N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran 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-A-2):
or a pharmaceutically acceptable salt thereof, wherein:
R d is (CH 2 ) m (CHR e ) n (CH 2 ) p H;
m, n, and p are each independently 0 or 1;
R e is H, OH, halo, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 4b1 and R 4b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;
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;
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; or
R 2c and R 3c , together with the carbon atoms to which they are attached, form a ring of formula:
Z 1 and Z 2 are each independently O or CH 2 ;
each R is independently H or halo; and
R 4c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.
2. The compound of claim 1 , wherein the compound has formula (I-B-2):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4b1 is H or C 1 -C 6 alkyl,
optionally wherein R 4b1 is H or CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4b2 is H or C 1 -C 6 alkyl,
optionally wherein R 4b2 is H or CH 3 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5b1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl,
optionally wherein R 5b1 is CH 3 or CF 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5b2 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl,
optionally wherein R 5b2 is CH 3 or CF 3 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2c is OH or C 1 -C 6 alkoxy,
optionally wherein R 2c is OH, OCH 3 , or OCH(CH 3 ) 2 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3c is halo or C 1 -C 6 haloalkyl,
optionally wherein R 3c is F, CHF 2 , or CF 3 .
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4c is H, halo, or C 1 -C 6 haloalkoxy,
optionally wherein R 4c is H, F, or OCHF 2 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R d is H.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R d is (CHR c ) n (CH 2 ) p H,
optionally wherein R d is CH 2 OH.
12. The compound of claim 1 , wherein the compound is selected from:
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 in non-salt form.
15. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
16. 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.
17. A method of treating or lessening the severity in a subject of pain comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18. 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.
19. A compound of formula (I-A):
or a pharmaceutically acceptable salt thereof, wherein:
X 2a is N, N + —O − , or C—R 2a ;
X 3a is N + —O − ;
X 5a is N, N + —O − , or C—R 5a ;
X 6a is N, N + —O − , or C—R 6a ;
R d is (CH 2 ) m (CHR e ) n (CH 2 ) p H;
m, n, and p are each independently 0 or 1;
R e is H, OH, halo, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 2a and R 6a are each independently H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 5a is H, halo, CH 2 OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4b1 and R 4b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;
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; or
X 3c is C—R 3c , and R 2c and R 3c , together with the carbon atoms to which they are attached, form a ring of formula:
Z 1 and Z 2 are each independently O or CH 2 ;
each R is independently H or halo;
R 4c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C1-C 6 alkoxy, or C1-C 6 haloalkoxy;
R 5c is H, halo, C 1 -C 6 alkyl, or C1-C 6 haloalkyl; and
R 6c is H, halo, C 1 -C 6 alkyl, or C1-C 6 haloalkyl;
provided that no more than two of X 2a X 3a X 5a , and X 6a are N or N + —O − ; and
provided that no more than one of X 3c , X 4c , X 5c , and X 6c is N.
20. A compound of formula (I-A):
or a pharmaceutically acceptable salt thereof, wherein:
X 2a is N, N + —O − , or C—R 2a ;
X 3a is N;
X 6a is N, N + —O − , or C—R 6a ;
R d is (CH 2 ) m (CHR e ) n (CH 2 ) p H;
m, n, and p are each independently 0 or 1;
R e is H, OH, halo, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 2a and R 6a are each independently H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4b1 and R 4b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;
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 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 4c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
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;
(i) X 5a is C—R 5a ;
R 5a is halo, CH 2 OH, C1-C 6 alkyl, or C 1 -C 6 haloalkyl;
X 3c is C—R 3c ; and
(a) R 3c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or
(b) R 2c and R 3c , together with the carbon atoms to which they are attached, form a ring of formula:
wherein
Z 1 and Z 2 are each independently O or CH 2 ; and
each R is independently H or halo; or
(ii) X 5a is N, N + —O − , or C—R 5a ;
R 5a is H; and
X 3c is N,
provided that no more than two of X 2a , X 3a , X 5a , and X 6a are N or N + —O − ; and
provided that no more than one of X 3c , X 4c , X 5c , and X 6c is N.
21. The compound of claim 19 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 20 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.