WO2024097171A1 - Imidazole compounds and their use as sodium channel inhibitors - Google Patents

Imidazole compounds and their use as sodium channel inhibitors Download PDF

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Publication number
WO2024097171A1
WO2024097171A1 PCT/US2023/036385 US2023036385W WO2024097171A1 WO 2024097171 A1 WO2024097171 A1 WO 2024097171A1 US 2023036385 W US2023036385 W US 2023036385W WO 2024097171 A1 WO2024097171 A1 WO 2024097171A1
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alkyl
methyl
aryl
chlorophenyl
alkoxy
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PCT/US2023/036385
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French (fr)
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Thomas E. Richardson
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Genep Inc.
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Publication of WO2024097171A1 publication Critical patent/WO2024097171A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • VGSC membrane-bound proteins
  • Some embodiments disclosed herein are directed to a compound of Formulas (I)- (XV): where the A, L, and R groups are defined as further described herein.
  • the compounds disclosed herein may possess useful sodium channel inhibiting activity.
  • Some embodiments herein are directed to treatment or prophylaxis of a disease or disorder in which sodium channel mediated activity plays an active role using the compounds disclosed herein.
  • 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 embodiments herein.
  • Some embodiments provide methods 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 compounds disclosed herein in the manufacture of a medicament for the treatment of a disease or disorder ameliorated by the inhibition of sodium channel mediated activity. Definitions [0007] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary.
  • the term “consisting essentially of” or “consists essentially of” means that the pharmaceutical composition, or the method includes only the elements, steps or ingredients specifically recited in the 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.
  • the only active ingredient(s) in the composition or method that treats the specified condition e.g., nutrient depletion
  • two embodiments are “mutually exclusive” when one is defined to be something which is different from the other.
  • inhibitor 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.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.
  • suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.
  • alkenyl may include “alkenylene” groups.
  • alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below.
  • alkyl ether radicals examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, and the like.
  • alkyl refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 8 carbon atoms. Alkyl groups may be optionally substituted as defined herein.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl and the like.
  • alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.
  • alkynyl refers to a straight- chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms.
  • alkynylene refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C ⁇ C-).
  • alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1- yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.
  • alkynyl may include “alkynylene” groups.
  • aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.
  • aryl embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes (e.g., tritium, deuterium) of the structures depicted.
  • cycloalkyl or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • said cycloalkyl will comprise from 5 to 7 carbon atoms.
  • cycloalkyl groups examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.
  • “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type.
  • halo or halogen, as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF 2 -), chloromethylene (-CHCl-) and the like.
  • heteroaryl 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, which contains at least one atom chosen from N, O, and S.
  • said heteroaryl will comprise from 1 to 4 heteroatoms as ring members.
  • said heteroaryl will comprise from 1 to 2 heteroatoms as ring members.
  • said heteroaryl will comprise from 5 to 7 atoms.
  • heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.
  • 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,
  • heterocyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring.
  • Heterocycloalkyl and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • heterocycle 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, quinolinonyl, and the like.
  • the heterocycle groups may be optionally substituted unless specifically prohibited.
  • Any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • a group is defined to be “null,” what is meant is that said group is absent.
  • the term “optionally substituted” means the anteceding group may be substituted or unsubstituted.
  • the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of 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 carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower hal
  • two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., - CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3).
  • the invention encompasses all stereoisomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d- isomers and 1- isomers, and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain defined stereochemical configurations or by separation of mixtures of stereoisomeric products by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of stereoisomers by chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular configurations are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti, endo, exo
  • E exo
  • Z isomers as well as the appropriate mixtures thereof.
  • compounds may exist as tautomers; all tautomeric isomers are provided by this invention.
  • the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
  • Compounds described herein may contain one or more stereogenic centers and may thus exists as stereoisomers. Embodiments herein includes all such possible stereoisomers as substantially pure resolved stereoisomers, racemic mixtures thereof, as well as mixtures of diastereomers.
  • the formulas are shown without a definitive stereochemistry at certain positions.
  • the compounds are isolated as single stereoisomers, but the absolute configurations of the stereogenic centers are unknown or only the relative stereochemical configuration (i.e., cis or trans isomerism) is known.
  • the formulas are shown with provisionally assigned absolute assignments to denote that they are single stereoisomers and relative stereochemical configuration is likewise described.
  • Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof.
  • Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column.
  • any stereoisomer of a compound of the general formula may be obtained by stereospecific or stereoselective synthesis using optically pure or enantioenriched starting materials or reagents of known configuration.
  • the scope of embodiments herein as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, stereoisomers and stereoisomer-enriched mixtures.
  • enantiomers include chiral synthesis from a suitable enantioenriched or optically pure precursors or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of embodiments herein (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • a 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
  • 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.
  • pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • pharmaceutically acceptable salts embraces 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, provided that it is pharmaceutically-acceptable. Such salts can be derived from pharmaceutically- acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of embodiments herein may be prepared from an inorganic acid or an organic acid. All of these salts may be prepared by conventional means from the corresponding compound of embodiments herein by treating, for example, the compound with the appropriate acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric and diphosphoric acid; and organic acids, for example formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, ⁇ -hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, ace
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropyl
  • X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate.
  • solvate is used herein to describe a molecular complex comprising a compound of embodiments herein and an amount of one or more pharmaceutically acceptable solvent molecules.
  • hydrate is employed when said solvent is water.
  • solvate forms include, but are not limited to, compounds of embodiments herein in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in embodiments herein one solvent molecule can be associated with one molecule of the compounds of embodiments herein, such as a hydrate. [0044] Furthermore, it is specifically contemplated that in embodiments herein, more than one solvent molecule may be associated with one molecule of the compounds of embodiments herein, such as a dihydrate.
  • Embodiments herein also include isotopically-labeled compounds of embodiments herein, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of embodiments herein include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 31 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically-labeled compounds of embodiments herein, for example, those incorporating a radioactive isotope are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • 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, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of embodiments herein.
  • the term deuterated derivative embraces compounds of embodiments herein where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
  • a deuterated derivative of a compound of embodiments herein has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
  • 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 site of deuteration is independent from the other deuteration sites. [0051] The isotopic enrichment factor can be determined using conventional analytical methods known to one of ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).
  • MS mass spectrometry
  • NMR nuclear magnetic resonance
  • prodrug refers to a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • Prodrugs of the compounds described herein are also within the scope of embodiments herein.
  • certain derivatives of the compounds of embodiments herein, which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of embodiments herein having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • a wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • Prodrugs in accordance with embodiments herein can, for example, be produced by replacing appropriate functionalities present in the compounds of embodiments herein with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • excipient and “pharmaceutically acceptable excipient” as used herein are intended to be generally synonymous, and is used interchangeably with, the terms “carrier,” “pharmaceutically acceptable carrier,” “diluent,” “pharmaceutically acceptable diluent.”
  • carrier pharmaceutically acceptable carrier
  • diluent pharmaceutically acceptable diluent
  • 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.
  • the term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • administering when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
  • administering when used in conjunction with a compound of embodiments herein, can include, but is not limited to, providing the compound into or onto the target tissue; providing the compound systemically to a patient by, e.g., intravenous injection whereby the therapeutic reaches the target tissue; providing the compound in the form of the encoding sequence thereof to the target tissue (e.g., by so-called gene-therapy techniques).
  • administering a composition may be accomplished by injection, topically, orally, or by any of these methods in combination with other known techniques.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans.
  • sodium channel inhibitor is used herein to refer to a compound that binds to and / or inhibits the target with measurable affinity.
  • a modulator has an IC 50 and/or binding constant of no more than about 35 ⁇ M, no more than about 34 ⁇ M, no more than about 33 ⁇ M, no more than about 32 ⁇ M, no more than about 31 ⁇ M, no more than about 30 ⁇ M, no more than about 29 ⁇ M, no more than about 28 ⁇ M, no more than about 27 ⁇ M, no more than about 26 ⁇ M, no more than about 25 ⁇ M, no more than about 24 ⁇ M, no more than about 23 ⁇ M, no more than about 22 ⁇ M, no more than about 21 ⁇ M, no more than about 20 ⁇ M, no more than about 19 ⁇ M, no more than about 18 ⁇ M, no more than about 17 ⁇ M, no more than about 16 ⁇ M, no more than about 15 ⁇ M, no more than about 14 ⁇ M, no more than about 13 ⁇ M, no more than about 12 ⁇ M, no more than about 11 ⁇ M, no more than about 10 ⁇ M, no more than about 35
  • a modulator has an IC 50 and/or binding constant of greater than about 5 ⁇ M, between about 1 ⁇ M and about 5 ⁇ M, or less than about 1 ⁇ M.
  • IC 50 is that concentration of inhibitor that reduces the activity of an enzyme (e.g., NaV1.6) to half-maximal level.
  • an enzyme e.g., NaV1.6
  • Certain compounds disclosed herein have been discovered to exhibit inhibition against NaV1.6.
  • the compounds of the present disclosure are selective for the sodium channel isoform Na V 1.6 over the sodium channel isoform Na V 1.5.
  • An example of how to measure IC 50 of the disclosed compounds is shown in Example 10.
  • terapéuticaally effective is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.
  • therapeutic or “therapeutic agent” or “pharmaceutically active agent” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
  • embodiments of the present invention are directed to the treatment of a disease or disorder associated with sodium channel mediated activity.
  • a “therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, e.g., to inhibit, block, or reverse the activation, migration, or proliferation of cells.
  • the activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate.
  • the specific dose of a compound administered according to this invention to obtain 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.
  • the compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.001 to 1000 mg/kg, more usually in the range of from 0.01 to 1000 mg/kg.
  • a therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.
  • therapeutically acceptable refers to those compounds, or a derivative thereof, which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • treat refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total, whether induction of or maintenance of), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Treatment may also be preemptive in nature, i.e., it may include prevention of disease.
  • Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression.
  • prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level.
  • Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease and prolonging disease-free survival as compared to disease-free survival if not receiving treatment and prolonging disease- free survival as compared to disease-free survival if not receiving treatment.
  • the term “neonate” refers to a human whoes age is from birth to less than 1 month.
  • infant refers to a human whoes age is from 1 month to less than 2 years.
  • child refers to a human whoes age is from 2 years to less than 12 years.
  • adjuent refers to a human whoes age is from 12 years to less than 17 years.
  • adult refers to a human whoes age is from 17 years or older.
  • Also provided is a compound chosen from the Examples disclosed herein.
  • the compounds of embodiments herein may also refer to 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 of the foregoing of the compounds of embodiments herein.
  • a salt thereof e.g., tritium, deuterium
  • Embodiments are directed to a compound of Formula (I): wherein: A is selected from -O-, -NH-, or -S(O)2NH-; L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C6-C10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -
  • Some embodiments are directed towards a compound of Formula (II): wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C 6 -C 10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 6 -C 10 aryl, C 2 -C 7 heteroaryl, C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently 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 heterocycl
  • Some embodiments are directed towards a compound of Formula (III): wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C 6 -C 10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 6 -C 10 aryl, C 2 -C 7 heteroaryl, C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkyl-C6-C10 aryl, C 1 -C 5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O
  • L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C 6 -C 10 aryl, and C(O)C 1 -C 5 alkyl
  • R 1 is selected from the group consisting of C 6 -C 10 aryl, C 2 -C 7 heteroaryl, C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl
  • each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently 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 - C5 alkoxy-C2-C9 heterocyclyl, C(O)2C 1 -C 5 alkyl, C 1 -
  • Some embodiments are directed towards a compound of Formula (V): wherein: A is selected from -O-, -NH-, or -S(O)2NH-; L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C6-C10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkyl-C6-C10 aryl, C 1 -C 5 alkoxy-C6-C10 aryl, C1-
  • Some embodiments are directed towards a compound of Formula (VI): wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C 6 -C 10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkyl-C6-C10 aryl, C 1 -C 5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C 1 -
  • Some embodiments are directed towards a compound of Formula (VII): wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C 6 -C 10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 6 -C 10 aryl, C 2 -C 7 heteroaryl, C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkyl-C6-C10 aryl, C 1 -C 5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(
  • Some embodiments are directed towards a compound of Formula (VIII): wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C6-C10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently 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 - C5 alkoxy-C2-C9 heterocyclyl, C(O)
  • Some embodiments are directed towards a compound of Formula (IX): wherein: L is C 1 -C 5 alkyl; R 1 is C 6 -C 10 aryl; wherein the aryl is optionally substituted with one or more halogens; R 2 is selected from H or C 1 -C 5 alkyl; and R 3 is halogen; or a derivative thereof.
  • Embodiments are directed to a compound of Formula (X): wherein: A is -O- or -NR 8 ; L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C 6 -C 10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 1 -C 5 alkyl, C 6 -C 10 aryl, C 2 -C 7 heteroaryl, C 3 -C 8 cyclcoalkyl, C 1 -C 5 alkyl-C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alky
  • Some embodiments are directed towards a compound of Formula (XI): wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C6-C10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 1 -C 5 alkyl, C 6 -C 10 aryl, C 2 -C 7 heteroaryl, C 3 -C 8 cyclcoalkyl, C 1 -C 5 alkyl-C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently 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 alky
  • Some embodiments are directed towards a compound of Formula (XII): ( ) wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C6-C10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 1 -C 5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C 1 -C 5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently 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
  • Some embodiments are directed towards a compound of Formula (XIII): wherein: A is -O- or -NR 8 -; L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C6-C10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 1 -C 5 alkyl, C 6 -C 10 aryl, C 2 -C 7 heteroaryl, C 3 -C 8 cyclcoalkyl, C 1 -C 5 alkyl-C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alky
  • Some embodiments are directed towards a compound of Formula (XIV): wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C6-C10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 1 -C 5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C 3 -C 8 cyclcoalkyl, C 1 -C 5 alkyl-C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently 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
  • Some embodiments are directed towards a compound of Formula (XV): wherein: L is selected from the group consisting of a bond, C 1 -C 5 alkyl, C 6 -C 10 aryl, and C(O)C 1 -C 5 alkyl; R 1 is selected from the group consisting of C 1 -C 5 alkyl, C 6 -C 10 aryl, C 2 -C 7 heteroaryl, C 3 -C 8 cyclcoalkyl, C 1 -C 5 alkyl-C 3 -C 8 cyclcoalkyl, and C 2 -C 9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently 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 al
  • the compound of Formula (I) may be selected from: Compoun d # Structure Name 2-(4-(benzyloxy)phenyl)-5-(4- 1 chlorophenyl)-4-methyl-1H-imidazole 5-(4-chlorophenyl)-2-(4-((2- 2 fluorobenzyl)oxy)phenyl)-4-methyl- 1H-imidazole 5-(4-chlorophenyl)-2-(4-((3- 3 fluorobenzyl)oxy)phenyl)-4-methyl- 1H-imidazole 5-(4-chlorophenyl)-2-(4-((4- 4 fluorobenzyl)oxy)phenyl)-4-methyl- 1H-imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-(1- 5 phenylethoxy)phenyl)-1H-imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-(1- 5
  • the compound of Formula (I) may be selected from: Compoun Structure Name d # 5-(4-chlorophenyl)-4-ethyl-2-(4-((3- 48 fluorobenzyl) oxy) phenyl)-1H-imidazole 2-chloro-6-((4-(5-(4-chlorophenyl)-4-methyl- 49 1H-imidazol-2-yl) phenoxy) methyl) pyridine (S)-5-(4-chlorophenyl)-2-(4-(1-(3- 50 fluorophenyl)ethoxy)phenyl)-4-methyl-1H- imidazole (R)-5-(4-chlorophenyl)-2-(4-(1-(3- 51 fluorophenyl)ethoxy)phenyl)-4-methyl-1H- imidazole 4-(5-(4-chlorophenyl)-4-methyl-1H- 52 imid
  • the compound of Formula (X) may be selected from: Compound Structure Name # 5-(4-chlorophenyl)-4-methyl-2-(4- 72 (2,2,2-trifluoroethoxy)phenyl)-1H- imidazole 4-(2-((4-(5-(4-chlorophenyl)-4-methyl- 73 1H-imidazol-2- yl)phenoxy)methyl)benzyl)morpholine 6-((4-(5-(4-chlorophenyl)-4-methyl- 74 1H-imidazol-2-yl)phenoxy)methyl)-N- methylpyridin-2-amine 4-(5-(4-chlorophenyl)-4-methyl-1H- 75 imidazol-2-yl)-N-(3-fluorobenzyl)-N- methylaniline (S)-1-benzyl-N-(4-(5-(4-chlorophenyl)- 76 4-methyl-1-benzyl-N-(
  • the compound of Formula (II) may be selected from compounds 1-44, 47-51, 60-63, and 66-71.
  • the compound of Formula (III) may be selected from compound 45, 52-59, 64, and 65.
  • the compound of Formula (IV) may be selected from compound 46.
  • the compound of Formula (V) may be selected from compounds 1-71.
  • the compound of Formula (VI) may be selected from compounds 1-44, 47-51, 60-63, and 66-71.
  • the compound of Formula (VII) may be selected from compound 45, 52-59, 64, and 65.
  • the compound of Formula (VIII), may be selected from compound 46.
  • the compound of Formula (IX) may be selected from compounds 3, 5, 6, and 7, 48, 50, 51.
  • the compound of Formula (X) may be selected from compounds 72-80.
  • the compound of Formula (XI) may be selected from compounds 72-74 and 79.
  • the compound of Formula (XII) may be selected from compounds 75-78 and 80.
  • the compound of Formula (XIII) may be selected from compounds 72-80.
  • the compound of Formula (XIV), may be selected from compounds 72-74 and 79.
  • the compound of Formula (XV), may be selected from compounds 75-78 and 80.
  • Pharmaceutical Compositions [0107] Also provided is a pharmaceutical composition comprising a compound as disclosed herein, and a pharmaceutically acceptable excipient. [0108] In certain embodiments, the pharmaceutical composition may comprise about 0.01% to about 50% of one or more compounds disclosed herein.
  • the one or more compounds is in an amount of about 0.01% to about 50%, about 0.01% to about 45%, about 0.01% to about 40%, about 0.01% to about 30%, about 0.01% to about 20%, about 0.01% to about 10%, about 0.01% to about 5%, about 0.05% to about 50%, about 0.05% to about 45%, about 0.05% to about 40%, about 0.05% to about 30%, about 0.05% to about 20%, about 0.05% to about 10%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.5% to about 50%, about 0.5% to about 45%, about 0.5% to about 40%, about 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 0.5% to about 30%, about 0.5% to about 20%
  • the compounds as disclosed herein are in a therapeutically effective amount.
  • the therapeutically effective amount may be 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 10 mg, about 0.01 mg to about 5 mg, about 0.1 mg to about 1000 mg, about 0.1 mg to about 900 mg, about 0.1 mg to about 800 mg, about 0.1 mg to about 700 mg, about 0.1 mg to about 600 mg, about 0.1 mg to about 500 mg, about 0.1 mg to about 400 mg, about 0.1 mg to about 300 mg, about 0.1 mg to about 200 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 10 mg, about 0.
  • 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 between the ranges disclosed above.
  • the compounds as disclosed herein may be administered at a dose 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, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 1000 mg/kg, about 0.1 mg/kg to about 900 mg/kg, about 0.1 mg/kg to about 800 mg/kg, about 0.1 mg/kg to about 700
  • Specific examples include, for example, 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, 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 between the ranges disclosed above.
  • compositions which comprise one or more of certain compounds disclosed herein, or a derivative thereof, together with one or more pharmaceutically acceptable excipients thereof and optionally one or more other therapeutic ingredients.
  • the excipient(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation of the pharmaceutical composition is dependent upon the route of administration chosen. Any of the well-known techniques and excipients may be used as suitable and as understood in the art.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the pharmaceutical compositions for use in accordance with embodiments herein can be formulated in conventional manner using one or more physiologically acceptable excipients.
  • the compounds When employed as pharmaceuticals, can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration of the disclosed compounds or compositions may be oral administration.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • the compounds can be contained in such formulations pharmaceutical compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the artisan can refer to various pharmacologic references for guidance.
  • a method of treating a disease or disorder associated with sodium channel mediated activity comprises administering a compound or a pharmaceutical composition of embodiments disclosed herein.
  • the compound is in a therapeutically effective amount.
  • the therapeutically effective amount is an amount disclosed herein.
  • Some embodiments disclosed herein also include pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds disclosed herein in combination with one or more pharmaceutically acceptable carriers (excipients).
  • a method of making a pharmaceutical composition comprises mixing the active ingredient with an excipient, diluting the active ingredient using an excipient, or enclosing the active ingredient within a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, as well as soft and hard gelatin capsules.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose, including eutectic solvents, eutectic-based ionic liquids, or ionic liquids.
  • the pharmaceutical compositions can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the pharmaceutical compositions can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. [0119]
  • the pharmaceutical compositions can be formulated in a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the 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, intradural, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, buccal, sublingual and intraocular), intravitreal, or intravaginal administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound disclosed herein or a derivative thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired composition.
  • Compositions of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may 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 binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All compositions for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the pharmaceutical composition so that the pharmaceutical composition can be readily subdivided into equally therapeutically effective unit dosage forms such as tablets, pills and capsules.
  • This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.01 to about 1000 mg of the active ingredient.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • the liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil 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.
  • compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the pharmaceutical compositions administered to a patient can be in the form of pharmaceutical compositions described above.
  • these compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered.
  • Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations 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 use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • Preferred unit dosage pharmaceutical compositions are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • 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.
  • the therapeutically effective amount can vary according to, for example, the particular use for which the treatment is made, the manner 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 upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, composition of the excipient, and its route of administration. Effective doses 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 upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. 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.
  • the active compound can be effective over a wide dosage range and can be generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. [0132] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. [0133] The precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • Some embodiments herein are directed to a method of treating a disease or disorder associated with sodium channel mediate 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.
  • the therapeutically effective amount of a compound as disclosed herein, a derivative thereof, or a combination thereof may be in the form of a pharmaceutical composition.
  • the pharmaceutical composition may include a pharmaceutically acceptable excipient, acceptable salt, solvate or prodrug thereof.
  • a compound as disclosed herein for use in the manufacture of a medicament for the treatment of a disease or disorder associated with sodium channel mediated activity is directed 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.
  • Some embodiments are directed to a method of treating a disease or disorder primarily 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.
  • the disease or disorder associated with sodium channel mediated activity is selected from a seizure disorder, depression, anxiety, neuropathic pain, chemotherapy-induced neuropathy, chronic pain, migraine, ischemia, diastolic dysfunction, arrhythmia, Dravet syndrome, neuromuscular conditions, Amyotrophic Lateral Sclerosis (ALS), restless leg syndrome, or a combination thereof.
  • ALS Amyotrophic Lateral Sclerosis
  • the seizure disorder is selected from epilepsy, acute seizures, chronic seizures, generalized tonic-clonic seizures refractory seizures, pharmaco-resistant seizure disorder, Early Infantile Epileptic Encephalopathy, or a combination thereof.
  • the seizure disorder is epilepsy.
  • the epilepsy is selected from partial epilepsy, generalized absence epilepsy, temporal lobe epilepsy, therapy resistant epilepsy, pharmaco-resistant epilepsy, epilepsy characterized by acute seizures, epilepsy characterized by chronic seizures, epilepsy characterized by generalized tonic-clonic seizures, epilepsy characterized by refractory seizures, or a combination thereof.
  • the patient is selected from a neonate, an infant, a child, an adolescent, or an 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.
  • General Synthetic Methods for Preparing Compounds [0148] The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformation proposed. This will sometimes require a judgement to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • the novel compounds of this invention may be prepared using the reactions and techniques described in this section.
  • reaction conditions including choice of solvents, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods then be use.
  • the compounds of the present invention may be prepared by the expemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures from the reactions appear hereinafter and in the working examples.
  • Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of the ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods.
  • Example 1 Synthetic Method A [0153] Synthesis of Int-3: [0154] To stirred a solution of 4-(hydroxymethyl)benzaldehyde (1.0 g, 8.2 mmol, 1.0 eq) in THF (10 mL) Then phenylmethanol ( 1.32 g ,12.3 mmol, 1.5 eq) and triphenyl phosphine ( 3.21 g , 12.3 mmol, 1.5 eq) was added at 0 °C, the reaction mixture was stirred for 10 min at 0 °C. DIAD (2.4 g, 12.3 mmol, 1.5 eq) was added to above solution at same temperature. The reaction was allowed to stirred at room temperature for 16 h.
  • Example 2 Synthetic Method B [0158] Step 1: To a stirred solution of 4-hydroxybenzaldehyde (0.500 g, 4.1 mmol, 1.0 eq) in DMF (5 mL) was added 1-(bromomethyl)-2-fluorobenzene (0.773 g, 4.1 mmol, 1.0 eq) and K2CO3 (1.69 g, 12.3 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC.
  • Step 2 To a stirred solution of 4-((2-fluorobenzyl)oxy)benzaldehyde (0.150 g, 0.65 mmol, 1.0 eq) in methanol (2.5 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.118 g, 0.65 mmol, 1.0 eq) and ammonium acetate (0.250 g, 3.2 mmol, 5.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC.
  • Step 1 To stirred a solution of 1-methyl-1H-pyrazol-3-yl (0.40 g, 3.6mmol, 1.0 eq) in dichloromethane (5 mL), was added trimethylamine (0.72 g, 7.1mmol, 2.0 eq), reaction mixture was stirred for 5 min at 0 ° C, was added methane sulfonyl chloride (0.61 g, 5.35 mmol, 1.5 eq) dropwise at 0 o C, reaction mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC.
  • reaction mixture was diluted with water (20 mL), extracted with dichlormethane (3 x 20 mL), combined organic layer was dehydrated with Na 2 SO 4 , concentrated under reduced pressure to get the crude product as (1-methyl-1H-pyrazol-3-yl) methyl methanesulfonate as yellow oil is used to direct next step reaction, (0.34 g, 50.1% yield).
  • m/z 191.04 [M+H] + .
  • Step 2 To a solution of (1-methyl-1H-pyrazol-3-yl) methyl methane sulfonate (0.300 g, 1.5771 mmol, 1.0 eq) in DMF (3 mL) was added 4-hydroxybenzaldehyde (0.192 g, 1.57mmol, 1.0 eq) and K 2 CO 3 (0.652 g, 4.73 mmol, 3.0 eq) at room temperature, reaction mixture stirred for 16 h at 90 o C. The progress of the reaction was monitored by TLC.
  • Step 3 To a solution of 4-((1-methyl-1H-pyrazol-3-yl) methoxy) benzaldehyde (0.200 g, 0.92 mmol, 1.0 eq) in methanol (2 mL) was added 1-phenylpropane-1,2-dione (0.168 g, 0.92 mmol, 1.0 eq) and ammonium acetate (0.356 g, 4.62 mmol., 5.0 eq) at room temperature, reaction mixture was stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC.
  • reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product, which was purified by combi flash chromatography using a mixture of n-hexane and EtOAc as mobile phase. Product was eluted at 50% ethyl acetate in hexanes to give 4-((1-methyl-1H-pyrazol-3- yl)methoxy)benzaldehyde as white solid (0.090 g, 25.7% yield).
  • Example 4 Synthesis of 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-1-methylpiperidine [0165]
  • Step 1 Synthesis of tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1- carboxylate (2): To a cooled solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.80 g, 3.72 mmol, 1.0 eq) in THF (8 mL) at 0°C, was added sodium hydride (60% in mineral oil, 0.10 g, 4.09 mmol, 1.1 eq) and Trimethylsilyl chloride (0.48 g, 4.46 mmol, 1.2 eq) at same temperature.
  • Step 2 Synthesis of tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1- carboxylate (4): To a solution of tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1- carboxylate (0.70 g, 2.79 mmol, 1.0 eq) in DMF (7 mL) was added 4-hydroxybenzaldehyde (0.30 g, 2.79 mmol, 1.0 eq) and K2CO3(1.01 g, 7.32 mmol, 3.0 eq) and reaction mixture was stirred at 80°C for 2 h. The progress of the reaction was monitored by TLC.
  • Step 3 Synthesis of tert-butyl 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)piperidine-1-carboxylate (6): To a solution of tert-butyl 4-((4- formylphenoxy)methyl)piperidine-1-carboxylate (0.20 g 0.63 mmol 1.0 eq) in methanol (2 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.11 g, 0.63 mmol 1.0 eq) and ammonium acetate (0.24 g, 3.13 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h.
  • 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 eq) in THF (3.0 mL), was added 2.5 M LAH solution in THF (0.50 mL, 1.24 mmol, 4.0 eq) at room temperature and the reaction mixture was stirred at 80°C for 6 h.
  • Step 1 Synthesis of 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)-N-(3- fluorobenzyl)aniline
  • Step 1 Synthesis of 4-((3-fluorobenzyl)amino)benzaldehyde (3): To a solution of 4- bromobenzaldehyde (0.5 g, 3.1 mmol, 1.0 eq) in toluene (5 mL), was added (3-fluorophenyl) methanamine (0.71 g, 4.66 mmol, 1.5 eq) and Cs2CO3 (0.99 g, 9.32 mmol, 3.0 eq) under nitrogen atmosphere and the reaction mixture degassed with N2 for 15 min.
  • 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 eq) in methanol (2.5 mL), 1-(4-chlorophenyl) propane-1,2-dione (0.34 g, 1.84 mmol, 1.0 eq) and ammonium acetate (0.71 g, 9.19 mmol, 5.0 eq) was added at room temperature. The reaction mixture was stirred at room temperature for 16 h.
  • 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 eq) in DCM (8 mL), was added thiazol-4-amine (0.784 g, 7.84 mmol, 2.0 eq) and pyridine (1.57 g, 19.9 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 5 h.
  • 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 eq) in methanol (1 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.07 g, 0.37 mmol, 1.0 eq) and ammonium acetate (0.14 g, 1.86 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h.
  • Step 2 Synthesis of 3-(N-methylsulfamoyl) benzyl methane sulfonate (3): To a solution of 3-(hydroxymethyl)-N-methylbenzenesulfonamide (0.9 g, 4.47 mmol, 1 eq) and TEA (0.9 g, 8.95 mmol, 2 eq) in DCM (9 mL) Methane sulfonyl chloride (0.77 g, 6.71 mmol, 1.5 eq) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC.
  • Step 3 Synthesis of 3-((4-formylphenoxy) methyl)-N-methylbenzenesulfonamide (5): To a solution of 3-(N-methylsulfamoyl) benzyl methane sulfonate (0.8 g, 2.86 mmol, 1 eq) and 4- hydroxybenzaldehyde (0.7 g, 5.73 mmol, 2 eq) in DMF (8 mL), was added K2CO3 (1.18 g, 8.60 mmol, 3 eq) and the reaction mixture was stirred at 90°C for 16 h. The progress of the reaction was monitored by TLC.
  • 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 eq) in methanol (1.5 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.1 g, 0.59 mmol, 1.2 eq) and ammonium acetate (0.19 g, 2.45 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h.
  • Example 8 Synthesis of 5-(4-(4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)phenyl)-1H-pyrazole [0177]
  • Step 1 Synthesis of 1-(4-(benzyloxy)phenyl)ethan-1-one (3): To a solution of 1-(4- hydroxyphenyl)ethan-1-one (5 g, 36.76 mmol, 1.0 eq) in DMF (50 mL) was added (bromomethyl)benzene (6.29 g, 36.76 mmol, 1.0 eq) and K 2 CO 3 (15.22 g, 110.29 mmol, 1.0 eq) at room temperature and the reaction mixture was stirred at 100°C for 16 h.
  • Step 2 Synthesis of €-1-(4-(benzyloxy)phenyl)-3-(dimethylamino)prop-2-en-1-one (4): To a solution of 1-(4-(benzyloxy)phenyl)ethan-1-one (2 g, 8.84 mmol, 1.0 eq) 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 progress of the reaction was monitored by TLC.
  • Step 3 Synthesis of 5-(4-(benzyloxy)phenyl)-1H-pyrazole (5): To a solution of (E)- 1-(4-(benzyloxy)phenyl)-3-(dimethylamino)prop-2-en-1-one (1.5 g, 5.33 mmol, 1.0 eq) in Ethanol (15 mL) was added Hydrazine hydrate (7.5 mL) and Acetic acid (Cat.) and the reaction mixture was stirred 80°C for 8 h. The progress of the reaction was monitored by TLC.
  • Step 4 Synthesis of 4-(1H-pyrazol-5-yl)phenol (6): To a suspension of 10% Pd/C (50% moist, 1 g, w/w) in methanol (10.0 mL) was added 5-(4-(benzyloxy)phenyl)-1H-pyrazole (1 g, 4.00 mmol, 1.0 eq) under nitrogen atmosphere and the reaction mass was and stirred at room temperature under hydrogen atmosphere for 3 h. The progress of the reaction was monitored by TLC.
  • Step 5 Synthesis of 4-(4-(1H-pyrazol-5-yl)phenoxy)benzaldehyde (8): To a solution of 4-(1H-pyrazol-5-yl)phenol (0.6 g, 3.75 mmol, 1.0 eq) in DMF (6 mL) was added 4- fluorobenzaldehyde (0.47 g, 3.75 mmol, 1.0 eq) and K2CO3 (1.55 g, 11.25 mmol, 3.0 eq) at room temperature and the reaction mixture was stirred at 100°C for 16 h. The progress of the reaction was monitored by TLC.
  • Step 6 Synthesis of 5-(4-(4-(5-(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 eq) in methanol (2.5 mL)
  • 1-(4- chlorophenyl)propane-1,2-dione (0.21 g, 1.14 mmol, 1.2 eq)
  • ammonium acetate 0.36 g, 4.73 mmol, 5.0 eq
  • reaction mixture was again cooled to -78 °C and was added methyl 4,4-difluorocyclohexane-1-carboxylate in tetrahydrofuran (3 g, 16.85 mmol, 1.0 eq) and stirred -78°C for 1 h.
  • iodomethane (9.38 mL, 151.68 mmol, 9.0 eq) at same temperature and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC.
  • reaction mixture was diluted with saturated ammonium chloride solution (75 mL) and extracted with EtOAc (3 x 70 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue.
  • EtOAc 3 x 70 mL
  • the residue was purified by flash chromatography and product was eluted in 10% ethyl acetate in hexanes to give methyl 4,4-difluoro-1-methylcyclohexane-1-carboxylate as light yellow liquid (1.2 g, 37.08% yield).
  • Step 2 Synthesis of (4,4-difluoro-1-methylcyclohexyl)methanol (3): To a solution of methyl 4,4-difluoro-1-methylcyclohexane-1-carboxylate (1.2 g, 6.25 mmol, 1.0 eq) in THF (10 mL) was added lithium aluminium hydride (1M in THF, 9.38 mL, 9.375 mmol, 1.5 eq) at 0°C and the reaction mixture was stirred at room temperature for 3 h.
  • Step 3 Synthesis of (4,4-difluoro-1-methylcyclohexyl)methyl methanesulfonate (4): To a solution of (4,4-difluoro-1-methylcyclohexyl)methanol (0.9 g, 5.48 mmol, 1.0 eq) in DCM (5 mL), was added triethylamine (1.54 mL, 10.97 mmol, 2 eq) at 0°C.
  • Step 4 Synthesis of 4-((4,4-difluoro-1-methylcyclohexyl)methoxy)benzaldehyde (6): To a solution of (4,4-difluoro-1-methylcyclohexyl)methyl methanesulfonate (0.7 g, 2.89 mmol, 1.0 eq) in DMF (5 mL), was added 4-hydroxybenzaldehyde (0.42 g, 3.47 mmol, 1.2 eq) and potassium carbonate (1.19 g, 8.67 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 110°C for 16 h. The progress of the reaction was monitored by TLC.
  • Step 5 Synthesis of 5-(4-chlorophenyl)-2-(4-((4,4-difluoro-1- methylcyclohexyl)methoxy)phenyl)-4-methyl-1H-imidazole: To a solution of 4-((4,4-difluoro- 1-methylcyclohexyl)methoxy)benzaldehyde (0.25 g, 0.93 mmol, 1.0 eq) in methanol (5 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.16 g, 0.93 mmol, 1.0 eq) and ammonium acetate (0.35 g, 4.66 mmol, 5 eq) and the reaction mixture was stirred at room temperature for 16 h.
  • Step 1 Synthesis of 4-(2,2,2-trifluoroethoxy) benzaldehyde (3): To a solution of 4- hydroxybenzaldehyde (0.50 g, 4.10 mmol, 1.0 eq) in DMF (5 mL) was added 1,1,1-trifluoro-2- iodoethane (0.86 g, 4.10 mmol, 1.0 eq) and K2CO3 (1.69 g, 12.29 mmol, 3.0 eq) and the reaction mixture was stirred at 80°C for 16 h.
  • Step 2 Synthesis of 5-(4-chlorophenyl)-4-methyl-2-(4-(2,2,2- trifluoroethoxy)phenyl)-1H-imidazole: To a solution of 4-(2,2,2-trifluoroethoxy) benzaldehyde (0.2 g, 0.98 mmol, 1.0 eq) in methanol (2 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.23 g, 1.27 mmol, 1.3 eq) and ammonium acetate (0.38 g, 4.90 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h.
  • Example 11 Synthesis of 4-(2-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl) benzyl)morpholine
  • 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 eq) was added 4- hydroxybenzaldehyde (0.36 g, 2.98 mmol, 1.2 eq) in THF (5 mL) and PPh3 (0.98 g, 3.7 mmol, 1.5 eq) at room temperature.
  • reaction mixture was cooled to 0°C, DIAD (0.75 g, 3.7 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes to give 4-((2- (bromomethyl) benzyl)oxy)benzaldehyde as oil (0.25 g, 32% yield).
  • Step 2 Synthesis of 4-((2-(morpholinomethyl)benzyl)oxy)benzaldehyde (5):. To a solution of 4-((2-(bromomethyl)benzyl)oxy)benzaldehyde (0.25 g, 0.81 mmol, 1.0 eq) in morpholine (1 mL) was added at room temperature. The reaction mixture was stirred at 120°C for 3 h. The progress of the reaction was monitored by TLC.
  • 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 eq) in methanol (1.8 mL) was added 1-(4- chlorophenyl) propane-1,2-dione (0.12 g, 0.57 mmol, 1.0 eq) and ammonium acetate (0.22 g, 2.89 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h.
  • Example 12 Synthesis of 6-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-N-methylpyridin-2-amine
  • 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 eq) in THF (20 mL), 1M Lithium aluminum hydride in THF (29.23 mL, 29.23 mmol, 2.5 eq) was added at -20°C and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC.
  • reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL), combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to get the residue.
  • 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 eq) in THF (10 mL), was added (6- chloropyridin-2-yl) methanol (1.2 g, 8.19 mmol, 1.0 eq) and triphenyl phosphine (3.22 g, 12.29 mmol, 1.5 eq) at room temperature. The reaction mixture cooled to 0°C, DIAD (2.48 g, 12.29 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 16 h.
  • DIAD 2.48 g, 12.29 mmol, 1.5 eq
  • Step 3 Synthesis of tert-butyl (6-((4-formyl phenoxy)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 eq) in dioxane (6 mL), was added tert-butyl methylcarbamate (0.47 g, 3.6 mmol, 1.5 eq) and Cs 2 CO 3 (2.36 g, 7.20 mmol, 3.0 eq) and the reaction mass was degassed using N 2.
  • Step 4 Synthesis of tert-butyl (6-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl) phenoxy) methyl) 65yridine-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 eq) in methanol (3 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.17 g, 0.87 mmol, 1.0 eq) and ammonium acetate (0.33 g, 4.38 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h.
  • 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 eq) in DCM (2 mL), was added 4M HCl in dioxane (0.75 mL) at 0°C and the reaction mixture was stirred at room temperature for 16 h.
  • Example 13 LCMS Method C1 Mobile phase (A) 2mM ammonium acetate followed by 0.1%formic acid in water (B) 0.1% formic acid in acetonitrile I nstrument : WATERS ACQUITY UPLC H Class with PDA and SQ D ETECTOR Column : BEH C18(50*2.1mm)1.7 ⁇ m Flow rate : 0.550 ml/min Column oven t emperature : Ambient Run time : 3.0 min Gradient: : Flow TIME: Rate %A %B (mL/min) 0.01 0.55 98 2 0.30 0.55 98 2 0.60 0.55 50 50 1.10 0.55 25 75 2.00 0.60 0 100 2.70 0.60 0 100 2.71 0.55 98 2 3.00 0.55 98 2 [0200]
  • Example 14 LCMS Method C2 Mobile phase (A) 2mM ammonium acetate followed by 0.1%formic acid in water (B) 0.1% formic acid in acetonitrile I
  • Example 19 LCMS Method H2 LCMS Method Project name : Method H2 Mobile Phase (A) 5mM Ammonium bicarbonate in water ( B) 100% Acetonitrile Instrument : Agilent 1290 Infinity RRLC attached with Agilent 6120 M ass detector and Diode array Detector Column : X-Bridge C18 (50*4.6 mm), 3.5 um or Equivalent Column oven temp.
  • Example 20 LCMS Method H3 Mobile Phase (A) 5mM Ammonium bicarbonate in water ( B) 100% Acetonitrile Instrument : Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector and D iode array Detector Column : WATERS, X-Bridge C18 (50*4.6 mm), 3.5 um Column oven t emp.
  • Example 21 LCMS Method J Mobile phase (A) 2mM ammonium acetate followed by 0.1%formic acid in water (B) 0.1% formic acid in acetonitrile Instrument : WATERS ACQUETY H Class with PDA and SQ DETECTOR Column : BEH C18(50*2.1mm)1.7 ⁇ m Flow rate : 0.450 ml/min Column oven temperature : Ambient Run time : 8.0 min Gradient: : TIME: Flow Rate ( mL/min) %A %B 0.01 0.450 98 2 0.50 0.450 98 2 5.00 0.450 10 90 6.00 0.450 5 95 7.00 0.450 5 95 7.01
  • Biological Activity Assays Compounds of the present disclosure were tested in several biological assays and their results were compared against the results for compound A (see USP 11,090,189 the disclosure of which is incorporated by reference in its entirety), a known inhibitor of Na V 1.6, the structure of which is as follows: .
  • Cell Culture CHO cells expressing either human NaV1.6, human NaV1.5 or human NaV1.2 cells are incubated at 37°C in a humidified atmosphere with 5% CO2 (rel. humidity > 95%).
  • Electrophysiology assays Data is collected using the Qube 384 (Sophion) automated voltage-clamp platform using either single hole or multi hole plates. Compounds were assessed against human NaV1.6, human NaV1.5 and human NaV1.2 using a half-inactivating voltage protocol. In addition, compounds were also assessed against human Na V 1.6 where the membrane potential is maintained at a voltage where inactivation is complete.
  • inward currents are evoked with a 20 ms step to -10 mV from a membrane potential of -120 mV, followed by 3 seconds at the half-inactivating voltage (previously determined using the adaptive protocol feature of the Qube 384), then a -10 mV voltage step for 20 ms is applied to determine inward current inactivation.
  • Each cell is exposed to the vehicle (0.3% DMSO) for 5 minutes to allow the inward current to stabilise. Following this period, compounds are applied as single concentration per well for 10 minutes.
  • the protocol described above is applied throughout the experiment with an Inter sweep interval of 30 seconds.
  • the membrane potential is maintained at -45 mV.
  • Audiogenic seizure measurement Mice were be tested for audiogenic seizures using a 10 second, 15 kHz pure tone ( ⁇ 80 to 100 dB), generated using Tone Generator software (NCH Software, Inc.), amplified with a Kinter K3118 stereo amplifier (Kinter USA), and converted to sound using a small 3-watt speaker lowered into the recording chamber. Mice were observed for 60 seconds and the occurrence of a behavioral seizure was be assessed visually by the experimenter and also recorded using a laptop webcam. Time to seizure onset and recovery from seizure was noted.
  • N1768D SCN8A mice (> 8 weeks of age) were euthanized with isoflurane, decapitated and brains rapidly removed and placed in ice-cold ( ⁇ 0 oC) artificial cerebrospinal fluid (ACSF) containing in mM: 125 NaCl, 2.5 KCl, 1.25 NaH 2 PO 4 , 2 CaCl 2 , 1 MgCl 2 , 0.5 L- ascorbic acid, 10 glucose, 25 NaHCO 3 , and 2 sodium pyruvate (osmolarity 300-312 mOsm), and oxygenated with 95% O 2 and 5% CO 2 .
  • mM 125 NaCl, 2.5 KCl, 1.25 NaH 2 PO 4 , 2 CaCl 2 , 1 MgCl 2 , 0.5 L- ascorbic acid, 10 glucose, 25 NaHCO 3 , and 2 sodium pyruvate (osmolarity 300-312 mOsm), and oxygenated with 95% O 2 and
  • Horizontal slices (300 ⁇ m thickness) were cut using a vibratome in an ice-chilled chamber, incubated in oxygenated ACSF heated to 37 oC for ⁇ 30 min and then stored at room temperature. For recordings, slices were held in a small chamber and superfused with oxygenated ACSF ( ⁇ 28 oC) at a rate of 1-2 mL/min. Layer 4 somatosensory pyramidal neurons were visually identified with 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) and were fire-polished and tested to have resistances of 2-3.5 M ⁇ when filled with an intracellular solution containing (in mM): 120 K-gluconate, 10 NaCl, 2 MgCl2, 0.5 K2EGTA, 10 HEPES, 4 Na 2 ATP, 0.3 NaGTP, and pH was adjusted to 7.2 with KOH (osmolarity 270-290 mOsm). Currents were amplified, low-pass filtered at 2 kHz and sampled at 33 kHz.
  • Action potentials were evoked using a series of current injection steps from - 20 pA to 400 pA in 10 pA steps with a 3 second interpulse interval.
  • a ramp of depolarizing current (0-400 pA) was injected into neurons over a 4 second time period. Recordings were made before, after 10 mins of administration at test concentrations and after 10 mins of washout. The frequency of APs was recorded before and after drug application.
  • a working solution of 0.5 mM was prepared by diluting the compound in acetonitrile:water (50:50).
  • the compound (1.8 ⁇ L of working solution) was spiked in 0.1 M potassium phosphate buffer (260.7 ⁇ L), pH 7.4 at a concentration of 3 ⁇ M (0.15% DMSO).
  • human/mouse liver microsomes (7.5 ⁇ L; final protein conc. 0.5 mg/mL) were added.
  • the aforementioned microsomes and buffer was pre incubated at 37°C.
  • test compound was determined in the buffer and Brain homogenate Chamber from the peak areas obtained (LCMS/MS analysis).
  • Fraction unbound (Fu) brain 1/(1+((1/fraction unbound brain homogenate)-1)*3) Note- 3 is the dilution factor for brain homogenate.

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Abstract

Disclosed herein are imidazole compounds and compositions useful in the treatment of a disease or disorder associated with sodium channel mediated activity, such as epilepsy, having the structures of Formulas (I)-(XV) wherein the R groups, A, and L are as defined in the detailed description. Methods of inhibition of disease or disorder associated with sodium channel mediated activity in a subject are also provided.

Description

IMIDAZOLE COMPOUNDS AND THEIR USE AS SODIUM CHANNEL INHIBITORS Cross-Reference to Related Applications [0001] 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 these applications are incorporated herein by reference. Summary [0002] Embodiments are directed to compounds disclosed herein, pharmaceutical compositions of such compounds, and methods of use of such compounds, as described herein. [0003] Voltage gated sodium channels (VGSC) are important regulators of cellular excitability. They comprise a family of nine known subtypes of membrane-bound proteins (NaV1.1–1.9) and their abnormal activity is related to several pathological processes, such as neuropathic pain, epilepsy, migraine, ischemia, diastolic dysfunction, and arrhythmias. Mutated VGSC genes have been found in different areas of the human body, leading to several disorders both in the central and in peripheral nervous system. In particular, the Na channel isoforms NaV1.2 and NaV1.6 are widely expressed in the central nervous system (CNS), with expression along neuronal axons, and there are several studies conducted in animal models that underline the importance of NaV1.6 subtype in controlling neuronal firing. Moreover, mutations in SCN2A, the gene encoding NaV1.2, have been identified in patients with generalized epilepsy. These findings suggest that these sodium channel isoforms represent an important target for the development of new antiepileptic drugs (AEDs). [0004] Some embodiments disclosed herein are directed to a compound of Formulas (I)- (XV):
Figure imgf000002_0001
Figure imgf000003_0001
where the A, L, and R groups are defined as further described herein. [0005] In some embodiments, the compounds disclosed herein may possess useful sodium channel inhibiting activity. Some embodiments herein are directed to treatment or prophylaxis of a disease or disorder in which sodium channel mediated activity plays an active 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 embodiments herein. [0006] Some embodiments provide methods 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 compounds disclosed herein in the manufacture of a medicament for the treatment of a disease or disorder ameliorated by the inhibition of sodium channel mediated activity. Definitions [0007] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of embodiments herein which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings 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 embodiments of embodiments herein, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that embodiments herein are not entitled to antedate such disclosure by virtue of prior invention. [0008] It must also be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference 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/modulator and equivalents thereof known to those skilled in the art, and so forth. [0009] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50 mg means in the range of 45 mg to 55 mg. [0010] In embodiments or claims where the term “comprising” is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of” or “consisting essentially of.” [0011] As used herein, the term “consists of” or “consisting of” means that the pharmaceutical composition, composition or the method includes only the elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim. [0012] As used herein, the term “consisting essentially of” or “consists essentially of” means that the pharmaceutical composition, or the method includes only the elements, steps or ingredients specifically recited in the 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 the composition or method that treats the specified condition (e.g., nutrient depletion) is the specifically recited therapeutic(s) in the particular embodiment or claim. [0013] As used herein, two embodiments are “mutually exclusive” when one is defined to be something which is different from the other. For example, an embodiment wherein two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl the other group is hydrogen. Similarly, an embodiment wherein one group is CH2 is mutually exclusive with an embodiment wherein 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 ranges of values are disclosed, and the notation “from n1 … to n2” or “between n1 … and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 μM (micromolar),” which is intended to include 1 μM, 3 μM, and everything in between to any number of significant figures (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-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 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” may include “alkenylene” groups. [0017] The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, wherein 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 herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 8 carbon atoms. Alkyl groups 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, iso-amyl, 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 attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. [0020] The term “alkynyl,” as used herein, alone or in combination, refers to a straight- chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term “alkynylene” refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -CŁC-). [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, and the like. Unless otherwise specified, the term “alkynyl” may 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 wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. [0023] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes (e.g., 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 wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane. [0025] The term “halo,” or “halogen,” as used herein, alone or in combination, refers 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 meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may 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 and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at 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, which contains at least one atom chosen from N, O, and S. In certain embodiments, said heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. 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 nonaromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and sulfur. In certain embodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle 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, quinolinonyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited. [0030] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group. [0031] When a group is defined to be “null,” what is meant is that said group is absent. [0032] The term “optionally substituted” means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of 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 carboxyester, lower carboxamido, 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. Where structurally feasible, two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., - CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.” [0033] Stereogenic 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 stereogenic center. It should be understood that the invention encompasses all stereoisomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d- isomers and 1- isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain defined stereochemical configurations or by separation of mixtures of stereoisomeric products by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of stereoisomers by chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular configurations are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, endo, exo entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms. [0034] Compounds described herein may contain one or more stereogenic centers and may thus exists as stereoisomers. Embodiments herein includes all such possible stereoisomers as substantially pure resolved stereoisomers, racemic mixtures thereof, as well as mixtures of diastereomers. In some embodiments, the formulas are shown without a definitive stereochemistry at certain positions. In other embodiments, the compounds are isolated as single stereoisomers, but the absolute configurations of the stereogenic centers are unknown or only the relative stereochemical configuration (i.e., cis or trans isomerism) is known. In such embodiments, the formulas are shown with provisionally assigned absolute assignments to denote that they are single stereoisomers and relative stereochemical configuration is likewise described. Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof. Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any stereoisomer of a compound of the general formula may be obtained by stereospecific or stereoselective synthesis using optically pure or enantioenriched starting materials or reagents of known configuration. The scope of embodiments herein as described and claimed encompasses 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 a suitable enantioenriched or optically pure precursors or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of embodiments herein (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g., "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994). [0036] As used herein, the term “a 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 salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. The term “pharmaceutically acceptable salts” embraces 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, provided that it is pharmaceutically-acceptable. Such salts can be derived from pharmaceutically- acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids. [0039] Suitable pharmaceutically acceptable acid addition salts of the compounds of embodiments herein may be prepared from an inorganic acid or an organic acid. All of these salts may be prepared by conventional means from the corresponding compound of embodiments herein by treating, for example, the compound with the appropriate acid or base. [0040] Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric and diphosphoric acid; and organic acids, for example formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, ȕ-hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, xinafoic (1-hydroxy-2-naphthoic acid), napadisilic (1,5-naphthalenedisulfonic acid) and the like. [0041] Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, 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 herein are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom. X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate. X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate. [0043] The compounds of embodiments herein may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of embodiments herein and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of embodiments herein in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in embodiments herein one solvent molecule can be associated with one molecule of the compounds of embodiments herein, such as a hydrate. [0044] Furthermore, it is specifically contemplated that in embodiments herein, more than one solvent molecule may be associated with one molecule of the compounds of embodiments herein, such as a dihydrate. Additionally, it is specifically contemplated that in embodiments herein less than one solvent molecule may be associated with one molecule of the compounds of embodiments herein, such as a hemihydrate. Furthermore, solvates of embodiments herein are contemplated as solvates of compounds of embodiments herein that retain the biological effectiveness of the non-solvate form of the compounds. [0045] Embodiments herein also include isotopically-labeled compounds of embodiments herein, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of embodiments herein include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 31Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of embodiments herein, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon-14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining 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, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. [0047] Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of embodiments herein. As used herein, the term deuterated derivative embraces compounds of embodiments herein where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %. [0048] Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial. [0049] Typically, a deuterated derivative of a compound of embodiments herein has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation). [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 site of deuteration is independent from the other deuteration sites. [0051] The isotopic enrichment factor can be determined using conventional analytical methods known to one of ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR). [0052] The term "prodrug" refers to a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Prodrugs of the compounds described herein are also within the scope of embodiments herein. Thus, certain derivatives of the compounds of embodiments herein, which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of embodiments herein having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs 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 compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. Prodrugs in accordance with embodiments herein can, for example, be produced by replacing appropriate functionalities present in the compounds of embodiments herein with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). [0054] The terms “excipient” and “pharmaceutically acceptable excipient” as used herein are intended to be generally synonymous, and is used interchangeably with, the terms “carrier,” “pharmaceutically acceptable carrier,” “diluent,” “pharmaceutically acceptable diluent.” [0055] In the case of compounds of embodiments herein that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to be within the scope of 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] The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position. [0058] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life. [0059] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a compound of embodiments herein, can include, but is not limited to, providing the compound into or onto the target tissue; providing the compound systemically to a patient by, e.g., intravenous injection whereby the therapeutic reaches the target tissue; providing the compound in the form of the encoding sequence thereof to the target tissue (e.g., by so-called gene-therapy techniques). “Administering” a composition may be accomplished by injection, topically, orally, or by 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, livestock 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] The term “sodium channel inhibitor” is used herein to refer to a compound that binds to and / or inhibits the target with measurable affinity. In certain embodiments, a modulator has an IC50 and/or binding constant of no more than about 35 μM, no more than about 34 μM, no more than about 33 μM, no more than about 32 μM, no more than about 31 μM, no more than about 30 μM, no more than about 29 μM, no more than about 28 μM, no more than about 27 μM, no more than about 26 μM, no more than about 25 μM, no more than about 24 μM, no more than about 23 μM, no more than about 22 μM, no more than about 21 μM, no more than about 20 μM, no more than about 19 μM, no more than about 18 μM, no more than about 17 μM, no more than about 16 μM, no more than about 15 μM, no more than about 14 μM, no more than about 13 μM, no more than about 12 μM, no more than about 11 μM, no more than about 10 μM, no more than about 9 μM, no more than about 8 μM, no more than about 7 μM, no more than about 6 μM, no more than about 5 μM, no more than about 4 μM, no more than about 3 μM, no more than about 2 μM, no more than about 1 μM, no more than about 0.5 μM, no more than about 0.1 μM, no more than about 0.05 μM, no more than about 0.01 μM. In certain embodiments, a modulator has an IC50 and/or binding constant of greater than about 5 μM, between about 1 μM and about 5 μM, or less than about 1 μM. IC50 is that concentration of inhibitor that reduces the activity of an enzyme (e.g., NaV1.6) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against NaV1.6. In some embodiments, the compounds of the present disclosure are selective for the sodium channel isoform NaV1.6 over the sodium channel isoform NaV1.5. An example of how to measure IC50 of the disclosed compounds is shown in Example 10. [0062] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint. [0063] As used herein, the term “therapeutic” or “therapeutic agent” or “pharmaceutically active agent” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In part, embodiments of the present invention are directed to the treatment of a disease or disorder associated with sodium channel mediated activity. [0064] A “therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, e.g., to inhibit, block, or reverse the activation, migration, or proliferation of cells. The activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate. The specific dose of a compound administered according to this invention to obtain 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. The compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.001 to 1000 mg/kg, more usually in the range of from 0.01 to 1000 mg/kg. However, it will be understood that the effective amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. A therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue. [0065] The term “therapeutically acceptable” refers to those compounds, or a derivative thereof, which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. [0066] The terms "treat," "treated," "treating", or “treatment” as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total, whether induction of or maintenance of), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease and prolonging disease-free survival as compared to disease-free survival if not receiving treatment and prolonging disease- free survival as compared to disease-free survival if not receiving treatment. [0067] The term “neonate” refers to a human whoes age is from birth to less than 1 month. [0068] The term “infant” refers to a human whoes age is from 1 month to less than 2 years. [0069] The term “child” refers to a human whoes age is from 2 years to less than 12 years. [0070] The term “adolescent” refers to a human whoes age is from 12 years to less than 17 years. [0071] The term “adult” refers to a human whoes age is from 17 years or older. [0072] Also provided is a compound chosen from the Examples disclosed herein. The compounds of embodiments herein may also refer to 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 of the foregoing of the compounds of 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 to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the disclosure. Any equivalent embodiments are intended to be within the scope of this disclosure. Indeed, various modifications of the disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description, which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims. [0074] All references cited in this specification are hereby incorporated by reference. The discussion of the references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art relevant to patentability. Applicant reserves the right to challenge the accuracy and pertinency of the cited references. Compounds [0075] Embodiments are directed to a compound of Formula (I):
Figure imgf000020_0001
wherein: A is selected from -O-, -NH-, or -S(O)2NH-; L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof. [0076] Some embodiments are directed towards a compound of Formula (II):
Figure imgf000020_0002
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof. [0077] Some embodiments are directed towards a compound of Formula (III):
Figure imgf000021_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof. [0078] Some embodiments are directed towards a compound of Formula (IV):
Figure imgf000022_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof. [0079] Some embodiments are directed towards a compound of Formula (V):
Figure imgf000022_0002
wherein: A is selected from -O-, -NH-, or -S(O)2NH-; L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof. [0080] Some embodiments are directed towards a compound of Formula (VI):
Figure imgf000023_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof. [0081] Some embodiments are directed towards a compound of Formula (VII):
Figure imgf000024_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof. [0082] Some embodiments are directed towards a compound of Formula (VIII):
Figure imgf000024_0002
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof. [0083] Some embodiments are directed towards a compound of Formula (IX):
Figure imgf000025_0001
wherein: L is C1-C5 alkyl; R1 is C6-C10 aryl; wherein the aryl is optionally substituted with one or more halogens; R2 is selected from H or C1-C5 alkyl; and R3 is halogen; or a derivative thereof. [0084] Embodiments are directed to a compound of Formula (X): wherein:
Figure imgf000025_0002
A is -O- or -NR8; L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl; R9 is H or halogen; and n is 1 or 2; or a derivative thereof. [0085] Some embodiments are directed towards a compound of Formula (XI):
Figure imgf000026_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R9 is H or halogen; and n is 1 or 2: or a derivative thereof. [0086] Some embodiments are directed towards a compound of Formula (XII):
Figure imgf000027_0001
( ) wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl; R9 is H or halogen; and n is 1 or 2; or a derivative thereof. [0087] Some embodiments are directed towards a compound of Formula (XIII): wherein:
Figure imgf000027_0002
A is -O- or -NR8-; L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl; R9 is H or halogen; and n is 1 or 2; or a derivative thereof. [0088] Some embodiments are directed towards a compound of Formula (XIV):
Figure imgf000028_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R9 is H or halogen; and n is 1 or 2; or a derivative thereof. [0089] Some embodiments are directed towards a compound of Formula (XV):
Figure imgf000029_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl; R9 is H or halogen; and n is 1 or 2; or a derivative thereof. [0090] In some embodiments, the compound of Formula (I), may be selected from: Compoun d # Structure Name 2-(4-(benzyloxy)phenyl)-5-(4- 1 chlorophenyl)-4-methyl-1H-imidazole 5-(4-chlorophenyl)-2-(4-((2- 2 fluorobenzyl)oxy)phenyl)-4-methyl- 1H-imidazole 5-(4-chlorophenyl)-2-(4-((3- 3 fluorobenzyl)oxy)phenyl)-4-methyl- 1H-imidazole 5-(4-chlorophenyl)-2-(4-((4- 4 fluorobenzyl)oxy)phenyl)-4-methyl- 1H-imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-(1- 5 phenylethoxy)phenyl)-1H-imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-(1- 6 phenylethoxy)phenyl)-1H-imidazole enantiomer 1 5-(4-chlorophenyl)-4-methyl-2-(4-(1- 7 phenylethoxy)phenyl)-1H-imidazole enantiomer 2 2-(4-(5-(4-chlorophenyl)-4-methyl-1H- 8 imidazol-2-yl)phenoxy)-1-(pyridin-2- yl)ethan-1-one 2-bromo-5-((4-(5-(4-chlorophenyl)-4- 9 methyl-1H-imidazol-2- yl)phenoxy)methyl)pyridine 5-(4-chlorophenyl)-2-(4-(2- 10 fluorophenethoxy)phenyl)-4-methyl- 1H-imidazole 5-(4-chlorophenyl)-2-(4-((3,4- 11 dichlorobenzyl)oxy)phenyl)-4-methyl- 1H-imidazole 3-((4-(5-(4-chlorophenyl)-4-methyl- 12 1H-imidazol-2- yl)phenoxy)methyl)pyridine 2-(4-((3-chlorobenzyl)oxy)phenyl)-5- 13 (4-chlorophenyl)-4-methyl-1H- imidazole 5-(4-chlorophenyl)-2-(4-((3- 14 methoxybenzyl)oxy)phenyl)-4-methyl- 1H-imidazole 4-((4-(5-(4-chlorophenyl)-4-methyl- 15 1H-imidazol-2- yl)phenoxy)methyl)pyridine 4-((4-(5-(4-chlorophenyl)-4-methyl- 1H-imidazol-2- 16 yl)phenoxy)methyl)quinolin-2(1H)- one 2-(4-(4-chlorophenethoxy)phenyl)-5- 17 (4-chlorophenyl)-4-methyl-1H- imidazole ethyl 4-((4-(5-(4-chlorophenyl)-4- 18 methyl-1H-imidazol-2- yl)phenoxy)methyl)benzoate 2-(4-(3-chlorophenethoxy)phenyl)-5- 19 (4-chlorophenyl)-4-methyl-1H- imidazole 5-(4-chlorophenyl)-4-methyl-2-(4- 20 phenethoxyphenyl)-1H-imidazole 3-((4-(5-(4-chlorophenyl)-4-methyl- 21 1H-imidazol-2- yl)phenoxy)methyl)benzonitrile 2-(4-((4-chlorobenzyl)oxy)phenyl)-5- 22 (4-chlorophenyl)-4-methyl-1H- imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-((4- 23 (trifluoromethoxy)benzyl)oxy)phenyl)- 1H-imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-((3- 24 methylbenzyl)oxy)phenyl)-1H- imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-((2- 25 methylbenzyl)oxy)phenyl)-1H- imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-((4- 26 methylbenzyl)oxy)phenyl)-1H- imidazole 2-((4-(5-(4-chlorophenyl)-4-methyl- 27 1H-imidazol-2- yl)phenoxy)methyl)pyridine 3-((4-(5-(4-chlorophenyl)-4-methyl- 28 1H-imidazol-2-yl)phenoxy)methyl)-5- methyl-1,2,4-oxadiazole 1-(4-(2-(4-(5-(4-chlorophenyl)-4- 29 methyl-1H-imidazol-2- yl)phenoxy)ethyl)phenyl)ethan-1-one 4-(2-(4-(5-(4-chlorophenyl)-4-methyl- 30 1H-imidazol-2- yl)phenoxy)ethyl)morpholine 4-((4-(5-(4-chlorophenyl)-4-methyl- 31 1H-imidazol-2-yl)phenoxy)methyl)- 3,5-dimethylisoxazole 5-(4-chlorophenyl)-4-methyl-2-(4-((1- 32 methyl-1H-imidazol-4- yl)methoxy)phenyl)-1H-imidazole 3-((4-(5-(4-chlorophenyl)-4-methyl- 33 1H-imidazol-2-yl)phenoxy)methyl)-1- methyl-1H-pyrazole 4-((4-(5-(4-chlorophenyl)-4-methyl- 34 1H-imidazol-2-yl)phenoxy)methyl)-1- methyl-1H-pyrazole 2-(4-((1H-imidazol-5- 35 yl)methoxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole 5-(4-chlorophenyl)-2-(4-((4,4- 36 difluorocyclohexyl)methoxy)phenyl)- 4-methyl-1H-imidazole 2-((4-(5-(4-chlorophenyl)-4-methyl- 37 1H-imidazol-2- yl)phenoxy)methyl)thiazole 3-((4-(5-(4-chlorophenyl)-4-methyl- 38 1H-imidazol-2-yl)phenoxy)methyl)-1- methylpiperidine 4-((4-(5-(4-chlorophenyl)-4-methyl- 39 1H-imidazol-2-yl)phenoxy)methyl)-1- methylpiperidine 2-(4-((2- 40 (benzyloxy)benzyl)oxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole 5-((4-(5-(4-chlorophenyl)-4-methyl- 41 1H-imidazol-2-yl)phenoxy)methyl)-2- methylpyrimidine 4-(2-((4-(5-(4-chlorophenyl)-4-methyl- 42 1H-imidazol-2- yl)phenoxy)methyl)benzyl)morpholine 2-(4-((1-benzyl-1H-imidazol-2- 43 yl)methoxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-(1- (3- 44 (trifluoromethyl)phenyl)ethoxy)phenyl )-1H-imidazole 4-(5-(4-chlorophenyl)-4-methyl-1H- 45 imidazol-2-yl)-N-(3- fluorobenzyl)aniline 4-(5-(4-chlorophenyl)-4-methyl-1H- 46 imidazol-2-yl)-N-(thiazol-4- yl)benzenesulfonamide 3-((4-(5-(4-chlorophenyl)-4-methyl- 47 1H-imidazol-2-yl)phenoxy)methyl)-N- methylbenzenesulfonamide or a derivative thereof. [0091] In some embodiments, the compound of Formula (I), may be selected from: Compoun Structure Name d # 5-(4-chlorophenyl)-4-ethyl-2-(4-((3- 48 fluorobenzyl) oxy) phenyl)-1H-imidazole 2-chloro-6-((4-(5-(4-chlorophenyl)-4-methyl- 49 1H-imidazol-2-yl) phenoxy) methyl) pyridine (S)-5-(4-chlorophenyl)-2-(4-(1-(3- 50 fluorophenyl)ethoxy)phenyl)-4-methyl-1H- imidazole (R)-5-(4-chlorophenyl)-2-(4-(1-(3- 51 fluorophenyl)ethoxy)phenyl)-4-methyl-1H- imidazole 4-(5-(4-chlorophenyl)-4-methyl-1H- 52 imidazol-2-yl)-N-((4,4- difluorocyclohexyl)methyl)aniline 4-(5-(4-chlorophenyl)-4-methyl-1H- 53 imidazol-2-yl)-N-(pyridin-2-ylmethyl)aniline 4-(5-(4-chlorophenyl)-4-methyl-1H- 54 imidazol-2-yl)-N-((1-methyl-1H-pyrazol-3- yl)methyl)aniline N-(3-chlorobenzyl)-4-(5-(4-chlorophenyl)-4- 55 methyl-1H-imidazol-2-yl)aniline (S)-4-(5-(4-chlorophenyl)-4-methyl-1H- 56 imidazol-2-yl)-N-(1-(3- fluorophenyl)ethyl)aniline (R)-4-(5-(4-chlorophenyl)-4-methyl-1H- 57 imidazol-2-yl)-N-(1-(3- fluorophenyl)ethyl)aniline (S)-4-(5-(4-chlorophenyl)-4-methyl-1H- 58 imidazol-2-yl)-N-(1-phenylpropyl)aniline (R)-4-(5-(4-chlorophenyl)-4-methyl-1H- 59 imidazol-2-yl)-N-(1-phenylpropyl)aniline 5-(4-chlorophenyl)-4-methyl-2-(4- 60 phenoxyphenyl)-1H-imidazole 5-(4-chlorophenyl)-2-(4-(2- 61 fluorophenoxy)phenyl)-4-methyl-1H- imidazole 5-(4-chlorophenyl)-2-(4-(3- 62 fluorophenoxy)phenyl)-4-methyl-1H- imidazole 5-(4-chlorophenyl)-2-(4-(4- 63 fluorophenoxy)phenyl)-4-methyl-1H- imidazole 4-(5-(4-chlorophenyl)-1H-imidazol-2-yl)-N- 64 (3-fluorobenzyl)aniline (S)-1-benzyl-N-(4-(5-(4-chlorophenyl)-4- 65 methyl-1H-imidazol-2-yl)phenyl)pyrrolidin- 3-amine 5-(4-chlorophenyl)-4-methyl-2-(4-(4- 66 (trifluoromethyl)phenoxy)phenyl)-1H- imidazole 5-(3-(4-(5-(4-chlorophenyl)-4-methyl-1H- 67 imidazol-2-yl)phenoxy)phenyl)-1H-pyrazole 5-(4-chlorophenyl)-4-methyl-2-(4-((4- 68 (trifluoromethyl)cyclohexyl)methoxy)phenyl) -1H-imidazole 5-(4-chlorophenyl)-4-methyl-2-(4-((1- methyl-4- 69 (trifluoromethyl)cyclohexyl)methoxy)phenyl) -1H-imidazole N Cl 5-(4-(4-(5-(4-chlorophenyl)-4-methyl-1H- 70 N N N H imidazol-2-yl)phenoxy)phenyl)-1H-pyrazole H O 5-(4-chlorophenyl)-2-(4-((4,4-difluoro-1- 71 methylcyclohexyl)methoxy)phenyl)-4- methyl-1H-imidazole or a derivative thereof. [0092] In some embodiments, the compound of Formula (X), may be selected from: Compound Structure Name # 5-(4-chlorophenyl)-4-methyl-2-(4- 72 (2,2,2-trifluoroethoxy)phenyl)-1H- imidazole 4-(2-((4-(5-(4-chlorophenyl)-4-methyl- 73 1H-imidazol-2- yl)phenoxy)methyl)benzyl)morpholine 6-((4-(5-(4-chlorophenyl)-4-methyl- 74 1H-imidazol-2-yl)phenoxy)methyl)-N- methylpyridin-2-amine 4-(5-(4-chlorophenyl)-4-methyl-1H- 75 imidazol-2-yl)-N-(3-fluorobenzyl)-N- methylaniline (S)-1-benzyl-N-(4-(5-(4-chlorophenyl)- 76 4-methyl-1H-imidazol-2-yl)phenyl)-N- methylpyrrolidin-3-amine 4-(5-(4-chlorophenyl)-4-methyl-1H- 77 imidazol-2-yl)-2,5-difluoro-N-(3- fluorobenzyl)aniline 4-(5-(4-chlorophenyl)-4-methyl-1H- 78 imidazol-2-yl)-3-fluoro-N-(3- fluorobenzyl)aniline 6-((4-(5-(4-chlorophenyl)-4-methyl- 79 1H-imidazol-2-yl) phenoxy) methyl)- N-methylpyridin-2-amine 2-chloro-4-(5-(4-chlorophenyl)-4- 80 methyl-1H-imidazol-2-yl)-N-(3- fluorobenzyl)aniline or a derivative thereof. [0093] In some embodiments, the compound of Formula (II), may be selected from compounds 1-44, 47-51, 60-63, and 66-71. [0094] In some embodiments, the compound of Formula (III), may be selected from compound 45, 52-59, 64, and 65. [0095] In some embodiments, the compound of Formula (IV), may be selected from compound 46. [0096] In some embodiments, the compound of Formula (V), may be selected from compounds 1-71. [0097] In some embodiments, the compound of Formula (VI), may be selected from compounds 1-44, 47-51, 60-63, and 66-71. [0098] In some embodiments, the compound of Formula (VII), may be selected from compound 45, 52-59, 64, and 65. [0099] In some embodiments, the compound of Formula (VIII), may be selected from compound 46. [0100] In some embodiments, the compound of Formula (IX), may be selected from compounds 3, 5, 6, and 7, 48, 50, 51. [0101] In some embodiments, the compound of Formula (X), may be selected from compounds 72-80. [0102] In some embodiments, the compound of Formula (XI), may be selected from compounds 72-74 and 79. [0103] In some embodiments, the compound of Formula (XII), may be selected from compounds 75-78 and 80. [0104] In some embodiments, the compound of Formula (XIII), may be selected from compounds 72-80. [0105] In some embodiments, the compound of Formula (XIV), may be selected from compounds 72-74 and 79. [0106] In some embodiments, the compound of Formula (XV), may be selected from compounds 75-78 and 80. Pharmaceutical Compositions [0107] Also provided is a pharmaceutical composition comprising a compound as disclosed herein, and a pharmaceutically acceptable excipient. [0108] In certain embodiments, the pharmaceutical composition may comprise about 0.01% to about 50% of one or more compounds disclosed herein. In some embodiments, the one or more compounds is in an amount of about 0.01% to about 50%, about 0.01% to about 45%, about 0.01% to about 40%, about 0.01% to about 30%, about 0.01% to about 20%, about 0.01% to about 10%, about 0.01% to about 5%, about 0.05% to about 50%, about 0.05% to about 45%, about 0.05% to about 40%, about 0.05% to about 30%, about 0.05% to about 20%, about 0.05% to about 10%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.5% to about 50%, about 0.5% to about 45%, about 0.5% to about 40%, about 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 a value 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. The foregoing all representing weight percentages of the pharmaceutical composition. [0109] In some embodiments, the compounds as disclosed herein are in a therapeutically effective amount. In some embodiments, the therapeutically effective amount may be 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 10 mg, about 0.01 mg to about 5 mg, about 0.1 mg to about 1000 mg, about 0.1 mg to about 900 mg, about 0.1 mg to about 800 mg, about 0.1 mg to about 700 mg, about 0.1 mg to about 600 mg, about 0.1 mg to about 500 mg, about 0.1 mg to about 400 mg, about 0.1 mg to about 300 mg, about 0.1 mg to about 200 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg, about 1 mg to about 1000 mg, about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, 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, from 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 between the ranges disclosed above. [0110] In some embodiments, the compounds as disclosed herein may be administered at a dose 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, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 1000 mg/kg, about 0.1 mg/kg to about 900 mg/kg, about 0.1 mg/kg to about 800 mg/kg, about 0.1 mg/kg to about 700 mg/kg, about 0.1 mg/kg to about 600 mg/kg, about 0.1 mg/kg to about 500 mg/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 0.1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 1000 mg/kg, about 1 mg/kg to about 900 mg/kg, about 1 mg/kg to about 800 mg/kg, about 1 mg/kg to about 700 mg/kg, about 1 mg/kg to about 600 mg/kg, about 1 mg/kg to about 500 mg/kg, about 1 mg/kg to about 400 mg/kg, about 1 mg/kg to about 300 mg/kg, about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 25 mg/kg, about 1 mg/kg to about 10 mg/kg, about 1 mg/kg to about 5 mg/kg, about 10 mg/kg to about 1000 mg/kg, about 50 mg/kg to about 1000 mg/kg, about 100 mg/kg to about 1000 mg/kg, about 200 mg/kg to about 1000 mg/kg, about 300 mg/kg to about 1000 mg/kg, about 400 mg/kg to about 1000 mg/kg, about 500 mg/kg to about 1000 mg/kg, about 10 mg/kg to about 500 mg/kg, about 50 mg/kg to about 500 mg/kg, about 100 mg/kg to about 500 mg/kg, about 10 mg/kg to about 300 mg/kg, about 50 mg/kg to about 300 mg/kg, from about 100 mg/kg to about 300 mg/kg, about 10 mg/kg to about 150 mg/kg, about 50 mg/kg to about 150 mg/kg, about 60 mg/kg to about 120 mg/kg, about 50 mg/kg to about 120 mg/kg or a range between any two of these values. Specific examples include, for example, 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, 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 between the ranges disclosed above. [0111] While it may be possible for the compounds described herein to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or a derivative thereof, together with one or more pharmaceutically acceptable excipients thereof and optionally one or more other therapeutic ingredients. The excipient(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation of the pharmaceutical composition is dependent upon the route of administration chosen. Any of the well-known techniques and excipients may be used as suitable and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. [0112] In some embodiments, the pharmaceutical compositions for use in accordance with embodiments herein can be formulated in conventional manner using one or more physiologically acceptable excipients. [0113] When employed as pharmaceuticals, the compounds can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. [0114] Administration of the disclosed compounds or compositions may be oral administration. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The compounds can be contained in such formulations pharmaceutical compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The artisan can refer to various pharmacologic references for guidance. For example, 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) can be consulted. [0115] In some embodiments, a method of treating a disease or disorder associated with sodium channel mediated activity comprises administering a compound or a pharmaceutical composition of 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 which contain, as the active ingredient, one or more of the compounds disclosed herein in combination with one or more pharmaceutically acceptable carriers (excipients). [0117] In some embodiments, a method of making a pharmaceutical composition comprises mixing the active ingredient with an excipient, diluting the active ingredient using an excipient, or enclosing the active ingredient within a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, as well as soft and hard gelatin capsules. [0118] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose, including eutectic solvents, eutectic-based ionic liquids, or ionic liquids. The pharmaceutical compositions can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The pharmaceutical compositions can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. [0119] The pharmaceutical compositions can be formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intradural, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, buccal, sublingual and intraocular), intravitreal, or intravaginal administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound disclosed herein or a derivative thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient 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 may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. [0121] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may 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 binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All compositions for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0122] For preparing solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the pharmaceutical composition so that the pharmaceutical composition can be readily subdivided into equally therapeutically effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing from, 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 compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [0124] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil 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 may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0126] In some embodiments, the pharmaceutical compositions administered to a patient can be in the form of pharmaceutical compositions described above. In some embodiments, these compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. In some embodiments, the pH of the compound preparations 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 use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. [0127] Preferred unit dosage pharmaceutical compositions are those containing an effective dose, 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, the therapeutically effective amount can vary according to, for example, the particular use for which the treatment is made, the manner 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 upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, composition of the excipient, and its route of administration. Effective doses 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 upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. 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 compound can be effective over a wide dosage range and can be generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. [0132] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. [0133] The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the 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. In addition, the route of administration may vary depending on the condition and its severity. Methods of Treatment [0134] Some embodiments herein are directed to a method of treating a disease or disorder associated with sodium channel mediate 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. In certain embodiments, the therapeutically effective amount of a compound as 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, acceptable salt, solvate or prodrug thereof. [0135] Also provided is a compound as 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 are directed 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 are directed to a method of treating a disease or disorder primarily 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. [0138] In some embodiments, the disease or disorder associated with sodium channel mediated activity is selected from a seizure disorder, depression, anxiety, neuropathic pain, chemotherapy-induced neuropathy, chronic pain, migraine, ischemia, diastolic dysfunction, arrhythmia, Dravet syndrome, neuromuscular conditions, Amyotrophic Lateral Sclerosis (ALS), restless leg syndrome, or a combination thereof. [0139] In some embodiments, the seizure disorder is selected from epilepsy, acute seizures, chronic seizures, generalized tonic-clonic seizures refractory seizures, pharmaco-resistant seizure disorder, Early Infantile Epileptic Encephalopathy, or a combination thereof. [0140] In some embodiments, the seizure disorder is epilepsy. [0141] In some embodiments, the epilepsy is selected from partial epilepsy, generalized absence epilepsy, temporal lobe epilepsy, therapy resistant epilepsy, pharmaco-resistant epilepsy, epilepsy characterized by acute seizures, epilepsy characterized by chronic seizures, epilepsy characterized by generalized tonic-clonic seizures, epilepsy characterized by refractory seizures, or a combination thereof. [0142] In some embodiments, the patient is selected from a neonate, an infant, a child, an adolescent, or an 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. General Synthetic Methods for Preparing Compounds [0148] The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformation proposed. This will sometimes require a judgement to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. [0149] The novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description for the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvents, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods then be use. [0150] The compounds of the present invention may be prepared by the expemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures from the reactions appear hereinafter and in the working examples. Protection and de-protection of functional groups in the processes belowmay be carried out by procedures generally known in the art (see, for example, Green, T. W. et al., Green’s Protecting Groups in Organic Synthesis, 4th Ed., Wiley (2006). General methods of organic synthesis and functional group transformations are found in: Trost, B. M. et al., eds,. Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, N.Y. (1991); March, J., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th Ed., Wiley & Sons, New York, N.Y. (1992); Katrizky, A. R. et al., eds., Comprehensive Organic Functional Groups Transformation II, Elsevier Science Inc., Tarrytown, N.Y. (2005); Larock, R. C., Comprehensive Organic Transformations, Wiley Publishers, Inc., New York, N.Y. (2018); and reference therein. [0151] Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of the ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods. [0152] Example 1: Synthetic Method A
Figure imgf000050_0001
[0153] Synthesis of Int-3: [0154] To stirred a solution of 4-(hydroxymethyl)benzaldehyde (1.0 g, 8.2 mmol, 1.0 eq) in THF (10 mL) Then phenylmethanol ( 1.32 g ,12.3 mmol, 1.5 eq) and triphenyl phosphine ( 3.21 g , 12.3 mmol, 1.5 eq) was added at 0 °C, the reaction mixture was stirred for 10 min at 0 °C. DIAD (2.4 g, 12.3 mmol, 1.5 eq) was added to above solution at same temperature. The reaction was allowed to stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 40 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product, which was purified by combi flash chromatography using a mixture of n-hexane and EtOAc as mobile phase Product was eluted at 10% ethyl acetate in hexanes to give 4-(benzyloxy)benzaldehyde as colourless oil (0.600 g, 34.52 yield). 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 eq) in methanol (2.5 mL). 1-(4-chlorophenyl) propane-1,2-dione (0.215 g, 1.2 mmol, 1.0 eq) and ammonium acetate (0.453 g, 5.9 mmol, 5.0 eq) was added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product, which was purified by Prep HPLC using 0.1% TFA in water/acetonitrile, followed by lyophilized the product fraction to give 2-(4-(benzyloxy)phenyl)-5-(4-chlorophenyl)-4-methyl-1H-imidazole as a white amorphous solid (0.080 g, 18.12% yield).m/z=375[M+H] +, ¹H NMR (400 MHz, DMSO d6): į 12.29 (s, 1H), 7.90 (d, J=7.2 Hz, 2H), 7.72 (br s, 2H), 7.50 – 7.36 (m, 7H), 7.12 (d, J= 8.4 Hz, 1H), 5.17 (s, 2H), 2.46 (s, 3H). [0157] Example 2: Synthetic Method B
Figure imgf000051_0001
[0158] Step 1: To a stirred solution of 4-hydroxybenzaldehyde (0.500 g, 4.1 mmol, 1.0 eq) in DMF (5 mL) was added 1-(bromomethyl)-2-fluorobenzene (0.773 g, 4.1 mmol, 1.0 eq) and K2CO3 (1.69 g, 12.3 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product, which was purified by combi flash chromatography using a mixture of n-hexane and EtOAc as mobile phase. Product was eluted at 15% ethyl acetate in hexanes to 4-((2-fluorobenzyl)oxy)benzaldehyde as oil (0.400 g, 42.43% yield). m/z=231[M+H]+. [0159] Step 2: To a stirred solution of 4-((2-fluorobenzyl)oxy)benzaldehyde (0.150 g, 0.65 mmol, 1.0 eq) in methanol (2.5 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.118 g, 0.65 mmol, 1.0 eq) and ammonium acetate (0.250 g, 3.2 mmol, 5.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product, which was purified by Prep HPLC using 0.1% TFA in water/acetonitrile, followed by lyophilized the product fraction 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 (400 MHz, DMSO d6) į 12.32 (s, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.74 (d, J=7.8 Hz, 2H), 7.60 (d, J=6.0 Hz, 1H), 7.46 (d, J=6.0 Hz, 3H), 7.30 - 7.27 (m, 2H), 7.14 (d, J=8.8 Hz, 2H), 5.20 (s, 2H), 2.47 (s, 3H). [0160] Example 3: Synthetic Method C [0161] Exemplary Synthesis of 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl) phenoxy) methyl)-1-methyl-1H-pyrazole (Compound 33)
[0162] Step 1: To stirred a solution of 1-methyl-1H-pyrazol-3-yl (0.40 g, 3.6mmol, 1.0 eq) in dichloromethane (5 mL), was added trimethylamine (0.72 g, 7.1mmol, 2.0 eq), reaction mixture was stirred for 5 min at 0°C, was added methane sulfonyl chloride (0.61 g, 5.35 mmol, 1.5 eq) dropwise at 0oC, reaction mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was diluted with water (20 mL), extracted with dichlormethane (3 x 20 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product as (1-methyl-1H-pyrazol-3-yl) methyl methanesulfonate as yellow oil is used to direct next step reaction, (0.34 g, 50.1% yield). m/z = 191.04 [M+H]+. [0163] Step 2: To a solution of (1-methyl-1H-pyrazol-3-yl) methyl methane sulfonate (0.300 g, 1.5771 mmol, 1.0 eq) in DMF (3 mL) was added 4-hydroxybenzaldehyde (0.192 g, 1.57mmol, 1.0 eq) and K2CO3 (0.652 g, 4.73 mmol, 3.0 eq) at room temperature, reaction mixture stirred for 16 h at 90oC. The progress of the reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product, which was purified by combi flash chromatography using a mixture of n-hexane and EtOAc as mobile phase. Product was eluted at 40% ethyl acetate in hexanes to give 4-((1-methyl-1H-pyrazol-3-yl)methoxy)benzaldehyde as a solid, (0.200 g, 58.6% yield). m/z = 217.09 [M+H]+. [0164] Step 3: To a solution of 4-((1-methyl-1H-pyrazol-3-yl) methoxy) benzaldehyde (0.200 g, 0.92 mmol, 1.0 eq) in methanol (2 mL) was added 1-phenylpropane-1,2-dione (0.168 g, 0.92 mmol, 1.0 eq) and ammonium acetate (0.356 g, 4.62 mmol., 5.0 eq) at room temperature, reaction mixture was stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product, which was purified by combi flash chromatography using a mixture of n-hexane and EtOAc as mobile phase. Product was eluted at 50% ethyl acetate in hexanes to give 4-((1-methyl-1H-pyrazol-3- yl)methoxy)benzaldehyde as white solid (0.090 g, 25.7% yield). m/z = 379.12 [M+H]+ ¹H NMR (400 MHz, DMSO): į 12.35 (s, 1H), 7.87 (d, J = 8.4Hz, 2H), 7.71 – 7.67 (m, 4H), 7.45 (d, J= 8.4 Hz, 2H), 7.09 (d, J= 8.4 Hz, 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 [0165] Step 1 Synthesis of tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1- carboxylate (2): To a cooled solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.80 g, 3.72 mmol, 1.0 eq) in THF (8 mL) at 0°C, was added sodium hydride (60% in mineral oil, 0.10 g, 4.09 mmol, 1.1 eq) and Trimethylsilyl chloride (0.48 g, 4.46 mmol, 1.2 eq) at same temperature. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was concentrated under reduced pressure to get tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine- 1-carboxylate as 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): To a solution of tert-butyl 4-(((trimethylsilyl)oxy)methyl)piperidine-1- carboxylate (0.70 g, 2.79 mmol, 1.0 eq) in DMF (7 mL) was added 4-hydroxybenzaldehyde (0.30 g, 2.79 mmol, 1.0 eq) and K2CO3(1.01 g, 7.32 mmol, 3.0 eq) and reaction mixture was stirred at 80°C for 2 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes to give tert-butyl 4- ((4-formylphenoxy)methyl)piperidine-1-carboxylate as 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): To a solution of tert-butyl 4-((4- formylphenoxy)methyl)piperidine-1-carboxylate (0.20 g 0.63 mmol 1.0 eq) in methanol (2 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.11 g, 0.63 mmol 1.0 eq) and ammonium acetate (0.24 g, 3.13 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified using flash chromatography and product was eluted in 50% ethyl acetate in hexanes to give tert-butyl 4-((4-(5-(4-chlorophenyl)- 4-methyl-1H-imidazol-2-yl)phenoxy)methyl)piperidine-1-carboxylate as 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 eq) in THF (3.0 mL), was added 2.5 M LAH solution in THF (0.50 mL, 1.24 mmol, 4.0 eq) 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 starting material, the reaction mixture was diluted with sat. NaHCO3 sol (50 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 60% ethyl acetate in hexanes to give 4-((4-(5-(4-chlorophenyl)-4- methyl-1H-imidazol-2-yl)phenoxy)methyl)-1-methylpiperidine as solid (0.045 g, 36.61% yield). m/z = 296.2 [M+H]+. 1H NMR (400 MHz, DMSO) į 8.18 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 3.90 (d, J = 5.8 Hz, 2H), 2.85 (d, J = 11.2 Hz, 2H), 2.45 (s, 3H), 2.20 (s, 3H), 2.08 – 1.97 (m, 1H), 1.79 (d, J = 12.5 Hz, 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 [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 eq) in toluene (5 mL), was added (3-fluorophenyl) methanamine (0.71 g, 4.66 mmol, 1.5 eq) and Cs2CO3 (0.99 g, 9.32 mmol, 3.0 eq) under nitrogen atmosphere and the reaction mixture degassed with N2 for 15 min. To this, and BINAP (0.23 g, 0.31 mmol, 0.1 eq) and Pd(OAc)2 (0.23 g, 0.31 mmol, 0.1 eq) were added 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 starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted at 35% ethyl acetate in hexanes to give 4-((3-fluorobenzyl) amino) benzaldehyde as yellow color 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 eq) in methanol (2.5 mL), 1-(4-chlorophenyl) propane-1,2-dione (0.34 g, 1.84 mmol, 1.0 eq) and ammonium acetate (0.71 g, 9.19 mmol, 5.0 eq) was added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted at 70% ethyl acetate in hexanes 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]+. 1H NMR (400 MHz, DMSO) į 11.98 (s, 1H), 7.70 - 7.62 (m, 4H), 7.45 – 7.34 (m, 3H), 7.22 – 7.16 (m, 2H), 7.05 (t, J = 8.0 Hz, 1H), 6.63 (d, J = 8.2 Hz, 2H), 6.54 (s, 1H), 4.34 (d, J = 8.2 Hz, 2H), 2.42 (s, 3H). Example 6: Synthesis of 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)-N-(thiazol-4- yl)benzenesulfonamide [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 eq) in DCM (8 mL), was added thiazol-4-amine (0.784 g, 7.84 mmol, 2.0 eq) and pyridine (1.57 g, 19.9 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 50% ethyl acetate in hexanes to give 4-formyl-N-(thiazol-4-yl)benzenesulfonamide as 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 eq) in methanol (1 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.07 g, 0.37 mmol, 1.0 eq) and ammonium acetate (0.14 g, 1.86 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to get the crude product, The residue was purified by Prep 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 (400 MHz, DMSO) į 12.73 (s, 1H), 11.11 (s, 1H), 8.86 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.88 – 7.72 (m, 2H), 7.70 (d, J = 8.0 Hz, 3H), 7.55 – 7.50 (m, 1H), 7.46 – 7.44 (m, 1H), 7.07 (d, J = 2.2 Hz, 1H), 2.74 (s, 3H). Example 7: Synthesis of 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl) phenoxy) methyl)-N-methylbenzene sulfonamide [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 eq) in THF (10 mL) was added 1 M borane-tetrahydrofuran complex in THF (13.9 mL, 13.9 mmol, 3 eq) and reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 80% ethyl acetate in hexanes to give 3-(hydroxymethyl)-N-methylbenzenesulfonamide as off white amorphous solid (0.9 g, 96.25% yield). m/z = 202 [M+H]+. [0174] Step 2 Synthesis of 3-(N-methylsulfamoyl) benzyl methane sulfonate (3): To a solution of 3-(hydroxymethyl)-N-methylbenzenesulfonamide (0.9 g, 4.47 mmol, 1 eq) and TEA (0.9 g, 8.95 mmol, 2 eq) in DCM (9 mL) Methane sulfonyl chloride (0.77 g, 6.71 mmol, 1.5 eq) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes to give 3-(N-methylsulfamoyl) benzyl methane sulfonate as 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 methane sulfonate (0.8 g, 2.86 mmol, 1 eq) and 4- hydroxybenzaldehyde (0.7 g, 5.73 mmol, 2 eq) in DMF (8 mL), was added K2CO3 (1.18 g, 8.60 mmol, 3 eq) and the reaction mixture was stirred at 90°C for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 50% ethyl acetate in hexanes to give of 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 eq) in methanol (1.5 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.1 g, 0.59 mmol, 1.2 eq) and ammonium acetate (0.19 g, 2.45 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by prep 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]+. 1H NMR (400 MHz, DMSO) į 12.28 (s, 1H), 7.89 (s, 3H), 7.74 (d, J = 7.9 Hz, 5H), 7.69 – 7.49 (m, 3H), 7.13 (d, J = 4.9 Hz, 2H), 5.22 (s, 2H), 2.45 (s, 3H), 2.41 (d, J = 4.9 Hz, 3H). Example 8: Synthesis of 5-(4-(4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)phenyl)-1H-pyrazole
Figure imgf000059_0001
[0177] Step 1 Synthesis of 1-(4-(benzyloxy)phenyl)ethan-1-one (3): To a solution of 1-(4- hydroxyphenyl)ethan-1-one (5 g, 36.76 mmol, 1.0 eq) in DMF (50 mL) was added (bromomethyl)benzene (6.29 g, 36.76 mmol, 1.0 eq) and K2CO3 (15.22 g, 110.29 mmol, 1.0 eq) 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 starting material, the reaction mixture was diluted with EtOAc (1000 mL) and washed with cold water (3 x 500 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes 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 €-1-(4-(benzyloxy)phenyl)-3-(dimethylamino)prop-2-en-1-one (4): To a solution of 1-(4-(benzyloxy)phenyl)ethan-1-one (2 g, 8.84 mmol, 1.0 eq) 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 progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get (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)prop-2-en-1-one (1.5 g, 5.33 mmol, 1.0 eq) in Ethanol (15 mL) was added Hydrazine hydrate (7.5 mL) and Acetic acid (Cat.) and the reaction mixture was stirred 80°C for 8 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (3 x 100 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes 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): To a suspension of 10% Pd/C (50% moist, 1 g, w/w) in methanol (10.0 mL) was added 5-(4-(benzyloxy)phenyl)-1H-pyrazole (1 g, 4.00 mmol, 1.0 eq) under nitrogen atmosphere and the reaction mass was and stirred at room temperature under hydrogen atmosphere for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mass was filtered through celite bed and washed with MeOH (80 mL), filtrate was concentrated under vacuum to give 4-(1H- pyrazol-5-yl)phenol as semisolid (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): To a solution of 4-(1H-pyrazol-5-yl)phenol (0.6 g, 3.75 mmol, 1.0 eq) in DMF (6 mL) was added 4- fluorobenzaldehyde (0.47 g, 3.75 mmol, 1.0 eq) and K2CO3 (1.55 g, 11.25 mmol, 3.0 eq) 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 starting material, the reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 50% ethyl acetate in hexanes 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-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)phenyl)-1H-pyrazole To a solution of 4-(4-(1H-pyrazol-5- yl)phenoxy)benzaldehyde (0.25 g, 0.95 mmol, 1.0 eq) in methanol (2.5 mL) was added 1-(4- chlorophenyl)propane-1,2-dione (0.21 g, 1.14 mmol, 1.2 eq) and ammonium acetate (0.36 g, 4.73 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 60% ethyl acetate in hexanes to give 5-(4-(4-(5-(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 (400 MHz, DMSO) į 12.87 (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 = 2.2 Hz, 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
Figure imgf000061_0001
[0183] Step 1 Synthesis of methyl 4,4-difluoro-1-methylcyclohexane-1-carboxylate (2): To a cooled solution of Diisopropylamine (8.54 mL, 60.67 mmol, 3.6 eq) in tetrahydrofuran (50 mL), was added n-butyl lithium (2.5 M in hexanes, 32.35 mL, 80.89 mmol, 4.8 eq) at -78 °C and the reaction mixture was stirred at 0 °C for 1 h. After 1 h, reaction mixture was again cooled to -78 °C and was added methyl 4,4-difluorocyclohexane-1-carboxylate in tetrahydrofuran (3 g, 16.85 mmol, 1.0 eq) and stirred -78°C for 1 h. After 1 h, was added iodomethane (9.38 mL, 151.68 mmol, 9.0 eq) at same temperature and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with saturated ammonium chloride solution (75 mL) and extracted with EtOAc (3 x 70 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 10% ethyl acetate in hexanes to give methyl 4,4-difluoro-1-methylcyclohexane-1-carboxylate as light yellow liquid (1.2 g, 37.08% yield). ¹H NMR (400 MHz, CDCl3): į 3.73 (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): To a solution of methyl 4,4-difluoro-1-methylcyclohexane-1-carboxylate (1.2 g, 6.25 mmol, 1.0 eq) in THF (10 mL) was added lithium aluminium hydride (1M in THF, 9.38 mL, 9.375 mmol, 1.5 eq) at 0°C and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with saturated ammonium chloride solution (50 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 20% ethyl acetate in hexanes to give (4,4-difluoro-1- methylcyclohexyl)methanol as colorless liquid (0.9 g, 87.79% yield). 1H NMR (400 MHz, CDCl3): į 3.41 (s, 2H), 2.01-1.81 (m, 4H), 1.63-43 (m, 4H), 0.99 (s, 3H). [0185] Step 3 Synthesis of (4,4-difluoro-1-methylcyclohexyl)methyl methanesulfonate (4): To a solution of (4,4-difluoro-1-methylcyclohexyl)methanol (0.9 g, 5.48 mmol, 1.0 eq) in DCM (5 mL), was added triethylamine (1.54 mL, 10.97 mmol, 2 eq) at 0°C. After 5 min was added methanesulfonyl chloride (0.63 mL, 8.23 mmol, 1.5 eq) at same temperature. The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 50% ethyl acetate in hexanes to give of (4,4- difluoro-1-methylcyclohexyl)methyl methanesulfonate as colorless liquid (0.7 g, 52.71% yield). 1H NMR (400 MHz, CDCl3): į 4.0 (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): To a solution of (4,4-difluoro-1-methylcyclohexyl)methyl methanesulfonate (0.7 g, 2.89 mmol, 1.0 eq) in DMF (5 mL), was added 4-hydroxybenzaldehyde (0.42 g, 3.47 mmol, 1.2 eq) and potassium carbonate (1.19 g, 8.67 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 110°C for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 30 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes to give 4-((4,4- difluoro-1-methylcyclohexyl)methoxy)benzaldehyde as 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: To a solution of 4-((4,4-difluoro- 1-methylcyclohexyl)methoxy)benzaldehyde (0.25 g, 0.93 mmol, 1.0 eq) in methanol (5 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.16 g, 0.93 mmol, 1.0 eq) and ammonium acetate (0.35 g, 4.66 mmol, 5 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 30 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 40% ethyl acetate in hexanes to give 5-(4-chlorophenyl)-2-(4-((4,4- difluoro-1-methylcyclohexyl)methoxy)phenyl)-4-methyl-1H-imidazole as white solid (0.05 g, 12.45% yield). m/z =429.0 [M-H]-, 1H NMR (400 MHz, DMSO) į 12.27 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.71 (s, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.05 (d, J = 8.8 Hz, 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
Figure imgf000063_0001
[0188] Step 1 Synthesis of 4-(2,2,2-trifluoroethoxy) benzaldehyde (3): To a solution of 4- hydroxybenzaldehyde (0.50 g, 4.10 mmol, 1.0 eq) in DMF (5 mL) was added 1,1,1-trifluoro-2- iodoethane (0.86 g, 4.10 mmol, 1.0 eq) and K2CO3 (1.69 g, 12.29 mmol, 3.0 eq) and the reaction mixture was stirred at 80°C for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes to give 4- (2,2,2-trifluoroethoxy) benzaldehyde as 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: To a solution of 4-(2,2,2-trifluoroethoxy) benzaldehyde (0.2 g, 0.98 mmol, 1.0 eq) in methanol (2 mL) was added 1-(4-chlorophenyl)propane-1,2-dione (0.23 g, 1.27 mmol, 1.3 eq) and ammonium acetate (0.38 g, 4.90 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 50% ethyl acetate in hexanes to give 5-(4-chlorophenyl)-4-methyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1H-imidazole as white solid (0.080 g, 22.26% yield). m/z = 368.07 [M+H]+. ¹H NMR (400 MHz, DMSO d6): į 12.08 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 7.8Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 4.77 (q, J = 8.4 Hz, 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 [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 eq) was added 4- hydroxybenzaldehyde (0.36 g, 2.98 mmol, 1.2 eq) in THF (5 mL) and PPh3 (0.98 g, 3.7 mmol, 1.5 eq) at room temperature. The reaction mixture was cooled to 0°C, DIAD (0.75 g, 3.7 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes to give 4-((2- (bromomethyl) benzyl)oxy)benzaldehyde as oil (0.25 g, 32% yield). m/z =306 [M+H]+. [0191] Step 2 Synthesis of 4-((2-(morpholinomethyl)benzyl)oxy)benzaldehyde (5):. To a solution of 4-((2-(bromomethyl)benzyl)oxy)benzaldehyde (0.25 g, 0.81 mmol, 1.0 eq) in morpholine (1 mL) was added at room temperature. The reaction mixture was stirred at 120°C for 3 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted at 20% ethyl acetate in hexanes to give 4-((2- (morpholinomethyl)benzyl)oxy)benzaldehyde as yellow color 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 eq) in methanol (1.8 mL) was added 1-(4- chlorophenyl) propane-1,2-dione (0.12 g, 0.57 mmol, 1.0 eq) and ammonium acetate (0.22 g, 2.89 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted at 20% ethyl acetate in hexanes to give 4-(2-((4-(5-(4-chlorophenyl)-4- methyl-1H-imidazol-2-yl)phenoxy)methyl)benzyl)morpholine as white amorphous solid (0.07 g, 25.55% yield). m/z =475 [M+H]+. 1H NMR (400 MHz, DMSO) į 12.26 (s, 1H), 7.99-7.80 (m, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.50-7.40 (m, 3H), 7.32 – 7.29 (m, 3H), 7.11 (d, J = 8.3 Hz, 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
Figure imgf000065_0001
[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 eq) in THF (20 mL), 1M Lithium aluminum hydride in THF (29.23 mL, 29.23 mmol, 2.5 eq) was added at -20°C and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL), combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes (6-chloropyridin- 2-yl) methanol as 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 eq) in THF (10 mL), was added (6- chloropyridin-2-yl) methanol (1.2 g, 8.19 mmol, 1.0 eq) and triphenyl phosphine (3.22 g, 12.29 mmol, 1.5 eq) at room temperature. The reaction mixture cooled to 0°C, DIAD (2.48 g, 12.29 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL), combined organic layer was dried over sodium sulfate, concentrated under reduced pressure to get the residue, The residue was purified by flash chromatography and product was eluted in 30% ethyl acetate in hexanes to give 4-((6-chloropyridin-2-yl)methoxy)benzaldehyde as colorless oil (0.6 g, 28.98% yield). m/z =248 [M+H]+. [0195] Step 3 Synthesis of tert-butyl (6-((4-formyl phenoxy)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 eq) in dioxane (6 mL), was added tert-butyl methylcarbamate (0.47 g, 3.6 mmol, 1.5 eq) and Cs2CO3 (2.36 g, 7.20 mmol, 3.0 eq) and the reaction mass was degassed using N2. To this, BINAP (0.15 g, 0.24 mmol 0.1 eq) and RuPhosPdG3 (0.10 g, 0.12 mmol, 0.1 eq) were added and the reaction mixture was stirred at 100 °C for 3 h in Microwave. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 80 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted at 35% ethyl acetate in hexanes to give of tert-butyl (6-((4-formylphenoxy) methyl) pyridin-2-yl) (methyl)carbamate as 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) 65yridine-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 eq) in methanol (3 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.17 g, 0.87 mmol, 1.0 eq) and ammonium acetate (0.33 g, 4.38 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the residue. The residue was purified by flash chromatography and product was eluted in 50% ethyl acetate in hexanes to give tert-butyl (6- ((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)phenoxy)methyl)pyridin-2- yl)(methyl)carbamate as 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 eq) in DCM (2 mL), was added 4M HCl in dioxane (0.75 mL) at 0°C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, concentrated under reduced pressure to get the residue. The residue was purified by Prep HPLC to give 6-((4-(5-(4- chlorophenyl)-4-methyl-1H-imidazol-2-yl) phenoxy) methyl)-N-methylpyridin-2-amine as white solid (0.07 g, 58.20% Yield). m/z = 405.2 [M+H]+. 1H NMR (400 MHz, DMSO) į 8.41 (s, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.45-7.37 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.0 Hz, 2H), 6.37 (d, J = 8.0 Hz, 2H), 4.99 (s, 2H), 2.70 (s, 3H), 2.42 (s, 3H). [0198] Analytical HPLC and HPLC/MS methods employed in characterization of the compounds disclosed herein are found in Examples 13-26. [0199] Example 13: LCMS Method C1 Mobile phase (A) 2mM ammonium acetate followed by 0.1%formic acid in water (B) 0.1% formic acid in acetonitrile Instrument : WATERS ACQUITY UPLC H Class with PDA and SQ DETECTOR Column : BEH C18(50*2.1mm)1.7μm Flow rate : 0.550 ml/min Column oven temperature : Ambient Run time : 3.0 min Gradient: : Flow TIME: Rate %A %B (mL/min) 0.01 0.55 98 2 0.30 0.55 98 2 0.60 0.55 50 50 1.10 0.55 25 75 2.00 0.60 0 100 2.70 0.60 0 100 2.71 0.55 98 2 3.00 0.55 98 2 [0200] Example 14: LCMS Method C2 Mobile phase (A) 2mM ammonium acetate followed by 0.1%formic acid in water (B) 0.1% formic acid in acetonitrile Instrument : WATERS ACQUITY UPLC H Class with PDA and SQ DETECTOR Column : WATERS, BEH C18(50*2.1mm)1.7μm Flow rate : 0.550 ml/min Column oven temperature : Ambient Run time : 2.0 min Gradient: : Flow TIME: Rate %A %B (mL/min) 0.00 0.550 95 5 0.60 0.600 30 70 0.80 0.650 10 90 1.10 0.650 0 100 1.70 0.650 0 100 1.71 0.550 95 5 2.00 0.550 95 5 [0201] Example 15: LCMS Method C3 LCMS METHOD METHOD-C3 Mobile phase (A) 2mM ammonium acetate followed by 0.1%formic acid in water (B) 0.1% formic acid in acetonitrile Instrument : WATERS ACQUITY UPLC H Class with PDA and SQ DETECTOR Column : BEH C18(50*2.1mm)1.7μm Flow rate : 0.550 ml/min Column oven temperature : Ambient Run time : 3.0 min Gradient: : TIME: Flow Rate (mL/min) %A %B 0.01 0.55 98 2 0.30 0.55 98 2 0.60 0.55 50 50 1.10 0.55 25 75 2.00 0.60 0 100 2.70 0.60 0 100 2.71 0.55 98 2 3.00 0.55 98 2 [0202] Example 16: LCMS Method F LCMS METHOD Project name : Method F Mobile phase (A) 10 mM ammonium acetate in water (B) 100 % Acetonitrile Instrument : Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector and Diode array Detector Column : YMC Triart C18 (150*4.6mm),5 μm Flow rate : 1.0 ml/min Column oven temperature : Ambient Run time : 12.0 min Gradient: : TIME: Flow Rate (mL/min) %A %B 0.01 1.00 90 10 5.00 1.00 10 90 7.00 1.00 0 100 11.00 1.00 0 100 11.01 1.00 90 10 12.00 1.00 90 10 [0203] Example 17: LCMS Method G1 LCMS METHOD Project name : Method G_1 Mobile phase (A) 0.05% Trifluoroacetic acid in water (B) 0.05% Trifluoroacetic acid in Acetonitrile Instrument : Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector and Diode array Detector Column : YMC Triart C18 (150*4.6mm),5 μm Flow rate : 1.0 ml/min Column oven temperature : Ambient Run time : 12.0 min Gradient: : TIME: Flow Rate (mL/min) %A %B 0.01 1.00 100 0 7.00 1.00 50 50 9.00 1.00 0 100 11.00 1.00 0 100 11.01 1.00 100 0 12.00 1.00 100 0 [0204] Example 18: LCMS Method H Mobile Phase (A) 5mM Ammonium bicarbonate in water (B) 100% Acetonitrile Instrument : Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector and Diode array Detector Column : X-Bridge C18 (50*4.6 mm), 3.5 um or Equivalent Column oven Temp. : Ambient Flow rate : 1.0 ml/min Run time : 10.0 min Gradient: : Flow TIME: Rate (mL/mi %A %B n) 0.01 1.0 95 5 5.00 1.0 10 90 5.80 1.0 5 95 7.20 1.0 5 95 7.21 1.0 95 5 10.00 1.0 95 5 [0205] Example 19: LCMS Method H2 LCMS Method Project name : Method H2 Mobile Phase (A) 5mM Ammonium bicarbonate in water (B) 100% Acetonitrile Instrument : Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector and Diode array Detector Column : X-Bridge C18 (50*4.6 mm), 3.5 um or Equivalent Column oven temp. : Ambient Flow rate : 1.0 ml/min Run time : 8.0 min Gradient: : TIME: Flow Rate (mL/min) %A %B 0.01 1.0 95 5 3.50 1.0 10 90 4.50 1.0 5 95 6.00 1.0 5 95 6.01 1.0 95 5 8.00 1.0 95 5 [0206] Example 20: LCMS Method H3 Mobile Phase (A) 5mM Ammonium bicarbonate in water (B) 100% Acetonitrile Instrument : Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector and Diode array Detector Column : WATERS, X-Bridge C18 (50*4.6 mm), 3.5 um Column oven temp. : Ambient Flow rate : 1.0 ml/min Run time : 6.0 min Gradient: : Flow TIME: Rate (mL/mi %A %B n) 0.01 1.0 95 5 2.80 1.0 15 85 3.50 1.0 5 95 5.00 1.0 5 95 5.01 1.0 95 5 6.00 1.0 95 5 [0207] Example 21: LCMS Method J Mobile phase (A) 2mM ammonium acetate followed by 0.1%formic acid in water (B) 0.1% formic acid in acetonitrile Instrument : WATERS ACQUETY H Class with PDA and SQ DETECTOR Column : BEH C18(50*2.1mm)1.7μm Flow rate : 0.450 ml/min Column oven temperature : Ambient Run time : 8.0 min Gradient: : TIME: Flow Rate (mL/min) %A %B 0.01 0.450 98 2 0.50 0.450 98 2 5.00 0.450 10 90 6.00 0.450 5 95 7.00 0.450 5 95 7.01 0.450 98 2 8.00 0.450 98 2 [0208] Example 22: LCMS Method J2 Mobile phase (A) 2mM ammonium acetate followed by 0.1%formic acid in water (B) 0.1% formic acid in acetonitrile Instrument : Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector and Diode array Detector Column : BEH C18(50*2.1mm)1.7μm Flow rate : 0.450 ml/min Column oven temperature : Ambient Run time : 6.0 min Gradient: : Flow TIME: Rate %A %B (mL/min) 0.01 0.450 98 2 0.50 0.450 98 2 3.00 0.450 30 70 4.00 0.500 5 95 5.50 0.500 5 95 5.51 0.450 98 2 6.00 0.450 98 2 [0209] Example 23: Chiral Prep HPLC Method 1 CHIRAL PREP HPLC METHOD-1 : ^ Instrument : Shimadzu LC-20AP with UV Detector Mobile Phase : (A) 0.1% DEA in Hexane (B) 0.1% DEA in IPA:ACN (70:30) Column : CHIRALPAK IG (250*20)mm, 5u Column Flow : 20 ml/min Isocratic : Line A:B (85:15) UV wavelength : 304 nm [0210] Example 24: Chiral Prep HPLC Method 2 CHIRAL PREP HPLC METHOD-2 : Instrument : Water's PSFC-200 with UV Detector (A) LIQUID.CO2 Mobile Phase : (B) 0.1% DEA IN IPA:ACN(50:50) Column : CHIRALPAK IH (250*21)mm, 5u Column Flow : 80 ml/min Back Pressure : 100 bar Isocratic : Line A:B (80:20) UV wavelength : 275 nm [0211] Example 25: Prep HPLC Method 1 Prep HPLC Method-1 : ATR No. : 692023-581072 (A) 0.1% FA IN WATER Mobile Phase : (B) 100% ACN Column : SUNFIRE C18(250*19)mm,5μ Column Flow : 16 ml/min Gradient : Time (min) % B 0.01 25 20.00 70 20.01 100 22.00 100 22.01 25 27.00 25 [0212] Example 26: Prep HPLC Method 2 Prep HPLC Method-2 : ATR No. : 3062023-507463 Mobile Phase : (A) 5mM ABC+ 0.1% NH3 IN WATER (B) 100% ACN Column : X-BRIDGE C18(250*50)mm,5μ Column Flow : 65 ml/min Time (min) % B 0.01 25 25.00 63 25.01 100 Gradient 27.00 100 27.01 25 32.00 25 [0213] 1H NMR spectra were obtained with Bruker Advance III HD with 5mm PABBO BB/19F-1H/D ZGRD probe spectrometer operating at 400 MHz frequency. Spectra data are reported in the format: chemical shift (multiplicity, coupling constants, and number of hydrogens). Chemical shifts are specified in ppm downfield of a tetramethylsilane internal standard (G units, tetramethylsilane = 0 ppm) and/or referenced to solvent peaks, which in 1H NMR spectra appear at 2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, and 7.24 ppm for CHCl3, and which in 13C NMR spectra appear at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. All 13C NMR spectra were proton decoupled. [0214] Compounds of the present invention were made according to any of synthetic methods A, B, C, as described in Examples 1-12 and LCMS methods as described in Examples 13-26. Spectroscopic data is presented in Table 1. Table 1 Compound LCMS 1H NMR Synthesis Method LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.29 (s, 1H), 7.90 1 375.0 [M+H]+, Ret. Time = (d, J=7.2 Hz, 2H), 7.72 (br s, 2H), 7.50 – 7.36 (m, 7H), 7. A 3.72 min 12 (d, J= 8.4 Hz, 1H), 5.17 (s, 2H), 2.46 (s, 3H) ¹H NMR (400 MHz, DMSO): į 12.32 (s, 1H), 7.90 LCMS Method H3 m/z = (d, J=7.8 Hz, 2H), 7.74 (d, J=7.8 Hz, 2H), 7.60 (d, 2 393.0 [M+H]+, Ret. time = J=6.0 Hz, 1H), 7.46 (d, J=6.0 Hz, 3H), 7.30 – 7.27 B 3.73 min (m, 2H), 7.14 (d, J=8.8 Hz, 2H), 5.20 (s, 2H), 2.47 (s, 3H) LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 12.70 (s, 1H), 7.89 3 393.0 [M+H]+, Ret. time = (s, 2H), 7.71 (s, 2H), 7.44 (d, J= 7.2 Hz, 3H), 7.31 – 7.26 (m, 2H), 7.16 – B 3.72 min 7.03 (m, 3H), 5.19 (s, 2H), 2.45 (s, 3H) LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 12.06 (s, 1H), 7.88 4 351.2 [M+H]+, Ret. time = (d, J=8.4 Hz, 2H), 7.69 (s, 2H), 7.52 (t, J=7.2 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), A 3.68 min 7.22 – 7.15 (m, 2H), 7.09 (d, J=8.4 Hz, 2H), 5.14 (s, 2H), 2.43 (s, 3H) LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 11.99 (s, 1H), 7.79 5 389.0 [M+H]+, Ret. time = (d, J=7.8 Hz, 2H), 7.68 (br s, 2H), 7.44 – 7.33(m, A 3.77 min 6H), 7.28 – 7.26 (m, 1H), 6.98 (d, J=8.4Hz, 2H), 5.55 (q, 1H), 2.42 (s, 3H), 1.57 (d, J=6.4Hz, 3H) LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.02 (s, 1H), 7.80 6 389.0 [M+H]+, Ret. time = (d, J=7.8 Hz, 2H), 7.71 (br s, 2H), 7.43 – 7.36 (m, 3.81 min 6H), 7.29 – 7.27 (m, 1H), 6.98 (d, J=6.4Hz, 2H), A Chiral HPLC =4.83 min 5.54 (q, 1H), 2.42 (s, 3H), 1.60 (d, J=6.4Hz, 3H) LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.03 (s, 1H), 7.80 7 389.0 [M+H]+, Ret. time = (d, J=7.8 Hz, 2H), 7.71 (br s, 2H), 7.43 – 7.35 (m, 3.76 min, Chiral HPLC 6H), 7.28 – 7.26 (m, 1H), 6.99 (d, J=6.4Hz, 2H), A =5.96 min 5.54 (q, 1H), 2.45 (s, 3H), 1.59 (d, J=6.4Hz, 3H) LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 12.03(s, 1H), 8.77 8 404.0 [M+H]+, Ret. time = (s, 1H), 8.1 (s, 1H), 8.01 (s, 1H), 7.88 (s, 2H), 7.72 (br s, 3H), 7.44 (d, J=6.4 Hz, 2H) B 3.32 min , 7.06 (d, J=6.4 Hz, 2H), 5.74 (s, 2H), 2.44 (s, 3H) LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.07 (s, 1H), 7.91 9 454.9 [M+H]+, Ret. time = (d, J=7.8 Hz, 2H), 7.72 (d, J=6.8 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.5 B 3.89 min 3 – 7.43 (m, 4H), 7.10 (d, J=8.0 Hz, 2H), 5.16 (s, 2H), 2.45 (s, 3H) LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 12.01(s, 1H), 7.87 10 412.0 [M+H]+, Ret. time = (d, J= 7.2 Hz, 2H), 7.73 (d, J= 7.2 Hz, 2H), 7.42 (s, 3H B 3.77 min ), 7.29 (s, 1H), 7.16 (s, 2H), 7.01 (d, J=7.8 Hz, 2H), 4.29 (s, 2H), 3.21(s, 2H), 2.46 (s, 3H) LCMS Method J m/z = ¹H NMR (400 MHz, DMSO): į 12.10 (s, 1H), 7.90 11 443.2 [M+H]+, Ret. time = (s, 3H), 7.71 (s, 3H), 7.65 (d, J=8.0 Hz, 1H), 7.44 B 3.94 min (s, 3H), 7.11 (s, 1H), 5.19 (s, 2H), 2.44 (s, 3H) LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.09 (s, 1H), 8.70 12 374.0 [M+H]+, Ret. time = (s, 1H), 8.56 (s, 1H), 7.89 (s, 3H), 7.72 (d, J=6.8 .17 min Hz, 2H), 7.42 (d, J=7. B 3 2 Hz, 3H), 7.13 (d, 8.0 Hz, 2H), 5.22 (s, 2H), 2.46 (s, 3H) LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 12.02(s, 1H), 7.89 13 407.0 [M+H]+, Ret. time = (s, 2H), 7.72 (s, 2H), 7.53 – 7.33 (m, 6H), 7.11 (d, B 3.85 min J=8.0 Hz, 2H), 5.19 (s, 2H), 2.49 (s, 3H) LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.13 (s, 1H), 7.90 14 403.2 [M+H]+, Ret. time = (s, 2H), 7.72 (s, 2H), 7.44 (s, 2H), 7.32 (d, J=8.0Hz, 1H), 7. B 3.69 min 11 (s, 2H), 7.05 (s, 2H), 6.91(s, 1H), 5.15 (s, 2H), 3.80 (s, 3H), 2.44 (s, 3H) LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 12.09 (s, 1H), 15 376.0 [M+H]+, Ret. time = 8.60(s, 2H), 7.91 (s, 2H), 7.71 (s, 2H), 7.44 (s, B 3.17 min 4H), 7.12 (s, 2H), 5.23 (s, 2H), 2.44 (s, 3H) ¹H NMR (400 MHz, DMSO): į 14.29 (s, 1H), 11.82 (s, 1H), 8.05 (d, J=8.4Hz, 2H), 7.84 (d, LCMS Method H3 m/z = J=8.0Hz, 1H), 7.73 (d, J=8.4Hz, 2H), 7.65 (d, 16 442.2 [M+H]+, Ret. time = J=8.0Hz, 2H), 7.57 (t, J=7.8Hz, 1H), 7.44 (d, B 3.13 min J=7.8Hz, 2H), 7.38 (d, J=8.0Hz, 1H), 7.26 (t, J=7.8Hz, 1H), 6.68 (s, 1H), 5.56 (s, 2H), 2.48 (s, 3H) LCMS Method H3 m/z = 17 423.0 [M+H]+, Ret. time = ¹H NMR (400 MHz, DMSO): į 12.06 (s, 1H), 7.88 (d, B 3.97 min J=8.4Hz, 2H), 7.70 (s, 2H), 7.43 (d, J=8.4Hz, 2H), 7.37 (s, 4H), 7.02 (d, J = 8.4 Hz, 2H), 4.28 (t, J = 6.4 Hz, 2H), 3.22 (s, 2H), 2.45 (s, 3H) ¹H NMR (400 MHz, DMSO): į 12.04 (s, 1H), 8.00 LCMS Method H m/z = (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.73 18 347.0 [M+H]+, Ret. time = (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0Hz, 2H), 7.10 B 3.77 min (d, J = 8.4 Hz, 2H), 5.26 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 8.46 (s, 3H), 1.34 (t, J = 6.8 Hz, 3H) ¹H NMR (400 MHz, DMSO): į 12.02 (s, 1H), 7.86 LCMS Method H m/z = (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.2 Hz, 2H), 7.40 19 223.0 [M+H]+, Ret. time = (s, 3H), 7.46 – 7.26 (m, 3H), 7.00 (d, J = 8.8 Hz, B 3.93 min 2H), 4.88 (t, J = 8.4 Hz, 2H), 3.08 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H) ¹H NMR (400 MHz, DMSO): į 12.01 (s, 1H), 7.85 LCMS Method H m/z = (d, J = 7.2 Hz, 2H), 7.72 (d, J = 6.8 Hz, 2H), 7.40 20 389.0 [M+H]+, Ret. time = (d, J = 6.8 Hz, 2H), 7.30 (s, 4H), 7.22 (s, 1H), 7.00 B 3.83 min (d, J = 7.8 Hz, 2H), 4.27 (t, J = 8.8 Hz, 2H), 3.03 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H). LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 12.06 (s, 1H), 7.95 21 400.4 [M+H]+, Ret. time = – 7.85(m, 3H), 7.83- 7.73 (m, 4H), 7.62 (t, J=8.0Hz, 1H), 7.42 (d, J=8.0 H B 3.59 min z, 2H), 7.12 (d, J=8.8Hz, 2H), 5.21(s, 2H), 2.47 (s, 2H). LCMS Method H2 m/z = ¹H NMR (400 MHz, DMSO): į 12.08 (s, 1H), 7.89 22 409.0 [M+H]+, Ret. time = (s, 2H), 7.73 (s, 2H), 7.56 – 7.34 (m, 6H), 7.09 (s, B 3.85 min 2H), 5.17 (s, 2H), 2.46 (s, 3H) LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.04 (s, 1H), 7.89 23 459.0 [M+H]+, Ret. time = (d, J=6.0 Hz, 2H), 7.71 (s, 2H), 7.60 (d, J=8.0Hz, 2H), 7.4 B 3.96 min 2 (s, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.11 (d, J=7.8 Hz, 2H), 5.20 (s, 2H), 2.45 (s, 3H). ¹H NMR (400 MHz, DMSO): į 12.03 (s, 1H), 7.87 LCMS Method H m/z = (d, J=6.0 Hz, 2H), 7.72 (s, 2H), 7.42 (d, J=6.0Hz, 24 389.0 [M+H]+, Ret. time = 2H), 7.26 (s, 3H), 7.13 (d, J=6.8 Hz, 1H), 7.09 (d, B 3.85 min J=8.4 Hz, 2H), 5.12 (s, 2H), 2.48 (s, 3H), 2.34 (s, 3H). LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.07 (s, 1H), 7.92 25 389.0 [M+H]+, Ret. time = (d, J=7.2 Hz, 2H), 7.72 (s, 2H), 7.46 (d, J=6.0Hz, 3H), 7.27 B 3.83 min (s, d, J=8.0 Hz, 3H), 7.14 (d, J=6.8 Hz, 2H), 5.17 (s, 2H), 2.46 (s, 3H), 2.39 (s, 3H). ¹H NMR (400 MHz, DMSO): į 12.07 (s, 1H), 7.86 LCMS Method H m/z = (d, J=8.8 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.40 (d, 26 389.0 [M+H]+, Ret. time = J=8.8 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 7.20 (d, J= B 3.95 min 8.0 Hz, 2H), 7.07 (d, J= 8.4 Hz, 2H), 5.11 (s, 2H), 2.46 (s, 3H), 2.32 (s, 3H). ¹H NMR (400 MHz, DMSO): į 12.03 (s, 1H), 8.58 LCMS Method J m/z = (d, J=4.0 Hz, 1H), 7.89 (d, J=7.2 Hz, 2H), 7.83 (t, 27 376.3 [M+H]+, Ret. time = J=6.8 Hz, 1H), 7.70 (d, J= 6.8 Hz, 2H), 7.53 (d, J= 7.8 Hz, 1H), 7.42 (d, J= 7.8 Hz, 2H), 7.3 B 2.97 min 4 (t, J= 6.8 Hz, 1H), 7.11 (d, J= 7.2 Hz, 2H), 5.23 (s, 2H), 2.43 (s, 3H) LCMS Method J m/z = ¹H NMR (400 MHz, DMSO): į 12.22 (s, 1H), 7.88 28 383.2 [M+H]+, Ret. time = (d, J=8.0Hz, 2H), 7.72 (d, J=7.8Hz, 2H), 7.42 (d, J=8.0Hz, 2H), 7.12 (d, J=8.0 B 2.97 min Hz, 2H), 5.28 (s, 2H), 2.62 (s, 3H), 2.46 (s, 3H). ¹H NMR (400 MHz, DMSO): į 12.03 (s, 1H), 7.87 LCMS Method H m/z = (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.43 (d, 30 357.2 [M+H]+, Ret. time = J=8.0 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 4.16 (t, B 3.03 min J=5.6 Hz, 2H), 3.60 (t, J=4.4 Hz, 4H), 3.10 (t, J=4.8 Hz, 4H), 2.74 (t, J=5.6 Hz, 2H), 2.46 (s, 3H) LCMS Method H3 m/z = ¹H NMR (400 MHz, DMSO): į 12.06 (s, 1H), 7.88 31 394.4 [M+H]+, Ret. time = (d, J=8.0Hz, 2H), 7.74 (d, J=8.0Hz, 2H), 7.42 (d, J=8.0Hz, 2 B 3.32 min H), 7.09 (d, J=8.0Hz, 2H), 4.98 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 2.24 (s, 3H) ¹H NMR (400 MHz, DMSO): į 12.32 (s, 1H), 7.87 LCMS Method H3 m/z = (d, J=8.4 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H), 7.67 (s, 33 379.4 [M+H]+, Ret. time = 2H), 7.45 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4Hz, C 3.10 min 1H), 6.32 (s, 1H), 5.04 (s, 2H), 3.83 (s, 3H), 2.32 (s, 3H). LCMS Method J2 m/z = ¹H NMR (400 MHz, DMSO): į 12.07(s, 1H), 7.87 34 379.3 [M+H]+, Ret. time = (d, J=6.8Hz, 2H), 7.73 (s, 3H), 7.47 (s, 1H), 7.42 (s, 2H), 7.05(d, J=8.4 Hz C 2.90 min , 2H), 5.01(s, 2H), 3.86 (s, 3H), 2.45 (s, 3H) ¹H NMR (400 MHz, DMSO): į 12.03 (s, 1H), 7.88 LCMS Method H m/z = (s, 2H), 7.72 (s, 2H), 7.42 (s, 2H), 7.0 (d, J=8.4 36 417.0 [M+H]+, Ret. time = Hz, 2H), 3.93 (d, J=5.6 Hz, 2H), 2.45 (s, 3H), 2.05 C 3.79 min (s, 2H), 1.19 (t, d=5.2 Hz, 4H), 1.81 (s, 1H), 1.41- 1.38 (m, 2H) LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.08 (s, 1H), 7.91 37 381.2 [M+H]+, Ret. time = (s, d= 8.4 Hz, 2H), 7.84 (s, 2H), 7.72 (s, 2H), 7.43 (s, d A 3.30 min =7.8 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 5.49 (s, 2H), 2.44 (s, 3H) ¹H NMR (400 MHz, DMSO): į 12.28 (s, 1H), 7.86 LCMS Method J2 m/z = (s, 2H), 7.72 (s, 2H), 7.43 (s, 2H), 7.0 (d, J=6.0 38 396.4 [M+H]+, Ret. time = Hz, 2H), 3.90-3.86 (m, 2H), 2.88 (s, 1H), 2.70 (s, 1H), 2.44 (s, 3H), 2.21 (s, 3H), 2.01 (s, 1H), 1 C 2.55 min .90 (s, 1H), 1.74 – 1.65 (m, 2H), 1.52 (s, 1H), 1.24 (s, 1H), 1.10 (s, 1H) LCMS Method H m/z = ¹H NMR (400 MHz, DMSO): į 12.05 (s, 1H), 7.88 40 481.2 [M+H]+, Ret. time = (d, J=7.2 Hz, 2H), 7.71 (br s, 2H), 7.47 – 7.43 (m, 5H), 7.38 – 7.30 (m, 4H), 7.15 - 6.97 (m A 4.02 min , 4H), 5.21(s, 2H), 5.19 (s, 2H), 2.44 (s, 3H) 1 LCMS Method H m/z = H NMR (400 MHz, DMSO) į 12.09 (s, 1H), 8.77 41 391.2 [M+H]+, Ret. time = (s, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.69 (s, 2H), 7.42 (d, J = 8.0 H C 2.99 min z, 2H), 7.12 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H), 2.63 (s, 3H), 2.43 (s, 3H). 1H NMR (400 MHz, DMSO) į 12.26 (s, 1H), 7.84 LCMS Method-H (d, J = 8.0 Hz, 2H), 7.70 (s, 2H), 7.44 (d, J = 8.1 43 m/z=455.2 [M+H]+, Hz, 2H), 7.35 – 7.25 (m, 4H), 7.23 – 7.18 (m, 2H), C Ret.Time =4.315 min 7.08 – 7.01 (m, 2H), 6.95 (s, 1H), 5.28 (s, 2H), 5.16 (s, 2H), 2.44 (s, 3H). 1H NMR (400 MHz, DMSO) į 11.99 (s, 1H), 7.82 LCMS Method-H (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.9 Hz, 2H), 7.68 44 m/z=457.2 [M+H]+, (s, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.2 Example Ret.Time =3.999 min Hz, 2H), 7.06 – 6.99 (m, 2H), 2.41 (s, 3H), 1.60 (d, 12 J = 6.4 Hz, 3H). 1 LCMS Method-J2 H NMR (400 MHz, DMSO) į 12.21 (s, 1H), 7.90 48 m/z=407.4 [M+H]+, (d, J = 8.2 Hz, 2H), 7.66 (s, 2H), 7.49 - 7.42 (m, Ret.Time =3.609 min 3H), 7.32 – 7.29 (m, 2H), 7.20 – 7.10 (m, 3H), 5.18 (s, 2H), 2.80 (s, 2H), 1.25 (t, J = 7.4 Hz, 3H). 1 LCMS Method-J2 H NMR (400 MHz, DMSO) į 12.07 (s, 1H), 8.10 49 m/z=410.3 [M+H]+, – 7.78 (m, 4H), 7.73 (d, J = 8.0 Hz, 2H), 7.53 (d, J Example Ret.Time =3.436 min = 7.2 Hz, 1H), 7.46 – 7.39 (m, 3H), 7.15 – 7.11 72 (m, 2H), 5.22 (s, 2H), 2.46 (s, 3H). 1H NMR (400 MHz, DMSO) į 12.30 (s, 1H), 7.79 LCMS Method-J m/z=407.4 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.47 50 [M+H]+, Ret. Time =3.661 – 7.35 (m, 3H), 7.31 – 7.22 (m, 2H), 7.14 – 7.04 Example min (m, 1H), 7.04 – 6.97 (m, 2H), 5.59 (d, J = 6.4 Hz, 72 2H), 2.46 (s, 3H), 1.57 (d, J = 6.3 Hz, 3H). 1H NMR (400 MHz, DMSO) į 12.26 (s, 1H), 7.79 LCMS Method-J m/z=407.4 (d, J = 8.5 Hz, 3H), 7.67 (d, J = 8.1 Hz, 2H), 7.47 51 [M+H]+, Ret. Time =3.645 – 7.35 (m, 3H), 7.31 – 7.22 (m, 2H), 7.14 – 7.04 Example min (m, 2H), 7.04 – 6.97 (m, 1H), 5.59 (d, J = 6.4 Hz, 72 2H), 2.46 (s, 3H), 1.57 (d, J = 6.3 Hz, 3H). 1H NMR (400 MHz, DMSO) į 11.91 (s, 1H), 7.69 LCMS Method-J m/z=416.2 (d, J = 7.8 Hz, 4H), 7.43 (d, J = 8.2 Hz, 2H), 6.62 52 [M+H]+, Ret. Time =3.860 (d, J = 8.3 Hz, 2H), 5.97 (s, 1H), 2.96 (s, 2H), 2.40 Example 5 min (s, 3H), 2.01 (s, 2H), 1.86 - 1.70 (m, 4H), 1.22 (d, J = 13.1 Hz, 3H). 1 LCMS Method-G1 H NMR (400 MHz, DMSO) į 11.98 (s, 1H), 8.53 53 m/z=475.2 [M+H]+, (d, J = 5.0, 1H), 7.76-7.72 (m, 5H), 7.42–7.34 (m, Ret.Time =7.829 min 3H), 7.27 – 7.24 (m, 1H), 6.64 – 6.58 (m, 3H), 4.40 (d, J = 6.1 Hz, 2H), 2.41 (s, 3H). 1 LCMS Method-J2 m/z=378 H NMR (400 MHz, DMSO) į 14.03 (s, 1H), 7.78 54 [M+H]+, Ret.Time =3.382 (d, J = 8.6 Hz, 2H), 7.69 – 7.60 (m, 5H), 6.82 (d, J min = 8.6 Hz, 3H), 6.15 (s, 1H), 4.27 (s, 2H), 3.79 (s, 3H), 2.42 (s, 3H). 1H NMR (400 MHz, DMSO) į 11.99 (s, 1H), 7.71- LCMS Method-J2 m/z=408 7.63 (m, 4H), 7.57 (s, 1H), 7.42 – 7.40 (m, 2H), 55 [M+H]+, Ret.Time =4.056 7.37-7.35 (m, 2H), 7.30 (s, 1H), 6.63 (d, J = 7.2 min Hz, 2H), 6.57(s, 1H), 4.33 (d, J = 6.2 Hz, 2H), 2.42 (s, 3H). 1H NMR (400 MHz, DMSO) į 11.97 (s, 1H), 7.63 LCMS Method-G1 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.27 56 m/z=406 [M+H]+, (d, J = 8.1 Hz, 2H), 7.36 – 7.30 (m, 1H), 7.25 – Ret.Time =7.657 min 7.18 (m, 2H), 7.02 – 6.98 (m, 1H), 6.55 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 8.8 Hz, 1H), 4.58 (t, J = 6.9 Hz, 1H), 2.45 (s, 3H), 2.38-1.90 (m, 3H). 1H NMR (400 MHz, DMSO) į 11.94 (s, 1H), 7.64 LCMS Method-H1 (s, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.42 - 7.32 (m, 57 m/z=406.2 [M+H]+, 3H), 7.25 - 7.18 (m, 2H), 7.02 – 6.98 (m, 1H), 6.59 Ret.Time =3.618 min – 6.45 (m, 3H), 4.58 (t, J = 6.8 Hz, 1H), 2.38 (s, 3H), 1.41 (d, J = 6.7 Hz, 3H). 1H NMR (400 MHz, DMSO) į 11.91 (s, 1H), 7.68 LCMS Method-J2 – 7.48 (m, 4H), 7.48 - 7.36 (m, 4H), 7.29 (t, J = 58 m/z=402.2 [M+H]+, 7.5 Hz, 2H), 7.20 – 7.17 (m, 1H), 6.56 (d, J = 8.8Hz, 2 Example 5 Ret.Time =3.434 min H), 6.40 (d, J = 7.6 Hz, 1H), 4.33 - 4.25 (m, 1H), 2.40 (s, 3H), 1.86-1.65 (m, 2H), 1.25 (s, 1H), 0.93-0.83 (m, 3H). 1H NMR (400 MHz, DMSO) į 11.91 (s, 1H), 7.66- LCMS Method-J2 7.54 (m, 4H), 7.51-7.36 (m, 4H), 7.29 (t, J = 7.2 59 m/z=402.1 [M+H]+, Hz, 2H), 7.19 – 7.16 (m, 1H), 6.57 (d, J = 8.5 Hz, 2H), 6.40 (d, J = 7.5 Hz, 1H), 4.31-4.25 Example 5 Ret.Time =3.435 min (m, 1H), 2.39 (s, 3H), 1.82-1.67(m, 2H), 1.24 (s, 1H), 0.93- 0.85 (m, 3H). LCMS Method-J m/z=361.2 1H NMR (400 MHz, DMSO) į 12.37 (s, 1H), 8.97 60 [M+H]+, Ret.Time =3.710 (s, 2H), 7.73 (s, 2H), 7.42 (s, 4H), 7.17 – 7.08 (m, Example min 5H), 2.49 (s, 3H). 12 LCMS Method-J m/z=379.2 1H NMR (400 MHz, DMSO) į 12.36 (s, 1H), 7.95 61 [M+H]+, Ret.Time =3.761 (d, J = 8.1 Hz, 2H), 7.71 (s, 2H), 7.43 (s, 3H), 7.25 Example min (s, 3H), 7.05 (d, J = 8 Hz, 2H), 2.45 (s, 3H). 12 LCMS Method -J m/z 1H NMR (400 MHz, DMSO) į 12.44 (s, 1H), 7.99 62 =379.2 [M+H]+, Ret. Time (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.43 Example = 3.873 min (d, J = 8.0 Hz, 3H), 7.15 (d, J = 8.0 Hz, 2H), 7.00 - 12 6.88 (m, 3H), 2.49 (s, 3H). LCMS Method J m/z= 1 63 379.2 [M+H]+, Ret. Time H NMR (400 MHz, DMSO) į 12.39 (s, 1H), 7.99- Example =3.853 min 7.92 (m, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 12 8.0 Hz, 2H), 7.26 (s, 2H), 7.13 (s, 2H), 7.05(d, J = 8.0 Hz, 2H), 2.48 (s, 3H). 1H NMR (400 MHz, DMSO) į 14.16 (s, 1H), 8.14 LCMS Method-J m/z=378.2 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.4 64 [M+H]+, Ret.Time =3.710 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.39 - 7.27 (m, Example 5 min 1H), 7.32 - 7.15 (m, 3H), 7.09 - 7.05 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 4.42 (s, 2H). 1H NMR (400 MHz, DMSO) į 11.98 (s, 1H), 7.79 - 7.59 (m, 4H), 7.42 (s, 2H), 7.29 (d, J = 4.4 Hz, LCMS Method H3 4H), 7.24 - 7.20 (m, 1H), 6.58 (d, J = 8.5 Hz, 2H), 65 m/z=443.3[M+H]+, Ret. 6.00 (d, J = 6.8 Hz, 1H), 3.92 (s, 1H), 3.63 - 3.53 Time =2.980 min (m, 2H), 2.80 (t, J = 9.3 Hz, 1H), 2.60 (t, J = 5.4 Hz, 1H), 2.49 - 2.32 (m, 5H), 2.30 - 2.18 (m, 1H), 1.64 - 1.57 (m, 1H). LCMS Method-H m/z=429 1H NMR (400 MHz, DMSO) į 12.47 (s, 1H), 8.10 66 [M+H]+, Ret.Time =3.964 – 8.0 (m, 2H), 7.78 – 7.73 (m, 4H), 7.55 – 7.44 (m, min 2H), 7.24 - 7.22 (m, 4H), 2.48 (s, 3H). 1 LCMS Method H m/z = H NMR (400 MHz, DMSO) į 12.91 (s, 1H), 12.41 (s, 1H), 7.96 (d, J = 8 7 4 + .4 Hz, 2H), 7.80 – 7.72 6 27.2 [M+H] , Ret. Time = 3.362 min (m, 3H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 – 7.43 (m, Example 8 4H), 7.12 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 2.46 (s, 3H). 1H NMR (400 MHz, DMSO): į 12.26 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.46 68 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.0 C (d, J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.37 (s, 1H), 2.10 (s, 1H), 1.76 – 1.53 (m, 8H). 1H NMR (400 MHz, DMSO): į 12.27 (s, 1H), 7.86 LCMS Method J m/z = (d, J = 8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.42 (d, 69 463.0 [M+H]+, Ret. Time = J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 3.86 (s, 4.147 min 2H), 2.45 (s, 3H), 2.26-2.23 (m, 1H), 1.83 (d, J = Example 9 13.2 Hz, 2H), 1.70 (d, J = 10.8 Hz, 2H), 1.50-1.39 (m, 2H), 1.33-1.22 (m, 3H), 1.01 (s, 3H). 1 LCMS Method-J2 m/z=406 H NMR (400 MHz, DMSO) į 11.87 (s, 1H), 7.77 75 [M+H]+, Ret.Time =3.776 (d, J = 8.2 Hz, 2H), 7.70 (s, 2H), 7.43 – 7.35 (m, min 3H), 7.11 - 7.02(m, 3H), 6.80 (d, J = 8.4 Hz, 2H), 4.64 (s, 2H), 3.07 (s, 3H), 2.43 (s, 3H). 1H NMR (400 MHz, DMSO) į 14.14 (s, 1H), LCMS Method J2 m/z 10.42 (s, 1H), 7.92 (s, 2H), 7.71 – 7.63 (m, 4H), 76 =458.2 [M+H]+, Ret. Time 7.57 - 7.48 (m, 4H), 7.12 - 6.90 (m, 3H), 5.08 (s, 1 Example 5 =3.476 H), 4.78 (s, 1H), 4.42 (s, 2H), 3.32 - 3.21 (m, 4H), 2.96 - 2.85 (m, 3H), 2.44 (s, 3H), 2.33 (s, 1H), 2.25 (s, 1H). 1H NMR (400 MHz, DMSO) į 11.82 (s, 1H), 7.70 LCMS Method-J2 (d, J = 8.2 Hz, 2H), 7.58 (s, 1H), 7.46 – 7.33 (m, 77 m/z=428.2 [M+H]+, 3H), 7.32 – 7.15 (m, 2H), 7.07 (t, J = 8.4 Hz, 1H), Example 5 Ret.Time =3.613 min 6.90 (s, 1H), 6.53 - 6.48 (m, 1H), 4.40 (d, J = 6.3 Hz, 2H), 2.42 (s, 3H). 1H NMR (400 MHz, DMSO) į 11.70 (s, 1H), 7.68 LCMS Method-J2 (s, 3H), 7.43 - 7.36 (m, 3H), 7.22 - 7.16 (m, 2H), 78 m/z=410.1 [M+H]+, 7.07 (t, J = 2.8 Hz, 1H), 6.89 (t, J = 6.4 Hz, 1H), Example 5 Ret.Time =3.320 min 6.52 (d, J = 8.7 Hz, 1H), 6.41 (d, J = 14.2 Hz, 1H), 4.36 (d, J = 6.4 Hz, 2H), 2.42 (s, 3H). 1H NMR (400 MHz, DMSO) į 12.27 (s, 1H), 7.87 LCMS Method-J2 (d, J = 8.0 Hz, 2H), 7.71 (s, 2H), 7.51 (t, J = 7.9 79 m/z=419.2 [M+H]+, Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.4 Example Ret.Time =3.272 min Hz, 2H), 6.67 (d, J = 7.2 Hz, 2H), 6.57 (d, J = 8.5 11 Hz, 1H), 5.04 (s, 2H), 3.02 (s, 6H), 2.44 (s, 3H). 1H NMR (400 MHz, DMSO) į 12.16 (s, 1H), 7.87 LCMS Method-J2 (s, 1H), 7.68-7.60 (m, 3H), 7.44-7.35 (m, 3H), 80 m/z=427.2 [M+H]+, 7.22.7.15 (m, 2H), 7.05 (s, 1H), 6.63 (d, J = 6.5 Example 5 Ret.Time =3.948 min Hz, 1H), 6.46 (s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 2.40 (s, 3H). Biological Activity Assays [0215] Compounds of the present disclosure were tested in several biological assays and their results were compared against the results for compound A (see USP 11,090,189 the disclosure of which is incorporated by reference in its entirety), a known inhibitor of NaV1.6, the structure of which is as follows: . Example 27: NaV Inhibition [0216] Cell Culture: CHO cells expressing either human NaV1.6, human NaV1.5 or human NaV1.2 cells are incubated at 37°C in a humidified atmosphere with 5% CO2 (rel. humidity > 95%). The 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 ^g/mL Hygromycin. The cells are maintained to a confluence of about 80% before being passaged. [0217] Electrophysiology assays: Data is collected using the Qube 384 (Sophion) automated voltage-clamp platform using either single hole or multi hole plates. Compounds were assessed against human NaV1.6, human NaV1.5 and human NaV1.2 using a half-inactivating voltage protocol. In addition, compounds were also assessed against human NaV1.6 where the membrane potential is maintained at a voltage where inactivation is complete. For the half- inactivating protocol, inward currents are evoked with a 20 ms step to -10 mV from a membrane potential of -120 mV, followed by 3 seconds at the half-inactivating voltage (previously determined using the adaptive protocol feature of the Qube 384), then a -10 mV voltage step for 20 ms is applied to determine inward current inactivation. Each cell is exposed to the vehicle (0.3% DMSO) for 5 minutes to allow the inward current to stabilise. Following this period, compounds are applied as single concentration per well for 10 minutes. The protocol described above is applied throughout the experiment with an Inter sweep interval of 30 seconds. For the complete inactivation protocol, the membrane potential is maintained at -45 mV. Every 25 seconds (0.04 Hz) a 60 ms repolarization step to -150 mV is applied, followed by a test pulse to 0 mV for 10 ms to evoke inward current. This voltage protocol is applied throughout the experiment. All wells are exposed to the vehicle (0.3% DMSO) for 20 minutes to allow the inward current to stabilise. Compounds were then applied at a single concentration for 20 minutes. [0218] Recording solutions: Intracellular solution: 15 mM NaCl, 120 mM CsF, 10 mM HEPES (4-(2-hydroxyethyl)–1-piperazineethanesulfonic acid buffer), 10 mM EGTA (ethylene glycol tetraacetic acid); adjusted to pH 7.2 with CsOH. Extracellular solution: 140 mM NaCl, 5 mM KCl, 3 mM CaCl2, 1.2 mM MgCl2, 5 mM HEPES 11.1 Glucose; adjusted to pH 7.4 with NaOH. The ICS and ECS osmolarities were adjusted with sucrose to 300 mOsm/kg and 310 mOsm/kg, respectively. [0219] Results are shown in Table 2. Table 2 Compound NaV1.2 IC50 (μM) NaV1.5 IC50 (μM) NaV1.6 IC50 (μM) Ratio 1.5/1.6 A ** ** ** + 1 ** ** ** + 2 ** * * - 3 * * ** + 4 * * * - 5 * * 6 * * * - 7 * * ** + 8 * * * - 9 * * * - 10 * * ** + 11 * * * - 12 * * * - 13 * * ** + 14 ** * ** + 15 * * * - 16 * * * - 17 ** * * + 18 ** * ** + 19 ** * ** + 20 ** * ** + 21 ** * * + 22 ** * * - 23 ** * ** + 24 ** * ** + 25 ** * * + 26 ** * * - 27 * * * + 28 ** * ** + 29 NT NT NT NT 30 ** * ** + 31 * * * + 32 NT NT NT NT 33 ** * ** + 34 * * * - 35 NT NT NT NT 36 ** * ** + 37 * * * + 38 * * * + 39 * * * + 40 * * * + 41 * * * - 42 ** * ** + 43 ** * * + 44 ** * ** + 45 ** * ** + 46 * * * - 47 * * * + 48 ** * ** + 49 ** * ** + 50 ** * * + 51 ** * ** + 52 ** * ** + 53 ** * ** + 54 ** * * + 55 ** * ** + 56 ** * * + 57 * ** * + 58 ** * ** + 59 ** * ** + 60 ** * ** + 61 ** * ** + 62 ** * ** + 63 ** * ** + 64 ** * * + 65 ** * ** + 66 ** * * + 67 * * * + 68 * * * - 69 * * * - 70 * * * - 71 * * * - 72 ** * * - 73 ** * ** + 74 ** * * + 75 ** * ** + 76 NT NT NT NT 77 ** * * + 78 NT NT NT NT 79 ** * ** + 80 ** * * + ** = 0-8 μM * = greater than 8 μM + = greater than 1 - = less than or equal to 1 NT = not tested Example 28: Audiogenic Testing [0220] N1768D SCN8A mice (6-12 weeks old) we administered compounds via intraperitoneal (i.p) injection. Mice were tested for audiogenic seizures 1 hour after drug administration. [0221] Audiogenic seizure measurement: Mice were be tested for audiogenic seizures using a 10 second, 15 kHz pure tone (~80 to 100 dB), generated using Tone Generator software (NCH Software, Inc.), amplified with a Kinter K3118 stereo amplifier (Kinter USA), and converted to sound using a small 3-watt speaker lowered into the recording chamber. Mice were observed for 60 seconds and the occurrence of a behavioral seizure was be assessed visually by the experimenter and also recorded using a laptop webcam. Time to seizure onset and recovery from seizure was noted. [0222] N1768D SCN8A mice (> 8 weeks of age) were euthanized with isoflurane, decapitated and brains rapidly removed and placed in ice-cold (~0 ºC) artificial cerebrospinal fluid (ACSF) containing in mM: 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 2 CaCl2, 1 MgCl2, 0.5 L- ascorbic acid, 10 glucose, 25 NaHCO3, and 2 sodium pyruvate (osmolarity 300-312 mOsm), and oxygenated with 95% O2 and 5% CO2. Horizontal slices (300 μm thickness) were cut using a vibratome in an ice-chilled chamber, incubated in oxygenated ACSF heated to 37 ºC for ~30 min and then stored at room temperature. For recordings, slices were held in a small chamber and superfused with oxygenated ACSF (~28 ºC) at a rate of 1-2 mL/min. Layer 4 somatosensory pyramidal neurons were visually identified with 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) and were fire-polished and tested to have resistances of 2-3.5 M^ when filled with an intracellular solution containing (in mM): 120 K-gluconate, 10 NaCl, 2 MgCl2, 0.5 K2EGTA, 10 HEPES, 4 Na2ATP, 0.3 NaGTP, and pH was 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 evoked using a series of current injection steps from - 20 pA to 400 pA in 10 pA steps with a 3 second interpulse interval. In order to measure intrinsic membrane and AP properties, a ramp of depolarizing current (0-400 pA) was injected into neurons over a 4 second time period. Recordings were made before, after 10 mins of administration at test concentrations and after 10 mins of washout. The frequency of APs was recorded before and after drug application. [0224] Results are shown in Table 3. Table 3 Seizure Mouse D/+MARS onset (10 sec max) / recovery time 30 mpk IP (1h post dose) (50 sec max) Compound Protection Seizure % Onset Recovery Protection (sec) (sec) A 4 2 67 3.5 39 1 4 1 80 4.0 42.0 2 0 7 0 4.8 20.2 3 5 1 83 3.0 19.0 4 2 4 33 4.0 48.2 5 2 4 33 4.5 23.3 6 1 4 20 4.3 33.3 7 4 1 80 4.0 18.0 8 0 6 0 2.2 24.5 9 0 6 0 3.4 35.8 10 2 4 33 3.0 34.8 11 0 6 0 3.7 27.6 12 3 3 50 4.0 30.3 13 6 2 60 6.5 33.5 14 2 3 40 5.3 24.7 15 0 5 0 3.4 43.0 16 0 6 0 3.3 25.7 17 1 5 17 4.2 41.0 18 2 3 40 2.7 30.0 19 0 6 0 2.3 28.7 20 2 3 40 5.0 19.6 21 3 2 60 5.0 34.0 22 1 6 14 3.8 25.2 23 0 5 0 2.6 25.4 24 1 5 17 3.8 28.2 25 0 6 0 2.7 28.5 26 0 6 0 2.8 26.8 27 3 2 60 5.0 35.0 28 2 3 40 5.7 27.0 30 0 5 0 3.2 30.2 31 1 4 20 4.3 34.8 33 3 2 60 3.0 24.0 34 0 5 0 3.2 30.6 34 (50 mpk) 2 3 40 3.7 28.3 35 36 3 2 60 5.5 41.0 37 1 3 25 4.7 25.0 38 0 5 0 3.0 30.6 39 1 5 0 2.5 26.3 40 0 5 0 3.8 24.0 41 1 4 20 2.5 26.3 44 1 4 20 3.8 20.8 Example 29: Microsomal Stability Testing [0225] Metabolic Stability in Liver Microsomes (HLM/MLM) - A 10 mM stock solution (in DMSO) was prepared for the compound. From the intermediate stock solution of 2 mM, a working solution of 0.5 mM was prepared by diluting the compound in acetonitrile:water (50:50). The compound (1.8 μL of working solution) was spiked in 0.1 M potassium phosphate buffer (260.7 μL), pH 7.4 at a concentration of 3 μM (0.15% DMSO). Following this, human/mouse liver microsomes (7.5 μL; final protein conc. 0.5 mg/mL) were added. The aforementioned microsomes and buffer was pre incubated at 37°C. Subsequently, 30 μL of 10 mM NADPH prepared in 0.1 M potassium phosphate buffer was added (as a co-factor) to initiate the reaction.The samples were then incubated at 37°C for desired time points. At each time point (0, 5, 15, 30 and 60 min), 40 μL of the samples were withdrawn and reactions were stopped using 360 μL chilled acetonitrile or methanol containing suitable internal standard (Carbamazepine). The samples were centrifuged and the supernatants was analyzed in duplicate by LC-MS/MS. The percent compound remaining at each time point was calculated with respect to that of the 0 min sample. The data were then analyzed in duplicate to calculate half-life and intrinsic clearance (CLint). Note that control samples were run without NADPH for initial and final time point and blank samples was prepared using DMSO (without the test compound). [0226] Mouse (C57) Brain Tissue Binding - Equilibrium Dialysis Method: A 10 mM stock of compound was prepared in DMSO. From the stock solution, a working solution of 1.25 mM was prepared in DMSO and further spike working solution in to brain homogenate ( Accuprec; C57 mice) master mix to achieve 5 μM concentration. The Brain homogenate-compound mixture was mixed and subsequently 25 μL aliquot from this mixture was added in 25 μL of DPBS (pH 7.4) for T=0 hour reaction. This reaction was terminated immediately with 300 μL of acetonitrile: water (90:10) containing internal standard and samples were stored at 4°C for 4 hours. To initiate the reaction, the RED device was placed onto the base plate following which 100 μL of the Brain homogenate-compound mixture was added in the chamber of the RED device which is encircled by a red ring (Red Chamber). In the other chamber (white chamber) 350 μL of buffer DPBS (pH 7.4) was added and sealed (with a sealer) to avoid any evaporation or spilling of the samples from the chamber. The base plate was then put on an orbital shaker at 400 rpm for 4 hours at 37°C. After this incubation period, the base plate was taken out and subsequently, 25 μL of post dialysis samples from the both chambers were collected in deep well plate. Following this, 25 μL of pertinent brain homogenate was added to the collected buffer sample from the white chamber and 25μL of buffer was added to the collected brain homogenate from the red chamber. The reaction were terminated with 300 μL of acetonitrile: water (90:10) containing internal standard in order to precipitate the protein and to release the compound. The resulting samples from T=0 hour as well as T=4 hour were mixed and kept for vortexing for 5 mins. The samples were then kept in ice for 30 mins to further aid the precipitation of the compound. The samples were taken out and centrifuged at 4000 rpm for 20 minutes. Supernatants from all the samples were collected in vials and analyzed in duplicates using LCMS/MS. The concentration of test compound was determined in the buffer and Brain homogenate Chamber from the peak areas obtained (LCMS/MS analysis). The fraction unbound in brain homogenate for test compound is calculated based on the following formula: Fu(Fraction unbound) = 1-(Concentration of Brain homogenate containing chamber- Concentration of Buffer chamber/Concentration of Brain homogenate containing chamber) % Recovery = {(V dialysate x C free + V brain homogenate x C total) / (V brain homogenate x C zero)} x 100% Whereas, V dialysate= Volume of buffer chamber C free = Concentration in the buffer chamber post dialysis V brain homogenate = Volume in brain homogenate chamber C total= Concentration in brain homogenate chamber post dialysis C zero= Initial concentration at T=0 min Fraction unbound (Fu) brain = 1/(1+((1/fraction unbound brain homogenate)-1)*3) Note- 3 is the dilution factor for brain homogenate. [0227] Results are shown in Table 4 Table 4 Mouse Protein Human Liver Mouse Liver Binding Microsomes (HLM) Microsomes (MLM) In vitro In vitro Compound Plasma Brain Half Life Intrinsic Half Life Intrinsic Clearance Clearance CLint CLi % Bound % Bound T1/2 (min) (μl T1/2 nt /min/mg (μl/min/mg protein) (min) protein) A 99.50 99.50 30.35 45.67 3.22 431.10 1 99.98 100.00 2 100.00 100.00 3 99.99 100.00 192.60 7.20 68.98 20.09 4 99.95 100.00 7 179.90 7.70 33.19 41.76 10 99.99 69.85 19.84 16.02 86.52 12 99.9 63.21 21.93 35.82 38.69 13 99.94 2150.00 0.64 83.82 16.54

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I):
Figure imgf000088_0001
wherein: A is selected from -O-, -NH-, or -S(O)2NH-; L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof.
2. A compound of Formula (II):
Figure imgf000088_0002
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof.
3. A compound of Formula (III):
Figure imgf000089_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof.
4. A compound of Formula (IV):
Figure imgf000090_0002
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof.
5. A compound of Formula (V):
Figure imgf000090_0001
wherein: A is selected from -O-, -NH-, or -S(O)2NH-; L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof.
6. A compound of Formula (VI):
Figure imgf000091_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof.
7. A compound of Formula (VII):
Figure imgf000092_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof.
8. A compound of Formula (VIII):
Figure imgf000092_0002
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1- C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1- C5 alkyl, C6-C10 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; and R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; or a derivative thereof.
9. A compound of Formula (IX):
Figure imgf000093_0001
wherein: L is C1-C5 alkyl; R1 is C6-C10 aryl; wherein the aryl is optionally substituted with one or more halogens; R2 is selected from H or C1-C5 alkyl; and R3 is halogen; or a derivative thereof.
10. A compound of Formula (X):
Figure imgf000093_0002
wherein: A is -O- or -NR8; L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl; R9 is H or halogen; and n is 1 or 2; or a derivative thereof.
11. A compound of Formula (XI):
Figure imgf000094_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R9 is H or halogen; and n is 1 or 2: or a derivative thereof.
12. A compound of Formula (XII):
Figure imgf000095_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl; R9 is H or halogen; and n is 1 or 2; or a derivative thereof.
13. A compound of Formula (XIII):
Figure imgf000095_0002
wherein: A is -O- or -NR8-; L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl; R9 is H or halogen; and n is 1 or 2; or a derivative thereof.
14. A compound of Formula (XIV):
Figure imgf000096_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R9 is H or halogen; and n is 1 or 2; or a derivative thereof.
15. A compound of Formula (XV):
Figure imgf000097_0001
wherein: L is selected from the group consisting of a bond, C1-C5 alkyl, C6-C10 aryl, and C(O)C1-C5 alkyl; R1 is selected from the group consisting of C1-C5 alkyl, C6-C10 aryl, C2-C7 heteroaryl, C3-C8 cyclcoalkyl, C1-C5 alkyl-C3-C8 cyclcoalkyl, and C2-C9 heterocyclyl; wherein each of the alkyl, aryl, heteroaryl, cyclcoalkyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl- NH-, C1-C5 alkyl-C6-C10 aryl, C1-C5 alkoxy-C6-C10 aryl, C1-C5 alkoxy-C2-C9 heterocyclyl, C(O)2C1-C5 alkyl, C1-C5 haloalkoxy, C(O)C1-C5 alkyl, C6-C10 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; R3, R4, R5, R6, and R7 are each independently selected from H, halogen, -CN, C1-C5 alkyl, or C1-C5 alkoxy; R8 is H or C1-C5 alkyl; R9 is H or halogen; and n is 1 or 2; or a derivative thereof.
16. The compound of Claim 1, wherein the compound is selected from: 2-(4-(benzyloxy)phenyl)-5-(4-chlorophenyl)-4- methyl-1H-imidazole, 5-(4-chlorophenyl)-2-(4-((2- fluorobenzyl)oxy)phenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-2-(4-((3- fluorobenzyl)oxy)phenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-2-(4-((4- fluorobenzyl)oxy)phenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4-(1- phenylethoxy)phenyl)-1H-imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4-(1- phenylethoxy)phenyl)-1H-imidazole enantiomer 1, 5-(4-chlorophenyl)-4-methyl-2-(4-(1- phenylethoxy)phenyl)-1H-imidazole enantiomer 2, 2-(4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)-1-(pyridin-2-yl)ethan-1-one, 2-bromo-5-((4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)phenoxy)methyl)pyridine, 5-(4-chlorophenyl)-2-(4-(2- fluorophenethoxy)phenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-2-(4-((3,4- dichlorobenzyl)oxy)phenyl)-4-methyl-1H- imidazole, 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)pyridine, 2-(4-((3-chlorobenzyl)oxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-2-(4-((3- methoxybenzyl)oxy)phenyl)-4-methyl-1H- imidazole, 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)pyridine, 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)quinolin-2(1H)-one, 2-(4-(4-chlorophenethoxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole, ethyl 4-((4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)phenoxy)methyl)benzoate, 2-(4-(3-chlorophenethoxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4- phenethoxyphenyl)-1H-imidazole, 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)benzonitrile, 2-(4-((4-chlorobenzyl)oxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4-((4- (trifluoromethoxy)benzyl)oxy)phenyl)-1H- imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4-((3- methylbenzyl)oxy)phenyl)-1H-imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4-((2- methylbenzyl)oxy)phenyl)-1H-imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4-((4- methylbenzyl)oxy)phenyl)-1H-imidazole, 2-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)pyridine, 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-5-methyl-1,2,4-oxadiazole, 1-(4-(2-(4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)phenoxy)ethyl)phenyl)ethan-1-one, 4-(2-(4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol- 2-yl)phenoxy)ethyl)morpholine, 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-3,5-dimethylisoxazole, 5-(4-chlorophenyl)-4-methyl-2-(4-((1-methyl-1H- imidazol-4-yl)methoxy)phenyl)-1H-imidazole, 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-1-methyl-1H-pyrazole, 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-1-methyl-1H-pyrazole, 2-(4-((1H-imidazol-5-yl)methoxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-2-(4-((4,4- difluorocyclohexyl)methoxy)phenyl)-4-methyl-1H- imidazole, 2-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)thiazole, 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-1-methylpiperidine, 4-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-1-methylpiperidine, 2-(4-((2-(benzyloxy)benzyl)oxy)phenyl)-5-(4- chlorophenyl)-4-methyl-1H-imidazole, 5-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-2-methylpyrimidine, 4-(2-((4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)phenoxy)methyl)benzyl)morpholine, 2-(4-((1-benzyl-1H-imidazol-2-yl)methoxy)phenyl)- 5-(4-chlorophenyl)-4-methyl-1H-imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4-(1-(3- (trifluoromethyl)phenyl)ethoxy)phenyl)-1H- imidazole, 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)- N-(3-fluorobenzyl)aniline, 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl)- N-(thiazol-4-yl)benzenesulfonamide, and 3-((4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol-2- yl)phenoxy)methyl)-N-methylbenzenesulfonamide, or a derivative thereof.
17. The compound of Claim 1, wherein the compound is selected from: 5-(4-chlorophenyl)-4-ethyl-2-(4-((3- fluorobenzyl) oxy) phenyl)-1H-imidazole, 2-chloro-6-((4-(5-(4-chlorophenyl)-4-methyl- 1H-imidazol-2-yl) phenoxy) methyl) pyridine, (S)-5-(4-chlorophenyl)-2-(4-(1-(3- fluorophenyl)ethoxy)phenyl)-4-methyl-1H- imidazole, (R)-5-(4-chlorophenyl)-2-(4-(1-(3- fluorophenyl)ethoxy)phenyl)-4-methyl-1H- imidazole, 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol- 2-yl)-N-((4,4- difluorocyclohexyl)methyl)aniline, 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol- 2-yl)-N-(pyridin-2-ylmethyl)aniline, 4-(5-(4-chlorophenyl)-4-methyl-1H-imidazol- 2-yl)-N-((1-methyl-1H-pyrazol-3- yl)methyl)aniline, N-(3-chlorobenzyl)-4-(5-(4-chlorophenyl)-4- methyl-1H-imidazol-2-yl)aniline, (S)-4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)-N-(1-(3- fluorophenyl)ethyl)aniline, (R)-4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)-N-(1-(3- fluorophenyl)ethyl)aniline, (S)-4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)-N-(1-phenylpropyl)aniline, (R)-4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)-N-(1-phenylpropyl)aniline, 5-(4-chlorophenyl)-4-methyl-2-(4- phenoxyphenyl)-1H-imidazole, 5-(4-chlorophenyl)-2-(4-(2- fluorophenoxy)phenyl)-4-methyl-1H- imidazole, 5-(4-chlorophenyl)-2-(4-(3- fluorophenoxy)phenyl)-4-methyl-1H- imidazole, 5-(4-chlorophenyl)-2-(4-(4- fluorophenoxy)phenyl)-4-methyl-1H- imidazole, 4-(5-(4-chlorophenyl)-1H-imidazol-2-yl)-N- (3-fluorobenzyl)aniline, (S)-1-benzyl-N-(4-(5-(4-chlorophenyl)-4- methyl-1H-imidazol-2-yl)phenyl)pyrrolidin-3- amine, 5-(4-chlorophenyl)-4-methyl-2-(4-(4- (trifluoromethyl)phenoxy)phenyl)-1H- imidazole, 5-(3-(4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)phenoxy)phenyl)-1H-pyrazole, 5-(4-chlorophenyl)-4-methyl-2-(4-((4- (trifluoromethyl)cyclohexyl)methoxy)phenyl)- 1H-imidazole, 5-(4-chlorophenyl)-4-methyl-2-(4-((1-methyl- 4- (trifluoromethyl)cyclohexyl)methoxy)phenyl)- 1H-imidazole, N 5-(4-(4-(5-(4-chlorophenyl)-4-methyl-1H- Cl N N imidazol-2-yl)phenoxy)phenyl)-1H-pyrazole, N H H and O 5-(4-chlorophenyl)-2-(4-((4,4-difluoro-1- methylcyclohexyl)methoxy)phenyl)-4-methyl- 1H-imidazole, or a derivative thereof.
18. The compound of Claim 10, wherein the compound is selected from: 5-(4-chlorophenyl)-4-methyl-2-(4- (2,2,2-trifluoroethoxy)phenyl)-1H- imidazole, 4-(2-((4-(5-(4-chlorophenyl)-4-methyl- 1H-imidazol-2- yl)phenoxy)methyl)benzyl)morpholine, 6-((4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)phenoxy)methyl)-N- methylpyridin-2-amine, 4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)-N-(3-fluorobenzyl)-N- methylaniline, (S)-1-benzyl-N-(4-(5-(4-chlorophenyl)- 4-methyl-1H-imidazol-2-yl)phenyl)-N- methylpyrrolidin-3-amine, 4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)-2,5-difluoro-N-(3- fluorobenzyl)aniline, 4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl)-3-fluoro-N-(3- fluorobenzyl)aniline, 6-((4-(5-(4-chlorophenyl)-4-methyl-1H- imidazol-2-yl) phenoxy) methyl)-N- methylpyridin-2-amine, and 2-chloro-4-(5-(4-chlorophenyl)-4- methyl-1H-imidazol-2-yl)-N-(3- fluorobenzyl)aniline, or a derivative thereof.
19. A pharmaceutical composition comprising a compound of any one of claims 1-18, or a derivatives thereof, and a pharmaceutically acceptable excipient.
20. A method of 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. The method of claim 20, wherein the disease or disorder associated with sodium channel mediated activity is selected from a seizure disorder, depression, anxiety, neuropathic pain, chemotherapy-induced neuropathy, chronic pain, migraine, ischemia, diastolic dysfunction, arrhythmia, Dravet syndrome, neuromuscular conditions, Amyotrophic Lateral Sclerosis (ALS), restless leg syndrome, or a combination thereof.
22. The method of claim 21, wherein the seizure disorder is selected from epilepsy, acute seizures, chronic seizures, generalized tonic-clonic seizures refractory seizures, pharmaco-resistant seizure disorder, Early Infantile Epileptic Encephalopathy, or a combination thereof.
23. The method of claim 22, wherein the seizure disorder epilepsy.
24. The method of claim 23, wherein the epilepsy is selected from partial epilepsy, generalized absence epilepsy, temporal lobe epilepsy, therapy resistant epilepsy, pharmaco-resistant epilepsy, epilepsy characterized by acute seizures, epilepsy characterized by chronic seizures, epilepsy characterized by generalized tonic-clonic seizures, epilepsy characterized by refractory seizures, or a combination thereof.
25. The method of claim 20, wherein the patient is a neonate, an infant, a child, an adolescent, or an adult.
26. The method of claim 25, wherein the patient is a neonate.
27. The method of claim 25, wherein the patient is an infant.
28. The method of claim 25, wherein the patient is a child.
29. The method of claim 25, wherein the patient is an adolescent.
30. The method of claim 25, wherein the patient is an adult.
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