How to use Kv7 channel activators

Abstract

SOLUTION: Provided herein are compounds and pharmaceutical compositions comprising a therapeutically effective amount of such compounds, or pharmaceutically acceptable salts, and a pharmaceutically acceptable excipient, as well as methods for treating neurodevelopmental diseases or disorders (NDDs) and developmental and epileptic encephalopathies (DEEs) comprising administering such compounds, or pharmaceutically acceptable salts, and pharmaceutical compositions to a pediatric patient.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 901,621, filed September 17, 2019, and U.S. Provisional Application No. 62 / 945,300, filed December 9, 2019, which are incorporated by reference in their entireties.

[0002] This invention was made with U.S. Government support under Grant No. U44NS093160 awarded by the NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE of the NATIONAL INSTITUTES OF HEALTH. The U.S. Government has certain rights in this invention. [Background technology]

[0003] Embodiments described herein are directed to methods of treating a neurodevelopmental disease or disorder comprising administering a therapeutically effective amount of Compound A or a pharma- ceutically acceptable salt thereof to a pediatric subject in need thereof. In some embodiments, the subject is a fetus, a newborn from birth to about 1 month, an infant from about 1 month to about 24 months, a child from about 2 years to about 11 years, or an adolescent from about 12 years to about 18 years. Summary of the Invention [Means for solving the problem]

[0004] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide, N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutical acceptable salt thereof;

[0005] Embodiments described herein are directed to a method for treating a neurodevelopmental disease or disorder (NDD) comprising administering a therapeutically effective amount of Compound A, or a pharma- ceutical acceptable salt thereof, the NDD being one of Angelman syndrome, neonatal drug withdrawal syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, and the like. Kleffner syndrome, status epilepticus with electrical seizures during sleep (ESES), Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, West syndrome, SCN8A-associated encephalopathic epilepsy (EIEE13), epilepsy of infancy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Doose syndrome, adrenoleukodystrophy (ALD), ATP6V1A encephalopathy, atypical childhood epilepsy with central-temporal spikes (ACECTS), autosomal dominant rolandic with speech disorder epileptic encephalopathy with persistent spikes and waves during slow wave sleep (ECSWS), GRIN1 encephalopathy, GRIN2A epileptic aphasia, GRIN2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, neuronal ceroid lipofuscinosis (NCL), nonsyndromic developmental disorders and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsy, STXBP1 encephalopathy, tuberous sclerosis complex (TS) / tuberous sclerosis complex (TSC), and combinations thereof.

[0006] Embodiments described herein are directed to a method of treating a neurodevelopmental disease or disorder (NDD) comprising administering a therapeutically effective amount of Compound A or a pharma- ceutically acceptable salt thereof, wherein the NDD is selected from the group consisting of Angelman syndrome, neonatal continence syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus of sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, West syndrome, SCN8A-associated encephalopathy epilepsy (EIEE13), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), and combinations thereof.

[0007] Embodiments described herein are directed to a method for treating a neurodevelopmental disease or disorder (NDD), comprising administering a therapeutically effective amount of Compound A, or a pharma- ceutically acceptable salt thereof, wherein the NDD is Doose Syndrome.

[0008] Atypical childhood epilepsy with central-temporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech impairment (ADRESD), CDKL5 encephalopathy, benign childhood epilepsy with central-temporal spikes (CECTS), epileptic encephalopathy with continuous spikes and waves during slow wave sleep (ECSWS), GRIN1 encephalopathy, GRIN2A epileptic aphasia, GRIN2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, neuronal ceroid lipofuscinosis (NCL), nonsyndromic developmental disorders and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsy, STXBP1 encephalopathy, tuberous sclerosis complex (TS) / tuberous sclerosis complex (TSC), and combinations thereof.

[0009] Embodiments described herein are directed to a method of treating developmental and epileptic encephalopathies (DEE), including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Dravet syndrome, early myoclonic encephalopathy, electrical status epilepticus during sleep (ESES), infantile epilepsy with migrating focal seizures (EIMFS), Landau-Kleffner syndrome, or other conditions that may be caused by developmental and epileptic encephalopathies (DEE), comprising administering a therapeutically effective amount of Compound A or a pharmacologic acceptable salt thereof. Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, SCN8A-related encephalopathy (EIEE13), West syndrome, Doose syndrome, ATP6V1A encephalopathy, autosomal dominant rolandic epilepsy with speech impairment (ADRESD), CDKL5 encephalopathy, epileptic encephalopathy with continuous spike-and-wave patterns during slow wave sleep (ECSWS), Grin1 encephalopathy, Grin2A epileptic aphasia, GRIN2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, nonsyndromic developmental and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsy, STXBP1 encephalopathy, and combinations thereof.

[0010] Embodiments described herein are directed to a method of treating developmental and epileptic encephalopathies (DEEs), comprising administering a therapeutically effective amount of Compound A or a pharma- ceutically acceptable salt thereof, wherein the developmental and epileptic encephalopathies (DEEs) are selected from the group consisting of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Dravet syndrome, early myoclonic encephalopathy, electrical status epilepticus during sleep (ESES), epilepsy of infancy with migrating focal seizures (EIMFS), Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, SCN8A-associated encephalopathic epilepsy (EIEE13), West syndrome, and combinations thereof.

[0011] Embodiments described herein are directed to a method for treating developmental and epileptic encephalopathy (DEE), comprising administering a therapeutically effective amount of Compound A, or a pharma- ceutically acceptable salt thereof, wherein the DEE is Doose syndrome.

[0012]

[0013] Embodiments described herein are directed to a method of treating developmental and epileptic encephalopathies (DEEs), comprising administering a therapeutically effective amount of Compound A or a pharma- ceutically acceptable salt thereof, wherein the DEEs are selected from the group consisting of ATP6V1A encephalopathy, autosomal dominant rolandic epilepsy with speech disorder (ADRESD), CDKL5 encephalopathy, CDKL5 encephalopathy, epileptic encephalopathy with continuous spikes and waves during slow wave sleep (ECSWS), GRIN1 encephalopathy, GRIN2A epileptic aphasia, GRIN2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migrating focal seizures, nonspecific developmental epileptic encephalopathy, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-associated neonatal epilepsy, STXBP1 encephalopathy, and combinations thereof. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows that compound A produces a more negative shift in the activation voltage dependence of KCNQ2 homomers than KCNQ2 / Q3 heteromers and KCNQ3 homomers. [Diagram 2] FIG. 2 shows that Compound A activates KCNQ2 homomers. [Diagram 3] FIG. 3 shows the membrane folding patterns of KCNQ2 subunits indicating the location of several recurrent pathogenic KCNQ2 EE variants. [Figure 4] FIG. 4 demonstrates that Compound A (0.3 μM and 1.0 μM) increases homomeric channel density at −40 mV of wild-type KCNQ2. [Diagram 5]FIG. 5 shows that compound A left-shifts the G / V curve of homomeric KCNQ2, with filled circles representing wild-type KCNQ2, open circles representing wild-type KCNQ2 in the presence of 0.3 μM compound A, and filled triangles representing wild-type KCNQ2 in the presence of 1.0 μM compound A. [Figure 6] FIG. 6 shows the half-activation voltage (mV) of homomeric wild-type KCNQ2 and homomeric wild-type KCNQ2 with Compound A (0.3 μM and 1.0 μM). [Figure 7] FIG. 7 depicts currents recorded from cells expressing wild-type KCNQ2 / wild-type KCNQ3 channel heteromers before and during application of 1.0 μM Compound A. [Figure 8] FIG. 8 shows that compound A left-shifts the G / V curve of heteromeric KCNQ2 / wild-type KCNQ3, where filled circles represent wild-type KCNQ2 / wild-type KCNQ3, open circles represent wild-type KCNQ2 / wild-type KCNQ3 in the presence of 1.0 μM compound A, and filled triangles represent wild-type KCNQ2 / wild-type KCNQ3 in the presence of 3.0 μM compound A. [Figure 9] FIG. 9 depicts the half-activation voltage (mV) of heteromeric wild-type KCNQ2 / KCNQ3 and heteromeric wild-type KCNQ2 / wild-type KCNQ3 channels by Compound A (1.0 μM and 3.0 μM). [Figure 10] FIG. 10 depicts traces recorded at −40 mV upon treatment of cells expressing wild-type KCNQ2 with 3.0 μM Compound A, 10.0 μM ezogabine, and 10.0 μM ICA-069679 (ICA). [Figure 11] FIG. 11 shows the current density of wild-type KCNQ2 channels after treatment with 10.0 μM ezogabine, 3.0 μM compound A, and 10.0 μM ICA. [Figure 12]FIG. 12 depicts the effects of Compound A and EZO on the G / V curve of KCNQ2, where filled circles are wild-type KCNQ2, open circles are wild-type KCNQ2 in the presence of 3.0 μM Compound A, and filled triangles are wild-type KCNQ2 in the presence of 10.0 μM EZO. [Figure 13] FIG. 13 depicts traces recorded at −40 mV from cells expressing KCNQ2 W236L upon treatment with 3.0 μM Compound A, 10.0 μM ezogabine, and 10.0 μM ICA-069679 (ICA). [Figure 14] FIG. 14 shows the current density of the KCNQ2 W236L channel after treatment with ezogabine 10.0 μM, compound A 3.0 μM, and ICA 10.0 μM. [Figure 15] FIG. 15 depicts the effects of Compound A and EZO on the G / V curve of KCNQ2 W236L, with filled circles representing KCNQ2 W236L, open circles representing KCNQ2 W236L in the presence of 3.0 μM Compound A, filled triangles representing KCNQ2 W236L in the presence of 10.0 μM EZO, and open triangles representing KCNQ2 W236L in the presence of 10.0 μM ICA. [Figure 16] FIG. 16 is a graph showing the half-activation voltage (mV) when compound A was added at 3.0 μM to wild-type KCNQ2 / wild-type KCNQ2 and EZO was added at 10.0 μM to wild-type KCNQ2 / wild-type KCNQ2. [Figure 17] FIG. 17 depicts the half-activation voltage (mV) of KCNQ2 W236L, KCNQ2 W236L with 3.0 μM compound A, KCNQ2 W236L / KCNQ2 W236L with 10.0 μM EZO, and KCNQ2 W236L / KCNQ2 W236L with 10.0 μM ICA. [Figure 18] FIG. 18 shows currents recorded from cells expressing homomeric R210H channels before and during application of 1.0 μM Compound A. [Figure 19] FIG. 19 shows the mean currents at +20 mV before and during treatment with Compound A. [Figure 20] FIG. 20 shows a comparison of the effects of Compound A on wild-type KCNQ2 and 1:1 co-expressed wild-type KCNQ2 and R210H at −40 mV. [Figure 21] Figure 21 outlines the V1 / 2 shift of channels with different subunit combinations after application of Compound A, with filled circles representing wild type KCNQ2 and open circles representing wild type KCNQ2 in the presence of 1. Filled triangles representing wild type KCNQ2 / R210H in the presence of 0 μM Compound A, open triangles representing wild type KCNQ2 / R210H in the presence of 1.0 μM Compound A, filled squares representing R210H, and open squares representing R210H. [Figure 22] FIG. 22 is a diagram showing the half-activation voltage (mV) when compound A was added at 1.0 μM to each of wild-type KCNQ2, wild-type KCNQ2 / R210H, and R210H. [Figure 23] FIG. 23 depicts traces recorded at −40 mV from cells expressing wild type KCNQ2 and cells expressing 1:1 KCNQ2 and KCNQ2A294V before and during application of 0.3 μM Compound A. [Figure 24] FIG. 24 shows the effect of 0.3 μM compounds on the current density of the wild-type KCNQ2 channel and the current density of channels in which wild-type KCNQ2 is co-expressed at 1:1 with R581L, T274M, or A294V. [Diagram 25] FIG. 25 depicts the current density of wild-type KCNQ2 / A294V / wild-type KCNQ3 (1:1:2 ratio) and wild-type KCNQ2 / wild-type KCNQ3 heteromeric channels following treatment with 1.0 μM Compound A. [Figure 26]FIG. 26 depicts an overview of the V1 / 2 shift of channels carrying different subunit combinations after application of Compound A, where filled circles represent wild-type KCNQ2 / wild-type KCNQ3, open circles represent wild-type KCNQ2 / wild-type KCNQ3 in the presence of 1.0 μM compound, filled triangles represent wild-type KCNQ2 / A294V / wild-type KCNQ3 (1:1:2 ratio), and open triangles represent wild-type KCNQ2 / A294V / wild-type KCNQ3 (1:1:2 ratio) in the presence of 1.0 μM Compound A. [Figure 27] FIG. 27 shows the half-activation voltage (mV) of wild-type KCNQ2 / wild-type KCNQ3 and wild-type KCNQ2 / A294V / wild-type KCNQ3 (1:1:2 ratio) at 1.0 μM compound A. [Figure 28] FIG. 28 depicts the current density of wild-type KCNQ2 / T274M / wild-type KCNQ3 (1:1:2 ratio) and wild-type KCNQ2 / wild-type KCNQ3 heteromeric channels following treatment with 1.0 μM Compound A. [Figure 29] FIG. 29 depicts an overview of the V1 / 2 shift of channels carrying different subunit combinations after application of Compound A, where filled circles represent wild-type KCNQ2 / wild-type KCNQ3, open circles represent wild-type KCNQ2 / wild-type KCNQ3 in the presence of 1.0 μM Compound A, filled triangles represent wild-type KCNQ2 / T274M / wild-type KCNQ3 (1:1:2 ratio), and open triangles represent wild-type KCNQ2 / T274M / wild-type KCNQ3 (1:1:2 ratio) in the presence of 1.0 μM Compound A. [Diagram 30] FIG. 30 shows the half-activation voltage (mV) of wild-type KCNQ2 / wild-type KCNQ3 and wild-type KCNQ2 / T274M / wild-type KCNQ3 (1:1:2 ratio) with 1.0 μM of compound A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Potassium (K +) channels are present on the plasma membrane of most cell types and are the most diverse class of all ion channels, being associated with a wide range of physiological functions including the control of the electrical properties of excitable cells. The primary pore-forming (α) subunits of these highly selective cation channels are divided into three main structural classes based on the number of transmembrane (TM) and pore (P) regions. Currently, there are 6TM / 1P, 2TM / 1P and 4TM / 2PK channels. + The Kv7 gene (originally called KCNQ and named by the HUGO Gene Nomenclature Committee (HGNC)) is a voltage-gated K + The Kv7 subfamily consists of five homologous pore-forming α-subunits, Kv7.1-7.5, which are voltage-gated K channels consisting of a 6TM-spanning region (S1-S6) between the intracellular N- and C-terminal domains, a typical voltage sensor domain in S4 with alternating positively charged residues, and a single P domain between S5 and S6 of each subunit. + It has a typical structure of a channel. The channel is formed as a tetramer of the primary α subunit, and can be formed as a homotetramer or heterotetramer. It is known that Kv7 channels consisting of Kv7.2-7.5 α subunits are expressed in neurons. Some of these gene products are present only in neurons, while others, such as Kv7.4 and Kv7.5, are present in other tissues, such as smooth and skeletal muscles.

[0015] The native M current was first characterized in amphibian sympathetic neurons. It is notable because it activates and deactivates slowly, is activated at or near the resting membrane potential of the neuron, and is reduced by muscarinic cholinergic agonists, and is associated with G protein-coupled receptors (GPCRs) and physiological K +A direct and inhibitory link between the currents was demonstrated. Not until the genes of this subfamily were cloned was the pharmacological and biophysical identity established between Kv7.2 / 7.3 (and presumably Kv7.3 / 7.5) heteromultimers and "M" currents, providing important new evidence for their importance in neuronal regulation.

[0016] The distribution of these channels, both regionally and developmentally, as well as their biophysical properties, support their role in providing durable resistance to depolarizing excitatory effects. Under physiological conditions, they are highly effective in controlling the subthreshold excitability of certain neuronal populations, as demonstrated by native M currents, and play a key role in controlling the frequency, and therefore the pattern, of action potential discharge in many types of neurons. Reducing the influence of Kv7.2 and Kv7.3 channels dramatically altered neuronal excitability, and the importance of Kv7 in neuronal control was highlighted by the discovery that neuronal mutations lead to benign familial neonatal convulsions (BFNC). Mutational analysis of Kv7.2 and Kv7.3 channels also revealed their involvement in BFNC, suggesting their usefulness as targets for antiepileptic drugs (AEDs).

[0017] Mutations in Kv7.2, and less well known mutations in Kv7.3, have been reported as causes of autosomal dominant benign neonatal seizures (BFNS), mainly due to haploinsufficiency. BFNS is an idiopathic epilepsy in which seizures occur within a few days of birth, and is known to be caused by mutations in both Kv7.2 and Kv7.3. Kv7.2 and Kv7.3 interact to give larger currents than the individual currents obtained as homomers. In situ hybridization showed that Kv7.2 is mainly present in the cerebellar cortex, neocortex, and hippocampal formation, including the dentate gyrus. These three structures have different susceptibility to epileptic seizures. Kv7.3 is also localized in the same area in the mouse brain. However, Kv7.2 expression appears earlier than Kv7.3 expression and increases rapidly within the first week of life. At birth, Kv7.2 is already expressed at significant levels, whereas Kv7.3 expression is negligible. Thus, it appears that Kv7.2 and Kv7.3 bind in distinct profiles during development.

[0018] BFNS usually has a good long-term prognosis, but recurrent seizures in adulthood have also been reported. Recently, de novo dominant-negative mutations in the KCNQ2 gene have been found to result in a rare pediatric epileptic encephalopathy, KCNQ2 epileptic encephalopathy (KCNQ2-EE), which accounts for 5–23% of early infantile epileptic encephalopathy (EIEE). KCNQ2-EE is a well-defined clinical disorder with neonatal-specific symptoms including hypotonia, treatment-resistant tonic seizures, interictal EEG abnormalities with prominent burst suppression, and moderate to severe global developmental delay, which has only recently been reported to result from a subset of missense variants in the KCNQ2 gene. Neuroimaging may reveal frontal lobe hypoplasia and transient MRI signal abnormalities in the basal ganglia and thalamus. Even if seizures are controlled by AED use in the first few months of life, all children suffer from adverse neurodevelopmental effects. It is proposed that the clinical features of KCNQ2-EE are associated with the functional impact of the mutations on M-currents and therefore can predict neurological prognosis. The impact of KCNQ2 mutations on Kv7.2 channel function is known to vary in relation to the Kv7.3 subunit, with significant disparities. Homomeric channel density may be the most reliable characteristic associated with Kv7.2 function and encephalopathy. It is hypothesized that Kv7.2 channel homomers play an essential role in fine-tuning neuronal connections during early brain development and correlate with the severity of the dominant-negative effect of encephalopathy-causing KCNQ2 mutations.

[0019] The compounds provided herein are effective activators of Kv7.2 homotetramers, Kv7.3 homotetramers, Kv7.2 / 7.3 heterotetramers, and Kv7.2 and Kv7.3 heterotetramers, based on expression of the three channels, such compounds are useful in treating disorders of early infant development, neurodevelopmental diseases or disorders (NDDs), and developmental and epileptic encephalopathies (DEEs), such as Angelman syndrome, neonatal continence syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, and other conditions that may be associated with the development of neurodevelopmental disorders (NDDs), ... Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, West syndrome, epilepsy with SCN8A-related encephalopathy (EIEE13), epilepsy of infancy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Doze syndrome, adrenoleukodystrophy (ALD), ATP6V1A encephalopathy, atypical childhood epilepsy with central-temporal spikes (ACECTS), autosomal dominant rolandic seizures with speech disorder It is effective in treating ADRESD, CDKL5 encephalopathy, benign childhood epilepsy with centrotemporal spikes (CECTS), epileptic encephalopathy with continuous spikes and waves during slow wave sleep (ECSWS), GRIN1 encephalopathy, GRIN2A epileptic aphasia, GRIN2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, neuronal ceroid lipofuscinosis (NCL), nonsyndromic developmental disorders and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsy, STXBP1 encephalopathy, tuberous sclerosis complex (TS) / tuberous sclerosis complex (TSC), and combinations thereof.

[0020] Before describing the compositions and methods of the present invention, it should be understood that any invention is not limited to the specific steps, compositions, or methodologies described, as these may vary. Moreover, the steps, compositions, and methodologies described in a particular embodiment are interchangeable. Thus, for example, a composition, administration regimen, route of administration, etc. described in a particular embodiment can be used in any of the methods described in other particular embodiments. It should also be understood that the terms used herein are only for the purpose of describing a particular version or embodiment, and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless expressly defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods are described herein. All publications and references mentioned herein are incorporated by reference. Nothing herein should be construed as an admission that the invention is not entitled to antedate such disclosure by prior invention.

[0021] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0022] As used herein, the term "about" means plus or minus 10% of the numerical value with which it is used. Thus, about 50% means in the range of 45% to 55%. Unless otherwise indicated, all numerical values ​​expressing the amounts of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims are to be understood in all cases as being modified by the term "about". Thus, unless indicated to the contrary, the numerical parameters set forth in the specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained. At the very least, no attempt is made to limit the application of the doctrine of equivalents to the scope of the claims, and each numerical parameter should be construed, at least in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0023] When used in connection with a therapeutic agent, "administration" means administering the therapeutic agent directly to or onto a target tissue, or administering the therapeutic agent to a subject such that the therapeutic agent positively affects the target tissue. "Administration" of a composition may be accomplished by any method, such as oral administration, injection, infusion, absorption, or in combination with other known techniques. "Administration" may include self-administration or administration by another person, such as a healthcare professional or device.

[0024] As used herein, the terms "comprising," "comprise," "comprises," and "comprised" are inclusive or open-ended and do not exclude additional, unrepresented elements or method steps.

[0025] As used herein, the terms "consists of" or "consisting of" mean that a composition or method includes only those elements, steps, or ingredients specifically recited in a particular embodiment or claim.

[0026] As used herein, the terms "consisting essentially of" or "consists essentially of" mean that a composition or method includes only specified materials or steps that do not materially affect the basic and novel characteristics of the claimed invention.

[0027] The term "improve" is used herein to convey that it refers to the overall physical condition of an individual to whom an active agent is administered. For example, an individual's overall physical condition may be "improved" if one or more symptoms of a condition, disease or disorder, such as epilepsy or a neurodegenerative disorder, are alleviated by administration of an active agent. "Improvement" may also refer to a change in the appearance, form, characteristics, and / or physical attributes of the tissue to which it is provided, applied, or administered, or any combination thereof.

[0028] "Inhibit," "suppress," "reduce," "hinder," and / or "reduce" (and similar terms) generally refer to the act of diminishing, directly or indirectly, a function, activity, or movement relative to its natural, expected, or average, or current state.

[0029] The terms "homomer" or "homotetramer" refer to a configuration of Kv7 channels in which all four subunits are of the same type, either wild-type, mutant, or any combination thereof. For example, KCNQ2 homomers and Kv7.2 homomers are collections of four α subunits of Kv7.2.

[0030] The terms "heteromer" or "heterotetramer" can be used interchangeably and are used to refer to the composition of Kv7 channels in that the four subunits are two or more subtypes that are wild-type, mutant, or any combination thereof. For example, KCNQ2 / 3 heteromers and Kv7.2 / Kv7.3 heteromers are composed of mixed combinations of Kv7.2 and Kv7.3 subunits.

[0031] In each of the embodiments disclosed herein, the compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as "in need." As used herein, the phrase "in need" means that the subject has been identified as having a need for a particular method or treatment, and that the treatment has been administered to the subject for that particular purpose.

[0032] As used herein, the term "treatment" refers to an agent utilized to treat, combat, ameliorate, or prevent an undesirable condition, disorder, or disease in a subject, or any combination thereof.

[0033] As used herein, the terms "patient" and "subject" are interchangeable and may be considered to mean any living organism that may be treated with a compound of the invention. Thus, the terms "patient" and "subject" may include, but are not limited to, any non-human mammal, primate, or human. In some embodiments, the "patient" or "subject" is an adult, child, infant, or fetus. In some embodiments, the "patient" or "subject" is a human. In some embodiments, the "patient" or "subject" is a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, primate, or human. In certain embodiments, the human is a newborn from birth to about 1 month. In certain embodiments, the human is an infant from about 1 month to about 24 months. In certain embodiments, the human is a fetus and is treated in utero. In certain embodiments, the human is a child from about 2 years to about 11 years. In certain embodiments, the human is an adolescent from about 12 years to about 18 years. In embodiments, the subject is a pediatric subject, which is a human fetus (treated in utero), a newborn from birth to about 1 month, an infant from about 1 month to about 24 months, a child from about 2 years to about 11 years, or an adolescent from about 12 years to about 18 years.

[0034] As used herein, the terms "therapeutically effective amount" or "therapeutic dose" are used interchangeably and may refer to an amount of an active agent or pharmaceutical compound or composition that induces a clinical, biological or medicinal response in a tissue, system, animal, individual or human that is desired by a researcher, veterinarian, medical doctor or other clinical professional. A clinical, biological or medical response may include, for example, one or more of the following: (1) prevention of a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but has not yet experienced or displayed the pathology or symptoms of the disease, condition or disorder; (2) inhibition of a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptoms of the disease, condition or disorder; or (3) ameliorating a disease, condition or disorder in an individual experiencing or displaying the pathology or symptoms of the disease, condition or disorder, or reversing the pathology or symptoms experienced or displayed by the individual.

[0035] The terms "treat," "treat," or "treating" may be taken to mean prevention of a particular disorder, disease, or condition, alleviation of symptoms associated with a particular disorder, disease, or condition, and / or prevention of symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term refers to slowing the progression of a disorder, disease, or condition, or alleviating symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term refers to alleviating symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term refers to alleviating symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term refers to restoring functionality that has been impaired or lost due to a particular disorder, disease, or condition.

[0036] "Pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (1977) J.Pharm.Sciences, Vol.6, 1-119 describes pharmaceutically acceptable salts in detail. Pharmaceutically acceptable "salts" include any acid addition salt, preferably including, but not limited to, halogen acid salts such as hydrobromic acid, hydrochloric acid, hydrofluoric acid, and hydroiodic acid salts, inorganic acid salts such as nitric acid, perchloric acid, sulfuric acid, and phosphoric acid salts. Examples of suitable acid addition salts include sulfonates (methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid), organic acid salts such as acetic acid, malic acid, fumaric acid, succinic acid, citric acid, benzoic acid, gluconic acid, lactic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, oxalic acid and maleic acid, and amino acid salts such as aspartic acid, glutamic acid, and the like. The acid addition salts may be mono- or di-acid addition salts and include, for example, dihydrohalogenates, disulfates, diphosphates, diorganoacid salts, and the like. In all cases, the acid addition salts used as achiral reagents are not selected based on any expected or known preference for interaction with or precipitation of a particular optical isomer of the products of the present disclosure.

[0037] Where stereochemistry is not indicated, the name or structural representation includes any stereoisomer or mixture of stereoisomers, and applicant reserves the right to specifically identify and claim the compound as a single stereoisomer or any particular mixture of stereoisomers.

[0038] The compounds described herein may contain asymmetric centers and therefore may exist as enantiomers. When compounds according to embodiments herein have two or more asymmetric centers, they may further exist as diastereomers. The embodiments herein include all such possible stereoisomers, as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. In some embodiments, the formulas are shown without a definitive stereochemistry at a particular position. The embodiments herein include all stereoisomers of such formulas and pharma-ceutically acceptable salts thereof. The diastereoisomeric set of enantiomers may be separated, for example, by fractional crystallization from a suitable solvent, and the set of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example, by using an optically active acid or base as a resolving agent, or on a chiral HPLC column. Additionally, any enantiomer or diastereomer of a compound of the general formula may be obtained by stereospecific or stereoselective synthesis using optically pure or enantiomerically enriched starting materials or reagents of known configuration. The scope of the embodiments described and claimed herein encompasses the racemates of the compounds, as well as individual enantiomers, diastereomers, and stereoisomer-enriched mixtures, and applicants reserve the right to specifically identify and claim the compounds in any such form.

[0039] The compounds disclosed herein may exist as all stereoisomers, conformational isomers and mixtures thereof in all proportions, as well as isotopic forms such as deuterated compounds, and therefore applicants reserve the right to specifically identify and claim any such forms of the compounds.

[0040] compound Embodiments described herein include the following: N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide, N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl)1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-di ... [d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;or N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof. The structures of these compounds can be set forth in Table 1. In embodiments, such compounds can be administered in a pharmaceutical composition as described herein; [ka] TIFF0007607864000002.tif191141TIFF0007607864000003.tif194141

[0041] How to use

[0010] The embodiments described herein are directed to a method of treating a disease or disorder that would benefit from activation of Kv7.2 homomers, comprising administering to the patient a therapeutically effective amount of N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; 3-Dimethylbutanamide;N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert- N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl) -3,3-Dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease or disorder is developmental and is diagnosed prenatally, neonatally, infancy, childhood, adolescence, and early adulthood. In certain embodiments, the human subject is diagnosed prenatally. In certain embodiments, the neonate is diagnosed about one week from birth, or between about one week and about one month. In certain embodiments, the infant is diagnosed at about 1 week from birth, about 1 week to about 1 month, about 1 month to about 24 months. In certain embodiments, the child is diagnosed at about 1 week from birth, about 1 week to about 1 month, about 1 month to about 24 months, about 2 years to about 11 years. In certain embodiments, the subject is a newborn from birth to about 1 month. In certain embodiments, the subject is an infant from about 1 month to about 24 months. In certain embodiments, the subject is a fetus and is treated in utero. In certain embodiments, the subject is a child from about 2 years to about 11 years. In certain embodiments, the subject is an adolescent child from about 12 years to about 18 years. In embodiments, the subject is a pediatric subject;

[0042] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In embodiments, the disease or disorder occurs early in life, from about 0 days to about 1 year. Neonatal and infant brains undergo early developmental changes and are susceptible to changes during this sensitive period. Rodent studies have shown that expression of KCNQ2 is dominant over KCNQ3 during the early postnatal period. Delayed expression of KCNQ3 results in a greater density of KCNQ2 homomers relative to KCNQ2 / KCNQ3 heteromers. In embodiments described herein, the method of treating a developmental disease or disorder is effective in restoring cellular electrical balance or normalizing hyperexcitability caused by KCNQ2-related genes or mechanisms. In an embodiment, the subject is a pediatric subject;

[0043] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof to a subject in need thereof. In an embodiment, the subject is a pediatric subject. In certain embodiments, the neurodevelopmental disease or disorder is Angelman syndrome, neonatal drug withdrawal syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, West syndrome, SCN8A-associated encephalopathy epilepsy (EIEE13), epilepsy of infancy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Doze syndrome, adrenoleukodystrophy (ALD), ATP6V1A encephalopathy, atypical childhood epilepsy with central-temporal spikes (ACECTS), autosomal dominant lobe epilepsy with speech impairment (SLE), or cerebrospinal fluid syndrome (CEFS). The present invention is selected from the group consisting of ADRESD, CDKL5 encephalopathy, benign childhood epilepsy with centro-temporal spikes (CECTS), epileptic encephalopathy with continuous spikes and waves during slow wave sleep (ECSWS), Grin1 encephalopathy, Grin2A epileptic aphasia, Grin2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, neuronal ceroid lipofuscinosis (NCL), nonsyndromic developmental disorders and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsy, STXBP1 encephalopathy, tuberous sclerosis complex (TS) / tuberous sclerosis complex (TSC), and the like, and combinations thereof;

[0044] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In an embodiment, the subject is a pediatric subject. In a particular embodiment, the neurodevelopmental disease or disorder is selected from the group consisting of Angelman syndrome, neonatal drug withdrawal syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, West syndrome, SCN8A-associated encephalopathy epilepsy (EIEE13), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), and combinations thereof;

[0045] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the neurodevelopmental disease or disorder is Doze syndrome. In embodiments, the subject is a pediatric subject.;

[0046] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In embodiments, the subject is a pediatric subject. In certain embodiments, the neurodevelopmental disease or disorder is selected from the group consisting of adrenoleukodystrophy (ALD), ATP6V1A encephalopathy, atypical childhood epilepsy with centro-temporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech impair- ment (ADRESD), CDKL5 encephalopathy, benign childhood epilepsy with centro-temporal spikes (CECTS), epileptic encephalopathy with continuous spikes and waves during slow wave sleep (ECSWS), GRIN1 encephalopathy, G selected from the group consisting of RIN2A epileptic aphasia, GRIN2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, neuronal ceroid lipofuscinosis (NCL), nonsyndromic developmental disorders and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsy, STXBP1 encephalopathy, tuberous sclerosis complex (TS) / tuberous sclerosis complex (TSC), and combinations thereof;

[0047] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In an embodiment, the subject is a pediatric subject. In certain embodiments, the developmental and epileptic encephalopathies (DEEs) include autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Dravet syndrome, early myoclonic encephalopathy, electrical status epilepticus during sleep (ESES), epilepsy of infancy with migratory focal seizures (EIMFS), Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, epilepsy with SCN8A-associated encephalopathy (EIEE13), West syndrome, Doze syndrome, ATP6V1A encephalopathy, ... selected from the group consisting of somatic dominant rolandic epilepsy (ADRESD), CDKL5 encephalopathy, epileptic encephalopathy with continuous spikes and waves during slow wave sleep (ECSWS), GRIN1 encephalopathy, GRIN2A epileptic aphasia, GRIN2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, nonspecific developmental and epileptic encephalopathy, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsy, STXBP1 encephalopathy, and combinations thereof;

[0048] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In an embodiment, the subject is a pediatric subject. In certain embodiments, the developmental and epileptic encephalopathy (DEE) is selected from the group consisting of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Dravet syndrome, early myoclonic encephalopathy, electrical status epilepticus during sleep (ESES), infantile epilepsy with migrating focal seizures (EIMFS), Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, SCN8A-associated epilepsy with encephalopathy (EIEE13), West syndrome, and combinations thereof;

[0049] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the developmental and epileptic encephalopathy (DEE) is Doze syndrome. In embodiments, the subject is a pediatric subject;

[0050] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In an embodiment, the subject is a pediatric subject. In certain embodiments, the developmental and epileptic encephalopathies (DEEs) are selected from the group consisting of ATP6V1A encephalopathy, autosomal dominant rolandic epilepsy with speech impairment (ADRESD), CDKL5 encephalopathy, epileptic encephalopathy with continuous spikes and waves during slow wave sleep (ECSWS), Grin1 encephalopathy, GRIN2A epileptic aphasia, GRIN2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, nonsyndromic developmental and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-associated neonatal epilepsy, STXBP1 encephalopathy, and combinations thereof;

[0051] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutical acceptable salt thereof, to a subject in need thereof. In an embodiment, the subject is a pediatric subject. Angelman syndrome is caused by loss of function of the UBE3A gene, which plays a role in normal development of the nervous system. Patients exhibit mental retardation, abnormal gait, speech impediment, seizures, and an inappropriate happy demeanor, including frequent laughing, smiling, and excitability. They are typically treated with anticonvulsants. The compounds described herein are effective in treating seizures associated with Angelman syndrome.;

[0052] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Neonatal drug withdrawal syndrome is seen in infants born dependent on drugs due to exposure in utero. At birth, they may experience withdrawal symptoms, including seizures. Withdrawal from opiates can cause changes in excitatory transmission. The compounds described herein reverse excitability and ameliorate withdrawal symptoms. In an embodiment, the subject is a pediatric subject;

[0053] Embodiments described herein include, but are not limited to, N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N -(1-Cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d ]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-1-cyclobutyl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Early myoclonic encephalopathy is diagnosed in infants who develop seizures early in life due to multiple factors. The seizures are refractory to standard treatments and have a poor prognosis. The compounds described herein are effective in treating early myoclonic encephalopathy. In an embodiment, the subject is a pediatric subject;

[0054] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutical acceptable salt thereof, to a subject in need thereof. Otahara syndrome (OS) or early infantile epileptic encephalopathy (EIEE) is a rare type of epilepsy that usually becomes evident between 1 and 3 months of age. OS can be caused by brain malformations, metabolic abnormalities, or mutations in genes such as KCNQ2. Infants have primarily tonic seizures, but may also have partial seizures and, rarely, myoclonic seizures. Many with the disease have severely underdeveloped parts or all of the cerebral hemispheres. The electroencephalogram of infants with Otahara syndrome shows a characteristic pattern of high-voltage spike-wave discharges followed by little activity. This pattern is called "burst suppression." The course of Otahara syndrome is severely progressive. Seizures become more frequent and are associated with delayed physical and cognitive development. Some children die in infancy, while others survive with significant disabilities. As they grow older, some children transition to other epileptic disorders, such as West syndrome or Lennox-Gastaut syndrome. Due to the early onset of the disease, Kv7 channel activators are an effective treatment option for this disease. In an embodiment, the subject is a pediatric subject;

[0055] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutical acceptable salt thereof, to a subject in need thereof. Several voltage-gated potassium channels, such as mutations or truncations in the KCNQ3 gene, have been implicated in autistic patients. Dysfunction of Kv7 may facilitate seizures and impair normal development, resulting in the autistic phenotype. Autism spectrum disorder (ASD) is a developmental disorder that affects communication and behavior. Autism can be diagnosed at any age, but symptoms generally appear within the first two years of life, hence the term "developmental disorder." According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a guide used by the American Psychiatric Association to diagnose mental disorders, individuals with ASD are characterized by: 1) difficulty communicating and interacting with others; 2) restricted interests and repetitive behaviors; and 3) symptoms that impair the ability to function properly in school, work, and other areas of life. Autism is known as a "spectrum" disorder because symptoms vary widely in type and severity. The compounds described herein restore synaptic transmission necessary for normal development. In an embodiment, the subject is a pediatric subject.;

[0056] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Mutations in the SCN1A gene, which encodes a voltage-gated sodium channel, are common in Dravet syndrome. The mutations cause a reduction in sodium current, leading to hyperexcitation of GABAergic inhibitory neurons and resulting in epilepsy. Recently, it has been found that mutations in KCNQ2 contribute to the clinical presentation of Dravet syndrome. Dravet syndrome, formerly known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare, treatment-resistant developmental epileptic encephalopathy with significant neurodevelopmental, motor, cognitive, and behavioral impacts that begin in infancy and continue into adulthood. Dravet syndrome is characterized by prolonged febrile and non-febrile seizures within the first year of life. The disease progresses to other seizure types, such as myoclonic and partial seizures, psychomotor delay, and ataxia. It is characterized by cognitive, behavioral, and motor disorders. Behavioral disorders often include hyperactivity, impulsivity, and in rare cases, autistic-like behavior. Seizures experienced by individuals with Dravet syndrome worsen as patients age. The compounds described herein are effective in Dravet syndrome by restoring the balance between excitation and inhibition in these neurons. In an embodiment, the subject is a pediatric subject;

[0057]

[0058] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Rett syndrome is a rare genetic neurological disorder that primarily affects girls. Patients appear normal early in life, but then experience slower growth and development with the onset of gait disturbances, seizures, and intellectual disability. Many cases involve mutations in the MECP2 gene, which is believed to control the function of many other genes, and have been found to inhibit normal function of nerve cells. Clinical diagnosis has revealed that patients have mutations in other genes, including KCNQ2. The compounds described herein are effective treatments for Rett syndrome. In an embodiment, the subject is a pediatric subject;

[0059] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. West syndrome is characterized by epileptic convulsions and intellectual disability that begin early in life. Often, spam in infancy also includes hypsalism, a chaotic and disorganized brain activity. Diagnosis is clinical, combining myoclonic seizures, developmental regression, and characteristic EEG (electroencephalogram) patterns. The underlying disease has many causes, including structural, metabolic, and genetic, all of which produce a seizure disorder. Due to the early onset of the disease, the compounds described herein are effective treatment options for the disease. In an embodiment, the subject is a pediatric subject;

[0060] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. EIEE13 is characterized by recurrent seizures, abnormal brain function, and intellectual disability, with symptoms beginning in infancy. Seizures are frequent, occurring several hundred times a day, and are unresponsive to current antiepileptic drugs. EIEE13 is caused by a mutation in the SCN8A gene that increases the function of Nav1.6. Increased Nav1.6 activity causes excitation of neurons in the brain. The compounds described herein reduce excitability in the brain and restore normal brain function during a critical neurodevelopmental period. In an embodiment, the subject is a pediatric subject.

[0061] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Epilepsy of Infancy with Migratory Focal Seizures (EIMFS) is also called migratory partial epilepsy of infancy, migratory partial seizures of infancy, or malignant migratory partial seizures of infancy. EIMFS is a rare epilepsy syndrome in which epileptic seizures begin within the first few weeks of life. Seizures are focal but migratory to various parts of the brain. Autonomic nervous system changes (respiratory arrest, turning blue, sweating, hiccups) are frequently observed during seizures. EIMFS is associated with mutations in several genes, including the KCNT1 potassium channel, which accounts for 40% of EIMFS cases. The KCNT1 channel contributes to resting membrane potential and neuronal firing. The compounds described herein are effective in treating EIMFS. In an embodiment, the subject is a pediatric subject.

[0062] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. ADNFLE is a rare type of epilepsy that begins in early childhood. Seizures usually occur during nighttime sleep. Seizures tend to occur in clusters and may be accompanied by sudden repetitive movements or vocalizations. ADNFLE is caused by mutations in the gene that codes for the nicotinic acetylcholine receptor, which plays a key role in communicating information between nerve cells and the brain. Seizures occur when the nerve cell network is compromised. Activation of Kv7 may restore normal brain function and prevent seizures during this critical developmental stage. The compounds described herein are effective in treating ADNFLE. In an embodiment, the subject is a pediatric subject;

[0063] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Dos syndrome, also known as myoclonic static epilepsy (MAE), is an early childhood epilepsy syndrome that affects more boys than girls, and typically begins between the ages of 2 and 6. Children with Dos syndrome develop multiple seizure types, including dropout seizures. Approximately one-third of children may also have episodes of nonconvulsive epilepsy. Childhood development before the onset of seizures is usually normal. Frequent seizures may result in slowed development and regression. The compounds described herein are effective in treating Dos syndrome. In an embodiment, the subject is a pediatric subject.;

[0064] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating adrenoleukodystrophy (ALD). In an embodiment, the subject is a pediatric subject;

[0065] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating ATP6V1A encephalopathy. In an embodiment, the subject is a pediatric subject;

[0066] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating atypical childhood epilepsy with central temporal spikes (ACECTS). In an embodiment, the subject is a pediatric subject;

[0067] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, comprising administering to a subject in need thereof a therapeutically effective amount of the compound. The compounds described herein are effective in treating Autosomal Dominant Rolandic Epilepsy with Speech Disorders (ADRESD). In an embodiment, the subject is a pediatric subject;

[0068] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating CDKL5 encephalopathy. In an embodiment, the subject is a pediatric subject;

[0069] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating benign childhood epilepsy with centro-temporal spikes (CECTS). In an embodiment, the subject is a pediatric subject;

[0070] The embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide ;N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazole -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-1-cyclobutyl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, comprising administering to a subject in need thereof a therapeutically effective amount of the compound. The compounds described herein are effective in treating Epileptic Encephalopathy with Continuous Spikes and Waves During Slow Wave Sleep (ECSWS). In an embodiment, the subject is a pediatric subject;

[0071] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating GRIN1 encephalopathy. In an embodiment, the subject is a pediatric subject;

[0072] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating GRIN2A epileptic aphasia. In an embodiment, the subject is a pediatric subject;

[0073] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating GRIN2B encephalopathy. In an embodiment, the subject is a pediatric subject;

[0074] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating intermediate epileptic aphasia (IEAD). In an embodiment, the subject is a pediatric subject;

[0075] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating KCNT1 infantile epilepsy with migratory focal seizures. In an embodiment, the subject is a pediatric subject;

[0076] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating neuronal ceroid lipofuscinosis (NCL). In an embodiment, the subject is a pediatric subject;

[0077] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating non-syndromic developmental disorders and epileptic encephalopathies. In an embodiment, the subject is a pediatric subject;

[0078] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating PTPN23 encephalopathy. In an embodiment, the subject is a pediatric subject;

[0079] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating Rasmussen's syndrome. In an embodiment, the subject is a pediatric subject;

[0080] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating SCN2A-associated neonatal epilepsy. In an embodiment, the subject is a pediatric subject;

[0081] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating STXBP1 encephalopathy. In an embodiment, the subject is a pediatric subject;

[0082] Embodiments described herein include N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[ N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The compounds described herein are effective in treating tuberous sclerosis (TS) / tuberous sclerosis complex (TSC). In an embodiment, the subject is a pediatric subject;

[0083] In some embodiments, administration of a therapeutically effective amount of a compound of Table 1 or a pharma- ceutically acceptable salt thereof is from about 0.1 mg to about 1,500 mg, from about 1 mg to about 1,500 mg, from about 10 mg to about 1,500 mg, from about 50 mg to about 1,500 mg, from about 75 mg to about 1,500 mg, from about 100 mg to about 1,500 mg, from about 125 mg to about 1,500 mg, from about 150 mg to about 1,500 mg, from about 175 mg to about 1,500 mg, from about 200 mg to about 1,500 mg, or from about 250 mg to about 1,500 mg. 00mg, about 225mg to about 1,500mg, about 250mg to about 1,500mg, about 275mg to about 1,500mg, about 300mg to about 1,500mg, about 350mg to about 1.500mg, about 400mg to about 1,500 mg, about 450 mg to about 1,500 mg, about 500 mg to about 1,500 mg, about 550 mg to about 1,500 mg, about 600 mg to about 1,500 mg, about 650 mg to about 1,500 mg, about 700 mg to about 1,500 mg. About 750 mg to about 1,500 mg, about 800 mg to about 1,500 mg, about 850 mg to about 1,500 mg, about 900 mg to about 1,500 mg, about 950 mg to about 1,500 mg, about 1,000 mg to about 1,500 mg, about 1200 mg to about 1,500 mg.

[0084] In some embodiments, the therapeutically effective amount of a compound of Table 1 or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 0.1 mg to about 1000 mg, about 50 mg to about 1000 mg per day, about 100 mg to about 1000 mg per day, about 150 mg to about 1000 mg per day, about 300 mg to about 1000 mg per day, about 50 mg to about 300 mg per day, and about 150 mg to about 300 mg per day.

[0085] Such therapeutically effective amounts may be administered once a day or in equal portions twice, three, or four times a day. In some embodiments, administering a therapeutically effective amount comprises administering a dose equal to about half the daily dose twice a day. In some embodiments, the doses are administered about every 12 hours. In some embodiments, administering a therapeutically effective amount comprises administering about 1 mg twice a day, about 5 mg twice a day, about 10 mg twice a day, about 25 mg twice a day, about 75 mg twice a day, about 150 mg twice a day, about 300 mg twice a day, or about 500 mg twice a day.

[0086] Pharmaceutical Compositions Embodiments herein include, but are not limited to, N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-( 1-Cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide -yl)-3,3-dimethylbutanamide;N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d ]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutical composition comprising such a compound and a suitable carrier, or a pharma- ceutical formulation comprising such a compound and a suitable carrier, can be in a variety of forms, including, but not limited to, a solid, a solution, a powder, a fluid emulsion, a fluid suspension, a semi-solid, and a dry powder, containing an effective amount of the compound of the invention. It is also known in the art that the active ingredient can be contained in such formulations together with pharma- ceutical acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, wetting agents, solubilizers, antioxidants, preservatives, and the like. Means and methods for administration are known in the art, and the skilled artisan can refer to various pharmaceutical literature for guidance. See, e.g., Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman's, The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980), both of which are incorporated herein by reference in their entireties.

[0087] In some embodiments, one unit dose of a compound of Table 1, or a pharma- ceutically acceptable salt thereof, is from about 0.1 mg to about 1,500 mg, from about 1 mg to about 1,500 mg, from about 10 mg to about 1,500 mg, from about 50 mg to about 1,500 mg, from about 75 mg to about 1,500 mg, from about 100 mg to about 1,500 mg, from about 125 mg to about 1,500 mg, from about 150 mg to about 1,500 mg, from about 175 mg to about 1,500 mg, from about 200 mg to about 1,500 mg, The amount is selected from the group consisting of about 225 mg to about 1,500 mg, about 250 mg to about 1,500 mg, about 275 mg to about 1,500 mg, about 300 mg to about 1,500 mg, about 400 mg to about 1,500 mg, about 450 mg to about 1,500 mg, about 500 mg to about 1,500 mg, about 600 mg to about 1,500 mg, about 700 mg to 1,500 mg, about 800 mg to 1,500 mg, about 1000 mg to about 1,500 mg, and about 1,200 mg.

[0088] In some embodiments, one unit dose of a compound in Table 1 or a pharma- ceutically acceptable salt thereof is from about 25 mg to about 5000 mg, from about 50 mg to about 5000 mg, from about 100 mg to about 5000 mg, from about 150 mg to about 5000 mg, from about 200 mg to about 5000 mg, from about 250 mg to about 5000 mg, from about 300 mg to about 5000 mg, from about 400 mg to about 5000 mg, from about 450 mg to about 5000 mg, from about 100 mg to about 3000 mg, from about 150 mg to about 3000 mg, from about 200 mg to about 3000 mg, from about 2 Selected from the group consisting of 50mg to about 3000mg, about 300mg to about 3000mg, about 400mg to about 3000mg, about 450mg to about 3000mg, about 100mg to about 1000mg, about 150mg to about 1000mg, about 150mg to about 1000mg, about 200mg to about 1000mg, about 250mg to about 1000mg, about 300mg to about 1000mg, about 400mg to about 1000mg, about 450mg to about 1000mg, about 500mg to about 1000mg, and about 600mg to about 1000mg. In some embodiments, the single unit dose may be 10mg / day to 1500mg / day, or about 100mg / day to 600mg / day. In some embodiments, such single unit doses may be administered once per day, or multiple times per day, such as twice per day or three times per day.

[0089] In some embodiments, the single unit dose further comprises a pharma- ceutically acceptable carrier.

[0090] The compound can be formulated for parenteral or intravenous administration by injection, for example, bolus injection or continuous infusion.The preparation for injection can be presented in a unit dose form, for example, in ampoules or multi-dose containers, with preservative added.The composition can take the form of suspension, solution, or emulsion in oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents.

[0091] Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol.Among acceptable vehicles and solvents that can be employed include water, Ringer's solution, and isotonic sodium chloride solution.

[0092] Other embodiments include the compound prepared as above, which is formulated as a solid dosage form for oral administration, including capsules, tablets, pills, powders, and granules.In such embodiments, the active compound may be mixed with one or more inert diluents, such as sucrose, lactose, or starch.Such dosage forms may also contain additional substances other than the inert diluent, such as lubricants, such as magnesium stearate, as is customary.In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents, and may further be prepared with enteric coating.

[0093] The preparation of the compounds of the present invention in solid dosage form can be varied.For example, in one embodiment, liquid or gelatin preparations can be prepared by combining the compounds as described above and adding a thickening agent to the liquid mixture to form gelatin.The gelatin can then be encapsulated in unit dosage form to form capsules.In another exemplary embodiment, the oily preparation of the compounds prepared as described above can be lyophilized to form a solid that can be mixed with one or more pharma-ceutically acceptable excipients, carriers or diluents to form a tablet.

[0094] Further embodiments that may be useful for oral administration of the compounds of the present invention include liquid dosage forms.In such embodiments, the liquid dosage forms may include pharma-ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs that contain inert diluents commonly used in the art, such as water.Such compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweeteners, flavoring agents, and perfumes.

[0095] In yet further embodiments, the compounds described herein can be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Depot injections can be administered at intervals of about 1 to about 6 months or more. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as sparingly soluble salts. EXAMPLES

[0096] Example 1: Activation of KCNQ2 M-current has been described as a non-activated potassium current resulting from activation of Kv7 channels. M-current is generated by the association of two different Kv7 subunits to form heteromers. Kv7.3 can associate with either Kv7.2 or Kv7.5. Furthermore, Kv7 subunits can form functional homomers. The subunits combine into homomers and heteromers due to developmental and specific expression regulation. Importantly, heteromers have distinct permeability and conductance properties as well as larger currents compared to homomers. The data herein explain the preferential activation of Kv7.2 over Kv7.2 / 7.3 or Kv7.3 by compound A.

[0097] Biological assay methods - Plasmids containing wild-type (wt) KCNQ2 alone, wt KCNQ3 alone, or both wt KCNQ2 and wt KCNQ3 subunits were expressed in Chinese hamster ovary (CHO) cells using lipid-mediated transfection. A whole-cell voltage clamp protocol was used to measure gating and conductance density of wt channels before, during, and after test article administration by focal pipette perfusion. Half-activation voltage (V 1 / 2 ) was determined by Boltzmann fitting of the conductance-voltage (G / V) curves.

[0098] Figure 1 shows that compound A (a compound listed in Table 1) shifts the activation voltage dependence in cells. Compound A significantly negatively shifts the activation voltage dependence for KCNQ2 and KCNQ3 homomers and KCNQ2 / Q3 heteromers. The magnitude of the shift depends on the KCNQ subunit composition, KCNQ2>KCNQ2 / Q3>KCNQ3.

[0099] Figure 2 demonstrates that Compound A has the ability to activate Kv7.2 homomers. The current density from 3 μM Compound A is significantly increased from the control. The current density activation from 3 μM Compound A is similar to that produced by 10 μM ezogabine or ICA-069673. EXAMPLES

[0100] Example 2: Comparison of Compound A and Ezogabine in Homomeric and Heteromeric KCNQ2 Channels KCNQ2 de novo variants (DNVs) are heterozygous mutations that cause KCNQ2 epileptic encephalopathy (KCNQ2-EE). Many KCNQ2-EE variants are missense and cluster in hotspots, domains of key functions of the protein, such as voltage sensing, transmembrane ion flux, and sites controlling PIP2 and calmodulin binding. Many KCNQ2-EE DNVs have been shown to exert dominant-negative effects under voltage clamp when co-expressed with wild-type subunits in heterozygous mimics. Ezogabine (EZO) increases the current of channels containing mutant subunits in vitro and is used in patients with KCNQ2-EE. Potential precision medicines for KCNQ2-EE include novel small molecules that act as potent neuronal KCNQ channel openers.

[0101] Four highly repetitive KCNQ2-EE missense mutations (Figure 3), R210H (located at S4 of the voltage sensor), T274M (located at the pore helix), A294V (located at the boundary between the pore loop and S6), and R581Q / L (located at intracellular helix C) were introduced into KCNQ2 cDNA by QuikChange site-directed mutagenesis. R210H is located at S4 of the voltage sensor, T274M at the pore helix, A294V at the boundary between the pore loop and S6, and R581Q at intracellular helix C. Plasmids containing the pathogenic mutants were coexpressed with wild-type KCNQ2 or KCNQ2 and KCNQ3 subunits by lipid-mediated transfection into Chinese hamster ovary (CHO) cells. The S5 helix mutation W236L of KCNQ2, which abolishes the regulatory function of EZO, was also used to characterize the binding of compound A. Gating and conductance of wild-type and mutant subunit-containing channels were measured using a whole-cell voltage clamp protocol before, during, and after compound application by focal pipette perfusion.

[0102] Compound A increased currents and shifted the G / V curves of wild-type homomeric (Figures 4-6) and heteromeric (Figures 7-9) channels. (Figure 4) Compound A (0.3 μM and 1.0 μM) increased homomeric channel density at -40 mV (Figure 5), (Figure 6) Compound A left-shifted the homomeric KCNQ2 G / V curve (Figure 7) Representative currents recorded from cells expressing heteromeric wild-type KCNQ2 / KCNQ3 channels before and during application of 1.0 μM Compound A (Figure 8) and (Figure 9) Compound A left-shifted these heteromeric wild-type channels (N=3-10 cells; * <0.05, ** <0.01, and *** <0.001). EXAMPLES

[0103] Example 3: Comparison of Compound A with Ezogabine and ICA-069673 in Activating KCNQ2 Homomeric Proteins Activation of KCNQ2 homomers by compound A requires W236, similar to EZO and unlike ICA-069673. (Figure 10, Figure 13) Representative current traces recorded at -40 mV from cells expressing wild-type KCNQ2 (Figure 10) and KCNQ2 W236L (Figure 13) before and after drug application. EZO and compound A increased the current density of wild-type KCNQ2 channels (Figure 11) but had no effect on the current density of W236L channels (Figure 14). Hyperpolarized G / V curves after drug application (N=3-12 cells; * <0.05, ** <0.01, and *** <0.001). EXAMPLES

[0104] Example 4: Activation by Compound A of channels incorporating the recurrent KCNQ2 voltage sensor domain pathogenic mutation, R210H Compound A activates channels incorporating the recurrent KCNQ2 voltage sensor domain pathogenic mutation R210H. (Figure 18) Current family recorded from homomeric R210H channels before and after application of 1.0 μM Compound A. R210H activation is very strongly depolarizing, and this effect is reversed by Compound A (Figure 19) Mean currents at +20 mV before and during application of Compound A. (Figure 20) Comparison of the effect of Compound A on wild-type KCNQ2 and 1:1 co-expressed wild-type and R210H at -40 mV. (Figures 21, 22) Summary of V1 / 2 shifts of channels with different subunit combinations after application of 1.0 μM Compound A (N=6-19; * <0.05, ** <0.01, and *** <0.001). EXAMPLES

[0105] Example 5: Activation of homomeric channels incorporating human KCNQ2 mutants by Compound A Compound A activates homomeric channels incorporating human pathogenic KCNQ2 mutants (pore domain and C-terminus). (Figure 23) Overlaid representative traces recorded at -40 mV from cells expressing wild-type KCNQ2, and 1:1 KCNQ2 and KCNQ2 A294V before and during application of 0.3 μM Compound A are shown. (Figure 24) Effect of 0.3 μM Compound A on the current density of wild-type channels and of channels formed by 1:1 co-expression of wild-type with the indicated pore domain and C-terminus mutants (N=4-8; * <0.05, ** <0.01, and *** <0.001). EXAMPLES

[0106] Example 6: Activation by Compound A of heteromeric channels incorporating the recurrent pathogenic KCNQ2 mutations T274M and A294V Compound A activated heterochannels incorporating recurrent pathogenic KCNQ2 mutants T274M and A294V (wild-type KCNQ2:mutant:wild-type KCNQ3 cDNA ratio = 1:1:2 mimicking heterozygotes). Average current density, conductance / voltage curves, and V1 / 2 shifts at -40 mV for channels with A294V (Figures 25-27) and T274M (Figures 28-30) are shown before and during application of 1.0 μM Compound A (N = 9-11; * <0.05, ** <0.01 and *** <0.001).

[0107] Compound A activates KCNQ2-containing homomers and KCNQ2 / 3 heteromers, shifting activation and increasing maximal current. Such modulation of KCNQ2 requires pore domain residue W236. Mutants from three different KCNQ2-EE mutation hotspots showed strong dominant-negative current inhibition under conditions mimicking heterozygotes. Compound A (0.3-1 μM) increased currents in cells expressing these mutants, increasing the current at -40 mV to wild-type levels. These results suggest that compound A may be effective against KCNQ2-EE.

[0108] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusions or deletions are made, the specification is deemed to include the modified group and thus conforms to all Markush group descriptions used in the appended claims.

[0109] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect that such variations will be adopted by those skilled in the art as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0110] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, and not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Thus, the claims are not limited to the embodiments exactly as shown and described. The present application also includes the following aspects. [Aspect 1] 1. A method of treating a neurodevelopmental disease or disorder, comprising administering a therapeutically effective amount of Compound A, or a pharma- ceutical acceptable salt thereof, to a pediatric subject in need thereof, The compound A or a pharma- ceutical acceptable salt thereof is N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; Tanamide;N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide;N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide;N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide; [Aspect 2] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide. [Aspect 3] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 4] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 5] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide. [Aspect 6] The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 7] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 8] The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 9] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide. [Aspect 10] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 11] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 12] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 13] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 14] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide. [Aspect 15] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide. [Aspect 16] 2. The method of embodiment 1, wherein compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide. [Aspect 17] 2. The method of claim 1, wherein the neurodevelopmental disease or disorder is selected from the group consisting of Angelman syndrome, neonatal drug withdrawal syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, West syndrome, SCN8A-associated encephalopathy epilepsy (EIEE13), epilepsy of infancy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Doze syndrome, adrenoleukodystrophy (ALD), ATP6V1A encephalopathy, atypical childhood epilepsy with central-temporal spikes (ACECTS), autosomal dominant epilepsy with speech impair 1. The method of claim 1, wherein the patient is selected from the group consisting of epilepsy with rolandic seizures (ADRESD), CDKL5 encephalopathy, benign childhood epilepsy with centro-temporal spikes (CECTS), epileptic encephalopathy with continuous spikes and waves during slow wave sleep (ECSWS), Grin1 encephalopathy, Grin2A epileptic aphasia, Grin2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, neuronal ceroid lipofuscinosis (NCL), nonsyndromic developmental disorders and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsy, STXBP1 encephalopathy, tuberous sclerosis complex (TS) / tuberous sclerosis complex (TSC), and the like, and combinations thereof.

Claims

1. 1. A medicament for use in treating a neurodevelopmental disease or disorder in a pediatric subject in need of such treatment comprising compound A or a pharma- ceutical acceptable salt thereof, The compound A or a pharma- ceutical acceptable salt thereof is selected from the group consisting of N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide; N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide;and N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide, or a pharma- ceutically acceptable salt thereof; The neurodevelopmental disease or disorder may be Angelman syndrome, neonatal drug withdrawal syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, West syndrome, SCN8A-associated encephalopathy epilepsy (EIEE13), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Doze syndrome, adrenoleukodystrophy (ALD), ATP6V1A encephalopathy, atypical childhood epilepsy with central-temporal spikes (ACECTS), autosomal dominant rolandic syndrome with speech disorder (ASD) epileptic encephalopathy with persistent spikes and waves during slow wave sleep (ECSWS), Grin1 encephalopathy, Grin2A epileptic aphasia, Grin2B encephalopathy, intermediate epileptic aphasia (IEAD), KCNT1 infantile epilepsy with migratory focal seizures, neuronal ceroid lipofuscinosis (NCL), nonsyndromic developmental disorders and epileptic encephalopathies, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-associated neonatal epilepsy, STXBP1 encephalopathy, tuberous sclerosis complex (TS) / tuberous sclerosis complex (TSC), and combinations thereof.

2. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutical acceptable salt thereof is N-(1-cyclobutyl-4-fluoro-6-(1-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide or a pharma- ceutical acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

4. The medicine according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(6-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutical acceptable salt thereof is N-(1-cyclobutyl-4-fluoro-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-(1-methylcyclopropyl)acetamide or a pharma- ceutical acceptable salt thereof.

6. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(6-cyano-1-cyclobutyl-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(1-cyclobutyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-6-cyano-4-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(7-cyano-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3-cyclopropyl-3-methylbutanamide or a pharma- ceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(6-chloro-7-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(1-cyclobutyl-5-fluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-6-cyano-4,7-difluoro-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(6-cyano-1-cyclobutyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(6-cyano-4,7-difluoro-1-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutically acceptable salt thereof is N-(1-(tert-butyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide or a pharma- ceutically acceptable salt thereof.

16. The pharmaceutical composition according to claim 1, wherein the compound A or a pharma- ceutical acceptable salt thereof is N-(1-(tert-butyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide or a pharma- ceutical acceptable salt thereof.

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