Hydroxy and (halo)alkoxy substituted tetrahydrofurans as modulators of sodium channels
Compounds of formula I 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)
or a pharmaceutically acceptable salt thereof, wherein:
X 2a is N, N + —O − , or C—R 2a ;
X 3a is N, N + —O − , C—R 3a , C—CONR 2 , or C—CH 1-n (R A )(OH)(CH 2 OH) n ;
X 4a is N, N + —O − , C—R 4a , C—CONR 2 , or C—CH 1-n (R A )(OH)(CH 2 OH) n ;
X 5a is N, N + —O − , or C—R 5a ;
X 6a is N, N + —O − , or C—R 6a ;
each R is independently H or C 1 -C 6 alkyl;
n is 0 or 1;
R A is H or CH 3 ;
R 2a , R 3a , R 4a , R 5a , and R 6a are each independently H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
one of R 4b1 and R 4b2 is OH, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy, and the other is H;
R 5b1 and R 5b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;
X 3c is N or C—R 3c ;
X 4c is N or C—R 4c ;
X 5c is N or C—R 5c ;
X 6c is N or C—R 6c ;
R 2c is H, OH, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;
L 1 is a bond or O;
L 2 is a bond or C 1 -C 6 alkylene;
R 3c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 5c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
R 6c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
provided that no more than two of X 2a , X 3a , X 4a , X 5a , and X 6a are N or N + —O − ;
provided that at least one of X 3a and X 4a is N, N + —O − , C—R 3a , or C—R 4a , and
provided that no more than one of X 3c , X 4c , X 5c , and X 6c is N.
2 . The compound of claim 1 , wherein the compound has formula (I-A)
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 , wherein the compound has formula (I-A-1)
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 , wherein the compound has formula (I-B)
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 , wherein the compound has formula (I-B-1)
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein X 2a is C—R 2a , and R 2a is H.
7 . The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein X 3a is N, C—CONR 2 , or C—CH 1-n (R A )(OH)(CH 2 OH) n .
8 . The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein X 4a is N, C—CONR 2 , or C—CH 1-n (R A )(OH)(CH 2 OH) n .
9 . The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein one of X 3a and X 4a is N and the other is C—CONR 2 , or C—CH 1-n (R A )(OH)(CH 2 OH) n .
10 . The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 5b1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; and/or R 5b2 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and/or R 3c is halo or C 1 -C 6 alkyl; and/or R 4c is halo; and/or R 5c is H; and/or R 6c is H.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4b2 is C 1 -C 6 alkoxy; or R 4b1 is C 1 -C 6 alkoxy.
13 . A compound selected from:
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 13 in non-salt form.
15 . A pharmaceutical composition comprising: (i) a therapeutically effective amount of the compound of claim 1 and one or more pharmaceutically acceptable carriers or vehicles; or (ii) the compound of claim 1 and one or more pharmaceutically acceptable carriers or vehicles.
16 . A method of inhibiting a voltage-gated sodium channel in a subject, wherein the voltage-gated sodium channel is Na V 1.8, comprising administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
17 . 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.
18 . The method of claim 17 , where the method comprises treating or lessening the severity in the subject of one or more of neuropathic pain, musculoskeletal pain, acute pain, postsurgical pain, or visceral pain.
19 . The method of claim 18 , wherein the neuropathic pain comprises one or more of post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, or diabetic neuropathy.
20 . The method of claim 17 , 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.