Compounds and their methods of use
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. 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 thereof, wherein:
each of X, Y, and Z is CR′;
A is phenyl or pyridyl, wherein phenyl and pyridyl are substituted by one or more R 3 ;
R′ is hydrogen or C 1-6 alkyl;
R 1 is selected from the group consisting of hydrogen, deuterium, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 4 ;
each R 3 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, fluoro, chloro, and —OR c , wherein C 1-6 alkyl or C 3-8 carbocyclyl is optionally substituted with one or more R 5 ;
each R 4 is independently selected from the group consisting of deuterium, fluoro, oxo, cyano, nitro, and —OR c ;
each R 5 is independently selected from the group consisting of C 1-6 alkyl, deuterium, halogen, oxo, cyano, nitro, and —OR c , wherein C 1-6 alkyl is optionally substituted by one or more R 7 ;
each R c is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, and C 3-8 carbocyclyl, wherein C 1-6 alkyl or C 3-8 carbocyclyl, is optionally substituted by one or more R 6 ;
each R 6 is independently selected from the group consisting of C 1-6 alkyl, deuterium, C 1-6 haloalkyl, C 3-8 carbocyclyl, halogen, cyano, nitro, and —OH; and
each R 7 is independently selected from the group consisting of C 1-6 alkyl, halogen, and oxo.
2. The compound of claim 1 , wherein R 3 is —OR c .
3. The compound of claim 2 , wherein R c is C 1-6 alkyl optionally substituted with R 6 .
4. The compound of claim 1 , wherein R 1 is C 1-6 alkyl.
5. The compound of claim 1 , wherein R 1 is C 1-4 alkyl substituted with 1-3 R 4 .
6. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (I-a):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is CR′;
R′ is hydrogen or C 1-6 alkyl;
R 1 is selected from the group consisting of hydrogen, deuterium, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 4 ;
each R 3a is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, fluoro, chloro, and —OR c , wherein C 1-6 alkyl or C 3-8 carbocyclyl is optionally substituted with one or more R 5 ;
n is selected from the group consisting of 0, 1, and 2;
each R 4 is independently selected from the group consisting of fluoro, oxo, cyano, nitro, and —OR c ;
each R 5 is independently selected from the group consisting of C 1-6 alkyl, halogen, oxo, cyano, nitro, and —OR c , wherein C 1-6 alkyl is optionally substituted by one or more R 7 ;
each R c is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-8 carbocyclyl, wherein C 1-6 alkyl or C 3-8 carbocyclyl, is optionally substituted by one or more R 6 ;
each R 6 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, halo, cyano, nitro, and —OH; and
each R 7 is independently selected from the group consisting of C 1-6 alkyl, halogen, and oxo.
7. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (I-b):
or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl or pyridyl, wherein phenyl and pyridyl are substituted by one or more R 3 ;
R 1 is selected from the group consisting of hydrogen, deuterium, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 4 ;
each R 3 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, fluoro, chloro, and —OR c , wherein C 1-6 alkyl or C 3-8 carbocyclyl is optionally substituted with one or more R 5 ;
each R 4 is independently selected from the group consisting of deuterium, fluoro, oxo, cyano, nitro, and —OR c ;
each R 5 is independently selected from the group consisting of C 1-6 alkyl, deuterium, halogen, oxo, cyano, nitro, and —OR c , wherein C 1-6 alkyl is optionally substituted by one or more R 7 ;
each R c is independently selected from the group consisting of hydrogen, deuterium, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more R 6 ;
each R 6 is independently selected from the group consisting of C 1-6 alkyl, deuterium, C 1-6 haloalkyl, C 3-8 carbocyclyl, halogen, cyano, nitro, and —OH; and
each R 7 is independently selected from the group consisting of C 1-6 alkyl, halogen, and oxo.
8. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (I-c):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is CR′;
R′ is hydrogen or C 1-6 alkyl;
R 1 is selected from the group consisting of hydrogen, deuterium, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 4 ;
each R 3a is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, fluoro, chloro, and —OR c , wherein C 1-6 alkyl or C 3-8 carbocyclyl is optionally substituted with one or more R 5 ;
n is selected from the group consisting of 0, 1, and 2;
R 3b is C 1-6 alkyl or C 3-8 carbocyclyl, wherein C 1-6 alkyl or C 3-8 carbocyclyl, is optionally substituted with one or more R 5 ;
each R 4 is independently selected from the group consisting of deuterium, fluoro, oxo, cyano, nitro, and —OR c ;
each R 5 is independently selected from the group consisting of C 1-6 alkyl, deuterium, halogen, oxo, cyano, nitro, and —OR c ;
each R c is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, and C 3-8 carbocyclyl, wherein C 1-6 alkyl or C 3-8 carbocyclyl, is optionally substituted by one or more R 6 ;
each R 6 is independently selected from the group consisting of C 1-6 alkyl, deuterium, C 3-8 carbocyclyl, halogen, cyano, nitro, and —OH; and
each R 7 is independently selected from the group consisting of C 1-6 alkyl, halogen, and oxo.
9. The compound of claim 8 , wherein R′ is hydrogen.
10. The compound of claim 8 , wherein each of R 4 is independently fluoro or —OR c .
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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.