Imidazole compounds and their use as sodium channel inhibitors

Abstract

Disclosed herein are imidazole compounds and compositions useful for treating diseases or disorders associated with sodium channel-mediated activity, such as epilepsy, which have the structure of Formulas (I)-(XV), including R groups, A, and L, as defined in the Detailed Description. Also provided are methods for inhibiting diseases or disorders associated with sodium channel-mediated activity in a subject.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 420,877, filed October 31, 2022, and U.S. Provisional Application No. 63 / 420,883, filed October 31, 2022, the disclosures of each of which are incorporated herein by reference.

[0002] overview Embodiments relate to compounds disclosed herein, pharmaceutical compositions of such compounds, and methods of using such compounds.

[0003] Voltage-gated sodium channels (VGSCs) are important factors controlling cell excitability. They are membrane-bound proteins (Na V VGSC gene mutations are found in various parts of the human body and are known to cause several disorders in both the central and peripheral nervous systems. In particular, the Na channel isoform Na V 1.2 and Na V 1.6 is widely expressed in the central nervous system (CNS), along nerve axons, and plays a key role in the regulation of neuronal firing. V Several studies in animal models have highlighted the importance of the 1.6 subtype. V Mutations in SCN2A, the gene encoding 1 and 2, have been identified in patients with generalized epilepsy. These findings suggest that these sodium channel isoforms are important targets for the development of novel antiepileptic drugs (AEDs).

[0004] Some embodiments disclosed herein relate to compounds of Formulas (I)-(XV), wherein the A, L, and R groups are defined as further described herein. [ka]

[0005] In some embodiments, the compounds disclosed herein may have useful sodium channel inhibitory activity. Some embodiments herein relate to the treatment or prevention of diseases or disorders in which sodium channel-mediated activity plays a role using the compounds disclosed herein. In some embodiments, a method of treating a disease or disorder associated with sodium channel-mediated activity in a subject comprises administering to the subject a compound of an embodiment herein.

[0006] Some embodiments provide a method for treating a disease or disorder associated with sodium channel-mediated activity in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound or composition according to the present disclosure. Also provided is the use of a compound disclosed herein in the manufacture of a medicament for the treatment of a disease or disorder ameliorated by inhibition of sodium channel-mediated activity.

[0007] definition Before describing the compositions and methods of the present invention, it should be understood that the present invention is not limited to the particular processes, compositions, or methodologies described. It should also be understood that the terminology used herein is for the purpose of describing particular versions or embodiments only, and is not intended to limit the scope of the embodiments herein, which are limited only by the appended claims. Unless otherwise defined, 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 and materials similar or equivalent to those described herein can be used in the practice or testing of the embodiments herein, the preferred methods, devices, and materials are described herein. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein should be construed as an admission that the embodiments herein are not entitled to antedate such disclosure by virtue of prior invention.

[0008] It should also be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a sodium channel inhibitor" is a reference to one or more sodium channel inhibitors / modulators and equivalents thereof known to those skilled in the art, and so forth.

[0009] As used herein, the term "about" is intended to modify the numerical value it modifies and indicates that such numerical value varies within a margin of error. Unless a specific error, such as a standard deviation for the average value shown in a data graph or table, is described, the term "about" should be understood to mean plus or minus 10% of the numerical value with which it is used. Thus, approximately 50 mg means a range of 45 mg to 55 mg.

[0010] In embodiments or claims where the term "comprising" is used as a transitional phrase, such embodiments can also be envisioned by replacing the term "comprising" with the terms "consisting of" or "consisting essentially of."

[0011] As used herein, the terms "consists of" or "consisting of" mean that the pharmaceutical composition, composition, or method includes only those elements, steps, or ingredients specifically recited in a particular claimed embodiment or claim.

[0012] As used herein, the terms "consisting essentially of" or "consists essentially of" mean that a pharmaceutical composition or method includes only those elements, steps, or ingredients specifically recited in a particular claimed embodiment or claim, and may optionally include additional elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the particular embodiment or claim. For example, the only active ingredient(s) in a composition or method for treating a particular condition (e.g., nutrient deficiency) are the therapeutic agent(s) specifically recited in a particular embodiment or claim.

[0013] As used herein, two embodiments are "mutually exclusive" if one is defined as being different from the other. For example, an embodiment in which two groups are linked to form a cycloalkyl is mutually exclusive from an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH2 is mutually exclusive from an embodiment in which the same group is NH.

[0014] The term "inhibit" means to limit, prevent, or block the action or function of a target enzyme and / or to prevent, alleviate, or eliminate the onset of one or more symptoms associated with a disease, condition, or disorder, or to prevent, alleviate, or eliminate a disease, condition, or disorder.

[0015] When a range of values ​​is disclosed and the notation "from n1 to n2" or "between n1 and n2," where n1 and n2 are numbers, is used, and unless otherwise specified, the notation is intended to include the numbers themselves and the range therebetween. The range may be an integral or continuous value. For example, the range "2 to 6 carbon atoms" is intended to include carbon numbers 2, 3, 4, 5, and 6, since the number of carbon atoms is an integer. "1 to 3 μM (micromolar)" is intended to include 1 μM, 3 μM, and all significant figures therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0016] The term "alkenyl," as used herein alone or in combination, refers to a straight- or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl contains 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can include "alkenylene" groups.

[0017] The term "alkoxy," as used herein alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0018] The term "alkyl," as used alone or in combination herein, refers to a straight- or branched-chain alkyl radical containing 1 to 20 carbon atoms. In certain embodiments, the alkyl will contain 1 to 10 carbon atoms. In further embodiments, the alkyl will contain 1 to 8 carbon atoms. An alkyl group may be optionally substituted as defined herein.

[0019] Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, nonyl, and the like. The term "alkylene," as used herein alone or in combination, refers to a saturated aliphatic group derived from a straight- or branched-chain saturated hydrocarbon bonded at two or more positions, such as methylene (-CH-). Unless otherwise specified, the term "alkyl" can include "alkylene" groups.

[0020] The term "alkynyl," as used herein alone or in combination, refers to a straight or branched chain hydrocarbon radical having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkynyl contains 2 to 6 carbon atoms. In further embodiments, the alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C::C-, -C≡C-).

[0021] Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, etc. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0022] The term "aryl," as used herein alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings to which such polycyclic ring systems are fused. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, phenanthryl, and the like.

[0023] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes (eg, tritium, deuterium) of the structures depicted.

[0024] The term "cycloalkyl," or alternatively, "carbocycle," as used herein alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, each cyclic moiety containing 3 to 12 carbon atom ring members, and optionally a benzo-fused ring system, optionally substituted as defined herein. In certain embodiments, the cycloalkyl contains 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include both fused ring systems, such as decahydronaphthalene and octahydronaphthalene, and saturated or partially unsaturated polycyclic (multi-center) types. The latter type of isomer is commonly exemplified by bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0025] The terms "halo" or "halogen," as used herein alone or in combination, refer to fluorine, chlorine, bromine, or iodine.

[0026] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0027] The term "haloalkyl," as used herein alone or in combination, refers to an alkyl radical having the above-defined meaning in which one or more hydrogen atoms have been replaced with halogen. Specific examples include monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. Monohaloalkyl radicals, for example, can have an iodo, bromo, chloro, or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, and the like. "Haloalkylene" refers to a haloalkyl group attached to two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like.

[0028] The term "heteroaryl," as used herein alone or in combination, refers to a 3- to 15-membered unsaturated heteromonocyclic ring or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic and contains at least one atom selected from N, O, and S. In further embodiments, the heteroaryl will contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl will contain 5 to 7 atoms. The term also encompasses fused polycyclic groups in which a heterocycle is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0029] The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic), monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, where each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl will contain 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl will contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will contain 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl will contain 3 to 7 ring members in each ring. In further embodiments, the heterocycloalkyl will contain 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, and carbocyclic and benzo-fused ring systems; further, both terms include systems in which a heterocycle is fused to an aryl group, as defined herein, or an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and quinolinonyl. The heterocyclic groups may be optionally substituted unless specifically prohibited.

[0030] Any definition herein can be used in combination with other definitions to describe a composite structural group. By convention, the last element of such a definition is the one that is attached to the parent moiety. For example, the composite group alkylamido represents an alkyl group attached to the parent molecule via an amide group, and alkoxyalkyl represents an alkoxy group attached to the parent molecule via an alkyl group.

[0031] When a group is defined as "null," it means that the group is absent.

[0032] The term "optionally substituted" means that the precursor group can be substituted or unsubstituted. If substituted, the substituents of the "optionally substituted" group can include, but are not limited to, one or more substituents independently selected from the following groups or a specific set of specified groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxy ester, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. If structurally possible, two substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring containing 0 to 3 heteroatoms, for example, to form methylenedioxy or ethylenedioxy. Optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted to a level intermediate between fully and monosubstituted (e.g., -CH2CF 3)

[0033] Optionally, any of the following may be present:

[0034] When substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are included. When a substituent is qualified as "substituted," the substituted form is expressly intended. Additionally, a different set of optional substituents for a particular substructure may be defined as needed, and in such cases, the optional substitutions are so defined as defined immediately following "optionally substituted with."

[0033] Stereoisomeric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the stereoisomeric center. It should be understood that the present invention encompasses all stereoisomeric forms, including diastereomers, enantiomers, and epimers, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing defined stereochemical configurations, or by separation of a mixture of stereoisomers by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of stereoisomers by chiral chromatographic columns, or other suitable methods known in the art. Starting compounds of specific configurations are commercially available or can be prepared and resolved by techniques known in the art. Furthermore, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, endo, exo-entogen (E), and zusanmen (Z) isomers, as well as appropriate mixtures thereof. Furthermore, compounds may exist as tautomers, and all tautomers are provided by the present invention. Furthermore, the compounds disclosed herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In general, solvated forms are considered equivalent to unsolvated forms.

[0034] The compounds described herein may contain one or more stereoisomeric centers and therefore may exist as stereoisomers. Embodiments herein include all such possible stereoisomers, including substantially pure resolved stereoisomers, racemic mixtures thereof, and mixtures of diastereomers. In some embodiments, formulas are shown without definitive stereochemistry at specific positions. In other embodiments, compounds are isolated as single stereoisomers, but the absolute configuration of the stereocenters is unknown, or only the relative stereochemical configuration (i.e., cis- or trans-isomers) is known. In such embodiments, chemical formulas are depicted with tentative absolute configuration assignments, indicating single stereoisomers, and the relative stereochemical configurations are also described. Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof. Diastereoisomeric pairs of enantiomers can be separated, for example, by fractional crystallization from a suitable solvent, and the resulting enantiomeric pairs can be separated into individual stereoisomers by conventional means, for example, using optically active acids or bases as resolving agents, or on a chiral HPLC column. Furthermore, any stereoisomer 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 embodiments of the invention described and claimed herein are within the scope of the racemic forms of the compounds, as well as the individual enantiomers, diastereomers, stereoisomers, and stereoisomer-enriched mixtures.

[0035] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate enantiomerically enriched or optically pure precursors, or separation of the racemate using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with an appropriate optically active compound, such as an alcohol, or, if the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both diastereoisomers can be converted to the corresponding pure enantiomer by means well known to those skilled in the art. The chiral compounds (and their chiral precursors) according to embodiments herein are obtained in enantiomerically enriched form by chromatography, typically using HPLC, on an asymmetric resin with a mobile phase consisting of 0-50%, typically 2-20%, isopropanol, and 0-5%, typically 0.1%, of a hydrocarbon, typically heptane or hexane, containing an alkylamine such as diethylamine. The eluate is concentrated to yield the enriched mixture. Stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art, see, for example, "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).

[0036] As used herein, the term "derivative thereof" refers to a salt thereof, a pharmaceutically acceptable salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a co-crystal thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.

[0037] By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0038] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from bases or acids that are acceptable for administration to patients, such as mammals. The term "pharmaceutically acceptable salts" encompasses salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, so long as it is pharmaceutically acceptable. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

[0039] Suitable pharmaceutically acceptable acid addition salts of the compounds of the embodiments herein can be prepared from inorganic or organic acids. All of these salts can be prepared by conventional means from the corresponding compound of the embodiments herein, for example, by treating the corresponding compound of the embodiments herein with the appropriate acid or base.

[0040] Pharmaceutically acceptable acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, phosphoric acid, diphosphoric acid, and the like, as well as carboxylic acids such as, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, mesylic acid, cyclohexylaminosulfonic acid, stearic acid, arginic acid, β-hydroxybutyric acid, malonic acid, lactic acid, galacturonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, galactic acid, and the like. These include both organic acids such as maleic acid, malic acid, mandelic acid, muconic acid, ascorbic acid, oxalic acid, pantothenic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, xinafoic acid (1-hydroxy-2-naphthoic acid), and napadisilic acid (1,5-naphthalenedisulfonic acid).

[0041] Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganic, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including alkylamines, arylalkylamines, heterocyclylamines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0042] Other preferred salts according to embodiments of the present disclosure are quaternary ammonium compounds in which an anion (X-) is bonded equivalent to the positive charge of the N atom. X- can be an anion of various mineral acids, such as chloride, bromide, iodide, sulfate, nitrate, or phosphate, or an anion of organic acids, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, and p-toluenesulfonate. X- is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate, or trifluoroacetate. More preferably, X- is chloride, bromide, trifluoroacetate, or methanesulfonate.

[0043] The compounds of the embodiments herein may exist in both undissolved and solvated forms. The term solvate is used herein to refer to a molecular complex comprising a compound of the embodiments herein and one or more pharmaceutically acceptable amounts of solvent molecules. The term hydrate is used when the solvent is water. Examples of solvate forms include, but are not limited to, compounds of the embodiments herein associated with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. In the embodiments herein, it is specifically contemplated that one solvent molecule may be associated with one molecule of the compound of the embodiments herein, such as a hydrate.

[0044] Furthermore, in embodiments herein, it is specifically contemplated that more than one solvent molecule may be associated with one molecule of the compound of the embodiments herein, such as a dihydrate. Furthermore, in embodiments herein, it is specifically contemplated that less than one solvent molecule may be associated with one molecule of the compound of the embodiments herein, such as a hemihydrate. Furthermore, the solvates of the embodiments herein are contemplated as solvates of the compounds of the embodiments herein that retain the biological effectiveness of the unsolvated form of the compound.

[0045] Embodiments herein also include isotopically labeled compounds of embodiments herein, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from that normally found in nature. Examples of isotopes suitable for inclusion in compounds of embodiments herein include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 31 chlorine such as Cl, 18 fluorine, such as F; 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen, such as N15 O. 17 O and 18 Oxygen, such as O 32 phosphorus, such as P, and 35 Certain isotope-labeled compounds of the present embodiments, for example compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, 3 H, and carbon-14, 14 C is particularly useful for this purpose in view of its ease of incorporation and ease of preparation of detection means. 2 Substitution with heavier isotopes, such as H, may be preferable in some situations because it may provide therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life and reduced dosage requirements. 11 C. 18 F, 15 O. 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy.

[0046] Isotopically labeled compounds of embodiments herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, by substituting the appropriate isotopically labeled reagent for the unlabeled reagent.

[0047] Preferred isotopically labeled compounds include deuterated derivatives of the compounds of the embodiments herein. As used herein, the term deuterated derivatives encompasses the compounds of the embodiments herein in which at least one hydrogen atom has been replaced with deuterium at a specified position. Deuterium (D or 2 H) is a stable isotope of hydrogen that occurs at a natural abundance of 0.015 mole %.

[0048] Hydrogen-deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced with a deuterium atom. The exchange (incorporation) reaction can be complete or partial.

[0049] Generally, deuterated derivatives of the compounds of embodiments herein have an isotopic enrichment factor (the ratio between the isotopic abundance and the natural abundance of that isotope, i.e., the fraction of deuterium incorporated at a given position in a molecule in place of hydrogen) of at least 3500 (52.5% deuterium incorporation) for each deuterium present at a site designated as a potential site of deuteration on the compound.

[0050] In some embodiments, the isotopic enrichment factor is at least 5000 (75% deuterium). In some embodiments, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a deuteration site is independent of other deuteration sites.

[0051] The isotopic enrichment factor can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

[0052] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the present invention. Prodrugs of the compounds described herein are also within the scope of the embodiments herein. Thus, certain derivatives of the compounds of the embodiments herein (which derivatives may themselves have little or no pharmacological activity) can be converted, when administered to the body, for example, by hydrolytic cleavage, to compounds of the embodiments herein that have the desired activity. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs can be found in Prodrugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association) or Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).

[0053] Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Furthermore, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they are easier to administer than the compound or parent drug. For example, prodrugs may be orally bioavailable, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolytic cleavage or oxidative activation of the prodrug. Non-limiting examples of prodrugs include compounds that are administered as esters ("prodrugs") and then metabolically hydrolyzed to the active carboxylic acid. Other examples include peptidyl derivatives of the compounds. Prodrugs according to embodiments herein can be prepared by replacing appropriate functional groups present in compounds of embodiments herein with specific moieties known to those skilled in the art as "promoieties," for example, as described in H. Bundgaard, Design of Prodrugs (Elsevier, 1985).

[0054] As used herein, the terms "excipient" and "pharmaceutically acceptable excipient" are generally intended to be synonymous and are used interchangeably with the terms "carrier," "pharmaceutically acceptable carrier," "diluent," and "pharmaceutically acceptable diluent."

[0055] For compounds of the embodiments herein that are solid, one of ordinary skill in the art will recognize that the compounds and salts of the invention may exist in different crystalline, polymorphic, or amorphous forms, all of which are intended to be within the scope of the embodiments herein.

[0056] The compounds disclosed herein can exist as and therefore include all stereoisomers, conformational isomers and mixtures thereof in all proportions, as well as isotopic forms such as deuterated compounds.

[0057] As used herein, the term "bond" means a covalent bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. Unless otherwise specified, the bond may be a single, double, or triple bond. A dashed line between two atoms in a molecular structure drawing indicates that an additional bond may or may not be present at that position.

[0058] As used herein, the term "disease" is generally synonymous with, and intended to be used interchangeably with, the terms "disorder," "syndrome," and "condition" (in medical terms), all of which reflect an abnormal condition of the human or animal body or parts thereof that impairs normal function, is typically manifested by characteristic signs and symptoms, and reduces the duration or quality of the human or animal's life.

[0059] As used herein, "administering," when used in conjunction with a therapeutic agent, refers to administering the therapeutic agent directly into or onto a target tissue, or to administering the therapeutic agent to a patient so that the therapeutic agent has a beneficial effect on the target tissue. Thus, the term "administering," when used in conjunction with a compound of the present invention, can include, but is not limited to, delivering the compound into or onto a target tissue, for example, systemically administering the compound to a patient via intravenous injection so that the therapeutic agent reaches the target tissue, or delivering the compound to the target tissue in the form of a sequence encoding the compound (e.g., via so-called gene therapy techniques). "Administering" a composition can be accomplished by injection, topical administration, oral administration, or any of these methods in combination with other known techniques.

[0060] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, domestic animals such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0061] As used herein, the term "sodium channel inhibitor" refers to a compound that binds to and / or inhibits a target with measurable affinity. In certain embodiments, the modulator has an affinity of about 35 μM or less, about 34 μM or less, about 33 μM or less, about 32 μM or less, about 31 μM or less, about 30 μM or less, about 29 μM or less, about 28 μM or less, about 27 μM or less, about 26 μM or less, about 25 μM or less, about 24 μM or less, about 23 μM or less, about 22 μM or less, about 21 μM or less, about 20 μM or less, about 19 μM or less, about 18 μM or less, about 17μM or less, about 16μM or less, about 15μM or less, about 14μM or less, about 13μM or less, about 12μM or less, about 11μM or less, about 10μM or less, about 9μM or less, about 8μM or less, about 7μM or less , about 6μM or less, about 5μM or less, about 4μM or less, about 3μM or less, about 2μM or less, about 1μM or less, about 0.5μM or less, about 0.1μM or less, about 0.05μM or less, about 0.01μM or less 50 and / or binding constant. In certain embodiments, the modulator has an IC of greater than about 5 μM, between about 1 μM and about 5 μM, or less than about 1 μM. 50 and / or binding constant, IC 50 is an enzyme (e.g., Na V 1.6) to half the maximum level. V In some embodiments, compounds of the present disclosure have been found to exhibit inhibition of sodium channel isoform Na V Sodium channel isoform Na 1.5 V 1.6. IC of the disclosed compounds 50 An example of the measurement method is shown in Example 10.

[0062] The phrase "therapeutically effective" is intended to define the amount of active ingredient used to treat a disease or disorder or to affect a clinical endpoint.

[0063] As used herein, the term "therapeutic agent" or "therapeutic agent" or "pharmaceutically active agent" means an agent utilized to treat, combat, ameliorate, prevent, or ameliorate an undesirable condition or disease in a patient. In part, embodiments of the present invention relate to the treatment of diseases or disorders associated with sodium channel-mediated activity.

[0064] A "therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to inhibit, block, or reverse a desired effect, e.g., cell activation, migration, or proliferation. The activity contemplated by the present method includes both medical and / or prophylactic treatment, as appropriate. The specific dose of a compound administered in accordance with the present invention to achieve therapeutic and / or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. Compounds are effective over a wide dosage range; for example, daily dosages typically fall within the range of 0.001 to 1000 mg / kg, more typically 0.01 to 1000 mg / kg. However, it will be understood that the effective amount to be administered will be determined by a physician in light of the relevant circumstances, including the condition being treated, the choice of compound to be administered, and the selected route of administration, and therefore, the above dosage ranges are not intended to limit the scope of the present invention in any way. A therapeutically effective amount of a compound of the invention is typically an amount sufficient to achieve an effective systemic concentration or local concentration in tissue when administered in a physiologically acceptable excipient composition.

[0065] The term "therapeutically acceptable" refers to a compound or derivative thereof that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use.

[0066] As used herein, the terms "treat," "treated," "treating," or "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or delay (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes of this invention, beneficial or desired clinical results include alleviation of symptoms; reduction in the extent of the condition, disorder, or disease; stabilization of the condition (i.e., not worsening), stabilization (i.e., not worsening) of the condition, disorder, or disease state, delay in the onset or slowing of progression of the condition, disorder, or disease, improvement in the condition of the condition, disorder, or disease, and remission (whether partial or total, whether induced or maintained), whether detectable or undetectable, or enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without undue side effects. Treatment includes eliciting an increase in survival compared to the expected survival if not receiving treatment. Treatment may also include prolonging disease. Treatment may also be preemptive in nature, i.e., preventing disease. Disease prevention may include complete protection from disease, such as preventing infection with a pathogen, or may include preventing the progression of disease. For example, disease prevention may not mean the complete abrogation of all effects associated with the disease at any level, but instead may mean preventing disease symptoms to a clinically significant or detectable level. Disease prevention may also mean preventing progression to a later stage of the disease, prolonging disease-free survival compared to the disease-free survival that would occur if the treatment were not given, and prolonging disease-free survival compared to the disease-free survival that would occur if the treatment were not given.

[0067] "Newborn" refers to a human being less than one month old.

[0068] "Infant" refers to a human being between one month and two years of age.

[0069] "Child" refers to a human being between the ages of 2 and less than 12 years.

[0070] "Adolescent" refers to a human being between the ages of 12 and 17 years.

[0071] "Adult" refers to a human being aged 17 or older.

[0072] Also provided is a compound selected from the examples disclosed herein. The compound of the embodiments herein is also a salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a co-crystal thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof of the compounds of the embodiments herein.

[0073] The detailed description set forth herein is provided to aid those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein is not limited in scope by the specific embodiments disclosed herein. Any equivalent embodiments are intended to be within the scope of the present disclosure. Indeed, various modifications of the present disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description, without departing from the spirit or scope of the inventive discovery. Such modifications are also intended to be within the scope of the appended claims.

[0074] All documents cited herein are incorporated herein by reference. The discussion of references herein is intended merely to summarize the assertions made by their authors and is not an admission that any reference is prior art relevant to patentability. Applicant reserves the right to challenge the accuracy and pertinence of the cited documents.

[0075] compound An embodiment is a compound of formula (I): [ka] During the ceremony, A is selected from -O-, -NH-, or -S(O)2NH-; L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C6-C 10 is selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy, and R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; Or, it relates to a derivative thereof.

[0076] Some embodiments are compounds of formula (II): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C6-C 10 is selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy, and R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; Or, it relates to a derivative thereof.

[0077] Some embodiments are compounds of formula (III): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10aryl, and C(O)C1-C5 alkyl; R 1 is C6-C 10 is selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy, and R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; Or, it relates to a derivative thereof.

[0078] Some embodiments are compounds of formula (IV): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C6-C 10is selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy, and R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; Or, it relates to a derivative thereof.

[0079] Some embodiments are compounds of formula (V): [ka] During the ceremony, A is selected from -O-, -NH-, or -S(O)2NH-; L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C6-C 10is selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy, and R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; Or, it relates to a derivative thereof.

[0080] Some embodiments are compounds of formula (VI): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C6-C 10is selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy, and R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; Or, it relates to a derivative thereof.

[0081] Some embodiments are compounds of formula (VII): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C6-C 10is selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy, and R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; Or, it relates to a derivative thereof.

[0082] Some embodiments are compounds of formula (VIII): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C6-C 10is selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy, and R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; Or, it relates to a derivative thereof.

[0083] Some embodiments are compounds of formula (IX): [ka] During the ceremony, L is C1-C5 alkyl; R 1 is C6-C 10 aryl, said aryl being optionally substituted with one or more halogens; R 2 is selected from H or C1-C5 alkyl, and R 3 is a halogen, Or, it relates to a derivative thereof.

[0084] Some embodiments are compounds of formula (X): [ka] During the ceremony, A is -O- or -NR 8 and L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C1-C5 alkyl, C6-C 10 and selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, C1-C5 alkyl-C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-NH—, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy; R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl, R 9 is H or a halogen, and n is 1 or 2, Or, it relates to a derivative thereof.

[0085] Some embodiments are compounds of formula (XI): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C1-C5 alkyl, C6-C 10 and selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, C1-C5 alkyl-C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-NH—, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy; R 3 , R 4 , R 5 , R 6 , and R 7are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; R 9 is H or a halogen, and n is 1 or 2, Or, it relates to a derivative thereof.

[0086] Some embodiments are compounds of formula (XII): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C1-C5 alkyl, C6-C 10 and selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, C1-C5 alkyl-C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-NH—, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy; R 3 , R 4 , R 5 , R6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; R 8 is H or C1-C5 alkyl, R 9 is H or a halogen, and n is 1 or 2, Or, it relates to a derivative thereof.

[0087] Some embodiments are compounds of formula (XIII): [ka] During the ceremony, A is -O- or -NR 8 - and L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C1-C5 alkyl, C6-C 10 and selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, C1-C5 alkyl-C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-NH—, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy; R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; R 8 is H or C1-C5 alkyl, R 9 is H or a halogen, and n is 1 or 2, Or, it relates to a derivative thereof.

[0088] Some embodiments are compounds of formula (XIV): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C1-C5 alkyl, C6-C 10 and selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, C1-C5 alkyl-C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-NH—, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10 Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy; R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; R 9 is H or a halogen, and n is 1 or 2, Or, it relates to a derivative thereof.

[0089] Some embodiments are compounds of formula (XV): [ka] During the ceremony, L is a bond, C1-C5 alkyl, C6-C 10 aryl, and C(O)C1-C5 alkyl; R 1 is C1-C5 alkyl, C6-C 10 and selected from the group consisting of aryl, C2-C7 heteroaryl, C3-C8 cycloalkyl, C1-C5 alkyl-C3-C8 cycloalkyl, and C2-C9 heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from halogen, —CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-NH—, C1-C5 alkyl-C6-C 10 Aryl, C1-C5 alkoxy-C6-C 10Aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C 10 optionally substituted with one or more groups independently selected from the group consisting of aryl-C1-C5 alkyl, C2-C7 heterocyclyl-C1-C5 alkyl, and —S(O)2NHC1-C5 alkyl; R 2 is selected from H, C1-C5 alkyl, halogen, or C1-C5 alkoxy; R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, —CN, C1-C5 alkyl, or C1-C5 alkoxy; R 8 is H or C1-C5 alkyl, R 9 is H or a halogen, and n is 1 or 2, Or, it relates to a derivative thereof.

[0090] In some embodiments, the compound of formula (I) may be selected from the following, or is a derivative thereof: TIFF2025536577000017.tif196153TIFF2025536577000018.tif190156TIFF2025536577000019.tif18715 6TIFF2025536577000020.tif194154TIFF2025536577000021.tif197155TIFF2025536577000022.tif77160

[0091] In some embodiments, the compound of formula (I) may be selected from, or is a derivative thereof: TIFF2025536577000023.tif186156TIFF2025536577000024.tif201157TIFF2025536577000025.tif112159

[0092] In some embodiments, the compound of formula (X) can be selected from, or is a derivative thereof: TIFF2025536577000026.tif190162TIFF2025536577000027.tif35160

[0093] In some embodiments, the compound of formula (II) can be selected from compounds 1-44, 47-51, 60-63, and 66-71.

[0094] In some embodiments, the compound of formula (III) can be selected from compounds 45, 52-59, 64, and 65.

[0095] In some embodiments, the compound of formula (IV) can be selected from compound 46.

[0096] In some embodiments, the compound of formula (V) can be selected from compounds 1-71.

[0097] In some embodiments, the compound of formula (VI) can be selected from compounds 1-44, 47-51, 60-63, and 66-71.

[0098] In some embodiments, the compound of formula (VII) can be selected from compounds 45, 52-59, 64, and 65.

[0099] In some embodiments, the compound of formula (VIII) can be selected from compound 46.

[0100] In some embodiments, the compound of formula (IX) can be selected from compounds 3, 5, 6, and 7, 48, 50, 51.

[0101] In some embodiments, the compound of formula (X) can be selected from compounds 72-80.

[0102] In some embodiments, the compound of formula (XI) can be selected from compounds 72-74 and 79.

[0103] In some embodiments, the compound of formula (XII) can be selected from compounds 75-78 and 80.

[0104] In some embodiments, the compound of formula (XIII) can be selected from compounds 72-80.

[0105] In some embodiments, the compound of formula (XIV) can be selected from compounds 72-74 and 79.

[0106] In some embodiments, the compound of formula (XV) can be selected from compounds 75-78 and 80.

[0107] Pharmaceutical Composition Also provided are pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0108] In certain embodiments, a pharmaceutical composition may contain from about 0.01% to about 50% of one or more compounds disclosed herein. In some embodiments, the one or more compounds may be present in an amount of from about 0.01% to about 50%, from about 0.01% to about 45%, from about 0.01% to about 40%, from about 0.01% to about 30%, from about 0.01% to about 20%, from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.05% to about 50%, from about 0.05% to about 45%, from about 0.05% to about 40%, or from about 0.01% to about 50%. 0.05% to approximately 30%, approximately 0.05% to approximately 20%, approximately 0.05% to approximately 10%, approximately 0.1% to approximately 50%, approximately 0.1% to approximately 45%, approximately 0.1% to approximately 40%, approximately 0.1% to approximately 30%, approximately 0.1% to approximately 20%, approximately 0.1% to approximately 10%, approximately 0.1% to approximately 5%, approximately 0.5% to approximately 50%, approximately 0.5% to approximately 45%, approximately 0.5% to approximately 40%, approximately 0. 5% to about 30%, about 0.5% to about 20%, about 0.5% to about 10%, about 0.5% to about 5%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 5% to about 45%, about 5% to about 40% , about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, or an amount within one of these ranges. Specific examples may include about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, or a range between any two of these values, all of which represent a weight percent of the pharmaceutical composition.

[0109] In some embodiments, the compound disclosed herein is in a therapeutically effective amount. In some embodiments, the therapeutically effective amount is about 0.01 mg to about 1000 mg, about 0.01 mg to about 900 mg, about 0.01 mg to about 800 mg, about 0.01 mg to about 700 mg, about 0.01 mg to about 600 mg, about 0.01 mg to about 500 mg, about 0.01 mg to about 400 mg, about 0.01 mg to about 300 mg, about 0.01 mg to about 200 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 50 mg, about 0.01 mg to about 25 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 50 mg, about 0.01 mg to about 25 mg, about 0.01 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.01 mg to about 150 mg, about 0.01 mg to about 2 ... Approximately 10mg, approximately 0.01mg to approximately 5mg, approximately 0.1mg to approximately 1000mg, approximately 0.1mg to approximately 900mg, approximately 0.1mg to approximately 800mg, approximately 0.1mg to approximately 700mg, approximately 0.1mg to approximately 600mg, approximately 0.1mg to approximately 500mg, approximately 0.1mg to about 400mg, about 0.1mg to about 300mg, about 0.1mg to about 200mg, about 0.1mg to about 100mg, about 0.1mg to about 50mg, about 0.1mg to about 25mg, about 0.1mg to about 10mg, about 0.1mg to about 5mg, About 1mg to about 1000mg, about 1mg to about 900mg, about 1mg to about 800mg, about 1mg to about 700mg, about 1mg to about 600mg, about 1mg to about 500mg, about 1mg to about 400mg, about 1mg to about 300mg, about 1mg to about 20 0mg, about 1mg to about 100mg, about 1mg to about 50mg, about 1mg to about 25mg, about 1mg to about 10mg, about 1mg to about 5mg, about 10mg to about 1000mg, about 50mg to about 1000mg, about 100mg to about 1000mg, about 200 mg to about 1000 mg, about 300 mg to about 1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 10 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 10 mg to about 150 mg, about 50 mg to about 150 mg, about 60 mg to about 120 mg, about 50 mg to about 120 mg, or a range between any two of these values.Specific examples include, for example, about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 750 mg, about 600 mg, about 500 mg, about 400 mg, about 450 mg, about 300 mg, about 250 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 30 mg, about 20 mg, about 10 mg, about 5 mg, about 1 mg, about 0.1 mg, about 0.01 mg, or any value in between the ranges disclosed above.

[0110] In some embodiments, the compounds disclosed herein may be administered in doses of about 0.01 mg / kg to about 1000 mg / kg, about 0.01 mg / kg to about 900 mg / kg, about 0.01 mg / kg to about 800 mg / kg, about 0.01 mg / kg to about 700 mg / kg, about 0.01 mg / kg to about 600 mg / kg, about 0.01 mg / kg to about 500 mg / kg, about 0.01 mg / kg to about 400 mg / kg, about 0.01 mg / kg to about 300 mg / kg, about 0.01 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 25 mg / kg, or about 0.01 mg / kg ~10mg / kg, 0.01mg / kg~5mg / kg, 0.1mg / kg~1000mg / kg, 0.1mg / kg~900mg / kg, 0 .1mg / kg ~ approx. 800mg / kg, approx. 0.1mg / kg ~ approx. 700mg / kg, approx. 0.1mg / kg ~ approx. 600mg / kg, approx. 0.1mg / kg ~ approx. 500m g / kg, about 0.1 mg / kg to about 400 mg / kg, about 0.1 mg / kg to about 300 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1mg / kg~about 5mg / kg, about 1mg / kg~about 1000mg / kg, about 1mg / kg~about 900mg / kg, about 1mg / kg~about 800mg / kg, about 1mg / kg~ About 700mg / kg, about 1mg / kg to about 600mg / kg, about 1mg / kg to about 500mg / kg, about 1mg / kg to about 400mg / kg, about 1mg / kg to about 300mg / kg kg, about 1mg / kg to about 200mg / kg, about 1mg / kg to about 100mg / kg, about 1mg / kg to about 50mg / kg, about 1mg / kg to about 25mg / kg, about 1mg / k g ~ about 10mg / kg, about 1mg / kg - about 5mg / kg, about 10mg / kg - about 1000mg / kg, about 50mg / kg - about 1000mg / kg, about 100mg / kg - about 1 1000mg / kg, about 200mg / kg to about 1000mg / kg, about 300mg / kg to about 1000mg / kg, about 400mg / kg to about 1000mg / kg, about 500mg / kg to about 1000mg / kg, about 10mg / kg to about 500mg / kg, about 50mg / kg to about 500mg / kg, about 100mg / kg to about 500mg / kg, about 10mg / kg to about 300mg / kg, about 50mg / kg to about 300mg / kg, about 100mg / kg to about 300mg / kg, about 10mg / kg to about 150mg / kg, about 50mg / kg to about 150mg / kg, about 60mg / kg to about 120mg / kg, about 50mg / kg to about 120mg / kg, or a dose in a range between any two of these values. Specific examples include about 1000 mg / kg, about 900 mg / kg, about 800 mg / kg, about 700 mg / kg, about 750 mg / kg, about 600 mg / kg, about 500 mg / kg, about 400 mg / kg, about 450 mg / kg, about 300 mg / kg, about 250 mg / kg, about 200 mg / kg, about 175 mg / kg, about 150 mg / kg, and about 125 mg / kg. , about 120 mg / kg, about 110 mg / kg, about 100 mg / kg, about 90 mg / kg, about 80 mg / kg, about 70 mg / kg, about 60 mg / kg, about 50 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 1 mg / kg, about 0.1 mg / kg, about 0.01 mg / kg, or any value in between the ranges disclosed above.

[0111] The compounds described herein can be administered as raw chemicals or can be provided as pharmaceutical compositions. Accordingly, provided herein are pharmaceutical compositions comprising one or more of the specific compounds disclosed herein or their derivatives, together with one or more pharmaceutically acceptable excipients and, optionally, one or more other therapeutic ingredients. An excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Appropriate formulation of a pharmaceutical composition depends on the chosen route of administration. Any well-known techniques and excipients may be used, as appropriate and understood in the art. The pharmaceutical compositions disclosed herein can be prepared by any method known in the art, such as conventional mixing, dissolving, granulating, confectioning, filling, emulsifying, encapsulating, entrapping, or compressing.

[0112] In some embodiments, pharmaceutical compositions for use in accordance with the embodiments herein may be formulated in a conventional manner using one or more physiologically acceptable excipients.

[0113] When used as pharmaceuticals, the compounds can be administered in the form of pharmaceutical compositions, which can be prepared by methods well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and on the area to be treated.

[0114] The disclosed compounds or compositions may be administered orally. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be necessary or desirable. The compounds may be contained in such pharmaceutical compositions along with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives, etc. Those skilled in the art can refer to various pharmacological literature for guidance. For example, see Modern Pharmaceutics, 5th Edition, Banker & Rhodes, CRC Press (2009) and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 13th Edition, McGraw Hill, New York (2018).

[0115] In some embodiments, the method of treating a disease or disorder associated with sodium channel-mediated activity comprises administering a compound or pharmaceutical composition of the embodiments disclosed herein. In some embodiments, the compound is in a therapeutically effective amount. In some embodiments, the therapeutically effective amount is an amount disclosed herein.

[0116] Some embodiments disclosed herein also include pharmaceutical compositions comprising, as an active ingredient, one or more of the compounds disclosed herein in combination with one or more pharmaceutically acceptable carriers (excipients).

[0117] In some embodiments, the method for preparing a pharmaceutical composition includes mixing an active ingredient with an excipient, diluting the active ingredient with the excipient, or encapsulating the active ingredient in a carrier in the form of a container such as a capsule, sachet, paper, etc. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, and soft and hard gelatin capsules.

[0118] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose, including eutectic solvents, eutectic-based ionic liquids, or ionic liquids. Pharmaceutical compositions can also include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propylhydroxybenzoates, sweeteners, and flavoring agents. Pharmaceutical compositions can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art.

[0119] Pharmaceutical compositions can be formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dose for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient. Compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intrathecal, transmucosal, transdermal, rectal, nasal, topical (including, for example, cutaneous, buccal, sublingual, and intraocular), intravitreal, or vaginal administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. Compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing a compound disclosed herein or a derivative thereof (the "active ingredient") into association with a carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired composition.

[0120] Compositions of the compounds disclosed herein suitable for oral administration can be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary or paste.

[0121] Orally usable pharmaceutical preparations include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide sustained or controlled release of the active ingredient therein. All compositions for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain the active ingredient in admixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. The sugar-coated cores are provided with a suitable coating. For this purpose, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions, which may optionally contain suitable organic solvents or solvent mixtures, can be used. Dyes or pigments can be added to the tablets or sugar coatings for identification or to characterize different combinations of active compound doses.

[0122] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When such preformulation compositions are described as homogeneous, the active ingredient is typically dispersed evenly throughout the pharmaceutical composition so that the pharmaceutical composition can be easily subdivided into uniformly therapeutically effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then divided into unit dosage forms of the type described above, containing, for example, about 0.01 to about 1000 mg of the active ingredient.

[0123] The tablets or pills of the present invention can be coated or otherwise prepared to provide a dosage form that offers the advantage of extended action. For example, the tablets or pills can be composed of an inner dosage component and an outer dosage component, the latter being in the form of an envelope surrounding the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay its release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0124] Liquid forms into which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0125] The compounds can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Injectable compositions can be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative. The pharmaceutical compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The compositions can be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and can be stored in powder form or in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, e.g., physiological saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0126] In some embodiments, the pharmaceutical composition administered to a patient may be in the form of the pharmaceutical compositions described above. In some embodiments, these compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for ready use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. In some embodiments, the pH of the compound formulation is about 3 to about 11, about 5 to about 9, about 5.5 to about 6.5, or about 5.5 to about 7.5. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0127] Preferred unit dosage pharmaceutical compositions are those containing an effective amount, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0128] It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions described above may include other agents conventional in the art having regard to the type of pharmaceutical composition in question; for example, those suitable for oral administration may include flavoring agents.

[0129] In some embodiments, a therapeutically effective amount can vary depending, for example, on the particular application for which the treatment is being made, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound in a pharmaceutical composition can vary depending on many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. The dosage will depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological potency of the selected compound, the composition of excipients, and its route of administration. Effective amounts can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0130] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.

[0131] The active compounds are effective over a wide dosage range and can generally be administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will typically be determined by a physician depending on the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, response, and severity of the patient's symptoms, etc.

[0132] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration.

[0133] The precise amount of compound administered to a patient is the responsibility of the attending physician. The specific dosage level for a particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Furthermore, the route of administration will vary depending on the condition and its severity.

[0134] Treatment method Some embodiments of the present disclosure relate to a method for treating a disease or disorder associated with sodium channel-mediated activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, a derivative thereof, or a combination thereof. In certain embodiments, the therapeutically effective amount of a compound disclosed herein, a derivative thereof, or a combination thereof may be in the form of a pharmaceutical composition. In embodiments, the pharmaceutical composition may include a pharmaceutically acceptable excipient, an acceptable salt, solvate, or prodrug thereof.

[0135] Also provided are compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or disorder associated with sodium channel-mediated activity.

[0136] Some embodiments relate to a method of treating a disease or disorder associated with sodium channel isoform NaV1.6 activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed herein, a derivative thereof, or a combination thereof.

[0137] Some embodiments include the sodium channel isoform Na V 1.6 activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed herein, a derivative thereof, or a combination thereof.

[0138] In some embodiments, the disease or disorder associated with sodium channel-mediated activity is selected from a convulsive disorder, depression, an anxiety disorder, neuropathic pain, chemotherapy-induced neuropathy, chronic pain, migraine, ischemia, diastolic dysfunction, arrhythmia, Dravet syndrome, neuromuscular conditions, amyotrophic lateral sclerosis (ALS), restless legs syndrome, or a combination thereof.

[0139] In some embodiments, the convulsive disorder is selected from epilepsy, acute seizures, chronic seizures, generalized tonic-clonic seizures refractory seizures, drug-resistant convulsive disorder, early childhood epileptic encephalopathy, or a combination thereof.

[0140] In some embodiments, the convulsive disorder is epilepsy.

[0141] In some embodiments, the epilepsy is selected from partial epilepsy, generalized absence epilepsy, temporal lobe epilepsy, treatment-resistant epilepsy, drug-resistant epilepsy, epilepsy characterized by acute seizures, epilepsy characterized by chronic seizures, epilepsy characterized by generalized tonic-clonic seizures, epilepsy characterized by intractable seizures, or a combination thereof.

[0142] In some embodiments, the patient is selected from a neonate, infant, child, adolescent, or adult.

[0143] In some embodiments, the patient is a neonate.

[0144] In some embodiments, the patient is an infant.

[0145] In some embodiments, the patient is a child.

[0146] In some embodiments, the patient is an adolescent.

[0147] In some embodiments, the patient is an adult.

[0148] General synthetic methods for preparing compounds The compounds of the present invention can be prepared in many ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the art of organic synthetic chemistry, or variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. Reactions are carried out in a solvent or solvent mixture appropriate to the reagents and materials used and suitable for the transformations being effected. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule should be consistent with the proposed transformations. Thus, judgment may be required to alter the order of synthetic steps or to select one particular process scheme over another in order to obtain the desired compounds of the present invention.

[0149] The novel compounds of the present invention can be prepared using the reactions and techniques described in this section. Also, in the following description of the described synthetic methods, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental time, and workup procedures, are selected to be standard conditions for the reaction and should be readily recognized by those skilled in the art. Substituent restrictions compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods can be used.

[0150] The compounds of the present invention can be prepared by the exemplary processes described in the following schemes and examples, as well as by relevant published literature procedures used by those skilled in the art. Exemplary reagents and procedures from the reactions appear below and in the examples. Protection and deprotection of functional groups in the following steps can be carried out by procedures commonly known in the art (see, for example, Green, TW et al., Green's Protecting Groups in Organic Synthesis, 4th Ed., Wiley (2006)). General methods of organic synthesis and functional group transformations are described in the following references: Trost, BM et al. Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); March, J., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th Ed., Wiley & Sons, New York, NY (1992); Katrizky, AR et al. eds., Comprehensive Organic Functional Groups Transformation II, Elsevier Science Inc., Tarrytown, NY (2005); Larock, RC, Comprehensive Organic Transformations, Wiley Publishers, Inc., New York, NY (2018); and citations therein.

[0151] Solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art. Starting materials are commercially available or can be readily prepared by known methods by one of ordinary skill in the art.

[0152] Example 1: Synthesis Method A TIFF2025536577000028.tif33152

[0153] Synthesis of Int-3:

[0154] To a stirred solution of 4-(hydroxymethyl)benzaldehyde (1.0 g, 8.2 mmol, 1.0 equiv.) in THF (10 mL) were added phenylmethanol (1.32 g, 12.3 mmol, 1.5 equiv.) and triphenylphosphine (3.21 g, 12.3 mmol, 1.5 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. DIAD (2.4 g, 12.3 mmol, 1.5 equiv.) was added to the above solution at the same temperature. The reaction was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After confirming complete conversion of the starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash chromatography using a mixture of n-hexane and EtOAc as the mobile phase. The product was eluted with 10% ethyl acetate in hexane to give 4-(benzyloxy)benzaldehyde (0.600 g, 34.52% yield) as a colorless oil, m / z=213 [M+H]+.

[0155] Synthesis of Compound 1:

[0156] To a stirred solution of 4-(benzyloxy)benzaldehyde (0.250 g, 1.2 mmol, 1.0 equiv.) in methanol (2.5 mL) were added 1-(4-chlorophenyl)propane-1,2-dione (0.215 g, 1.2 mmol, 1.0 equiv.) and ammonium acetate (0.453 g, 5.9 mmol, 5.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After confirming complete conversion of the starting material, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC using 0.1% TFA in water / acetonitrile. The product fractions were lyophilized to give 2-(4-(benzyloxy)phenyl)-5-(4-chlorophenyl)-4-methyl-1H-imidazole (0.080 g, 18.12% yield) as a white amorphous solid. m / z = 375 [M+H] + , 1 H NMR (400MHz, DMSO d6): δ12.29(s,1H),7.90(d,J=7.2Hz,2H),7.72(brs,2H),7.50-7.36(m,7H),7.12(d,J=8.4Hz,1H),5.17(s,2H),2.46(s,3H).

[0157] Example 2: Synthesis Method B TIFF2025536577000029.tif33157

[0158] Step 1: To a stirred solution of 4-hydroxybenzaldehyde (0.500 g, 4.1 mmol, 1.0 equiv.) in DMF (5 mL), 1-(bromomethyl)-2-fluorobenzene (0.773 g, 4.1 mmol, 1.0 equiv.) and K2CO3 (1.69 g, 12.3 mmol, 3.0 equiv.) were added at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After confirming complete conversion of the starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash chromatography using a mixture of n-hexane and EtOAc as the mobile phase. The product was eluted with 15% ethyl acetate in hexane to give 4-((2-fluorobenzyl)oxy)benzaldehyde as an oil (0.400 g, 42.43% yield). m / z=231 [M+H] + .

[0159] Step 2: 4-((2-fluorobenzyl)oxy)benzaldehyde (0.150 g, 0.65 mmol, 1.0 equiv) was dissolved in methanol (2.5 mL) under stirring, and 1-(4-chlorophenyl)propane-1,2-dione (0.118 g, 0.65 mmol, 1.0 equiv) and ammonium acetate (0.250 g, 3.2 mmol, 5.0 equiv) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After confirming complete conversion of the starting material, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC using a mobile phase of water / acetonitrile containing 0.1% TFA, and the resulting fractions were lyophilized to give 2-(4-(benzyloxy)phenyl)-5-(4-chlorophenyl)-4-methyl-1H-imidazole as a white amorphous solid (0.040 g, 15.63% yield). m / z=393 [M+H] + 1H NMR(400MHz,DMSO d6)δ12.32(s,1H),7.90(d,J=7.8Hz,2H),7.74(d,J=7.8Hz,2H),7.60(d,J=6.0Hz,1H),7 .46(d,J=6.0Hz,3H),7.30-7.27(m,2H),7.14(d,J=8.8Hz,2H),5.20(s,2H),2.47(s,3H).

[0160] Example 3: Synthesis Method C

[0161] Synthesis example of 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-1-methyl-1H-pyrazole (compound 33) TIFF2025536577000030.tif79160

[0162] Step 1: 1-Methyl-1H-pyrazol-3-yl (0.40 g, 3.6 mmol, 1.0 equiv.) was dissolved in dichloromethane (5 mL) under stirring, and trimethylamine (0.72 g, 7.1 mmol, 2.0 equiv.) was added. The reaction mixture was stirred at 0 °C for 5 minutes, followed by the dropwise addition of methanesulfonyl chloride (0.61 g, 5.35 mmol, 1.5 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After confirming complete conversion of the starting material, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The resulting (1-methyl-1H-pyrazol-3-yl)methyl methanesulfonate was a yellow oil and was used directly in the next reaction step (0.34 g, yield 50.1%). m / z = 191.04 [M+H] + .

[0163] Step 2: (1-Methyl-1H-pyrazol-3-yl)methyl methanesulfonate (0.300 g, 1.5771 mmol, 1.0 equiv.) was dissolved in DMF (3 mL). 4-Hydroxybenzaldehyde (0.192 g, 1.57 mmol, 1.0 equiv.) and K2CO3 (0.652 g, 4.73 mmol, 3.0 equiv.) were added at room temperature. The reaction mixture was then stirred at 90 °C for 16 h. The reaction progress was monitored by TLC. After confirming complete conversion of the starting material, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi Flash chromatography using a mixture of n-hexane and ethyl acetate as the mobile phase. The product was eluted with 40% ethyl acetate in hexane and obtained as a solid, 4-((1-methyl-1H-pyrazol-3-yl)methoxy)benzaldehyde (0.200 g, 58.6% yield). m / z = 217.09 [M+H]. + .

[0164] Step 3: 4-((1-methyl-1H-pyrazol-3-yl)methoxy)benzaldehyde (0.200 g, 0.92 mmol, 1.0 equiv.) was dissolved in methanol (2 mL), and 1-phenylpropane-1,2-dione (0.168 g, 0.92 mmol, 1.0 equiv.) and ammonium acetate (0.356 g, 4.62 mmol, 5.0 equiv.) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After complete conversion of the starting material, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by Combi Flash chromatography using a mixture of n-hexane and EtOAc as the mobile phase. The product was eluted with 50% ethyl acetate in n-hexane to give 4-((1-methyl-1H-pyrazol-3-yl)methoxy)benzaldehyde as a white solid (0.090 g, 25.7% yield). m / z=379.12 [M+H] + 1H NMR(400MHz,DMSO):δ12.35(s,1H),7.87(d,J=8.4Hz,2H),7.71-7.67(m,4H),7.45(d,J =8.4Hz,2H),7.09(d,J=8.4Hz,1H),6.32(s,1H),5.04(s,2H),3.83(s,3H),2.43(s,3H). Example 4: Synthesis of 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-1-methylpiperidine TIFF2025536577000031.tif50156

[0165] Step 1: Synthesis of tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1-carboxylate (2): tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.80 g, 3.72 mmol, 1.0 equiv.) was dissolved in THF (8 mL) and cooled to 0 °C. To the solution, sodium hydride (60% in mineral oil, 0.10 g, 4.09 mmol, 1.1 equiv.) and trimethylsilyl chloride (0.48 g, 4.46 mmol, 1.2 equiv.) were added at the same temperature. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was concentrated under reduced pressure to give tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1-carboxylate as an oil (0.70 g, 65.53% yield). m / z=288.1[M+H] + .

[0166] Step 2: Synthesis of tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1-carboxylate (4): tert-Butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1-carboxylate (0.70 g, 2.79 mmol, 1.0 equiv.) was dissolved in DMF (7 mL), 4-hydroxybenzaldehyde (0.30 g, 2.79 mmol, 1.0 equiv.) and potassium carbonate (1.01 g, 7.32 mmol, 3.0 equiv.) were added, and the reaction mixture was stirred at 80 °C for 2 h. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography eluting with a solvent system of ethyl acetate / hexane (30% ethyl acetate) to give tert-butyl 4-((4-formylphenoxy)methyl)piperidine-1-carboxylate as an oil (0.55 g, 70.69% yield). m / z=220.1 [M+H] + .

[0167] Step 3 Synthesis of tert-butyl 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)piperidine-1-carboxylate (6): tert-butyl 4-((4-formylphenoxy)methyl)piperidine-1-carboxylate (0.20 g, 0.63 mmol, 1.0 equiv.) was dissolved in methanol (2 mL), 1-(4-chlorophenyl)propane-1,2-dione (0.11 g, 0.63 mmol, 1.0 equiv.) and ammonium acetate (0.24 g, 3.13 mmol, 5.0 equiv.) were added, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 50% ethyl acetate in hexane to give tert-butyl 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)piperidine-1-carboxylate as a solid (0.16 g, 52.95% yield). m / z=283.2 [M+H] + .

[0168] Step 4 Synthesis of tert-butyl 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)piperidine-1-carboxylate (0.15 g, 0.31 mmol, 1.0 equiv) in THF (3.0 mL) was added 2.5 M LAH solution in THF (0.50 mL, 1.24 mmol, 4.0 equiv) at room temperature, and the reaction mixture was stirred at 80° C. for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 60% ethyl acetate in hexane to give 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-1-methylpiperidine as a solid (0.045 g, 36.61% yield). m / z = 296.2 [M+H] + . 1 H NMR(400MHz,DMSO)δ8.18(s,1H),7.70(d,J=8.4Hz,2H),7.72(d,J=8.3Hz,2H),7.44(d,J=8.5Hz,2H),7.02(d,J=8.5Hz,2H),3.90 (d,J=5.8Hz,2H),2.85(d,J=11.2Hz,2H),2.45(s,3H),2.20(s,3H),2.08-1.97(m,1H),1.79(d,J=12.5Hz,2H),1.43-1.38(m,2H). Example 5: Synthesis of 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)-N-(3-fluorobenzyl)aniline TIFF2025536577000032.tif34159

[0169] Step 1: Synthesis of 4-((3-fluorobenzyl)amino)benzaldehyde (3): To a solution of 4-bromobenzaldehyde (0.5 g, 3.1 mmol, 1.0 equiv.) in toluene (5 mL), (3-fluorophenyl)methanamine (0.71 g, 4.66 mmol, 1.5 equiv.) and CsCO (0.99 g, 9.32 mmol, 3.0 equiv.) were added under a nitrogen atmosphere, and the reaction mixture was degassed with N for 15 min. To this was added BINAP (0.23 g, 0.31 mmol, 0.1 equiv.) and Pd(OAc) (0.23 g, 0.31 mmol, 0.1 equiv.) at room temperature, and the reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 35% ethyl acetate in hexane to give 4-((3-fluorobenzyl)amino)benzaldehyde as a yellow oil (0.35 g, 70.62% yield).

[0170] Step 2 Synthesis of 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)-N-(3-fluorobenzyl)aniline: To a solution of 4-((3-fluorobenzyl)amino)benzaldehyde (0.25 g, 1.84 mmol, 1.0 equiv) in methanol (2.5 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.34 g, 1.84 mmol, 1.0 equiv) and ammonium acetate (0.71 g, 9.19 mmol, 5.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 70% ethyl acetate in hexane to give 5-(4-chlorophenyl)-2-(2-methoxyphenyl)-4-methyl-1H-imidazole as a white amorphous solid (0.11 g, 25.74% yield), m / z=392.2 [M+H]. + . 1 H NMR(400MHz,DMSO)δ11.98(s,1H),7.70-7.62(m,4H),7.45-7.34(m,3H),7.22-7.16(m,2H),7 .05(t,J=8.0Hz,1H),6.63(d,J=8.2Hz,2H),6.54(s,1H),4.34(d,J=8.2Hz,2H),2.42(s,3H). Example 6: Synthesis of 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)-N-(thiazol-4-yl)benzenesulfonamide TIFF2025536577000033.tif26156

[0171] Step 1: Synthesis of 4-formyl-N-(thiazol-4-yl)benzenesulfonamide (3): To a solution of 4-formylbenzenesulfonyl chloride (0.8 g, 3.92 mmol, 1.0 equiv.) in DCM (8 mL) was added thiazol-4-amine (0.784 g, 7.84 mmol, 2.0 equiv.) and pyridine (1.57 g, 19.9 mmol, 5.0 equiv.), and the reaction mixture was stirred at room temperature for 5 h. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 50% ethyl acetate in hexane to give 4-formyl-N-(thiazol-4-yl)benzenesulfonamide as an oil (0.1 g, 9.53% yield). m / z=269[M+H] + .

[0172] Step 2 Synthesis of 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)-N-(thiazol-4-yl)benzenesulfonamide: To a solution of 4-formyl-N-(thiazol-4-yl)benzenesulfonamide (0.1 g, 0.37 mmol, 1.0 equiv.) in methanol (1 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.07 g, 0.37 mmol, 1.0 equiv.) and ammonium acetate (0.14 g, 1.86 mmol, 5.0 equiv.), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, and the residue was purified by preparative HPLC to give 5-(4-chlorophenyl)-2-(2-methoxyphenyl)-4-methyl-1H-imidazole as a white amorphous solid (0.125 g, 22.79% yield). m / z=430.8 [M+H] + . 1H NMR(400MHz,DMSO)δ12.73(s,1H),11.11(s,1H),8.86(d,J=2.2Hz,1H),8.14(d,J=8.3Hz,2H),7.88-7.72 (m,2H),7.70(d,J=8.0Hz,3H),7.55-7.50(m,1H),7.46-7.44(m,1H),7.07(d,J=2.2Hz,1H),2.74(s,3H). Example 7: Synthesis of 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-N-methylbenzenesulfonamide TIFF2025536577000034.tif45158

[0173] Step 1: Synthesis of 3-(hydroxymethyl)-N-methylbenzenesulfonamide (2): To a solution of 3-(N-methylsulfamoyl)benzoic acid (1 g, 4.65 mmol, 1.0 equiv.) in THF (10 mL) was added 1 M borane-tetrahydrofuran complex in THF (13.9 mL, 13.9 mmol, 3.0 equiv.), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 80% ethyl acetate in hexane to give 3-(hydroxymethyl)-N-methylbenzenesulfonamide as an off-white amorphous solid (0.9 g, 96.25% yield). m / z=202[M+H] + .

[0174] Step 2: Synthesis of 3-(N-methylsulfamoyl)benzyl methanesulfonate (3): To a solution of 3-(hydroxymethyl)-N-methylbenzenesulfonamide (0.9 g, 4.47 mmol, 1.0 equiv.) and TEA (0.9 g, 8.95 mmol, 2.0 equiv.) in DCM (9 mL) was added methanesulfonyl chloride (0.77 g, 6.71 mmol, 1.5 equiv.) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 30% ethyl acetate in hexane to give 3-(N-methylsulfamoyl)benzyl methanesulfonate as an oil (0.8 g, 64.04% yield), m / z=280 [M+H]. + .

[0175] Step 3: Synthesis of 3-((4-formylphenoxy)methyl)-N-methylbenzenesulfonamide (5): To a solution of 3-(N-methylsulfamoyl)benzyl methanesulfonate (0.8 g, 2.86 mmol, 1.0 equiv.) and 4-hydroxybenzaldehyde (0.7 g, 5.73 mmol, 2.0 equiv.) in DMF (8 mL), potassium carbonate (1.18 g, 8.60 mmol, 3.0 equiv.) was added, and the reaction mixture was stirred at 90 °C for 16 h. The reaction progress was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 50% ethyl acetate in hexane to give ethyl 3-((4-formylphenoxy)methyl)-N-methylbenzenesulfonamide (0.7 g, 35%). m / z=306 [M+H] + .

[0176] Step 4 Synthesis of 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-N-methylbenzenesulfonamide: To a solution of 3-((4-formylphenoxy)methyl)-N-methylbenzenesulfonamide (0.15 g, 0.49 mmol, 1.0 equiv.) in methanol (1.5 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.1 g, 0.59 mmol, 1.2 equiv.) and ammonium acetate (0.19 g, 2.45 mmol, 5.0 equiv.), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-N-methylbenzenesulfonamide as a white amorphous solid (0.07 g, 30.45% yield). m / z=468.4 [M+H] + , 1 H NMR (400MHz,DMSO)δ12.28(s,1H),7.89(s,3H),7.74(d,J=7.9Hz,5H),7.69-7.49( m,3H),7.13(d,J=4.9Hz,2H),5.22(s,2H),2.45(s,3H),2.41(d,J=4.9Hz,3H). Example 8: Synthesis of 5-(4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)phenyl)-1H-pyrazole TIFF2025536577000035.tif41158

[0177] Step 1: To a solution of 1-(4-hydroxyphenyl)ethan-1-one (5 g, 36.76 mmol, 1.0 equiv.) in DMF (50 mL), (bromomethyl)benzene (6.29 g, 36.76 mmol, 1.0 equiv.) and K2CO3 (15.22 g, 110.29 mmol, 3.0 equiv.) were added at room temperature, and the reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with ethyl acetate (1000 mL) and washed with cold water (3 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 30% ethyl acetate in hexane to give 1-(4-(benzyloxy)phenyl)ethan-1-one (3.5 g, 42.12% yield). m / z=227.10[M+H] + .

[0178] Step 2: Synthesis of (E)-1-(4-(benzyloxy)phenyl)-3-(dimethylamino)propen-2-one (4): To a solution of 1-(4-(benzyloxy)phenyl)ethan-1-one (2 g, 8.84 mmol, 1.0 equiv.) in DMF (20 mL) was added Bredereck's reagent (1 mL) at room temperature, and the reaction mixture was stirred at 110 °C for 16 h. The reaction progress was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (E)-1-(4-(benzyloxy)phenyl)-3-(dimethylamino)prop-2-en-1-one (1.5 g, 60.32% yield), m / z = 282.14 [M+H]. + .

[0179] Step 3 Synthesis of 5-(4-(benzyloxy)phenyl)-1H-pyrazole (5): To a solution of (E)-1-(4-(benzyloxy)phenyl)-3-(dimethylamino)propen-2-one (1.5 g, 5.33 mmol, 1.0 equiv) in ethanol (15 mL) was added hydrazine monohydrate (7.5 mL) and acetic acid (catalytic amount), and the reaction mixture was stirred at 80 °C for 8 h. The reaction progress was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 30% ethyl acetate in hexane to give 5-(4-(benzyloxy)phenyl)-1H-pyrazole (1 g, 74.93% yield), m / z=251.1 [M+H] + .

[0180] Step 4 Synthesis of 4-(1H-pyrazol-5-yl)phenol (6): 5-(4-(benzyloxy)phenyl)-1H-pyrazole (1 g, 4.00 mmol, 1.0 equiv.) was added to 10% Pd / C (50% aqueous, 1 g, w / w) suspended in methanol (10.0 mL) under nitrogen atmosphere and stirred at room temperature under hydrogen atmosphere for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of Celite and washed with MeOH (80 mL). The filtrate was concentrated under vacuum to give 4-(1H-pyrazol-5-yl)phenol as a semi-solid (0.6 g, 93.75% yield). m / z=266 [M+H] + .

[0181] Step 5 Synthesis of 4-(4-(1H-pyrazol-5-yl)phenoxy)benzaldehyde (8): 4-(1H-pyrazol-5-yl)phenol (0.6 g, 3.75 mmol, 1.0 equiv) was dissolved in DMF (6 mL), 4-fluorobenzaldehyde (0.47 g, 3.75 mmol, 1.0 equiv) and K2CO3 (1.55 g, 11.25 mmol, 3.0 equiv) were added at room temperature, and the reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 50% ethyl acetate in hexane to give 4-(4-(1H-pyrazol-5-yl)phenoxy)benzaldehyde (0.25 g, 25.25% yield). m / z=265.2 [M+H] + .

[0182] Step 6 Synthesis of 5-(4-(4-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)phenyl)-1H-pyrazole 4-(4-(1H-pyrazol-5-yl)phenoxy)benzaldehyde (0.25 g, 0.95 mmol, 1.0 equiv) was dissolved in methanol (2.5 mL), 1-(4-chlorophenyl)propane-1,2-dione (0.21 g, 1.14 mmol, 1.2 equiv) and ammonium acetate (0.36 g, 4.73 mmol, 5.0 equiv) were added, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction of the starting material was complete, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 60% ethyl acetate in hexane to give 5-(4-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)phenyl)-1H-pyrazole (0.07 g, 17.35% yield), m / z=428.12 [M+H] + . 1H NMR(400MHz,DMSO)δ12.87(s,1H),12.41(s,1H),8.15-7.90(m,2H),7.89-7.84(m,2H),7. 85-7.69(m,3H),7.48-7.35(m,2H),7.19-7.08(m,4H),6.69(d,J=2.2Hz,2H),2.47(s,3H). Example 9: Synthesis of 5-(4-chlorophenyl)-2-(4-((4,4-difluoro-1-methylcyclohexyl)methoxy)phenyl)-4-methyl-1H-imidazole TIFF2025536577000036.tif52156

[0183] Step 1: Synthesis of methyl 4,4-difluoro-1-methylcyclohexane-1-carboxylate (2): Diisopropylamine (8.54 mL, 60.67 mmol, 3.6 equiv.) was dissolved in tetrahydrofuran (50 mL) under cooling, and n-butyllithium (2.5 M in hexane, 32.35 mL, 80.89 mmol, 4.8 equiv.) was added at −78° C. The reaction mixture was stirred at 0° C. for 1 hour. After 1 hour, the reaction mixture was cooled again to −78° C., and methyl 4,4-difluorocyclohexane-1-carboxylate (3 g, 16.85 mmol, 1.0 equiv.) was added in tetrahydrofuran and stirred at −78° C. for 1 hour. After 1 hour, methyl iodide (9.38 mL, 151.68 mmol, 9.0 equiv.) was added at the same temperature, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with saturated aqueous ammonium chloride (75 mL) and extracted with EtOAc (3×70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 10% ethyl acetate in hexane to give methyl 4,4-difluoro-1-methylcyclohexane-1-carboxylate as a pale yellow liquid (1.2 g, 37.08% yield). 1 H NMR (400MHz, CDCl3): δ3.73(s, 3H), 2.21-1.94(m, 4H), 1.89-1.49(m, 4H), 1.22(s, 3H).

[0184] Step 2: Synthesis of (4,4-difluoro-1-methylcyclohexyl)methanol (3): Methyl 4,4-difluoro-1-methylcyclohexane-1-carboxylate (1.2 g, 6.25 mmol, 1.0 equiv.) was dissolved in THF (10 mL). 1 M lithium aluminum chloride in THF (9.38 mL, 9.375 mmol, 1.5 equiv.) was added at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 20% ethyl acetate in hexane to give (4,4-difluoro-1-methylcyclohexyl)methanol as a colorless liquid (0.9 g, 87.79% yield). 1 H NMR (400MHz, CDCl3): δ3.41 (s, 2H), 2.01-1.81 (m, 4H), 1.63-43 (m, 4H), 0.99 (s, 3H).

[0185] Step 3: Synthesis of methyl (4,4-difluoro-1-methylcyclohexyl)methanesulfonate (4): (4,4-Difluoro-1-methylcyclohexyl)methanol (0.9 g, 5.48 mmol, 1.0 equiv.) was dissolved in DCM (5 mL) and triethylamine (1.54 mL, 10.97 mmol, 2 equiv.) was added at 0 °C. After 5 min, methanesulfonyl chloride (0.63 mL, 8.23 ​​mmol, 1.5 equiv.) was added at the same temperature. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 50% ethyl acetate in hexane to give methyl (4,4-difluoro-1-methylcyclohexyl)methanesulfonate as a colorless liquid (0.7 g, 52.71% yield). 1H NMR (400MHz, CDCl3: δ4.0(s, 2H), 3.04(s, 3H), 1.99-1.92(m, 4H), 1.66-1.52(m, 4H), 1.08(s, 3H).

[0186] Step 4 Synthesis of 4-((4,4-difluoro-1-methylcyclohexyl)methoxy)benzaldehyde (6): (4,4-Difluoro-1-methylcyclohexyl)methyl methanesulfonate (0.7 g, 2.89 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), and 4-hydroxybenzaldehyde (0.42 g, 3.47 mmol, 1.2 equiv.) and potassium carbonate (1.19 g, 8.67 mmol, 3.0 equiv.) were added at room temperature. The reaction mixture was stirred at 110° C. for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 30% ethyl acetate in hexane to give 4-((4,4-difluoro-1-methylcyclohexyl)methoxy)benzaldehyde as an off-white solid (0.25 g, 32.25% yield). m / z=269.10 [M+H] + .

[0187] Step 5 Synthesis of 5-(4-chlorophenyl)-2-(4-((4,4-difluoro-1-methylcyclohexyl)methoxy)phenyl)-4-methyl-1H-imidazole: 4-((4,4-difluoro-1-methylcyclohexyl)methoxy)benzaldehyde (0.25 g, 0.93 mmol, 1.0 equiv) was dissolved in methanol (5 mL), 1-(4-chlorophenyl)propane-1,2-dione (0.16 g, 0.93 mmol, 1.0 equiv) and ammonium acetate (0.35 g, 4.66 mmol, 5.0 equiv) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 40% ethyl acetate in hexane to give 5-(4-chlorophenyl)-2-(4-((4,4-difluoro-1-methylcyclohexyl)methoxy)phenyl)-4-methyl-1H-imidazole as a white solid (0.05 g, 12.45% yield). m / z=429.0 [MH]-. 1 H NMR(400MHz,DMSO)δ12.27(s,1H),7.89(d,J=8.0Hz,2H),7.71(s,2H),7.45(d,J=7.2Hz,2H),7.05(d,J=8. 8Hz,2H),3.82(s,2H),2.44(s,3H),2.05-1.85(m,4H),1.77-1.67(m,2H),1.53-1.49(m,2H),1.08(s,3H). Example 10: Synthesis of 5-(4-chlorophenyl)-4-methyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1H-imidazole TIFF2025536577000037.tif31149

[0188] Step 1: Synthesis of 4-(2,2,2-trifluoroethoxy)benzaldehyde (3): 4-Hydroxybenzaldehyde (0.50 g, 4.10 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), 1,1,1-trifluoro-2-iodoethane (0.86 g, 4.10 mmol, 1.0 equiv.) and potassium carbonate (1.69 g, 12.29 mmol, 3.0 equiv.) were added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 30% ethyl acetate in hexane to give 4-(2,2,2-trifluoroethoxy)benzaldehyde as an oil (0.20 g, 23.93% yield), m / z=205.04 [M+H]. + .

[0189] Step 2 Synthesis of 5-(4-chlorophenyl)-4-methyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1H-imidazole: 4-(2,2,2-trifluoroethoxy)benzaldehyde (0.2 g, 0.98 mmol, 1.0 equiv.) was dissolved in methanol (2 mL), 1-(4-chlorophenyl)propane-1,2-dione (0.23 g, 1.27 mmol, 1.3 equiv.) and ammonium acetate (0.38 g, 4.90 mmol, 5.0 equiv.) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 50% ethyl acetate in hexane to give 5-(4-chlorophenyl)-4-methyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1H-imidazole as a white solid (0.080 g, 22.26% yield). m / z=368.07 [M+H] + . 1H NMR(400MHz,DMSOd6):δ12.08(s,1H),7.94(d,J=8.0Hz,2H),7.71(d,J=7.2Hz,2H) ,7.44(d,J=7.8Hz,2H),7.15(d,J=7.8Hz,2H),4.77(q,J=8.4Hz,2H),2.45(s,3H). Example 11: Synthesis of 4-(2-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)benzyl)morpholine TIFF2025536577000038.tif66137

[0190] Step 1. Synthesis of 44-((2-(bromomethyl)benzyl)oxy)benzaldehyde (3): To a solution of (2-(bromomethyl)phenyl)methanol (0.5 g, 2.48 mmol, 1.0 equiv.), 4-hydroxybenzaldehyde (0.36 g, 2.98 mmol, 1.2 equiv.), THF (5 mL), and PPh3 (0.98 g, 3.7 mmol, 1.5 equiv.) were added at room temperature. The reaction mixture was cooled to 0 °C, and DIAD (0.75 g, 3.7 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 30% ethyl acetate in hexane to give 4-((2-(bromomethyl)benzyl)oxy)benzaldehyde as an oil (0.25 g, 32% yield). m / z=306 [M+H] + .

[0191] Step 2 Synthesis of 4-((2-(morpholinomethyl)benzyl)oxy)benzaldehyde (5): A solution of 4-((2-(bromomethyl)benzyl)oxy)benzaldehyde (0.25 g, 0.81 mmol, 1.0 equiv) in morpholine (1 mL) was prepared at room temperature. The reaction mixture was stirred at 120 °C for 3 h. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 20% ethyl acetate in hexane to give 4-((2-(morpholinomethyl)benzyl)oxy)benzaldehyde as a yellow oil (0.2 g, 78% yield). m / z = 312 [M+H] + .

[0192] Step 3 Synthesis of 4-(2-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)benzyl)morpholine: To a solution of 4-((2-(morpholinomethyl)benzyl)oxy)benzaldehyde (0.18 g, 0.57 mmol, 1.0 equiv) in methanol (1.8 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.12 g, 0.57 mmol, 1.0 equiv) and ammonium acetate (0.22 g, 2.89 mmol, 5.0 equiv), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by flash chromatography and the product was eluted with 20% ethyl acetate in hexane to give 4-(2-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)benzyl)morpholine as a white amorphous solid (0.07 g, 25.55% yield). m / z=475 [M+H] + . 1H NMR(400MHz,DMSO)δ12.26(s,1H),7.99-7.80(m,2H),7.71(d,J=8.1Hz,2H),7.50-7.40(m,3H) ,7.32-7.29(m,3H),7.11(d,J=8.3Hz,2H),5.33(s,2H),3.54(s,6H),2.44(s,3H),2.34(s,4H). Example 12: Synthesis of 6-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-N-methylpyridin-2-amine TIFF2025536577000039.tif44144

[0193] Step 1: Synthesis of (6-chloropyridin-2-yl)methanol (2): To a cooled solution of methyl 6-chloropicolinate (2 g, 11.69 mmol, 1.0 equiv.) in tetrahydrofuran (20 mL), 1 M lithium aluminum chloride in THF (29.23 mL, 29.23 mmol, 2.5 equiv.) was added at -20 °C, and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexane to give (6-chloropyridin-2-yl)methanol as an oil (1.2 g, 65.73% yield), m / z = 144 [M+H]. + .

[0194] Step 2: Synthesis of 4-((6-chloropyridin-2-yl)methoxy)benzaldehyde (3): To a solution of 4-hydroxybenzaldehyde (1 g, 8.19 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL), (6-chloropyridin-2-yl)methanol (1.2 g, 8.19 mmol, 1.0 equiv.) and triphenylphosphine (3.22 g, 12.29 mmol, 1.5 equiv.) were added at room temperature. The reaction mixture was cooled to 0 °C, and DIAD (2.48 g, 12.29 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography and the product was eluted with 30% ethyl acetate in hexane to give 4-((6-chloropyridin-2-yl)methoxy)benzaldehyde as a colorless oil (0.6 g, 28.98% yield). m / z=248 [M+H] + .

[0195] Step 3: Synthesis of tert-butyl (6-((4-formylphenoxy)methyl)pyridin-2-yl)(methyl)carbamate (4): To a solution of 4-((6-chloropyridin-2-yl)methoxy)benzaldehyde (0.6 g, 2.4 mmol, 1.0 equiv.) in dioxane (6 mL), tert-butyl methylcarbamate (0.47 g, 3.6 mmol, 1.5 equiv.) and cesium carbonate (2.36 g, 7.20 mmol, 3.0 equiv.) were added, and the reaction mixture was degassed with N. To this was added BINAP (0.15 g, 0.24 mmol, 0.1 equiv.) and RuPhosPdG (0.10 g, 0.12 mmol, 0.1 equiv.), and the reaction mixture was stirred in a microwave at 100 °C for 3 h. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 35% ethyl acetate in hexane to give tert-butyl (6-((4-formylphenoxy)methyl)pyridin-2-yl)(methyl)carbamate as a yellow oil (0.3 g, 36.17% yield). m / z = 343 [M+H] + .

[0196] Step 4 Synthesis of tert-butyl (6-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)pyridin-2-yl)(methyl)carbamate (5): To a solution of tert-butyl (6-((4-formylphenoxy)methyl)pyridin-2-yl)(methyl)carbamate (0.3 g, 0.87 mmol, 1.0 equiv.) in methanol (3 mL), 1-(4-chlorophenyl)propane-1,2-dione (0.17 g, 0.87 mmol, 1.0 equiv.) and ammonium acetate (0.33 g, 4.38 mmol, 5.0 equiv.) were added, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography, and the product was eluted with 50% ethyl acetate in hexane to give tert-butyl (6-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)pyridin-2-yl)(methyl)carbamate as an off-white solid (0.07 g, 19.82% yield). m / z = 506 [M+H] + .

[0197] Step 5 Synthesis of 6-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-N-methylpyridin-2-amine: To a cooled solution of tert-butyl (6-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)pyridin-2-yl)(methyl)carbamate (0.15 g, 0.29 mmol, 1.0 equiv) in dichloromethane (2 mL) was added hydrochloric acid in 1,4-dioxane (4 M, 0.75 mL) at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 6-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)-N-methylpyridin-2-amine as a white solid (0.07 g, 58.20% yield). m / z=405.2 [M+H] + . 1 H NMR(400MHz,DMSO)δ8.41(s,2H),7.89(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.45-7.37(m,2H),7.08 (d,J=8.4Hz,2H),6.60(d,J=8.0Hz,2H),6.37(d,J=8.0Hz,2H),4.99(s,2H),2.70(s,3H),2.42(s,3H).

[0198] Analytical HPLC and HPLC / MS methods employed to characterize the compounds disclosed herein are described in Examples 13-26.

[0199] Example 13: LCMS Method C1 TIFF2025536577000040.tif113158

[0200] Example 14: LCMS Method C2 TIFF2025536577000041.tif108156

[0201] Example 15: LCMS Method C3 TIFF2025536577000042.tif113144

[0202] Example 16: LCMS Method F TIFF2025536577000043.tif91153

[0203] Example 17: LCMS Method G1 TIFF2025536577000044.tif90154

[0204] Example 18: LCMS method H TIFF2025536577000045.tif82158

[0205] Example 19: LCMS Method H2 TIFF2025536577000046.tif91159

[0206] Example 20: LCMS method H3 TIFF2025536577000047.tif81152

[0207] Example 21: LCMS method J TIFF2025536577000048.tif103156

[0208] Example 22: LCMS Method J2 TIFF2025536577000049.tif107153

[0209] Example 23: Chiral Preparative HPLC Method 1 TIFF2025536577000050.tif58153

[0210] Example 24: Chiral Preparative HPLC Method 2 TIFF2025536577000051.tif65157

[0211] Example 25: Preparative HPLC Method 1 TIFF2025536577000052.tif85138

[0212] Example 26: Preparative HPLC Method 2 TIFF2025536577000053.tif80135

[0213] 1 H NMR spectra were recorded at 400 MHz using a Bruker Advance III HD with a 5 mm PABBO BB / 19F-1H / D ZGRD probe spectrometer. Spectral data are reported in the form of chemical shifts (multiplicity, coupling constants, and hydrogen numbers). Chemical shifts are specified in ppm downfield of the tetramethylsilane internal standard (δ units, tetramethylsilane = 0 ppm) and / or referenced to the solvent peak. 1 In the H NMR spectrum, CD2HSOCD3 is at 2.49 ppm, CD2HOD is at 3.30 ppm, and CHCl3 is at 7.24 ppm. 13 In the C NMR spectrum, solvent peaks appear at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. 13 C NMR spectra are proton decoupled.

[0214] The compounds of the present invention were prepared according to either of the synthetic methods A, B, and C described in Examples 1 to 12 and the LCMS method described in Examples 13 to 26. Spectroscopic data are shown in Table 1. [Table 1] TIFF2025536577000055.tif198158TIFF2025536577000056.tif201155TIFF2025536577000057.tif199154TIFF2025536577000058.tif195156

[0215] Biological activity assays The compounds of the present disclosure were tested in several biological assays and the results showed that they were comparable to known Na VThe results were compared to those for Compound A, a 1.6 inhibitor (US Pat. No. 11,090,189, the disclosure of which is incorporated herein by reference in its entirety). [ka]

[0216] Example 27: Na V Inhibition Cell culture: Human Na V 1.6, human Na V 1.5, or human Na V CHO cells expressing either 1.2 are incubated at 37°C in a humidified atmosphere of 5% CO2 (relative humidity greater than 95%). Cells are continuously maintained and passaged in sterile culture flasks containing F12 (HAM) medium supplemented with 10% fetal bovine serum, 1.0% penicillin / streptomycin solution, and 200 μg / mL hygromycin. Cells are maintained at approximately 80% confluence before passage.

[0217] Electrophysiological assays: Data were collected using a Qube 384 (Sophion) automated voltage clamp platform, using either single-hole or multi-hole plates. Compounds were administered to human NaCl using a half-inactivation voltage protocol. V 1.6, human Na V 1.5, Na V Furthermore, the membrane potential was maintained at the voltage at which inactivation was complete. V The compound was also evaluated against 1.6. The half-activation protocol involved eliciting inward currents from a membrane potential of -120 mV to -10 mV in 20 ms steps, followed by a half-activation voltage (adapted Na of the Qube 384). VInactivation of the inward current was determined by applying a voltage step of -10 mV for 3 seconds (predetermined using the 1 function), followed by a 20-ms voltage step to -10 mV. Each cell was exposed to vehicle (0.3% DMSO) for 5 minutes to allow the inward current to stabilize. After this time, compounds were applied at a single concentration per well for 10 minutes. This protocol, with a 30-second intersweep interval, was applied throughout the experiment. For the full inactivation protocol, the membrane potential was maintained at -45 mV. Every 25 seconds (0.04 Hz), a 60-ms repolarization step to -150 mV was performed, followed by a 10-ms test pulse to 0 mV to elicit inward currents. This voltage protocol was applied throughout the experiment. All wells were exposed to vehicle (0.3% DMSO) for 20 minutes to allow the inward current to stabilize. Compounds were then applied at a single concentration for 20 minutes.

[0218] Recording solutions: The intracellular solution contained 15 mM NaCl, 120 mM CsF, 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer), and 10 mM EGTA (ethylene glycol tetraacetic acid), adjusted to pH 7.2 with CsOH. The extracellular solution contained 140 mM NaCl, 5 mM KCl, 3 mM CaCl2, 1.2 mM MgCl2, 5 mM HEPES, and 11.1 mM glucose, adjusted to pH 7.4 with NaOH. The osmolarity of the ICS and ECS was adjusted to 300 mOsm / kg and 310 mOsm / kg, respectively, with sucrose.

[0219] The results are shown in Table 2. [Table 2] TIFF2025536577000061.tif164134

[0220] Example 28: Hearing test N1768D SCN8A mice (6-12 weeks old) were injected intraperitoneally (ip) with the compounds and tested for the presence of auditory seizures 1 hour after drug administration.

[0221] Measurement of audiogenic seizures: Mice were tested for auditory-induced seizures using a 10-second 15 kHz pure tone (~80-100 dB) generated using Tone Generator software (NCH Software, Inc.), amplified by a Kinter K3118 stereo amplifier (Kinter USA), and transduced through a 3-watt mini-speaker lowered into the recording chamber. Mice were observed for 60 seconds, and the occurrence of behavioral seizures was visually assessed by the experimenter and videotaped using a laptop webcam. Seizure onset and recovery times were recorded.

[0222] N1768D SCN8A mice (>8 weeks old) were euthanized with isoflurane, decapitated, and the brains were rapidly removed and placed in ice-cold (~0°C) artificial cerebrospinal fluid (ACSF) containing 5% KCl, 1.25% NaH2PO4, 2% CaCl2, 1% MgCl2, 0.5% L-ascorbic acid, 10% glucose, 25% NaHCO3, and 2% sodium pyruvate (osmolality 300–312 mOsm), oxygenated with 95% O2 and 5% CO2. Horizontal sections (300 μm thick) were cut using a vibratome in an ice-cooled chamber and incubated in oxygenated ACSF preheated to 37°C for 30 min before being stored at room temperature. For recording, the sections were placed in a small chamber and perfused with oxygenated ACSF (~28°C) at a rate of 1–2 mL / min. Layer 4 somatosensory pyramidal neurons were visually identified using a Zeiss Axioscope microscope. Whole-cell current-clamp recordings were performed using an Axopatch 700B amplifier (Molecular Devices, pCLAMP 10 software) and a Digidata 1322A digitizer (Molecular Devices). Borosilicate electrodes were pulled using a Brown-flaming puller (model P1000; Sutter Instruments), flame-polished, and tested to have a resistance of 2–3.5 MΩ when filled with an intracellular solution with the following composition (in mM): 120 K-gluconate, 10 NaCl, 2 MgCl2, 0.5 K2EGTA, 10 HEPES, 4 Na2ATP, and 0.3 NaGTP, pH adjusted to 7.2 with KOH (osmolarity 270–290 mOsm). Currents were amplified, low-pass filtered at 2 kHz, and sampled at 33 kHz.

[0223] Action potentials (APs) were elicited using successive current injection steps from -20 pA to 400 pA in 10 pA increments with a 3-second interpulse interval. To measure the intrinsic membrane and AP properties, depolarizing currents (0-400 pA) were injected into neurons for 4 seconds. Recordings were made before administration of the test concentrations, 10 minutes after administration, and 10 minutes after washout. The frequency of APs was recorded before and after drug administration.

[0224] The results are shown in Table 3. [Table 3]

[0225] Example 29: Microsome stability study Metabolic stability in liver microsomes (HLM / MLM) - A 10 mM stock solution of compound (in DMSO) was prepared. From a 2 mM intermediate stock solution, the compound was diluted with acetonitrile:water (50:50) to prepare a 0.5 mM working solution. Compound (1.8 μL of working solution) was spiked into 0.1 M potassium phosphate buffer (260.7 μL), pH 7.4, at a concentration of 3 μM (0.15% DMSO). Subsequently, human / mouse liver microsomes (7.5 μL, final protein concentration 0.5 mg / mL) were added. The microsomes and buffer were pre-incubated at 37°C. The reaction was then initiated by adding 30 μL of 10 mM NADPH (as a coenzyme) prepared in 0.1 M potassium phosphate buffer. At each time point (0, 5, 15, 30, and 60 min), 40 μL samples were withdrawn and the reaction was stopped with 360 μL of chilled acetonitrile or methanol containing the appropriate internal standard (carbamazepine). The samples were centrifuged, and the supernatants were analyzed in duplicate by LC-MS / MS. The percentage of compound remaining at each time point was calculated relative to that of the 0-min sample. The data were then analyzed in duplicate to calculate half-lives and intrinsic clearance (CLint). Control samples were prepared without NADPH at the initial and final time points, and blank samples were prepared using DMSO (without test compound).

[0226] Mouse (C57) brain tissue binding assay - equilibrium dialysis: A 10 mM stock of compound was prepared in DMSO. From this stock solution, a 1.25 mM working solution was prepared in DMSO, and the working solution was added to a brain homogenate (Accuprec; C57 mouse) master mix to a concentration of 5 μM. The brain homogenate and compound mixture were mixed, and a 25 μL aliquot of this mixture was added to 25 μL of DPBS (pH 7.4) for T = 0 h. The reaction was immediately terminated with 300 μL of acetonitrile:water (90:10) containing an internal standard. The sample was stored at 4 °C for 4 h. To initiate the reaction, the RED device was placed on the baseplate, and 100 μL of the brain homogenate / compound mixture was then added to the chamber of the RED device surrounded by the red ring (red chamber). The other chamber (white chamber) was filled with 350 μL of buffer solution DPBS (pH 7.4) and sealed (with a sealer) to prevent sample evaporation and spillage. The base plate was then placed on an orbital shaker at 400 rpm and incubated at 37°C for 4 hours. After this incubation period, the base plate was removed, and 25 μL of dialyzed samples from both chambers were transferred to a deep-well plate. 25 μL of brain homogenate corresponding to the buffer sample collected from the white chamber was then added, and 25 μL of buffer solution was added to the brain homogenate collected from the red chamber. The reaction was terminated with 300 μL of acetonitrile:water (90:10) containing an internal standard to precipitate proteins and release compounds. The T=0 and T=4 hour samples were mixed and vortexed for 5 minutes. The samples were then placed on ice for 30 minutes to further promote compound precipitation. The samples were then removed and centrifuged at 4000 rpm for 20 minutes. The supernatants of all samples were collected in vials and analyzed in duplicate using LCMS / MS. The concentrations of the test compounds in the buffer and brain homogenate chambers were determined from the peak areas obtained (LCMS / MS analysis).The unbound fraction of test compound in the brain homogenate was calculated based on the following formula: Fu (unbound fraction) = 1 - (brain homogenate chamber concentration - buffer chamber concentration / brain homogenate chamber concentration), recovery rate = {(V dialysate × C free + V brain homogenate × C total) / (V brain homogenate × C zero)} × 100%, where V dialysate = buffer chamber volume, C free = concentration in the buffer chamber after dialysis, V brain homogenate = brain homogenate chamber volume, C total = concentration in the brain homogenate chamber after dialysis, and C zero = initial concentration at T = 0 min. Unbound fraction (Fu) brain = 1 / (1 + ((1 / unbound fraction brain homogenate) - 1) * 3), where 3 is the dilution factor of the brain homogenate.

[0227] The results are shown in Table 4. [Table 4]

Claims

1. A compound of formula (I) During the ceremony, A is —O—, —NH—, or —S(O) ２ NH—, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ cycloalkyl, and C ２ -C ９ and each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy, and R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy, Or its derivatives.

2. A compound of formula (II) During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ cycloalkyl, and C ２ -C ９ and each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy, and R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy, Or its derivatives.

3. A compound of formula (III): During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ cycloalkyl, and C ２ -C ９ and each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy, and R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy, Or its derivatives.

4. A compound of formula (IV), During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ cycloalkyl, and C ２ -C ９ and each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy, and R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy, Or its derivatives.

5. A compound of formula (V) During the ceremony, A is —O—, —NH—, or —S(O) ２ NH—, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ cycloalkyl, and C ２ -C ９ and each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy, and R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy, Or its derivatives.

6. A compound of formula (VI) During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ cycloalkyl, and C ２ -C ９ and each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy, and R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy, Or its derivatives.

7. A compound of formula (VII) During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ cycloalkyl, and C ２ -C ９ and each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy, and R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy, Or its derivatives.

8. A compound of formula (VIII): During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ cycloalkyl, and C ２ -C ９ and each of said aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy, and R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy, Or its derivatives.

9. A compound of formula (IX), During the ceremony, L is C １ -C ５ is alkyl, R １ is C ６ -C １０ aryl, said aryl being optionally substituted with one or more halogens; R ２ is H or C １ -C ５ alkyl, and R ３ is a halogen, Or its derivatives.

10. A compound of formula (X): During the ceremony, A is —O— or —NR ８ and L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C １ -C ５ Alkyl, C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ Cycloalkyl, C １ -C ５ Alkyl-C ３ -C ８ cycloalkyl, and C ２ -C ９ and heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-NH-, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy; R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy; R ８ is H or C １ -C ５ is alkyl, R ９ is H or a halogen, and n is 1 or 2; Or its derivatives.

11. A compound of formula (XI) During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C １ -C ５ Alkyl, C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ Cycloalkyl, C １ -C ５ Alkyl-C ３ -C ８ cycloalkyl, and C ２ -C ９ and heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-NH-, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy; R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy; R ９ is H or a halogen, and n is 1 or 2; Or its derivatives.

12. A compound of formula (XII) During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C １ -C ５ Alkyl, C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ Cycloalkyl, C １ -C ５ Alkyl-C ３ ~C ８ cycloalkyl, and C ２ -C ９ and heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-NH-, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy; R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy; R ８ is H or C １ -C ５ is alkyl, R ９ is H or a halogen, and n is 1 or 2; Or its derivatives.

13. A compound of formula (XIII): During the ceremony, A is —O— or —NR ８ - and L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C １ -C ５ Alkyl, C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ Cycloalkyl, C １ -C ５ Alkyl-C ３ -C ８ cycloalkyl, and C ２ -C ９ and heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-NH-, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy; R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy; R ８ is H or C １ -C ５ is alkyl, R ９ is H or a halogen, and n is 1 or 2; Or its derivatives.

14. A compound of formula (XIV) During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C １ -C ５ Alkyl, C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ Cycloalkyl, C １ -C ５ Alkyl-C ３ -C ８ cycloalkyl, and C ２ -C ９ and heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-NH-, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy; R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy; R ９ is H or a halogen, and n is 1 or 2; Or its derivatives.

15. A compound of formula (XV) During the ceremony, L is a bond, C １ -C ５ Alkyl, C ６ -C １０ Aryl, and C(O)C １ -C ５ is selected from the group consisting of alkyl, R １ is C １ -C ５ Alkyl, C ６ -C １０ Aryl, C ２ -C ７ Heteroaryl, C ３ -C ８ Cycloalkyl, C １ -C ５ Alkyl-C ３ -C ８ cycloalkyl, and C ２ -C ９ and heterocyclyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is selected from the group consisting of halogen, —CN, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C １ -C ５ Alkyl-NH-, C １ -C ５ Alkyl-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ６ -C １０ Aryl, C １ -C ５ Alkoxy-C ２ -C ９ Heterocyclyl, C(O) ２ C １ -C ５ Alkyl, C １ -C ５ Haloalkoxy, C(O)C １ -C ５ Alkyl, C ６ -C １０ Aryl-C １ -C ５ Alkyl, C ２ -C ７ Heterocyclyl-C １ -C ５ Alkyl, and —S(O) ２ NHC １ -C ５ optionally substituted with one or more groups independently selected from the group consisting of alkyl; R ２ is H, C １ -C ５ Alkyl, halogen, or C １ -C ５ alkoxy; R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, halogen, —CN, C １ -C ５ Alkyl, or C １ -C ５ alkoxy; R ８ is H or C １ -C ５ is alkyl, R ９ is H or a halogen, and n is 1 or 2; Or its derivatives.

16. 10. The compound of claim 1, wherein the compound can be selected from the following: or a derivative thereof.

17. 10. The compound of claim 1, wherein the compound can be selected from the following: or a derivative thereof.

18. 11. The compound of claim 10, wherein the compound can be selected from: or a derivative thereof.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a derivative thereof and a pharmaceutically acceptable excipient.

20. 20. A method for treating a disease or disorder associated with sodium channel-mediated activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claims 1-18.

21. 21. The method of claim 20, wherein the disease or disorder associated with sodium channel-mediated activity is selected from a convulsive disorder, depression, anxiety disorder, neuropathic pain, chemotherapy-induced neuropathy, chronic pain, migraine, ischemia, diastolic dysfunction, arrhythmia, Dravet syndrome, neuromuscular disease, amyotrophic lateral sclerosis (ALS), restless legs syndrome, or a combination thereof.

22. 22. The method of claim 21, wherein the convulsive disorder is selected from epilepsy, acute seizures, chronic seizures, generalized tonic-clonic seizures, refractory seizures, drug-resistant convulsive disorders, early childhood epileptic encephalopathy, or a combination thereof.

23. 23. The method of claim 22, wherein the convulsive disorder is epilepsy.

24. 24. The method of claim 23, wherein the epilepsy is selected from partial epilepsy, generalized absence epilepsy, temporal lobe epilepsy, treatment-resistant epilepsy, drug-resistant epilepsy, epilepsy characterized by acute seizures, epilepsy characterized by chronic seizures, epilepsy characterized by generalized tonic-clonic seizures, epilepsy characterized by intractable seizures, or a combination thereof.

25. 21. The method of claim 20, wherein the patient is a neonate, infant, child, adolescent, or adult.

26. 26. The method of claim 25, wherein the patient is a neonate.

27. 26. The method of claim 25, wherein the patient is an infant.

28. 26. The method of claim 25, wherein the patient is a child.

29. 26. The method of claim 25, wherein the patient is an adolescent.

30. 26. The method of claim 25, wherein the patient is an adult.

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