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 (I-1):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is O or C(R 2a )( R2b );
A is phenyl or 5-6 membered heteroaryl, wherein phenyl and 5-6 membered heteroaryl are substituted by one or more R 3 ;
R′ is selected from the group consisting of hydrogen, C 1-6 alkyl, OR c , and halogen;
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 ;
each of R 2a and R 2b is independently hydrogen or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by 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 deuterium, C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halo, oxo, cyano, nitro, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R c , —S(O) 2 N(R d ) 2 , and —C(O)N(R d ) 2 , wherein C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl 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, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted by one or more R 6 ; or two R d , taken together with the atoms to which they are attached, form a 3-10 membered heterocyclyl optionally substituted with —OH, C 1-6 alkoxy, or C 1-6 alkyl optionally substituted with C 1-6 alkoxy;
each R c is C 1-6 alkyl;
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; and each R 7 is independently selected from the group consisting of C 1-6 alkyl, halo, oxo, —C(O)R c , and —C(O)OR c ;
wherein the compound is not one of the following:
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein each of X, Y, and Z is independently CR′.
3. The compound of claim 1 , wherein M is O.
4. The compound of claim 1 , wherein A is phenyl substituted by 1 R 3 .
5. The compound of claim 1 , wherein R 3 is —OR c .
6. The compound of claim 5 , wherein R 3 is —OCF 3 .
7. The compound of claim 1 , wherein R 1 is C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 4 .
8. The compound of claim 1 , wherein R 4 is selected from the group consisting of deuterium, halo, —OR c , oxo, C 3-8 carbocyclyl, 5-6 membered heteroaryl, —C(O)OR c , and —C(O)N(R d ) 2 .
9. The compound of claim 8 , wherein R 4 is selected from the group consisting of deuterium, fluoro, tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, OH, C(O)N(CH 3 ) 2 , C(O)N(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )(CH 2 CF 3 ), and C(O)N-tetrahydropyrrolyl.
10. The compound of claim 1 , wherein the compound of Formula (I-1) is a compound of Formula (I-2):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is 0 or C(R 2a )(R 2b );
R′ is selected from the group consisting of hydrogen, C 1-6 alkyl, —OR c , and halogen;
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 ;
each of R 2a and R 2b is independently hydrogen or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more R 4 ;
each R 3a 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 deuterium, C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 N(R d ) 2 , and —OR c , wherein C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl 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, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or C 1-6 alkyl optionally substituted with one or more halogen;
or two R d , taken together with the atoms to which they are attached, form a 3-10 membered heterocyclyl optionally substituted with —OH, C 1-6 alkoxy, or C 1-6 alkyl optionally substituted with C 1-6 alkoxy;
each R c is C 1-6 alkyl;
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;
each R 7 is independently selected from the group consisting of C 1-6 alkyl, oxo, halo, —C(O)R c , and —C(O)R c ; n is selected from the group consisting of 0, 1, 2, 3, and 4, wherein the compound is not one of the following:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , wherein the compound of formula 1-2 is a compound of formula 1-3:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 10 , wherein each of X, Y, and Z is CR′, wherein R′ is hydrogen.
13. The compound of claim 10 , wherein M is O.
14. The compound of claim 10 , wherein R 1 is C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 4 .
15. The compound of claim 10 , wherein each of R 4 and R 5 is independently selected from the group consisting of deuterium, C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)CH 3 , —C(O)OCH 3 , —SO 2 CH 3 , —S(O) 2 N(R d ) 2 , and —OR c , wherein C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is optionally substituted by one or more R 7 .
16. The compound of claim 10 , wherein each of R 4 and R 5 is independently selected from the group consisting of deuterium, C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —SO 2 CH 3 , —S(O) 2 N(R d ) 2 , and —OR c , wherein C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is optionally substituted by one or more R 7 .
17. The compound of claim 10 , wherein each of R 4 and R 5 is independently selected from the group consisting of deuterium, C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, halo, cyano, nitro, and —OR c , wherein C 1-6 alkyl, C 3-8 carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is optionally substituted by one or more R 7 .
18. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 , wherein the neurological disorder is epilepsy, an epilepsy syndrome, a neurodevelopmental disorder, or a neuromuscular disorder.
22. A pharmaceutical composition comprising a compound of claim 18 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
23. A method of treating a neurological disorder or a psychiatric disorder,
wherein the method comprises administering to a subject in need thereof a compound of claim 18 , or a pharmaceutically acceptable salt thereof.
24. The method of claim 23 , wherein the neurological disorder is epilepsy, an epilepsy syndrome, a neurodevelopmental disorder, or a neuromuscular disorder.