Substituted [1,2,4]triazolo[4,3-a]pyrazines as modulators of sodium channel activity
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 (VII):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen, CH 3 , C 1-6 haloalkyl, O-phenyl, C 3-8 carbocyclyl, or phenyl, wherein the CH 3 , C 1-6 haloalkyl, O-phenyl, C 3-8 carbocyclyl, or phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, OR c , and 3-8 membered heterocyclyl;
each R 2 is independently hydrogen, halo, or C 1-6 alkyl;
R 3 is halo, cyano, nitro, C 1-6 alkyl, C(O)R c , C(O)N(R d ) 2 , C(O)OR c , N(R d ) 2 , OR 7 , C 3-8 carbocyclyl, or 3-8 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-8 carbocyclyl, or 3-8 membered heterocyclyl is optionally substituted with one or more independently selected R 5 substituents;
R 4 is cyano, nitro, C 1-6 alkyl, C(O)R c , C(O)N(R d ) 2 , C(O)OR c , N(R d ) 2 , OR c , C 3-8 carbocyclyl, or 3-8 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-8 carbocyclyl, or 3-8 membered heterocyclyl is optionally substituted with one or more independently selected R 5 substituents;
each R 5 is independently halo, cyano, nitro, C 1-6 alkyl, C(O)N(R d ) 2 , N(R d ) 2 , NR d C(O)R c , OR c , S(O) 2 R c , S(O) 2 N(R d ) 2 , S(O) 2 OR c , C 3-8 carbocyclyl, or 3-8 membered heterocyclyl;
each R c is independently hydrogen or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally and independently substituted with one or more independently selected R 6 substituents;
each R d is independently hydrogen or C 1-6 alky];
each R 6 is independently halo, cyano, C 3-8 carbocyclyl, or 3-8 membered heterocyclyl, wherein each C 3-8 carbocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo and cyano;
R 7 is C 1-6 alkyl or C 3-8 carbocyclyl, wherein the C 1-6 alkyl or C 3-8 carbocyclyl is optionally substituted with one or more independently selected R 6 substituents; and
m is 0, 1, or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, CH 3 , C 1-6 haloalkyl, or C 3-8 carbocyclyl, wherein the CH 3 , C 1-6 haloalkyl, or C 3-8 carbocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, OR c , and 3-8 membered heterocyclyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CHF 2 or CF 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one R 2 is hydrogen.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is OR 7 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-6 alkyl or OR c .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CH 3 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is:
(i) C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and cyano; or
(ii) C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one C 3-8 carbocyclyl, and further wherein the C 3-8 carbocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and cyano; or
(iii) C 3-8 carbocyclyl, wherein the C 3-8 carbocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and cyano.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one, two, or three independently selected halo substituents.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
12. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method for treating a neurological disorder or a psychiatric disorder in a subject, wherein the method comprises administering to a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.