Heteroaryl compounds for the treatment of pain
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):
or a pharmaceutically acceptable salt thereof, wherein:
L is —O—, a single bond, —O—C(R) 2 —, —C(R) 2 —, —C(R) 2 —O—, or —N(R)—;
each R is independently H, halo, or C 1 -C 6 alkyl;
X 2 , Y 1 , Y 2 , and Y 3 are defined as follows:
(i) X 2 is CR 2 , Y 1 is CR 1a , Y 2 is CR 2a , and Y 3 is CR 3a ; or
(ii) X 2 is N, Y 1 is CR 1a , Y 2 is CR 2a , and Y 3 is CR 3a ; or
(iii) X 2 is CR 2 , Y 1 is N, Y 2 is CR 2a , and Y 3 is CR 3a ; or
(iv) X 2 is CR 2 , Y 1 is CR 1a , Y 2 is N, and Y 3 is CR 3a ; or
(v) X 2 is CR 2 , Y 1 is CR 1a , Y 2 is + N—O − , and Y 3 is CR 3a ; or
(vi) X 2 is CR 2 , Y 1 is CR 1a , Y 2 is CR 2a , and Y 3 is N;
X 4 , X 5 , X 6 , and X 7 are defined as follows:
(i) X 4 is CR 4 , X 5 is CR 5 , X 6 is CR 6 , and X 7 is CR 7 ; or
(ii) X 4 is N, X 5 is CR 5 , X 6 is CR 6 , and X 7 is CR 7 ; or
(iii) X 4 is CR 4 , X 5 is N, X 6 is CR 6 , and X 7 is CR 7 ; or
(iv) X 4 is CR 4 , X 5 is CR 5 , X 6 is N, and X 7 is CR 7 ; or
(v) X 4 is CR 4 , X 5 is CR 5 , X 6 is CR 6 , and X 7 is N; or
(vi) X 4 is CR 4 , X 5 is N, X 6 is CR 6 , and X 7 is N; or
(vii) X 4 is CR 4 , X 5 is N, X 6 is N, and X 7 is CR 7 ; or
(viii) X 4 is CR 4 , X 5 is CR 5 , X 6 is N, and X 7 is N;
R 2 is H, halo, C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-NR 8 R 9 , C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, C(O)OR 8 , or CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H;
R 4 , R 5 , R 6 , and R 7 are defined as follows:
(i) R 4 , R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl optionally substituted with one or more alkyl, halo, or OH;
(ii) R 4 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl optionally substituted with one or more halo; and
R 5 and R 6 , together with the carbon atoms to which they are attached, form a ring of formula:
or
(iii) R 4 and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted with one or more halo; and
R 5 and R 6 , together with the carbon atoms to which they are attached, form a ring of formula:
R 8 and R 9 are each independently H or C 1 -C 6 alkyl;
each R 10 is independently H or halo;
R 1a is H, halo, CN, C 1 -C 6 alkyl, OH, C(O)NR 12 R 13 , C 1 -C 6 alkoxy, NR 12 R 13 , NR 8 C(O)NR 8 R 9 , (C 1 -C 6 alkylene)-C(O)NR 8 R 9 , (C 1 -C 6 alkylene)-OH, C(O)OR 12 , OR 12 , CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, N═S(═O)(CH 3 ) 2 , N═S(═O)R′R″, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the heterocyclyl or heteroaryl in said 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted with 1-4 substituents selected from OH, halo, oxo, C(O)NR 8 R 9 , NR 8 R 9 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, (C 1 -C 6 alkylene)-O—(C 1 C 6 alkyl), and (C 1 -C 6 alkylene)-NR 8 R 9 ;
R′ and R″, together with the S atom to which they are attached, form a 4-7 membered heterocyclyl;
R 11 , R 2a , and R 3a are each independently H, halo, CN, C 1 -C 6 alkyl, C(O)NR 8 R 9 , or C 1 -C 6 alkoxy;
R 12 and R 13 are each independently H, C(O)(C 1 -C 6 alkyl), (C 1 -C 6 alkylene)-NR 8 R 9 , CH 2 CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, C 1 -C 6 alkyl optionally substituted with one or more OH, indanyl, (C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkylene)-phenyl, (C 1 -C 6 alkylene)-(5-membered heterocyclyl), C 4 -C 7 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the indanyl, (C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkylene)-phenyl, (C 1 -C 6 alkylene)-(5 membered heterocyclyl), C 4 -C 7 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from OH, oxo, C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-OH, and C 1 -C 6 alkoxy;
Z 1 is, 3-7 membered cycloalkenyl, phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl, wherein said 3-7 membered cycloalkenyl, phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents selected from halo, OH, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, CH 2 OH, C(O)H, and C 1 -C 6 haloalkoxy;
m, n, and p are each independently 0 or 1; and
q is 1, 2, or 3,
wherein when X 2 is N, then:
(i) L is O, and Z 1 is phenyl, wherein said phenyl is substituted with 2-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; or
(ii) L is a single bond, and Z 1 is 4-10 membered heterocyclyl, wherein said 4-10 membered heterocyclyl is substituted with 2-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; and
wherein when X 2 , X 4 , X 5 , X 6 and X 7 are each CH, L is a single bond, and Z 1 is phenyl, then said phenyl is substituted with 1-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1a is H, halo, CN, C 1 -C 6 alkyl, OH, C(O)NR 12 R 13 , C 1 -C 6 alkoxy, NR 12 R 13 , (C 1 -C 6 alkylene)-C(O)NR 8 R 9 , (C 1 -C 6 alkylene)-OH, C(O)OR 12 , CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, or N═S(═O)(CH 3 ) 2; and
R 12 and R 13 are each independently H, C(O)(C 1 -C 6 alkyl), (C 1 -C 6 alkylene)-NR 8 R 9 , CH 2 CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, or C 1 -C 6 alkyl optionally substituted with one or more OH.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl optionally substituted with one or more alkyl, halo, or OH.
4 . The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , wherein the compound is selected from:
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 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 4 ; X 5 is N; X 6 is CR 6 ; X 7 is CR 7 .
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 4 ; X 5 is N; X 6 is CR 6 ; X 7 is N.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 4 ; X 5 is CR 5 ; X 6 is N; X 7 is CR 7 .
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 4 ; X 5 is CR 5 ; X 6 is CR 6 ; X 7 is N.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
X 2 is CR 2 ;
Y 1 is CR 1a ;
Y 2 is N or CR 2a ;
Y 3 is CR 3a ;
R 11 , R 2a , and R 3a are each H;
R 1a is C(O)NR 12 R 13 , NR 12 R 13 , NR 8 C(O)NR 8 R 9 , OR 12 , N═S(═O)R′R″, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the heterocyclyl or heteroaryl in said 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted with 1-4 substituents selected from OH, halo, oxo, C(O)NR 8 R 9 , NR 8 R 9 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, (C 1 -C 6 alkylene)-O—(C 1 C 6 alkyl), and (C 1 -C 6 alkylene)-NR 8 R 9 ;
R′ and R″, together with the S atom to which they are attached, form a 4-7 membered heterocyclyl; and
R 12 and R 13 are each independently H, C(O)(C 1 -C 6 alkyl), (C 1 -C 6 alkylene)-NR 8 R 9 , CH 2 CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, C 1 -C 6 alkyl optionally substituted with one or more OH, indanyl, (C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkylene)-phenyl, (C 1 -C 6 alkylene)-(5 membered heterocyclyl), C 4 -C 7 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the indanyl, (C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkylene)-phenyl, (C 1 -C 6 alkylene)-(5-membered heterocyclyl), C 4 -C 7 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from OH, oxo, C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-OH, and C 1 -C 6 alkoxy.
16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is N.
17 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 4 ; X 5 is N; X 6 is CR 6 ; X 7 is CR 7 .
18 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 4 ; X 5 is N; X 6 is CR 6 ; X 7 is N.
19 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 4 ; X 5 is CR 5 ; X 6 is N; X 7 is CR 7 .
20 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 4 ; X 5 is CR 5 ; X 6 is CR 6 ; X 7 is N.
21 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein:
L is a single bond or —C(R) 2 —;
X 2 is CR 2 ;
Z is 3-7 membered cycloalkenyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-7 membered cycloalkenyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
22 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein:
L is a single bond;
X 2 is CR 2 ;
R 1a is H, halo, CN, OH, C(O)NR 12 R 13 , C 1 -C 6 alkoxy, —NR 12 R 13 , (C 1 -C 6 alkylene)-C(O)NR 8 R 9 , (C 1 -C 6 alkylene)-OH, C(O)OR 12 , CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, or N═S(═O)(CH 3 ) 2; and
Z 1 is 4-10 membered heterocyclyl, wherein said 4-10 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
23 . The compound of claim 22 , wherein the compound has formula (I-B-2)
or a pharmaceutically acceptable salt thereof, wherein:
r is 0, 1, 2, 3, or 4; and
each R 14 is independently selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
24 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein:
L is O, —O—C(R) 2 —, or —C(R) 2 —O—;
Z 1 is phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl, wherein said phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, CH 2 OH, C(O)H, and C 1 -C 6 haloalkoxy.
25 . The compound of claim 24 , wherein the compound has formula (I-C-1)
or a pharmaceutically acceptable salt thereof.
26 . The compound of claim 24 , wherein the compound has formula (I-C-2)
or a pharmaceutically acceptable salt thereof, wherein:
r is 0, 1, 2, 3, or 4; and
each R 14 is independently selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
27 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 , and Ry are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl optionally substituted with one or more alkyl, halo, or OH.
28 . A compound, wherein the compound is:
or a pharmaceutically acceptable salt thereof.
29 . The compound of claim 28 , wherein the compound is in non-salt form.
30 . A pharmaceutical composition comprising the compound of claim 1 , 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 1 , or a pharmaceutically acceptable salt thereof.
32 . 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.
33 . A pharmaceutical composition comprising the compound of claim 6 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
34 . A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 6 , or a pharmaceutically acceptable salt thereof.
35 . 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 6 , or a pharmaceutically acceptable salt thereof.