Substituted [1,2,4]triazolo[4,3-a]pyrazines as ion channel modulators
The present invention is directed to, in part, fused heteroaryl compounds of Formula (II-II): and compositions thereof, 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. 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 Formula (II-II):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is halo;
R 2 is C 1-4 haloalkyl;
R 3 is H or C 1-4 alkyl;
R 4 is H or C 1-4 alkyl; or
R 3 and R 4 , taken together with the carbon atom to which they are attached, form a C 3-6 carbocyclyl;
R 5 is C 1-4 alkyl; and
t is 0 or 1.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is F.
3. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is CF 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 3 is CH 3 ; and
R 4 is CH 3 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 and R 4 , taken together with the carbon atom to which they are attached, form a cyclobutyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is CH 3 or CH 2 CH 3 .
7. The compound of claim 1 , or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
9. A method for modulating sodium ion channel activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
10. The method of claim 9 , wherein the subject has a condition relating to aberrant function of a sodium ion channel selected from the group consisting of a neurological disorder and a psychiatric disorder.
11. The method of claim 10 , wherein the neurological disorder or psychiatric disorder is epilepsy or an epilepsy syndrome.
12. The method of claim 9 , wherein the subject has a condition relating to aberrant function of a sodium ion channel selected from the group consisting of autosomal dominant nocturnal frontal lobe epilepsy, a benign familial neonatal-infantile seizure, cryptogenic pediatric partial epilepsy with a SCN3A mutation, Dravet syndrome, epileptic encephalopathy, focal epilepsy with a SCN3A mutation, generalized epilepsy with a febrile seizure, an infantile spasm, intractable childhood epilepsy with a generalized tonic-clonic seizure, a malignant migrating partial seizure of infancy, Rasmussen encephalitis, and sudden unexpected death in epilepsy (SUDEP).
13. The method of claim 12 , wherein the Dravet syndrome is Dravet syndrome with a SCN1A mutation.
14. The method of claim 12 , wherein the epileptic encephalopathy is selected from the group consisting of an epileptic encephalopathy with a SCN1A mutation, an epileptic encephalopathy with a SCN2A mutation, an epileptic encephalopathy with a SCN8A mutation, early infantile epileptic encephalopathy, KCNQ2 epileptic encephalopathy, KCNT1 epileptic encephalopathy, SCN2A epileptic encephalopathy, and SCN8A epileptic encephalopathy.
15. The method of claim 9 , wherein the subject has a trigeminal autonomic cephalalgia.
16. The method of claim 15 , wherein the trigeminal autonomic cephalalgia is selected from the group consisting of hemicrania continua, paroxysmal hemicrania, a long-lasting autonomic symptom with hemicrania, a short-lasting unilateral neuralgiform headache attack with a cranial autonomic symptom, and a short-lasting unilateral neuralgiform headache attack with conjunctival injection and tearing.