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. The fused heteroaryl compounds of the disclosure are represented by Formula (I): wherein X, Y, Z, A, R 1 and R 2 are as defined in the specification. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
wherein X and Z are both CH, and Y is N;
A is phenyl or 5-6 membered heteroaryl, wherein phenyl and 5-6 membered heteroaryl are optionally substituted by one or more R 3 ;
R 1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, halo, and cyano, wherein C 1-6 alkyl, C 3-8 carbocyclyl, and 3-10 membered heterocyclyl are optionally substituted with one or more R 4 ;
R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, halo, and cyano, wherein each 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, 3-10 membered heterocyclyl, halo, cyano, nitro, and —OR c , wherein C 1-6 alkyl, C 3-8 carbocyclyl, and 3-10 membered heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halo, cyano, nitro, and —OR c ;
each R c is independently selected from the group consisting of hydrogen, C 1-6 alkyl, phenyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, and 5-6 membered heteroaryl, wherein C 1-6 alkyl, phenyl, or 5-6 membered heteroaryl is optionally substituted by one or more R 6 ; and
each R 6 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, halo, cyano, nitro, and —OH, wherein C 1-6 alkyl is optionally substituted with one or more halo.
2. The compound of claim 1 , wherein A is phenyl.
3. The compound of claim 1 , wherein A is phenyl substituted by one R 3 .
4. The compound of claim 1 , wherein R 3 is —OR c .
5. The compound of claim 1 , wherein R 1 is C 1-6 alkyl substituted with 1-4 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:
X and Z are both CH, and Y is N;
R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 carbocyclyl, and 3-10 membered heterocyclyl, wherein C 1-6 alkyl, C 3-8 carbocyclyl, and 3-10 membered heterocyclyl are optionally substituted with one or more R 4 ;
R 2 is hydrogen or C 1-6 alkyl;
each R 3 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, halo, cyano, nitro, and —OR c , wherein C 1-6 alkyl, C 3-8 carbocyclyl, and 3-10 membered heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halo, cyano, nitro, and —OR c ;
each R c is independently selected from the group consisting of hydrogen, C 1-6 alkyl, phenyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, and 5-6 membered heteroaryl, wherein C 1-6 alkyl, phenyl, or 5-6 membered heteroaryl 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, 3-10 membered heterocyclyl, halo, cyano, nitro, and —OH, wherein C 1-6 alkyl is optionally substituted with one or more halo; and
n is selected from the group consisting of 1, 2, 3, 4, and 5.
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:
wherein X and Z are both CH, and Y is N;
R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 carbocyclyl, and 3-10 membered heterocyclyl, wherein C 1-6 alkyl, C 3-8 carbocyclyl, and 3-10 membered heterocyclyl are optionally substituted with one or more R 4 ;
R 2 is hydrogen or C 1-6 alkyl;
each R 3 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, halo, cyano, nitro, and —OR c , wherein C 1-6 alkyl, C 3-8 carbocyclyl, and 3-10 membered heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently selected from the group consisting of C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halo, cyano, nitro, and —OR c ;
each R c is independently selected from the group consisting of hydrogen, C 1-6 alkyl, phenyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, and 5-6 membered heteroaryl, wherein C 1-6 alkyl, phenyl, or 5-6 membered heteroaryl 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, 3-10 membered heterocyclyl, halo, cyano, nitro, and —OH, wherein C 1-6 alkyl is optionally substituted with one or more halo; and
m is selected from the group consisting of 0, 1, 2, and 3.
8. The compound of claim 6 , wherein R 1 is hydrogen or C 1-6 alkyl optionally substituted with one or more halogen.
9. The compound of claim 6 , wherein R 1 is selected from the group consisting of hydrogen, —CF 3 , and —CHF 2 .
10. The compound of claim 6 , wherein each R 3 is selected from the group consisting of —OR c , C 1-6 alkyl, and halo.
11. 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:
m is selected from the group consisting of 0, 1, 2, 3, and 4, and
R 1 , X, Y, Z, R c , and R 3 are as defined in claim 6 .
12. The compound of claim 1 , wherein the compound of Formula (I) is a compound of formula (I-k)
or a pharmaceutically acceptable salt thereof, wherein:
p is selected from the group consisting of 0, 1, 2, and 3, and
R 1 , R c , and R 3 are as defined in claim 7 .
13. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. The compound of claim 7 , wherein R 1 is C 1-6 alkyl optionally substituted with one or more halogen or —OR c .
16. The compound of claim 7 , wherein each R 3 is selected from the group consisting of —OR c , C 1-6 alkyl, and halo.