Ion channel modulators
Provided, in part, are compounds of Formula I: pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of conditions associated with the activity of sodium channels. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.
1. A compound having the Formula I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of —CR 2 R 3 R 4 , monocyclic C 3-6 cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more R a ;
R 2 is C 1-4 haloalkyl or a monocyclic C 3-6 cycloalkyl optionally substituted with one or more R b ;
R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
R 4 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
R 5 is halo;
R 6 is C 1-4 haloalkyl or C 3-6 monocyclic cycloalkyl, wherein said cycloalkyl for R 6 is optionally substituted with one or more R c ;
t is 1 or 2; and
R a , R b , and R c are each independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.
2. The compound of claim 1 , wherein the compound is of the Formula II:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is of the Formula III:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein R 6 is C 1-4 haloalkyl.
5. The compound of claim 4 , wherein R 6 is —CF 3 or —CHF 2 .
6. The compound of claim 1 , wherein R 1 is oxetanyl or cyclobutyl, wherein said oxetanyl and cyclobutyl are each optionally substituted with one or more R a .
7. The compound of claim 1 , wherein R 1 is —CR 2 R 3 R 4 .
8. The compound of claim 7 , wherein R 2 is C 1-4 haloalkyl.
9. The compound of claim 7 , wherein R 3 is C 1-4 alkyl and R 4 is hydrogen or C 1-4 alkyl.
10. The compound of claim 7 , wherein R 3 and R 4 are each hydrogen.
11. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method of treating a condition relating to aberrant function of a sodium ion channel in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the condition is a neurological or psychiatric disorder.
15. The method of claim 13 , wherein the condition is epilepsy or an epilepsy syndrome.
16. The method of claim 13 , wherein the condition is a genetic or pediatric epilepsy or a genetic or pediatric epilepsy syndrome.
17. The method of claim 13 , wherein the condition is epileptic encephalopathy.
18. The method of claim 17 , wherein the epileptic encephalopathy comprises Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.
19. The method of claim 13 , wherein the condition is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.
20. A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.