Substituted pyridines as ion channel modulators
Inventors
Griffin, Andrew Mark • Marron, Brian Edward • MARTINEZ BOTELLA, Gabriel • Reddy, Kiran
Assignees
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Publication Number
US-12344615-B2
Publication Date
2025-07-01
Expiration Date
Abstract
Provided, in part, are compounds of Formula I. pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of conditions associated with the activity of sodium channels. 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 invention relates to compounds defined by Formula (I) and to modulating a voltage gated sodium ion channel current in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound having Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. Formula (I) is defined by specific structural variables X1 and X2 and detailed constraints on R1 through R6, together with related substituent sets and provisos that exclude certain substituent combinations.
Formula (I) constrains X1 and X2 such that X1 is N and X2 is CRd, or X1 is CRd and X2 is N, with Rd being hydrogen, halo, or C1-4 alkyl. R1 is CR2R3R4, monocyclic C3-6 cycloalkyl, or monocyclic 4- to 7-membered heterocyclyl, optionally substituted; R2 is C1-4 haloalkyl or monocyclic C3-6 cycloalkyl, optionally substituted; R3 and R4 are hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R5 is halo; and R6 is C1-4 haloalkyl or monocyclic C3-6 cycloalkyl, optionally substituted.
The disclosure includes Ra, Rb, and Rc substituent sets and provisos that exclude specific fluorinated and cycloalkyl combinations, including cases involving CF2Cl, cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, difluorocyclobutyl, CHF2, and CF3. The examples section describes stereodefined and chiral analogs of triazolo[4,3-a]pyrazine and triazolo[4,3-b]pyridazine scaffolds, fluorinated heteroaryl compounds, and chiral separation and characterization of selected examples.
Claims Coverage
The consolidated claim coverage includes one independent method claim and dependent claims that narrow the indication and compound selection. The inventive features center on administering a Formula (I) compound to modulate voltage gated sodium ion channel current, with additional limitations directed to specific epilepsy and epileptic encephalopathy conditions, pain indications, familial hemiplegic migraine, and selected chemical structures.
Administering a Formula (I) compound to modulate voltage gated sodium ion channel current
A method for modulating a voltage gated sodium ion channel current in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound having Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.
Formula (I) structural definition with X1/X2 selection and substituent provisos
Formula (I) is defined with X1 being N and X2 being CRd, or X1 being CRd and X2 being N, together with specified selections for R1 through R6 and related substituent sets, including provisos that exclude certain combinations involving R3, R4, R6, CF2Cl, cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, difluorocyclobutyl, CHF2, and CF3.
Therapeutic targeting of epilepsy and epileptic encephalopathy conditions
The method is applied to a subject having a condition selected from epilepsy, an epilepsy syndrome, epileptic encephalopathy, and related epileptic disorders and epileptic encephalopathies, including mutation-associated subtypes referenced for SCN1A, SCN2A, SCN3A, SCN8A, KCNQ2, and KCNT1.
Pain and encephalitis indications
The method is used for pain, including cerebellar ataxia, cluster headache, migraine, neuropathic pain, or trigeminal neuralgia, and for Rasmussen’s encephalitis.
Familial hemiplegic migraine indication
The method is further limited to familial hemiplegic migraine.
Selection from the shown chemical structures
The compound is selected from the group of the shown specific chemical structures, or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage is anchored on administering a therapeutically effective amount of a Formula (I) compound to modulate voltage gated sodium ion channel current, with dependent claims narrowing the subject conditions to specified epilepsy and epileptic encephalopathy disorders, pain categories, Rasmussen’s encephalitis, and familial hemiplegic migraine, and with compound selection limited by explicit structural provisos.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Modulating a voltage gated sodium ion channel current in a subject by administering therapeutically effective amounts of Formula (I) compounds.
Treating epilepsy, epileptic encephalopathy, pain, and Rasmussen’s encephalitis.
Treating pain selected from cerebellar ataxia, cluster headache, migraine, neuropathic pain, or trigeminal neuralgia.
Treating familial hemiplegic migraine.
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