Substituted [1,2,4]triazolo[4,3-a]pyrazines as ion channel modulators
Inventors
Reddy, Kiran • Botella, Gabriel Martinez • Griffin, Andrew Mark • Marron, Brian Edward • LOYA, Carlos
Assignees
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Publication Number
US-12145939-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present invention is directed to, in part, fused heteroaryl compounds of Formula (III-II):and compositions thereof, 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 neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.
Core Innovation
The disclosure describes compounds of Formula (III-II), including pharmaceutically acceptable salts or stereoisomers thereof, with defined substituent choices for R5, R6, R7, Rc, and a variable m of 0, 1, or 2. The compounds include substituted fused heteroaryl compounds of the triazolo[4,3-a]pyrazine scaffold and related heteroaromatic compounds, including fluorinated derivatives and chiral stereoisomers.
R5 is selected from halo, C1-4 alkyl, or C3-6 cycloalkyl; R6 is selected from C1-4 alkyl or C1-4 haloalkyl substituted with one ORc substituent; and R7 is a monocyclic C3-6 cycloalkyl substituted with one or more independently selected Ra substituents. Ra is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, or OC1-4 haloalkyl, and Rc is selected as C1-4 alkyl or C3-6 cycloalkyl, where the C1-4 alkyl is optionally substituted with one C3-6 cycloalkyl or phenyl substituent.
The compounds are directed to modulating voltage-gated sodium ion channel activity, with emphasis on abnormal late/persistent sodium current (INaL) and inhibition of late sodium current in hNaV1.6 expressing HEK-293 cells. The disclosure identifies therapeutic disease and condition targets associated with aberrant voltage-gated sodium ion channel activity, including epilepsy, epilepsy syndromes, pain, and other listed neurological and psychiatric disorders.
Claims Coverage
The independent claims cover a compound of Formula (III-II) with defined substituent options for R5, R6, R7, Ra, Rc, and m, optionally as pharmaceutically acceptable salts or stereoisomers. The claim set also includes methods for modulating sodium ion channel activity by administering the compound, with narrowing to epilepsy, epilepsy syndromes, and conditions involving aberrant sodium ion channel function.
Formula (III-II) compound with defined substituents
A compound of Formula (III-II), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is halo, C1-4 alkyl, or C3-6 cycloalkyl; R6 is C1-4 alkyl or C1-4 haloalkyl substituted with one ORc substituent; R7 is a monocyclic C3-6 cycloalkyl substituted with one or more independently selected Ra substituents; each Ra is independently halo, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, or OC1-4 haloalkyl; Rc is C1-4 alkyl or C3-6 cycloalkyl, where the C1-4 alkyl is optionally substituted with one C3-6 cycloalkyl or phenyl substituent; and m is 0, 1, or 2.
Modulating sodium ion channel activity by administration
A method for modulating sodium ion channel activity in a subject by administering a therapeutically effective amount of a compound of claim 1, including a pharmaceutically acceptable salt or stereoisomer.
Treating epilepsy or an epilepsy syndrome
The method where the neurological or psychiatric disorder is epilepsy or an epilepsy syndrome.
Treating conditions involving aberrant sodium ion channel function
The method for subjects whose condition involves aberrant sodium ion channel function, including specified epilepsy-related conditions and other listed disorders.
Claim coverage centers on structurally defined Formula (III-II) compounds with specified substituent classes and m equal to 0, 1, or 2, optionally as pharmaceutically acceptable salts or stereoisomers. The claims also extend to administration-based modulation of sodium ion channel activity and to treatment of epilepsy, epilepsy syndromes, and other conditions involving aberrant sodium ion channel function.
Stated Advantages
Prevention and/or treatment of diseases and conditions associated with aberrant voltage-gated sodium ion channel activity.
Modulation of voltage-gated sodium ion channel activity, with emphasis on abnormal late/persistent sodium current (INaL).
Documented Applications
Preventing and/or treating diseases and conditions associated with aberrant voltage-gated sodium ion channel activity, including neurological and psychiatric disorders such as epilepsy syndromes and other SCN-mutation-associated epilepsies.
Treating pain.
Therapeutic use directed to epilepsy-related conditions and disorders involving aberrant sodium ion channel function, including specified examples such as Dravet syndrome, SUDEP, and infantile spasms.
Inhibition of late sodium current (INaL) in hNaV1.6 expressing HEK-293 cells using a PatchXpress™ platform, with results classified into percent inhibition categories (A/B/C) for compounds including III-10 through III-20.
Treatment contexts for modulating sodium ion channel activity, including epilepsy or an epilepsy syndrome.
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