US2023219938A1PendingUtilityA1
Compounds and their methods of use
Est. expiryFeb 13, 2037(~10.6 yrs left)· nominal 20-yr term from priority
A61K 31/423C07D 413/06A61K 45/06A61K 31/4184A61K 31/429A61K 31/4439A61K 31/497A61K 31/506A61K 31/5377C07D 235/26C07D 263/58C07D 498/04C07D 209/34C07D 413/10
70
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . 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 Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is O, C(R 2a )(R 2b ), or N(R 2c );
A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ;
R′ is hydrogen, alkyl, —OR c , or halogen;
R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl, wherein each 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 ring;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and
each R 7 is independently alkyl, halo, or oxo.
2 . 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 Formula (I-1):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is O, C(R 2a )(R 2b ), or N(R 2c );
A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ;
R′ is hydrogen, alkyl, —OR c , or halogen;
R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl, wherein each 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 heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
each R e is alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and
each R 7 is independently alkyl, halo, oxo, —C(O)R c , or —C(O)OR c ;
wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof.
3 - 24 . (canceled)
25 . The method of claim 2 , 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 O or C(R 2a )(R 2b );
R′ is hydrogen, alkyl, —OR c , or halogen;
R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
each of R 2a and R 2b is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl optionally substituted with one or more halogen;
or two R d , taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with-OH, alkoxy, or alkyl optionally substituted with alkoxy;
each R e is alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
each R 7 is independently alkyl, oxo, halo, —C(O)R c , or —C(O)OR c ; n is 0, 1, 2, 3, or 4.
26 . The method of claim 25 , wherein the compound of formula I-2 is a compound of formula I-3:
or a pharmaceutically acceptable salt thereof.
27 . The method of claim 25 , wherein the compound of formula I-2 is a compound of formula I-4:
or a pharmaceutically acceptable salt thereof.
28 . The method of claim 25 , wherein the compound of formula I-2 is a compound of formula I-5:
or a pharmaceutically acceptable salt thereof.
29 . The method of claim 25 , wherein the compound of formula I-2 is a compound of formula I-6:
or a pharmaceutically acceptable salt thereof.
30 - 35 . (canceled)
36 . The method of claim 25 , wherein the compound of Formula (I-1) is a compound of Formula (I-7):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is N(R 2c );
R′ is hydrogen, alkyl, —OR c , or halogen;
R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
each of R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl optionally substituted with one or more halogen;
or two R d , taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
each R e is alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
each R 7 is independently alkyl, oxo, halo, —C(O)R c , or —C(O)OR c ; n is 0, 1, 2, 3, or 4;
wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof.
37 - 41 . (canceled)
41 . The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
42 . 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, C(R 2a )(R 2b ), or N(R 2c ); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ;
R′ is hydrogen, alkyl, —OR c , or halogen;
R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl, wherein each 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 heterocyclyl optionally substituted with -OH, alkoxy, or alkyl optionally substituted with alkoxy;
each R e is alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and
each R 7 is independently alkyl, halo, oxo, —C(O)R c , or —C(O)OR c ;
wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof.
43 - 59 . (canceled)
60 . The compound of claim 42 , 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 O or C(R 2a )(R 2b );
R′ is hydrogen, alkyl, —OR c , or halogen;
R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
each of R 2a and R 2b is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R c , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl optionally substituted with one or more halogen;
or two R d , taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
each R e is alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
each R 7 is independently alkyl, oxo, halo, —C(O)R c , or —C(O)OR c ; n is 0, 1, 2, 3, or 4, wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof.
61 . The compound of claim 60 , wherein the compound of formula I-2 is a compound of formula I-3:
or a pharmaceutically acceptable salt thereof.
62 . The compound of claim 60 , wherein the compound of formula I-2 is a compound of formula I-4:
or a pharmaceutically acceptable salt thereof.
63 . The compound of claim 60 , wherein the compound of formula I-2 is a compound of formula I-5:
or a pharmaceutically acceptable salt thereof.
64 . The compound of claim 60 , wherein the compound of formula I-2 is a compound of formula I-6:
or a pharmaceutically acceptable salt thereof.
65 - 72 . (canceled)
73 . The compound of claim 42 , wherein the compound of Formula (I-1) is a compound of Formula (I-7):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is N(R 2c );
R′ is hydrogen, alkyl, —OR c , or halogen;
R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
each of R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R c , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
each R d is independently hydrogen or alkyl optionally substituted with one or more halogen;
or two R d , taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with-OH, alkoxy, or alkyl optionally substituted with alkoxy;
each R e is alkyl;
each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
each R 7 is independently alkyl, oxo, halo, —C(O)R c , or —C(O)OR c ; n is 0, 1, 2, 3, or 4;
wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof
74 - 78 . (canceled)
79 . The compound of claim 42 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
80 . A pharmaceutical composition comprising a compound of claim 42 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
81 . The method of claim 1 , wherein the method comprises administering the pharmaceutical composition of claim 80 .
82 . A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof the compound of claim 42 .Join the waitlist — get patent alerts
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