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 Dravet syndrome or epilepsy are also provided herein.
1. A compound of Formula (II), (III) or (IV), wherein the compound of Formula (II) is:
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR 2 ;
R 1 is independently alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, and heteroaryl are optionally substituted with one or more R 4 ;
R 2 is hydrogen, alkyl or halogen;
each R 3 is independently alkyl, halo, cyano, nitro, carbocyclyl, heterocyclyl, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each R 4 and R 5 is independently alkyl, halo, cyano, nitro, 5 or 6-membered heteroaryl, or —OR c , wherein the 5 or 6 membered heteroaryl is optionally substituted with alkyl;
each R c is independently hydrogen, alkyl, aryl, carbocyclyl, or heteroaryl, wherein alkyl, aryl, carbocyclyl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, and
n is 0, 1, 2, or 3;
wherein the compound is not a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof;
wherein the compound of Formula (III) is:
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR 2 ;
R 1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 4 ;
R 2 is hydrogen, alkyl or halogen;
R 7 is carbocyclyl optionally substituted with one or more R 5 ;
each R 3 is independently alkyl, halo, cyano, nitro, carbocyclyl, heterocyclyl, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each R 4 and R 5 is independently alkyl, halo, cyano, nitro, 5 or 6-membered heteroaryl, or —OR c , wherein the 5 or 6 membered heteroaryl is optionally substituted with alkyl;
each R c is independently hydrogen, alkyl, aryl, carbocyclyl, or heteroaryl, wherein alkyl, aryl, carbocyclyl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, and
n is 0, 1, 2, or 3; or
wherein the compound of Formula (IV) is:
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR 2 ;
R 1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 4 ;
R 2 is hydrogen, alkyl or halogen;
each R 3 is independently alkyl, halo, cyano, nitro, carbocyclyl, heterocyclyl, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each R 4 and R 5 is independently alkyl, halo, cyano, nitro, 5 or 6-membered heteroaryl, or —OR c , wherein the 5 or 6 membered heteroaryl is optionally substituted with alkyl;
each R c is independently hydrogen, alkyl, aryl, carbocyclyl, or heteroaryl, wherein alkyl, aryl, carbocyclyl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, and
n is 0, 1, 2, or 3;
wherein the compound is not a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound of Formula (II) is a compound of Formula (II-a):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR 2 ;
R 1 is independently alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, and heteroaryl are optionally substituted with one or more R 4 ;
R 2 is hydrogen, alkyl or halogen;
each R 3 is independently alkyl, halo, cyano, nitro, carbocyclyl, heterocyclyl, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each R 4 and R 5 is independently alkyl, halo, cyano, nitro, 5 or 6-membered heteroaryl, or —OR c , wherein the 5 or 6 membered heteroaryl is optionally substituted with alkyl;
each R c is independently hydrogen, alkyl, aryl, carbocyclyl, or heteroaryl, wherein alkyl, aryl, carbocyclyl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, and
n is 0, 1, 2, or 3.
3. The compound of claim 1 , wherein:
X is N, and Y and Z are CR 2 ; or
Y is N, and X and Z are CR 2 ; or
Z is N, and Y and X are CR 2 ; or
X and Z are N, and Y is CR 2 ; or
X and Y are N, and Z is CR 2 ; or
Z and Y are N, and X is CR 2 .
4. The compound of claim 1 , wherein R 2 is hydrogen.
5. The compound of claim 1 , wherein R 1 is alkyl optionally substituted with 1, 2, or 3 of R 4 .
6. The compound of claim 1 , wherein:
R 3 is alkyl or —OR c , wherein alkyl is optionally substituted with one or more R 5 .
7. The compound of claim 1 , wherein:
R 4 is halo or 5 or 6-membered heteroaryl, wherein the 5 or 6 membered heteroaryl is optionally substituted with alkyl; or
R 4 is halo.
8. The compound of claim 1 , wherein R 5 is cyano or —OR c .
9. The compound of claim 1 , wherein R c is alkyl or carbocyclyl, wherein the alkyl or carbocyclyl is optionally substituted with 1, 2, or 3 of R 6 .
10. The compound of claim 1 , wherein R 6 is halo.
11. The compound of claim 1 , wherein n is 0 or 1.
12. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound of Formula (IV) is a compound of Formula (IV-a):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR 2 ;
R 1 is independently alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R 4 ;
R 2 is hydrogen, alkyl or halogen;
R 7 and each R 3 are independently, for each occurrence, alkyl, halo, cyano, nitro, carbocyclyl, heterocyclyl, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each R 4 and R 5 is independently alkyl, halo, cyano, nitro, 5 or 6-membered heteroaryl, or —OR c , wherein the 5 or 6 membered heteroaryl is optionally substituted with alkyl;
each R c is independently hydrogen, alkyl, aryl, carbocyclyl, or heteroaryl, wherein alkyl, aryl, carbocyclyl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, and
m is 0, 1, or 2.
14. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.