculoskeletal pain comprises osteoarthritis pain.
77. The method of claim 71 , wherein the method comprises treating or lessening the severity in the subject of acute pain.
78. The method of claim 77 , wherein the acute pain comprises acute post-operative pain.
79. The method of claim 71 , wherein the method comprises treating or lessening the severity in the subject of postsurgical pain.
80. The method of claim 79 , wherein the postsurgical pain comprises bunionectomy pain.
81. The method of claim 79 , wherein the postsurgical pain comprises abdominoplasty pain.
82. The method of claim 71 , wherein the method comprises treating or lessening the severity in the subject of visceral pain.
83. The method of claim 71 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, or pharmaceutically acceptable salt thereof.
84. The compound of claim 1 , wherein the compound is
4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
85. The compound of claim 84 .
86. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 84 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
87. A pharmaceutical composition comprising the compound of claim 84 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
88. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 84 , or a pharmaceutically acceptable salt thereof.
89. The method of claim 88 , wherein the voltage-gated sodium channel is Nav1.8.
90. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound claim 84 , or a pharmaceutically acceptable salt thereof.
91. The method of claim 90 , where the method comprises treating or lessening the severity in the subject of neuropathic pain.
92. The method of claim 91 , wherein the neuropathic pain comprises post-herpetic neuralgia.
93. The method of claim 91 , wherein the neuropathic pain comprises idiopathic small-fiber neuropathy.
94. The method of claim 90 , wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain.
95. The method of claim 94 , wherein the musculoskeletal pain comprises osteoarthritis pain.
96. The method of claim 90 , wherein the method comprises treating or lessening the severity in the subject of acute pain.
97. The method of claim 96 , wherein the acute pain comprises acute post-operative pain.
98. The method of claim 90 , wherein the method comprises treating or lessening the severity in the subject of postsurgical pain.
99. The method of claim 98 , wherein the postsurgical pain comprises bunionectomy pain.
100. The method of claim 98 , wherein the postsurgical pain comprises abdominoplasty pain.
101. The method of claim 90 , wherein the method comprises treating or lessening the severity in the subject of visceral pain.
102. The method of claim 90 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, or pharmaceutically acceptable salt thereof.
103. The compound of claim 1 , wherein the compount has formula (I-B- 1 )
or a pharmaceutically acceptable salt thereof, wherein:
L, R, R 2a , R 3a , R 4a , R 8 , R 9 , R 10 , and R 11 , are as defined in claim 36 ;
X 2a is N or N + −O − ;
R 5 , R 6 , and R 7 are each independently H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, or-W-(CH 2 ) n -R w ; and
R 12 and R 13 are each independently H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or -W-(CH 2 ) n -R w .
104. The compound of claim 103 , or a pharmaceutically acceptable salt thereof, wherein L is O; X 2a is N.
105. The compound of claim 104 , or a pharmaceutically acceptable salt thereof, wherein each R is independently H or CH 3 .
106. The compound of claim 105 , or a pharmaceutically acceptable salt thereof, wherein R 3a is H or C 1 -C 6 alkyl; and R 4a is H, halo, or C 1 -C 6 alkyl; R 5 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 alkylamino; R 6 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or -W-(CH 2 ) n -R w ; R 7 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or -W-(CH 2 ) n -R w ; R 8 is H; R 9 is H, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 10 is H or halo; R 11 is halo, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; R 12 is H; and R 13 is H.