Substituted pyridines as 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 of Formula (I):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
(i) X 1 is N; and
X 2 is CR d ; or
(ii) X 1 is CR d ; and
X 2 is N;
R 1 is CR 2 R 3 R 4 , C 3-6 cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the C 3-6 cycloalkyl and 4- to 7-membered heterocyclyl are each monocyclic and optionally substituted with one or more independently selected R a substituents;
R 2 is C 1-4 haloalkyl or C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is monocyclic and optionally substituted with one or more independently selected R 5 substituents;
R 3 is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl;
R 4 is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl;
R 5 is halo;
R 6 is C 1-4 haloalkyl or C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is monocyclic and optionally substituted with one or more independently selected R c substituents;
each R a is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;
each R b is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;
each R c is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;
R d is hydrogen, halo, or C 1-4 alkyl; and
t is 0, 1, or 2;
with the provisos that:
(1) when R 3 and R 4 are each hydrogen, then R 6 is not chlorodifluoromethyl, cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, or difluorocyclobutyl;
(2) when R 6 is difluoromethyl or trifluoromethyl, then R 1 is not difluorocyclobutyl;
(3) when R 6 is difluoromethyl or trifluoromethyl and R 3 and R 4 are each hydrogen, then R 2 is not trifluoromethyl;
(4) when R 6 is difluoromethyl or trifluoromethyl, one of R 3 or R 4 is hydrogen, X 1 is N, and X 2 is CH, then R 2 is not trifluoromethyl; and
(5) when R 6 is trifluoromethyl, one of R 3 or R 4 is hydrogen, X 1 is CH, and X 2 is N, then R 2 is not trifluoromethyl.
2. The compound of claim 1 , wherein the compound is of Formula (II) or Formula (III):
or a pharmaceutically acceptable salt or stereoisomer thereof.
3. The compound of claim 1 , wherein the compound is of Formula (IV) or Formula (V):
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. The compound of claim 1 , wherein the compound is of Formula (VI) or Formula (VII):
or a pharmaceutically acceptable salt or stereoisomer thereof.
5. The compound of claim 1 , wherein the compound is of Formula (VIII) or Formula (IX):
or a pharmaceutically acceptable salt or stereoisomer thereof.
6. The compound of claim 1 , wherein the compound is of Formula (X) or Formula (XI):
or a pharmaceutically acceptable salt or stereoisomer thereof.
7. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is CR 2 R 3 R 4 .
8. The compound of claim 7 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is C 1-4 haloalkyl or cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more independently selected R b substituents.
9. The compound of claim 7 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 3 is C 1-4 alkyl; and
R 4 is hydrogen or C 1-4 alkyl.
10. The compound of claim 7 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 3 is hydrogen; and
R 4 is hydrogen.
11. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is cyclobutyl or oxetanyl, wherein the cyclobutyl or oxetanyl is optionally substituted with one or more independently selected R a substituents.
12. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 is C 1-4 haloalkyl, cyclopropyl, or cyclobutyl, wherein the cyclopropyl or cyclobutyl is optionally substituted with one or more independently selected R c substituents.
13. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R a is independently halo or C 1-4 haloalkyl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R b is independently halo.
15. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R c is independently halo.
16. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R d is hydrogen, chloro, or methyl.
17. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
18. A method for modulating a voltage gated sodium ion channel 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.
19. The method of claim 18 , wherein the subject has a gastrointestinal disorder, a neurological disorder, a psychiatric disorder, or pain.
20. The method of claim 18 , wherein the subject has epilepsy, an epilepsy syndrome, epileptic encephalopathy, a neurodevelopment disorder, a neuromuscular disorder, or Rasmussen's encephalitis.
21. The method of claim 18 , wherein the subject has epilepsy or an epilepsy syndrome.
22. The method of claim 18 , wherein the subject has autosomal dominant nocturnal frontal lobe epilepsy, a benign familial neonatal-infantile seizure, cryptogenic pediatric partial epilepsy with a SCN3A mutation, Dravet syndrome, early infantile 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, KCNQ2 epileptic encephalopathy, KCNT1 epileptic encephalopathy, a malignant migrating partial seizure of infancy, or sudden unexpected death in epilepsy.
23. The method of claim 18 , wherein the subject has epileptic encephalopathy with a SCN1A mutation, epileptic encephalopathy with a SCN2A mutation, or epileptic encephalopathy with a SCN8A mutation, or a combination thereof.
24. The method of claim 18 , wherein the subject has Dravet syndrome with a SCN1A mutation.
25. A method for treating a neurological disorder or a psychiatric disorder 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.
26. A compound, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.