Treatment of neurological disorders

Abstract

The present disclosure relates generally to methods of treating a disease, disorder, or condition using a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in some embodiments, the compounds may be useful in the treatment of neurological disorders, such as neurological disorders, disorders associated with excessive neuronal excitability, or disorders associated with de novo function acquisition or defunction mutations in major central nervous system sodium channel genes such as SCN1A, SCN2A, and SCN8A.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 335,204, filed on April 26, 2022, U.S. Provisional Application No. 63 / 349,402, filed on June 6, 2022, and U.S. Provisional Application No. 63 / 357,944, filed on July 1, 2022. The entire contents of each of the foregoing applications are hereby incorporated herein by reference. Technical Field

[0003] The present disclosure generally relates to methods of treating a disease, disorder or condition, such as a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with de novo gain-of-function or loss-of-function mutations in central nervous system sodium channel genes, such as SCN1A, SCN2A, and SCN8A. Background Art

[0004] Sodium ion (Na + ) channels open primarily in an instantaneous manner and rapidly inactivate, generating fast Na + The late sodium current or sustained sodium current (I Na L) is the fast sodium of myocardial cells and neurons + The continuous component of the current. Many common neurological and cardiac conditions are associated with abnormal I Na L enhancement correlation, the abnormal I Na L enhancement leads to the pathogenesis of electrical and contractile dysfunction in mammals (see, eg, Pharmacol. Ther., 2008, 119: 326-339).

[0005] 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 conditions that are classified into syndromes based on etiology, seizure type, and comorbidities. The most common cause of genetic epilepsy is a defect in voltage-gated sodium channels (Na V ) gene results in gain-of-function and / or loss-of-function alterations in channel activity. Affected patients are typically children or neonates, and the prognosis ranges from benign seizures with spontaneous remission to devastating developmental epileptic encephalopathy (DEE).

[0006] Na V Channels are important therapeutic targets for antiepileptic drugs (AEDs). Blocking them and subsequently inhibiting neuronal sodium currents (I Na ) is ideally positioned to reduce excitability because of the peak I in the axon initial segment and node of Ranvier Na are responsible for the initiation and propagation of action potentials (APs), respectively.V The clinical utility of targeted AEDs is limited because current agents, including carbamazepine (CBZ), oxcarbazepine, and phenytoin, can exhibit severe toxicity at therapeutic doses. This toxicity includes ataxia, somnolence, vomiting, and seizures and is reflected by excessive peak I Na Inhibition or off-target (non-Na V Therefore, it is necessary to identify novel I with improved tolerability. Na Inhibitors would represent a clinically meaningful alternative treatment option.

[0007] Physiological persistence I Na It is a small subthreshold current that helps amplify synaptic responses and enhance repetitive firing. SCN2A (encodes Na V 1.2) and SCN8A (encoding Na V 1.6) Functional studies of DEE variants have shown that persistence I Na A small increase in Na+ may lead to hyperexcitability, seizures, and developmental complications. V Targeted AEDs will suppress peak I at or near therapeutic concentrations (high μmol / L range). Na and persistence I Na , while the excessive peak I Na Inhibition impairs physiological neuronal activity. V Selectivity of activity and preferential targeting of persistence I Na Tolerability may be significantly improved.

[0008] Therefore, there is a need for additional therapeutic options with improved efficacy and tolerability to treat epilepsy, achieve seizure freedom, or both. Summary of the invention

[0009] Disclosed herein are methods of treating a disease, disorder or condition, such as a neurological disorder, a disorder associated with excessive neuronal excitability and / or abnormal late sodium currents, or a disorder associated with de novo gain-of-function (GoF) or loss-of-function mutations (variants) in major central nervous system sodium channel genes, such as SCN1A, SCN2A, and SCN8A, by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] X and Y are each independently CR d or N;

[0013] R1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by;

[0014] R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl;

[0015] R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0016] R 4 is hydrogen or C 1-4 alkyl;

[0017] R 5 is halogenated;

[0018] R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by;

[0019] t is 0, 1, or 2;

[0020] R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0021] R c For optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0022] R d is hydrogen or C 1-4 alkyl;

[0023] Provided that the compound is not a compound having the formula:

[0024] or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound is a compound of formula (Ia):

[0026]

[0027] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0028] In some embodiments, the compound is a compound of formula (Ib):

[0029]

[0030] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0031] In some embodiments, the compound is a compound of formula (Ic):

[0032]

[0033] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0034] In some embodiments, the compound is a compound of formula (II):

[0035]

[0036] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0037] In some embodiments, the compound is a compound of Formula III:

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0040] In some embodiments, the compound is a compound of Formula IV:

[0041]

[0042] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0043] In some embodiments, the compound is Compound 1 having the following formula:

[0044]

[0045] or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the methods provided are directed to treating a disorder associated with excessive neuronal excitability. In some embodiments, the disorder is epilepsy or an epileptic syndrome, or is an encephalopathy, such as hereditary or pediatric epilepsy or a hereditary or pediatric epilepsy syndrome. In some embodiments, the disorder is developmental epileptic encephalopathy. In some embodiments, the disorder is tuberous sclerosis complex (TSC).

[0047] In some embodiments, the methods reduce the frequency of seizures experienced by a subject within 24 hours after administration of the compound or a pharmaceutically acceptable salt thereof, compared to the frequency of seizures prior to administration.

[0048] In some embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to a subject in an amount ranging from about 0.1 mg / kg to about 1 g / kg. In other embodiments, the compound or a pharmaceutically 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.

[0049] In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are administered to the subject in an amount ranging from about 2.5 mg to about 150 mg per day, such as about 90 mg or about 120 mg per day. In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are administered to the subject in an amount ranging from about 30 mg to about 120 mg per day in multiple doses.

[0050] In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are orally administered to the subject. In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are administered to the subject daily for at least 14 days. In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are administered to the subject in a fasting state. In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are administered to the subject in a fed state.

[0051] In some embodiments, the subject is a human. In some embodiments, the subject is a human between 2 and 17 years old.

[0052] In some aspects, the present disclosure provides a method of treating a condition associated with abnormal function of a sodium ion channel in a subject in need thereof, the method comprising administering to the subject a compound of formula (I):

[0053]

[0054] or a pharmaceutically acceptable salt thereof, in a dosage of about 1 mg to about 150 mg; wherein:

[0055] X and Y are each independently CRd or N;

[0056] R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by;

[0057] R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl;

[0058] R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0059] R 4 is hydrogen or C 1-4 alkyl;

[0060] R 5 is halogenated;

[0061] R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by;

[0062] t is 0, 1, or 2;

[0063] R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0064] R c For optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0065] R d is hydrogen or C 1-4 alkyl;

[0066] Provided that the compound is not a compound having the formula:

[0067] or a pharmaceutically acceptable salt thereof.

[0068] 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.

[0069] In some aspects, the present disclosure provides a method of treating a condition associated with abnormal function of a sodium ion channel in a subject in need thereof, the method comprising administering to the subject a compound of formula (I):

[0070]

[0071] or a pharmaceutically acceptable salt thereof, at a dose of about 0.25 mg / kg / day to about 1 mg / kg / day; wherein:

[0072] X and Y are each independently CR d or N;

[0073] R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by;

[0074] R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl;

[0075] R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0076] R 4 is hydrogen or C 1-4 alkyl;

[0077] R 5 is halogenated;

[0078] R 6 C 1-4 Alkyl or C 1-4haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by;

[0079] t is 0, 1, or 2;

[0080] R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0081] R c For optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0082] R d is hydrogen or C 1-4 alkyl;

[0083] Provided that the compound is not a compound having the formula:

[0084] or a pharmaceutically acceptable salt thereof.

[0085] 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.

[0086] In some embodiments, administration of the compound results in a reduction in the severity, number, and / or frequency of epileptic seizures experienced by the subject, compared to the severity, number, and / or frequency of epileptic seizures experienced by the subject prior to administration of the compound.

[0087] In some embodiments, administration of the compound does not cause ataxia, lethargy, and vomiting in the subject.

[0088] In some aspects, the present disclosure provides a method of reducing the severity, number and / or frequency of epileptic seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I):

[0089]

[0090] or a pharmaceutically acceptable salt thereof, wherein:

[0091] X and Y are each independently CR d or N;

[0092] R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by;

[0093] R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl;

[0094] R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0095] R 4 is hydrogen or C 1-4 alkyl;

[0096] R 5 is halogenated;

[0097] R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by;

[0098] t is 0, 1, or 2;

[0099] R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0100] R c For optional C 3-6 Cycloalkyl or C1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0101] R d is hydrogen or C 1-4 alkyl;

[0102] Provided that the compound is not a compound having the formula:

[0103] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the subject suffers from a condition related to abnormal function of a sodium ion channel. In some embodiments, the condition related to abnormal function of a sodium ion channel is a neurological disorder. In some embodiments, a neurological disorder is a disorder associated with excessive neuronal excitability. In some embodiments, a neurological disorder is associated with one or more de novo gain of function or loss of function mutations in a central nervous system sodium ion channel gene.

[0105] In some embodiments, the condition is epilepsy or an epilepsy syndrome or encephalopathy. In some embodiments, the condition is genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is pediatric epilepsy or a pediatric epilepsy syndrome.

[0106] In some embodiments, the condition is selected from malignant migrating focal seizures of infancy (MMFSI), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental epileptic encephalopathy, Raynaud-Gasteaux 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.

[0107] In some embodiments, the condition is selected from epileptic encephalopathy with SCN1A, SCN2A and / or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory epilepsy in childhood with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in childhood with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0108] In some embodiments, the condition is tuberous sclerosis complex (TSC).

[0109] In some embodiments, the compound has Formula (Ia):

[0110]

[0111] or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound has Formula (Ib):

[0113]

[0114] or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the compound has Formula (Ic):

[0116]

[0117] or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the compound has formula (II):

[0119]

[0120] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the compound has Formula III:

[0122]

[0123] or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the compound has Formula IV:

[0125]

[0126] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the compound is Compound 1 having the following formula:

[0128]

[0129] or a pharmaceutically acceptable salt thereof.

[0130] In some aspects, the present disclosure also provides a method of preferentially inhibiting sustained sodium current (INa) over peak sodium current (INa) in a neuron, the method comprising treating the neuron with an effective amount of a compound of formula (I):

[0131]

[0132] or a pharmaceutically acceptable salt thereof, wherein:

[0133] X and Y are each independently CR d or N;

[0134] R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by;

[0135] R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl;

[0136] R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0137] R 4 is hydrogen or C 1-4 alkyl;

[0138] R 5 is halogenated;

[0139] R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by;

[0140] t is 0, 1, or 2;

[0141] R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0142] R c For optional C 3-6Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0143] R d is hydrogen or C 1-4 alkyl;

[0144] Provided that the compound is not a compound having the formula:

[0145] or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the neuron is in a subject.

[0147] In some embodiments, the subject suffers from a condition related to abnormal function of a sodium ion channel. In some embodiments, the condition related to abnormal function of a sodium ion channel is a neurological disorder. In some embodiments, a neurological disorder is a disorder associated with excessive neuronal excitability. In some embodiments, a neurological disorder is associated with one or more de novo gain of function or loss of function mutations in a central nervous system sodium ion channel gene.

[0148] In some embodiments, the condition is epilepsy or an epilepsy syndrome or encephalopathy. In some embodiments, the condition is genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is pediatric epilepsy or a pediatric epilepsy syndrome.

[0149] In some embodiments, the condition is selected from malignant migrating focal seizures of infancy (MMFSI), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental epileptic encephalopathy, Raynaud-Gasteaux 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.

[0150] In some embodiments, the condition is selected from epileptic encephalopathy with SCN1A, SCN2A and / or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory epilepsy in childhood with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in childhood with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0151] In some embodiments, the condition is tuberous sclerosis complex (TSC).

[0152] In some embodiments, the compound has Formula (Ia):

[0153]

[0154] or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the compound has Formula (Ib):

[0156]

[0157] or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the compound has Formula (Ic):

[0159]

[0160] or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the compound has formula (II):

[0162]

[0163] or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound has Formula III:

[0165]

[0166] or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the compound has Formula IV:

[0168]

[0169] or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound is Compound 1 having the following formula:

[0171]

[0172] or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the subject is a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0174] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments and, together with the written description, serve to explain certain principles of the methods and apparatus disclosed herein.

[0175] Figure 1A-1B Depicted are the effects of Compound 1 at 0.3 or 3 μM on action potential firing in wild-type CA1 pyramidal neurons. Figure 1A : Representative action potential traces from CA1 pyramidal neurons during baseline recording and after application of 3 μM Compound 1. Figure 1B : Compound 1 significantly reduced the frequency of action potential firing in CA1 pyramidal neurons of wild-type mice at both 0.3 and 3 μM.

[0176] Figures 2A-2C Depicted using (Molecular Devices) electrophysiology platform, compound 1 ( Figure 2A )、Lamotrigine (LTG) ( Figure 2B ) and carbamazepine (CBZ) ( Figure 2C ) V 1.6 channel impact.

[0177] Figure 3 Depicted are the effects of Compound 1 on maximal electric shock-induced seizures (MES) in male CD-1 mice.CD-1 mice: n=12 / group; **p<0.01 vs. Veh.

[0178] Figure 4 Depicted are the effects 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.

[0179] Figure 5 Compound 1 is shown to reduce the persistent sodium current increase in Scn2a Q54Effects on the frequency of focal motor seizures in a mouse model. Sidak's post hoc test; *P < 0.05 vs. Veh, **P < 0.001 vs. Veh.

[0180] Figure 6 The inhibition of audiogenic seizures by compound 1 (1-10 mg / kg, po) is shown. The results of an in vivo proof-of-concept study in N1768D D / + mice showed that compound 1 inhibited audiogenic-induced seizures. ** Significant protection relative to Veh; χ 2 2 = 16.0, Fisher p value = 0.0002.

[0181] Figure 7A-7B Depicted are the effects of Compound 1 (10 mg / kg) in the KCNQ2 K556E and KCNC1R320H PTZ seizure models. Fig. 7A : Effects of compound 1 in the KCNQ2 K556EPTZ epileptic seizure model. Figure 7B : Effects of compound 1 in the KCNC1 R320H PTZ seizure model.

[0182] Figures 8A-8D Compound 1 showed a strong V 1.6 Continuous sodium current (I Na Compound 1 inhibited ATX-II-induced hNa V 1.6 Persistence I Na ( Fig. 8A ) and hNa V 1.6-N1768D (developmental or epileptic encephalopathy variant) expression persistence I Na . ( Figure 8B ). Figure 8C : Relative to standard Na V Targeted anti-epileptic drugs, compound 1 for persistent I Na Shows higher efficacy. Fig.8D :Compound 1 inhibited the V Isoforms and orthologs expressed in ATX-II- or N1768D-induced persistent I Na The voltage scheme is included as an inset, pharmacological measurements are at the arrows, and points represent mean ± SEM. NMDG, N-methyl-D-glucamine.

[0183] Figures 9A-9F Plotted relative to standard Na V Targeting the anti-epileptic drugs carbamazepine (CBZ) and lamotrigine (LTG), compound 1 has an inhibitory effect on hNa V 1.6 Continuous sodium current (I Na) Alignment Peak I Na showed a higher preference. Using tension block (resting state; Fig. 9A ), use-dependent block (rate / activity-dependent; Fig. 9B ) or voltage-dependent block (depolarization-dependent; Fig. 9C ) Determination of peak I Na of inhibition. Fig.9D : For all assay conditions, compound 1 is relative to peak I Na Showing persistence Na preference (red arrow). CBZ ( Fig.9E ) and LTG( Fig.9F ) showed lower efficacy and had a negative impact on the persistence of I Na No preference (red arrows). Voltage schemes are included as insets, pharmacology was measured at blue arrows, and points represent mean ± SEM.

[0184] Figures 10A-10F Compound 1 is shown to reduce the intrinsic excitability of hippocampal CA1 pyramidal neurons without impairing action potential (AP) amplitude. Compound 1 (blue) and carbamazepine (CBZ; red) at equivalent effective concentrations (peak sodium current [I Na ] half-maximal inhibitory concentration [IC 50 ]) on AP firing recorded from CA1 pyramidal neurons of wild-type mice. Representative AP traces show the pre-dose (black, baseline) and post-dose recordings of 0.3 μmol / L Compound 1 (Figure 10, blue) or 45 μmol / L CBZ (Figure 10, red). Input-output relationship of Compound 1 and CBZ under current injection of +200 pA ( Fig. 10B and Fig. 10E ) and AP amplitude adjustment ( Fig. 10C and Fig.10F ). Data are presented as mean ± SEM. *p<0.05, **p<0.01, ****p<0.0001.

[0185] Figures 11A-11E Compound 1 (0.3-10 mg / kg po) produced a dose-dependent increase in the latency to tonic extension seizures in the maximal electroconvulsive seizure (SEM) model. Fig.11A ) and a reduction in the relative number of developmental epileptic seizures in mice ( Fig. 11B The maximum effect was equivalent to that of the positive control valproic acid (VPA; 400 mg / kg ip). Fig. 11CCompound 1 (10-40 mg / kg po) produced a dose-dependent reduction in distance traveled in the spontaneous locomotor activity (sLMA) assay. Fig.11D : Total brain concentrations of Compound 1 associated with anticonvulsant efficacy (green symbols, left y-axis) separated from total brain concentrations associated with a reduction in total distance moved (red symbols, right y-axis). Fig.11E : The range of calculated free brain concentrations (green bars) associated with anticonvulsant effects and calculated free brain concentrations (red bars) associated with reduction in motor activity for Compound 1, CBZ, and LTG is shown. The PI of each molecule is shown. Data are presented 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 relative to vehicle (Veh), **p < 0.01 relative to Veh.

[0186] Figures 12A-12B The combination of Compound 1 and the standard of care sodium channel blocker carbamazepine ("CBZ") produces greater efficacy in vivo ( Fig. 12A ) and does not change tolerance ( Fig. 12B ).for Fig. 12A , n=8 / group veh, n=10 compound 1, Mann-Whitenet (VPA), ANOVA / Dunn (compound 1), * vs. Veh / Veh, p<0.05, ** vs. Veh / Veh, p<0.005. Fig. 12B , n=10 / group, 4 patients were excluded from the CBZ / Compound 1 group due to ataxia, ANOVA / Dunn, **p<0.01 vs. Veh.

[0187] Figures 13A-13B It is shown that the exposure of compound 1 after a single dose is above the therapeutic range ( Fig.13A ) and approached steady state after 28 days of once-daily dosing and auto-titration ( Fig. 13B ). Fig. 13B C Max Represents the concentration 2.5 hours after administration.

[0188] Fig.14A FIG2 is a graph showing the relationship between the percentage of protection against spontaneous epileptic seizures and the administered dose of Compound 1 in the Scn2a DEE mouse model.

[0189] Fig. 14B FIG2 is a graph showing the relationship between the percentage of protection against spontaneous epileptic seizures and the administered dose of Compound 1 in the Scn8a DEE mouse model.

[0190] Fig. 14CGraph showing the change in percentage of resistance to hindlimb extension over time in the Kcnq2 DEE mouse model administered vehicle or Compound 1.

[0191] Fig.14D Graph showing the change in percentage of resistance to hindlimb extension over time in the Kcnc1 DEE mouse model to which vehicle or Compound 1 was administered.

[0192] Fig.14E Graph showing the change in percentage of resistance to hindlimb extension over time in the Hcn1 DEE mouse model to which vehicle or Compound 1 was administered. DETAILED DESCRIPTION

[0193] 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 enable the reader to more fully understand the details of certain embodiments, features and aspects of the present disclosure, and should not be construed as limiting the scope of the present disclosure.

[0194] definition

[0195] In order to more easily understand the present disclosure, certain terms are first defined below. The following terms and additional definitions of other terms may be set forth in the specification. If the definition of a term set forth below is inconsistent with a definition in an application or patent incorporated by reference, the definition set forth in this application should be used to understand the meaning of the term.

[0196] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents 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 which will become apparent to those skilled in the art upon reading this disclosure and so forth.

[0197] The term "about" is used herein to mean within the typical tolerance range of this field. For example, "about" can be understood as about 2 standard deviations from the mean value. According to certain embodiments, when referring to measurable values ​​such as amounts, "about" is intended to cover a change 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 a specified value, because such a change is suitable for performing the disclosed method and / or making and using the disclosed device. When there is "about" before a series of numbers or ranges, it should be understood that "about" can modify each number in the series or range.

[0198] As used herein, the terms "administer," "administering," or "administration" refer to directly administering a compound or a pharmaceutically acceptable salt or ester of the compound or a composition comprising the compound or a pharmaceutically acceptable salt or ester of the compound to a patient.

[0199] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so combined, i.e., elements that are present in combination in some cases and separately in other cases. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified, unless expressly stated to the contrary. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising," a reference to "A and / or B" may refer to A without B (optionally including elements other than B) in one embodiment; to B without A (optionally including elements other than A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; and so on.

[0200] The term "at least" preceding a number or a series of numbers (e.g., "at least two") should be understood to include the number adjacent to the term "at least" and all subsequent numbers or integers that can be logically included, as is apparent from the context. When "at least" is present before a series of numbers or a range, it should be understood that "at least" can modify each number in the series or range.

[0201] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0202] As used herein, the term "in some embodiments" refers to embodiments of all aspects of the present disclosure, unless the context clearly dictates otherwise.

[0203] As used herein, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. One of ordinary skill in the art will appreciate that the effective amount of a compound of the invention may vary with factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount includes both therapeutic and prophylactic treatments.

[0204] 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 formulated with it. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0205] As used herein, a "subject" contemplated for administration includes, but is not limited to, 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 young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal such as a primate (e.g., a cynomolgus monkey or a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and / or a dog. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0206] As used herein, the terms "treat," "treatment," or "treating" a condition or disorder (e.g., epilepsy or an epileptic syndrome, such as focal epilepsy) in a subject in need thereof include partially, substantially, or completely achieving one or more of: alleviating, ameliorating, or achieving a reduction in the severity of at least one symptom or indicator associated with the condition or disorder; or arresting the progression or worsening of the condition or disorder.

[0207] As used herein, and unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder / disorder, or condition or an amount sufficient to delay or minimize one or more symptoms associated with a disease, disorder / disorder, or condition. A therapeutically effective amount of a compound refers to 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 / disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the efficacy of another therapeutic agent.

[0208] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are determined according to the CAS version of the periodic table of the elements on the inside back cover of the 75th edition of Handbook of Chemistry and Physics, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in, for example, the following documents: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th 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, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0209] When a range of values ​​is listed, it is intended to include every value and sub-range within the range. For example, "C 1–6 "Alkyl" is intended to cover 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.

[0210] "Alkyl" refers to a group such as a straight-chain 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, an alkyl group has 1 to 9 carbon atoms (“C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8In 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 1 carbon atom ("C1 alkyl"). 1–6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0211] "Alkenyl" refers to a straight or branched chain hydrocarbon radical 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). 2–20 In certain embodiments, alkenyl groups do not contain any triple bonds. In some embodiments, alkenyl groups have 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2–4Examples 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 the alkenyl group include the aforementioned C 2–4 Alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0212] "Alkynyl" refers to a straight or branched chain hydrocarbon radical ("C-carbon") 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). 2–20 In some embodiments, an alkynyl group does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2–10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2–9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2–8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2–7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2–6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2–5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2–4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2–3 In some embodiments, an alkynyl group has 2 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). C 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 the alkenyl group include the aforementioned C 2–4 Alkynyl groups and pentynyl (C5), hexynyl (C6), etc. Further examples of alkynyl groups include heptynyl (C7), octynyl (C8), etc.

[0213] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in common in the ring array) ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from vinylanthracene, vinylnaphthalene, vinylphenanthrene, anthracene, azulene, benzene, In some embodiments, the aryl group includes phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0214] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen or sulfur atoms. Hetero can be applied to any of the above alkyl groups, such as alkyl, for example, heteroalkyl; alkenyl, for example, heteroalkenyl; alkynyl, for example, heteroalkynyl; carbocyclyl, for example, heterocyclyl; aryl, for example, heteroaryl, and similar groups having 1 to 5, particularly 1 to 3 heteroatoms.

[0215] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the ring array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such a case, the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring contains no heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0216] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). 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.

[0217] "Carbocyclyl" or "carbocycle" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3–10 In some embodiments, the 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 3–6In 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 5–10 "Carbocyclyl"). Exemplary C 3-6 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. Exemplary C 3–5 Carbocyclic groups include but are not limited to the aforementioned C 3–6 Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) etc. As illustrated by the foregoing examples, in certain embodiments, the carbocyclyl group is a monocyclic ring ("monocyclic carbocyclyl") or contains a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic carbocyclyl") and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the carbocyclic ring system.

[0218] "Heterocyclyl" or "heterocycle" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyl radicals containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom when valence permits. Heterocyclyl radicals may be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; or ring systems wherein a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members continues to refer to the number of ring members in the heteroaryl ring system.

[0219] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5-10 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-8 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0220] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic 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, isoindolyl, 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.

[0221] "Cyano" refers to -CN.

[0222] "Halo" or "halogen" refers to a fluorine atom (ie, F or -F), a chlorine atom (ie, C or -Cl), a bromine atom (ie, B or -Br), and an iodine atom (ie, I or -I). In certain embodiments, the halo group is fluorine or chlorine.

[0223] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0224] "Nitro" refers to -NO2.

[0225] In general, the term "substituted", whether or not 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 a permitted 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 specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent may be the same or different at each position.

[0226] The embodiments disclosed herein are not intended to be limited in any way by the exemplary listing of the above-mentioned chemical groups and substituents. Those skilled in the art will recognize that within the scope and spirit of the present disclosure, there may be several embodiments. The following description illustrates the present disclosure, and, of course, should not be interpreted in any way as limiting the scope of the invention described herein.

[0227] Compounds and compositions

[0228] In one aspect, provided herein is a compound of formula (I):

[0229]

[0230] or a pharmaceutically acceptable salt thereof, wherein:

[0231] X and Y are each independently CR d or N;

[0232] R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by;

[0233] R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl;

[0234] R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0235] R 4 is hydrogen or C1-4 alkyl;

[0236] R 5 is halogenated;

[0237] R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by;

[0238] t is 0, 1, or 2;

[0239] R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0240] R c For optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0241] R d is hydrogen or C 1-4 alkyl;

[0242] Provided that the compound is not a compound having the formula:

[0243]

[0244] or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the compound is a compound of formula (Ia):

[0246]

[0247] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0248] In some embodiments, the compound is a compound of formula (Ib):

[0249]

[0250] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0251] In some embodiments, the compound is a compound of formula (Ic):

[0252]

[0253] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0254] In some embodiments, the compound is a compound of formula (II):

[0255]

[0256] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0257] In some embodiments, the compound is a compound of Formula III:

[0258]

[0259] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0260] In some embodiments, the compound is a compound of Formula IV:

[0261]

[0262] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0263] In some embodiments, the compound is Compound 1 having the following formula:

[0264]

[0265] or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, compound 1 is in crystalline form. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction pattern including 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 including 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 including 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 hereby incorporated by reference herein.

[0267] The compounds described herein may include one or more asymmetric centers and may therefore exist in various isomeric forms, 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 may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including the formation and crystallization of chiral high pressure liquid chromatography (HPLC) and chiral salts; preferred isomers may be prepared by asymmetric synthesis. See, e.g., 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 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Embodiments disclosed herein also encompass compounds described herein in the form of individual isomers that are substantially free of other isomers and alternatively in the form of mixtures of various isomers.

[0268] As used herein, an enantiomerically pure compound is substantially free of (i.e., in enantiomeric excess of) other enantiomers or stereoisomers of the compound. In other words, the "S" form of a compound is substantially free of the "R" form of the compound, and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than about 75% by weight, such as more than about 80% by weight, more than about 85% by weight, more than about 90% by weight, more than about 91% by weight, more than about 92% by weight, more than about 93% by weight, more than about 94% by weight, more than about 95% by weight, more than about 96% by weight, more than about 97% by weight, more than about 98% by weight, more than about 98.5% by weight, more than about 99% by weight, more than about 99.2% by weight, more than about 99.5% by weight, more than about 99.6% by weight, more than about 99.7% by weight, more than about 99.8% by weight, or more than about 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0269] In certain aspects, compositions comprising compounds described herein, such as Compound 1, are provided. In some embodiments, the composition is a pharmaceutical composition comprising a compound described herein, such as Compound 1, and a pharmaceutically acceptable carrier. In some embodiments, the compound contained in the disclosed composition is a compound of formula (I) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound contained in the disclosed composition is a compound of formula (Ia) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound contained in the disclosed composition is a compound of formula (Ib) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound contained in the disclosed composition is a compound of formula (Ic) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound contained in the disclosed composition is a compound of formula (II) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound contained in the disclosed composition is a compound of formula (III) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed composition is a compound of formula (IV) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound included in the disclosed composition is compound 1 having the following formula:

[0270]

[0271] or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the enantiomerically pure compound can be present in the composition with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound can include, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition can, for example, contain at least about 95% by weight of the R-compound and up to 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 can contain, for example, about 90% of an excipient and about 10% of the enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition can, for example, contain at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with very little or no excipient or carrier.

[0273] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2H (D or deuterium) and 3 H (T or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C. O can be in any isotopic form, including 16 O and 18 O and F can be in any isotopic form, including 18 F and 19 F.

[0274] Treatment

[0275] The compounds and compositions described herein are generally useful for modulating the activity of sodium channels and are useful for treating disorders related to abnormal function of sodium channel ion channels, such as abnormal late sodium (I Na L) Current-related conditions. 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 pharmaceutically acceptable salts, or compositions comprising them may also modulate all sodium ion channels, or may be specific to only one or more sodium ion channels, such as Na V 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 and / or 1.9. In some embodiments, the compounds of the present disclosure have an effect on the sodium ion channel Na V 1.6 has specificity. In some embodiments, the compounds disclosed herein are pan-Na V Blockers that block all or substantially all sodium channels (e.g., Na V 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 and 1.9) are specific.

[0276] In typical embodiments, the present disclosure is intended to encompass the compounds disclosed herein and pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present disclosure includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of the compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or Compound 1), tautomeric forms, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (pure or as a racemic or non-racemic mixture).

[0277] The compounds and compositions described herein, such as Compound 1, can be used to treat neurological disorders, conditions associated with excessive neuronal excitability, or conditions 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, conditions associated with excessive neuronal excitability, or conditions associated with de novo gain-of-function or loss-of-function mutations in ion channel genes such as Kcnq2, Kcnc1, and Hcn1.

[0278] In some aspects, there is provided a method for treating a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a de novo gain of function or loss of function mutation in a major central nervous system sodium channel gene, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it. 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it. 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it. 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it. 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it. In some embodiments, the compound used in the treatment of the disclosed methods is a compound of formula (III) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed methods is a compound of formula (IV) as defined elsewhere herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the compound used in the treatment of the disclosed methods is Compound 1 having the following formula:

[0279]

[0280] or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0281] Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathy (e.g., malignant migrating focal epileptic seizures of infancy (MMFSI) or epilepsy of infancy with migrating focal epileptic seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, developmental epileptic encephalopathy (DEE), early infantile epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, and Raynaud-Gasteaux syndrome), drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal epileptic seizures, The invention relates to a variety of diseases and conditions including myopathy, ataxia, leukodystrophy, hypomyelinating leukodystrophy and leukoencephalopathy, cardiac dysfunction (e.g., arrhythmias, Brugada syndrome, myocardial infarction), pulmonary vascular disease / hemorrhage, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, cramping muscle spasms, spasticity), itching and pruritus, movement disorders (e.g., ataxia and cerebellar ataxia), psychiatric disorders (e.g., major depression, anxiety disorders, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder), neurodevelopmental disorders, learning disabilities, intellectual disability, fragile X, neuronal plasticity and autism spectrum disorders.

[0282] Epilepsy is a CNS disorder in which the activity of nerve cells in the brain is disrupted, causing seizures or abnormal behaviors, sensations, and sometimes loss of consciousness that last for a period of time. Seizure symptoms vary greatly, from a simple blank stare for a few seconds to repeated twitching of an arm or leg during a seizure. Epilepsy may involve a generalized seizure or a partial or focal seizure. A generalized seizure involves all areas of the brain. A person experiencing a generalized seizure may cry out loudly or make some noises, freeze for a few seconds to a minute, and then make rhythmic movements of the limbs. The eyes are roughly open, the person may appear to be unable to breathe and may actually be blue. Recovery of consciousness is gradual, and the person may be confused for several minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In a partial or focal seizure, only one part of the brain is involved, and therefore only one part of the body is affected. Depending on the part of the brain that has the abnormal electrical activity, the symptoms may vary.

[0283] As used herein, epilepsy includes generalized, partial, complex partial, tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile convulsions, or temporal lobe epilepsy.

[0284] In some embodiments, the epilepsy syndrome is early-onset DEE. In certain embodiments, the epilepsy syndrome is DEE, including, for example, Ohtahara syndrome; epilepsy in infancy with migratory focal epileptic seizures (EIMFS); infantile and childhood DEE, such as West syndrome and Raynaud-Gasteaux syndrome; Dravet syndrome; idiopathic / generalized epilepsy (IGE / GGE); temporal lobe epilepsy; myoclonic-astatic epilepsy (MAE); migratory partial epilepsy in infancy (MMPSI); and familial hemiplegic migraine with or without epilepsy. In certain embodiments, the epilepsy syndrome is an epileptic encephalopathy with delayed onset of epileptic seizures.

[0285] In some embodiments, the compounds described herein (e.g., compounds of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1) can be used to treat epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused at least in part by certain aspects of epilepsy are also referred to as epileptic encephalopathy. These are associated with frequent seizures and severe cognitive dysfunction (e.g., West syndrome) that are resistant to treatment. In some embodiments, epilepsy syndromes include epileptic encephalopathy, such as Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Klevner syndrome, Raynaud-Gasteaux syndrome, Ohtawara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0286] In certain embodiments, the epilepsy or epilepsy syndrome is a hereditary epilepsy or hereditary epilepsy syndrome. In some embodiments, epilepsy or epilepsy syndromes include epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory epilepsy with generalized tonic-clonic seizures in children, infantile spasms, benign familial neonatal-infantile epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in children with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexplained death in epilepsy (SUDEP), Rasmussen encephalitis, malignant migratory partial epileptic seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0287] In some embodiments, the methods described herein further comprise identifying a subject with epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, developmental epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, or epilepsy with epilepsy syndrome) prior to administering a compound described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1). Subjects with idiopathic epilepsy, refractory epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in children with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexplained death in epilepsy (SUDEP), Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy).

[0288] In one aspect, the disclosure features a method for treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, developmental epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory epilepsy of childhood with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, focal epilepsy with SCN3A mutations A method for treating cryptogenic partial epilepsy in children, SCN8A epileptic encephalopathy, unexplained sudden death in epilepsy (SUDEP), Rasmussen encephalitis, malignant migrating partial seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) 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 pharmaceutically acceptable salt thereof, or a composition comprising the same.

[0289] The compounds of the invention (e.g., compounds of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1) can also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more of the following genes: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CACNA1G, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRA2, GABRB3, GABRG2, GNAO1, GOSR2, GRIK1, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCN1A, KCNA2 , KCNB1, KCNC1, KCNMA1, KCNN2, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH7, PCD H19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8 A. SCN9A, SHANK3, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1 , SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TRIM3, UNC79 and WWOX.

[0290] In some embodiments, the methods described herein further include identifying a subject having a mutation in one or more of the following prior to administering a compound described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (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, KCNMA1, KCNN2, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH7 , PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, S CN8A, SCN9A, SHANK3, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN 1. SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TRIM3, UNC79 and WWOX.

[0291] The compounds described herein (e.g., compounds of Formula (I), (la), (lb), (lc), (II), (III) or (IV) or Compound 1) can also be used in a method of improving at least one symptom or marker of epilepsy or an epilepsy syndrome (including, for example, early-onset DEE) in a subject in need thereof. In certain embodiments, the symptoms or markers include early-onset epileptic seizures and / or global developmental delay. In certain embodiments, the symptoms or markers include epileptic seizures, hypotonia, sensory problems such as sensory integration disorders, motor dysfunction, intellectual and cognitive dysfunction, movement and balance dysfunction such as choreoathetosis, dystonia and ataxia, anxiety, sensory problems, urinary retention problems, irritability, behavioral problems, visual dysfunction, language and speech delays, gastrointestinal disorders (e.g., gastroesophageal reflux, diarrhea, constipation, movement disorders, etc.), neurodevelopmental delays, sleep problems, unexplained sudden death in epilepsy (SUDEP), motor development delays, delayed social milestones, repetitive movements, oral motor incoordination One or more. In certain embodiments, seizures include focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (typically lasting more than 10 minutes), and frequent seizures (e.g., convulsive, myoclonic, absence, focal, tonic, and tonic seizures).

[0292] In one aspect, the present disclosure provides a method of ameliorating at least one symptom or marker of epilepsy or 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 pharmaceutically acceptable salt thereof, or a composition comprising the same. In certain embodiments, the symptom or marker comprises early-onset epileptic seizures and / or global developmental delay. In certain embodiments, symptoms or signs include epileptic seizures, hypotonia, sensory problems such as sensory integration disorders, motor dysfunction, intellectual and cognitive dysfunction, movement and balance dysfunction such as choreoathetosis, dystonia and ataxia, anxiety, sensory problems, urinary retention problems, irritability, behavioral problems, visual dysfunction, language and speech delay, gastrointestinal disorders (e.g., gastroesophageal reflux, diarrhea, constipation, movement disorders, etc.), neurodevelopmental delays, sleep problems, unexplained sudden death in epilepsy (SUDEP), motor development delays, social milestone delays, repetitive movements, oral motor incoordination. One or more. In certain embodiments, epileptic seizures include focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (usually lasting more than 10 minutes) and frequent seizures (e.g., convulsive, myoclonic, absence, focal, retardation, and tonic seizures).

[0293] In some aspects, the present disclosure provides a method of reducing the severity, number and / or frequency of epileptic seizures in a subject in need thereof, 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 pharmaceutically acceptable salt thereof. In some embodiments, the subject suffers from early-onset DEE. In some embodiments, the compound is Compound 1 or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or Compound 1) can be used to treat tuberous sclerosis complex (TSC). TSC is a genetic disorder that is often associated with the growth of non-cancerous (benign) tumors in various parts of the body. TSC often affects the brain, and some affected individuals have benign growths called cortical tubers on the outer surface of the brain (cerebral cortex). Individuals with TSC often develop a behavioral pattern called TSC-associated neuropsychiatric disorder (TAND), which can be characterized by one or more of the following: hyperactivity, aggression, mental illness, intellectual disability, and communication and social interaction problems (autism spectrum disorder). In addition, individuals with tuberous sclerosis may develop attention-deficit / hyperactivity disorder (ADHD) or seizures. Individuals with TSC often have skin abnormalities, including patches of abnormally light-colored skin, raised and thickened areas of skin, and subungual growths. Facial tumors called facial angiofibromas are also common and often begin in childhood.

[0295] In one aspect, the present 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 pharmaceutically acceptable salt thereof, or a composition comprising the same.

[0296] The compounds described herein can be used to treat pain. In some embodiments, the pain includes neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder. In some embodiments, the methods described herein also include identifying a subject suffering from 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 a related headache disorder) prior to administering a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV) or Compound 1).

[0297] In one aspect, the present disclosure provides 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 a related headache disorder), comprising administering to a subject in need thereof a compound described herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (II), (III), or (IV) or Compound 1) or a pharmaceutically acceptable salt thereof, or a composition comprising the same.

[0298] In one aspect, the present invention provides a method for inhibiting peak sodium current (I Na ) preferentially inhibits the persistent sodium current (I Na ), the method comprising contacting the neuron with 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). As described in Example 8 herein, an exemplary compound of the present disclosure, Compound 1, has an effect on inhibiting persistent I Na Comparative inhibition of peak sodium current I Na Specifically, compound 1 inhibits the persistence of hNav1.6 in I Na , and with peak I Na Compared with the inhibition of Na The inhibition preference of peak I Na and persistence I Na The ratio of peak I is 60. Na Compared with the inhibition of persistent I Na The inhibition preference of peak I Na and persistence I NaThe ratio of peak I to peak I is less than 60. Specifically, for various AEDs, peak I Na and persistence I Na The ratios of 24 (cenobamate), 30 (carbamazepine), 8 (oxcarbazepine) and 16 (lamotrigine) were obtained. As described herein, the ratio of inhibition of peak I Na Preferential inhibition of persistent I Na This may be related to the improved tolerability of compound 1.

[0299] In some embodiments, provided herein is a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0300] 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 pharmaceutically acceptable salt thereof, or a composition comprising the same, is administered to a subject in an effective amount or therapeutically effective amount, which is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the 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 pharmaceutically acceptable salt thereof, or a composition comprising the same, is administered in an amount of about 0.1 mg / kg to about 1 g / kg, such as about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 2.5 mg / kg, about 0.1 mg / kg to about 1. In some embodiments, the present invention provides an amount within the range of about 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 is administered to a subject. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1) or a pharmaceutically 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, such as 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, a compound described herein is administered to a subject at a dose of about 0.8 mg / kg / day. In some embodiments, the compounds described herein are administered to a subject at a dose of about 0.9 mg / kg / day. In some embodiments, the compounds described herein are administered to a subject at a dose of about 1 mg / kg / day.In some embodiments, a compound described herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, is administered to a subject once daily. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, is administered to a subject orally.

[0301] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1) or a pharmaceutically acceptable salt thereof, or a composition comprising the same is administered as a single dose in a range of about 1 mg to about 180 mg or about 2.5 mg to about 150 mg, such as about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, About 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg is 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 pharmaceutically 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), (la), (lb), (Ic), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, is administered to a subject once daily. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, is administered to a subject orally.

[0302] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1), or a pharmaceutically 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, such as about 30 mg to about 120 mg, such as 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), (la), (lb), (lc), (II), (III), or (IV) or Compound 1), or a pharmaceutically 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), (la), (lb), (lc), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, is administered to a subject once a day.

[0303] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, or a composition comprising the same, is administered to a subject as multiple doses, with the maximum dose amount ranging from about 30 mg to about 150 mg, such as 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), (la), (lb), (lc), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, or a composition comprising the same, is administered to a subject as multiple doses, with the maximum dose amount being about 90 mg or about 120 mg.

[0304] 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 pharmaceutically acceptable salt thereof, or a composition comprising the 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 pharmaceutically acceptable salt thereof, or a composition comprising the same, is administered to a subject daily. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a subject daily for at least 14 days. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered to a subject in ascending doses, with a starting dose of about 20 mg to about 100 mg, such as 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.

[0305] 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 pharmaceutically acceptable salt thereof, or a composition comprising the same, is administered to a subject in a fasted state, such as more than about 10 hours after the last meal and / or at least about 4 hours before the next meal. In some embodiments, a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, or a composition comprising the same, is administered to a subject in a fed state, such as after a meal normally consumed by the subject, including but not limited to a high-fat and high-calorie meal.

[0306] In some embodiments, a compound described herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (II), (III), or (IV) or Compound 1) or a pharmaceutically acceptable salt thereof, or a composition comprising the same, is effective to achieve a maximum plasma concentration (t) between about 1.5 to about 5 hours, such as about 1.5 to about 4 hours, about 2.5 to about 5 hours, about 2.5 to about 4 hours, about 2 to about 4 hours, or about 2 to about 3 hours. max ) is orally administered to a subject.

[0307] 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 pharmaceutically 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, the time from administration (AUC) to infinity time (AUC inf ), the time to the final quantifiable concentration (AUC last ), to 24 hours (AUC 0-24 ) of the plasma concentration-time curve, the maximum observed plasma concentration (C max ), the time of maximum observed plasma concentration (t max ) and apparent plasma terminal elimination half-life (t 1 / 2 )wait.

[0308] In some embodiments, administration of a compound described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1), or a pharmaceutically acceptable salt thereof, or a composition comprising the 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 treatment (e.g., any compound described herein), whether or not considered related to the treatment. Thus, an AE can be any unfavorable and unexpected sign (including abnormal laboratory test results), symptom, or disease (new or worsening) that is temporally associated with the use of a treatment, whether or not considered related to the treatment.

[0309] Combination therapy

[0310] The compounds or compositions described herein (e.g., compounds of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1) can be administered in combination with another agent or therapy. The subject to whom the compounds disclosed herein are administered may have a disease, disorder / 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 an epileptic syndrome.

[0311] In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1) is administered in combination with an anti-epileptic agent. Antiepileptic agents 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), (la), (lb), (lc), (II), (III), or (IV) or Compound 1) is administered in combination with carbamazepine.

[0312] In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (la), (lb), (lc), (II), (III), or (IV) or Compound 1) is administered in combination with any of caffeine, dextromethorphan, midazolam, ciprofloxacin, itraconazole, and oxcarbazepine.

[0313] In some embodiments, the disclosed methods 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 anti-epileptic agent. In some embodiments, the disclosed methods 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.

[0314] Thus, one aspect of the present disclosure provides a composition 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 composition comprises 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 comprises any compound 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 compound 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 compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III), or (IV) or Compound 1) and at least five therapeutic agents.

[0315] 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 one or more additional therapeutic agents, substantially simultaneous administration of more than one 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 one or more additional therapeutic agents, and 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 one or more additional therapeutic agents in any order, wherein preferably there is a time period 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 one or more additional therapeutic agents simultaneously exert a therapeutic effect.

[0316] Dosage forms and compositions

[0317] In one aspect, the disclosure provides dosage forms or compositions useful for treating a disease, disorder, or condition described herein, such as a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder 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.

[0318] Thus, the present disclosure provides pharmaceutical compositions containing a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or Compound 1) or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and adjuvants. The pharmaceutical composition can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition. (G.S. Banker and C.T. Rhodes, eds.).

[0319] The pharmaceutical composition can be administered in single or multiple doses by any of the accepted modes of administration of pharmaceuticals with similar efficacy, for example, as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical administration, as an inhalant, or, for example, via an impregnated or coated device such as a stent, or an arterial inserted cylindrical polymer. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure are administered orally.

[0320] One mode of administration is parenteral, particularly by injection. Compositions of the present disclosure may be incorporated to be administered by injection in the form of aqueous or oil suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles. Saline solutions are also commonly used for injection, but are not preferably used in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. Suitable fluidity may be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Prevention of the effects of microorganisms may be achieved by a variety of antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0321] Sterile injectable solutions are prepared by incorporating the desired amount of the compound according to the invention into a suitable solvent as needed with the various other ingredients listed above, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other ingredients required from those listed above. In the case where sterile powders are used to prepare sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze drying techniques that produce a powder of the active ingredient plus any additional desired ingredients from its previous sterile filtered solution.

[0322] Oral administration is another route of administration of the compounds according to the present disclosure. It can be administered via capsules or tablets or the like. In the process of manufacturing a pharmaceutical composition comprising at least one compound as described herein, the active ingredient is usually diluted by an excipient and / or encapsulated in the carrier that can be in the form of a capsule, a sachet, paper or other container. When an excipient is used as a diluent, it can be in the form of a solid, semisolid or liquid material (as described above), which serves as a medium, carrier or medium for the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, medicine bags, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0323] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may additionally include: lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, such as methyl benzoate and hydroxypropyl benzoate; sweeteners; and flavoring agents.

[0324] The compositions of the present disclosure may be formulated to provide rapid, sustained or delayed release of the active ingredient after being applied to a subject using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems, which include polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patents No. 3,845,770; No. 4,326,525; No. 4,902,514; and No. 5,616,345. Another formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusions of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 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.

[0325] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of active substances calculated to produce the desired therapeutic effect, and suitable pharmaceutical excipients (e.g., tablets, capsules, ampoules). The compound is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains about 1 mg to about 2 g of the compound described herein, and for parenteral administration, preferably about 0.1 to about 700 mg of the compound described herein. However, it should be understood that the amount of the compound actually administered will generally be determined by the doctor in view of the relevant circumstances, including the condition to be treated; the route of administration selected; the compound actually administered and its relative activity; the age, weight and response of the individual subject; the severity of the subject's symptoms; and the like.

[0326] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is generally dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0327] Tablet of the present invention or pill can be coated or otherwise mixed to provide dosage form, which has the advantage of long action time or protection from the effect of the acidic conditions of the stomach.For example, tablet or pill can include inner dosage component and outer dosage component, and the latter adopts the form of coating on the former.Two kinds of components can be separated by enteric layer, and described enteric layer is used to resist the disintegration in the stomach and allows inner component to be transmitted into the duodenum intact or delayed release.Multiple materials can be used for this type of enteric layer or coating, and this type of material comprises many polymeric acids and polymeric acids and the mixture of materials such as shellac, hexadecanol and cellulose acetate.

[0328] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by oral or nasal respiratory route for local or systemic effect. Compositions preferably in pharmaceutically acceptable solvents may be atomized by the use of an inert gas. Atomized solutions may be inhaled directly from an atomizing device, or the atomizing device may be connected to a mask holder or an intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may preferably be administered orally or nasally from a device for delivering the formulation in an appropriate manner.

[0329] In one aspect, provided herein is a dosage form or a composition in a dosage form comprising: about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or Compound 1; and a pharmaceutically acceptable excipient.

[0330] In some embodiments, the dosage form or a composition in a dosage form comprises 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 In some embodiments, the dosage form or composition in the dosage form is for oral administration.

[0331] In some embodiments, the dosage form or a composition in a dosage form contains about 1 mg to about 100 mg (e.g., about 1 mg to about 80 mg, about 1 mg to about 50 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about mg, about 5 mg to about 100 mg, about 5 mg to about 80 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg) of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or Compound 1.

[0332] In some embodiments, the dosage form or a composition in a dosage form comprises 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 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), (la), (lb), (lc), (II), (III) or (IV) or Compound 1.

[0333] In another aspect, the present disclosure provides a dosage form or a composition in a dosage form, comprising: a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or multiple particles of Compound 1; and a pharmaceutically acceptable excipient, wherein the amount of the compound of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or multiple particles of Compound 1 in the dosage form 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).

[0334] In some embodiments, the dosage form or the composition includes a plurality of particles of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or Compound 1 of about 2.5 mg to about 150 mg (e.g., about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, about 50 mg).

[0335] In some embodiments, the dosage form or the composition is configured for oral administration. In some embodiments, the dosage form is a solid form. In some embodiments, the dosage form is in the form of a capsule. In some embodiments, the pharmaceutical excipient in the capsule is a filler (e.g., a cellulose derivative (e.g., microcrystalline cellulose), a starch (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, sugar alcohol (e.g., sorbitol, xylitol, and mannitol).

[0336] 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 fillers (e.g., polymers (e.g., PEG400)), emulsifiers (e.g., castor oil derivatives (e.g., Kolliphor RH40), surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), vitamin derivatives (e.g., vitamin E TPGS)), solvents (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)).

[0337] In some embodiments, the concentration of the compound of Formula (I), (Ia), (Ib), (Ic), (II), (III) or (IV) or Compound 1 in the solution is from about 0.1 mg / mL to about 10 mg / mL (e.g., from about 0.5 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 8 (e.g., 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).

[0338] In some embodiments, the concentration of the compound of Formula (I), (la), (lb), (lc), (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.

[0339] In some embodiments, the dosage form is in the form of 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 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL.

[0340] 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 from about 0.1 mg / mL to about 10 mg / mL (e.g., from about 0.5 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 8 (e.g., 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).

[0341] Example

[0342] In order that the embodiments described herein may be more fully understood, the following examples are given.The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting the scope thereof in any way.

[0343] Example 1. Effects of Compound 1 on the excitability of wild-type mouse CA1 pyramidal neurons using whole-cell patch clamp electrophysiology in brain slices

[0344] The aim of this study was to determine the effect of Compound 1 on the intrinsic excitability of CA1 pyramidal neurons in brain slices obtained from wild-type mice.

[0345] 1. Materials and Methods

[0346] i. Brain Slice Preparation

[0347] Mice (p17-p21) were anesthetized with 2% isoflurane, and the brains were removed and placed in an ice 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, pH 7.4, maintained by continuous bubbling with carbogen gas (95% O2–5% CO2). Three hundred micrometer coronal hippocampal slices were cut on a vibratome (VT1200; Leica) for whole-cell patch clamp experiments. The slices were incubated in the incubation solution for a minimum of 1 hour at room temperature before patch clamp experiments.

[0348] ii. Current clamp electrophysiological recordings

[0349] Brain slices were transferred to an immersion recording chamber on an upright microscope (Slicescope Pro 1000; Scientifica) and perfused (2 ml / min) with an 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, with a pH of 7.4 maintained by continuous bubbling with carbogen gas (95% O2–5% CO2).

[0350] CA1 pyramidal neurons were visually identified in the pyramidal layer of the CA1 region of the hippocampus using a camera (Dage IR-2000; Dage) using an infrared oblique illumination microscope and a 40x water immersion objective (Olympus). Cell identity was also confirmed using action potential emission characteristics, where the action potential adapts to high current injection and has a wide action potential half-width. Patch clamp recordings were performed using a micromanipulator (MPC-200; Sutter) and an Axon Multiclamp 700B patch clamp amplifier (MDS). Data were acquired using pClamp software (v10; MDS) using a sampling rate of 50kHz and a low-pass Bessel (Digidata 1550b; Axon) filtered at 10kHz. Patch pipettes (3–7 MΩ; GC150F-7.5; Harvard Instruments) pulled using a Flaming / brown micropipette puller (model P-1000; Sutter) were filled with intracellular recording solution containing: 125 mM potassium gluconate, 5 mM KCl, 2 mM MgCl2·6H2O, 10 mM HEPES, 4 mM ATP-Mg, 0.3 mM GTP-Na, 10 mM creatine phosphate, 0.1 mM EGTA, and 0.2% biocytin, pH 7.2 (adjusted with KOH), and an osmotic pressure of 292 mOsm was measured.

[0351] iii. Intrinsic excitability measurement (evoked action potential)

[0352] The whole-cell current clamp recording mode was used for the study. The experimental timeline is Figure 1A After the whole-cell configuration was obtained for 2 minutes, a holding current was injected to maintain a membrane potential of approximately -70 mV. Current steps were applied in current clamp mode (currents between -60 and 340 pA were injected in steps of 20 pA, 400 ms duration) ( Figure 1B )). The amplitude of the current injection was related to the holding current. Test pulses (-5pA amplitude, 50ms duration) were applied 650ms after termination of the main current step. The inter-scan interval was 5 seconds (0.2Hz). To be included in the study, cells had to have an access resistance of less than 20MΩ and a holding current of less than -200pA. Once baseline action potential firing was established in the presence of extracellular aCSF recording solution (baseline), Compound 1 (300nM or 3μM) was washed onto the slices for 5 minutes and the action potential generation protocol was repeated ( Figure 1B ).

[0353] iv. Data analysis to generate input-frequency relationships

[0354] Data were analyzed using Axograph X software. An amplitude threshold of +50mV relative to the baseline before the event was used to identify and count individual action potentials. The frequency of the action potentials generated by each current injection was plotted to create an input-frequency relationship for each cell. The average frequency of the action potentials induced by each current injection was calculated and reported in Tables 1 and 4. For each cell, the action potential amplitude was determined relative to the baseline before the event under the +200pA current injection step. The average action potential amplitude of each induced action potential was calculated and reported in Tables 3 and 6. Once there were less than three cells contributing to the average amplitude in the action potential count, they were excluded from the analysis. In order to perform statistical comparisons between groups, the total number of action potentials emitted by each cell was calculated. The 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 the compound on the action potential emission compared to the baseline. In all cases, the significance of the analysis was set to α value 0.05.

[0355] 2. Results

[0356] In slices from wild-type mice, both 0.3 μM and 3 μM of compound 1 significantly reduced the number of action potentials generated when compared to baseline ( Figure 1A-1B Compound 1 reduced the intrinsic excitability of CA1 pyramidal neurons in a concentration-dependent manner, as measured using evoked action potential firing ( Figure 1B ).

[0357] Example 2. Use (Molecular Devices) electrophysiology platform, compound 1 for human Na V 1.6 Channel Impact

[0358] The purpose of this study was to determine the effect of compound 1 on human Na V 1.6 Effects of tonic block (TB) of late (persistent) current and peak current and use-dependent block (UDB) of peak current.

[0359] 1. Materials and Methods

[0360] i. Cell Preparation

[0361] Using stably expressed human Na V 1.6 (NP_055006), mouse Na V 1.6 (NP_035453.2) or rat Na V 1.6 (NP_062139) HEK-293 cell line. All cells were cultured at 2 x 10 6Cells were seeded / Nunc T75 flask and cultured for 2 days. At the time of harvesting for assay, cell counts were approximately 6 x 10 6 cells. Wash the cells (1X) in DPBS (Hyclone, catalog #SH30028.03) for approximately 30 seconds. Add 1 mL 1X 0.05% trypsin-EDTA (GIBCO catalog #25300-054), swirl to cover the bottom of the flask, and let sit on the cells for approximately 4 minutes (±90% of the cells are lifted by tapping the flask). Add 10 mL of warm culture medium (DMEM high glucose medium Hyclone SH30022.02 supplemented with 10% fetal bovine serum, 2 mM sodium pyruvate, 10 mM HEPES, and 400 μg / mL G418) to inactivate trypsin. Grind the cells until a single cell suspension is obtained. Perform a cell count and centrifuge the cells at 2 x 10 5 / mL concentration into 250mL centrifuge tubes ± 30mL of pre-warmed culture medium. Place the 250mL centrifuge tube on a rocker in an incubator set at 28°C and gently shake for approximately 1 hour to allow the cells to recover. Aliquot 5mL of cells (1x 10 6 100 μL of external recording solution was added to the pellet and triturated 20 times to obtain a single cell suspension, which was then transferred to a 1.5 mL tube to be placed in a centrifuge tube. (Molecular Devices).

[0362] ii. Test Reagent Preparation

[0363] Compound 1 was provided as a powder and prepared as a 10 mM DMSO stock solution in a 1 dram glass vial prior to the assay. Compound 1 was diluted with DMSO to 300x the designated final assay concentration immediately prior to the assay. 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 assay. (Molecular Devices) recording protocol.

[0364] iii. (Molecular Devices) Recording Solution

[0365] Persistence and Peak I NaThe assay used the same intracellular recording solution, which contained: 135 mM CsF, 10 mM CsCl, 5 mM NaCl, 10 mM HEPES, 5 mM EGTA, pH 7.4 (adjusted with CsOH), and the measured osmotic pressure was 298 mOsm (adjusted with mannitol). Na For the measurement, the external recording solution contained: 135 mM NaCl, 5.4 mM KCl, 5 mM glucose, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES and 200 nM ATX-II (sea anemone toxin, Alomone Labs; Jerusalem, Israel), pH 7.4 (adjusted with NaOH), and the measured osmotic pressure was 300 mOsm (adjusted with mannitol). For Peak I 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 osmotic pressure of 300 mOsm (adjusted with mannitol).

[0366] iv. Experimental plan

[0367] All studies used The automated patch clamp platform (Molecular Devices) was used in 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). During the recordings, cell acceptance criteria were continuously monitored by custom scripts. Acceptance criteria for all assays were: baseline peak I Na >800pA, R seal >200MΩ and, where appropriate, continuous I Na >100 pA. Compensation was 50% and no leak subtraction was applied. Currents were filtered at 5 kHz and digitized at 32.5 kHz. R was monitored throughout the recording. access and R seal , and automatically terminate R through the script access >10MΩ or R seal Cells with <200 MΩ.

[0368] Late (persistent) current block: Inhibition of the late current activated by ATX-II was measured using a 200 ms voltage step to 0 mV. The protocol used a low stimulation rate (approximately 0.1 Hz) and a negative potential (-120 mV) to keep the channel in the closed (resting) state. The mean I Na Pharmacology was measured and no leak subtraction was applied.

[0369] Tonic block (TB): The tonic block (TB) protocol uses a low stimulation rate (approximately 0.1 Hz) and a negative potential (-120 mV) to keep the channel in a closed (resting) state. Na Pharmacology was measured during the period. No leak subtraction should be applied.

[0370] Usage-dependent block (UDB-10 Hz): The UDB protocol uses an increasing stimulation rate (10 Hz) to cycle channels between closed (resting), open, and fast inactivation states. Slow inactivation was minimized by using negative potentials (-120 mV) between steps. Peak I in response to a step to 0 mV was Na Pharmacology was measured during the period. No leak subtraction should be applied.

[0371] Voltage-dependent block (VDB): The VDB protocol uses a depolarizing voltage to hold the channel in a semi-inactivated (resting) state. This allows accurate determination of equilibrium binding and subtype selectivity (in the absence of biological features). For each cell, the channel was inactivated using a 5,000 ms step increase in voltage (10 mV increments), immediately followed by a 2 ms step to 0 mV to maximally activate the channel to determine the inactivation midpoint (V 0.5 The holding potential between steps (V hold ) is -120 mV. The peak I measured in response to the step to 0 mV Na Plot and fit the Boltzmann equation to determine V 0.5 This value is then used for the VDB scheme. In response to a step to 0 mV peak I Na Pharmacology was measured during the period. No leak subtraction should be applied.

[0372] GraphPad Prism (GraphPad Software) was used for plotting and fitting. Percent inhibition was calculated as mean ± SEM and plotted against the tested concentration. The Hill equation [Max_Effect / (1+(IC 50 / x)^Hill_Slope] to estimate the half inhibition (IC 50) Compound concentrations and Hill slopes were determined. For the usage-dependent blocking (UDB) assay, MaxEffect was allowed to vary, but for all other assays, MaxEffect was fixed at 100.

[0373] 2. Results

[0374] Compound 1 produces hNa at 10 Hz stimulation frequency (UDB) V Compound 1 blocked hNa from resting state (TB) V 1.6 channels were also concentration-dependent, however the extent of block was less than that observed for state-dependent or use-dependent assays ( Figure 2A ). For all the determination conditions, compound 1 is relative to peak 1 Na Showing persistence Na Preferences ( Figure 2A ). In contrast, the two standard Na V Targeted antiepileptic drugs lamotrigine (LTG) and carbamazepine (CBZ) show low efficacy and are ineffective for persistent I Na No preference ( Figure 2B (LTG) and Figure 2C (arrow in CBZ).

[0375] Example 3. Effect of Compound 1 on Maximum Electric Shock-Induced Seizures in a Mouse Model

[0376] The maximum electric shock (MES) test is a validated model for evaluating the anti-epileptic potential of compounds. Valproic acid (VPA) is used clinically for its anticonvulsant properties and is an effective treatment for tonic seizures. The purpose of these studies was to evaluate the effect of Compound 1 (0.3, 1, 3 and 10 mg / kg po (oral)) in attenuating MES-induced seizures in male CD-1 mice.

[0377] 1. Materials and Methods

[0378] i. Animals

[0379] Male CD-1 mice aged 6 weeks were obtained from Vital River (Beijing, China). At the time of the experiment, the average body weight was approximately 35 g. The mice were divided into 3-5 groups and housed under controlled conditions (temperature: 20-26°C; humidity: 40-70%; air exchange rate: 10-15 times / hour; 12:12 light-dark cycle, lights on at 5:00 am). Food and water were available ad libitum. The mice were allowed to adapt to these conditions for 6 days before starting behavioral testing.

[0380] ii. Pharmaceutical formulations

[0381] Dosing solutions were prepared on each experimental day. A stock solution of the highest dose of Compound 1 was prepared in 35% HPBCD (Vehicle 2) and diluted to prepare lower doses. VPA was prepared in saline (Vehicle 1). All solutions were protected from light. All compounds and vehicles were dosed at 10 ml / kg.

[0382] iii. Research plan

[0383] The MES test was performed for two days, with 6 of the 12 mice from each treatment group tested each day. The mice were brought to the testing room at least one hour before the start of the experiment. All animals were marked on the tail with a permanent marker and weighed. The mice were randomly assigned to one of the six treatment groups.

[0384] Animals were orally (po) administered Compound 1 or 35% HPBCD (Vehicle 2), or intraperitoneally (ip) administered VPA or saline (Vehicle 1) 30 minutes before MES testing.Possible side effects, such as overt sedation, were recorded immediately before the start of MES testing.

[0385] A Grass S88x (Grass Technologies of Astro-Med, Inc. (West Warwick, Rhode Island)) stimulation isolation unit (A385, WPI Inc., USA) was set to deliver 50 mA square wave stimulation with a duration of 0.8 seconds, a pulse width of 10 msec, and a frequency of 50 Hz. A pair of custom stainless steel electrodes were soaked in 0.2% agar, and the subjects then received bilateral transauricular stimulation via ear clip electrodes. During stimulation, the mice were restrained by hand. They were then placed in an observation cage immediately after stimulation for 60 seconds of convulsion observation. Each mouse was continuously observed by an individual who was blind to the treatment conditions and the results were recorded.

[0386] Sedation endpoints were assessed as follows: (1) None: mice exhibited normal motor behavior; (2) Mild: mice exhibited little movement or immobility when alone in their home cages, but exhibited normal motor activity if provoked by the observer's hand touch; (3) Moderate: mice exhibited immobility when alone in their home cages, and exhibited reduced motor activity when propelled or provoked by the observer's hand touch; and (4) Severe: mice completely lost the ability to move.

[0387] The endpoints for the evaluation of anti-epileptic seizures were: (1) latency to tonic flexion of the hind limbs; (2) latency to tonic extension of the hind limbs; (3) total number of tonic flexion of the hind limbs; (4) total number of tonic extension of the hind limbs; (5) latency to death; and (6) mortality.

[0388] 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 in a tube with 10 μL of EDTAK2. The tube was then placed in wet ice until centrifuged at 2,000g for 5 minutes at 4°C. The supernatant plasma was pipetted into an Eppendorf tube. Both brain and plasma samples were stored at -80°C until the concentration of compound 1 in each sample was determined.

[0389] iv. Plasma sample preparation

[0390] Aliquots of 20 μL of unknown samples, calibration standards, quality controls, diluted quality controls, single blanks, and double blanks were added to 1.5 mL tubes. Each sample (except the double blank) was quenched with 300 μL of IS solution (300 μL of ACN for the double blank), and the mixture was then vortexed thoroughly (at least 15 seconds) and centrifuged at 12000 g, 4°C for 15 minutes. 70 μL of supernatant was transferred to a 96-well plate and centrifuged at 3220 g, 4°C for 5 minutes. 5 μL of supernatant was then injected for LC-MS / MS analysis.

[0391] v. Brain Sample Preparation

[0392] Brain homogenate was prepared by homogenizing brain tissue with 5 volumes (w:v) of homogenization solution (cold 15mM PBS / MeOH (V:V, 2:1)). Aliquots of 20 μL of unknown samples, calibration standards, quality controls, diluted quality controls, single blanks, and double blanks were added to 1.5 mL tubes. Each sample (except the double blank) was quenched with 300 μL of IS solution (300 μL of ACN was used for the double blank), and the mixture was then vortexed thoroughly (at least 15 seconds) and centrifuged at 12000g, 4°C for 15 minutes. 70 μL of supernatant was transferred to a 96-well plate and centrifuged at 3220g, 4°C for 5 minutes. 5 μL of supernatant was then injected for LC-MS / MS analysis.

[0393] vi. Statistical analysis

[0394] All statistical analyses were performed using GraphPad Prism 7.0. Data are presented as mean ± sem. And p < 0.05 was considered statistically significant. The Mann-Whitney test was used to detect significant differences in latency and number of seizures between the saline group and the VPA group. The Kruskal-Wallis test, followed by the Dunn test, was used to detect significant differences in latency and number of seizures between 35% HPBCD and compound 1.

[0395] vii. Calculate ED 50 and EC 50value

[0396] Dose-response and concentration-response curves for plasma and brain were fitted for each endpoint using GraphPad Prism. Based on these fitted curves, ED 50 and EC 50 value.

[0397] 2. Results

[0398] like Figure 3 As shown in Figure 2, at 3 mg / kg (po), Compound 1 significantly increased the latency to seizure onset after bilateral transauricular stimulation. At 10 mg / kg (po), the ability of Compound 1 to increase the latency to seizure onset after MES was even more pronounced. Compound 1 had a calculated ED of 2 mg / kg. 50 These data suggest that compound 1 possesses anti-epileptic properties in the MES-induced seizure model.

[0399] Example 4. Effect of Compound 1 on spontaneous locomotor activity (sLMA) in a mouse model

[0400] 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 effects of Compound 1 (10, 20 and 40 mg / kg, po) on spontaneous locomotor activity (sLMA) in male CD-1 mice 30 minutes after dosing.

[0401] 1. Materials and Methods

[0402] i. Animals

[0403] Male CD-1 mice aged 6 weeks were obtained from Vital River (Beijing, China). At the time of the experiment, the average body weight was 25-35 g. The mice were divided into 3-5 groups and housed under controlled conditions (temperature: 20-26°C; humidity: 40-70%; air exchange rate: 10-15 times / hour; 12:12 light-dark cycle, lights on at 5:00 am). Food and water were available ad libitum. The mice were allowed to adapt to these conditions for 6 days before the start of the study.

[0404] ii. Pharmaceutical formulations

[0405] 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 prepare lower doses. The stock solution was stirred and sonicated for at least 20 minutes to obtain a uniform suspension. All solutions were protected from light. Samples from the dosing solutions were stored at 4°C. Both the compound and the vehicle were dosed at 10 ml / kg.

[0406] iii. Research plan

[0407] The sLMA test was performed for two days. Five of the ten mice from each treatment group were tested each day. All animals were marked on the tail with a permanent marker and weighed. Mice were randomly assigned to one of the four treatment groups. Animals were allowed to acclimate to the test room at least 30 minutes before starting the experiment.

[0408] Compound 1 or 35% HPBCD (vehicle) was administered orally (po) to the animals 30 minutes before the sLMA test.Possible side effects, such as overt sedation, were recorded just before the start of the sLMA test.

[0409] Sedation endpoints were assessed as follows: (1) None: mice exhibited normal motor behavior; (2) Mild: mice exhibited little movement or immobility when alone in their home cages, but exhibited normal motor activity if touched by an observer; (3) Moderate: mice exhibited immobility when alone in their home cages, and exhibited reduced motor activity when pushed or touched by an observer; and (4) Severe: mice completely lost the ability to move.

[0410] 30 minutes after administration of compound 1 or vehicle, mice were placed in the center of the test room (40x40x 30cm, floor illumination 45±5 lux) for 30 minutes of sLMA video recording. Using a 1-minute sampling window in the isolation room, each mouse was automatically tracked with an overhead camera. Spontaneous motor activity was then analyzed offline using an animal behavior video tracking analysis system (Ji Liang Software Technology Co., Ltd. (Shanghai, China)).

[0411] The movement state was defined as moving >2 mm in every 200 ms (the frame rate of the recording was 20 frames / second. The movement state was identified once every 4 inter-frame intervals. The cumulative displacement of the tracking points exceeding 2 mm in every 4 frame intervals was identified as a movement period). The travel distance was automatically calculated from all movement periods and analyzed. After the test, 2-3 representative mice showing side effects in each compound 1 treatment group were recorded for a short video (10 seconds).

[0412] All mice were anesthetized with CO2. Then, terminal plasma and brain tissue samples were collected from animals in the drug treatment group. 500 μL of whole blood was collected via cardiac puncture and placed in a tube with 10 μL of EDTAK2. The tube was then placed in wet ice until centrifuged at 2000g for 5 minutes at 4°C. The supernatant plasma was pipetted into an Eppendorf tube. Brain and plasma samples were stored at -80°C until drug concentration analysis of compound 1 levels was performed.

[0413] iv. Plasma sample preparation

[0414] Aliquots of 20 μL unknown samples, calibration standards, quality controls, diluted quality controls, single blanks and double blanks were added to 1.5 mL tubes. Each sample (except the double blank) was quenched with 300 μL IS solution (the double blank was quenched with 300 μL ACN), and the mixture was then vortexed thoroughly for at least 15 seconds and centrifuged at 12000 g, 4°C for 15 minutes. 65 μL of supernatant was transferred to a 96-well plate and centrifuged at 3220 g, 4°C for 5 minutes. 3 μL of supernatant was then injected directly for LC-MS / MS analysis.

[0415] v. Brain Sample Preparation

[0416] Brain homogenate was prepared by homogenizing brain tissue with 5 volumes (w:v) of cold 15mM PBS / MeOH (V:V, 2:1). Aliquots of 40 μL unknown samples, calibration standards, quality controls, diluted quality controls, single blanks and double blanks were added to 1.5 mL tubes. Each sample (except the double blank) was quenched with 600 μL IS solution (600 μL ACN was quenched for the double blank sample), and the mixture was then vortexed for at least 15 seconds and centrifuged at 12000g, 4°C for 15 minutes. 65 μL of supernatant was transferred to a 96-well plate and centrifuged at 3220g, 4°C for 5 minutes. 3 μL of supernatant was then injected directly for LC-MS / MS analysis.

[0417] vi. Statistical analysis

[0418] 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 and Dunnett post hoc test were used to detect significant differences in the distance traveled per 5-minute bin between the vehicle group and the compound 1 treatment group. ANOVA followed by Dunnett's test was used to detect significant differences in the total distance traveled over 30 minutes between the vehicle group and the compound 1 treatment group.

[0419] vii. Calculate TD 50 and TC 50 value

[0420] Dose-response and concentration-response curves for plasma and brain were fitted for each endpoint using GraphPad Prism. TD was calculated from these fitted curves. 50 and TC 50 value.

[0421] 2. Results

[0422] like Figure 4As shown in Figure 2, in the 30-minute sLMA test, 20 and 40 mg / kg doses of Compound 1 significantly reduced the total distance traveled. Compound 1 had a calculated TD of 44 mg / kg. 50 These data indicate that compound 1 at doses of 20 mg / kg and 40 mg / kg reduced locomotor activity.

[0423] Example 5. Effect of Compound 1 on Scn2a with elevated persistent sodium current Q54 Effects on seizure frequency in mouse models

[0424] The purpose of this study was to evaluate the efficacy of compound 1 (0.3 mg / kg, 1 mg / kg, 3 mg / kg or 10 mg / kg, po) in I Na SCN2A and SCN8A gain-of-function mutations have been identified in children with various forms of epileptic encephalopathy (EE) and these mutations increase Na V 1.2 and Na V 1.6 Continuous sodium current (I Na Scn2a was developed by introducing three consecutive point mutations (G879Q, A880Q, L881Q) into the full-length SCN2A gene. Q54 Mouse strain I Na The mutant gene encodes the CNS sodium channel Na V 1.2 Large pathological neuron persistence I Na (Kearney et al., A gain-of-function mutation in the sodium channel gene Scn2aresults in seizures and behavioral abnormalities, Neuroscience, 2001, 102(2):307-317; PMID 11166117). As in EE patients, Scn2a Q54 The mice exhibited early seizures, status epilepticus, and premature death.

[0425] 1. Materials and Methods

[0426] i. Animals

[0427] Scn2a was generated as described Q54Transgenic mice were generated and maintained as congenic strains on a C57BL / 6J (Jax#000664) background (B6.Q54) (Kearney et al., 2001; PMID 11166117). For experiments, B6.Q54 hemizygous transgenic males were crossed with SJL / J (Jax#000686) females and Scn2a was expressed. Q54 Transgenics were genotyped to generate F1 generation mice. The experimental animals used in this study were male and female mice at postnatal day 18-21 (P18-21), with the majority being P19-P20.

[0428] Mice were group housed in a specific pathogen-free mouse facility under standard laboratory conditions (14 / 10 h light / dark cycle). Mice had ad libitum access to food and water except during experiments to monitor seizures. All manipulations were performed during the light cycle of the animals.

[0429] ii. Compound Formulation and Administration

[0430] Dosing solutions were freshly prepared on the morning of the study day. Dosing solutions containing 0.5% methylcellulose and 0.2% Tween-80 were prepared with 1 mL of 10% Tween-80 (in ddH2O) and 49 mL of 0.5% methylcellulose (in ddH2O) 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 administration of vehicle or Compound 1 by oral gavage.

[0431] iii. Research design

[0432] To monitor seizures, two mice were placed in a monitoring cage (23 cm x 13 cm) and two side-viewing cameras were placed to record baseline spontaneous seizure activity. Q54Extensive video electroencephalogram (EEG) monitoring of transgenic mice demonstrated a strong correlation between behavior 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 minutes of recording, mice were administered compound 1 or vehicle and returned to their home cages. After 30 minutes, both mice were returned to the monitoring cage and recorded for another 30 minutes to assess post-treatment seizure activity. The number of focal motor seizures with forelimb clonus and repetitive movements lasting 1-5 seconds and generalized tonic-clonic seizures (GTCS) with retreat and falls lasting approximately 1 minute were counted. Seizures were scored offline by an observer who was blinded to the pre / post status of the treatment and video files.

[0433] iv. Computation and statistical analysis

[0434] The number of seizures before and after treatment was counted for each animal by an auditor blinded to the treatment and pre / post status of the video recordings. Mice with fewer than three 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 with Sidak multiple comparisons, and p < 0.05 was considered statistically significant (GraphPad Prism 8.4). The change in mean seizure frequency, expressed as a percentage, was determined by averaging each group and then calculating the relative change as [(avg.post–avg.pre) / avg.pre].

[0435] v. Plasma and brain collection

[0436] At the end of the seizure observation period, animals were sacrificed and blood was collected and transferred to heparinized blood collection tubes. The blood collection tubes were centrifuged at 5,000 g for 10 min and the plasma was moved to 1.5 mL Eppendorf tubes on dry ice. After blood collection, the brains were removed, frozen on dry ice and stored individually in 1.5 mL Eppendorf tubes. Rodent plasma and brain tissue were stored at -80 °C until shipped on dry ice for bioanalysis.

[0437] 2. Results

[0438] Scn2a was measured 30 min before treatment with compound 1 or vehicle. Q54Seizure frequency in mice was measured again 30 minutes after treatment. Treatment of Scn2a with Compound 1 at 1, 3, and 10 mg / kg was compared to pre-treatment baseline. Q54 The mice showed a significant reduction in the frequency of epileptic seizures ( Figure 5 At doses of 1 mg / kg and higher, seizure frequency was reduced by 50%, and no mice showed any seizures after dosing at 10 mg / kg.

[0439] In conclusion, compound 1 has an important role in Scn2a Q54 These data suggest that compound 1 has a significant anti-epileptic effect in persistent I Na It exhibits anticonvulsant activity in models of epilepsy and has potential for the treatment of epilepsy, particularly in syndromes where elevated persistent sodium currents are a genetic etiology.

[0440] Example 6. Effect of Compound 1 on Scn8a N1768 D / + Effects of audiogenic-induced epileptic seizures in a transgenic mouse model

[0441] The aim of this study was to evaluate the effects of compound 1 on audiogenic-induced seizures in the N1768D gain-of-function SCN8A epileptic encephalopathy mouse model (D / +). N1768 D / + Transgenic mice carrying Na V 1. Gain-of-function mutation in 6 (Wagnon et al., Convulsive seizures and SUDEP in a mouse model of SCN8 Aepileptic encephalopathy, Human Molecular Genetics, 2015, 24(2): 506-515).

[0442] Male and female N1768D (D / +) mice aged 8-12 weeks were used in the study. Compound 1 was administered orally (po) at three doses (1mg / kg, 3mg / kg, 10mg / kg) and the vehicle was also administered 1 hour before the test. Mice were randomly divided into groups so that each mouse was evaluated for compound 1 and vehicle at each test dose at the end of the study. The mice were retested after at least 3 days of waiting. During the test, mice were taken out of their home cages and transferred to a clean test cage in a separate test room, where they were allowed to adapt for about 20 seconds before starting acoustic stimulation. In order to induce audiogenic epileptic seizures, a 15kHz signal was generated using Tone Generator software (NCH Software, Inc.), amplified using a Kinter K3118 stereo amplifier (Kinter USA), and converted into sound using a small 3-watt speaker dropped into the test room. Stimulation was applied for 30 seconds, unless an epileptic seizure was detected before the 30-second time point, in which case audiogenic stimulation was terminated. Video of the event was recorded using a laptop webcam. On the last day of testing, brain and plasma were collected from D / + mice immediately after audiogenic seizure testing to determine the concentration of Compound 1. A separate cohort of 8 age-matched WT mice (n=2 / dose level) was also included to achieve a sample size of n=4 for PK per dose level. Brain and plasma samples were submitted for bioanalysis.

[0443] like Figure 6 As shown in , oral administration of Compound 1 resulted in a dose-dependent inhibition of audiogenic seizures in D / + mice. 10 mg / kg of Compound 1 (po) completely prevented audiogenic seizures.

[0444] In summary, in a human knock-in mouse model of SCN8A epileptic encephalopathy (EIEE13), compound 1 was shown to suppress audiogenic seizures in a dose-dependent manner. These studies confirm the efficacy of compound 1 in suppressing seizures associated with gain-of-function SCN8A mutations.

[0445] Example 7. Effect of Compound 1 on the duration of epileptic seizures induced by pentylenetetrazol

[0446] Pentylenetetrazol (PTZ) is a GABA receptor antagonist that can be used to create a common chemically induced seizure model, namely the generalized seizure model. PTZ experiments were performed in heterozygous Kcnq2K556E, Kcnc1 R320H, or Hcn1 M294L mice or their wild-type (WT) littermates (P35-P45, male and female).

[0447] Mice were allowed to acclimate to the experimental area for at least 30 min prior to the experiment. All experiments were performed between 10:00 AM and 12:30 PM. Treatment compounds and PTZ were always freshly prepared.

[0448] Mice were randomly assigned to different doses of Compound 1 (10 mg / kg, 1 mg / kg or 0.1 mg / kg) or a vehicle control group containing 0.5% methylcellulose and 0.2% Tween 80 and dosed via oral gavage (po). Compound 1 and vehicle control were administered 60 minutes before PTZ injection.

[0449] Retigabine (4 mg / kg) was also used as a positive control in Kcnq2 K556E mice. Retigabine was dissolved in 10% DMSO and 10% solutol and administered by intraperitoneal (ip) route 30 minutes before PTZ injection.

[0450] PTZ (100 mg / kg) was dissolved in saline and administered subcutaneously (sc) to experimental mice. The latency to a full tonic-clonic seizure with hindlimb extension was measured. Animals were sacrificed at hindlimb extension or 40 minutes after PTZ administration if no hindlimb extension was recorded.

[0451] Data were analyzed using the Mantel-Cox log-rank test.At the PTZ endpoint, brain tissue and plasma were collected from some mice for each dose of Compound 1 for PK analysis.

[0452] like Figure 7A-7B As shown in Figure 2, at a dose of 10 mg / kg, compound 1 had an Fig. 7A ) and KCNC1( Figure 7B ) has high efficacy in epilepsy models.

[0453] Example 8. Compound 1 has potent anticonvulsant activity with improved protection index compared to standard of care sodium channel blockers

[0454] This study compared compound 1 with two standard voltage-gated sodium channels (Na V ) blockers on sodium current (I Na ), intrinsic neuronal excitability, and resistance to seizure-inducing influences to determine priority persistence I Na Whether inhibitors such as Compound 1 show improved preclinical efficacy and tolerability.

[0455] Characterization of I using patch clamp analysis NaThe effects on intrinsic excitability were measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electric shock seizure (MES) model, and tolerability was assessed by measuring spontaneous motor activity (sLMA). All assays are described in the previous examples.

[0456] 1. Compound 1 potently inhibits persistent I Na

[0457] Compound 1 potently inhibited the expression of wild-type hNa V 1.6 Expression of ATX-II induces persistent I Na ( Fig. 8A ;IC 50 =141nmol / L) and hNa mutant by DEE V 1.6-Persistence of N1768D expression I Na ( Figure 8B ;IC 50 =75 nmol / L). By maintaining a hyperpolarized holding potential (-120 mV), persistent I was activated from the resting / closed channel conformation. Na Extracellular sodium (NMDG + ) completely inhibited the sodium-dependent conduction. Na The potency is higher than that of standard Na V Targeted AEDs are at least 550 times more potent ( Figure 8C , Table 1). Compound 1 has a positive effect on Na V Subtype (hNa V 1.1(NP_008851.3), hNa V 1.2(NP_066287.2), hNa V 1.5 (NP_000326.2)) and the rat, dog, and mouse orthologs (rNa V 1.2(NP_036779.1), dNa V 1.2(XP_013966299.1), mNa V 1.6 (NP_035453.2) and rNa V 1.6 (NP_062139)) Persistence of expression I Na showed similar inhibitory potency, IC 50 The value is in the range of 109-180nmol / L ( Fig.8D ).

[0458] 2. Effect of Compound 1 on Persistent I Na Alignment Peak I Na Shows enhanced inhibitory preference

[0459] Use of a glycosylated chromatin with increased hNa V 1.6 Three determinations of activation levels to study Peak I Na Physiological peak I was measured from the resting / closed channel conformation at low stimulation frequency (.1 Hz). Na Tension block ( Fig. 9A Compound 1 showed less potent tonic blockade (IC 50 =8470nmol / L), confirming the effect of sustained I Na Compound 1 also has a 60-fold preference for other V Subtypes show persistence I Na Alignment Peak I Na Preference for tension block: hNa V 1.1 (173 times, 109 nmol / L vs. 18 870 nmol / L), hNa V 1.2 (80 times, 172 nmol / L vs. 13 690 nmol / L) and hNa V 1.5 (>174-fold, 172 nmol / L vs. 12% inhibition at 30 000 nmol / L).

[0460] The effect of compound 1 on hNa was measured using a series of short voltage steps at a frequency of 10 Hz. V Use of (activity) dependent block of 1.6 to represent periods of elevated neuronal firing (e.g., during an epileptic seizure), where peak I Na Compound 1 exhibits hNa V 1.6 Peak I Na Use-dependent blockade, IC 50 is 271nmol / L, and the maximum inhibition is 75% (blue trace, Fig. 9B ; Table 1). Notably, no use-dependent block was observed for either CBZ or LTG at a stimulation frequency of 10 Hz (blue traces, respectively, Fig.9E and Fig.9F ). By increasing the depolarization frequency from 10 Hz to 30 Hz or 50 Hz, a use-dependent blockade can be observed for CBZ. At all frequencies, the extent of the use-dependent blockade observed for Compound 1 was significantly higher compared to CBZ, indicating that Compound 1 has a greater ability to respond to acute changes in neuronal activity (acute hyperexcitability).

[0461] Peak I Na Voltage-dependent block was measured using a continuous nonphysiological inactivation voltage step to the midpoint of steady-state inactivation (V 1 / 2) (determined in real time for each cell) to keep half of the channels in the inactive state. This approach effectively explores subtype selectivity because differences in voltage sensing that regulate binding site access are minimized, and the extended time allows most inhibitors to reach binding equilibrium. Compound 1 exhibited a voltage-dependent block IC of 317 nmol / L 50 ( Fig. 9C , Table 1). These data confirm that, with channel inactivation, the persistence of I Na The 2.2-fold preference was retained (red arrow, Fig.9D ; Table 1). Compound 1 to hNa V 1.1 (6.3 times), hNa V 1.2 (8.2 times) and hNa V 1.5 (5.8 times) showed a persistent I Na Alignment Peak I Na Compound 1 also induced hNa V 1.6 Concentration-dependent stabilization of inactivation, as shown by the V of the steady-state inactivation curve 1 / 2 This was confirmed by a significant left shift of DMSO / control at -2.6 mV, 0.3 μmol / L Compound 1 at -6.2 mV, and 1 μmol / L Compound 1 at -11.7 mV. Only V of the activation curve was observed. 1 / 2 There were small shifts: DMSO / control shifted -1.3 mV, 0.3 μmol / L Compound 1 shifted -2.3 mV, and 1 μmol / L Compound 1 shifted -2.7 mV. These data indicate that Compound 1 enhances fast inactivation with minimal effect on activation gating.

[0462] In the same persistence Na Hefeng I Na A set of standard Na V Targeted AEDs. All tested inhibitors were less potent in all assays compared to compound 1 (Table 1). As the channel transitions to a more activated / inactivated state, the tonic blockade assays for other I Na Moderate persistence observed with inhibitors I Na Preference was lost (eight-fold to 30-fold), as was the case in the voltage-dependent block assay (0.3-fold to 0.9-fold preference). Na The voltage-dependent blockade of I Na more potent (0.6-fold and 0.5-fold, respectively), indicating that under these conditions the peak I Na preferences.

[0463] Table 1. Standard Na VCompared with targeted anti-epileptic drugs, compound 1 showed a strong V 1.6 Persistence I Na of higher efficacy and preference.

[0464]

[0465]

[0466] Abbreviation: IC 50 , half-maximal inhibitory concentration; I Na , sodium current; MAX, maximum value; nd, not determined; n / a, not available; Na V , voltage-gated sodium channel; TB, tonic block; UDB, use-dependent block; VDB, voltage-dependent block.

[0467] a The amount could not be determined due to solubility limitations of the compound.

[0468] 3. Compound 1 reduces the intrinsic excitability of wild-type CA1 pyramidal neurons

[0469] Prediction of persistence Na Preferential inhibition of α would reduce neuronal hyperexcitability without excessively disrupting AP morphology, including AP amplitude, since this feature depends on peak I Na Using Peak I Na Voltage-dependent blocking IC 50 The effects of compound 1 and CBZ on the intrinsic excitability of neurons were measured by evoked AP firing (input-output curve) at equivalent effective concentrations of 0.3 μmol / L (Table 1). At 0.3 μmol / L, compound 1 significantly reduced the intrinsic excitability as measured by the number of evoked APs ( Fig. 10A ). In contrast, 45 μmol / L CBZ produced a more robust reduction in neuronal excitability ( Fig. 10D ). Compared with compound 1, CBZ caused a more significant decrease in AP amplitude, indicating that its effect on peak I Na Greater inhibition ( Fig.10F These data suggest that although both agents produce a decrease in the excitability of wild-type CA1 neurons, compound 1 may do so by preserving peak I at a higher rate. Na It reduces excitability in a manner that maintains physiological activity over a wider concentration range than CBZ.

[0470] 4. Compound 1 achieves full anticonvulsant efficacy without affecting motor activity

[0471] To evaluate the persistence of compound 1 with its in vitro characteristics NaTo investigate whether the inhibitor can prevent epileptic seizures, the anticonvulsant activity was investigated in the mouse MES model. This model has predictive validity for clinical anticonvulsant activity. Compound 1 was compared with standard Na V The targeted AEDs, CBZ, and LTG were compared. Compound 1 induced dose-dependent protection (prolonged latency) against MES-induced tonic hindlimb seizures in mice ( Fig.11A Nearly 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. Calculation of ED for increasing latency to tonic extension seizures 50 The value is 2 mg / kg, and the calculated EC in plasma and brain 50 The values ​​were 90.1 ng / ml (free concentration 17.9 nmol / L) and 116 ng / g (free concentration 4.3 nmol / L), respectively (Table 2).

[0472] Table 2. Compound 1 has improved preclinical PI compared to CBZ and LTG.

[0473]

[0474] Note: Shown with MES ED 50 / EC 50 and sLMA TD 50 / TC 50 The mean drug concentration was calculated as 50 / brainEC 50 .

[0475] Abbreviations: CBZ, carbamazepine; EC 50 , half maximal effective concentration; ED 50 , half maximal effective dose; LTG, lamotrigine; MES, maximum electroconvulsive seizure; PI, protection index; sLMA, spontaneous motor activity; TC 50 , half maximum tolerated concentration; TD 50 , half the maximum tolerated dose.

[0476] CBZ and LTG also provided dose-dependent protection to mice against MES-induced tonic hindlimb seizures, with CBZ (30 mg / kg) protecting all mice, while LTG protected eight of 12 mice at the highest dose tested (10 mg / kg). Calculation of the ED for increasing the latency to tonic extension seizures for CBZ and LTG 50 The values ​​were 5 and 3.4 mg / kg respectively (Table 2).

[0477] To determine the tolerability of Compound 1, the effect on sLMA was measured. Compound 1 produced a decrease in the distance moved at 20 and 40 mg / kg ( Fig. 11C The dose of compound 1 (10 mg / kg) that resulted in prevention of seizures in 11 of 12 mice had no effect on motor function. The dose of compound 1 required to reduce sLMA by 50% (TD 50 ) was 44 mg / kg. The concentration of compound 1 associated with 50% effect (TC 50 ) were 1553 ng / ml (free concentration 308.9 nmol / L) and 1899 ng / g (free concentration 69.7 nmol / L) in plasma and brain, respectively (Table 2).

[0478] CBZ and LTG also produced dose-dependent decreases in sLMA, ED 50 The values ​​were 37.6 and 26.5 mg / kg, respectively (Table 2). Notably, CBZ produced a significant decrease in sLMA at the dose required to completely prevent seizures.

[0479] By reducing sLMA in the brain or plasma TC 50 divided by the brain or plasma EC that increases seizure latency 50 To calculate the tolerability to efficacy ratio (PI) of each molecule ( Fig.11D Compound 1 had a significantly improved PI of approximately 16-fold (based on calculated free brain concentrations) and 17-fold (based on free plasma concentrations). This represents a significant improvement compared to CBZ (brain, 5.9×; plasma, 3.4×) and LTG (brain, 4.7×; plasma, 6.4×; Fig.11E ) compared with the control group, PI was improved.

[0480] 5. Combination of Compound 1 with standard-of-care sodium channel blockers produces greater efficacy in vivo and does not alter tolerability

[0481] The effects of Compound 1 in combination with the standard of care sodium channel blocker CBZ were tested in the MES model and sLMA assay.

[0482] In the MES model, 2 mg / kg Compound 1 and 5 mg / kg CBZ were tested alone or in combination in CD-1 mice. Compound 1 and CBZ were prepared in 35% HPBCD, respectively. Animals were dosed with any of the following 30 minutes before MES testing: 1) 35% HPBCD ip + 35% HPBCD po; 2) 35% HPBCD ip + Compound 1 p.o.; 3) CBZ i.p. + 35% HPBCD po; 4) CBZ ip + Compound 1 p.o.; 5) Positive control group valproate (VPA) or saline ip, 30 minutes before MES testing. All solutions were administered at 10 mL / kg. Possible side effects, such as obvious sedation, were recorded immediately before the start of the MES test. Fig. 12A As shown in Figure 2, the combination of Compound 1 and CBZ was more effective than Compound 1 or CBZ alone in the MES model. The exposures in all groups were consistent and at expected levels.

[0483] In the sLMA assay, 10 mg / kg Compound 1 and 30 mg / kg CBZ were tested alone or in combination in CD-1 mice. Compound 1 and CBZ were prepared in 35% HPBCD, respectively. Animals were dosed with any of the following 30 minutes before the sLMA test: 1) 35% HPBCD ip + 35% HPBCD po; 2) 35% HPBCD ip + Compound 1 p.o.; 3) CBZ ip + 35% HPBCD po; 4) CBZ ip + Compound 1 p.o. All solutions were dosed at 10 mL / kg. Possible side effects, such as significant sedation, were recorded immediately before the start of the sLMA test. Fig. 12B As shown in Figure 2, the combination of Compound 1 and CBZ did not impair tolerability. The exposures in all groups were consistent and at the expected levels.

[0484] Example 9. Study on the safety, tolerability, efficacy and pharmacokinetics of compound 1 in patients with developmental epileptic encephalopathy

[0485] As shown in animal models, compound 1 mediated a persistent sodium current (I Na ) blockade can produce anti-epileptic efficacy at a well-tolerated dose. Na , and the persistence I NaCompared with less selective standard of care (SOC) sodium channel blockers (SCBs), compound 1 may provide greater efficacy in reducing seizures. Due to its lower activity at peak current, compound 1 will be better tolerated than SOC, resulting in fewer on-target AEs. Therefore, when used as first-line monotherapy, compound 1 may be effective and well tolerated, allowing for improved patient outcomes and treatment continuity from infancy to adulthood.

[0486] Preclinical data and emerging clinical data suggest that compound 1 has potential for the treatment of disease states with Na V The selectivity of enhanced channel superexcitability, wide therapeutic window and convenient automated titration scheme, as well as stable PK, all contribute to its excellent safety and efficacy in animal models and its expected therapeutic utility in human patients with epilepsy such as SCN2A, SCN8A and other DEEs.

[0487] The objectives of this study were to evaluate the safety and tolerability of compound 1, assess the effect of compound 1 on motor seizure frequency, and characterize the pharmacokinetics (PK) of an oral suspension of compound 1 in patients with developmental epileptic encephalopathy (DEE).

[0488] This is an open-label proof-of-concept study in 3 cohorts of DEE patients (SCN2A, SCN8A, and tuberous sclerosis complex (TSC)) aged 2 to 17 years. There will be an 8-week screening period, followed by a 16-week treatment period consisting of an 8-week dose optimization period and an 8-week maintenance period, with a 4-week safety follow-up period or transfer to LTE. The 16-week treatment period is based on the current understanding of the pharmacokinetics of compound 1, which is expected to take approximately 6 weeks to achieve 90% steady state. The 8-week dose optimization period allows for adjustment of concomitant SCBs, and an additional 8 weeks will allow for evaluation of tolerability and efficacy signals during the maintenance period.

[0489] For efficacy endpoints, each cohort will be reviewed in parallel with each other as a separate cohort and analyzed separately. The primary objective is the safety and tolerability of compound 1, and the main secondary objective is the efficacy of compound 1, as determined by the average monthly (28-day) motor seizure frequency during the maintenance period compared to baseline. The main elements of the study schedule are provided in Table 3.

[0490] Table 3. Main elements of the study timeline.

[0491]

[0492]

[0493] Dosing will be based on preclinical data (EC from the MES model 50With EC 90 The target concentration between 1 mg / kg and 2 mg / d is used as a guide, and the duration of the dose optimization phase will be based on the adult PK data. During the dose optimization phase, the dose is adjusted as follows. The starting dose is 1 mg / kg / day of compound 1. If there is no improvement in seizure frequency (reduction by 30%) and no tolerability issues within the first 6 weeks, the dose can be increased to 1.5 mg / kg / day. If there are tolerability issues, the dose is reduced back to 1 mg / kg / day. If there are tolerability issues at 1 mg / kg / day of compound 1 during the dose optimization phase, the concomitant SCB is first reduced by ≥25% while continuing the administration of compound 1 and evaluating after 1 week. If tolerability issues persist, the concomitant SCB is reduced by another ≥25% while continuing the administration of compound 1 and evaluating after 1 week. If tolerability issues persist, compound 1 is reduced to 0.5 mg / kg / day. If there is no tolerability at 0.5 mg / kg / day of compound 1, the patient is withdrawn from the study.

[0494] Participants will be selected based on the following eligibility criteria: (1) a documented diagnosis of SCN2A, SCN8A, or TSC; (2) male and female patients aged ≥2 years and ≤17 years at the time of informed consent;

[0495] (3) an average of ≥8 motor seizures per month in the 3 months immediately before screening based on the investigator's assessment, and ≥8 motor seizures during the 1-month baseline period based on diary collection (motor seizures were defined as: tonic, tonic-clonic, focal with secondary generalization, focal with motor symptoms, and epileptic spasms, excluding myoclonus alone or without myoclonus);

[0496] (4) The Epilepsy Research Alliance Eligibility Review Committee agreed to enroll; (5) Receiving a stable dose of anti-epileptic medication (ASM) 1 month prior to screening, of which no more than 2 ASMs could be sodium channel blocking ASMs; and (6) Agreeing to keep all anti-seizure therapies (ASM, CBD / THC products, VNS settings, ketogenic or other dietary parameters, etc.) stable throughout the study, unless otherwise indicated by the investigator or required by the protocol. Benzodiazepines used daily to treat seizures Drugs of this class are considered ASMs. If using CBD and / or THC products, the CBD and / or THC products must be at a stable dose for 1 month prior to screening. If using VNS, the VNS must have been placed at least 3 months prior to screening and maintained a stable setting for at least 1 month prior to screening, and the VNS is not counted as an ASM. If the patient is on a ketogenic diet or other diet to manage seizures, the patient must have started that diet at least 3 months prior to screening and maintained stable parameters for at least 1 month prior to screening, and the diet is not counted as an ASM.

[0497] Eligibility criteria for exclusion included: (1) loss-of-function mutations and / or clinical evidence of exacerbation of seizures by prior exposure to sodium channel blocking drugs; (2) two or more episodes of convulsive status epilepticus requiring hospitalization and intubation within 6 months prior to screening; (3) a history of left bundle branch block, Brugada syndrome, or congenital heart disease (a PFO without clinical significance was not considered an exclusion); (4) abnormal ECG readings at screening or before randomization, including a QT interval corrected by the Fridericia correction method (QTcF) >xxx msec (male) or >xxx nsec (female); (5) any of the following abnormal laboratory test results at screening: serum total bilirubin value >1.5x upper limit of normal (ULN) and / or serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2xULN; (6) previous use of any gene therapy; (7) receipt of any other experimental or investigational drug, device or other therapy within 30 days or 5 half-lives (whichever is longer) prior to screening; (8) previous participation or current participation in any other Compound 1 clinical trial; (9) known hypersensitivity reaction to any component of the formulation of Compound 1; and (10) drugs / classes that are about to be contraindicated.

[0498] Preliminary data from the first 12 participants enrolled in the study showed that exposure of Compound 1 on Day 1 was above the predicted therapeutic level ( Fig.13A ), and compound 1 approached steady-state after 28 days of once-daily dosing and auto-titration, which was well above the predicted therapeutic exposure ( Fig. 13B ).

[0499] Example 10. Safety, tolerability, pharmacokinetics and food effect study of compound 1 in healthy volunteers

[0500] The purpose 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 the PK of a single dose in healthy adults.

[0501] This is a 3-part Phase 1 clinical trial conducted in healthy participants aged 18-55 years. Parts A and B were randomly assigned, placebo-controlled, and evaluated the effects of single oral doses (2.5-150 mg) and multiple (30-120 mg, 14 days QD (daily)) increasing oral doses of compound 1, respectively. Part C was an open-label, randomized, crossover design to evaluate the PK of a single oral dose (90 mg) in the fasting and fed state. In Part A (n=64) and Part B (n=32), participants were randomly assigned 3:1 to the compound 1 group or the placebo group (n=8 / cohort). In Part C (n=16), participants were randomly assigned 1:1 to one of two treatment sequences of receiving a single dose of 90 mg compound 1 in the fed state (after a high-fat / high-calorie meal) or in the fasting state (≥10 hours after the last meal and 4 hours before the next meal).

[0502] In this clinical trial, the PD activity of Compound 1 was evaluated in healthy participants using electroencephalogram (EEG)-based auditory steady-state response (ASSR) measurements and resting-state EEG (qEEG)-based spectral power measurements in eyes-open and eyes-closed states.

[0503] ASSR-based phase-locking factor (PLF) data indicate that plasma exposures of compound 1 sufficient to modulate ASSR signaling were achieved at 90 mg and 120 mg compound 1 QD doses. In Part B, PLF was observed to be reduced by approximately 30% and 60% relative to baseline on Day 14 (2 hours and 35 minutes after dosing) 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 measurement. No statistically significant differences were observed between placebo and any compound 1 dose level for absolute induced gamma power based on ASSR. Nevertheless, these data indicate that in healthy participants, the exposures of compound 1 achieved with the 90-mg and 120-mg QD dosing regimens were sufficient to modulate the cortical excitation / inhibition balance in the brain.

[0504] Resting-state EEG (qEEG) was collected only in the 120-mg single-dose and multiple-dose cohorts in Part A and Part B, respectively. Increases in delta (1.5-6 Hz) and theta (6-8.5 Hz) band spectral power relative to baseline were observed in both the 120-mg Compound 1 single-dose group and the 120-mg Compound 1 QD group.

[0505] A total of 112 participants were enrolled in the trial (Compound 1, n=88; Placebo, n=24). Compound 1 was well tolerated, with no clinically significant safety issues identified in vital signs, clinical laboratory results, physical examinations, electrocardiograms (ECGs), or Columbia-Suicidality Severity Rating Scale (C-SSRS) data. Treatment-emergent adverse events (TEAEs) were mild (>92%); the most common were catheter site reactions, headache, and dizziness. 34% of participants experienced typical Na V blocker events and were reported more frequently at higher doses (120 mg and 150 mg).

[0506] Exposure increased in a dose-proportional manner over the dose range evaluated. Compound 1 rapidly appeared in plasma, with the maximum concentration observed (t max ) between 2 and 3 hours and were present at detectable levels throughout the dosing interval. Administration of a 90-mg dose in the fed state resulted in C max Slightly increased (9%), t max Delay (4 hours vs. 2.5 hours) and modest increase in AUC (14%).

[0507] In healthy participants, Compound 1 was well tolerated when administered in both the fed and fasted states at a single dose of up to 150 mg in Part A (fasting), multiple doses of up to 120 mg QD for 14 days in Part B (fasting), and a single dose of 90 mg in Part C. These findings further suggest that Compound 1 can be administered without regard to food.

[0508] Example 11. Phase 1 trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of compound 1 in healthy volunteers

[0509] This was a 2-part, randomized, placebo-controlled, Phase I trial in healthy participants aged 18-55 years. Part A evaluated the effects of 90 mg Compound 1 over 28 days (QD) relative to placebo. Part B evaluated the effects of oxcarbazepine (OXC) in combination with 120 mg Compound 1 (QD) relative to OXC alone over 28 days. PD effects were examined on quantitative EEG (qEEG; resting and alert states) and stimulated EEG using auditory steady-state response (ASSR). A total of 48 participants were recruited; Part A, n=30; Part B, n=18.

[0510] There were no clinically significant safety issues in vital signs, physical examinations, ECGs, or C-SSRS data. TEAEs were primarily mild or moderate (100% in Part A; 96% in Part B). In Part A, 90 mg of Compound 1 was well tolerated in healthy adults. In Part A, there were 35 TEAEs in 13 participants: 71% mild, 29% moderate, and 0% severe in severity.

[0511] In Part B, there were 74 TEAEs in 16 participants: 51% mild, 45% moderate, and 4% severe in severity. TEAEs were observed in 13 (92.9%) patients receiving OXC + Compound 1 and in 3 (75%) patients receiving OXC + placebo. Review of ALT / AST elevations and rhabdomyolysis found no causal relationship to Compound 1. One Part B participant experienced 3 study drug-related SAEs, leading to study drug discontinuation. The majority of AEs in Part B, including SAEs, were considered to be due to co-administration of expected supratherapeutic doses of Compound 1 (120 mg) with OXC and possibly additive NaV blocking effects.

[0512] In Part A, steady state was approached after 28 days of administration of 90 mg of Compound 1. In Part B, exposure to OXC and its major metabolite 10-hydroxycarbamazepine appeared similar when administered concomitantly with Compound 1 compared to administration alone, as shown in the table below. Specifically, the table below shows a summary of Compound 1 exposure on Day 7 (120 mg, Part B).

[0513]

[0514] In Part B, Compound 1 exposure did not appear to be altered by co-administration of OXC (data not shown). Part A PK results indicated that Compound 1 concentrations were 13-fold higher than the human equivalent dose required to achieve efficacy as measured in a preclinical maximal electric seizure model.

[0515] PD biomarker changes observed on qEEG and ASSR were exposure dependent; qEEG changes were observed across all spectral frequencies. In Part A, statistically significant differences between placebo and Compound 1 were observed on qEEG (delta and theta power) and ASSR (phase-locked factor (PLF) and evoked power). The effects on both low-frequency qEEG power and ASSR appeared to be Compound 1 concentration-dependent. In Part B, statistically significant differences were observed on qEEG delta between participants receiving OXC + Compound 1 and OXC alone, but no statistically significant differences were observed on qEEG theta or ASSR. The PD results suggest that Compound 1 achieves CNS modulation and intended target engagement across multiple qEEG measures.

[0516] Example 12. Phase 1, open-label trial evaluating the drug interaction potential of Compound 1 in healthy participants

[0517] This is a Phase 1, open-label trial in healthy male or female participants to investigate the effects of co-administration of Compound 1 on the PK of caffeine, dextromethorphan, and midazolam, and the effects of co-administration of ciprofloxacin and itraconazole on the PK of Compound 1. The trial will be conducted in 2 parts: a non-randomized single-sequence crossover (Part A) and a randomized parallel design (Part B). Each part will consist of 3 different phases: screening, intervention, and follow-up.

[0518] Goals and End Points

[0519]

[0520]

[0521]

[0522] Screening period

[0523] Participants will be screened for eligibility during a 27-day screening phase (from Day -28 to Day -2). Participants will provide written informed consent prior to any clinical trial procedures. Screening assessments will be completed to assess the eligibility of participants to enter the trial.

[0524] Intervention period

[0525] Section A

[0526] Fifteen participants who meet all inclusion criteria and do not meet any exclusion criteria will go to the clinical site for admission on Day -1 and stay at the clinical site from the date of admission until discharge. On the morning of Day 1, a single oral dose of caffeine 100 mg, dextromethorphan 30 mg, and midazolam 2 mg will be administered. From Day 2 to Day 18, participants will take a 120 mg oral dose of Compound 1 every morning. On Day 16, a single oral dose of caffeine 100 mg, dextromethorphan 30 mg, and midazolam 2 mg will be administered, followed immediately by Compound 1. Safety assessments and PK sampling will be performed on CYP probes and their metabolites (caffeine / paraxanthine, dextromethorphan / dextrphan, midazolam / 1-hydroxymidazolam) and Compound 1. Participants will be discharged on Day 19 after satisfactory safety review and completion of trial-related procedures.

[0527] Section B

[0528] Forty-five participants who meet all inclusion criteria and do not meet any exclusion criteria will be randomly assigned to one of three treatment groups, with 15 participants in each group. Participants in each treatment group will visit the clinical site for admission on Day -1 and will stay at the clinical site from the date of admission until discharge. Participants will be orally administered the trial medication as follows:

[0529] Treatment Group 1: Single dose of Compound 1 120 mg on Day 1.

[0530] Treatment Group 2: Ciprofloxacin 500 mg twice daily (Day 1 to Day 18). Single dose of compound 1120 mg on Day 5.

[0531] Treatment Group 3: Itraconazole 200 mg twice daily (Day 1) and 200 mg once daily (Day 2 to Day 18). Day 5 Single dose of Compound 1 120 mg.

[0532] Safety assessments and PK sampling will be performed for Compound 1, ciprofloxacin, and itraconazole. Participants will be discharged from the clinic on Day 19 following satisfactory safety review and completion of trial-related procedures.

[0533] Safety follow-up period

[0534] The safety follow-up period will be from discharge from the clinic to 28 days (±2 days) after the last dose administration. On Day 26 (±2 days) of Part A and Part B, participants will return to the clinic for the final clinical trial assessment. At the end of the safety follow-up period, participants will receive a phone call to assess AEs and concomitant medications.

[0535] Pharmacokinetic evaluation

[0536] Blood samples will be collected to measure the plasma concentrations of Compound 1, caffeine (and metabolite paraxanthine), dextromethorphan (and metabolite dextrorphan), midazolam (and 1-hydroxymidazolam), ciprofloxacin, and itraconazole. The collected samples may also be used to evaluate safety related to issues that arise during or after clinical trials. The samples may also be used for additional exploratory method development and / or metabolite characterization purposes.

[0537] Adverse events and serious adverse events

[0538] AEs will be reported by the participant (or, where appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative) and may include:

[0539] Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital sign measurements), including those that are worsening from baseline and considered clinically significant (i.e., not related to progression of underlying disease) in the medical and scientific judgment of the investigator.

[0540] An exacerbation of a chronic or intermittent pre-existing condition, including an increase in the frequency and / or intensity of the condition.

[0541] · A new condition is detected or diagnosed after administration of the study drug, even though it may have existed before the start of the clinical trial.

[0542] Signs, symptoms, or clinical sequelae of suspected drug interactions.

[0543] Suspected signs, symptoms, or clinical sequelae of overdose of study drug or concomitant medications.

[0544] Overdose itself is not reported as an AE / SAE unless it is an intentional overdose with possible suicidal / self-harming intent. Such overdoses should be reported regardless of whether there are sequelae.

[0545] Each AE and SAE reported during a clinical trial will be assigned to one of the following categories:

[0546] Mild: Events that are easily tolerated by the participant, cause minimal discomfort, and do not interfere with daily activities.

[0547] Moderate: Events that cause sufficient discomfort to interfere with normal daily activities

[0548] Severe: An event that interferes with normal daily activities. AEs assessed as severe should not be confused with SAEs. Severity is a category used to rate the intensity of an event; both AEs and SAEs can be assessed as severe.

[0549] Example 13. A Phase 2, Double-Blind, Randomized Clinical Trial Exploring the Safety, Tolerability, Efficacy, and Pharmacokinetics of Compound 1 in Pediatric Participants with Developmental Epileptic Encephalopathy, Followed by an Open-Label Extension

[0550] This Phase 2, multicenter, double-blind, randomized clinical trial followed by an open-label extension (OLE) was designed to explore the safety, tolerability, efficacy, and PK of Compound 1 when administered to pediatric participants with epileptic seizures associated with early-onset SCN2A-DEE and SCN8A-DEE.

[0551] Eligible male and female participants aged 2 to 18 years (inclusive) diagnosed with early-onset SCN2A DEE (n≈10) and SCN8A-DEE (n≈10) will be enrolled in 2 different cohorts in the clinical trial.

[0552] Part A (randomized, double-blind) will consist of the following phases: screening phase (including a 28-day baseline observation period), double-blind treatment phase, and safety follow-up phase. Part B (OLE) will consist of the following phases: OLE treatment phase and safety follow-up phase.

[0553] Goals and End Points

[0554]

[0555]

[0556]

[0557]

[0558] Section A

[0559] Screening period

[0560] Participants will provide written informed consent / assent prior to commencing any study procedures. The Screening Period will last up to 6 weeks, including a 28-day baseline observation period. If necessary and approved by the Sponsor's Medical Director, the Screening Period may be extended by up to 2 weeks to complete all screening procedures.

[0561] After completing the screening assessment, participants will begin a 28-day baseline observation period. At the beginning of the screening period, participants will be given an electronic diary to record the frequency of countable motor seizures daily (as defined in the trial inclusion criteria), and audio / video equipment (Nelli) will be provided to monitor nocturnal seizure activity if permitted locally. The countable motor seizure data recorded in the diary during this 28-day observation period will be used to determine eligibility for the clinical trial and establish a baseline for efficacy analysis. In addition, a baseline video electroencephalogram (vEEG) will be performed during the screening period.

[0562] Double-blind treatment period

[0563] The double-blind treatment period will last for 16 weeks. Participants will return to the clinic on the first day for additional baseline assessments and eligibility confirmation. Participants who continue to meet all trial inclusion criteria will be enrolled in the appropriate cohort based on their clinical diagnosis (SCN2A-DEE or SCN8ADEE). Participants in each cohort will be randomly assigned in a double-blind manner (1:1 ratio) to receive compound 1 once a day (QD) for 16 weeks (compound 1 arm) or compound 1 QD for 12 weeks and matching placebo QD for 4 weeks (compound 1 / placebo arm). Participants randomized to the compound 1 / placebo arm will receive placebo for 4 consecutive weeks at a certain time point during the 16-week treatment period.

[0564] 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). The dose levels of concomitant SCBs (if applicable) and study drugs will be adjusted based on tolerability and / or efficacy as described below. The dose levels of other ASMs and related concomitant medications should remain unchanged during the double-blind treatment period.

[0565] Safety follow-up period

[0566] After completing the double-blind treatment period, participants may choose to discontinue study drug dosing or continue into the long-term OLE treatment period (in Part B) to receive an additional 48 weeks of Compound 1. Participants who choose not to move into the OLE treatment period will discontinue study drug at Week 16 / End of Treatment (EOT) and then continue into the Safety Follow-up Period (in 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).

[0567] Section B

[0568] Open-label extension period

[0569] Participants who complete the double-blind treatment period (in Part A) and choose to continue study drug treatment will enter the OLE treatment period (in Part B). The OLE treatment period will last for 48 weeks.

[0570] Participants will provide written informed consent / assent prior to commencing any study procedures. Visit 1 (Day 1) of the OLE treatment period will be the end-of-treatment visit for the double-blind treatment period (in Part A); participants entering the OLE treatment period will receive uninterrupted study drug treatment.

[0571] During the OLE treatment period, participants will continue to receive study medication once daily at home. Study medication should be administered at approximately the same time each day and may be administered without regard to food.

[0572] Participants who cross over to the OLE treatment period will continue to receive the same dose of Compound 1 as the last dose they received in Part A, not associated with severe or moderate tolerability issues. The dose of Compound 1 may be adjusted based on tolerability and / or efficacy, as described below. During the OLE treatment period, the dose level of concomitant medications (including ASM or other related medications) may be adjusted at the investigator's discretion.

[0573] Safety follow-up period

[0574] After completing the OLE treatment period, participants will continue into the safety follow-up period (in Part B). During this 4-week follow-up period, participants' concomitant medications (including ASM or other relevant medications) may be adjusted at the investigator's discretion. Given the half-life of Compound 1 of approximately 4 days, it is recommended that the investigator restart the participant's SCB baseline dose (if the dose is reduced) at least 1 week after discontinuation 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.

[0575] Dose Modifications

[0576] For each participant, the starting dose of study drug during the double-blind treatment period will be based on the participant's body weight on Day 1 in Part A. During 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 study drug dose may be adjusted, if necessary, based on the participant's body weight at these visits.

[0577] Section A

[0578] Each participant will receive study drug at a starting dose of 0.5 mg / kg / day, once daily orally or via G / J tube, beginning on Day 1 of the double-blind treatment period of Part A. During the double-blind treatment period, the dose level of the concomitant SCB or study drug will be adjusted based on tolerability and / or efficacy, as further described below.

[0579] The dose levels of other ASM and related concomitant medications should remain unchanged during the double-blind treatment period.

[0580] Dosage changes during the double-blind treatment period based on efficacy

[0581] At Week 8 of the double-blind treatment period of Part A, if participants have a <30% reduction in the number of seizures during the previous 4 weeks compared with the 28-day baseline observation period and have no tolerability issues, the study drug dose will be increased to 1.0 mg / kg / day. This will be the maximum dose allowed in this trial.

[0582] Section B

[0583] Participants who cross over to the OLE treatment period will continue to receive the same dose of Compound 1 as the last dose they received in Part A, 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 up to a maximum of 1.0 mg / kg / day at the discretion of the investigator for efficacy purposes. If tolerability issues arise, the dose of Compound 1 or concomitant SCB may be titrated downward as described above for the double-blind treatment period of Part A.

[0584] During the OLE treatment period, the dose level of concomitant medications (including ASM or other related medications) may be adjusted at the investigator's discretion.

[0585] Treatment-emergent adverse events

[0586] An AE is any untoward medical occurrence in a patient or clinical trial participant that is temporally associated with the use of an investigational drug, whether or not considered related to the investigational drug. Events that meet the definition of an adverse event may include:

[0587] Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, or vital sign measurements), including those that are worsening relative to baseline, considered clinically significant (i.e., not related to progression of the underlying disease) in the medical and scientific judgment of the investigator.

[0588] An exacerbation of a chronic or intermittent pre-existing condition, including an increase in the frequency and / or intensity of the condition.

[0589] · A new condition is detected or diagnosed after administration of the study drug, even though it may have existed before the start of the clinical trial.

[0590] Signs, symptoms, or clinical sequelae of suspected drug interactions.

[0591] Suspected signs, symptoms, or clinical sequelae of overdose of study drug or concomitant medication. Overdose itself is not reported as an AE / SAE unless it is an intentional overdose with possible suicidal / self-harm intent. Such overdoses should be reported regardless of sequelae.

[0592] For efficacy studies: "Lack of efficacy" or "failure to achieve the intended pharmacological effect" per se will not be reported as an AE or SAE. Such instances will be recorded in the efficacy evaluation. However, if signs, symptoms, and / or clinical sequelae due to lack of efficacy meet the definition of an AE or SAE, they will be reported as an AE or SAE.

[0593] Each AE and SAE reported during a clinical trial will be assigned to one of the following categories:

[0594] Mild: Events that are easily tolerated by the participant, cause minimal discomfort, and do not interfere with daily activities.

[0595] Moderate: Events that cause sufficient discomfort to interfere with normal daily activities.

[0596] Severe: An event that interferes with normal daily activities. AEs assessed as severe should not be confused with SAEs. Severity is a category used to rate the intensity of an event; AEs, AESIs, and SAEs can all be assessed as severe.

[0597] Seizure Diary

[0598] During the clinical trial, the frequency of countable motor seizures will be recorded daily using an electronic diary. In addition, study drug administration and concomitant medication information will also be recorded in this diary.

[0599] The parent / legal guardian of each participant 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, and then daily throughout the double-blind treatment period of Part A and daily for at least 1 week prior to each clinic visit during the OLE treatment period of Part B. Countable motor seizure data recorded during this 28-day Baseline Observation Period will be used to determine eligibility for the clinical trial and to establish a baseline for efficacy analyses. In addition to spontaneous reporting, prompts may be used to ensure adequate data recording. The diary will be completed by the same parent / legal guardian whenever possible.

[0600] Video EEG

[0601] As permitted by local regulations, a vEEG will be performed by a trained technician to record brain wave activity and assess changes over time. The vEEG can be done at home or in a clinic, and ideally, the recording is continuous for a minimum of 1 hour and a maximum of 24 hours.

[0602] Audio / Video Based Epileptic Seizure Detection (Nelli)

[0603] Where locally permitted, a video / audio-based automated detection system (Nelli) will be used to collect and quantify movement and sound activity that would indicate seizure behavior in participants. Where feasible, the Nelli system will be placed in the participant's home and collect audio / video data during the clinical trial. The audio / video data will be analyzed in a semi-automatic manner to classify nocturnal seizures by selecting relevant epochs for subsequent review by human experts.

[0604] Clinical Global Impression-Severity and Clinical Global Impression-Improvement

[0605] The CGI scale was developed for use in clinical trials of individuals with mental health disorders funded by the National Institutes of Health. The CGI scale provides an overall assessment of improvement over a specified time period. The scale includes two 7-point Likert rating scales: the CGI-S scale and the CGI-I scale. The CGI scale will be anchored with reference to the dimensions / symptoms experienced by participants with SCN2A-DEE or SCN8A-DEE. Clinicians will use the CGI-S to assess the severity of participants' SCN2A-DEE or SCN8A-DEE symptoms at baseline (Day 1) and at the end-of-treatment visit. Clinicians will use the CGI-I to assess changes in SCN2A-DEE or SCN8A-DEE symptoms relative to baseline.

[0606] Caregiver Global Impression-Severity and Caregiver Global Impression-Improvement

[0607] The Caregiver Global Impression-Severity (CgCGI-S) and CgCGI-I scales are similar to the CGI-S and CGI-I scales, respectively. Caregivers will assess the severity of participants' SCN2A-DEE or SCN8A-DEE symptoms using the CgGI-S at baseline (Day 1). Caregivers will assess the change in SCN2A-DEE or SCN8A-DEE symptoms from baseline using the CgGI-I.

[0608] Physical examination

[0609] A comprehensive physical examination will include, at a minimum, evaluation of the cardiovascular, respiratory, gastrointestinal, and neurologic systems.

[0610] Electrocardiogram

[0611] A 12-lead ECG will be obtained using an electrocardiograph that automatically calculates heart rate and measures PR, QRS, QT, and corrected QT intervals. Participants should rest for at least 5 minutes before ECG measurements are taken. Triple measurements will be taken at Screening and all other time points in Part A, and single measurements will be taken at all time points in Part B, as indicated in the SoAs. When triplicate ECGs are required, 3 separate ECG tracings should be obtained as consecutively as possible but no more than 2 minutes apart.

[0612] Pharmacokinetic evaluation

[0613] Whole blood samples will be collected to measure the plasma concentration of Compound 1. The collected samples can also be used to evaluate safety or efficacy aspects related to issues that arise during or after clinical trials. The samples can also be used for additional exploratory method development and / or metabolite characterization purposes.

[0614] Example 14.

[0615] To test the anticonvulsant activity of Compound 1 in vivo, Compound 1 was administered to a developmental epileptic encephalopathy (DEE) mouse model with mutations in the Scn2a and Scn8a genes. The Scn2a mutant mice had a Q54 mutation, and the Scn8a mice had a N1768D mutation.

[0616] Fig.14A FIG2 is a graph showing the relationship between the percentage of protection against spontaneous epileptic seizures and the administered dose of Compound 1 in the Scn2a DEE mouse model. Fig. 14B FIG2 is a graph showing the relationship between the percentage of protection against spontaneous epileptic seizures and the administered dose of Compound 1 in the Scn8a DEE mouse model. Fig.14A and 14B The results shown in indicate that compound 1 has potent anticonvulsant activity and can completely block epileptic seizures in both Scn2a and Scn8a DEE mouse models.

[0617] The anticonvulsant activity of compound 1 was also tested in a non-Nav DEE mouse model. Specifically, compound 1 was tested in a pentylenetetrazol-induced seizure (PTZ) mouse model with mutations in the Kcnq2, Kcnc1, and Hcn1 genes. The Kcnq2 mice had a K556E mutation, the Kcnc1 mice had an R320H mutation, and the Hcn1 mice had an M305L mutation.

[0618] Fig. 14C Graph showing the change in percentage of resistance to hindlimb extension over time in the Kcnq2 DEE mouse model administered vehicle or Compound 1. Fig.14D Graph showing the change in percentage of resistance to hindlimb extension over time in the Kcnc1 DEE mouse model to which vehicle or Compound 1 was administered.

[0619] Fig.14E Graph showing the change in percentage of resistance to hindlimb extension over time in the Hcn1 DEE mouse model to which vehicle or Compound 1 was administered. Figures 14A-14C The results presented in demonstrate that compound 1 exhibits robust anticonvulsant activity in mechanistically distinct models of human epilepsy.

[0620] Although the foregoing disclosure has been described in some detail by way of illustration and example for the purpose of clarity and understanding, it will be clear to those skilled in the art from a reading of the present disclosure that various changes in form and detail may be made without departing from the true scope of the present disclosure and may be practiced within the scope of the appended claims. For example, all constructs, methods and / or component features, steps, elements or other aspects thereof may be used in various combinations.

[0621] Unless otherwise indicated or otherwise obvious from the context, a claim or description including "or" between one or more members in a group is deemed to satisfy the existence, use of one, more than one or all group members, or one, more than one or all group members in a given product or method. The present disclosure includes embodiments in which there is, one or more group members are used, or one or more group members are otherwise related to a given product or method in a given product or method. The present disclosure also includes embodiments in which there is, one or more group members are used, or more than one or all group members are otherwise related to a given product or method in a given product or method. In addition, it should be understood that the present disclosure covers all variations, combinations and arrangements of one or more limitations, elements, clauses, descriptive items, etc. from one or more listed claims, introduced into another claim (or, as relevant, any other claim) belonging to the same basic claim, unless otherwise stated or it is obvious to a person of ordinary skill in the art that contradictions or inconsistencies will occur. In the case where the elements are presented in a list (e.g., in a Markush group or similar format), it should be understood that each subgroup of the elements is also disclosed, and any one or more elements can be removed from the group. In general, where embodiments or aspects of the present disclosure are referred to as comprising particular elements, features, etc., certain embodiments or aspects consist of, or consist essentially of, such elements, features, etc. For simplicity, those embodiments are not specifically described herein with so many words in every case. It is also understood that any embodiment or aspect of the present disclosure may be explicitly excluded from the claims, regardless of whether a specific exclusion is recited in the specification.

[0622] All patents, patent applications, websites, other publications or documents, accession numbers, etc. cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual item was specifically and individually indicated to be so incorporated by reference.

Claims

1. A method for treating a condition associated with abnormal function of a sodium ion channel in a subject in need thereof, the method comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable salt thereof, in a dosage of about 1 mg to about 150 mg; wherein: X and Y are each independently CR d or N; R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by; R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl; R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 4 is hydrogen or C 1-4 alkyl; R 5 is halogenated; R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by; t is 0, 1, or 2; R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy, R c For optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and R d is hydrogen or C 1-4 alkyl; Provided that the compound is not a compound having the formula: or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein 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.

3. A method for treating a condition associated with abnormal function of a sodium ion channel in a subject in need thereof, the method comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable salt thereof, at a dose of about 0.25 mg / kg / day to about 1 mg / kg / day; wherein: X and Y are each independently CR d or N; R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by; R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl; R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 4 is hydrogen or C 1-4 alkyl; R 5 is halogenated; R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by; t is 0, 1, or 2; R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy, R c For optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and R d is hydrogen or C 1-4 alkyl; Provided that the compound is not a compound having the formula: or a pharmaceutically acceptable salt thereof.

4. The method of claim 3, wherein 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.

5. The method of any one of claims 1-4, wherein administration of the compound results in a reduction in the severity, number, and / or frequency of epileptic seizures experienced by the subject compared to the severity, number, and / or frequency of epileptic seizures experienced by the subject prior to administration of the compound.

6. The method of any one of claims 1-5, wherein administration of the compound does not result in ataxia, lethargy, and vomiting in the subject.

7. A method of reducing the severity, number and / or frequency of epileptic seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X and Y are each independently CR d or N; R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by; R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl; R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 4 is hydrogen or C 1-4 alkyl; R 5 is halogenated; R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by; t is 0, 1, or 2; R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy, R c For optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and R d is hydrogen or C 1-4 alkyl; Provided that the compound is not a compound having the formula: or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the subject suffers from a condition associated with abnormal function of a sodium ion channel.

9. The method according to any one of claims 1-6 and 8, wherein the condition associated with abnormal function of sodium ion channels is a neurological disorder.

10. The method of claim 9, wherein the neurological disorder is a condition associated with excessive neuronal excitability.

11. The method of claim 9 or 10, wherein the neurological disorder is associated with one or more de novo gain-of-function or loss-of-function mutations in a central nervous system sodium channel gene.

12. The method of any one of claims 8-11, wherein the condition is epilepsy, an epileptic syndrome, or an encephalopathy.

13. The method of claim 12, wherein the condition is genetic epilepsy or a genetic epilepsy syndrome.

14. The method of claim 12 or 13, wherein the condition is pediatric epilepsy or a pediatric epilepsy syndrome.

15. The method of any one of claims 1-6 and 8-14, wherein the condition is selected from malignant migrating focal seizures of infancy (MMFSI), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental epileptic encephalopathy, Raynaud-Gasteaux syndrome, epileptic seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia.

16. The method of claim 15, wherein the condition is epileptic encephalopathy.

17. The method of any one of claims 1-6 and 8-14, wherein the condition is selected from epileptic encephalopathy with SCN1A, SCN2A and / or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory epilepsy in childhood with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in childhood with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

18. The method of any one of claims 1-6 and 8-14, wherein the condition is tuberous sclerosis complex (TSC).

19. The method according to any one of claims 1 to 18, wherein the compound has formula (Ia): or a pharmaceutically acceptable salt thereof.

20. The method according to any one of claims 1 to 19, wherein the compound has formula (Ib): or a pharmaceutically acceptable salt thereof.

21. The method according to any one of claims 1 to 20, wherein the compound has formula (Ic): or a pharmaceutically acceptable salt thereof.

22. The method according to any one of claims 1 to 21, wherein the compound has formula (II): or a pharmaceutically acceptable salt thereof.

23. The method according to any one of claims 1 to 22, wherein the compound has formula III: or a pharmaceutically acceptable salt thereof.

24. The method of any one of claims 1-23, wherein the compound has formula IV: or a pharmaceutically acceptable salt thereof.

25. The method according to any one of claims 1 to 24, wherein the compound is compound 1 of the following formula: or a pharmaceutically acceptable salt thereof.

26. A method for preferentially inhibiting sustained sodium current (INa) over peak sodium current (INa) in a neuron, the method comprising treating the neuron with an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X and Y are each independently CR d or N; R 1 for Monocyclic C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replaced by; R 2 is optionally replaced by one or more R b The replaced C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl; R 3 For hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 4 is hydrogen or C 1-4 alkyl; R 5 is halogenated; R 6 C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each replaced by OR c replaced by; t is 0, 1, or 2; R a and R b Each independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy, R c For optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and R d is hydrogen or C 1-4 alkyl; Provided that the compound is not a compound having the formula: or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the neuron is in a subject.

28. The method of claim 27, wherein the subject suffers from a condition associated with abnormal function of a sodium ion channel.

29. The method of claim 28, wherein the condition associated with abnormal function of sodium ion channels is a neurological disorder.

30. The method of claim 29, wherein the neurological disorder is a condition associated with excessive neuronal excitability.

31. The method of claim 28 or 29, wherein the neurological disorder is associated with one or more de novo gain-of-function or loss-of-function mutations in a central nervous system sodium ion channel gene.

32. The method of any one of claims 28-31, wherein the condition is epilepsy, an epileptic syndrome, or an encephalopathy.

33. The method of claim 32, wherein the condition is genetic epilepsy or a genetic epilepsy syndrome.

34. The method of claim 32 or 33, wherein the condition is pediatric epilepsy or a pediatric epilepsy syndrome.

35. The method of any one of claims 28-34, wherein the condition is selected from malignant migrating focal seizures of infancy (MMFSI), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental epileptic encephalopathy, Raynaud-Gasteaux syndrome, epileptic seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia.

36. The method of claim 35, wherein the condition is epileptic encephalopathy.

37. The method of any one of claims 28-36, wherein the condition is selected from epileptic encephalopathy with SCN1A, SCN2A and / or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory epilepsy in childhood with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in childhood with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

38. The method of any one of claims 28-36, wherein the condition is tuberous sclerosis complex (TSC).

39. The method of any one of claims 28-38, wherein the compound has formula (Ia): or a pharmaceutically acceptable salt thereof.

40. The method of any one of claims 28-39, wherein the compound has formula (Ib): or a pharmaceutically acceptable salt thereof.

41. The method of any one of claims 28-40, wherein the compound has formula (Ic): or a pharmaceutically acceptable salt thereof.

42. The method according to any one of claims 28-41, wherein the compound has formula (II): or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 28-42, wherein the compound has Formula III: or a pharmaceutically acceptable salt thereof.

44. The method of any one of claims 28-43, wherein the compound has Formula IV: or a pharmaceutically acceptable salt thereof.

45. The method according to any one of claims 28-44, wherein the compound is Compound 1 of the following formula: or a pharmaceutically acceptable salt thereof.

46. ​​The method of any one of claims 1-45, wherein the subject is a human.

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