Treatment of neuropathy

Abstract

The present disclosure is generally directed to methods of treating a disease, disorder, or condition, such as, for example, a neurological disorder, a disorder associated with excessive neural excitability, or a disorder associated with a de novo gain-of-function or loss-of-function mutation in the major central nervous system sodium channel genes, such as, for example, SCN1A, SCN2A, and SCN8A, using compound 1 of the following formula, or a pharma- ceutically acceptable salt thereof. In some embodiments, the methods provided include treating a disorder associated with excessive neural excitability. In some embodiments, the disorder is epilepsy, an epilepsy syndrome, or an encephalopathy, such as genetic or pediatric epilepsy, or genetic or pediatric epilepsy syndrome. JPEG2025514192000022.jpg3268

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 334,942, filed April 26, 2022, U.S. Provisional Patent Application No. 63 / 349,408, filed June 6, 2022, and U.S. Provisional Patent Application No. 63 / 349,250, filed June 6, 2022. The entire contents of each of the foregoing applications are incorporated herein by reference.

[0002] The present disclosure is generally directed to methods of treating a disease, disorder, or condition, such as, for example, a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a de novo gain-of-function or loss-of-function mutation in a central nervous system sodium channel gene, such as, for example, SCN1A, SCN2A, and SCN8A. [Background technology]

[0003] Sodium ion (Na + ) channels are primarily open transiently and rapidly inactivated, thereby allowing fast Na + A current is generated to initiate an action potential. The delayed or persistent sodium current (I Na L) Fast Na+ receptors in cardiomyocytes and neurons. + Many common neurological and cardiac conditions are due to abnormal I Na It is associated with L augmentation, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther., 2008, 119:326-339).

[0004] Epilepsy is the fourth most common neurological disorder affecting 3.4 million people in the United States, including 470,000 children. Epilepsy is a heterogeneous group of disorders that are classified into distinct syndromes according to etiology, seizure type, and comorbidities. The most common cause of genetic epilepsy is a defect in the voltage-gated sodium channel (Na V) gene, leading to gain-of-function and / or loss-of-function changes in channel activity. Affected patients typically present in childhood or neonatology, with prognosis ranging from self-limited benign seizures to devastating developmental epileptic encephalopathy (DEE).

[0005] Na V Channels are important therapeutic targets for antiepileptic drugs (AEDs). Their blockade, and the resulting inhibition of neuronal sodium currents (I Na ) inhibition at the axon origin and at peak I of the nodes of Ranvier Na are ideally positioned to reduce excitability because they are involved in the initiation and propagation of action potentials (APs), respectively. However, current agents, including cenobamate, oxcarbazepine, and phenytoin, can be severely toxic at therapeutic doses, making standard Na V The clinical utility of targeted AEDs is limited. Toxicities include ataxia, lethargy, vomiting, and seizures, and excessive peak I Na Inhibition or off-target (non-Na V This reflects a decrease in physiological neuronal function due to neurotransmitter (neuronal) activity. Therefore, novel I Na Identification of inhibitors would represent clinically relevant alternative therapeutic options.

[0006] Physiological Durability I Na is a small subthreshold current that contributes to the amplification of synaptic responses and the enhancement of repetitive firing. V 1.2) and SCN8A (Na V Functional studies of DEE variants in the 1.6 gene have been shown to mediate persistent I Na The current study shows a slight increase in Na, which can lead to hyperexcitability, seizures, and developmental comorbidities. V Targeted AEDs are designed to target the peak I Na and Persistence I Na It is predicted to inhibit both the excess peak I Na Inhibition impairs physiological neuronal activity. VImproved selectivity and duration of activity I Na Priority in targeting could meaningfully improve tolerability. Thus, additional therapeutic options with improved efficacy and tolerability are needed to treat epilepsy, to achieve seizure freedom, or both. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Zaza, Antonio, Luiz Belardinelli, and John C. Shryock. Pharmacology & therapeutics 119.3 (2008): 326-339. Summary of the Invention [Means for solving the problem]

[0008] Provided herein is a method for treating a disease, disorder, or condition, such as, for example, a neurological disorder, a disorder associated with excessive neuronal excitability, and / or a disorder associated with abnormal late sodium currents, or a disorder associated with a de novo gain-of-function (GoF) or loss-of-function mutation (variant) in major central nervous system sodium channel genes, such as, for example, SCN1A, SCN2A, and SCN8A, comprising administering to a subject in need thereof a therapeutically effective amount of a compound 1 having the following formula: [ka] or a pharma- ceutically acceptable salt thereof is disclosed.

[0009] In some embodiments, provided methods include treating a disorder associated with excessive neural excitability. In some embodiments, the disorder is epilepsy, an epilepsy syndrome, or an encephalopathy, such as genetic or childhood epilepsy, or a genetic or childhood epilepsy syndrome. In some embodiments, the disorder is focal epilepsy.

[0010] In some embodiments, the method reduces the frequency of seizures experienced by the subject within 24 hours after administration of the compound or a pharma- ceutically acceptable salt thereof, compared to the frequency of seizures prior to administration.

[0011] In some embodiments, the compound of the present disclosure or a pharma- ceutically acceptable salt thereof is administered to a subject in an amount ranging from about 0.1 mg / kg to about 1 g / kg, hi other embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered to a subject in an amount ranging from about 10 mg / kg to about 100 mg / kg, for example, about 30 mg / kg.

[0012] In some embodiments, the subject is a human, hi some embodiments, the subject is an adult suffering from or suspected of having focal epilepsy.

[0013] In some aspects, the disclosure provides a method of treating a condition associated with abnormal functioning of a sodium ion channel in a subject in need thereof, comprising administering to the subject a dose of about 1 mg to about 150 mg of Compound 1, or a pharma- ceutically acceptable salt thereof, wherein Compound 1 is of the following structural formula: [ka] In some embodiments, the condition associated with abnormal function of a sodium ion channel is a neurological disorder. In some embodiments, the neurological disorder is a disorder associated with excessive neuronal excitability. In some embodiments, the neurological disorder is associated with one or more de novo gain-of-function or loss-of-function mutations in central nervous system sodium ion channel genes.

[0014] In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is childhood epilepsy or a childhood epilepsy syndrome. In some embodiments, the condition is selected from the group consisting of malignant migratory infantile focal seizures (MMFSI), infantile epilepsy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia.

[0015] In some embodiments, the condition is epileptic encephalopathy. In some embodiments, the condition is focal epilepsy.

[0016] In some embodiments, the seizures are generalized tonic-clonic seizures or asymmetric tonic seizures.

[0017] In some embodiments, the subject is a human.

[0018] In some embodiments, Compound 1 is administered at a dose of about 5 mg to about 130 mg. In some embodiments, Compound 1 is administered at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, or about 130 mg.

[0019] In some embodiments, administration of Compound 1 results in a reduction in the severity, number, and / or frequency of seizures experienced by the subject compared to the severity, number, and / or frequency of seizures experienced by the subject prior to administration of Compound 1.

[0020] In some embodiments, administration of Compound 1 does not result in ataxia, lethargy, and vomiting in the subject.

[0021] In some aspects, the disclosure provides a method of reducing the severity, number, and / or frequency of attacks in a subject in need thereof, the method comprising administering an effective amount of a compound of the following structural formula: [ka] or a pharma- ceutically acceptable salt thereof to a subject.

[0022] In some embodiments, the subject has a condition associated with abnormal functioning of a sodium ion channel. In some embodiments, the condition associated with abnormal functioning of a sodium ion channel is a neurological disorder. In some embodiments, the neurological disorder is a disorder associated with excessive neuronal excitability. In some embodiments, the neurological disorder is associated with one or more de novo gain-of-function or loss-of-function mutations in central nervous system sodium ion channel genes.

[0023] In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is childhood epilepsy or a childhood epilepsy syndrome. In some embodiments, the condition is selected from the group consisting of malignant migratory infantile focal seizures (MMFSI), infantile epilepsy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia.

[0024] In some embodiments, the condition is epileptic encephalopathy. In some embodiments, the condition is focal epilepsy.

[0025] In some embodiments, the seizures are generalized tonic-clonic seizures or asymmetric tonic seizures.

[0026] In some embodiments, the subject is a human.

[0027] In some embodiments, Compound 1 is administered at a dose of about 1 mg to about 150 mg. In some embodiments, Compound 1 is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg.

[0028] In some embodiments, administration of Compound 1 does not result in ataxia, lethargy, and vomiting in the subject.

[0029] In some aspects, the present disclosure provides a method for measuring peak sodium current (I Na ) than persistent sodium current (I Na The present invention provides a method for preferentially inhibiting a neuron from activating a cellular signaling pathway, comprising administering to the neuron an effective amount of a compound of the following structural formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0030] In some embodiments, the neuron is in a subject. In some embodiments, the subject has a condition associated with abnormal functioning of a sodium ion channel. In some embodiments, the condition associated with abnormal functioning of a sodium ion channel is a neurological disorder. In some embodiments, the neurological disorder is a disorder associated with excessive neuronal excitability. In some embodiments, the neurological disorder is associated with one or more de novo gain-of-function or loss-of-function mutations in central nervous system sodium ion channel genes.

[0031] In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is childhood epilepsy or a childhood epilepsy syndrome. In some embodiments, the condition is selected from the group consisting of malignant migratory infantile focal seizures (MMFSI), infantile epilepsy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia.

[0032] In some embodiments, the condition is epileptic encephalopathy. In some embodiments, the condition is focal epilepsy.

[0033] In some embodiments, the seizures are generalized tonic-clonic seizures or asymmetric tonic seizures.

[0034] In some embodiments, the subject is a human.

[0035] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate specific embodiments and, together with the written description, serve to explain certain principles of the methods and devices disclosed herein. [Brief description of the drawings]

[0036] [Figure 1A] The effects of Compound 1 (FIG. 1A), reference compound (FIG. 1B), lamotrigine (LTG) (FIG. 1C), and carbamazepine (CBZ) (FIG. 1D) on human NaV1.6 channels using the PatchXpress® (Molecular Devices) electrophysiology platform: ● Tonic INa inhibition, Δ peak INa, UDV-10Hz (disease-state dependent) inhibition, ◇ peak INa, Tonic Block inhibition. [Figure 1B] Same as above. [Figure 1C] Same as above. [Figure 1D] Same as above. [Diagram 2] Figure 1 shows the effect of Compound 1 on maximal electroshock-induced seizures (MES) in male CD-1 mice. CD-1 mice: n=8 / group Veh, n=10 / group Compound 1, ANOVA / Dunnett (Compound 1), **p<0.01 vs. Veh. [Diagram 3] Figure 1 shows the effect of Compound 1 on spontaneous locomotor activity (sLMA) in male CD-1 mice. CD-1 mice: n=10 / group, ANOVA / Dunnett, **p<0.01 vs. Veh. [Figure 4] Calculated free plasma concentration ranges of Compound 1, reference compounds, CBZ, and LTG associated with anticonvulsant effects (effective exposure) and reduced locomotor activity (unacceptable exposure) are shown. Protection indices for each molecule are shown. [Diagram 5] Pharmacokinetic (PK) modeling of Compound 1 and reference compounds based on a single dose of 90 mg. Preclinical simulation of human PK reproduces clinical data of the reference compounds. [Figure 6A] 1 shows the results of evaluation of INa block using an assay for sustained block in HEK cells. [Figure 6B] 1 shows the results of evaluation of INa blockade using an assay of use-dependent blockade in HEK cells. [Figure 6C]Results of evaluation of INa block using an assay of voltage-dependent block in HEK cells. Peak INa was measured at the onset of the voltage step. Figures 6A-6C show that Compound 1 exhibited enhanced activity-dependent block, which is suggested to provide beneficial activity during periods of hyperexcitability. [Figure 7A] 1 is a graph showing the percent inhibition of hNaV1.6 as a function of Compound 1 concentration. [Figure 7B] 1 is a graph showing the percent inhibition of hNaV1.6 as a function of carbamazepine concentration. [Figure 7C] 1 is a graph showing percent inhibition of hNaV1.6 as a function of lamotrigine concentration. [Figure 8A] Results of Compound 1-induced reduction in ATX-II-induced hNav1.6 persistent INa are shown. Voltage protocols are included as panel inserts and pharmacological measurements are indicated by arrows. [Figure 8B] Figure 1 is a graph showing the percent inhibition of hNav1.6 as a function of concentration of Compound 1 and standard Nav-targeted ASMs (lamotrigine, phenytoin, carbamazepine, sembamate, lacosamide, and valproic acid). Points represent the mean ± SEM. [Figure 8C] Figure 1 is a graph showing the percent inhibition of various Nav isoforms and orthologs as a function of the concentration of compound 1. Points represent the mean ± SEM. [Figure 9A] The incidence of inhibition (apparent binding) for 3 μM compound 1 and controls is shown. [Figure 9B] FIG. 1 is a graph showing normalized INa as a function of inactivation time, showing the occurrence of inactivation in the absence and presence of 3 μM Compound 1. [Figure 9C] 1 is a graph showing normalized INa as a function of inactivation time, showing the occurrence of inhibition in the presence of compound 1 at concentrations of 0.3 μM, 1 μM, 3 μM, 4.5 μM, and 6 μM. [Figure 9D]FIG. 1 is a graph showing the rate of inhibition as a function of compound 1 concentration, showing that the apparent KON for compound 1 is 4.2 s−1*μM−1. [Figure 9E] Recovery from inhibition (apparent unbinding) for 3 μM compound 1 and the control is shown. [Figure 9F] FIG. 1 is a graph showing normalized INa as a function of recovery time, showing recovery from inactivation in the absence and presence of 3 μM Compound 1. [Figure 9G] FIG. 13 is a graph showing normalized INa as a function of recovery time, showing recovery from inhibition (normalized to exclude compound-independent deactivation), with a KOFF of 1.7 s−1 for Compound 1. [Figure 9H] Graph showing binding KON and dissociation KOFF of Nav-targeted ASM of compound 1 and standard of care. [Figure 10A] FIG. 1 is a graph showing total distance traveled in the sLMA assay plotted as a percent of control versus dose of Compound 1. [Figure 10B] FIG. 1 is a graph showing the total distance traveled in the sLMA assay plotted as a percent of control against the concentration of Compound 1 in plasma. [Figure 10C] 1 is a graph showing the total distance traveled in the sLMA assay plotted as a percent of control against the concentration of Compound 1 in the brain. Data are presented as mean±SEM, n=20 per group. [Figure 11A] 1 is a graph showing protection from MES-induced strong paw extension as a function of Compound 1 dose. [Figure 11B] 1 is a graph showing protection from MES-induced strong paw extension as a function of the concentration of Compound 1 in plasma. [Figure 11C] Graph showing protection from MES-induced strong hind limb extension as a function of the concentration of Compound 1 in the brain. Data are presented as mean ± SEM, n=30 per group. Curves represent fits to a 4-parameter log function, and EC50 values ​​are included in the figure. [Figure 11D]1 is a graph showing protection from MES-induced strong hind limb extension as a function of dose for Compound 1, carbamazepine, cenobamate, lamotrigine, and XEN1101. Curves represent fits to a 4-parameter log function, and error bars have been removed for clarity. [Figure 12A] 1 is a graph showing percent protection from PTZ-induced clonic seizures as a function of Compound 1 dose. [Figure 12B] 1 is a graph showing percent protection from PTZ-induced clonic seizures as a function of the concentration of Compound 1 in plasma. [Figure 12C] Figure 1 is a graph showing percent protection from PTZ-induced clonic seizures as a function of concentration of Compound 1 in the brain. Data are expressed as mean ± SEM, n = 10-20 per group. Curves represent fits to a 4-parameter log function, and EC50 values ​​are included in the figure. [Figure 13A] 1 is a bar graph showing seizure scores in a 6-Hz acute seizure model at a stimulation current of 32 mA as a function of Compound 1 dose. [Figure 13B] 1 is a bar graph showing seizure scores in a 6-Hz acute seizure model at a stimulation current of 44 mA as a function of Compound 1 dose. [Figure 13C] 1 is a graph showing percent protection from 6-Hz induced seizures at stimulation currents of 32 mA (solid symbols, solid line) and 44 mA (open symbols, dashed line) as a function of concentration of Compound 1 in plasma. [Figure 13D] Graph showing percent protection from 6-Hz induced seizures at stimulation currents of 32 mA (solid symbols, solid line) and 44 mA (open symbols, dashed line) as a function of the concentration of Compound 1 in the brain. Data are expressed as mean ± SEM, n=10 per group. Curves represent fits to a 4-parameter log function, and EC50 values ​​are shown in the table below. [Figure 14A] FIG. 1 is a diagram of the dosing scheme for Part A (single ascending dose) of a Phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of Compound 1 in healthy volunteers. [Figure 14B] FIG. 1 is a diagram of the dosing scheme for Part B (multiple ascending doses) of a Phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of Compound 1 in healthy volunteers. [Figure 14C] FIG. 1 is a diagram of the dosing scheme for Part C (optional food effect assessment) of a Phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of Compound 1 in healthy volunteers. [Figure 15] FIG. 1 is a diagram of the dosing scheme for a Phase 2 study to evaluate the photoictal EEG response, safety, tolerability, and pharmacokinetics of Compound 1 in participants with epilepsy and photoictal EEG response to intermittent photic stimulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] Reference will now be made in detail to various exemplary embodiments, examples of which are illustrated in the accompanying drawings. It is understood that the following detailed description is provided to provide the reader with a more complete understanding of certain embodiments, features, and details of aspects of the present disclosure, and should not be construed as a limitation on the scope of the present disclosure.

[0038] definition In order to more readily understand this disclosure, certain terms are first defined below. Additional definitions for the following terms and other terms may be set forth throughout this specification. In the event that a definition of a term set forth below conflicts with a definition in an application or patent incorporated by reference, the definition set forth in this application shall be used to understand the meaning of that term.

[0039] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods and / or steps of the type described herein and / or that will become apparent to those skilled in the art upon reading this disclosure.

[0040] The term "about" is used herein to mean within a typical tolerance in the art. For example, "about" can be understood as about 2 standard deviations from the mean. According to certain embodiments, when referring to a measurable value, such as a quantity, "about" means to encompass a variation of ±20%, ±10%, ±5%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, or ±0.1% from the specified value, as appropriate for carrying out the disclosed method and / or for manufacturing and using the disclosed device. When "about" is present before a series of numbers or ranges, it is understood that "about" can modify each of the series of numbers or ranges.

[0041] As used herein, the terms "administer", "administering" or "administration" refer to the direct administration of either a compound or a pharma- ceutically acceptable salt or ester of a compound, or a composition comprising a compound or a pharma- ceutically acceptable salt or ester of a compound, to a subject.

[0042] As used in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are present conjunctively in some cases and disjunctively in other cases. Other elements, whether related or unrelated to those elements specifically identified, may optionally be present other than the elements specifically identified by the "and / or" clause, unless expressly indicated to the contrary. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," may refer in one embodiment to A without B (optionally including elements other than B), in another embodiment to B without A (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), and so forth.

[0043] The term "at least" preceding a number or series of numbers (e.g., "at least two") is understood to include the number adjacent to the term "at least," and all subsequent numbers or integers that may be logically included, as is clear from the context. When "at least" is present before a series of numbers or ranges, it is understood that "at least" can modify each of the numbers in the series or range.

[0044] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0045] As used herein, the term "in some embodiments" refers to embodiments of all aspects of the present disclosure, unless the context clearly indicates otherwise.

[0046] As used herein, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health, and condition of the subject.The effective amount includes therapeutic and prophylactic treatment.

[0047] As used herein, "pharmaceutical acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound in which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0048] As used herein, "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Pharmaceutically acceptable salts include, but are not limited to, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0049] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., male or female of any age group, e.g., a fetus, a pediatric subject (e.g., infant, child, adolescent), or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)), and / or a non-human animal, e.g., a mammal such as a primate (e.g., a cynomolgus or rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, or dog. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0050] As used herein, the terms "treating," "treatment," or "treating" a condition or disorder, e.g., epilepsy or an epilepsy syndrome such as focal epilepsy, in a subject in need of such treatment includes partially, substantially, or completely achieving one or more of the following: ameliorating, reversing, or achieving a reduction in the severity of at least one symptom or indicator associated with the condition or disorder, or arresting the progression or worsening of the condition or disorder.

[0051] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0052] The embodiments disclosed herein are not intended to be limited in any manner by the above exemplary enumeration of chemical groups and substituents. Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the present disclosure. The following description is illustrative of the present disclosure and, of course, should not be construed as limiting the scope of the invention described herein.

[0053] Compounds and Compositions In one aspect, provided herein is compound 1 having the formula: [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0054] In some embodiments, compound 1 is in a crystalline form. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction pattern that includes X-ray powder diffraction peaks at the following diffraction angles (°2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction pattern that includes X-ray powder diffraction peaks at the following diffraction angles (°2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.2. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction pattern comprising X-ray powder diffraction peaks at the following diffraction angles (°2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2, and 22.6±0.2. Crystalline forms of Compound 1 are described, for example, in WO2019 / 232209, the entire contents of which are incorporated herein by reference.

[0055] Compound 1 or its pharma- ceutically acceptable salts described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), and the formation and crystallization of chiral salts, and preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The embodiments disclosed herein additionally encompass the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0056] As used herein, an enantiomerically pure compound is substantially free of the other enantiomer or stereoisomer of the compound (i.e., is in enantiomeric excess). In other words, the "S" forms of the compound are substantially free from the "R" forms of the compound and are thus in enantiomeric excess of the "R" forms. The term "enantiomerically pure" or "pure enantiomer" means that a compound contains more than about 75% by weight of an enantiomer, e.g., more than about 80%, more than about 85%, more than about 90%, more than about 91%, more than about 92%, more than about 93%, more than about 94%, more than about 95%, more than about 96%, more than about 97%, more than about 98%, more than about 98.5%, more than about 99%, more than about 99.2%, more than about 99.5%, more than about 99.6%, more than about 99.7%, more than about 99.8%, or more than about 99.9% by weight. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0057] In certain aspects, compositions are provided that include Compound 1 as described herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition is a pharmaceutical composition that includes Compound 1 as described herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

[0058] In some embodiments, the enantiomerically pure compound may be present in a composition with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound may comprise, for example, about 90% of excipients and about 10% of an enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may comprise, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound may comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may comprise, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0059] The compounds described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3 H may be any isotope, including T or tritium. C may be 12 C. 13 C, and 14 C may be any isotope, including O. 16 O and 18 may be any isotope including O, and F is 18 F and 19 It may be any isotope containing F.

[0060] Treatment method The compounds and compositions described herein are generally useful for modulating the activity of sodium channels and for preventing abnormal functioning of sodium channel ion channels, such as abnormal slow sodium (I NaL) current-related conditions. In some embodiments, the compounds provided by the present disclosure are useful for treating epilepsy or epilepsy syndromes. The compounds provided, pharma- ceutically acceptable salts thereof, or compositions comprising same can also modulate all sodium ion channels, or modulate one or more sodium ion channels, e.g., Na V In some embodiments, the compounds of the present disclosure are specific for only the sodium ion channel Na V Has specificity for 1.6.

[0061] In typical embodiments, the disclosure is intended to encompass the compounds disclosed herein, as well as pharma- ceutically acceptable salts, pharma-ceutically acceptable esters, tautomers, polymorphs, and prodrugs of such compounds. In some embodiments, the disclosure includes pharma- ceutically acceptable addition salts, pharma-ceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomeric forms, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (pure or as racemic or non-racemic mixtures) of Compound 1.

[0062] Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, and compositions described herein, can be used to treat neurological disorders, disorders associated with excessive neuronal excitability, or disorders associated with de novo gain-of-function or loss-of-function mutations in central nervous system sodium channel genes, such as, for example, SCN1A, SCN2A, and SCN8A.

[0063] In some embodiments, a method for treating a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a de novo gain-of-function or loss-of-function mutation in a major central nervous system sodium channel gene is provided, the method comprising administering to a subject in need thereof an effective amount of Compound 1 as disclosed herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0064] Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., malignant migratory infantile focal seizures (MMFSI) or infantile epilepsy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathies, developmental epileptic encephalopathies (DEE), early infantile epileptic encephalopathies (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, Lennox-Gastaut syndrome), drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures).

[0065] Epilepsy is a CNS disorder in which the activity of nerve cells in the brain is disrupted, causing seizures or abnormal behavior, sensations, and sometimes loss of consciousness. Seizure symptoms vary greatly, from a simple blank stare for a few seconds to repetitive twitching of the arms or legs during a seizure. Epilepsy may include generalized or partial or focal seizures. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may scream or make some noise, stiffen for a few seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are normally open, and the person may appear not to be breathing and may actually turn blue. Consciousness returns gradually, and the person may be confused for a few minutes to a few hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic. In partial or focal seizures, only part of the brain is involved, so only one part of the body is affected. Depending on the part of the brain that has abnormal electrical activity, symptoms may vary.

[0066] Epilepsy as referred to herein includes generalized seizures, partial seizures, complex partial seizures, tonic-clonic seizures, clonic seizures, tonic seizures, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0067] In some embodiments, the epilepsy syndrome is an early onset DEE. In certain embodiments, the epilepsy syndrome is a DEE, such as Ohtahara syndrome, infantile epilepsy with migratory focal seizures (EIMFS), infantile and pediatric DEE, such as West syndrome and Lennon-Gastaut syndrome, Dravet syndrome, idiopathic / generalized epilepsy (IGE / GGE), temporal lobe epilepsy, myoclonic astatic epilepsy (MAE), malignant focal migrating partial seizures of infancy (MMPSI), and familial hemiplegic migraine with or without epilepsy. In certain embodiments, the epilepsy syndrome is late onset epileptic encephalopathy.

[0068] In some embodiments, the epilepsy syndrome is focal epilepsy, including, for example, idiopathic localization-related epilepsy (ILRE), frontal lobe epilepsy, temporal lobe epilepsy, parietal lobe epilepsy, and occipital lobe epilepsy, hi some embodiments, the epilepsy syndrome is adult focal epilepsy.

[0069] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, may be used to treat epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused at least in part by some aspects of epilepsy are also called epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment, and severe cognitive dysfunction, e.g., West syndrome. In some embodiments, epilepsy syndromes include epileptic encephalopathies, e.g., Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0070] In some embodiments, compound 1 or its pharma- ceutically acceptable salt disclosed herein, or pharmaceutical compositions comprising it, can be used to treat focal epilepsy, including, for example, idiopathic localization-related epilepsy (ILRE), frontal lobe epilepsy, temporal lobe epilepsy, parietal lobe epilepsy, and occipital lobe epilepsy. In some embodiments, the epilepsy syndrome is adult focal epilepsy. Focal epilepsy is a neurological condition whose primary symptom is recurrent seizures that affect one hemisphere (half) of the brain. Thus, focal epilepsy is generally characterized by seizures originating from a specific part (lobe) of the brain.

[0071] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy (SUDEP), Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0072] In some embodiments, the methods described herein include administering to the patient a compound disclosed herein, or a pharmacologic salt thereof, or a pharmaceutical composition comprising the same, a therapeutic agent for treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory pediatric epilepsy with generalized tonic-clonic seizures, or the like) prior to administration of the compound disclosed herein, or a pharmacologic salt thereof, or a pharmaceutical composition comprising the same. The method further includes identifying a subject with epilepsy, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy (SUDEP), Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0073] In one aspect, the present disclosure relates to a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, developmental epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, SCN3A The present invention features a method for treating a patient suffering from a pulmonary embolism syndrome (PES), including cryptogenic childhood partial epilepsy with a mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy (SUDEP), Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy, comprising administering to a subject in need of such treatment Compound 1 or a pharma- ceutical acceptable salt thereof as disclosed herein, or a pharmaceutical composition comprising the same.

[0074] Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising same, can also be used in the treatment of a subject having a genetic disorder characterized by a gene expression profile similar to that described herein, including the following genes: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CACNA1G, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRA2, GABRB3, GABRG2, GNAO1, GOSR2, GRIK1, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCN1A, KCNA2, KCNB1, KCNC1, KCNMA1, KCNN2, KCNQ2, KCNQ3, KCNQ4, KCNQ5, KCNQ6, KCNQ7, KCNQ8, KCNQ9, KCNQ10, KCNQ11, KCNQ12, KCNQ13, KCNQ14, KCNQ15, KCNQ16, KCNQ17, KCNQ18, KCNQ19, KCNQ20, KCNQ21, KCNQ22, KCNQ23, KCNQ24, KCNQ25, KCNQ26, KCNQ27, KCNQ28, KCNQ30, KCNQ31, KCNQ32, KCNQ33, KCNQ34, KCNQ35, KCNQ36, KCNQ37, KCNQ38, KCNQ39 ... It can be used to treat epileptic encephalopathies having mutations in one or more of CNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH7, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SHANK3, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TRIM3, UNC79, and WWOX.

[0075] In some embodiments, the methods described herein include administering to the patient a compound 1 or a pharma- ceutical acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, prior to administration of the compound 1 or a pharma- ceutical acceptable salt thereof disclosed herein, ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CACNA1G, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRA2, GABRB3, GABRG2, GNAO1, GOSR2, GRIK1, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCN1A, KCNA2, KCNB1, KCNC1, KCNMA1, KCNN2, or a combination thereof. , KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH7, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SHANK3, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TRIM3, UNC79, and WWOX.

[0076] Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, may also be used in a method for improving at least one symptom or characteristic of epilepsy or epilepsy syndrome, including, for example, early-onset DEE, in a subject in need thereof. In certain embodiments, the symptom or characteristic includes one or more of the following: seizures, hypotonia, sensory problems, such as sensory integration disorders, motor dysfunction, intellectual and cognitive dysfunction, motor and balance dysfunction, such as choreoathetosis, dystonia, and ataxia, anxiety, sensory problems, urinary retention problems, irritability, behavioral problems, visual dysfunction, language and speech delays, gastrointestinal disorders (e.g., gastroesophageal reflux disease, diarrhea, constipation, movement disorders, etc.), neurodevelopmental delays, sleep problems, sudden unexpected death in epilepsy (SUDEP), motor developmental delays, delayed social milestones, repetitive behaviors, and uncoordinated oral movements. In certain embodiments, seizures include focal seizures, clonic seizures, tonic seizures, and generalized tonic-clonic seizures, prolonged seizures (often lasting longer than 10 minutes), and frequent seizures (e.g., convulsive seizures, myoclonic seizures, absence seizures, focal seizures, obtundation status seizures, and tonic seizures).

[0077] In one aspect, the present disclosure provides a method for improving at least one symptom or characteristic of epilepsy or epilepsy syndrome, including, for example, focal epilepsy, comprising administering to a subject in need thereof compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same. In certain embodiments, the symptom or characteristic comprises one or more of seizures, hypotonia, sensory problems, such as sensory integration disorders, motor dysfunction, intellectual and cognitive dysfunction, motor and balance dysfunction, such as choreoathetosis, dystonia, and ataxia, anxiety, sensory problems, urinary retention problems, irritability, behavioral problems, visual dysfunction, language and speech delays, gastrointestinal disorders (e.g., gastroesophageal reflux disease, diarrhea, constipation, movement disorders, etc.), neurodevelopmental delays, sleep problems, sudden unexpected death in epilepsy (SUDEP), motor developmental delays, delayed social milestones, repetitive behaviors, and uncoordinated oral movements. In certain embodiments, seizures include focal seizures, clonic seizures, tonic seizures, and generalized tonic-clonic seizures, prolonged seizures (often lasting longer than 10 minutes), and frequent seizures (e.g., convulsive seizures, myoclonic seizures, absence seizures, focal seizures, confusional state seizures, and tonic seizures).

[0078] In some aspects, the disclosure provides a method of reducing the severity, number, and / or frequency of seizures in a subject in need thereof, comprising administering to the subject an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has epilepsy or an epilepsy syndrome. In some embodiments, the subject has focal epilepsy.

[0079] In some embodiments, provided herein is a method for treating a neurological or psychiatric disorder, the method comprising administering Compound 1, or a pharma- ceutically acceptable salt thereof, as disclosed herein, or a pharmaceutical composition comprising same, to a subject in need of such treatment.

[0080] In one embodiment, peak sodium current (I Na ) than persistent sodium current (I NaProvided herein is a method for preferentially inhibiting a peak sodium current, I, comprising contacting the neuron with an effective amount of Compound 1. As described in Example 7 herein, Compound 1 inhibits the peak sodium current, I Na More sustainable than I Na Specifically, compound 1 exhibited a preference for inhibiting the persistent I Na Inhibits peak I Na Compared with inhibition of sustained I Na Peak I shows a preference for inhibition of Na and Sustainability I Na The ratio of 68 to 100 was 68. In contrast, standard-of-care antiepileptic drugs (AEDs) Na Compared with inhibition of sustained I Na It shows low preference for inhibition of peak I Na and Sustainability I Na The ratio of peak I to the AEDs was less than 68. Na and Sustainability I Na The ratios of Cenobamate to Lamotrigine were 24 (Cenobamate), 30 (Carbamazepine), 8 (Oxacarbazepine), and 16 (Lamotrigine). Na More sustainable than I Na The preferential inhibition of may be associated with improved tolerability of compound 1.

[0081] In various embodiments, the therapeutic methods provided herein provide an advantage over any other therapy, e.g., an advantage over standard therapy. In some embodiments, the methods herein provide enhanced selectivity for a hyperexcitable neuronal condition, preserve normal neuronal function, or provide a wider therapeutic window than another therapy.

[0082] In any of the methods disclosed herein, compound 1 or its pharma- ceutically acceptable salt, or a pharmaceutical composition comprising it, as disclosed herein, is administered to a subject in an effective amount, which is an amount sufficient to induce a desired biological response.An effective amount includes a therapeutically effective amount, which is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition.An effective amount also includes a prophylactically effective amount. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, is administered to a subject in an amount ranging from about 0.1 mg / kg to about 1 g / kg, e.g., from about 0.1 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 5 mg / kg, from about 0.1 mg / kg to about 2.5 mg / kg, from about 0.1 mg / kg to about 1.5 mg / kg, from about 0.2 mg / kg to about 15 mg / kg, from about 0.2 mg / kg to about 5 mg / kg, from about 0.5 mg / kg to about 20 mg / kg, from about 0.5 mg / kg to about 10 mg / kg, or from about 0.5 mg / kg to about 5 mg / kg. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising same, is administered to a subject in an amount ranging from about 10 mg / kg to about 100 mg / kg, e.g., about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg / kg.

[0083] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, is administered to a subject as a single dose in an amount ranging from about 1 mg to about 180 mg or from about 2.5 mg to about 150 mg, for example, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, Compound 1 disclosed herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, is administered to a subject as a single dose in an amount of about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 5 mg to about 130 mg, or about 10 mg to about 120 mg). In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same is administered to a subject as a single dose in an amount of up to 150 mg, for example, about 30 mg to about 120 mg, for example, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same is administered to a subject as a single dose in an amount of about 90 mg or about 120 mg. In some embodiments, the dose is an oral dose.

[0084] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, is administered to a subject as multiple doses in an amount ranging from about 30 mg to about 150 mg, such as about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. ...

[0085] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, is orally administered to a subject. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, is administered to a subject daily. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, is administered to a subject daily for at least 14 days. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, is administered to a subject in increasing doses from an initial dose of about 5 mg to about 150 mg, e.g., about 5 mg to about 25 mg, about 20 mg to about 100 mg, e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg.

[0086] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same is administered to a subject in a fasted state, such as more than about 10 hours after the last meal and / or at least about 4 hours before the next meal. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same is administered to a subject in a fed state, such as after a meal normally consumed by the subject, including, but not limited to, a high-fat and high-calorie meal.

[0087] In some embodiments, Compound 1 disclosed herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, has a maximum plasma concentration (t max The compound is orally administered to a subject in an amount effective to achieve the desired therapeutic effect.

[0088] In some embodiments, Compound 1 disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same, has a plasma TC of about 1500 ng / g to about 800 ng / g, e.g., about 1400 ng / g to about 900 ng / g, about 1300 ng / g to about 1000 ng / g, about 1200 ng / g to about 1100 ng / g, or about 1150 ng / g to about 1100 ng / g. 50 In some embodiments, Compound 1 or a pharma- ceutical composition comprising the same ... 50 is orally administered to a subject in an amount effective to achieve this.

[0089] In some embodiments, Compound 1 disclosed herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same, has a brain EC of about 85 ng / g to about 50 ng / g, e.g., about 85 ng / g to about 60 ng / g, about 80 ng / g to about 65 ng / g, about 75 ng / g to about 60 ng / g, about 70 ng / g to about 60 ng / g, or about 70 ng / g to about 65 ng / g. 50 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising same, is orally administered to a subject in an amount effective to achieve a brain EC of about 85 ng / g, 80 ng / g, 75 ng / g, 70 ng / g, 65 ng / g, 60 ng / g, 55 ng / g, or 50 ng / g. 50 is orally administered to a subject in an amount effective to achieve this.

[0090] Combination therapy Compound 1 or its pharmaceutically acceptable salt disclosed herein, or pharmaceutical composition comprising it, may be administered in combination with another drug or therapy. The subject to whom the compound disclosed herein is to be administered may have a disease, disorder, or condition, or symptoms thereof, that benefit from treatment with another drug or therapy. These diseases or conditions may be related to epilepsy or epilepsy syndrome.

[0091] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, is administered in combination with an antiepileptic drug, including, but not limited to, brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol. In some embodiments, Compound 1 disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same, is administered in combination with carbamazepine.

[0092] In some embodiments, the methods of the present disclosure include administering to a subject in need thereof a compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, in combination with an antiepileptic drug. In some embodiments, the methods of the present disclosure include administering to a subject in need thereof a compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same, in combination with carbamazepine.

[0093] Thus, one aspect of the disclosure provides a composition comprising compound 1 as disclosed herein, or a pharma- ceutically acceptable salt thereof, and at least one additional therapeutic agent. In some embodiments, the composition comprises compound 1 as disclosed herein, or a pharma- ceutically acceptable salt thereof, and at least two additional therapeutic agents. In some embodiments, the composition comprises compound 1 as disclosed herein, or a pharma- ceutically acceptable salt thereof, and at least three additional therapeutic agents, compound 1 as disclosed herein, or a pharma- ceutically acceptable salt thereof, and at least four additional therapeutic agents, or compound 1 as disclosed herein, or a pharma- ceutically acceptable salt thereof, and at least five additional therapeutic agents.

[0094] Methods of combination therapy include the simultaneous administration of a single formulation containing Compound 1, or a pharma- ceutically acceptable salt thereof, as disclosed herein and the additional therapeutic agent(s); the essentially simultaneous administration of two or more formulations containing Compound 1, or a pharma- ceutically acceptable salt thereof, as disclosed herein and the additional therapeutic agent(s); as well as the sequential administration of Compound 1, or a pharma- ceutically acceptable salt thereof, as disclosed herein and the additional therapeutic agent(s) in any order, preferably with a period during which Compound 1, or a pharma- ceutically acceptable salt thereof, as disclosed herein and the additional therapeutic agent(s) exert their therapeutic effects simultaneously.

[0095] Dosage forms and compositions In one aspect, the disclosure provides dosage forms or compositions useful for treating a disease, disorder, or condition described herein, e.g., a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a de novo gain-of-function or loss-of-function mutation in the major central nervous system sodium channel genes, e.g., SCN1A, SCN2A, and SCN8A.

[0096] Thus, the present disclosure provides pharmaceutical compositions that contain, as an active ingredient, Compound 1 as disclosed herein or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutical acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0097] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of drugs, including, for example, rectal, buccal, intranasal, and transdermal routes, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via impregnated or coated devices, such as, for example, stents, or arterially inserted cylindrical polymers, having similar utilities as those described in those patents and patent applications incorporated by reference. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure are administered orally.

[0098] One mode of administration is parenterally, particularly by injection. Forms in which the compositions of the present disclosure may be incorporated for administration by injection include aqueous or oily suspensions or emulsions including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but are less preferred in the context of the present invention. Also, ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be provided by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0099] Sterile injectable solution is prepared by incorporating the compound according to the present invention in the required amount in a suitable solvent containing various other ingredients as listed above, as necessary, and then sterilizing by filtration.In general, dispersion is prepared by incorporating various sterilized active ingredients in a sterile vehicle containing a basic dispersion medium and other ingredients as listed above.In the case of sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains powder of active ingredient and any additional desired ingredient from its sterile solution that has been previously sterilized and filtered.

[0100] Oral administration is another route for administration of the compounds according to the present disclosure. Administration can be via capsules or tablets, etc. In making pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier, which can be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0101] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents, emulsifying and suspending agents, preserving agents such as methyl and propylhydroxy-benzoates, sweeteners, and flavoring agents.

[0102] The compositions of the present disclosure can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Pat. Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents is well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0103] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharma- ceutical effective amount. Preferably, for oral administration, each dosage unit contains about 1 mg to about 2 g of a compound described herein, and for parenteral administration, preferably about 0.1 to about 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will usually be determined by a physician in view of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.

[0104] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogenous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0105] The tablets or pills of the present disclosure may be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former.The two components may be separated by an enteric layer, which functions to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be released in a delayed manner.A variety of materials may be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0106] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharma- ceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0107] In one aspect, the present specification provides a dosage form or a composition in a dosage form comprising about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of Compound 1 disclosed herein or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0108] In some embodiments, the dosage form or composition in the dosage form contains from about 2.5 mg to about 150 mg (e.g., from about 10 mg to about 150 mg, from about 20 mg to about 150 mg, from about 40 mg to about 150 mg, from about 60 mg to about 150 mg, from about 80 mg to about 150 mg, from about 100 mg to about 150 mg, from about 10 mg to about 120 mg, from about 20 mg to about 120 mg, from about 40 mg to about 120 mg, from about 60 mg to about 120 mg, from about 80 mg to about 120 mg, from about 100 mg to about 120 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 40 mg to about 100 mg, from about 6 0 mg to about 100 mg, about 80 mg to about 100 mg, about 10 mg to about 80 mg, about 20 mg to about 80 mg, about 40 mg to about 80 mg, about 60 mg to about 80 mg, about 10 mg to about 60 mg, about 20 mg to about 60 mg, about 40 mg to about 60 mg, about 70 mg to about 120 mg, about 70 mg to about 100 mg, about 50 mg to about 120 mg, about 50 mg to 90 mg, about 30 mg to about 120 mg, about 30 mg to about 60 mg, about 30 mg to about 80 mg, about 30 mg to about 100 mg) of compound 1 disclosed herein or a pharma- ceutical acceptable salt thereof. In some embodiments, the dosage form is an oral dosage form.

[0109] In some embodiments, the dosage form or composition of the dosage form contains from about 1 mg to about 100 mg (e.g., from about 1 mg to about 80 mg, from about 1 mg to about 50 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 5 mg to about 100 mg, from about 5 mg to about 80 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg) of Compound 1 disclosed herein or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments, the dosage form or composition of the dosage form contains about 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, 100 mg, about 99 mg, about 98 mg, about 97 mg, about 96 mg, about 95 mg, about 94 mg, about 93 mg, about 92 mg, about 91 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 69 mg, about 68 mg, about 67 mg, about 66 mg, about 65 mg, About 64 mg, about 63 mg, about 62 mg, about 61 mg, about 60 mg, about 59 mg, about 58 mg, about 57 mg, about 56 mg, about 55 mg, about 54 mg, about 53 mg, about 52 mg, about 51 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 7 mg, about 5 mg, about 2.5 mg, about 2 mg, about 1.5 mg, or about 1 mg of Compound 1 as disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form or composition of the dosage form is configured for oral administration.

[0111] In another aspect, the present disclosure provides a dosage form or composition of the dosage form comprising a plurality of particles of Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein and a pharma- ceutically acceptable excipient, wherein the amount of the plurality of particles of Compound 1 or a pharma- ceutically acceptable salt thereof disclosed herein in the dosage form is from about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg).

[0112] In some embodiments, the particles of Compound 1 or a pharma- ceutically acceptable salt thereof in the dosage form or composition are from about 2.5 mg to about 150 mg (e.g., from about 10 mg to about 150 mg, from about 20 mg to about 150 mg, from about 70 mg to about 120 mg, from about 30 mg to about 60 mg, about 100 mg, about 50 mg).

[0113] In some embodiments, the dosage form or composition is configured for oral administration. In some embodiments, the dosage form is in solid form. In some embodiments, the dosage form is in the form of a capsule. In some embodiments, the pharmaceutical excipients in the capsule are fillers (e.g., cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0114] In some embodiments, the dosage form is in liquid form. In some embodiments, the dosage form is in the form of a solution. In some embodiments, the pharmaceutical excipient in the solution is selected from the group consisting of bulking agents (e.g., polymers (e.g., PEG400)), emulsifiers (e.g., castor oil derivatives (e.g., Kolliphor RH40), surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), vitamin derivatives (e.g., Vitamin ETPGS)), solvents (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)).

[0115] In some embodiments, the concentration of Compound 1 disclosed herein or a pharma- ceutically acceptable salt thereof in the solution is about 0.1 mg / mL to about 10 mg / mL (e.g., about 0.5 mg / mL to about 10 mg / mL, about 1 mg / mL to about 10 mg / mL, about 2 mg / mL to about 10 mg / mL, about 3 mg / mL to about 10 mg / mL, about 4 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 6 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 8 mg / mL, about 1 The preferred range is about 2 mg / mL to about 8 mg / mL, about 3 mg / mL to about 8 mg / mL, about 4 mg / mL to about 8 mg / mL, about 5 mg / mL to about 8 mg / mL, about 6 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 6 mg / mL, about 2 mg / mL to about 6 mg / mL, about 3 mg / mL to about 6 mg / mL, about 4 mg / mL to about 6 mg / mL, about 0.5 mg / mL to about 4 mg / mL, about 1 mg / mL to about 4 mg / mL, or about 2 mg / mL to about 4 mg / mL).

[0116] In some embodiments, the concentration of Compound 1 disclosed herein or a pharma- ceutically acceptable salt thereof in the solution is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, or about 10 mg / mL.

[0117] In some embodiments, the dosage form is in the form of a suspension. In some embodiments, the concentration of compound 1 disclosed herein or its pharma- ceutically acceptable salt in the suspension is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL.

[0118] In some embodiments, the concentration of Compound 1 disclosed herein or a pharma- ceutically acceptable salt thereof in the suspension is about 0.1 mg / mL to about 10 mg / mL (e.g., about 0.5 mg / mL to about 10 mg / mL, about 1 mg / mL to about 10 mg / mL, about 2 mg / mL to about 10 mg / mL, about 3 mg / mL to about 10 mg / mL, about 4 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 6 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 8 mg / mL, about 1 The preferred range is about 2 mg / mL to about 8 mg / mL, about 3 mg / mL to about 8 mg / mL, about 4 mg / mL to about 8 mg / mL, about 5 mg / mL to about 8 mg / mL, about 6 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 6 mg / mL, about 2 mg / mL to about 6 mg / mL, about 3 mg / mL to about 6 mg / mL, about 4 mg / mL to about 6 mg / mL, about 0.5 mg / mL to about 4 mg / mL, about 1 mg / mL to about 4 mg / mL, or about 2 mg / mL to about 4 mg / mL). EXAMPLES

[0119] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as limiting the scope thereof in any manner.

[0120] Example 1. Effects of Compound 1 on mouse wild-type CA1 pyramidal neuron excitability using brain slice whole-cell patch clamp electrophysiology The goal of this study was to determine the effects of Compound 1 on the intrinsic excitability of CA1 pyramidal neurons from brain slices obtained from wild-type mice.

[0121] Mice (p17-p21) were anesthetized with 2% isoflurane. Brains were removed and placed in an icy slurry of brain slice cutting solution containing 125 mM choline chloride, 2.5 mM KCl, 1.25 mM NaH2PO4, 26 mM NaHCO3, 20 mM D-glucose, 0.4 mM CaCl2·2H2O, and 6 mM MgCl2·6H2O, maintained at pH 7.4 by continuous bubbling with carbogen gas (95% O2-5% CO2). For whole-cell patch clamp experiments, 300-micrometer coronal hippocampal slices were cut with a vibratome (VT1200, Leica). Slices were incubated in brain slice cutting solution at room temperature for a minimum of 1 h before patching.

[0122] Brain slices were transferred to a submerged recording chamber on an upright microscope (Slicescope Pro 1000, Scientifica) and perfused (2 ml / min) with extracellular artificial cerebrospinal fluid (aCSF) recording solution at 32° C. The extracellular aCSF recording solution contained 125 mM NaCl, 2.5 mM KCl, 1.25 mM NaH2PO4, 26 mM NaHCO3, 10 mM D-glucose, 2 mM CaCl2·2H2O, and 2 mM MgCl2·6H2O and was maintained at pH 7.4 by continuous bubbling with carbogen gas (95% O2-5% CO2).

[0123] CA1 pyramidal neurons were visually identified in the pyramidal cell layer of the CA1 region of the hippocampus using an infrared oblique illumination microscope (Olympus) equipped with a 40× water-immersion objective using a camera (Dage IR-2000, Dage). Cell identity was also confirmed using action potential firing characteristics, which were accommodated with high current injections and had a wide action potential half-width. Patch clamp recordings were performed using a micromanipulator (MPC-200, Sutter) and an Axon Multiclamp 700B patch clamp amplifier (MDS). Data were acquired using pClamp software (v10, MDS) with a sampling rate of 50 kHz and low-pass Bessel filtered at 10 kHz (Digidata 1550b, Axon). Patch pipettes (3–7 MΩ, GC150F-7.5, Harvard Instruments) pulled using a Flaming / brown micropipette puller (model P-1000, Sutter) were filled with intracellular recording solution containing 125 mM K-gluconate, 5 mM KCl, 2 mM MgCl2·6H2O, 10 mM HEPES, 4 mM ATP-Mg, 0.3 mM GTP-Na, 10 mM creatine phosphate, 0.1 mM EGTA, and 0.2% biotin at pH 7.2 (adjusted with KOH) and a measured osmolarity of 292 mOsm.

[0124] Studies were performed using whole-cell current clamp recording mode. Once the whole-cell configuration was obtained for 2 min, a holding current was injected to maintain a membrane potential of approximately -70 mV. Current steps (injection currents from -60 to 340 pA in 20 pA steps, 400 ms duration) were applied in current clamp mode. The amplitude of the current injection was relative to the holding current. A test pulse (amplitude -5 pA, duration 50 ms) was applied 650 ms after the end of the main current step. The interval between sweeps was 5 s (0.2 Hz). To be included in the study, cells were required to have an access resistance of less than 20 MΩ and a holding current of less than -200 pA. Once baseline action potential firing was determined in the presence of extracellular aCSF recording solution (baseline), compound 1 (300 nM or 3 μM) was washed onto the slices for 5 min, after which the action potential generation protocol was repeated.

[0125] Data were analyzed using Axograph X software. Individual action potentials were identified and counted using a +50 mV amplitude threshold relative to the pre-event baseline. The frequency of generated action potentials was plotted against each current injection, and an input-frequency relationship was generated for each cell. Cells whose action potential counts yielded fewer than three cells contributing to the mean amplitude were excluded from the analysis. Statistical analysis was performed using GraphPad Prism software (v8). A paired two-tailed Student's t-test was used to test the effect of compounds on action potential firing compared to baseline. In all cases, the significance of the analysis was set as an alpha value of 0.05.

[0126] Example 2. Human Na+ using the PatchXpress® (Molecular Devices) electrophysiology platform V Effect of Compound 1 on 1.6 Channels The purpose of this study is to VThe aim of the study was to determine the effects of Compound 1 on 1.6 delayed (persistent) currents and peak current tonic block (TB), as well as peak current Use-Dependent Block (UDB).

[0127] 1. Materials and Methods i. Cell preparation Human Na V A HEK-293 cell line stably expressing 1.6 (NP_055006) was used. All cells were cultured at 2 × 10 per Nunc T75 flask. 6 Cells were seeded and cultured for 2 days. At the time of harvest for the assay, the cell number was approximately 6 × 10 6 The cells were washed (1x) in DPBS (Hyclone, Cat# SH30028.03) for approximately 30 seconds. 1mL of 1X 0.05% Trypsin-EDTA (GIBCO Cat# 25300-054) was added, swirled to cover the bottom of the flask and left on the cells for approximately 4 minutes (±90% of the cells were lifted by tapping the flask). Trypsin was inactivated by adding 10mL of warmed media (DMEM High Glucose Media Hyclone, SH30022.02, supplemented with 10% fetal bovine serum, 2mM sodium pyruvate, 10mM HEPES, and 400μg / mL G418). Cells were triturated until a single cell suspension was achieved. A cell count was performed and the cells were diluted to 2x10 in ±30ml of pre-warmed media. 5 The cells were then dispensed into 250 ml centrifuge tubes at a concentration of 1 x 10 / mL. The 250 ml centrifuge tubes were placed on a rocker in an incubator set at 28°C and gently rocked for approximately 1 hour to allow the cells to recover. 5 ml cell aliquots (1 x 10 6 The cells) were placed in a 15 mL centrifuge tube and centrifuged at 100×g for 2 minutes. The supernatant was removed, leaving a cell pellet. 100 μL of external recording solution was added to the pellet and triturated 20 times to achieve a single cell suspension, which was then transferred to a 1.5 mL tube for placement in a PatchXpress® (Molecular Devices).

[0128] ii. Preparation of test agents Compound 1 was provided as a powder and prepared as a 10 mM DMSO stock in a 1 dram glass vial prior to the assay. Just prior to the assay, compound 1 was diluted in DMSO to 300x the specified final concentration. Assay dilutions (1x concentration) were prepared by pipetting 3 μL of diluted compound 1 into 897 μL of extracellular solution in a 1 mL glass shell vial. The vial was capped and vortexed until the start of the PatchXpress® (Molecular Devices) recording protocol.

[0129] iii. PatchXpress® (Molecular Devices) Recording Solution Persistence and peak I Na The same intracellular recording solution was used for the assay, containing 135 mM CsF, 10 mM CsCl, 5 mM NaCl, 10 mM HEPES, 5 mM EGTA, with a pH of 7.4 (adjusted with CsOH) and a measured osmolality of 298 mOsm (adjusted with mannitol). Na For the assay, the external recording solution contained 135 mM NaCl, 5.4 mM KCl, 5 mM glucose, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 200 nM ATX-II (sea anemone toxin, Alomone Labs, Jerusalem, Israel) at pH 7.4 (adjusted with NaOH) and a measured osmolality of 300 mOsm (adjusted with mannitol). Na For the assay, the external recording solution contained 100 mM NaCl, 35 mM NMDG, 5.4 mM KCl, 5 mM glucose, 2 mM CaCl2, 1 mM MgCl2, and 10 mM HEPES at pH 7.4 (adjusted with NaOH) and a measured osmolality of 300 mOsm (adjusted with mannitol).

[0130] iv. Experimental Protocol All studies were performed using the PatchXpress® (Molecular Devices) automated patch clamp platform (Molecular Devices) using the whole-cell configuration. Recordings were performed at room temperature. Data were collected using Patch Commander software (Molecular Devices) and processed using DataXpress 2.0 (Molecular Devices). Cellular acceptance criteria were continuously monitored by custom scripts during recordings. Acceptance criteria for all assays were the I Na >800pA, R seal >200 MΩ and, if appropriate, persistent I Na >100 pA. Compensation was 50% and no leak subtraction was used. Currents were filtered at 5 kHz and digitized at 32.5 kHz. access and R seal was monitored throughout the recording. access >10MΩ or R seal Cells <200 MΩ were automatically terminated by a script.

[0131] Delayed (sustained) current block: Inhibition of ATX-II-activated delayed currents was measured using a 200 ms voltage step to 0 mV. The protocol used a low stimulation rate (approximately 0.1 Hz) and negative potentials (-120 mV) to keep channels in the closed (resting) state. Pharmacology was measured by measuring the mean I during the last 20 ms of the step to 0 mV. Na and no leak subtraction was used.

[0132] Tonic block (TB): The tonic block (TB) protocol used a low stimulation rate (approximately 0.1 Hz) and a negative potential (-120 mV) to maintain the channels in the closed (resting) state. Pharmacology was performed by increasing the peak I in response to a step to 0 mV. Na The measurements were taken during 0.5 h. No leak subtraction was used.

[0133] Use-dependent block (UDB-10Hz): The UDB protocol used a high stimulation rate (10Hz) to cycle channels between the closed (resting), open, and fast inactivation states. Slow inactivation was minimized by using a negative potential (-120mV) between steps. Pharmacology was performed to measure the peak I in response to a step to 0mV. Na The measurements were taken during 0.5 h. No leak subtraction was used.

[0134] Plots and fitting were performed using GraphPad Prism (GraphPad Software). Percent inhibition was calculated, expressed as the mean ± SEM, and plotted against the concentrations tested. Data were expressed according to the Hill equation [Max_Effect / (1 + (IC 50 / x)^Hill_Slope] and the half inhibition (IC 50 ) and the concentration of compound that produces a Hill slope was estimated. MaxEffect was varied for the use-dependent block (UDB) assay but was fixed at 100 for all other assays.

[0135] 2.Results Compound 1 is a human Na V Compound 1 was found to produce a concentration-dependent inhibition of the delayed sodium current induced by application of ATX-II in the 1.6 channel (Figure 1A). Compared to reference compounds also under investigation as potential sodium channel blockers, compound 1 exhibited a distinct "Na V The compound 1 appeared to have a “microbiome fingerprint” (compare FIG. 1A (compound 1) and FIG. 1B (reference compound)). Nevertheless, like the reference compound, compound 1 was found to have a “microbiome fingerprint” (comparison FIG. 1B (reference compound)) in peak I for all assay conditions. Na Compared to persistence I Na In contrast, the two standard Na V The targeted antiepileptic drugs lamotrigine (LTG) and carbamazepine (CBZ) showed lower efficacy and prolonged I AN The IL-10 expression did not show any preference for the LTG or CBZ (arrows in Fig. 1C (LTG) and Fig. 1D (CBZ)).

[0136] Example 3. Effect of Compound 1 on maximal electroshock-induced seizures in a mouse model The maximal electroshock (MES) test is a validated model for evaluating the anti-seizure potential of compounds. Valproic acid (VPA) is used clinically for its anticonvulsant properties and is an effective treatment for tonic seizures. The aim of these studies was to evaluate the effect of compound 1 (0.3, 1, 3, and 10 mg / kg administered orally (p.o.)) to attenuate MES-induced seizures in male CD-1 mice.

[0137] 1. Materials and Methods i.Animals Six-week-old male CD-1 mice were obtained from Vital River (Beijing, China). At the time the experiments were performed, the average body weight was approximately 35 g. Mice were housed in groups of 3–5 under controlled conditions (temperature: 20–26°C, humidity: 40–70%, ventilation rate: 10–15 cycles / h, 12:12 light:dark cycle with lights on at 5:00 a.m.). Food and water were available ad libitum. Mice were allowed to acclimate to these conditions for 6 days before the start of behavioral testing.

[0138] ii. Drug Formulations Dosing solutions were prepared on each experimental day. The highest dose stock solution of Compound 1 was prepared in 35% HPBCD (Vehicle 2) and diluted to make lower doses. VPA was prepared in saline (Vehicle 1). All solutions were protected from light. All compounds and vehicles were administered at 10 ml / kg.

[0139] iii. Study protocol The MES test was performed over two days, with half of the mice from each treatment group tested on each day. Mice were brought into the testing room at least one hour before the start of the experiment. All animals were tail-marked with a permanent marker and weighed. Mice were randomly assigned to one of six treatment groups.

[0140] Animals were administered Compound 1 or 35% HPBCD (vehicle 2) or VPA or saline (vehicle 1) intraperitoneally 30 min prior to the MES test. Immediately prior to the start of the MES test, possible side effects, such as overt sedation, were recorded.

[0141] A Grass S88x (Grass Technologies of Astro-Med, Inc., West Warwick, RI) stimulus isolation unit (A385, WPI Inc., USA) was set to deliver 50 mA square wave stimuli with a duration of 0.8 seconds, a pulse width of 10 milliseconds, and a frequency of 50 Hz. A pair of custom stainless steel electrodes was immersed in 0.2% agar, and the subject then received bilateral transauricular stimulation via ear clip electrodes. The mouse was manually restrained during stimulation. It was then released into an observation cage for seizure observation for 60 seconds immediately after stimulation. Each mouse was continuously observed by an individual blinded to the treatment condition, and the results were recorded.

[0142] Sedation assessment endpoints were as follows: (1) none: mice exhibit normal motor behavior; (2) mild: mice exhibit less movement or immobility in their home cage alone, but exhibit normal motor activity when stimulated by touching with the observer's hand; (3) moderate: mice exhibit immobility in their home cage alone, and exhibit reduced motor activity when pushed or stimulated by touching with the observer's hand; and (4) severe: mice completely lose the ability to move.

[0143] Anti-seizure endpoints were: (1) latency to hindlimb tonic flexion, (2) latency to hindlimb tonic extension, (3) total number of hindlimb tonic flexions, (4) total number of hindlimb tonic extensions, (5) latency to death, and (6) mortality.

[0144] After the experiment, mice were anesthetized with CO2 and terminal plasma and brain tissue samples were collected. 500 μL of whole blood was collected via cardiac puncture and placed into a tube containing 10 μL of EDTAK2. The tube was then placed in wet ice until centrifuged at 2,000 g for 5 minutes at 4°C. The supernatant plasma was pipetted into an Eppendorf tube. Both brain and plasma samples were stored at -80°C until the Compound 1 concentration in each sample was determined.

[0145] iv. Preparation of Plasma Samples Aliquots of 20 μL of unknown samples, calibration standards, quality controls, dilution quality controls, single blanks and double blank samples were added to 1.5 mL tubes. Each sample (except double blanks) was quenched with 300 μL of IS solution (double blank samples were quenched with 300 μL of ACN), and then the mixtures were thoroughly vortex mixed (at least 15 s) and centrifuged at 12000 g for 15 min at 4° C. 70 μL of the supernatant was transferred to a 96-well plate and centrifuged at 3220 g for 5 min at 4° C. 5 μL of the supernatant was then injected for LC-MS / MS analysis.

[0146] v. Preparation of brain samples Brain homogenates were prepared by homogenizing brain tissue in 5 volumes (w:v) of homogenization solution (cold 15 mM PBS / MeOH (V:V, 2:1)). Aliquots of 20 μL of unknown samples, calibration standards, quality controls, dilution quality controls, single blanks and double blank samples were added to 1.5 mL tubes. Each sample (except double blanks) was quenched with 300 μL of IS solution respectively (double blank samples were quenched with 300 μL of ACN), then the mixture was thoroughly vortex mixed (at least 15 s) and centrifuged at 12000 g for 15 min at 4 °C. 70 μL of the supernatant was transferred to a 96-well plate and centrifuged at 3220 g for 5 min at 4 °C. 5 μL of the supernatant was then injected for LC-MS / MS analysis.

[0147] vi.Statistical analysis All statistical analyses were performed using GraphPad Prism 7.0. Data are presented as mean ± sem and p<0.05 was considered statistically significant. Mann-Whitney test was used to detect significant differences in latency and seizure number between saline and VPA groups. Kruskal-Wallis followed by Dunn's test was used to detect significant differences in latency and seizure number between 35% HPBCD and Compound 1.

[0148] vii.ED 50 Value and EC 50 Calculating values Plasma and brain dose-response and concentration-response curves were fitted for each endpoint using GraphPad Prism. From these fitted curves, ED 50 Value and EC 50 values ​​were calculated.

[0149] 2.Results As shown in Figure 2, at 1 mg / kg (oral dose), Compound 1 significantly increased the latency to seizures following bilateral transurethral stimulation. The ability of Compound 1 to increase the latency to seizures following MES was even more pronounced at 3 and 10 mg / kg (oral doses). Compound 1 had a calculated ED of 0.67 mg / kg. 50 These data suggest that compound 1 has anti-seizure properties in the MES-induced seizure model.

[0150] Example 4. Effect of Compound 1 on locomotor activity (sLMA) in a mouse model The spontaneous locomotor activity (sLMA) test is a validated model for evaluating potential motor side effects of compounds. The aim of this study was to evaluate the effect of compound 1 (3, 5.6, 10, and 20 40 mg / kg, orally administered) on spontaneous locomotor activity (sLMA) in male CD-1 mice at 30 min post-administration.

[0151] 1. Materials and Methods i.Animals Six-week-old male CD-1 mice were obtained from Vital River (Beijing, China). At the time the experiments were performed, the average body weight was 25-35 g. Mice were housed in groups of 3-5 under controlled conditions (temperature: 20-26°C, humidity: 40-70%, ventilation rate: 10-15 cycles / h, 12:12 light:dark cycle with lights on at 5:00 a.m.). Food and water were available ad libitum. Mice were acclimated to these conditions for 6 days before the start of the study.

[0152] ii. Drug Formulations Dosing solutions were prepared on each experimental day. Stock solutions of the highest dose of Compound 1 were prepared in 35% HPBCD (vehicle) and diluted to make lower doses. Stocks were stirred and sonicated for at least 20 minutes to obtain a homogenous suspension. All solutions were protected from light. Samples of dosing solutions were stored at 4° C. Both compounds and vehicle were administered at 10 ml / kg.

[0153] iii. Study protocol The sLMA test was carried out over two days. Half of the mice from each treatment group were tested on each day. All animals were tail marked with a permanent marker and weighed. Mice were randomly assigned to one of four treatment groups. Animals were acclimated to the testing room at least 30 minutes before the start of the experiment.

[0154] Animals were orally dosed with Compound 1 or 35% HPBCD (vehicle) 30 min prior to the sLMA test. Potential side effects, such as overt sedation, were recorded immediately prior to the start of the sLMA test.

[0155] Sedation assessment endpoints were as follows: (1) none: mice exhibit normal motor behavior; (2) mild: mice exhibit less movement or immobility in their home cage alone, but exhibit normal motor activity when stimulated by touching with the observer's hand; (3) moderate: mice exhibit immobility in their home cage alone, and exhibit reduced motor activity when pushed or stimulated by touching with the observer's hand; and (4) severe: mice completely lose the ability to move.

[0156] Thirty minutes after administering Compound 1 or vehicle, mice were placed in the center of the test chamber (40×40×30 cm, 45±5 Lux above floor) for 30 minutes of sLMA video recording. Each mouse was automatically tracked by an overhead camera with a 1-minute sampling window in an isolated chamber. Then, the locomotor activity was analyzed offline using an animal behavior video tracking analysis system (Ji Liang Software Technology Co., Ltd., Shanghai, China).

[0157] A spontaneous motor state was defined as a movement of >2 mm every 200 ms (recorded frame rate was 20 frames / s. A motor state was identified every 4-frame interval. A cumulative shift of the tracking spot of more than 2 mm every 4-frame interval was identified as a motor epoch). Distance traveled was automatically calculated and analyzed from all motor epochs. After testing, short video recordings (10 s) of 2-3 representative mice showing adverse events from each of the Compound 1 treatment groups were taken.

[0158] All mice were anesthetized with CO2. Terminal plasma and brain tissue samples were then collected from animals in the drug treatment groups. 500 μL of whole blood was collected via cardiac puncture and placed into a tube containing 10 μL of EDTAK2. The tube was then placed in wet ice until centrifugation at 2000 g for 5 minutes at 4°C. The supernatant plasma was pipetted into an Eppendorf tube. Both brain and plasma samples were stored at -80°C until drug concentration analysis for compound 1 levels.

[0159] iv. Preparation of Plasma Samples Aliquots of 20 μL of unknown samples, calibration standards, quality controls, dilution quality controls, single blanks and double blank samples were added to 1.5 mL tubes. Each sample (except double blanks) was quenched with 300 μL of IS solution (double blank samples were quenched with 300 μL of ACN), then the mixture was thoroughly vortex mixed for at least 15 seconds and centrifuged at 12000 g for 15 min at 4° C. 65 μL of the supernatant was transferred to a 96-well plate and centrifuged at 3220 g for 5 min at 4° C. Then 3 μL of the supernatant was directly injected for LC-MS / MS analysis.

[0160] v. Preparation of brain samples Brain homogenates were prepared by homogenizing brain tissue in 5 volumes (w:v) of cold 15 mM PBS / MeOH (V:V, 2:1). Aliquots of 40 μL of unknown samples, calibration standards, quality controls, dilution quality controls, single blanks and double blank samples were added to 1.5 mL tubes. Each sample (except double blanks) was quenched with 600 μL of IS solution (double blank samples were quenched with 600 μL of ACN), and then the mixture was thoroughly vortex mixed for at least 15 s and centrifuged at 12000 g for 15 min at 4 °C. 65 μL of the supernatant was transferred to a 96-well plate and centrifuged at 3220 g for 5 min at 4 °C. Then, 3 μL of the supernatant was directly injected for LC-MS / MS analysis.

[0161] vi.Statistical analysis All statistical analyses were performed using GraphPad Prism 7.0. Data are presented as mean ± sem, and p < 0.05 was considered statistically significant. Two-way ANOVA with Dunnett's post-hoc test was used to detect significant differences in distance traveled per bin over a 5-minute period between vehicle- and compound 1-treated groups. ANOVA followed by Dunnett's test was used to detect significant differences in total distance traveled over a 30-minute period between vehicle- and compound 1-treated groups.

[0162] vii.TD 50 Value and TC 50 Calculating values Plasma and brain dose-response and concentration-response curves were fitted for each endpoint using GraphPad Prism. From these fitted curves, TD 50 Value and TC 50 values ​​were calculated.

[0163] 2.Results As shown in Figure 3, Compound 1 at doses of 10 and 20 mg / kg significantly reduced the total distance traveled in the 30-min sLMA test. Compound 1 at 10.3 mg / kg significantly reduced the calculated TD 50 These data suggest that Compound 1 at doses of 10 mg / kg and 20 mg / kg reduces locomotor activity.

[0164] Example 5. Compound 1 has potent anticonvulsant activity with improved protective index compared to standard of care sodium channel blockers. This study aimed to determine the sodium current (I Na The effects of Compound 1 on intrinsic neuronal excitability and protection from induced seizures were examined using two standard voltage-gated sodium channels (Na V ) blockers, such as compound 1, which exhibit preferential long-lasting I Na It was determined whether inhibitors would exhibit improved preclinical efficacy and tolerability.

[0165] I Na Inhibition of was characterized using patch clamp analysis. Effects on intrinsic excitability were measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was assessed using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA). All assays are described in the preceding examples.

[0166] As shown in FIG. 1A, compound 1 has a similar but different “Na V Wild-type hNa with "fingerprint" V 1.6 ATX-II-induced persistent I NaOn the other hand, it strongly inhibited the two standard Na V The targeted antiepileptic drugs LTG and CBZ have long-acting I Na Compound 1 showed lower efficacy and no preference for sLMA (Fig. 1C (LTG) and Fig. 1D (CBZ)). As shown in Fig. 2, Compound 1 provided dose-dependent protection (increased latency) of mice against MES-induced strong hind limb seizures. Compound 1 (10 mg / kg) was superior to sLMA (TD 50 10.27mg / kg, plasma TC 50 1123ng / g) without affecting induced seizures (MES ED 50 0.67mg / kg, brain EC 50 As shown in Figure 3, Compound 1 at doses of 10 mg / kg and 20 mg / kg significantly reduced locomotor activity. CBZ and LTG also provided dose-dependent protection from MES-induced seizures and dose-dependent reduction in sLMA, but the tolerability-to-efficacy ratios (protection indices) differed and full anticonvulsant efficacy was not achieved without reduction in sLMA. The reduction in sLMA was associated with increased brain or plasma TC. 50 , increased latency to seizures, brain or plasma EC 50 A protection index was calculated for each molecule by dividing by

[0167] As shown in Figure 4, Compound 1 (10 mg / kg) had a significantly improved protection index of approximately 16-fold (based on calculated free plasma concentration) and was similar to the reference compound with approximately 17-fold (based on calculated free plasma concentration). This indicates an improved protection index compared to both CBZ (plasma, 3.4-fold) and LTG (plasma, 6.4-fold) as shown in Figure 4. Thus, Compound 1 was shown to be more effective than standard of care NaCl. V Compound 1 exhibited significantly improved preclinical tolerability compared to peak I blockers. Without intending to be bound by any theory, the improved tolerability of Compound 1 may be due to its increased activity against peak I blockers. Na Persistence I Na Its demonstrated preference for, and peak I Na This may be due to an improvement in activity-dependent inhibition of

[0168] Example 6. Safety, tolerability, efficacy, and pharmacokinetic studies of Compound 1 in patients with focal epilepsy As shown in animal models, Compound 1 inhibited persistent sodium currents (I Na ) blockade and may provide anti-seizure efficacy at well-tolerated doses. Na By specifically blocking I Na Compound 1 can provide greater efficacy in seizure reduction compared to standard of care (SOC) sodium channel blockers (SCBs) that are less selective for schizophrenia. Compound 1 is less active at peak currents, making it better tolerated than SOCs and causing fewer targeted AEs. Thus, Compound 1 can be effective and well tolerated when utilized as a first-line monotherapy, allowing for improved patient outcomes and continuation of treatment from infancy into adulthood.

[0169] Preclinical data show that compound 1 inhibits the inhibition of Na+ in disease states. V Compound 1 has been demonstrated to have enhanced selectivity against channel hyperexcitability and a broad therapeutic window, which contributes to its excellent safety and efficacy in animal models and expected therapeutic utility in human patients with epilepsy, such as focal epilepsy. Furthermore, as shown in Figure 5, the predicted half-life of Compound 1 is approximately 36 hours, allowing for acute administration of Compound 1 in a broader epilepsy patient population. A 28-day pharmacological GLP toxicity study is currently underway with the goal of understanding the onset, severity, and length of time until a particular dose of Compound 1 shows any toxic effects. A Phase 1 clinical trial with healthy volunteers focusing on a single ascending dose / multiple ascending dose (SAD / MAD) study in a 14-day treatment period, followed by a Phase 2 clinical trial with focal epilepsy patients, will be conducted to study the safety of Compound 1 as well as its efficacy in seizure reduction.

[0170] Example 7. Human Na V Effect of Compound 1 on peak activity of 1.6 channels Voltage-gated sodium channels (Na V) are important therapeutic targets for antiepileptic drugs (AEDs) due to their role in the initiation and propagation of action potentials. V Human Na, such as SCN8A, which encodes 1.6 V Variants in the gene are the most common cause of de novo inherited epilepsy and can exhibit a gain-of-function profile leading to neuronal hyperexcitability. V Blockade (activity-dependent) has been proposed as a pharmacological target to reduce pathological neuronal activity, but not physiological peak I Na Preserving hNa is important to ensure normal neuronal function. V 1.6 Expressed by I Na The effect of Compound 1 on

[0171] method Na expressed in HEK cells V (hNa V 1.6) Tonic and peak I using automated patch clamp recording Na The voltage protocols studied included several modes of inhibition: tonic I Na (Vm-120mV, 200ms), tonic block (TB, Vm-120mV, 0.2Hz), voltage-dependent block (VDB, Vm inactivation V 1 / 2 ), and activity / use-dependent block (UDB, Vm-120mV, 10Hz), I Na Inhibition was measured. Compound 1 was compared to a panel of AEDs, non-AEDs, and investigational compounds.

[0172] The binding kinetics were estimated from the inhibition kinetics. ON ) during the variable-length conditioning pulse Na The apparent dissociation rate (K OFF ) after the inactivation conditioning pulse, Na The time-dependent delay in recovery of the stimuli was measured using the

[0173] result FIG. 6A shows the effect of I using a tonic block assay in HEK cells. Na Shows the result of the block evaluation.

[0174] FIG. 6B shows the use-dependent block assay in HEK cells. Na Shows the result of the block evaluation.

[0175] Figure 6C shows the voltage-dependent block assay in HEK cells using I Na The results of the block evaluation are shown below. At the beginning of the voltage step, a peak I Na 6A-6C show that Compound 1 exhibited enhanced activity-dependent block, suggesting that it provides beneficial activity during periods of hyperexcitability.

[0176] FIG. 7A shows the hNa as a function of compound 1 concentration. V FIG. 7A is a graph showing the percent inhibition of sustained I Na Strong inhibition of peak I Na 4 shows activity-dependent enhancement of inhibition of .

[0177] FIG. 7B shows the hNa as a function of carbamazepine concentration. V 1 is a graph showing percent inhibition of 1.6.

[0178] FIG. 7C shows the hNa as a function of lamotrigine concentration. V 7B and 7C are graphs showing the percent inhibition of sustained I Na (short arrow), which shows lower potency and preference for peak I Na The activity-dependent block of β-aminobutyric acid (β-aminobutyric acid) was minimal in humans. Voltage protocols are included as panel inserts, pharmacology is measured with green arrows, and points represent the mean ± SEM.

[0179] Figure 8A shows ATX-II-induced hNav1.6 persistent I NaFigure 8A shows the results of Compound 1-induced reduction in I. The voltage protocol is included as the panel insert and pharmacology is measured at the arrow. Figure 8B shows that Compound 1 reduced the tonic I Na It has been shown that it is a potent inhibitor of

[0180] Figure 8B is a graph showing the percent inhibition of hNav1.6 as a function of concentration of Compound 1 and standard NaV-targeted ASMs (lamotrigine, phenytoin, carbamazepine, sembamate, lactosamide, and valproic acid). Points represent mean ± SEM. Figure 8B shows that Compound 1 inhibited sustained I inhibition compared to standard NaV-targeted ASMs. Na These results demonstrate increased efficacy against

[0181] Figure 8C is a graph showing the percent inhibition of various NaV isoforms and orthologues as a function of the concentration of Compound 1. Points represent the mean ± SEM. Figure 8C shows that Compound 1 inhibits ATX-II-induced persistent I-cell activation expressed by multiple NaV isoforms and orthologues. Na It is shown to inhibit

[0182] The inhibition parameters of hNav1.6 by Compound 1 and standard Nav-targeted ASMs are shown in the table below. The results presented in the table below show that Compound 1 inhibited peak I Na We show that the activity dependence of β-catenin on β-catenin is greater than that of β-catenin. [Table 1-1] [Table 1-2] Data is IC 50 (nM) and Hill slope in parentheses. **Could not be determined due to solubility limit of compound. nd = undetermined, Pers. = persistent, TB = tonic block, UDB = use-dependent block, VDB = voltage-dependent block.

[0183] FIG. 9A shows the incidence of inhibition (apparent binding) for 3 μM compound 1 and controls.

[0184] Figure 9B shows normalized I as a function of inactivation time. Na 2 is a graph showing the occurrence of inactivation in the absence and presence of 3 μM Compound 1.

[0185] Figure 9C shows the normalized I as a function of inactivation time. Na 2 is a graph showing the occurrence of inhibition in the presence of Compound 1 at concentrations of 0.3 μM, 1 μM, 3 μM, 4.5 μM, and 6 μM.

[0186] FIG. 9D is a graph showing the inhibition rate as a function of the concentration of Compound 1. ON 4.2s -1 *μM -1 This indicates that.

[0187] FIG. 9E shows recovery from inhibition (apparent dissociation) for 3 μM compound 1 and the control.

[0188] Figure 9F shows normalized I as a function of recovery time. Na 3 is a graph showing recovery from inactivation in the absence and presence of 3 μM Compound 1.

[0189] FIG. 9G is a graph showing normalized In as a function of recovery time, indicating recovery from inhibition (normalized to exclude compound-independent deactivation), and the K of compound 1. OFF is 1.7s -1 It is.

[0190] FIG. 9H shows the binding K of compound 1 and standard of care Nav-targeted ASM. ON and dissociation K OFF Figure 9H shows that Compound 1 exhibits fast apparent binding and moderate apparent dissociation compared to standard of care Nav-targeted ASM. ONwas faster compared to the other compounds tested (>1,500-fold faster compared to carbamazepine). OFF suggested a slower, but not excessive, residence time than carbamazepine (33-fold). A representative hNav1.6 isoform-selective inhibitor exhibits a very slow dissociation rate (2,079-fold slower than carbamazepine).

[0191] The results presented in Figures 9A-9H demonstrate that the potency and activity-dependent increase in Compound 1 occurs with moderate dissociation rates (apparent K OFF =1.7s -1 ) combined with rapid onset of inhibition (apparent K ON =4.2s -1 *μM -1 Without wishing to be bound by any particular theory, it is believed that the combination of rapid onset and recovery from inhibition may selectively target pathological neuronal hyperexcitability while sparing physiological activity.

[0192] conclusion Compound 1 showed a strong activity-dependent (IC value of 200 nM for UDB 50 Compound 1 also exhibited an IC of 128 nM, suggesting that it may provide beneficial activity during periods of hyperexcitation. 50 (68-fold preference over TB) and hNa V 1.6 Persistence I Na This is the same as other tested I Na This profile was at least 550 times more potent than CBZ (long-acting I Na IC of 77,490 nM 50 , 30-fold preference for TB, no UDB observed) and cenobamate (persistent I Na IC of 71,690nM 50 The profiles of UDB and UDB (1.6-fold preference for TB, 24-fold preference for TB, and 2.3-fold preference for TB, respectively) differed from those observed for the other isoforms and orthologs tested.

[0193] Persistence I exhibited by compound 1 Na The preference for VDB was not retained compared to activity in the more depolarized VDB assay (0.56-fold preference for VDB), suggesting a sustained preferential I Na This was in contrast to the inhibitor (2.2-fold preference over VDB), the reference compound.

[0194] The enhanced activity dependence of compound 1 was observed in the rapid K ON (4.168s -1 *μM -1 ) and moderate K OFF (1.72s -1 ) This kinetics is consistent with standard I Na Blockers (0.011 and 0.019s, respectively) -1 *μM -1 K ON ) compared to peak I Na This explains the rapid development of

[0195] Compound 1 is in peak I Na Increased efficacy and activity dependence on, and persistence I Na Next-generation Na with higher efficacy against V The profile of compound 1 is shown in peak I. Na This may suggest efficacy in epilepsy and other indications caused by neuronal hyperexcitability, without the tolerability problems caused by excessive tonic blockade of the vasodilator.

[0196] Example 8. Effect of Compound 1 on Locomotor Activity in CD-1 Mice The spontaneous locomotor activity (sLMA) test is a validated model to evaluate the potential effects of compounds on motor function. This study evaluated the effect of Compound 1 on spontaneous locomotor activity in male CD-1 mice. The doses of Compound 1 used were 3 mg / kg, 5.6 mg / kg, 10 mg / kg, and 20 mg / kg administered orally (po).

[0197] Test animals and treatments Male CD-1 mice (Vital River, Beijing, China) approximately 6 weeks old were used in the study. At the time of the experiment, their body weight was 25g-35g. The mice were housed under controlled conditions (temperature: 20-26°C, humidity: 40-70%, ventilation rate: 10-15 cycles / h, 12:12 light-dark cycle with lights on at 5am. Food and water were available ad libitum.

[0198] Treatment was performed using Compound 1 and 35% 2-hydroxypropyl-β-cyclodextrin (35% HPBCD, used as negative control). Compound 1 stock solution was freshly prepared in 35% HPBCD on each experimental day and protected from light. Stock solution was diluted with vehicle to obtain low doses. Both compound and vehicle were administered at 10 mL / kg.

[0199] Study Protocol Each test of spontaneous locomotor activity (sLMA) was performed over three days, with mice from each treatment group being tested daily. Treatment groups included mice administered vehicle (35% HPBCD) and mice administered Compound 1 at doses of 3 mg / kg, 5.6 mg / kg, 10 mg / kg, and 20 mg / kg. Mice were randomly assigned to one of the treatment groups. Animals were acclimated to the testing room at least 30 minutes prior to the experiment.

[0200] Mice were administered a single dose of Compound 1 (3 mg / kg, 5.6 mg / kg, 10 mg / kg, and 20 mg / kg) or vehicle (35% HPBCD) via oral gavage 30 minutes prior to testing. A brief neurological assessment was performed immediately prior to performing the sLMA test. Each animal was visually assessed for sedation and ataxia. Sedation assessment included assessments based on the following categories: a) no sedation (animals exhibit normal locomotor behavior; b) mild sedation (animals exhibit less movement or immobility in their home cage when alone, but exhibit normal locomotor activity when stimulated by touch by the observer; c) moderate sedation (animals exhibit immobility in their home cage when alone, and exhibit reduced locomotor activity when pushed or stimulated by touch by the observer; d) severe sedation (animals lose all mobility).

[0201] Mice were then placed in the center of the testing arena (40 x 40 x 30 cm, 45 ± 5 Lux on the floor) by an experimenter blinded to treatment group and allowed to explore uninterrupted for 30 min. Activity was recorded by an overhead camera and analyzed offline. Video tracking analysis software was used to determine the total distance traveled in millimeters. Distance traveled was also calculated in 5-minute bins.

[0202] Upon completion of the study, a short video (~10 seconds) showing adverse effects was recorded for a representative mouse from each treatment group. Mice were anesthetized with CO2 until loss of paw withdrawal reflex, whole blood was collected, and brains were harvested from treatment groups. Whole blood (500 μL) was collected into tubes containing 10 μL EDTAK2 and stored on wet ice until centrifugation. Whole blood samples were centrifuged at 2000×g for 5 min at 4° C. to isolate plasma. Plasma and brain samples were stored at -80° C. and subsequently analyzed to determine compound 1 levels.

[0203] All statistical analyses were performed using GraphPad Prism 9.3. Mean values ​​were combined and standard errors were calculated using Sutter-Waite approximation to combine standard deviations. Plasma and brain dose-response and concentration-response curves were fitted to a four-parameter log function. TD 50 Value and TC 50 Values ​​were calculated from these fit curves.

[0204] result FIG. 10A is a graph showing the total distance traveled in the sLMA assay plotted as a percent of control versus dose of Compound 1.

[0205] FIG. 10B is a graph showing the total distance traveled in the sLMA assay plotted as a percent of the control against the concentration of Compound 1 in plasma.

[0206] 10C is a graph showing the total distance traveled in the sLMA assay plotted as a percent of control against the concentration of Compound 1 in the brain. Data are presented as mean±SEM, n=20 per group.

[0207] The experimental results showed that compound 1 reduced the distance in a dose-dependent manner, and the TD 50 was 10.4 mg / kg, and plasma TC 50 was 1256ng / mL, and brain TC 50 The results show that the total motor activity was 1914ng / g. No sedation or ataxia was observed in mice treated with compound 1 at concentrations of 3mg / kg and 5.6mg / kg. At the higher doses of 10mg / kg and 20mg / kg, sedation and / or ataxia was observed in 5 and 8 mice, respectively. Thus, total motor activity was reduced at higher doses of compound 1 (10mg / kg and 20mg / kg), resulting in ataxia and sedation.

[0208] Example 9. Effects of Compound 1 on MES-induced seizures in male CD-1 mice The maximal electroshock (MES) acute seizure model of generalized seizures is validated to evaluate the anticonvulsant potential of compounds. The positive control valproic acid is used clinically for its anticonvulsant properties and is an effective treatment for generalized seizures. The aim of this study was to evaluate the effect of Compound 1 on maximal electroshock-induced seizures in male CD-1 mice.

[0209] Test animals and treatments Male CD-1 mice (Vital River, Beijing, China) approximately 6 weeks old were obtained for the study. At the time the experiment was performed, the body weight was 20.5 g to 38.5 g. Mice were housed under controlled conditions (temperature: 20-26°C, humidity: 40-70%, ventilation rate: 10-15 cycles / h, 12:12 light / dark cycle with lights on at 5:00 a.m.). Food and water were available ad libitum.

[0210] Treatment was performed using Compound 1 and 35% 2-hydroxypropyl-β-cyclodextrin (35% HPBCD, used as negative control). Compound 1 stock solution was freshly prepared in 35% HPBCD on each experimental day and protected from light. Stock solution was diluted with vehicle to obtain low doses. Both compound and vehicle were administered at 10 mL / kg.

[0211] Study Protocol Mice were brought into the testing room at least 1 hour before the start of the experiment. Mice were administered valproic acid (VPA; 400 mg / kg, i.p.), or vehicle (35% HPBCD, 10 mL / kg, i.p.), or Compound 1 (0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg, p.o.) 30 minutes before the MES test. Possible side effects, such as overt sedation, were recorded immediately before the start of the MES test. Sedation assessment included an assessment based on the following categories: a) no sedation (animals exhibit normal locomotor behavior; b) mild sedation (animals exhibit less movement or immobility in their home cage when alone, but exhibit normal locomotor activity when stimulated by touch by the observer; c) moderate sedation (animals exhibit immobility in their home cage when alone, and exhibit reduced locomotor activity when pushed or stimulated by touch by the observer; d) severe sedation (animals lose all mobility).

[0212] The electroshock device was set to deliver a 50 mA square wave stimulus with a duration of 0.8 seconds, a pulse width of 10 milliseconds, and a frequency of 50 Hz. A pair of custom stainless steel electrodes was immersed in 0.2% agar, and subjects then received bilateral transauricular stimulation via ear clip electrodes. During stimulation, mice were manually restrained and then immediately released into an observation cage and continuously monitored for 60 seconds by an observer blinded to the treatment group. Mice were observed for the presence or absence of generalized tonic-clonic seizures with complete hindlimb extension (hindlimb at a 180 degree angle to the torso).

[0213] Mice were anesthetized with CO2 and terminal plasma and brain tissue samples were collected. A total of 500 μl of whole blood was collected via cardiac puncture and placed into a tube containing 10 μl of EDTAK2. The tube was then placed on wet ice until centrifuged at 2,000×g for 5 minutes at 4°C. The supernatant plasma was pipetted into an Eppendorf tube. Both brain and plasma samples were stored at -80°C and then analyzed to determine the levels of Compound 1.

[0214] All statistical analyses were performed using GraphPad Prism 9.3. Means were combined and standard errors were calculated using the Sutter-Waite approximation to combine standard deviations. Plasma and brain dose-response and concentration-response curves were fitted to a four-parameter log function. ED 50 Value and EC 50 Values ​​were calculated from these fitted curves.

[0215] result FIG. 11A is a graph showing protection from MES-induced strong limb extension as a function of Compound 1 dose.

[0216] FIG. 11B is a graph showing protection from MES-induced strong limb extension as a function of the concentration of Compound 1 in plasma.

[0217] FIG. 11C is a graph showing protection from MES-induced strong hind limb extension as a function of the concentration of Compound 1 in the brain. Data are presented as mean ± SEM, n=30 per group. Curves represent fits to a four-parameter log function, EC 50 Values ​​are included in the figure.

[0218] Referring to Figures 11A-11C, protection from MES-induced hindlimb extension by Compound 1 was dose-dependent, with a calculated ED of 0.42 mg / kg. 50 The positive control, valproic acid, protected against MES-induced hindlimb extension compared to the negative control (total mice n=24 were seizure-free).

[0219] At the highest dose of Compound 1 (10 mg / kg), some mice exhibited sedation or ataxia. No sedation or ataxia was observed for any of the other doses of Compound 1 tested. Valproic acid-treated mice exhibited mild to moderate sedation.

[0220] The dose-response curve of Compound 1 for protection from MES-induced strong limb extension was compared to those of other standard of care anti-seizure mediators (ASMs), namely, carbamazepine, canobamate, lamotrigine, and XEN1101.

[0221] 11D is a graph showing protection from MES-induced strong hind limb extension as a function of dose for Compound 1, carbamazepine, cenobamate, lamotrigine, and XEN1101. Curves represent fits to a 4-parameter log function, and error bars have been removed for clarity.

[0222] The ED50 values ​​of the various compounds tested are given in the table below. [Table 2]

[0223] The results presented in FIG. 11D and in the table below show that the ED 50 The ED value (0.42 mg / kg) is approximately 10-fold lower than the ED values ​​(range 3.8-5.4 mg / kg) of carbamazepine, cenobamate, lamotrigine, and XEN1101. These results indicate that compound 1 is active at low doses compared to the standard of care ASM in the MES acute seizure model.

[0224] conclusion Compound 1 acted as an anticonvulsant in the MES acute seizure model, as it dose-dependently protected mice against strong hind limb extension. No sedation was observed in mice treated with 0.3-3 mg / kg compound 1. At the highest dose of compound 1, 10 mg / kg, 6 of 30 mice showed mild to moderate sedation, 7 and 13 mice showed ataxia with mild to moderate sedation, and 6 mice showed ataxia without sedation. The positive control valproic acid protected mice from MES-induced strong hind limb extension, however, nearly all valproic acid-treated mice showed mild to moderate sedation.

[0225] The results also show that Compound 1 is active at lower doses compared to the standard of care ASM in the MES acute stroke model.

[0226] Example 10. Effect of Compound 1 on pentylenetetrazole (PTZ)-induced seizures The subcutaneous pentylenetetrazole (scPTZ) test is a validated model for evaluating the anti-seizure potential of compounds. The positive control valproic acid is an approved anti-seizure medication (ASM). This study evaluated the efficacy of compound 1 to attenuate scPTZ-induced seizures in wild-type CD-1 mice. The doses of compound 1 used were 1 mg / kg, 3 mg / kg, 6 mg / kg, and 10 mg / kg administered orally. Valproic acid (600 mg / kg, administered intraperitoneally) was used as a positive control since it has a broad spectrum of anticonvulsant activity.

[0227] Test animals and treatments Male CD-1 mice (Charles River Laboratories, St. Constant, Quebec, Canada) were used in the study. Body weights ranged from 27 to 39 grams at the time the experiments were performed. Mice were group-housed in polycarbonate cages according to standard operating procedures. Animals were maintained on a 12-h light / 12-h dark cycle, with all experimental activities occurring during the light phase. Food and water were available ad libitum. Mice were acclimated to the testing facility for at least 72 hours prior to testing.

[0228] Treatments were performed using Compound 1 and 35% 2-hydroxypropyl-β-cyclodextrin (35% HPBCD, used as a negative control). Compound 1 stock solution was freshly prepared in 35% HPBCD on each experimental day. Stock solutions were diluted with vehicle to provide low doses. Both compound and vehicle were administered at 10 mL / kg. Valproic acid was freshly prepared in saline vehicle on each experimental day and administered at 10 mL / kg.

[0229] Mice were administered vehicle (35% HPBCD), a single dose of Compound 1 (1 mg / kg, 3 mg / kg, or 6 mg / kg), or valproic acid (600 mg / kg). Vehicle and Compound 1 were administered via oral gavage 30 min prior to administration of PTZ. Valproic acid was administered as an intraperitoneal injection 60 min prior to administration of PTZ.

[0230] Study Protocol Immediately prior to administration of PTZ, a brief neurological assessment was performed. Each animal was visually assessed and scored from 0 to 3 according to the following scoring system: a neurological score of 0 corresponds to a normal state, a neurological score of 1 corresponds to a slight decrease in spontaneous activity, a neurological score of 2 corresponds to a marked decrease in spontaneous activity, and a neurological score of 3 corresponds to a loss of the righting reflex.

[0231] PTZ (85 mg / kg, 10 mL / kg) was administered as a subcutaneous (sc) injection. After injection of PTZ, each mouse was continuously observed by an observer blinded to treatment until the onset of the first generalized clonic seizure or a time of 30 min was reached. The latency of the generalized clonic seizure was recorded. Seizures were also scored using a seizure scale. Mice were scored using the following scale: 0) no seizure activity, 1) "flat body posture" myoclonic seizure, 2) generalized clonus with loss of posture lasting approximately 2 seconds, 3) generalized clonus with loss of posture lasting approximately 10 seconds, or 4) strong immediate limb extension. Seizure scores were used as a qualitative measure to assess the incidence of seizures and not as a quantitative measure of pharmacological activity. Mice that did not show generalized clonic seizure activity within 30 minutes (score of 0 or 1) were considered protected. Plasma and brain samples were collected at the end of the PTZ-induced seizure procedure, either at the time of generalized clonic seizure or 30 min.

[0232] Mice were anesthetized with isoflurane, whole blood was collected via cardiac puncture, and brains were harvested. Whole blood was collected into potassium EDTA tubes and centrifuged at approximately 3300 g for 5 minutes at 4° C. to isolate plasma. Plasma and brain samples were stored at −80° C. and analyzed to determine levels of Compound 1.

[0233] The experiment was repeated using the study protocol described above, except that an additional 10 mg / kg treatment group and an adjusted scale for scoring seizures was used. Seizures were scored using a modified seizure scale. Mice were scored using the following scale: 0) no seizure activity, 1) myoclonic seizures / twitches, 2) myoclonic seizures with "flat body posture", 3) generalized clonus with loss of posture, or 4) strong hindlimb extension. Seizure scores were used as a qualitative measure to assess the incidence of seizures and not as a quantitative measure of pharmacological activity. Mice that did not show general clinic seizure activity within 30 minutes (score of 0, 1 or 2) were considered protected.

[0234] All statistical analyses were performed using GraphPad Prism 9.3. Mean values ​​of plasma and brain concentrations were combined and standard errors were calculated using Satterthwaite's approximation to combine standard deviations. Plasma and brain dose-response and concentration-response curves were fitted to a four-parameter logarithmic function. ED 50 Value and EC 50 Values ​​were calculated from these fitted curves.

[0235] result FIG. 12A is a graph showing percent protection from PTZ-induced clonic seizures as a function of Compound 1 dose.

[0236] FIG. 12B is a graph showing percent protection from PTZ-induced clonic seizures as a function of the concentration of Compound 1 in plasma.

[0237] FIG. 12C is a graph showing percent protection from PTZ-induced clonic seizures as a function of the concentration of Compound 1 in the brain. Data are presented as mean ± SEM, n = 10-20 per group. Curves represent fits to a four-parameter log function, EC 50 Values ​​are included in the figure.

[0238] conclusion Compound 1 acted as an anticonvulsant in the PTZ acute seizure model, since the mice were protected from generalized clonus. The neurological scores for all but one of the mice treated with Compound 1 were normal, indicating that no sedation or any neurological impairment was observed in the dose range tested. A slight reduction in spontaneous activity was observed in one mouse treated with Compound 1 at a dose of 10 mg / kg.

[0239] Example 11. Effects of Compound 1 in the 6-Hz Seizure Model The 6-Hz test is a validated model of focal seizures to evaluate the anti-seizure potential of compounds. The 6-Hz seizure model can be performed at different stimulation intensities (32 or 44 mA), with the higher intensity (44 mA) being used as a model of drug-resistant seizures. The positive control valproic acid is an approved anti-seizure drug (ASM).

[0240] This study evaluated the efficacy of Compound 1 in attenuating psychomotor seizures induced by 6-Hz electrical stimulation at two different stimulation intensities (32 and 44 mA) in wild-type CD-1 mice. Psychomotor seizures are defined as the appearance of at least one of the following behaviors within 30 seconds of stimulation: stun / immobility, forelimb clonus, tail lift, or lateral head movement. Protection is defined as the complete absence of the above behaviors within 30 seconds of stimulation. The doses of Compound 1 used were 1 mg / kg, 3 mg / kg, and 6 mg / kg administered orally. Valproic acid (600 mg / kg, administered intraperitoneally) was used as a positive control.

[0241] Test animals and treatments Male CD-1 mice (Charles River Laboratories, St. Constant, Quebec, CAN) were used in the study. They weighed 30-40 grams at the time the experiments were performed. Mice were group-housed in polycarbonate cages according to standard operating procedures. Animals were maintained on a 12-h light / 12-h dark cycle, with all experimental activities occurring during the light phase. Food and water were available ad libitum. Mice were acclimated to the testing facility for at least 72 h prior to testing.

[0242] Treatment was performed using Compound 1 and 35% 2-hydroxypropyl-β-cyclodextrin (35% HPBCD, used as negative control). Compound 1 stock solution was freshly prepared in 35% HPBCD on each experimental day. Both compound and vehicle were administered at 10 mL / kg. Valproic acid was freshly prepared in saline vehicle on each experimental day and administered at 10 mL / kg.

[0243] Mice were administered vehicle (35% HPBCD), a single dose of Compound 1 (1 mg / kg, 3 mg / kg, or 6 mg / kg), or valproic acid (600 mg / kg). Vehicle and Compound 1 were administered via oral gavage 30 min prior to administration of PTZ. Valproic acid was administered as an intraperitoneal injection 60 min prior to electrical stimulation.

[0244] Study Protocol A brief neurological assessment was performed immediately prior to performing the 6-Hz seizure test. Each animal was visually assessed and scored from 0 to 3 according to the following scoring system: a neurological score of 0 corresponds to a normal state, a neurological score of 1 corresponds to a slight decrease in spontaneous activity, a neurological score of 2 corresponds to a marked decrease in spontaneous activity, and a neurological score of 3 corresponds to a loss of the righting reflex.

[0245] Electrical stimulation (6 Hz, 0.2 ms pulse width, 3 s duration) was delivered using saline-moistened corneal electrodes (ECT unit 57800, Ugo Basile). The delivered current was either 32 mA or 44 mA. Immediately after electrical stimulation, each mouse was continuously monitored for 30 s by an observer blinded to the treatment group. Mice were observed for psychomotor seizure activity, defined as stunned / immobility, forelimb clonus, tail lift or lateral head movement. Mice were scored for the presence or absence of each seizure behavior, with a maximum total score of 4. Mice that did not show psychomotor seizure activity within 30 s of electrical stimulation were considered protected and received a score of 0. At the end of the 6-Hz seizure test, plasma and brain samples were collected.

[0246] Mice were anesthetized with isoflurane, whole blood was collected via cardiac puncture, and brains were harvested. Whole blood was collected into potassium EDTA tubes and centrifuged at approximately 3300 g for 5 minutes at 4° C. to isolate plasma. Plasma and brain samples were stored at −80° C. and analyzed to determine levels of Compound 1.

[0247] All statistical analyses were performed using GraphPad Prism 9.3. Seizure scores were compared using the Kruskal-Wallis test followed by Dunn's post-hoc test, with p<0.05 considered statistically significant.

[0248] result FIG. 13A is a bar graph showing seizure scores in a 6-Hz acute seizure model at a stimulation current of 32 mA as a function of Compound 1 dose.

[0249] FIG. 13B is a bar graph showing seizure scores in a 6-Hz acute seizure model at a stimulation current of 44 mA as a function of Compound 1 dose.

[0250] FIG. 13C is a graph showing percent protection from 6-Hz induced seizures at stimulation currents of 32 mA (solid symbols, solid line) and 44 mA (open symbols, dashed line) as a function of concentration of Compound 1 in plasma.

[0251] FIG. 13D is a graph showing percent protection from 6-Hz induced seizures at stimulation currents of 32 mA (solid symbols, solid line) and 44 mA (open symbols, dashed line) as a function of concentration of Compound 1 in the brain. Data are presented as mean ± SEM, n = 10 per group. Curves represent fits to a four-parameter log function, EC 50 The values ​​are as shown in the table below. [Table 3] Values ​​in brackets represent 95% confidence intervals.

[0252] Additionally, a dose-response curve for protection from psychomotor seizures was generated using a fit to a four-parameter log function, yielding an ED of 1.9 mg / kg. 50 Plasma concentration-response curves for protection against psychomotor seizures were generated using a fit to a four-parameter function, yielding an EC value of 147 mg / kg. 50 Got the value.

[0253] As evidenced by the data presented in Figures 13A-13D, Compound 1 acted as an anticonvulsant in the 6-Hz psychomotor seizure model. A dose of 6 mg / kg administered orally significantly reduced seizure scores at both 32 mA and 44 mA stimulation currents. More than 50% of mice treated with 6 mg / kg Compound 1 were protected against 32 mA stimulation. Mice treated with either dose of Compound 1 appeared normal, so all neurological scores were zero. Valproic acid-treated mice exhibited moderate to marked reduction in spontaneous activity (neurological score d 1-2, mean score 1.2).

[0254] conclusion Compound 1 (6 mg / kg, orally administered) was anticonvulsant in the 6-Hz acute seizure model, as it significantly reduced the incidence of seizures at 32 mA current and reduced seizure scores at both 32 mA and 44 mA stimulation intensities compared to vehicle (negative control). Specifically, more than 50% of mice treated with 6 mg / kg of Compound 1 were protected against 32 mA stimulation. Neurological scores for all doses of Compound 1 tested were normal, indicating that no sedation was observed. In contrast, valproic acid-treated mice exhibited a slight to marked decrease in spontaneous activity.

[0255] Example 12. Phase I clinical trial evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of Compound 1 in healthy volunteers. This is a study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of Compound 1 in healthy participants aged 18 to 55 years (inclusive). The study will initially consist of two parts, with one additional optional part added as follows:

[0256] Part A is randomized, double-blind, placebo-controlled. Part A is designed to investigate the safety, PK, and PD of single ascending doses of Compound 1.

[0257] Part B is randomized, double-blind, placebo-controlled. Part B is designed to investigate the safety, PK, and PD of multiple ascending doses of Compound 1 (selected based on the results from Part A).

[0258] Part C (optional) is a randomized, open-label, crossover design food effect evaluation to investigate the PK of a single dose of Compound 1 (selected based on the results from Part A) under fasted and fed states.

[0259] Part B will begin after completion of at least Cohort A3 of Part A. Based on the results of Parts A and B, initiation of Part C is optional. Parts A, B, and C may be conducted simultaneously. Parts A and B are double-blind. Parts A, B, and C consist of three periods: Screening / Baseline, Intervention, and Safety Follow-up.

[0260] Safety and tolerability assessments in Parts A, B, and C included vital signs, 12-lead ECG, physical examination, laboratory tests, and (for Part B) C-SSRS.

[0261] Number of participants The expected number of participants is as follows:

[0262] Part A: Approximately 32, up to 56 participants (8 per cohort) Part B: Approximately 24, up to 40 participants (8 per cohort) Part C: Approximately 16 participants The total number of participants planned across Parts A, B, and C is approximately 72, with up to 112 depending on optional cohorts. Participants in Parts A and B may participate in Part C, provided there is sufficient washout between participation in the study parts.

[0263] The duration of the clinical trials is outlined in the table below. [Table 4]

[0264] The objectives and endpoints for Part A (single ascending dose) of the clinical trial are outlined in the table below. [Table 5] Baseline PD measurements are defined as the mean value pre-dose on the morning of Day 1 of each treatment period.

[0265] The objectives and endpoints for Part B (multiple ascending doses) of the clinical trial are outlined in the table below. [Table 6] Baseline PD measurements are defined as the mean value pre-dose on the morning of Day 1 of each treatment period.

[0266] The objectives and endpoints for Part C of the clinical trial (effect of ad libitum food) are outlined in the table below. [Table 7-1] [Table 7-2]

[0267] Screening / Baseline Period The screening period for all three parts will be a maximum of 42 days (day -43 to day -2). Prior to the clinical trial procedures, participants will provide written informed consent to participate in the study. A complete medical screening will be conducted to assess subjects' eligibility for this trial. After confirmation of continued eligibility, participants will check into the clinic at baseline (day -1, the day before study drug administration).

[0268] Intervention period In Parts A and B, participants remain in the unit from baseline (day -1) until discharge (day 3 in Part A and day 11 in Part B). In Part C, participants remain in the unit from baseline (day -1) to day 3 (first dosing period) and from day 6 to day 9 (second dosing period). In Part A, participants return to the Clinical Trials Unit for safety and PK assessments on days 4 and 6. In Part B, participants return to the Clinical Trials Unit for safety and PK assessments on day 13. In Part C, participants return to the Clinical Trials Unit for safety and PK assessments on days 4 and 10. If participants experience a clinically significant AE during the confinement period, they may remain at the clinical site for further observation at the discretion of the Principal Investigator (PI) after consultation with the sponsor.

[0269] Part A (Single Ascending Dose) Healthy participants will be enrolled to receive a single ascending dose of Compound 1 or placebo on Day 1. Figure 14A is a diagram of the dosing scheme for Part A (single ascending dose) of the study. Dose escalation in Part A will be conducted initially in up to four total planned cohorts (Cohorts A1-A4). Following completion of Cohort A4, up to three additional escalation cohorts may be added. These additional three cohorts will use incremental-based escalation with a maximum increment of 3x the highest pre-dose tested (Note: if predicted concentrations of Compound 1 are >100% relative to the mouse sLMA EC 50 (If >415 ng / mL, a measure of tolerability, dose escalation increments will be ≦1.5-fold). Doses may be adjusted upward or downward based on safety, tolerability, and PK data from preceding cohorts. Cohorts after A4 will be numbered sequentially (A5, A6, etc.). Dose escalation will be based on the mean AUC inf However, the AUC of 7500 hr.ng / mL (half the NOAEL in rats) inf The study will be stopped if progression is predicted to exceed 8. Eight participants will be enrolled in each cohort and randomized in a 3:1 ratio to receive either Compound 1 or placebo.

[0270] The dosing regimen for Part A is summarized in the table below. [Table 8]

[0271] Compound 1 will be administered to Cohort A1 participants at a starting dose of 5 mg. Dosing in all cohorts will begin with two sentinel participants, one of whom will be randomized to receive Compound 1 and the other randomized to receive placebo. Safety and tolerability of each sentinel participant will be monitored through Day 2 and reviewed prior to dosing of the remaining participants in the cohort. The PI will review the safety / tolerability information available for the sentinel participant on Day 2 and, with sponsor consent, decide to dose the remaining six participants in the cohort.

[0272] Cohorts will be dosed in an escalating fashion. After at least 6 of 8 participants in each dose cohort have completed dosing, the blinded cumulative safety data collected through Day 4 (72 hours post-dose) and the available blinded PK data will be reviewed by a Safety Review Committee (SRC) to determine the safety and tolerability of the investigational drug. If the current dose level is deemed safe and tolerable by the SRC, the next dose cohort will be randomized to receive the selected dose of active compound 1 or placebo. Additional cohorts may be considered to accommodate dose repeats, dose reductions, or slower than planned dose escalation.

[0273] Part B (multiple ascending doses) After evaluation of Compound 1 administered as a single dose in Part A through at least Cohort A3, the study will begin evaluating the safety, tolerability, PK, and PD of Compound 1 on a multiple dose schedule. Figure 14B is a diagram of the dosing scheme for Part B (multiple ascending doses) of the study. The starting dose level for Part B will be determined based on the safety, tolerability, and PK data obtained in Part A. The dose level of Compound 1 evaluated in Part B will not exceed the dose evaluated in Part A.

[0274] Cohorts will be numbered consecutively (B1, B2, etc.) with a minimum of three cohorts and up to two additional cohorts (maximum of five cohorts). Eight participants will be enrolled in each cohort and randomized in a 3:1 ratio to receive either Compound 1 or placebo.

[0275] The Part B dosing regimen is summarized in the table below. [Table 9]

[0276] Healthy participants are enrolled to receive multiple ascending oral doses of Compound 1 or placebo once daily. Dosing begins on day 1 and continues through day 10. The final dose is administered on the morning of day 10. Participants are discharged from the clinical trial unit 24 hours after the final dose.

[0277] After at least 6 of 8 participants in each dose cohort in Part B have been dosed by Day 10, blinded safety data (including safety assessments performed on Day 10) and available PK data will be reviewed to determine the safety and tolerability of the investigational drug. If the current dose level is determined to be safe and tolerable, the next dose cohort will be randomized to receive the selected dose of active compound 1 or placebo. Additional cohorts may be considered to accommodate dose repeats, dose reductions, or slower than planned dose escalation. Additionally, the SRC may also consider additional cohorts if maximum exposure has not been reached at any of the planned dose levels and discontinuation criteria have not been met.

[0278] Part C (Evaluation of the impact of optional meals) Based on the results of Parts A and B, initiation of Part C is optional. Part C may be initiated once the safety and PK of Compound 1 have been adequately evaluated in Part A (Note: Parts A, B, and C may be conducted simultaneously). Figure 14C is a diagram of the dosing scheme for Part C (optional food effect assessment) of the study. Approximately 16 participants will receive two oral doses of Compound 1 in a randomized crossover design, one after a minimum of 10 hours of fasting and one after ingestion of a high-fat, high-calorie meal (administered within 30 minutes). Participants will remain in the clinical trial unit from day -1 to day 3 for each separate dosing visit with a 7-day washout. The 7-day washout period will depend on the PK data of Parts A and B. Based on the half-life observed in Part A, an additional washout day may be added between the fasted and fed doses. The dose used in Part C will not exceed 50% of the maximum dose achieved in Part A. Part C is unblinded and not placebo controlled.

[0279] Safety follow-up period Part A: Day 9 (± 2 days) Part B: Day 18 (± 2 days) Part C: Day 16 (± 2 days) Number of participants Eight participants per cohort are planned in Parts A and B. The total number of participants required will depend on the number of titration steps. The clinical trial is expected to include approximately 72, or up to 112 participants across the three parts (Parts A, B, and C). In Part A, approximately 32, or up to 56 participants are expected to receive Compound 1 or placebo. In Part B, approximately 24, or up to 40 participants are expected to receive Compound 1 or placebo. In Part C, up to 16 participants are expected to receive Compound 1.

[0280] Clinical Trial Interventions In Part A of the study, on dosing days, single ascending doses of Compound 1 (starting at 5 mg) or matching placebo will be administered orally (fasted) and provided to participants in single-dose containers.

[0281] In Part B of the study, on all dosing days, participants will receive multiple ascending doses of Compound 1 (starting at a dose selected from Part A up to the maximum dose tested in Part A) or matching placebo orally once daily (fasted) in single-dose containers.

[0282] In Part C of the study, on all dosing days, a single dose of Compound 1 (the dose selected from Part A) will be administered orally (either fasted or fed) and provided to participants in a single-dose container.

[0283] Preliminary findings Compound 1 was observed to be safe and generally well tolerated in healthy participants at all single doses up to 45 mg tested in Part A of the study. All treatment-emergent adverse events (TEAEs) reported to date were mild in severity and resolved without administration of concomitant medication. No severe TEAEs were reported. The most frequently reported TEAEs were headache and fatigue. No deaths or TEAEs leading to discontinuation of study drug were reported. No safety findings were observed with respect to clinical laboratory results, electrocardiograms (ECGs), and vital signs.

[0284] Example 13. A Phase 2 Study Evaluating the Photoictal Electroencephalographic Response, Safety, Tolerability, and Pharmacokinetics of Compound 1 in Participants with Epilepsy and Photoictal Electroencephalographic Response to Intermittent Photic Stimulation Compound 1 is a currently available inhibitor of the sodium channel (Na V ) blockers, which are being developed for the treatment of adult focal onset epilepsy. Na ) inhibitors. Focal epilepsy is characterized by localized (focal) areas of neuronal / network hyperexcitability that cause periods of abnormal network synchronization (seizures) and disrupt normal brain function. V Blockers are commonly used to treat focal epilepsy, thereby reducing the hyperexcitability of pathological neurons to prevent the onset of seizures or to terminate the seizure state.V Blocking agents are poorly tolerated, presumably because they cannot selectively target the hyperexcitability state.

[0285] Background and Clinical Trial Rationale Better tolerated Na for patients with focal epilepsy V There is a great need for blockers. Compound 1 may be a safe and effective treatment for patients with this condition and has shown efficacy in rodent models of epilepsy. The currently available standard of care used to treat epilepsy is Na+. V Blockers are limited by a narrow therapeutic index and the need to titrate to effective concentrations while managing tolerability. The most significant class-related adverse effects are those related to the central nervous system (CNS), including ataxia, drowsiness, and dizziness, which may be due to the peak I Na This may be due to excessive and prolonged inhibition of Na V Blocking drugs are no longer able to selectively reduce hyperexcitability while preserving normal brain function.

[0286] Preclinical data indicates that compound 1 is a candidate for several approved Na V Unlike blockers, it has been shown to lead to an increase in the preclinical protection index (the range between effective exposure in the maximal electroshock assay MES seizure model and exposure that reduces spontaneous movement in the locomotor activity assay model). This increased protection index may predict greater clinical tolerability of Compound 1. Compound 1 features that may support this increased protection index include the duration and peak I Na Increased efficacy against, rapid I Na Inhibition kinetics, peak I Na Increased activity-dependent inhibition of and non-Na V It has been proposed that this is due to increased selectivity for mediating activity.

[0287] The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of Compound 1 are currently being evaluated in healthy volunteers in an ongoing first-in-human study (see Example 12). Compound 1 was observed to be safe and generally well tolerated in healthy participants at all single doses up to 45 mg tested in Part A of the study. All treatment-emergent adverse events (TEAEs) reported to date were mild in severity and resolved without the administration of concomitant medication. No severe TEAEs were reported. The most frequently reported TEAEs were headache and fatigue. No deaths or TEAEs leading to study drug discontinuation were reported. No safety findings were observed in terms of laboratory results, electrocardiogram (ECG), and vital signs.

[0288] Scientific basis for clinical trial design The evaluation of potential new drugs for the treatment of epilepsy remains challenging. Epilepsy is characterized by a variety of etiologies and pathophysiological mechanisms. This leads to unpredictable EEG manifestations and clinical manifestations of the disease. Clinical assessments that can be performed simply and reproducibly are useful to determine the potential of new therapies under development. Suppression of photoparoxysmal EEG responses (PPR) has emerged over the past decades as a valuable translational tool in early clinical development for the evaluation of potential antiseizure drugs (ASDs) with various mechanisms of action.

[0289] Visual hypersensitive epilepsy is a reflex epilepsy in which epileptogenic responses can be systematically elicited at any time in response to flashing light.

[0290] Photosensitivity, defined as generalized epileptiform reactions induced by intermittent photic stimulation (IPS), is seen in approximately 5% of all epilepsy patients. Photosensitivity is more prevalent in idiopathic generalized epilepsy, but can also be present in other types of epilepsy, especially in certain genetically determined syndromes such as Dravet syndrome.

[0291] Patients with significant visual sensitivity are usually sensitive to IPS within well-defined limits of flash frequency (mainly 10-30 Hz). This photosensitivity range is the difference between the highest and lowest flash rates that consistently evoke PPR and can be used as a quantitative measure of photosensitivity and therefore epileptogenicity. The photosensitivity range is associated with the likelihood of visually induced seizures in daily life and is remarkably stable under controlled conditions. Previous studies have shown that administration of commercial and experimental ASDs, either in single or repeated dose regimens, can affect PPR and reduce or even eliminate the response to IPS. Pharmacodynamic effects, as measured by EEG responses to IPS, are also not necessarily time-locked to the pharmacokinetic profile of the drug, as demonstrated with single doses of valproic acid, levetiracetam, and carisbamate. This study design, combined with blood level monitoring, will provide information on the time to onset and duration of antiepileptic action and any effects of the tolerability of the drug.

[0292] The use of a standardized and carefully performed IPS procedure (delivery of brief flashes, determination of the threshold frequency at which the patient exhibits an epileptiform EEG response, simultaneous recording of the EEG, and observation of the patient) makes the likelihood of inducing a significant clinical seizure extremely low. Moreover, IPS, like hyperventilation, is a standard procedure in any routine EEG recording.

[0293] In summary, using the PPR model, valuable preliminary information can be obtained. These studies are usually of short duration and carried out in a limited number of patients under maximally standardized and controlled conditions. Positive results would indicate target engagement and support further clinical development of the agent investigated.

[0294] Single-blind, placebo-controlled, fixed-sequence designs have been used by many others to successfully evaluate IPS-induced PPR as proof of principle for antiepileptic drugs. This study design is recommended for three main reasons. First, this is the first inpatient study of compound 1. Therefore, blinding only to participants and EEG readers can provide more thorough safety monitoring during the intervention period. Second, each participant can serve as its own placebo control, which allows fewer participants to be exposed to the investigational drug to achieve the study objectives. Given the rare prevalence of the patient population, reducing the total sample size allows for more efficient study conduct. Third, PD effects may be observed after a single dose of antiepileptic drugs in a limited number of participants. Therefore, if PD effects are not observed after low doses of investigational drug in a limited number of participants, dose escalation should be considered.

[0295] Dosage justification A single dose is sufficient to observe inhibition of IPS-induced PPR.

[0296] Dose levels for this first-in-patient study are being determined based on the results of an ongoing first-in-human study designed to investigate the safety, tolerability, PK, and PD of single and multiple ascending doses of Compound 1 in healthy volunteers. All single doses evaluated to date (5 mg, 15 mg, and 45 mg) have been safe and generally well tolerated. At their peak, mean Compound 1 plasma concentrations for the 15 mg and 45 mg doses were within the mouse MES EC 50 The estimated human equivalent exposure of 15 mg and 45 mg of Compound 1 exceeded the EC 70 and E.C. 90Given these data, it is anticipated that the 15 mg dose level in Part A will be able to suppress the PPR response in participants. Further details can be found in the investigator's brochure.

[0297] Purpose of the test The primary objective of this study is to evaluate the pharmacodynamic effects of Compound 1 compared to placebo on intermittent photic stimulation (IPS)-induced photoparoxysmal electroencephalographic responses (IPS-induced PPR) in participants with epilepsy and IPS-induced PPR. [Table 10]

[0298] Overall Design This is a Phase 2, single-blind, placebo-controlled, fixed-sequence design study to evaluate the photoictal EEG response, safety, tolerability, and pharmacokinetics of Compound 1 in participants aged 18-65 years (inclusive) with epilepsy and IPS-induced PPR. The study initially includes one part (Part A) and an additional optional part (Part B). Both parts have an identical design and differ only in the dose of Compound 1.

[0299] The clinical trial consists of three periods: screening / baseline, intervention, and safety follow-up. Figure 15 is a diagram of the dosing scheme of the study.

[0300] Screening / Baseline Period The screening period will last up to 42 days (day -42 to day -2). Prior to any clinical trial procedures, participants will provide written informed consent to participate in the study. After confirmation of continued eligibility, participants will check into the clinic at baseline (day -1, the day before study drug administration).

[0301] Intervention period Participants will remain on the unit from baseline (day -1) until discharge (day 3). If participants experience a clinically significant AE during hospitalization, they may remain at the clinical site for further observation at the discretion of the principal investigator (PI) after discussion with the sponsor.

[0302] Participants with epilepsy and IPS-induced PPR will receive a single dose of placebo on the morning of day 1 and a single dose of Compound 1 on the morning of day 2. IPS-induced PPR will be measured pre-dose and 1, 2, 3, 4, 6, and 8 hours post-dose on days 1 and 2. Assessment on day 3 will occur 24 hours after dosing on day 2. Quantitative EEG (qEEG) will be performed pre-dose and before IPS assessment at 3 hours post-dose on days 1 and 2. Blood sampling for PK parameters will occur 30 minutes after assessment of IPS-induced PPR.

[0303] In Part A, up to 12 participants will receive 15 mg of Compound 1. The sponsor may recommend progression to optional Part B if less than 75% of participants cumulatively assessed in Part A show insufficient reduction in PPR, i.e., a reduction in the standardized photosensitivity range (SPR) of less than 3 points in ≥1 eye state (eyes open, eyes closed, and / or both eyes closed) over ≥3 test periods within 1 day compared to the range at the same time point on Day 1. The dose in Part B will be established, as appropriate, based on emerging data from Part A and ongoing open-label review of the results of the study described in Example 12.

[0304] On each dosing day, safety assessments will be performed pre-dose (within 2 hours prior to dosing) and 4 hours post-dose, including a neurological examination (including cranial nerves, coordination, and gait) and a symptom-oriented physical examination. In addition, clinical laboratory parameters, including chemistry and hematology, will be assessed at baseline, day -1, pre-dose on day 2, and at optional time points for all other visits. Vital signs will be performed pre-dose (within 2 hours prior to dosing), then 2, 4, 6, and 8 hours (± 15 minutes) post-dose. ECGs will be performed pre-dose (within 2 hours prior to dosing), then 2, 4, and 6 hours (± 15 minutes) post-dose. Participants will be discharged on day 3 after passing safety screening and completing study-related procedures. If a participant discontinues the intervention period early, an early termination (ET) visit will be performed.

[0305] Safety follow-up period A safety follow-up visit will be conducted on Day 8 (± 2 days).

[0306] Number of participants Up to 12 participants will be enrolled in this study (up to 12 participants total in both Part A and optional Part B). Participants who withdraw or are withdrawn from the study before completion of nominal clinical conduct for reasons other than the occurrence of a serious adverse event (SAE) may be replaced.

[0307] Clinical Trial Interventions For Parts A and B, each study participant will receive a placebo capsule on Day 1 and a Compound 1 capsule on Day 2. On each dosing day, a single dose of Compound 1 (15 mg for Part A, to be determined for Part B) or matching placebo will be administered orally (fasted) and provided to participants in a single-dose container.

[0308] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art upon reading this disclosure that various changes in form and detail may be made therein without departing from the true scope of the disclosure and may be practiced within the purview of the appended claims. For example, the features, steps, elements, or other aspects of all of the configurations, methods, and / or components may be used in various combinations.

[0309] A claim or specification including "or" between one or more elements of a group is considered satisfied if one, more than one, or all of the group elements are present in, employed in, or relevant to a given product or process, unless otherwise indicated to the contrary or clear from the context. The disclosure includes embodiments in which exactly one element of a group is present in, employed in, or relevant to a given product or process. The disclosure also includes embodiments in which more than one, or all of the group elements are present in, employed in, or relevant to a given product or process. Furthermore, the disclosure should be understood to encompass all variations, combinations, and permutations of one or more limitations, elements, clauses, descriptive language, etc., from one or more of the enumerated claims that are introduced into another claim that is dependent on the same base claim (or any other related claim), unless otherwise indicated or unless it is clear to one of ordinary skill in the art that a contradiction or inconsistency would result. When elements are presented as a list (e.g., Markush group or similar format), it is understood that each subgroup of elements is also disclosed and any element can be removed from the group. In general, when an embodiment or aspect is referred to as including certain elements, features, etc., the particular embodiment or aspect consists of, or consists essentially of, such elements, features, etc. For purposes of brevity, these embodiments have not been specifically described in so many words in all instances herein. It should also be understood that any embodiment or aspect of the present disclosure may be expressly excluded from the claims, regardless of whether a specific exclusion is recited in the specification.

[0310] All patents, patent applications, websites, other publications or documents, accession numbers, and the like cited in this specification are incorporated by reference in their entirety for all purposes as if each individual item was specifically and individually indicated to be so incorporated by reference.

Claims

1. A composition for treating a condition in which treatment is required for a condition related to abnormal function of sodium ion channels, wherein the composition has the following structural formula: 【Transformation 6】 It comprises compound 1 or a pharmaceutically acceptable salt thereof, The method is characterized by administering compound 1 or a pharmaceutically acceptable salt thereof to the subject in a dose of approximately 10 mg to approximately 60 mg. The aforementioned condition is generalized epilepsy or focal epilepsy. A composition in which the subject is a human being.

2. The composition according to claim 1, wherein the state is generalized epilepsy.

3. The composition according to claim 1, wherein the state is focal epilepsy.

4. The composition according to claim 1, wherein administration of compound 1 or a pharmaceutically acceptable salt thereof results in suppression of a photoparoxysmal (PPR) response.

5. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in doses of about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

6. The composition according to claim 5, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in a dose of about 15 mg.

7. The composition according to claim 5, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in a dose of about 20 mg.

8. The composition according to claim 5, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in a dose of about 30 mg.

9. The composition according to claim 5, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in a dose of about 40 mg.

10. The composition according to claim 5, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in a dose of about 45 mg.

11. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

12. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered once daily.

13. The composition according to claim 1, wherein the subject is a fetus or a child.

14. The composition according to claim 13, wherein the pediatric subject is an infant, a child, or a young adult.

15. The composition according to claim 1, wherein the subject is an adult subject.

16. The composition according to claim 15, wherein the subject is a young adult, a middle-aged adult, or an elderly adult.

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