Fused heteroaryl compounds, and methods thereof for treating diseases, disorders, and conditions relating to aberrant function of a sodium channel
The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. For example, such compounds include those having the structure: or pharmaceutically acceptable salts thereof. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel, including Dravet syndrome or epilepsy, using such compounds are also provided herein.
1. A compound of formula (VIIa):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-6 alkyl, cyano, C 1-6 haloalkyl, or C 3-8 carbocyclyl optionally substituted with one or more halogen,
R 2 is hydrogen, cyano, or C 1-6 haloalkyl,
R 3 is selected from the group consisting of: C 1-6 alkyl, cyano, C 3-10 carbocyclyl, —OR c , —C(O)R c , —C(O)OR c , and —C(O)N(R d ) 2 , wherein C 1-6 alkyl or C 3-10 carbocyclyl is optionally substituted with one or more R 5 ;
R 4 is C 1-6 alkyl, halo, or OR c , wherein C 1-6 alkyl is optionally substituted with one or more R 5 ;
m is 0, 1, or 2;
R 5 is independently C 1-6 alkyl, halo, cyano, nitro, or —OR c ;
each R c is independently hydrogen, C 1-6 alkyl, C 3-8 carbocyclyl, C 1-6 alkylene-(C 3-8 carbocyclyl), 3-8 membered heterocyclyl, or 5-8 membered heteroaryl, wherein C 1-6 alkyl, C 3-8 carbocyclyl, C 1-6 alkylene-(C 3-8 carbocyclyl), 3-8 membered heterocyclyl, or 5-8 membered heteroaryl is optionally substituted by one or more R 7 ;
each R d is independently hydrogen or C 1-6 alkyl;
each R 7 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 carbocyclyl, 3-8 membered heterocyclyl, halo, cyano, nitro, or —OH,
wherein the compound is not:
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: —CH 3 , CF 3 , CHF 2 , and cyclopropyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is cyano or C 1-6 haloalkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of CF 3 , —OCF 3 , —OCH 2 CF 3 , —CH 2 —CH 2 -cyclopropyl optionally substituted with —CN or CF 3 , and cyclopropyl optionally substituted with —CN or CF 3 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —OR c , wherein R c is C 1-6 alkyl substituted with 1, 2, or 3 halogens or C 3-8 carbocyclyl optionally substituted with cyano or CF 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising a compound of claim 6 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. A method of treating epilepsy or epileptic encephalopathy in a subject in need thereof, comprising: administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein the subject is a human, and wherein the neurological disorder is epilepsy.
11. The method of claim 9 , wherein the subject is a human, and wherein the neurological disorder is an epileptic encephalopathy.
12. The method of claim 11 , wherein the epileptic encephalopathy comprises Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.
13. The method of claim 9 , wherein the compound is
a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the subject is a human, and wherein the method comprises treating epilepsy.
15. The method of claim 13 , wherein the subject is a human, and wherein the method comprises treating an epileptic encephalopathy.
16. The method of claim 15 , wherein the epileptic encephalopathy comprises Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.