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 neuronal excitability, or a disorder associated with a de novo gain- or loss-of-function mutation in the major central nervous system sodium channel genes, such as SCN1A, SCN2A, and SCN8A, using a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 335,204, filed April 26, 2022, U.S. Provisional Patent Application No. 63 / 349,402, filed June 6, 2022, and U.S. Provisional Patent Application No. 63 / 357,944, filed July 1, 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, 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 central nervous system sodium channel genes, such as, for example, SCN1A, SCN2A, and SCN8A. [Background technology]

[0003] Sodium ion (Na + ) channels are primarily open transiently and are rapidly inactivated, thereby allowing fast Na + A current is generated to initiate an action potential. The delayed or persistent sodium current (I Na L) is a fast Na+ receptor in cardiac myocytes and neurons. + Many common neurological and cardiac conditions are caused by 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 classified into distinct syndromes according to etiology, seizure type, and comorbidities. The most common cause of genetic epilepsy is genetic alteration of voltage-gated sodium channels (NaV Affected patients typically present as children or newborns and have a prognosis ranging from benign seizures that spontaneously remit to devastating developmental and epileptic encephalopathy (DEE).

[0005] Na V Channels are important therapeutic targets for antiepileptic drugs (AEDs). Neuronal sodium current (I Na ) and the resulting inhibition of the axon initial segments and peak I of the node of Ranvier. Na These drugs are ideally positioned to reduce excitability because they are involved in the initiation and propagation of action potentials (APs), respectively. However, current agents, including carbamazepine (CBZ), 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 includes the decline in physiological neuronal function due to I-mediated (interstitial) activity. Therefore, novel I-mediated (interstitial) drugs with improved tolerability are being developed. Na Identification of inhibitors would represent clinically relevant alternative therapeutic options.

[0006] Physiological Durability I Na are small subthreshold currents that contribute 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 IFN-γ-coding RNA (encoding IFN-γ-1.6) have demonstrated persistent IGF-1 deficiency, which may cause hyperexcitability, seizures, and developmental disorders. Na The current Na 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. Thus, sustained I NaNa in targeting V Improved activity and selectivity may significantly improve tolerability. Thus, additional therapeutic options with improved efficacy and tolerability for treating epilepsy, achieving seizure freedom, or both are needed. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Pharmacol Ther(2008)119:326-339 Summary of the Invention [Means for solving the problem]

[0008] Disclosed herein are methods of treating a disease, disorder, or condition, such as a neuropathy, a disorder associated with excessive neuronal excitability and / or abnormal slow sodium currents, or a disorder associated with a de novo gain-of-function (GoF) or loss-of-function mutation (variant) in the major central nervous system sodium channel genes, such as SCN1A, SCN2A, and SCN8A, comprising administering to the patient a therapeutically effective amount of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X and Y each independently represent CR d or N, R 1 teeth [ka] , monocyclic C 3-6 cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently one or more R a , optionally replaced by R 2 is one or more R b Optionally replaced by C 1-4Haloalkyl, phenyl, or monocyclic C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-4 Alkyl, or C 1-4 is haloalkyl, R 4 is hydrogen or C 1-4 is alkyl, R 5 is a halo, R 6 is C 1-4 Alkyl or C 1-4 haloalkyl, 1-4 Alkyl or C 1-4 Haloalkyl is OR c is replaced by t is 0, 1, or 2; R a and R b each independently represents halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; R c is C 3-6 Cycloalkyl or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, or C 3-6 is cycloalkyl, and R d is hydrogen or C 1-4 is alkyl, provided that the compound has the following formula: [ka] or [ka] or a pharma- ceutically acceptable salt thereof.

[0009] In some embodiments, the compound is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein.

[0010] In some embodiments, the compound is a compound of formula (Ib): [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the compound is a compound of formula (Ic): [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments, the compound is a compound of formula (II): [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0013] In some embodiments, the compound is a compound of formula III: [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, the compound is a compound of formula IV: [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0015] In some embodiments, the compound is Compound 1, having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0016] In some embodiments, the method provided comprises treating a disorder associated with excessive neural excitability.In some embodiments, the disorder is epilepsy, epilepsy syndrome, or encephalopathy, such as genetic or childhood epilepsy, genetic or childhood epilepsy syndrome.In some embodiments, the disorder is developmental and epileptic encephalopathy.In some embodiments, the disorder is tuberous sclerosis complex (TSC).

[0017] 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.

[0018] 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, such as about 30 mg / kg.

[0019] In some embodiments, the disclosed compound or pharma- ceutically acceptable salt thereof is administered to the subject in an amount ranging from about 2.5 mg to about 150 mg per day, for example, about 90 mg or about 120 mg per day. In some embodiments, the disclosed compound or pharma- ceutically acceptable salt thereof is administered to the subject in multiple doses in an amount ranging from about 30 mg to about 120 mg per day.

[0020] In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt is orally administered to the subject.In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt is administered to the subject daily for at least 14 days.In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt is administered to the subject in a fasting state.In some embodiments, the compound of the present disclosure or its pharmaceutically acceptable salt is administered to the subject in a fed state.

[0021] In some embodiments, the subject is a human. In some embodiments, the subject is a human between 2 and 17 years of age.

[0022] In some embodiments, the present disclosure provides a method of treating a condition related to abnormal functioning of a sodium ion channel in a subject in need thereof, the method comprising administering to the subject a compound represented by formula (I): [ka] or a pharma- ceutically acceptable salt thereof, at a dose of about 1 mg to about 150 mg, wherein X and Y each independently represent CR d or N, R 1 teeth [ka] , monocyclic C 3-6 cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently one or more R a Optionally replaced by R 2 is one or more R b C optionally replaced by 1-4 Haloalkyl, phenyl, or monocyclic C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-4 Alkyl, or C 1-4 is haloalkyl, R 4 is hydrogen or C1-4 is alkyl, R 5 is a halo, R 6 is C 1-4 Alkyl or C 1-4 haloalkyl, 1-4 Alkyl or C 1-4 Haloalkyl is OR c is replaced by t is 0, 1, or 2; R a and R b each independently represents halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; R c is C 3-6 Cycloalkyl or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, or C 3-6 is cycloalkyl, and R d is hydrogen or C 1-4 is alkyl, provided that the compound has the following formula: [ka] or [ka] or a pharma- ceutically acceptable salt thereof.

[0023] In some embodiments, the compound is administered at a dose of about 1 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.

[0024] 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, the method comprising administering to a subject a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof at a dose of about 0.25 mg / kg / day to about 1 mg / kg / day, X and Y each independently represent CR d or N, R 1 teeth [ka] , monocyclic C 3-6 cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently one or more R a , optionally replaced by R 2 is one or more R b Optionally replaced by C 1-4 Haloalkyl, phenyl, or monocyclic C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-4 Alkyl, or C 1-4 is haloalkyl, R 4 is hydrogen or C 1-4 is alkyl, R 5 is a halo, R 6 is C 1-4 Alkyl or C 1-4 haloalkyl, 1-4 Alkyl or C 1-4 Haloalkyl is OR c is replaced by t is 0, 1, or 2; R a and R b each independently represents halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; R c is C 3-6 Cycloalkyl or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, or C 3-6 is cycloalkyl, and R d is hydrogen or C 1-4 is alkyl, provided that the compound has the following formula: [ka] or [ka] or a pharma- ceutically acceptable salt thereof.

[0025] In some embodiments, the compound is administered at a dose of about 0.25 mg / kg / day, about 0.30 mg / kg / day, about 0.35 mg / kg / day, about 0.40 mg / kg / day, about 0.45 mg / kg / day, about 0.50 mg / kg / day, about 0.55 mg / kg / day, about 0.60 mg / kg / day, about 0.65 mg / kg / day, about 0.65 mg / kg / day, about 70 mg / kg / day, about 0.75 mg / kg / day, about 0.80 mg / kg / day, about 0.85 mg / kg / day, about 0.90 mg / kg / day, about 0.95 mg / kg / day, or about 1.0 mg / kg / day.

[0026] In some embodiments, administration of the compound 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 the compound.

[0027] In some embodiments, administration of the compound does not result in ataxia, lethargy, and vomiting in the subject.

[0028] In some aspects, the disclosure provides a method of reducing the severity, number, and / or frequency of seizures in a subject in need thereof, the method comprising administering to a subject an effective amount of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X and Y each independently represent CR d or N, R 1 teeth [ka] , monocyclic C 3-6 cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently one or more R a Optionally replaced by R 2 is one or more R b C optionally replaced by 1-4 Haloalkyl, phenyl, or monocyclic C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-4 Alkyl, or C 1-4 is haloalkyl, R 4 is hydrogen or C 1-4 is alkyl, R 5 is a halo, R 6 is C 1-4 Alkyl or C1-4 haloalkyl, 1-4 Alkyl or C 1-4 Haloalkyl is OR c is replaced by t is 0, 1, or 2; R a and R b are each independently halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; R c is C 3-6 Cycloalkyl or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, or C 3-6 is cycloalkyl, and R d is hydrogen or C 1-4 is alkyl, provided that the compound has the following formula: [ka] or [ka] or a pharma- ceutically acceptable salt thereof.

[0029] In some embodiments, the subject has a condition associated with abnormal function of sodium ion channel. In some embodiments, the condition associated with abnormal function of 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.

[0030] In some embodiments, the condition is epilepsy, an epilepsy syndrome, or an encephalopathy. 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.

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

[0032] In some embodiments, the condition is selected from the group consisting of epileptic encephalopathy with SCN1A, SCN2A and / or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant migrating partial epilepsy of childhood, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, KCNT1 epileptic encephalopathy.

[0033] In some embodiments, the condition is tuberous sclerosis complex (TSC).

[0034] In some embodiments, the compound is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0035] In some embodiments, the compound is a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt thereof.

[0036] In some embodiments, the compound is a compound of formula (Ic): [ka] or a pharma- ceutically acceptable salt thereof.

[0037] In some embodiments, the compound is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0038] In some embodiments, the compound is a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof.

[0039] In some embodiments, the compound is a compound of formula IV: [ka] or a pharma- ceutically acceptable salt thereof.

[0040] In some embodiments, the compound is Compound 1 of the following formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0041] In some aspects, the disclosure also provides a method for preferentially inhibiting sustained sodium current (INa) over peak sodium current (INa) in a neuron, the method comprising administering to the neuron an effective amount of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X and Y each independently represent CR d or N, R 1 teeth [ka] , monocyclic C 3-6 cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently one or more R a Optionally replaced by R 2 is one or more R b C optionally replaced by 1-4 Haloalkyl, phenyl, or monocyclic C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-4 Alkyl, or C 1-4 is haloalkyl, R 4 is hydrogen or C 1-4 is alkyl, R 5 is a halo, R 6 is C 1-4 Alkyl or C 1-4 haloalkyl, 1-4 Alkyl or C 1-4 Haloalkyl is OR c is replaced by t is 0, 1, or 2; R a and R b are each independently halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, and C 1-4 haloalkoxy; R c is C 3-6 Cycloalkyl or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, or C 3-6 is cycloalkyl, and R d is hydrogen or C 1-4 is alkyl, provided that the compound has the following formula: [ka] or [ka] or a pharma- ceutically acceptable salt thereof.

[0042] In some embodiments, the neuron is present in a subject.

[0043] In some embodiments, the subject has a condition associated with abnormal function of sodium ion channel. In some embodiments, the condition associated with abnormal function of 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.

[0044] In some embodiments, the condition is epilepsy, an epilepsy syndrome, or an encephalopathy. 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.

[0045] In some embodiments, the condition is selected from the group consisting of infantile malignant focal migrating partial seizures (MMFSI), infantile epilepsy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia. In some embodiments, the condition is epileptic encephalopathy.

[0046] In some embodiments, the condition is selected from the group consisting of epileptic encephalopathy with SCN1A, SCN2A and / or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant migrating partial epilepsy of childhood, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, KCNT1 epileptic encephalopathy.

[0047] In some embodiments, the condition is tuberous sclerosis complex (TSC).

[0048] In some embodiments, the compound is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0049] In some embodiments, the compound is a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In some embodiments, the compound is a compound of formula (Ic): [ka] or a pharma- ceutically acceptable salt thereof.

[0051] In some embodiments, the compound is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, the compound is a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof.

[0053] In some embodiments, the compound is a compound of formula IV: [ka] or a pharma- ceutically acceptable salt thereof.

[0054] In some embodiments, the compound is Compound 1 of the following formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0055] In some embodiments, the subject is a human.

[0056] 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]

[0057] [Figure 1A]Figures 1A-1B show the effects of 0.3 or 3 μM Compound 1 on action potential firing from wild-type CA1 pyramidal neurons. Figure 1A: Representative action potential traces from a CA1 pyramidal neuron during baseline recording and after application of 3 μM Compound 1. Figure 1B: Both 0.3 and 3 μM Compound 1 significantly reduced action potential firing frequency in CA1 pyramidal neurons from wild-type mice. [Figure 1B] Figures 1A-1B show the effects of 0.3 or 3 μM Compound 1 on action potential firing from wild-type CA1 pyramidal neurons. Figure 1A: Representative action potential traces from a CA1 pyramidal neuron during baseline recording and after application of 3 μM Compound 1. Figure 1B: Both 0.3 and 3 μM Compound 1 significantly reduced action potential firing frequency in CA1 pyramidal neurons from wild-type mice. [Figure 2A] 2A-2C show the effects of Compound 1 (FIG. 2A), lamotrigine (LTG) (FIG. 2B), and carbamazepine (CBZ) (FIG. 2C) on human NaV1.6 channels using the PatchXpress® Molecular Devices electrophysiology platform. [Figure 2B] 2A-2C show the effects of Compound 1 (FIG. 2A), lamotrigine (LTG) (FIG. 2B), and carbamazepine (CBZ) (FIG. 2C) on human NaV1.6 channels using the PatchXpress® Molecular Devices electrophysiology platform. [Figure 2C] 2A-2C show the effects of Compound 1 (FIG. 2A), lamotrigine (LTG) (FIG. 2B), and carbamazepine (CBZ) (FIG. 2C) on human NaV1.6 channels using the PatchXpress® Molecular Devices electrophysiology platform. [Diagram 3] FIG. 3 shows the effect of compound CD-1 on maximal electroshock-induced seizures (MES) in male CD-1 mice. CD-1 mice: n=12 / group, **p<0.01 vs. Veh. [Figure 4]FIG. 4 shows the effect of Compound 1 on spontaneous locomotor activity (sLMA) in male CD-1 mice. CD-1 mice: n=20 / group, ANOVA / Dunnett, **p<0.01 vs. Veh. [Diagram 5] FIG. 5 shows the effect of Compound 1 on reducing focal motor seizure frequency in the Scn2a Q54 mouse model of elevated persistent sodium current. Sidak's post-hoc comparison test, *P<0.05 vs. Veh., **P<0.001 vs. Veh. [Figure 6] Figure 6 shows inhibition of audiogenic seizures by Compound 1 (1-10 mg / kg, orally administered). Results of an in vivo proof-of-concept study in N1768D D / + mice show Compound 1 inhibition of auditory-induced seizures. **Significant protection against Veh χ2=16.0, Fisher's p=0.0002. [Figure 7A] Figures 7A-7B show the effect of Compound 1 (10 mg / kg) in KCNQ2 K556E and KCNC1 R320H seizure models. Figure 7A: Effect of Compound 1 in KCNQ2 K556E PTZ seizure model. Figure 7B: Effect of Compound 1 in KCNC1 R320H PTZ seizure model. [Figure 7B] Figures 7A-7B show the effect of Compound 1 (10 mg / kg) in KCNQ2 K556E and KCNC1 R320H seizure models. Figure 7A: Effect of Compound 1 in KCNQ2 K556E PTZ seizure model. Figure 7B: Effect of Compound 1 in KCNC1 R320H PTZ seizure model. [Figure 8A]Figures 8A-8D show that Compound 1 exhibits potent inhibition of NaV1.6 persistent sodium current (INa). Compound 1 inhibited ATX-II-induced hNaV1.6 persistent INa (Figure 8A) and hNaV1.6-N1768D (developmental or epileptic encephalopathy variant) expressed persistent INa. (Figure 8B). Figure 8C: Compound 1 showed increased potency against persistent INa compared to standard hNaV-targeted antiepileptic drugs. Figure 8D: Compound 1 inhibited ATX-II or N1768D-induced persistent INa expressed by multiple NaV isoforms and orthologs. Voltage protocols are included as panel inserts, pharmacology is measured with arrows, and points represent mean ± SEM. NMDG: N-methyl-D-glucamine [Figure 8B] Figures 8A-8D show that Compound 1 exhibits potent inhibition of NaV1.6 persistent sodium current (INa). Compound 1 inhibited ATX-II-induced hNaV1.6 persistent INa (Figure 8A) and hNaV1.6-N1768D (developmental or epileptic encephalopathy variant) expressed persistent INa. (Figure 8B). Figure 8C: Compound 1 showed increased potency against persistent INa compared to standard hNaV-targeted antiepileptic drugs. Figure 8D: Compound 1 inhibited ATX-II or N1768D-induced persistent INa expressed by multiple NaV isoforms and orthologs. Voltage protocols are included as panel inserts, pharmacology is measured with arrows, and points represent mean ± SEM. NMDG: N-methyl-D-glucamine [Figure 8D] Figures 8A-8D show that Compound 1 exhibits potent inhibition of NaV1.6 persistent sodium current (INa). Compound 1 inhibited ATX-II-induced hNaV1.6 persistent INa (Figure 8A) and hNaV1.6-N1768D (developmental or epileptic encephalopathy variant) expressed persistent INa. (Figure 8B). Figure 8C: Compound 1 showed increased potency against persistent INa compared to standard hNaV-targeted antiepileptic drugs. Figure 8D: Compound 1 inhibited ATX-II or N1768D-induced persistent INa expressed by multiple NaV isoforms and orthologs. Voltage protocols are included as panel inserts, pharmacology is measured with arrows, and points represent mean ± SEM. NMDG: N-methyl-D-glucamine [Figure 8C] Figures 8A-8D show that Compound 1 exhibits potent inhibition of NaV1.6 persistent sodium current (INa). Compound 1 inhibited ATX-II-induced hNaV1.6 persistent INa (Figure 8A) and hNaV1.6-N1768D (developmental or epileptic encephalopathy variant) expressed persistent INa. (Figure 8B). Figure 8C: Compound 1 showed increased potency against persistent INa compared to standard hNaV-targeted antiepileptic drugs. Figure 8D: Compound 1 inhibited ATX-II or N1768D-induced persistent INa expressed by multiple NaV isoforms and orthologs. Voltage protocols are included as panel inserts, pharmacology is measured with arrows, and points represent mean ± SEM. NMDG: N-methyl-D-glucamine [Figure 9A] Figures 9A-9F show that Compound 1 shows increased preference for hNaV1.6 persistent sodium currents (INa) over peak INa compared to standard NaV-targeted antiepileptic drugs carbamazepine (CBZ) and lamotrigine (LTG). Inhibition of peak INa assessed using assays for tonic block (resting state, Figure 9A), use-dependent block (rate / activity-dependent, Figure 9B), or voltage-dependent block (depolarization-dependent, Figure 9C). Figure 9D: Compound 1 shows preference for persistent INa over peak INa for all assay conditions (red arrows). CBZ (Figure 9E) and LTG (Figure 9F) showed lower potency and no preference for persistent INa (red arrows). Voltage protocols are included as panel inserts, pharmacology is measured with blue arrows, and points represent mean ± SEM. [Figure 9B] Same as above [Figure 9C] Same as above [Figure 9D] Same as above [Figure 9E] Same as above [Figure 9F] Same as above [Figure 10A]Figures 10A-10F show that Compound 1 reduces the intrinsic excitability of hippocampal CA1 pyramidal neurons without impairing action potential (AP) amplitude. The effects of Compound 1 (blue) and carbamazepine (CBZ; red) at equivalent effective concentrations (half-maximal inhibitory concentration [IC50] for peak sodium current [INa] voltage-dependent block [VDB]) on AP firing recorded from CA1 pyramidal neurons from wild-type mice are shown. Representative AP traces show predrug (black, baseline) and post-drug recordings of 0.3 μmol / L Compound 1 (Figure 10, blue) or 45 μmol / L CBZ (Figure 10, red). Amino acid sequences of input-output relationships (Figures 10B and 10E) and AP amplitude fits (Figures 10C and 10F) for Compound 1 and CBZ at +200 pA current injections are included. Data are expressed as mean ± SEM. *p<0.05, **p<0.01, ****p<0.0001. [Figure 10BC] Same as above [Figure 10D] Same as above [Fig. 10EF] Same as above [Figure 11A]Figures 11A-11E show that Compound 1 has an improvement in the preclinical protection index (PI) compared to carbamazepine (CBZ) or lamotrigine (LTG). Compound 1 (0.3-10 mg / kg po) produced a dose-dependent increase in the latency to tonic extension seizures (Figure 11A) and a decrease in the relative number of mice that developed seizures (Figure 11B) in the maximal electroshock seizure (MES) model. The maximal effect was comparable to the positive control valproic acid (VPA; 400 mg / kg ip). Figure 11C: Compound 1 (10-40 mg / kg po) produced a dose-dependent decrease in the distance traveled in the locomotor activity (sLMA) assay. Figure 11D: Compound 1 total brain concentrations associated with anticonvulsant efficacy (green symbols, left y-axis) were separated from those associated with the decrease in total distance traveled (red symbols, right y-axis). FIG. 11E: Calculated free brain concentration ranges of Compound 1, CBZ, and LTG associated with anticonvulsant effects (green bars) and reduction in locomotor activity (red bars). PI for each molecule is shown. Data are expressed as mean ± SEM. MES: n=12-24 / group, analysis of variance (ANOVA) / Dunn's test, sLMA: n=20 / group, ANOVA / Dunnett's test. *p<0.05 vs. vehicle (Veh), **p<0.01 vs. Veeh. [Figure 11B] Same as above [Figure 11C] Same as above [Figure 11D] Same as above [Figure 11E] Same as above [Figure 12A] Figures 12A-12B show that the combination of Compound 1 with the standard of care sodium channel blocker carbamazepine (CBZ) results in greater efficacy in vivo (Figure 12A) without altering tolerability (Figure 12B). Figure 12A, n=8 / group Veh, n=10 Compound 1, Mann-Whitnett (VPA), ANOVA / Dunn (Compound 1), *p<0.05 vs. Veeh / Veh, **p<0.005 vs. Veeh / Veh. Figure 12B, n=10 / group, 4 excluded from CBZ / Compound 1 for ataxia, ANOVA / Dunn, **p<0.01 vs. Vee. [Figure 12B] Same as above [Figure 13A]Figures 13A-13B show that Compound 1 was exposed above the therapeutic range after a single dose (Figure 13A) and approached steady state after 28 days of dosing with once-daily dosing and auto-titration (Figure 13B). CMax in Figure 13B represents the concentration 2.5 hours after dosing. [Figure 13B] Same as above [Figure 14A] FIG. 14A is a graph depicting percent protection from spontaneous seizures in the Scn2a DEE mouse model as a function of administered dose of Compound 1. [Figure 14B] FIG. 14B is a graph depicting percent protection from spontaneous seizures in the Scn8a DEE mouse model as a function of administered dose of Compound 1. [Figure 14C] FIG. 14C is a graph showing percent protection from hindlimb outgrowth as a function of time in the Kcnq2 DEE mouse model administered vehicle or Compound 1. [Figure 14D] FIG. 14D is a graph showing percent protection from hindlimb outgrowth as a function of time in the Kcnc1 DEE mouse model administered vehicle or Compound 1. [Figure 14E] FIG. 14E is a graph showing percent protection from hindlimb outgrowth as a function of time in the Hcn1 DEE mouse model administered vehicle or Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] Reference will now be made in detail to various exemplary embodiments, examples of which are illustrated in the accompanying drawings. It should be 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.

[0059] 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.

[0060] As used in this specification and the appended claims, the singular forms 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.

[0061] 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 an amount, "approximately" 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.

[0062] 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.

[0063] As used herein in the specification and claims, the term "and / or" should be understood to mean "one or both" of the elements so conjoined, i.e., elements present in the conjunctiva in some cases and present in the conjunctiva 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 language such as "comprising," in one embodiment, can refer to A without B (optionally including elements other than B), in another embodiment, B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements), etc.

[0064] The term "at least" before a number or series of numbers (e.g., at least 2) 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 series of numbers or ranges.

[0065] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0066] As used herein, the term "in some embodiments" refers to embodiments of all aspects of the present disclosure, unless the context clearly indicates otherwise.

[0067] 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 invention may 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.

[0068] As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound that it is formulated with.The pharmaceutically acceptable carrier, adjuvant, or vehicle that can be used in the compositions described herein includes, but is 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, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and wool fat.

[0069] As used herein, a "subject" to which administration is contemplated includes a human (i.e., a male or female of any age group, e.g., a fetus, a pediatric subject (such as an infant, child, or adolescent), or an adult subject (e.g., a mammal, such as a primate (e.g., a cynomolgus or rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and / or dog. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0070] As used herein, the term treating a condition or disorder, e.g., epilepsy or an epilepsy syndrome such as focal epilepsy, refers to the amelioration, improvement, or reduction in the severity of at least one symptom or indicator associated with the condition or disorder, or the halting of the progression or worsening of the condition or disorder.

[0071] 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.

[0072] Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In the present specification, the general principles of organic chemistry are identified according to the inside cover of Ed., and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, can be found in, for example, Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0073] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C1-6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0074] "Alkyl" refers to, for example, the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has one carbon atom (C alkyl). 1-6Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0075] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-20 In certain embodiments, an alkenyl does not contain a triple bond. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0076] "Alkynyl" refers to the radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-20 In certain embodiments, alkynyl does not contain a double bond. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups include, as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0077] "Aryl" refers to a radical of a 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) that is monocyclic or polycyclic (e.g., bicyclic or tricyclic) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl", e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such instances the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0078] "Hetero", when used to describe a compound or a group present in a compound, means that one or more carbon atoms in the compound or group are replaced with a heteroatom of nitrogen, oxygen, or sulfur. Hetero can apply to any of the alkyl groups listed above, such as alkyl, e.g., heteroalkyl; alkenyl, e.g., heteroalkenyl, alkynyl, e.g., heteroalkynyl, carbocyclyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, etc., having 1 to 5, especially 1 to 3, heteroatoms.

[0079] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic arrangement) ("5-10 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system, and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused with one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in such instances the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring defined above is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, and in such instances the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing a heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0080] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system ("5-10 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system ("5-8 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0081] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10Exemplary C3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. ... 3-5 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-6 Illustrative examples of carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3-10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, in such instances the number of carbons continues to designate the number of carbons in the carbocyclic ring system.

[0082] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system ("3- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl"), or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), which may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl or heterocyclyl ring or ring system, and a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, in such instances the number of ring members continues to specify the number of ring members in the heterocyclyl ring system.

[0083] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0084] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0085] "Cyano" refers to -CN.

[0086] "Halo" or "halogen" refers to fluorine atoms (i.e., fluoro or -F), chlorine atoms (i.e., chloro or -Cl), bromine atoms (i.e., bromo or -Br), and iodine atoms (i.e., iodo or -I). In certain embodiments, the halo group is fluoro or chloro.

[0087] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0088] "Nitro" refers to -NO2.

[0089] In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions in the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position.

[0090] The embodiments disclosed herein are not intended to be limited in any way by the above exemplary list of chemical groups and substituents.Those skilled in the art will recognize that some embodiments are possible within the scope and spirit of the present disclosure.The following description illustrates the present disclosure and, of course, should not be interpreted as limiting the scope of the invention described herein.

[0091] Compounds and Compositions In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X and Y each independently represent CR d or N, R 1 teeth [ka] , monocyclic C 3-6 cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently one or more R a , optionally replaced by R 2 is one or more R b Optionally replaced by C 1-4 Haloalkyl, phenyl, or monocyclic C 3-6 is cycloalkyl, R 3 is hydrogen, C 1-4 Alkyl, or C 1-4 is haloalkyl, R 4 is hydrogen or C 1-4 is alkyl, R 5 is a halo, R 6 is C 1-4 Alkyl or C 1-4 haloalkyl, 1-4 Alkyl or C 1-4 Haloalkyl is OR c is replaced by t is 0, 1, or 2; R a and R b each independently represents halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; R c is C 3-6 Cycloalkyl or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, or C 3-6is cycloalkyl, and R d is hydrogen or C 1-4 is alkyl, provided that the compound has the following formula: [ka] or [ka] or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, the compound is a compound of formula (Ia): [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0093] In some embodiments, the compound is a compound of formula (Ib): [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, the compound is a compound of formula (Ic): [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0095] In some embodiments, the compound is a compound of formula (II): [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0096] In some embodiments, the compound is a compound of formula III: [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0097] In some embodiments, the compound is a compound of formula IV: [ka] wherein the variables are as defined herein or a pharma- ceutically acceptable salt thereof.

[0098] In some embodiments, the compound is Compound 1, having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0099] 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 comprising X-ray powder diffraction peaks at the following diffraction angles (°2θ) 9.3±0.2, 18.8±0.2, and 21.4±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) 16.1±0.2, 21.1±0.2, and 21.6±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) 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, and 21.6±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) 16.1±0.2, 21.1±0.2, 21.6±0.2, 22.6±0.2, 23.9±0.2, 26.0±0.2, and 26.4±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) 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, 21.6±0.2, 22.6±0.2, 23.9±0.2, 26.0±0.2, and 26.4±0.2. Crystalline forms of Compound 1 are described, for example, in WO 2019 / 232209, the entire contents of which are incorporated herein by reference.

[0100] The compounds described herein may contain one or more asymmetric centers and therefore may exist in the form of various isomers, for example, enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers can 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 can 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 further include the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0101] As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" forms of the compounds are substantially free of the "R" forms of the compounds and are thus in enantiomeric excess of the "R" forms. The term "enantiomerically pure" or "pure enantiomer" means that the compound comprises about 75% by weight or more of an enantiomer, such as about 80% by weight or more, about 85% by weight or more, about 90% by weight or more, about 91% by weight or more, about 92% by weight or more, about 93% by weight or more, about 94% by weight or more, about 95% by weight or more, about 96% by weight or more, about 97% by weight or more, about 98% by weight or more, about 98.5% by weight or more, about 99% by weight or more, about 99.2% by weight or more, about 99.5% by weight or more, about 99.6% by weight or more, about 99.7% by weight or more, about 99.8% by weight or more, or about 99.9% by weight or more. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0102] In certain aspects, compositions are provided that include a compound described herein, such as Compound 1. In some embodiments, the composition is a pharmaceutical composition that includes a compound described herein, such as Compound 1, and a pharma- ceutically acceptable carrier. In some embodiments, the compound included in the disclosed composition is a compound of formula (I), as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed composition is a compound of formula (Ia), as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed composition is a compound of formula (Ib), as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed composition is a compound of formula (Ic), as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed composition is a compound of formula (II), as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed composition is a compound of formula (III), as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed compositions is a compound of formula (IV) as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed compositions is compound 1, having the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0103] 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 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.

[0104] 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 O may be in any isotopic form, including F. 18 F and 19 It may be any isotopic form containing F.

[0105] 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) currents. In some embodiments, the compounds provided by the present disclosure are effective in treating epilepsy or epilepsy syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders. The compounds provided, their pharma- ceutically acceptable salts, or compositions comprising same can 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 In some embodiments, the compounds of the present disclosure inhibit all or substantially all of the sodium ion channels (e.g., Na V 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and all or substantially all of 1.9) V It is a blocker.

[0106] In typical embodiments, the present disclosure is intended to encompass the compounds disclosed herein, as well as pharma- ceutically acceptable salts, pharma-ceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present 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 the compounds described herein, such as compounds of formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV), or compound 1).

[0107] The compounds and compositions described herein, such as Compound 1, can be used to treat neurological disorders, disorders associated with excessive neural excitability, or disorders associated with de novo gain-of-function or loss-of-function mutations in major central nervous system sodium channel genes, such as SCN1A, SCN2A, and SCN8A. The compounds and compositions described herein, such as Compound 1, can also be used to treat neurological disorders, disorders associated with excessive neural excitability, or disorders associated with de novo gain-of-function or loss-of-function mutations in ion channel genes, such as Kcnq2, Kcnc1, and Hcn1.

[0108] In some aspects, a method for treating a neurological disorder is provided, the disorder being associated with excessive neuronal excitability or associated with a de novo gain-of-function or loss-of-function mutation in a major central nervous system sodium channel gene, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof, or comprising a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed method is a compound of formula (Ia) as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed method is a compound of formula (Ib) as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed method is a compound of formula (Ic) as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed method is a compound of formula (II) as defined elsewhere herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed method is a compound of formula (III) as defined elsewhere herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed method is a compound of formula (IV) as defined elsewhere herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed method is compound 1 having the formula: [ka] or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0109] Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., malignant focal migrating partial seizures of infancy (MMFSI), infantile epilepsy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathies, developmental and 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 clonic seizures, focal seizures), nodular sclerosis, leukodystrophies, myelinating leukodystrophies, and leukoencephalopathy), cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), pulmonary vascular disorders / bleeding, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itch and pruritus, movement disorders (e.g., ataxia, and cerebellar ataxia), psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder), neurodevelopmental disorders, learning disabilities, intellectual disability, fragile X, neuroplasticity, and autism spectrum disorders.

[0110] Epilepsy is a CNS disorder in which neuronal activity in the brain is disrupted, causing seizures or periods of abnormal behavior, sensations, and sometimes loss of consciousness. Seizure symptoms vary greatly, from a simple blank stare for a few seconds to repeated twitching of the arms or legs during a seizure. Epilepsy may include generalized seizures 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 generally 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. Symptoms can vary, depending on the part of the brain that has abnormal electrical activity.

[0111] Epilepsy as referred to herein includes generalized, partial, complex partial, tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0112] In some embodiments, the epilepsy syndrome is early-onset DEE. In certain embodiments, the epilepsy syndrome is DEE including, for example, Ohtahara syndrome, epilepsy with migratory focal seizures in infancy (EIMFS), infantile and pediatric DEE, for example, West syndrome and Lennox-Gastaut syndrome; Dravet syndrome, idiopathic / generalized epilepsy (IGE / GGE), temporal lobe epilepsy, myoclonic atonic epilepsy (MAE), migratory partial epilepsy of infancy (MMPSI); and familial hemiplegic migraine with or without epilepsy. In certain embodiments, the epilepsy syndrome is late-onset seizure-onset epileptic encephalopathy.

[0113] In some embodiments, the compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) 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, the 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.

[0114] 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 with SCN1A mutations, including Dravet syndrome, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile spasms, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden epileptic death (SUDEP), Rasmussen's encephalitis, malignant migrating partial epilepsy of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0115] In some embodiments, the methods described herein include administering a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) to a patient suffering from epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, developmental and epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, febrile seizures, In some embodiments, the method further comprises identifying a subject having a condition characterized by a genetic predisposition to epilepsy, such as generalized epilepsy, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden onset of epileptic death (SUDEP), Rasmussen's encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0116] In one aspect, the 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 and epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory pediatric epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic pediatric partial seizures with SCN3A mutations, etc.). The treatment of epilepsy, SCN8A epileptic encephalopathy, sudden epileptic death (SUDEP), Rasmussen's encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) comprises administering to a subject in need thereof a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same.

[0117] The compounds of the invention (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) may also be used to treat a subject with a gene that is a member of the following families: 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, KCNN3, KCNN4, KCNN5, KCNN6, KCNN7, KCNN8, KCNN9, KCNN10, KCNN11, KCNN12, KCNN13, KCNN14, KCNN15, KCNN16, KCNN17, KCNN18, KCNN19, KCNN20, KCNN21, KCNN22, KCNN23, KCNN24, KCNN25, KCNN26, KCNN27, KCNN28, KCNN29 ...9, KCNN21, KCNN22, KCNN23 The present invention may be used to treat epileptic encephalopathies having a mutation in one or more of CNQ2, 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.

[0118] In some embodiments, the methods described herein include administering to the patient an effective amount of one or more of the following compounds prior to administration of a composition described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1): 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, The method further comprises identifying a subject having one or more mutations in KCNMA1, KCNN2, 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.

[0119] The compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) may also be used in methods of ameliorating at least one symptom or feature of epilepsy or epilepsy syndrome, including, for example, early onset DEE, in a subject in need thereof. In certain embodiments, the symptom or feature includes early onset seizures and / or global developmental delay. In certain embodiments, the symptoms or characteristics include one or more of seizures, hypotonia, sensory problems such as impaired sensory integration, motor dysfunction, intellectual and cognitive dysfunction, motor and balance dysfunction such as choreoathetosis, dystonia, and ataxia, visual dysfunction including one or more of anxiety, sensory problems, urinary retention problems, irritability, behavioral problems, speech and language delays, gastrointestinal problems (such as gastroesophageal reflux, diarrhea, constipation, movement disorders), neurodevelopmental delays, sleep disorders, sudden death in epilepsy (SUDEP), motor developmental delays, social developmental delays, repetitive behaviors, uncoordinated oral movements. In certain embodiments, seizures include focal, clonic, tonic, and generalized tonic-clonic seizures, tonic seizures (often lasting more than 10 minutes), and recurrent seizures (e.g., convulsive, myoclonic, fainting, focal, blunting, and tonic seizures).

[0120] In one aspect, the disclosure provides a method of ameliorating at least one symptom or characteristic of epilepsy or an epilepsy syndrome, including, for example, early onset DEE, comprising administering to a subject in need thereof a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same. In certain embodiments, the symptom or characteristic comprises early onset seizures and / or global developmental delay. In certain embodiments, the symptoms or characteristics include one or more of seizures, hypotonia, sensory problems such as impaired sensory integration, motor dysfunction, intellectual and cognitive dysfunction, motor and balance dysfunction such as choreoathetosis, dystonia, and ataxia, visual dysfunction including one or more of anxiety, sensory problems, urinary retention problems, irritability, behavioral problems, speech and language delays, gastrointestinal problems (such as gastroesophageal reflux, diarrhea, constipation, movement disorders), neurodevelopmental delays, sleep disorders, sudden death in epilepsy (SUDEP), motor developmental delays, social developmental delays, repetitive behaviors, uncoordinated oral movements. In certain embodiments, the seizures include focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (often lasting more than 10 minutes), and frequent seizures (e.g., convulsive seizures, myoclonic seizures, absence seizures, focal seizures, blunted state seizures, and tonic seizures).

[0121] In some aspects, the disclosure provides methods of reducing the severity, occurrence, and / or frequency of attacks in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1), or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has early-onset DEE. In some embodiments, the compound is Compound 1, or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments, the compounds described herein (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or compound 1) may be used to treat tuberous sclerosis complex (TSC). TSC is a genetic disorder that is typically associated with the growth of noncancerous (benign) tumors across different parts of the body. TSC often affects the brain, and some affected individuals have benign growths on the outer surface of the brain (cerebral cortex) known as cortical tubers. Individuals with TSC often develop behavioral patterns called TSC-associated neuropsychiatric disorders (TAND), which may be characterized by one or more of hyperactivity, aggression, mental conditions, intellectual disability, and communication and social interaction problems (autism spectrum disorder). Additionally, individuals with tuberous sclerosis may experience attention-deficit / hyperactivity disorder (ADHD) or seizures. Individuals with TSC typically have skin abnormalities, including patches of abnormally light-colored skin, areas of raised and thickened skin, and growths under the nails. Facial tumors called facial angiofibromas are also common and typically begin during childhood.

[0123] In one aspect, the disclosure provides a method of treating tuberous sclerosis complex (TSC), comprising administering to a subject in need thereof a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same.

[0124] The compounds described herein may be useful in the treatment of pain. In some embodiments, pain includes neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorder. In some embodiments, the methods described herein further include identifying a subject with pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorder) before administering a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or compound 1).

[0125] In one aspect, the disclosure includes a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorder) in a subject in need of treatment with a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same.

[0126] In one embodiment, the peak sodium current (I Na ) than persistent sodium current (I Na Provided herein is a method of preferentially inhibiting peak sodium current, I, comprising contacting the neuron with an effective amount of a compound described herein (e.g., Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1). As described in Example 8 herein, an exemplary compound of the disclosure, i.e., Compound 1, inhibits peak sodium current, I Na More sustainable than I Na Specifically, compound 1 showed selectivity in inhibiting the persistent I Na Inhibits peak I NaCompared with inhibition of sustained I Na Peak I shows a preference for inhibition of Na and Sustainability I Na The ratio of 100 to 600 was 60. In contrast, standard treatment antiepileptic drugs (AEDs) Na Compared with inhibition of sustained I Na It has low preference for inhibition of peak I Na and Sustainability I Na The ratio of peak I to ... Na and Sustainability I Na The ratios of Cenobamate to Lamotrigine were 24 (cenobamate), 30 (carbamazepine), 8 (oxcarbazepine), and 16 (lamotrigine). Na More sustainable than I Na The preferential inhibition of may be associated with improved tolerability of Compound 1.

[0127] In some embodiments, provided herein is a method of treating a neurological or psychiatric disorder, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, to a subject in need of such treatment.

[0128] In any of the methods disclosed herein, a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, is administered to said subject in an effective amount, or a therapeutically effective amount, 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 said disease, disorder or condition. In some embodiments, a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, is administered to said 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, The subject is administered an amount in the range of about 0.1 mg / kg to about 1.5 mg / kg, about 0.2 mg / kg to about 15 mg / kg, about 0.2 mg / kg to about 5 mg / kg, about 0.25 mg / kg to about 1 mg / kg, about 0.25 mg / kg to about 0.75 mg / kg, about 0.25 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 0.5 mg / kg to about 10 mg / kg, or about 0.5 mg / kg to about 5 mg / kg. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising the 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. In some embodiments, a compound described herein is administered to a subject at a dose of about 0.5 mg / kg / day. In some embodiments, a compound described herein is administered to a subject at a dose of about 0.6 mg / kg / day. In some embodiments, a compound described herein is administered to a subject at a dose of about 0.7 mg / kg / day.In some embodiments, the compound described herein is administered to the subject at a dose of about 0.8 mg / kg / day. In some embodiments, the compound described herein is administered to the subject at a dose of about 0.9 mg / kg / day. In some embodiments, the compound described herein is administered to the subject at a dose of about 1 mg / kg / day. In some embodiments, the compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1), or a pharma- ceutically acceptable salt thereof, is administered to the subject once a day. In some embodiments, the compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1), or a pharma-ceutically acceptable salt thereof, is administered orally to the subject.

[0129] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, is administered in an amount ranging from about 1 mg to about 180 mg or from about 2.5 mg to about 150 mg, e.g., about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 40 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, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a 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, or about 10 mg to about 120 mg). In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, is administered to a subject once daily. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1), or a pharma- ceutically acceptable salt thereof, is orally administered to a subject.

[0130] In some embodiments, a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising the same, is administered to a subject as a single dose in an amount of up to 150 mg, e.g., about 30 mg to about 120 mg, e.g., about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 mg. In some embodiments, a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or compound 1) or a pharma- ceutically acceptable salt thereof, or a 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, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1), or a pharma- ceutically acceptable salt thereof, is administered to a subject once daily.

[0131] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, is administered to a subject in multiple doses of about 30 mg to about 150 mg, e.g., a maximum dose of about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 mg. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, is administered to a subject as multiple doses, with a maximum dose amount of about 90 mg or about 120 mg.

[0132] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, is orally administered to a subject. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, is administered daily to a subject. In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is administered daily to a subject for at least 14 days. In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is administered to a subject in escalating doses from a starting dose of about 20 mg to about 100 mg, e.g., 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, or about 100 mg.

[0133] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, is administered to a subject in a fasted state, more than about 10 hours after the last meal and / or at least about 4 hours before the next meal. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising 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.

[0134] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, has a maximum plasma concentration (t max The subject is orally administered an amount effective to achieve the desired therapeutic effect.

[0135] In some embodiments, administration of a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1), or a pharma- ceutically acceptable salt thereof, does not significantly affect the pharmacokinetic parameters of a co-administered agent or therapy contemplated herein. In some embodiments, co-administration with an agent or therapy contemplated herein does not significantly affect the pharmacokinetic parameters of a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1). Pharmacokinetic parameters include, for example, area under administration (AUC) to infinity (AUC inf ), time to final quantifiable concentration (AUC last ), 24 hours (AUC 0~24 ), maximum observed plasma concentration (C max ), the time of maximum observed plasma concentration (t max ), and the apparent terminal plasma elimination half-life (t 1 / 2 ) are included in the area under the plasma concentration-time curve.

[0136] In some embodiments, administration of a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) or a pharma- ceutically acceptable salt thereof, or a composition comprising same, does not result in frequent or severe adverse events. An "adverse event" or "AE" is any untoward medical occurrence in a subject that is temporally associated with the use of a therapy (such as, for example, any of the compounds described herein), whether or not considered related to said therapy. Thus, an AE can be any untoward and unintended sign (including clinical laboratory abnormalities), symptom, or disease (new or worsening) that is temporally associated with the use of a therapy, whether or not considered related to said therapy.

[0137] Combination therapy The compounds or compositions described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) may be administered in combination with another agent or therapy. The subject to whom the compounds disclosed herein are to be administered may have a disease, disorder, or condition, or symptoms thereof, that would benefit from treatment with another agent or therapy. These diseases or conditions may be associated with epilepsy or epilepsy syndromes.

[0138] In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) is administered in combination with an antiepileptic agent. Antiepileptic drugs include, but are 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, a compound or composition described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) is administered in combination with carbamazepine.

[0139] In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) is administered in combination with any one of caffeine, dextramethorphan, midazolam, ciprofloxacin, itraconazole, and oxcarbazepine.

[0140] In some embodiments, the methods of the disclosure include administering to a subject in need thereof a compound or composition described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) in combination with an antiepileptic agent. In some embodiments, the methods of the disclosure include administering to a subject in need thereof a compound or composition described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) in combination with carbamazepine.

[0141] Accordingly, one aspect of the disclosure provides compositions comprising any of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and at least one additional therapeutic agent. In some embodiments, the compositions comprise any of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and at least two additional therapeutic agents. In some embodiments, the composition is any of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and at least three additional therapeutic agents, any of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and at least four additional therapeutic agents, or any of the compounds described herein (a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and at least five therapeutic agents.

[0142] Methods of combination therapy include co-administration of a single formulation containing any of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and an additional therapeutic agent or drug, administration of any of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and an additional therapeutic agent or drug, and administration of a single formulation containing .... The present invention includes sequential administration of any of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and the additional therapeutic agent or drug in any order, preferably during which there is a period of time during which any of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1) and the additional therapeutic agent or drug exert their therapeutic effect simultaneously.

[0143] 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 novel gain- or loss-of-function mutations in major central nervous system sodium channel genes, such as, e.g., SCN1A, SCN2A, and SCN8A.

[0144] Thus, the present disclosure provides pharmaceutical compositions comprising, as an active ingredient, a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1), or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0145] The pharmaceutical compositions may be administered in single or multiple doses by any of the accepted modes of administration of drugs, including, for example, rectal, oral, intranasal, and transdermal routes, intraarterial injection, 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.

[0146] One mode of administration is parenterally, particularly by injection. Forms in which the composition 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 microbial action can be provided by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0147] 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, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients in a sterile vehicle that contains 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.

[0148] 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 in 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.

[0149] 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 formulations can further 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.

[0150] The compositions of the present disclosure can be formulated to provide immediate, sustained, or delayed release of active ingredients after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems that contain polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the method of the present invention employs a transdermal delivery device ("patch"). 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 pharmaceuticals is well known in the art. See, for example, U.S. Patent 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.

[0151] 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 pharmacologic 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 contains 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.

[0152] To prepare solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition, such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0153] The tablet or pill of the present invention 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 covering 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 delayed released.Such enteric layer or coating may use a variety of materials, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0154] 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 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.

[0155] In one aspect, provided herein is 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 a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or a dosage form or composition comprising Compound 1, and a pharma- ceutically acceptable excipient.

[0156] In some embodiments, the dosage form or composition of 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 60 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 about 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 a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1. In some embodiments, the dosage form or composition in the dosage form is for oral administration.

[0157] 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 a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1.

[0158] In some embodiments, the dosage form or the composition in 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 a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1.

[0159] In another aspect, the disclosure provides a dosage form or composition in a dosage form comprising: a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or a plurality of particles of Compound 1, and a pharma- ceutically acceptable excipient, wherein the amount of the compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or the plurality of particles of Compound 1 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).

[0160] In some embodiments, the amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or a plurality of particles of Compound 1 in a dosage form or composition is 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).

[0161] 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).

[0162] 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., PEG 400)), 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)).

[0163] In some embodiments, the concentration of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1 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 about 8 mg / mL, about 1 mg / mL to about 8 mg / mL, 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).

[0164] In some embodiments, the concentration of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1 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.

[0165] In some embodiments, the dosage form is a suspension.In some embodiments, the concentration of the compound of formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or compound 1 in the suspension is about 0.1mg / mL, about 0.5mg / mL, about 1mg / mL, about 1.5mg / mL, about 2mg / mL, about 2.5mg / mL, about 3mg / mL, about 3.5mg / mL, about 4mg / mL, about 4.5mg / mL, about 5mg / mL, about 6mg / mL, about 7mg / mL, about 8mg / mL, about 9mg / mL, about 10mg / mL, about 11mg / mL, about 12mg / mL, about 13mg / mL, about 14mg / mL, about 15mg / mL, about 20mg / mL, about 25mg / mL.

[0166] In some embodiments, the concentration of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV), or Compound 1 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 about 8 mg / mL, about 1 mg / mL to about 8 mg / mL, 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

[0167] 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.

[0168] 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.

[0169] 1. Materials and Methods i. Preparation of brain slices Mice (p17-p21) were anesthetized with 2% isoflurane, the brains removed, and placed in an iced slurry of incubation 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 at pH 7.4, maintained 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 incubation solution at room temperature for a minimum of 1 h before patching.

[0170] ii. Current-clamp electrophysiological recordings Brain slices were transferred to an immersion 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 at pH 7.4 maintained by continuous bubbling with carbogen gas (95% O2–5% CO2).

[0171] CA1 pyramidal neurons were visually identified in the pyramidal layer of the CA1 region of the hippocampus using an infrared oblique illumination microscope with a 40× water-immersion objective (Olympus) using a camera (Dage IR-2000, Dage). Cell identity was also confirmed using action potential firing characteristics, where action potentials 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 a sampling rate of 50 kHz and low-pass Bessel filtered at 10 kHz (Duidata 1550b; Axon) using pClamp software (v10; MDS). Patch pipettes (3–7 MΩ; GC150F-7.5; Harvard Instruments) were pulled using a Flaming / Blown micropipette puller (model P-1000; Sutter) and 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 phosphocreatine, 0.1 mM EGTA, and 0.2% biotin at pH 7.2 (adjusted with KOH) and a measured osmolality of 292 mOsm.

[0172] iii. Intrinsic excitability assay (evoked action potentials) Tests were performed using whole-cell current clamp recording mode. The experimental timeline is shown in Figure 1A. Once the whole-cell configuration was obtained for 2 min, a holding current was injected to maintain the membrane potential at approximately -70 mV. Current steps (injection currents from -60 to 340 pA in 20 pA steps, 400 ms duration (Figure 1B)) 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 sweep interval was 5 s (0.2 Hz). To be included in the study, cells were required to have an access resistance less than 20 MΩ and a holding current 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 slice for 5 min, after which the action potential generation protocol was repeated (Figure 1B).

[0173] iv. Data analysis for generation of input frequency relationships Data were analyzed using Axograph X software. Individual action potentials were identified and counted using a +50 mV amplitude threshold against the pre-event baseline. The frequency of action potentials generated was plotted against each of the current injections to generate an input-frequency relationship for each cell. The mean frequency of action potentials evoked against each of the current injections was calculated and reported in Tables 1 and 4. Action potential amplitude was determined against the pre-event baseline at the +200 pA current injection step for each cell. The mean action potential amplitude of each evoked action potential was calculated and reported in Tables 3 and 6. Cells with fewer than three action potential counts contributing to the mean amplitude were excluded from the analysis. For statistical comparison between groups, the total number of action potentials fired per cell was calculated. Mean values ​​are reported in Tables 2 and 5. 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, significance of the analyses was set at an alpha level of 0.05.

[0174] 2.Results In slices from wild-type mice, both 0.3 and 3 µM Compound 1 significantly reduced the number of action potentials generated compared to baseline (Figure 1A-1B). The reduction in CA1 pyramidal neuron intrinsic excitability by Compound 1 was concentration-dependent, as measured using evoked action potential firing (Figure 1B).

[0175] 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 V The aim of the study was to determine the effect of Compound 1 on tonic block (TB) of 1.6 late (sustained) and peak currents, as well as peak current use-dependent block (UDB). 1. Materials and Methods i. Preparation of cells

[0176] Human Na V 1.6 (NP_055006), mouse Na V 1.6 (NP_035453.2), or rat Na V HEK-293 cell lines stably expressing either NP_062139 or NP_062140 were used. All cells were grown at 2 × 10 per Nunc T75 flask for 2 days in culture. 6 At the time of harvest for the assay, the cell number was approximately 6 × 10 6The cells were washed (1x) in DPBS (Hyclone, Cat# SH30028.03) for approximately 30 seconds. 1mL of 1X0.05% Trypsin-EDTA (GIBCO Cat# 25300-054) was added, swirled around 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 Medium 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 resuspended in ±30ml of pre-warmed media at 2x10 5 The cells were then dispensed into 250 mL centrifuge tubes at a concentration of 1 × 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 × 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).

[0177] 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 a final assay concentration of 300x. 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.

[0178] iii. PatchXpress® (Molecular Devices) Recording Solution The same intracellular recording solution was used for sustained and peak I Na The assay contained 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 (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, with a pH of 7.4 (adjusted with NaOH) and a measured osmolality of 300 mOsm (adjusted with mannitol).

[0179] 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). Cell acceptance criteria were continuously monitored by custom scripts during recording. The acceptance criteria for all assays was a baseline peak I Na >800pA, R seal >200 MΩ and, if appropriate, sustained 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 the script.

[0180] Late (sustained) current block: Inhibition of ATX-II-activated late 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 the channels in the closed (resting) state. Pharmacology was measured by increasing the mean I to 0 mV during the last 20 ms of the step. Na and no leak subtraction was used.

[0181] 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 monitored by measuring the peak I in response to a step to 0 mV. Na The measurements were taken during the experiment. No leak subtraction was used.

[0182] Use a 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 by measuring the peak I in response to a step to 0mV. Na The measurements were taken during the experiment. No leak subtraction was used.

[0183] Voltage-dependent block (VDB): The VDB protocol used depolarizing voltages to maintain channels in a semi-inactivated (resting) state. This allowed for precise determination of equilibrium binding and isoform selectivity (in the absence of biological signatures). For each cell, the midpoint of inactivation (V 0.5) was determined using 5,000 ms steps of increasing voltage (10 mV increments) to inactivate the channels, followed by a 2 ms step to 0 mV to maximize the channel holding potential (V hold ) was −120 mV between steps. Peak I measured in response to a step to 0 mV Na Plot and fit to the Boltzmann equation to obtain V 0.5 This value was then used in the VDB protocol. Pharmacology was performed by measuring the peak I in response to a step to 0 mV. Na The measurements were taken during the experiment. No leak subtraction was used.

[0184] Plotting and fitting was performed using GraphPad Prism (GraphPad Software). Percentage of inhibition was calculated, expressed as mean ± SEM, and plotted against the concentrations tested. Data were expressed using 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 hillock gradient was estimated. The maximal effect was varied for the use-dependent block (UDB) assay but was fixed at 100 for all other assays.

[0185] 2.Results Compound 1 stimulated hNa at 10 Hz stimulation frequency (UDB). V Compound 1 produced a concentration-dependent inhibition of hNa+ from resting state (TB) of 1.6. V Block of the 1.6 channel was also concentration-dependent, although the extent of block was less than that observed in either the state- or use-dependent assays (Figure 2A). Compound 1 inhibited peak I channels 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 sustained I Na(Figure 2B (LTG) and Figure 2C (CBZ)).

[0186] 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 antiseizure 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 effects of compound 1 (0.3, 1, 3, and CD-10 mg / kg administered orally (p.o.)) to attenuate MES-induced seizures in male CD-1 mice.

[0187] 1. Materials and Methods i.Animals Six-week-old male CD-1 mice were obtained from Vital River (Beijing, China). The average body weight was approximately 35 g at the time the experiments were performed. Mice were housed in groups of 3–5 under controlled conditions (temperature: 20–26 °C, humidity: 40–70%, air exchange 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 behavioral testing.

[0188] 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.

[0189] iii. Clinical trial protocol The MES test was performed over two days, with 6 of 12 mice from each treatment group tested each day. Mice were brought into the testing room at least 1 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.

[0190] Animals were administered Compound 1 or 35% HPBCD (Vehicle 2) or VPA or saline (Vehicle 1) intraperitoneally (IP) 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.

[0191] 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 subjects then received bilateral transauricular stimulation via ear-lip electrodes. Mice were manually restrained during stimulation. They were 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.

[0192] Sedation assessment endpoints were: (1) none: mice exhibit normal locomotor behavior; (2) mild: mice exhibit less locomotion or immobility in their home cage alone, but normal locomotor activity when evoked by touching the observer's hand; (3) moderate: mice exhibit immobility in their home cage alone and reduced locomotor activity when pushed or evoked by touching the observer's hand; and (4) severe: mice completely lose the ability to move.

[0193] Antiseizure 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.

[0194] 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 on wet ice until centrifuged at 2,000 g for 5 min 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.

[0195] 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 vortex mixed in a vortex mixing well (at least 15 s) and centrifuged at 12000 g, 4 °C for 15 min. 70 μL of the supernatant was transferred to a 96-well plate and centrifuged at 3220 g, 4 °C for 5 min. 5 μL of the supernatant was then injected for LC-MS / MS analysis.

[0196] v. Preparation of brain samples Brain homogenates were prepared by homogenizing brain tissue in 5 volumes (w:v) of homogenization solution (chilled 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 vortex mixed in a vortex mixing well (at least 15 s) and centrifuged at 12000g, 4 °C for 15 min. 70 μL of the supernatant was transferred to a 96-well plate and centrifuged at 3220g, 4 °C for 5 min. 5 μL of the supernatant was then injected for LC-MS / MS analysis.

[0197] vi.Statistical analysis All statistical analyses were performed using GraphPad Prism 7.0. Data are expressed as mean ± sem. p<0.05 was considered statistically significant. Mann-Whitney test was used to detect significant differences in latency and number of seizures between saline and VPA groups. Kruskal-Wallis followed by Dunn's test was used to detect significant differences in latency and number of seizures between 35% HPBCD and Compound 1.

[0198] 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.

[0199] 2.Results As shown in Figure 3, at 3 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 10 mg / kg (oral dose). Compound 1 exceeded the calculated ED of 2 mg / kg. 50 These data suggest that compound 1 has anti-seizure properties in the MES-induced seizure model.

[0200] 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 (10, 20, and 40 mg / kg, orally administered) on spontaneous locomotor activity (sLMA) in male CD-1 mice 30 min after administration.

[0201] 1. Materials and Methods i.Animals Six-week-old male CD-1 mice were obtained from Vital River (Beijing, China). The average body weight was 25-35 g at the time the experiments were performed. Mice were housed in groups of 3-5 under controlled conditions (temperature: 20-26 °C, humidity: 40-70%, air exchange rate: 10-15 cycles / h, 12:12 light-dark cycle with lights on at 5:00 am). Food and water were available ad libitum. Mice were acclimated to these conditions for 6 days before the start of the study.

[0202] ii. Drug Formulations Dosing solutions were prepared on each experimental day. A stock solution of the highest dose of Compound 1 was prepared in 35% HPBCD (vehicle) and diluted to make lower doses. The stock was vortexed and sonicated for at least 20 minutes to obtain a homogenous suspension. All solutions were protected from light. Samples from the dosing solutions were stored at 4° C. Both compound and vehicle were administered at 10 ml / kg.

[0203] iii. Clinical trial protocol The sLMA test was carried out over two days. Five of 10 mice from each treatment group were tested 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.

[0204] Compound 1 or 35% HPBCD (vehicle) was administered orally (po) to animals 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.

[0205] Sedation assessment endpoints were: (1) none: mice exhibit normal locomotor behavior; (2) mild: mice exhibit less locomotion or immobility in their home cage alone, but normal locomotor activity when touched by the observer; (3) moderate: mice exhibit immobility in their home cage alone and reduced locomotor activity when pushed or touched by the observer; and (4) severe: mice completely lose mobility.

[0206] Thirty minutes after administration of Compound 1 or vehicle, mice were placed in the center of the test chamber (40×40×30 cm, 45±5 Lux on the 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).

[0207] A locomotor state was defined as a movement >2 mm every 200 ms (recorded frame rate was 20 frames / s. A locomotor state was identified every 4-frame interval. A cumulative shift of the tracking spot >2 mm every 4-frame interval was identified as a locomotor epoch). Distance traveled was automatically calculated and analyzed from all locomotion 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.

[0208] All mice were anesthetized with CO2. Final plasma and brain tissue samples were then taken 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 on wet ice until centrifugation at 2000g for 5 min 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.

[0209] 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 mixture was poured into a vortex-mixed well for at least 15 seconds and centrifuged at 12000 g, 4 °C for 15 min. 65 μL of the supernatant was transferred to a 96-well plate and centrifuged at 3220 g, 4 °C for 5 min. Then, 3 μL of the supernatant was directly injected for LC-MS / MS analysis.

[0210] 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 vortex mixed in a vortex mixing well for at least 15 seconds and centrifuged at 12000 g, 4 °C for 15 min. 65 μL of the supernatant was transferred to a 96-well plate and centrifuged at 3220 g, 4 °C for 5 min. 3 μL of the supernatant was then directly injected for LC-MS / MS analysis.

[0211] 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 5-min bin between vehicle- and compound 1-treated groups. ANOVA followed by Dunnett's test was used to detect significant differences in total distance traveled over 30 min between vehicle- and compound 1-treated groups.

[0212] 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, the TD 50 Value and TC 50 values ​​were calculated.

[0213] 2.Results As shown in Figure 4, Compound 1 at doses of 20 and 40 mg / kg significantly reduced the total distance traveled in the 30-min sLMA test. Compound 1 significantly reduced the calculated TD of 44 mg / kg. 50 These data suggest that Compound 1 at doses of 20 mg / kg and 40 mg / kg reduces locomotor activity.

[0214] Example 5. Scn2a increases persistent sodium current Q54 Effect of Compound 1 on seizure frequency in mouse models The purpose of this study was to determine whether increased I Na The aim of this study was to evaluate the potential anticonvulsant properties of compound 1 (0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg, administered orally) in genetic models of mouse strains. V 1.2 and Na V A persistent sodium current (I Na Gain-of-function mutations in SCN2A and SCN8A, which increase Scn2a and SCN8A, respectively, have been identified in children with various forms of epileptic encephalopathy (EE). Q54 The mouse line was engineered to be I by introducing three consecutive point mutations (G879Q, A880Q, and L881Q) into the full-length SCN2A gene. Na The mutant gene is involved in the regulation of the CNS sodium channel Na V 1.2 Large Pathological Neuronal Persistence I Na(Kearney et al., A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities, Neuroscience, 2001, 102(2):307-317; PMID 11166117). As in EE patients, Scn2a Q54 Mice exhibit early-life seizures, status epilepticus, and early mortality.

[0215] 1. Materials and Methods i.Animals Scn2a Q54 Transgenic mice were generated as described and maintained as a congenic strain on a C57BL / 6J (Jax #000664) background (B6.Q54) (Kearney et al., 2001; PMID 11166117). For experiments, F1 generation mice were generated by mating B6.Q54 hemizygous transgenic males with SJL / J (Jax #000686) females to express Scn2a Q54 The experimental animals used in this study were male and female mice aged between postnatal days 18 and 21 (P18-21), with the majority being P19-P20.

[0216] Mice were group-housed in a specific pathogen-free mouse facility under standard laboratory conditions (14 / 10 h light / dark cycle). Mice had free access to food and water, except during the experimental period for seizure monitoring. All manipulations were performed during the animal's light cycle.

[0217] ii. Compound Formulation and Administration Dosing solutions were freshly formulated on the morning of the study. Dosing solutions containing 0.5% methylcellulose with 0.2% Tween-80 were made with 1 mL of 10% Tween-80 (ddH20) and 49 mL of 0.5% methylcellulose (ddH20) with or without (vehicle) Compound 1 (0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg). Each animal received a single dose of vehicle or Compound 1 by oral gavage.

[0218] iii. Study design For seizure monitoring, two mice were placed in a monitoring cage (23 cm × 13 cm) equipped with two side-view cameras to record baseline spontaneous seizure activity. Q54 Previous extensive video-electroencephalography (EEG) monitoring of transgenic mice showed a strong correlation between behavioral and EEG seizures (κ=0.988) (Anderson et al., Antiepileptic activity of preferential inhibitors of persistent sodium current, Epilepsia, 2014, 55(8):1274-1283 (PMID: 24862204); Kearney et al., 2001). After 30 min of recording, mice were administered Compound 1 or vehicle and returned to their home cages. After 30 min, two mice were returned to the monitoring cage and recorded for an additional 30 min to assess post-treatment seizure activity. The number of focal motor seizures with forelimb clonus and repetitive movements lasting 1–5 s, as well as generalized tonic-clonic seizures (GTCS) with rearing and falling lasting approximately 1 min, were counted. Seizures were scored offline by an observer blinded to treatment and pre- and post-status on the video files.

[0219] iv. Computational and statistical analysis The number of pre- and post-treatment seizures was counted for each animal by a reviewer blinded to the treatment and condition before and after video recording. Mice with less than 3 seizures or more than 35 seizures during the baseline period were excluded from the analysis, as predefined in the study design. Statistical analysis was performed using two-way repeated measures ANOVA and Sidak's multiple comparisons, and p<0.05 was considered statistically significant (GraphPad Prism 8.4). The change in mean seizure frequency was determined by averaging each group and then calculating the relative change as [(mean post-mean pre) / mean. pre], expressed as a percentage.

[0220] v. Plasma and brain collection At the end of the seizure observation period, the animals were sacrificed and blood was collected and transferred to heparin blood collection tubes. The blood collection tubes were centrifuged at 5,000 g for 10 minutes, and the plasma was removed into 1.5 mL Eppendorf tubes on dry ice. After blood collection, the brains were removed, frozen on dry ice, and stored separately in 1.5 mL Eppendorf tubes. Rodent plasma and brain tissue were stored at -80°C until shipped on dry ice for bioanalysis.

[0221] 2.Results Seizure frequency was measured using Scn2a 30 min before and then again 30 min after treatment with Compound 1 or vehicle. Q54 Measured in mice. Scn2a with Compound 1 at 1, 3, and 10 mg / kg Q54 Treatment of the mice resulted in a significant reduction in seizure frequency compared to pre-treatment baseline (Figure 5). At doses of 1 mg / kg and above, there was a 50% reduction in seizure frequency, with no seizures observed after administration of 10 mg / kg. Overall, compound 1 inhibited Scn2a Q54 These data indicate that Compound 1 has a significant anti-seizure effect in mice with long-lasting I Na These compounds have demonstrated anticonvulsant activity in models of elevated sodium current, suggesting that they may have potential for the treatment of epilepsy, particularly in syndromes with persistent elevated sodium current as a genetic etiology.

[0222] Example 6. Scn8a N1768 D / + Effect of Compound 1 on audiogenic-induced seizures in a transgenic mouse model The purpose of this study was to evaluate the effect of compound 1 on audiogenic seizures in N1768D gain-of-function SCN8A epileptic encephalopathy model mice (D / +). N1768 D / + The transgenic mice were V Carries a gain-of-function mutation in l.6 (Wagnon et al., Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy, Human Molecular Genetics, 2015, 24(2):506-515).

[0223] Both male and female N1768D (D / +) mice aged 8-12 weeks were used in the study. Compound 1 was administered orally (p.o.) in three doses (1 mg / kg, 3 mg / kg, 10 mg / kg), and also vehicle, 1 hour prior to testing. Upon completion of testing, mice were randomized such that each individual mouse was evaluated at each test dose of Compound 1 and vehicle. A minimum of 3 days was allowed to elapse before mice were retested. At the time of testing, mice were removed from their home cages and transferred to clean test cages located in a separate testing room and allowed to acclimate for approximately 20 seconds before the onset of acoustic stimulation. To induce auditory seizures, a 15 kHz signal amplified using a Kinter K3118 stereo amplifier (Kinter USA, NCH Software, Inc.) was generated and converted to sound using a small 3 watt speaker lowered into the testing chamber. Stimuli were applied for 30 seconds unless a seizure was detected at the 30 second time point, in which case auditory stimulation was terminated. Video of the event was recorded using a laptop webcam. On the final day of testing, brain and plasma were collected from D / + mice immediately after auditory seizure testing to determine the concentration of Compound 1. A separate cohort of eight age-matched WT mice was also included (n=2 / dose level) to achieve a sample size of n=4 for the PK of each dose level. Brain and plasma samples were submitted for bioanalytical analysis.

[0224] As shown in Figure 6, oral administration of Compound 1 produced a dose-dependent inhibition of auditory seizures in D / + mice. Compound 1 at 10 mg / kg (oral) produced complete protection from audiogenic seizures.

[0225] Overall, compound 1 was shown to dose-dependently inhibit audiogenic seizures in a human knock-in mouse model of SCN8A epileptic encephalopathy (EIEE13). These studies demonstrate the efficacy of compound 1 in inhibiting seizures associated with gain-of-function SCN8A mutations.

[0226] Example 7. Effect of Compound 1 on time to pentylenetetrazol-induced seizures A common chemically induced seizure model, generalized seizures, can be produced using pentylenetetrazole (PTZ), a GABA receptor antagonist. PTZ experiments were performed on heterozygous Kcnq2 K556E, Kcnc1 R320H, or Hcn1 M294L mice, or their wild-type (WT) littermates (P35–P45, both males and females).

[0227] Mice were allowed to acclimate to the experimental area for at least 30 min before the experiment. All experiments were performed between 10:00 AM and 12:30 PM. Treatment compounds and PTZ were always freshly prepared.

[0228] Mice were randomly assigned to receive either different doses of Compound 1 (10 mg / kg, 1 mg / kg, or 0.1 mg / kg) or a vehicle control containing 0.5% methylcellulose and 0.2% tween 80, administered via oral gavage (po). Compound 1 and vehicle control were administered 60 min prior to injection of PTZ.

[0229] In Kcnq2 K556E mice, retigabine (4 mg / kg) was also used as a positive control. Retigabine was dissolved in 10% DMSO and 10% solutol and administered by the intraperitoneal (ip) route 30 min before injection of PTZ.

[0230] PTZ (100 mg / kg) was dissolved in saline and administered subcutaneously (sc) to experimental mice. The latency to a complete tonic-clonic seizure with hindlimb extension was measured. Animals were sacrificed either 40 min after PTZ administration upon hindlimb extension or if no hindlimb extension was recorded.

[0231] Data were analyzed using the Mantel-Cox log-rank test. Brain tissue and plasma were collected from some mice for each dose of Compound 1 at the PTZ endpoint for PK analysis.

[0232] 7A-7B show that at a dose of 10 mg / kg, compound 1 is highly effective in KCNQ2 (Figure 7A) and KCNQ1 (Figure 7B) seizure models.

[0233] Example 8. 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 ), intrinsic neuronal excitability, and protection from induced seizures were examined by transduction of two standard voltage-gated sodium channels (Na V ) blockers, such as compound 1, show preferential long-lasting I Na It was determined whether inhibitors would demonstrate improved preclinical efficacy and tolerability.

[0234] 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.

[0235] 1. Compound 1 is a long-acting Na Strongly inhibits Compound 1 is a wild-type hNa V 1.6 potently inhibited ATX-II-induced sustained Na+ expression (Figure 8A, IC 50 =141nmol / L), and DEE mutant hNa V Persistence I expressed by V1.6-N1768D Na (Fig. 8B, IC 50 = 75 nmol / L). By maintaining the hyperpolarized holding potential (-120 mV), sustained I Na Activated the NMDG channel from its resting / closed structure. + ) completely inhibited sodium-dependent conductance. The potency of Compound 1 against ATX-II or N1768D was comparable to that of standard NaV Compound 1 was at least 550-fold more potent than other targeted AEDs (Figure 8C, Table 1). V Isoforms (hNaV1.1 (NP_008851.3), hNa V 1.2(NP_066287.2), hNa V 1.5 (NP_000326.2)) and its rat, dog, and mouse orthologues (rNa V 1.2(NP_036779.1), dNa V 1.2(XP_013966299.1), mNa V 1.6 (NP_035453.2), and rNa V Persistent I expressed by 1.6 (NP_062139) Na showed similar potency in inhibiting 50 Values ​​ranged from 109 to 180 nmol / L (Figure 8D).

[0236] 2. Compound 1 is in peak I Na More sustainable than I Na show enhanced preference for inhibition hNa V 1.6 Using three assays with increasing levels of activation, peak I Na Inhibition of physiological peak I was investigated. Na Tonic block is measured at low stimulation frequency (0.1 Hz) from a resting / closed channel structure (Figure 9A). Compound 1 exhibits a tonic block with low efficacy (IC 50 =8470nmol / L), persistent I Na Compound 1 also showed a 60-fold preference for hNa V 1.1 (173 times, 109 nmol / L vs. 18 870 nmol / L), hNa V 1.2 (80-fold, 172 nmol / L vs. 13 690 nmol / L), and hNa V 1.5 (>174-fold, 12% inhibition at 172 nmol / L vs. 30 000 nmol / L) compared with other human Na V Peak I for Soform Na Persistent I for Tonic Block Nashowed a preference for

[0237] hNa by Compound 1 V 1.6 Use-dependent block was measured using a train of short voltage steps at a frequency of 10 Hz, resulting in peak I Na These data represent periods of elevated neuronal firing (e.g., during seizures) where use-dependent blockade of may have therapeutic benefit. Compound 1 exerted an IC 50 and 75% maximum inhibition, hNa V 1.6 Peak I Na (blue trace, Figure 9B, Table 1). Notably, use-dependent block was not observed with either CBZ or LTG at a stimulation frequency of 10 Hz (blue trace, Figure 9E and Figure 9F, respectively). By increasing the frequency of depolarization from 10 Hz to either 30 Hz or 50 Hz, use-dependent block was observed for CBZ. The degree of use-dependent block observed for Compound 1 was significantly greater compared to CBZ at all frequencies, suggesting an increased ability of Compound 1 to respond to acute changes in neuronal activity (acute hyperexcitability).

[0238] Peak I Na Voltage-dependent block assays use a voltage-dependent block assay to place half of the channels in an inactivated state at the midpoint of steady-state inactivation (V 1 / 2 ) are employed, which are determined in real time for each cell. This approach effectively explores isoform selectivity, as differences in voltage sensing that regulate access to binding sites are minimized and the extended time allows most inhibitors to reach binding equilibrium. Compound 1 exhibits a voltage-dependent block IC of 317 nmol / L. 50 These data indicate that as the channel is inactivated, a sustained I Na Compound 1 retains a 2.2-fold preference for hNa (red arrow, FIG. 9D; Table 1). V 1.1 (6.3 times), hNa V 1.2 (8.2 times), and hNa V1.5 (5.8x), Peak I Na Tonic rather than voltage-dependent block I Na Compound 1 also showed a similar preference for V 1 / 2 As evidenced by the significant left shift in V 1.6 induced a concentration-dependent stabilization of inactivation: a shift of -2.6 mV for dimethyl sulfoxide (DMSO) / control, -6.2 mV for 0.3 μmol / L compound 1, and -11.7 mV for 1 μmol / L compound 1. The V of the activation curve 1 / 2 Only small shifts in activation were observed: −1.3 mV for DMSO / control, −2.3 mV for 0.3 μmol / L compound 1, and −2.7 mV for 1 μmol / L compound 1. These data suggest that compound 1 enhances rapid inactivation with minimal effects on activation gating.

[0239] Standard Na V A panel of targeted AEDs was Na Assay and Peak I Na Compared to compound 1, all tested inhibitors were less potent in all assays (Table 1). Na Moderate persistence observed for inhibitors I Na Preference was lost as the channel was shifted to a more activated / inactivated state, as in the voltage-dependent block assay (0.3-fold–0.9-fold preference). Notably, both CBZ and LTG inhibited the sustained I Na Compared with the voltage-dependent block peak I Na (0.6-fold and 0.5-fold, respectively) and peak I Na showed a preference for [Table 1]

[0240] 3. Compound 1 reduces the intrinsic excitability of wild-type CA1 pyramidal neurons Durability I Na The preferential inhibition of Na Because compound 1 and CBZ are dependent on the expression of β-catenin, they are predicted to reduce neuronal hyperexcitability without excessive disruption of AP morphology, including AP amplitude. The effects of compound 1 and CBZ on neuronal intrinsic excitability were measured using the equivalent effective concentrations of peak I Na Voltage Dependent Block IC 50 At 0.3 μmol / L, Compound 1 significantly reduced intrinsic excitability, as measured by the number of APs evoked (Figure 10A). In contrast, CBZ at 45 μmol / L produced a more robust reduction in neuronal excitability (Figure 10D). CBZ caused a more pronounced reduction in AP amplitude compared to Compound 1, with a peak I Na These data suggest that although both drugs produced a decrease in excitability in wild-type CA1 neurons, Compound 1 suppressed a greater proportion of peak I Na These results indicate that by leaving β-lactamase intact, it reduces excitability in a manner that is likely to maintain physiological activity over a wider range of concentrations than CBZ.

[0241] 4. Compound 1 achieves full anticonvulsant efficacy without affecting locomotor activity Persistence I with in vitro profile of compound 1 Na To assess whether the inhibitors can prevent seizures, anticonvulsant activity was investigated in the mouse MES model, which has predictive validity for clinical anticonvulsant activity. Compound 1 was administered in a standard NaCl solution. V Compound 1 produced a dose-dependent protection (increased latency) of mice against MES-induced tonic right limb seizures (FIG. 11A). Near complete protection was achieved at 10 mg / kg, with 11 of 12 mice showing no tonic seizures (FIG. 11B). This effect was comparable to that observed with the positive control, VPA. ED1 to increase the latency to tonic extension seizures 50The calculated value is 2 mg / kg, and the calculated EC 50 Values ​​were 90.1 ng / ml (17.9 nmol / L free) and 116 ng / g (4.3 nmol / L free) in plasma and brain, respectively (Table 2). [Table 2]

[0242] CBZ and LTG also provided dose-dependent protection in mice against MES-induced tonic limb seizures, with CBZ (30 mg / kg) protecting 8 of 12 mice at the highest dose tested (10 mg / kg). EDs for increased latency to tonic extension seizures 50 The calculated values ​​were 5 and 3.4 mg / kg for CBZ and LTG, respectively (Table 2).

[0243] To determine the tolerability of Compound 1, the effect on sLMA was measured. Compound 1 caused a decrease in the distance traveled at 20 and 40 mg / kg (FIG. 11C). The dose of Compound 1 (10 mg / kg) that caused seizure prevention in 11 of 12 mice did not affect motor function. 50 The dose of Compound 1 required to reduce the 50% effect (TC 50 ) were calculated to be 1553 ng / ml (308.9 nmol / L free) and 1899 ng / g (69.7 nmol / L free) in plasma and brain, respectively (Table 2).

[0244] CBZ and LTG also produced a dose-dependent reduction in sLMA and reduced ED 50 The values ​​were 37.6 and 26.5 mg / kg, respectively (Table 2). Notably, CBZ produced a significant reduction in sLMA at doses required for complete seizure prevention.

[0245] The efficacy-tolerability ratio (PI) is the brain or plasma EC50 value for increasing the latency to seizures. 50 by reducing sLMA in brain or plasma TC50 was calculated for each molecule by dividing (Figure 11D). Compound 1 had a significant improvement in PI of approximately 16-fold (based on calculated free brain concentration) and 17-fold (based on free plasma concentration), which was higher than CBZ (brain, 5.9x; plasma, 3.4x) and LTG (brain, 4.7x; plasma, 6.4x; Figure 11E).

[0246] 5. Combination of Compound 1 with standard of care sodium channel blockers results in greater efficacy in vivo and does not alter tolerability The effects of Compound 1 in combination with the standard of care sodium channel blocker CBZ were tested in the MES model and in the sLMA assay.

[0247] In the MES model, 2 mg / kg of compound 1 and 5 mg / kg of CBZ were tested alone or in combination in CD-1 mice. Compound 1 and CBZ were prepared individually in 35% HPBCD. Animals were administered 1) 35% HPBCD i.p. + 35% HPBCD po; 2) 35% HPBCD ip + compound 1 po, 3) CBZ ip + 35% HPBCD po; 4) CBZ ip + compound 1 po, 5) positive control group valproic acid (VPA) or saline i.p. 30 min before the MES test. All solutions were administered at 10 mL / kg. Possible side effects, such as overt sedation, were recorded immediately before the start of the MES test. As shown in Figure 12A, the combination of compound 1 and CBZCBZ was more effective in the MES model than compound 1 or CBZ alone. Exposure was consistent for all groups and at the intended levels.

[0248] In the sLMA assay, 10 mg / kg of Compound 1 and 30 mg / kg of CBZ were tested alone or in combination in CD-1 mice. Compound 1 and CBZ were prepared separately in 35% HPBCD. Animals were administered intraperitoneally 30 min prior to the sLMA test: 1) 35% HPBCD + 35% HPBCD po; 2) 35% HPBCD ip + Compound 1 po; 3) CBZ ip + 35% HPBCD po; 4) CBZ ip + Compound 1 po. All solutions were administered at 10 mL / kg. Possible side effects, such as overt sedation, were recorded immediately prior to the start of the sLMA test. As shown in Figure 12B, the combination of Compound 1 with CBZ does not compromise tolerability. Exposure was consistent for all groups and at the intended levels.

[0249] Example 9. Safety, tolerability, efficacy, and pharmacokinetics study of Compound 1 in patients with developmental and epileptic encephalopathies As shown in animal models, persistent sodium current (I Na Compound 1-mediated blockade of I-receptor agonists can provide anti-seizure efficacy at well-tolerated doses. Naを By specifically blocking the long-lasting I Na Compound 1 can provide greater efficacy in seizure reduction compared to the less selective standard of care (SOC) sodium channel blockers (SCBs). Compound 1 is less active at peak currents, making it better tolerated than SOCs and with fewer on-target 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.

[0250] Preclinical and emerging clinical data demonstrate that compound 1 has robust PK and is a potent inhibitor of pathologic Na+ VWe show that enhanced selectivity for channel hyperexcitability, a wide therapeutic window, and a convenient autotitration regimen all contribute to its excellent safety and efficacy in animal models, as well as anticipated therapeutic utility in human patients with epilepsy, including SCN2A, SCN8A, and other DEEs.

[0251] The objectives of this study are to evaluate the safety and tolerability of Compound 1, to evaluate the effect of Compound 1 on motor seizure frequency, and to characterize the pharmacokinetics (PK) of oral suspension Compound 1 in patients with developmental and epileptic encephalopathy (DEE).

[0252] This is an open-label, proof-of-concept study with three cohorts of DEE patients aged 2-17 years (SCN2A, SCN8A, and tuberous sclerosis complex (TSC)). There will be a 16-week treatment period consisting of an 8-week screening period followed by an 8-week dose optimization period and an 8-week maintenance period, with a 4-week safety follow-up period or rollover to LTE. The rationale for the 16-week treatment period is based on current knowledge of the pharmacokinetics of compound 1, which is predicted to take approximately 6 weeks to achieve 90% steady state. The 8-week dose optimization period allows for adjustments to the concurrent SCB, and the additional 8 weeks allow for evaluation of tolerability and efficacy signals during the maintenance period.

[0253] For efficacy endpoints, each cohort will be reviewed as an individual cohort in parallel with each other and analyzed separately. The primary objective is the safety and tolerability of Compound 1, with a key secondary objective being efficacy of Compound 1 as determined by mean monthly (28 days) motor seizure frequency compared to baseline during the maintenance period. The main elements of the study schedule are shown in Table 3. [Table 3]

[0254] Dosing was based on preclinical data (EC 50 and E.C. 90The dose optimization phase is guided by modeling from adult PK data (target concentration between 0.01 mg / kg / day and 0.1 mg / kg / day) and the duration of the dose optimization phase is projected relative to the adult PK data. During the dose optimization period, dose adjustments are as follows: The starting dose is 1 mg / kg / day of compound 1. If there is no improvement in seizure frequency (30% reduction) within the first 6 weeks and there are no tolerability issues, the dose may be increased to 1.5 mg / kg / day. If there are tolerability issues, the dose is returned to 1 mg / kg / day. During the dose optimization period, if there are tolerability issues with 1 mg / kg / day of compound 1, first, compound 1 is continued and the concurrent SCB is reduced by ≥ 25%, with evaluation after 1 week. If tolerability issues persist, compound 1 is continued and the concurrent SCB is further reduced by ≥ 25%, with evaluation after 1 week. If tolerability issues still persist, compound 1 is reduced to 0.5 mg / kg / day. If compound 1 is not tolerated at 0.5 mg / kg / day, the patient is withdrawn from the study.

[0255] Participants will be selected based on the following eligibility criteria: (1) with a documented diagnosis of SCN2A, SCN8A, or TSC, (2) male and female patients aged 2 years or older and 17 years or younger at the time of informed consent, and (3) on average, ≥8 motor seizures per month during the 3 months immediately preceding screening based on investigator assessment and a history of ≥8 motor seizures during the 1-month baseline period based on diary collection (motor seizures were classified as tonic, tonic-clonic, focal with secondary generalization, focal with motor symptoms, and myoclonus only or absent). (defined as epileptic seizures not including seizures), (4) agreement for enrollment by the Epilepsy Trials Consortium Eligibility Review Committee, (5) receiving a stable dose of antiseizure medication (ASM) for one month prior to screening, of which no more than two may be sodium channel blocking ASMs, and (6) agreeing to keep all antiseizure therapy (ASM, CBD / THC product, VNS setting, ketogenic or other dietary parameters, etc.) stable for the duration of the study unless otherwise directed by the investigator or as per the protocol. Benzodiazepines used with a daily frequency to treat seizures are considered ASMs. If CBD and / or THC products are used, the CBD and / or THC products must be at a stable dose for one month prior to screening. If VNS is used, the VNS must be in place at least 3 months prior to screening in a stable setting for at least one month prior to screening, and VNS will not be counted as an ASM. If patients are on a ketogenic or other diet for seizure control, they must start the diet at least 3 months prior to screening with stable parameters for at least 1 month prior to screening, and the diet will not be counted as ASM.

[0256] Exclusion criteria included: (1) having clinical evidence of loss-of-function mutations and / or previous exposure to sodium channel blockers that exacerbated seizures, (2) having two or more episodes of convulsive status epilepsy requiring hospitalization and effusion within 6 months prior to screening, (3) a history of left bundle branch block, Brugada syndrome, or congenital heart disease (non-clinically significant PFO is not considered exclusionary), (4) having abnormal ECG measurements at screening or prior to randomization, including a QT interval with Fridericia correction (QTcF) >xxx milliseconds (males) or >xxx milliseconds (females), (5) having any of the following tests at screening: Abnormal values: serum total bilirubin >1.5 times the upper limit of normal (ULN) and / or serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the ULN; (6) any previous use of gene therapy; (7) receipt of any other experimental or investigational drug, device, or other treatment within 30 days or 5 half-lives (whichever is longer) prior to screening; (8) previous or current participation in any other Compound 1 clinical trial; (9) known hypersensitivity to any component of the Compound 1 formulation; and (10) prohibited drugs / classes.

[0257] Preliminary data from the first 12 participants enrolled in the study showed Compound 1 exposure above predicted therapeutic levels on Day 1 (FIG. 13A), and that Compound 1 approached steady state after 28 days of dosing, using once-daily dosing and auto-titration, far exceeding predicted therapeutic exposure (FIG. 13B).

[0258] Example 10. Safety, tolerability, pharmacokinetics, and food effect study of Compound 1 in healthy volunteers The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of Compound 1, and the effect of food on single-dose PK in healthy adults.

[0259] This was a three-part Phase I clinical trial in healthy participants aged 18-55 years. Parts A and B were randomized, placebo-controlled, and evaluated the effects of single oral doses (2.5-150 mg) and multiple oral doses (30-120 mg, QD (daily) for 14 days) of Compound 1, respectively. Part C was an open-label, randomized, crossover design evaluating the PK of a single oral dose (90 mg) in fasted and fed states. In Parts A (n=64) and B (n=32), participants were randomized 3:1 to Compound 1 or placebo (n=8 / cohort). In Part C (n=16), participants were randomized 1:1 to one of two treatment sequences receiving a single dose of Compound 1 at 90 mg in the fed state (after a high-fat / high-calorie meal) or fasted state (≥10 hours after the last meal and 4 hours before the next meal).

[0260] In this clinical trial, the PD activity of compound 1 was assessed in healthy participants using electroencephalogram (EEG)-based auditory steady-state response (ASSR) measurements and resting-state EEG (qEEG)-based spectral power measurements under eyes-open and eyes-closed conditions.

[0261] ASSR-based phase-locking factor (PLF) data suggested that sufficient Compound 1 plasma exposure to modulate ASSR signaling was reached at the 90 mg and 120 mg Compound 1 QD doses. In Part B, reductions from baseline in PLF on day 14 (2 h 35 min post-dose) of approximately 30% and 60% were observed in the 90 mg and 120 mg Compound 1 QD groups, respectively. The reduction in PLF appeared to be dose-dependent between the 90 mg and 120 mg QD dose levels. No statistical analysis was performed on this measure. No statistically significant differences were observed between placebo and any Compound 1 dose level for ASSR-based absolute evoked gamma power. Nevertheless, these data suggested that Compound 1 exposure reached at the 90 mg and 120 mg QD dose regimens was sufficient to modulate the cortical excitatory / inhibitory balance in the brain in healthy participants.

[0262] Resting-state EEG (qEEG) was collected only in the 120 mg single-dose and multiple-dose cohorts in Parts A and B, respectively. Increases from baseline in delta (1.5-6 Hz) and theta (6-8.5 Hz) band spectral power were observed in both the 120 mg Compound 1 single-dose and 120 mg Compound 1 QD groups.

[0263] One hundred and twelve participants were enrolled in the entire study (n=88 Compound 1, n=24 placebo). Compound 1 was well tolerated, with no clinically significant safety findings in vital signs, clinical laboratory results, physical examination, electrocardiogram (ECG), or Columbia-Suicide Severity Rating Scale (C-SSRS) data. Treatment-emergent adverse events (TEAEs) were mild (>92%); the most common were catheter site-related, headache, and dizziness. Typical Na V Blocker events were experienced by 34% of participants and were reported more frequently at higher doses (120 mg and 150 mg).

[0264] Exposure was dose proportionally increased over the dose range evaluated. Compound 1 was administered at 2–3 h with the maximum concentration (t max ) and appeared rapidly in plasma with detectable levels over the dose interval. Administration of a 90 mg dose in the fed state reduced C max A slight increase (9%) in t max 1. The effect of serotoninib on the efficacy and safety of serotoninib was delayed (4 vs. 2.5 hours) and a small increase in AUC (14%).

[0265] Compound 1 was well tolerated in healthy participants at single doses up to 150 mg (fasted) in Part A, multiple doses up to 120 mg QD for 14 days (fasted) in Part B, and at a single dose of 90 mg in fed and fasted states in Part C. These findings further indicate that Compound 1 can be administered without regard to food.

[0266] Example 11. Phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 in healthy volunteers This was a two-part randomized, placebo-controlled Phase I study in healthy participants aged 18-55 years. Part A evaluated the effects of 90 mg compound 1 over 28 days (QD) compared with placebo. Part B evaluated the effects of oxcarbazepine (OXC) in combination with 120 mg compound 1 (QD) and OXC alone over 28 days. PD effects were examined with quantitative EEG (qEEG, resting and awake states) and stimulated EEG using auditory steady-state response (ASSR). A total of 48 participants were enrolled; Part A, n=30; Part B, n=18.

[0267] There were no clinically significant safety findings in vital signs, physical exam, ECG, or C-SSRS data. TEAEs were mostly mild or moderate (100% Part A, 96% Part B). Compound 1 was well tolerated in healthy adults at 90 mg in Part A. In Part A, there were 35 TEAEs across 13 participants: 71% mild, 29% moderate, and 0% severe in severity.

[0268] In Part B, there were 74 TEAEs across 16 participants: 51% mild, 45% moderate, and 4% severe in severity. TEAEs were observed in 13 patients (92.9%) who received OXC + Compound 1, and 3 patients (75%) who received OXC + placebo. Review of ALT / AST increases and rhabdomyolysis did not identify a causal relationship to Compound 1. One Part B participant experienced 3 study drug-related SAEs leading to study drug discontinuation. The majority of AEs, including SAEs, in Part B were deemed attributable to the expected combination therapy dose of Compound 1 (120 mg) with OXC, and possibly to coadministration of additive NaV blockade effects.

[0269] Compound 1, 90 mg, administered for 28 days approached steady state in Part A. As shown in the table below, exposure to OXC and its major metabolite, 10-hydroxycarbamezapine, appeared to be similar when administered in combination with Compound 1 compared to when administered alone in Part B. Specifically, the table below shows the Compound 1 exposure summary on Day 7 (120 mg, Part B). [Table 4]

[0270] Compound 1 exposure did not appear to be altered with OXC coadministration in Part B (data not shown). PK findings in Part A indicate a 13-fold increase in Compound 1 concentration above the human equivalent dose required to achieve efficacy as measured in a preclinical maximal electroshock seizure model.

[0271] PD biomarker changes observed in qEEG and ASSR were exposure dependent; qEEG changes were observed across all spectral frequencies. Statistically significant differences between placebo and Compound 1 were observed in Part A in qEEG (Delta and Theta power) and ASSR (Phase Locking Factor (PLF) and Evoked Power). Effects on both low frequency qEEG power and ASSR appeared to be Compound 1 concentration dependent. Statistically significant differences were observed in Part B participants who received OXC+Compound 1 versus OXC alone on qEEG delta, but not qEEG theta or ASSR. PD findings indicate CNS modulation and expected target engagement of Compound 1 across multiple qEEG measures.

[0272] Example 12. A Phase I, open-label study in healthy participants to evaluate the potential for drug-drug interactions of Compound 1 This is a Phase I, open-label study in healthy male or female participants to investigate the effect of coadministration of Compound 1 on the PK of caffeine, dextromethorphan, and midazolam, as well as the effect of coadministration of ciprofloxacin and itraconazole on the PK of Compound 1. The study will be conducted in two parts: a nonrandomized single sequence crossover (Part A) and a randomized parallel design (Part B). Each part will consist of three periods: screening, intervention, and follow-up.

[0273] Objectives and Evaluation Items [Table 5]

[0274] Screening Period Participants will be screened for eligibility during a 27-day screening phase (days -28 to -2). Prior to any clinical trial procedures, participants will provide written informed consent. Screening assessments will be completed to assess participants' eligibility to participate in the study.

[0275] Intervention period Part A Fifteen participants who meet all inclusion criteria and do not violate any of the exclusion criteria will be admitted to the clinical facility on day -1 for the admission procedure, from which they will continue to reside at the clinical facility until the discharge date. On the morning of day 1, a single oral dose of 100 mg caffeine, 30 mg dextromethorphan, and 2 mg midazolam will be administered. On days 2-18, participants will receive a daily oral dose of 120 mg compound 1. On day 16, a single oral dose of 100 mg caffeine, 30 mg dextromethorphan, and 2 mg midazolam will be administered, followed immediately by administration of compound 1. Safety assessments, and PK sampling of CYP probes and their metabolites (caffeine / paraxanthine, dextromethorphan / dextrolphan, midazolam / 1-hydroxyidazolam), and compound 1 will be performed. Participants will be discharged on day 19 after the completion of a satisfactory safety review and study-related procedures.

[0276] Part B Forty-five participants who meet all inclusion criteria, and none of the exclusion criteria, will be randomized to one of three treatment arms of 15 participants each. Participants in each treatment arm will present to the clinical site on day -1 for admission procedures and will remain at the clinical site from that day until their discharge date. Participants will receive the study drug orally as follows: Treatment group 1: A single dose of 120 mg of Compound 1 on day 1. Treatment group 2: ciprofloxacin 500 mg twice daily (days 1-18). A single dose of compound 1 120 mg was administered on day 5. Treatment group 3: Itraconazole 200 mg twice daily (day 1) and 200 mg once daily (days 2-18). A single dose of Compound 1 120 mg was administered on day 5.

[0277] Safety assessments and PK sampling for Compound 1, ciprofloxacin, and itraconazole will be performed. Following completion of sufficient safety and study-related procedures, participants will be discharged from the clinic on Day 19.

[0278] Safety follow-up period The safety follow-up period extends from discharge from the clinic to 28 days (± 2 days) after the last dose. On Day 26 (± 2 days) of Part A and Part B, participants return to the clinic for final clinical trial evaluations. At the end of the safety follow-up period, participants will be called to assess AEs and concomitant medications.

[0279] Pharmacokinetic evaluation Blood samples will be collected for measurement of plasma concentrations of Compound 1, caffeine (and metabolite paraxanthine), dextromethorphan (and metabolite dextrorphan), midazolam (and 1-hydroxyidazolam), ciprofloxacin, and itraconazole. Collected samples may also be used to assess safety related concerns that arise during or after the trial. Samples may also be used for the purposes of additional exploratory method development and / or metabolite characterization.

[0280] Adverse events and serious adverse events AEs were reported by the participant (or, where appropriate, the caregiver, surrogate, or legally authorized representative of the participant) and may include: Any abnormality in clinical laboratory results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiology scans, vital sign measurements), including any deterioration from baseline that is deemed clinically significant in the investigator's medical and scientific judgment (i.e., not related to progression of the underlying disease). · A worsening of a chronic or intermittent pre-existing condition, including either an increase in the frequency and / or intensity of the condition. A new condition detected or diagnosed after administration of the investigational drug, but which may have been present before the start of the trial. ·Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction. Signs, symptoms, or clinical sequelae of suspicion of overdose of either the investigational product or the concomitant medication. Overdoses by themselves are not reported as AEs / SAEs unless they are intentional overdoses possibly with suicidal / self-harming intent. Such overdoses should be reported regardless of sequelae.

[0281] Each AE and SAE reported during a clinical trial is assigned to one of the following categories: Mild: An event that is easily tolerated by the participant, causes minimal discomfort, and does not interfere with daily activities. Moderate: An event that causes enough discomfort to interfere with normal daily activities. Severe: An event that interferes with normal daily activities. AEs rated as serious should not be confused with SAEs. Severity is a category used to rate the intensity of the event. Both AEs and SAEs can be rated as severe.

[0282] Example 13. A Phase 2, Double-Blind, Randomized Clinical Trial to Investigate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Compound 1 in Pediatric Participants with Developmental and Epileptic Encephalopathy Followed by an Open-Label Extension This Phase 2 multicenter, double-blind, randomized clinical trial, followed by an open-label extension (OLE), is designed to investigate the safety, tolerability, efficacy, and PK of Compound 1 when administered to pediatric participants with seizures associated with early-onset SCN2A-DEE and SCN8A-DEE.

[0283] Eligible male and female participants aged 2–18 years with a diagnosis of early-onset SCN2A DEE (n = 10) and SCN8A-DEE (n = 10) will be enrolled in the clinical trial in two separate cohorts.

[0284] Part A (randomized, double-blind) consists of a screening period (including a 28-day baseline observation period), a double-blind treatment period, and a safety follow-up period. Part B (OLE) consists of the following periods: the OLE treatment period and the safety follow-up period.

[0285] Objectives and Evaluation Items [Table 6] [Table 7]

[0286] Part A Screening Period Prior to the start of study procedures, participants will provide written informed consent / assent. The screening period will be for a maximum of 6 weeks, including a 28-day baseline observation period. The screening period may be extended for up to an additional 2 weeks to complete all screening procedures, if necessary and approved by the sponsor's medical director.

[0287] After completing the screening assessments, participants will begin a 28-day baseline observation period. At the start of the screening period, participants will be administered an electronic diary to record countable motor seizure frequency daily (as defined in the study inclusion criteria) and, if locally tolerated, will be given an audio / visual device (Nelli) to monitor nocturnal seizure activity. Countable motor seizure data recorded in the diary during this 28-day observation period will be used to determine clinical trial eligibility and establish a baseline for efficacy analyses. In addition, a baseline video-electroencephalogram (vEEG) will be performed during the screening period.

[0288] Double-blind treatment period The double-blind treatment period will be 16 weeks. Participants will return to the clinic on day 1 for additional baseline assessments and confirmation of eligibility. Participants who continue to meet all study entry criteria will be enrolled into the appropriate cohort based on clinical diagnosis (SCN2A-DEE or SCN8ADEE). Participants in each cohort will be randomly assigned in a double-blind fashion (1:1 ratio) to receive either compound 1 once daily (QD) for 16 weeks (compound 1 group) or compound 1 QD for 12 weeks and a corresponding placebo QD for 4 weeks (compound 1 / placebo group). Participants randomized to the compound 1 / placebo group will receive placebo for 4 consecutive weeks at some point during the 16-week treatment period.

[0289] The starting dose of study drug for all participants during the double-blind treatment period is 0.5 mg / kg / day administered orally or via a gastrostomy / jejunostomy tube (G / J tube). Dose levels of concomitant SCBs (if applicable) and study drug will be adjusted for tolerability and / or efficacy as described below. Dose levels of other ASMs and relevant concomitant medications should not change during the double-blind treatment period.

[0290] Safety follow-up period After completion of the double-blind treatment period, participants may choose to either discontinue study drug or continue into the extended OLE treatment period (Part B) to receive Compound 1 for an additional 48 weeks. Participants who choose not to roll over to the OLE treatment period will discontinue study drug at Week 16 / end of treatment (EOT) and then continue into the safety follow-up period (Part A). At the end of the safety follow-up period, all participants will complete a safety follow-up visit at Week 20 / end of study (EOS).

[0291] Part B Open-label extension treatment period Participants who complete the double-blind treatment period (Part A) and elect to continue study drug treatment will enter the OLE treatment period (Part B), which will last 48 weeks.

[0292] Prior to the start of study procedures, participants will provide written informed consent / assent. Visit 1 (Day 1) of the OLE Treatment Period is the End-of-Treatment Visit of the Double-Blind Treatment Period (Part A). Participants entering the OLE Treatment Period will receive uninterrupted treatment with the investigational drug.

[0293] During the OLE treatment period, participants will continue to receive study medication QD at home. Study medication should be administered at approximately the same time each day and may be administered without regard to food.

[0294] Participants who rolled over into the OLE treatment period continued to receive Compound 1 at the same dose as the last dose administered in Part A, which was not associated with severe or moderate tolerability issues. Compound 1 doses may be adjusted for tolerability and / or efficacy, as described below. Dose levels of concomitant medications (including ASMs or other associated agents) may be adjusted at the investigator's discretion during the OLE treatment period.

[0295] Safety follow-up period After completion of the OLE treatment period, participants will continue into the safety follow-up period (Part B). During this 4-week follow-up period, participants' concomitant medications (including ASMs or other relevant agents) may be adjusted at the investigator's discretion. Investigators are encouraged to resume participants' baseline doses of SCB if reduced at least 1 week after discontinuation of Compound 1, taking into account the approximately 4-day half-life of Compound 1. At the end of the safety follow-up period, all participants will complete a safety follow-up visit at Week 52 / EOS.

[0296] Dose adjustment For each participant, the starting dose of investigational drug in the double-blind treatment period will be calculated based on the participant's body weight on Day 1 of Part A. At Week 8 of the double-blind treatment period in Part A, and Weeks 16, 32, and 48 of the OLE treatment period in Part B, the investigational drug dose may be adjusted, if necessary, based on the participant's body weight at these visits.

[0297] Part A Beginning on Day 1 of the double-blind treatment period of Part A, each participant will receive study drug at a starting dose of 0.5 mg / kg / day QD orally or via G / J tube. During the double-blind treatment period, dose levels of concomitant SCB or study drug will be adjusted for tolerability and / or efficacy, as further described below.

[0298] Dose levels of other ASMs and related concomitant medications should not change during the double-blind treatment period.

[0299] Dose Modifications for Efficacy During the Double-Blind Treatment Period At week 8 of the double-blind treatment period of Part A, if the participant has a <30% reduction in the number of seizures in the past 4 weeks compared to the 28-day baseline observation period and has no tolerability issues, the study drug dose will be increased to 1.0 mg / kg / day, the maximum dose tolerated in this study.

[0300] Part B Participants who rolled over to the OLE treatment period continued to receive Compound 1 at the same dose as the last dose administered in Part A, which was not associated with severe or moderate tolerability issues. The dose of Compound 1 may be increased in increments of 0.25 mg / kg / day every 4 weeks, at the investigator's discretion, up to a maximum of 1.0 mg / kg / day for efficacy. If tolerability issues arise, the dose of Compound 1 or concomitant SCB may be tapered as outlined for the double-blind treatment period in Part A above.

[0301] Dose levels of concomitant medications (including ASMs or other associated agents) may be adjusted at the investigator's discretion during the OLE treatment period.

[0302] Emergency Adverse Events An AE is any adverse medical occurrence in a patient or clinical trial participant that is temporally related to the use of an investigational drug, whether or not it is considered related to the investigational drug. Events that meet the definition of an adverse event may include the following: Abnormalities in clinical laboratory results (hematology, clinical chemistry, or urinalysis) or other safety assessments (such as ECG, radiology scan, or vital sign measurements), including any deterioration from baseline, are deemed clinically significant (i.e., not related to progression of the underlying disease) in the medical and scientific judgment of the investigator. · A worsening of a chronic or intermittent pre-existing condition, including either an increase in the frequency and / or intensity of the condition. A new condition detected or diagnosed after administration of the investigational drug, but which may have been present before the start of the trial. ·Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction. Signs, symptoms, or clinical sequelae of suspicion of overdose of either the investigational or concomitant medication. An overdose by itself is not reported as an AE / SAE unless it is an intentional overdose possibly with suicidal / self-harming intent. Such overdoses should be reported regardless of sequelae. For efficacy studies, a "lack of efficacy" or a "failure to achieve the expected pharmacological effect" per se is not reported as an AE or SAE. Such instances are captured in the efficacy evaluation. However, signs, symptoms, and / or clinical sequelae attributable to the lack of efficacy are reported as AEs or SAEs if they meet the definition of an AE or SAE.

[0303] Each AE and SAE reported during a clinical trial is assigned to one of the following categories: Mild: An event that is easily tolerated by the participant, causes minimal discomfort, and does not interfere with daily activities. Moderate: An event that causes enough discomfort to interfere with normal daily activities. Severe: An event that interferes with normal daily activities. AEs rated as serious should not be confused with SAEs. Severity is a category used to rate the intensity of an event. As well as AEs, AESIs, and SAEs can be rated as severe.

[0304] Seizure diary An electronic diary will be used to record countable motor seizure frequency each day during the clinical trial. In addition, information regarding dosing of investigational drug and concomitant medications will also be recorded in the diary.

[0305] Each participant's parent / legal guardian will record seizure frequency in an electronic diary daily during the screening period, ensuring that at least 28 days of data are collected during the baseline observation period, then daily throughout the double-blind treatment period in Part A, and daily for at least 1 week prior to each clinic visit during the OLE treatment period in Part B. Countable motor seizure data recorded during the 28-day baseline observation period will be used to determine clinical trial eligibility and establish a baseline for efficacy analyses. Prompts may be used to ensure adequate data capture, in addition to spontaneous reporting. Diaries will be completed by the same parent / legal guardian whenever possible.

[0306] Video EEG To the extent permitted by local regulations, vEEG is performed by trained technicians to record brainwave activity and assess for changes over time. vEEG can be completed at home or in a clinic, ideally with a minimum of 1 hour and a maximum of 24 hours of continuous recording.

[0307] Audio / Video-Based Seizure Detection (Nelli) If locally permissible, a video / audio-based automated detection system (Nelli) will be used to collect and quantify movement and sound activity suggestive of participants' seizure behavior. The Nelli system will be deployed in participants' homes when feasible, and audio / video data will be collected throughout the clinical trial period. The audio / video data will be semi-automatically analyzed to classify nocturnal seizures by selecting relevant epochs for subsequent review by human experts.

[0308] Clinical Global Impression-Severity and Clinical Global Impression-Improvement The CGI scale was developed for use in National Institutes of Health-sponsored clinical trials in individuals with psychiatric disorders. The CGI scale provides an overall assessment of improvement over a specific period of time. The scale includes two 7-point Likert rating scales, the CGI-S scale and the CGI-I scale. The CGI scale is anchored with reference to the domains / symptoms experienced by participants with SCN2A-DEE or SCN8A-DEE. Participants are assessed by clinicians at baseline (day 1) and at the end-of-treatment visit for the severity of their SCN2A-DEE or SCN8A-DEE symptoms using the CGI-S. Changes from baseline in SCN2A-DEE or SCN8A-DEE symptoms are assessed by clinicians using the CGI-I.

[0309] Caregiver Global Impression-Severity and Caregiver Global Impression-Improvement The Caregiver Global Impression-Severity (CgCGI-S) and CgCGI-I scales are similar to the CGI-S and CGI-I scales, respectively. Participants will be rated by caregivers at baseline (day 1) for the severity of SCN2A-DEE or SCN8A-DEE symptoms using the CgGI-S. Changes from baseline in SCN2A-DEE or SCN8A-DEE symptoms will be rated by caregivers using the CgGI-I.

[0310] Physical Examination A complete physical examination includes, at a minimum, evaluation of the cardiovascular, respiratory, gastrointestinal, and neurological systems.

[0311] electro-cardiogram A 12-lead ECG will be obtained using an ECG device that automatically calculates heart rate and measures PR, QRS, QT, and corrected QT intervals. Participants should rest for at least 5 minutes before ECG measurement. Triplicate measurements in Part A will be performed at screening, and single measurements will be performed at all time points in Part B, as indicated in the SoA. If triplicate ECGs are required, three individual ECG tracings should be obtained as close as possible to each other in succession, but within 2 minutes of each other.

[0312] Pharmacokinetic evaluation Whole blood samples are collected for measurement of plasma concentrations of Compound 1. Collected samples may also be used to evaluate safety or efficacy aspects related to concerns that arise during or after clinical trials. Samples may also be used for the purposes of additional exploratory method development and / or metabolite characterization.

[0313] Example 14. To test the anticonvulsant activity of Compound 1 in vivo, Compound 1 was administered to a mouse model of developmental and epileptic encephalopathy (DEE) harboring mutations in the Scn2a and Scn8a genes. The Scn2a mutant mice harbored the Q54 mutation, and the Scn8a mice harbored the N1768D mutation.

[0314] Figure 14A is a graph showing the percent protection from spontaneous seizures in the Scn2a DEE mouse model as a function of administered dose of Compound 1. Figure 14B is a graph showing the percent protection from spontaneous seizures in the Scn8a DEE mouse model as a function of administered dose of Compound 1. Figures 14A and 14B show that Compound 1 has potent anticonvulsant activity and can completely block seizures in the Scn2a and Scn8a DEE mouse models.

[0315] The anticonvulsant activity of Compound 1 was also tested in a non-Nav DEE mouse model. Specifically, Compound 1 was tested in a pentylenetetrazole-induced seizure (PTZ) mouse model with mutations in the Kcnq2 and Kcnc1 genes. Hcn1 Kcnq2 mice had a K556E mutation, Kcnc1 mice had a R320H mutation, and Hcn1 mice had a M305L mutation.

[0316] FIG. 14C is a graph showing percent protection from hindlimb outgrowth as a function of time in the Kcnq2 DEE mouse model administered vehicle or Compound 1. FIG. 14D is a graph showing percent protection from hindlimb outgrowth as a function of time in the Kcnc1 DEE mouse model administered vehicle or Compound 1. FIG. 14E is a graph showing percent protection from hindlimb outgrowth as a function of time in the Hcn1 DEE mouse model administered vehicle or Compound 1. FIGS. 14A-14C show that Compound 1 exhibits robust anticonvulsant activity across mechanically branched models of human epilepsy.

[0317] 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 from a reading of this disclosure that various changes in form and detail can be made without departing from the true scope of the present disclosure. For example, the features, steps, elements, or other aspects of all of the structures, methods, and / or components can be used in various combinations.

[0318] A claim or specification including "or" between one or more elements of a group is deemed satisfied if one, more than one, or all of the group elements are present in, employed in, or otherwise 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 the group is present in, employed in, or relevant to a given product or process. The disclosure also includes embodiments in which one or more, or the entire group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the disclosure is to be understood to encompass all variations, combinations, and permutations of one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the enumerated claims that are introduced into another claim with reliance on the same base claim (or any other claim associated therewith), 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 to be 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 of the disclosure is referred to as consisting / consisting of certain elements, features, etc., the particular embodiment or aspect consists of, or consists essentially of, such elements, features, etc. For the sake of brevity, these embodiments have not in all cases been specifically defined in so many words herein. It should be understood that any embodiment or aspect of the disclosure may be expressly excluded from the claims, regardless of whether a specific exclusion is recited herein.

[0319] All patents, patent applications, websites, other publications or documents, accession numbers, and the like cited herein 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 relating to a dysfunction of sodium ion channels in a subject, wherein the composition is of the following formula: 【Chemical 84】 The compound comprises compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 is administered to the subject once daily at a dose of approximately 0.1 mg / kg to approximately 10 mg / kg. The aforementioned condition is hereditary epilepsy or hereditary epilepsy syndrome, The subject is a human, Administration of compound 1 or a pharmaceutically acceptable salt thereof 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 before administration of compound 1 or a pharmaceutically acceptable salt thereof. composition.

2. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.1 mg / kg / day to about 5 mg / kg / day.

3. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.5 mg / kg / day to about 5 mg / kg / day.

4. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.1 mg / kg / day to about 2.5 mg / kg / day.

5. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.25 mg / kg / day to about 1 mg / kg / day.

6. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject in doses of about 0.25 mg / kg / day, about 0.30 mg / kg / day, about 0.35 mg / kg / day, about 0.40 mg / kg / day, about 0.45 mg / kg / day, about 0.50 mg / kg / day, about 0.55 mg / kg / day, about 0.60 mg / kg / day, about 0.65 mg / kg / day, about 0.65 mg / kg / day, about 70 mg / kg / day, about 0.75 mg / kg / day, about 0.80 mg / kg / day, about 0.85 mg / kg / day, about 0.90 mg / kg / day, about 0.95 mg / kg / day, or about 1.0 mg / kg / day.

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 0.25 mg / kg / day, about 0.50 mg / kg / day, or about 1.0 mg / kg / day.

8. The composition according to claim 5, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.0 mg / kg / day.

9. The composition according to claim 1, wherein the seizure is selected from the group consisting of focal seizures, clonic seizures, tonic seizures, generalized tonic seizures and clonic seizures, myoclonus seizures, absence seizures, focal seizures and blunt seizures.

10. The composition according to claim 1, wherein the seizure is a motor seizure.

11. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered orally or via a gastrostomy / jejunostomy tube (G / J tube).

12. The composition according to claim 1, wherein the condition is childhood epilepsy or childhood epileptic syndrome.

13. The composition according to claim 1, wherein the condition is selected from the group consisting of epileptic encephalopathy with SCN1A mutation, epileptic encephalopathy with SCN2A mutation, epileptic encephalopathy with SCN8A mutation, Dravet syndrome with SCN1A mutation, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

14. The composition according to claim 13, wherein the condition is epileptic encephalopathy with an SCN2A mutation or epileptic encephalopathy with an SCN8A mutation.

15. The composition according to claim 1, wherein the subject is a child subject.

16. A composition for reducing the severity, number, and / or frequency of seizures in a subject who requires such reduction, wherein the composition is of the following formula: 【Chemical 85】 The compound comprises compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 is administered to the subject once daily at a dose of approximately 0.1 mg / kg to approximately 10 mg / kg. The subject has hereditary epilepsy or hereditary epilepsy syndrome, A composition in which the subject is a human.

17. The composition according to claim 16, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.1 mg / kg / day to about 5 mg / kg / day.

18. The composition according to claim 16, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.5 mg / kg / day to about 5 mg / kg / day.

19. The composition according to claim 16, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject in a dose of about 0.1 mg / kg / day to about 2.5 mg / kg / day.

20. The composition according to claim 16, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.25 mg / kg / day to about 1 mg / kg / day.

21. The composition according to claim 20, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject in doses of about 0.25 mg / kg / day, about 0.30 mg / kg / day, about 0.35 mg / kg / day, about 0.40 mg / kg / day, about 0.45 mg / kg / day, about 0.50 mg / kg / day, about 0.55 mg / kg / day, about 0.60 mg / kg / day, about 0.65 mg / kg / day, about 0.65 mg / kg / day, about 70 mg / kg / day, about 0.75 mg / kg / day, about 0.80 mg / kg / day, about 0.85 mg / kg / day, about 0.90 mg / kg / day, about 0.95 mg / kg / day, or about 1.0 mg / kg / day.

22. The composition according to claim 20, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject in a dose of about 0.25 mg / kg / day, about 0.50 mg / kg / day, or about 1.0 mg / kg / day.

23. The composition according to claim 20, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.0 mg / kg / day.

24. The composition according to claim 16, wherein the seizure is selected from the group consisting of focal seizures, clonic seizures, tonic seizures, generalized tonic seizures and clonic seizures, myoclonus seizures, absence seizures, focal seizures and blunt seizures.

25. The composition according to claim 16, wherein the seizure is a motor seizure.

26. The composition according to claim 16, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered orally or via a gastrostomy / jejunostomy tube (G / J tube).

27. ​​The composition according to claim 16, wherein the subject has childhood epilepsy or childhood epileptic syndrome.

28. The composition according to claim 16, wherein the subject has a condition selected from the group consisting of epileptic encephalopathy with SCN1A mutation, epileptic encephalopathy with SCN2A mutation, epileptic encephalopathy with SCN8A mutation, Dravet syndrome with SCN1A mutation, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

29. The composition according to claim 28, wherein the condition is epileptic encephalopathy with an SCN2A mutation or epileptic encephalopathy with an SCN8A mutation.

30. The composition according to claim 16, wherein the subject is a child subject.

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