Formulations of ion channel modulators and methods of preparing and using ion channel modulators

Abstract

The present invention is directed, in part, to compositions or dosage forms comprising fused heteroaryl compounds useful for preventing and / or treating diseases or conditions associated with abnormal function of voltage-gated sodium ion channels, e.g., abnormal slow / sustained sodium currents. Also provided herein are methods for treating diseases or conditions associated with abnormal function of sodium ion channels, including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, neuromuscular disorders, trigeminal autonomic headache (TAC), migraine, cranial neuropathy or cranial polyneuropathy, and cortical spreading depression (CSD). In another aspect, the present invention provides methods for making ion channel modulators.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 941,322, filed November 27, 2019, U.S. Provisional Patent Application No. 62 / 941,319, filed November 27, 2019, U.S. Provisional Patent Application No. 63 / 001,906, filed March 30, 2020, U.S. Provisional Patent Application No. 63 / 001,801, filed March 30, 2020, U.S. Provisional Patent Application No. 63 / 028,229, filed May 21, 2020, U.S. Provisional Patent Application No. 63 / 082,864, filed September 24, 2020, and U.S. Provisional Patent Application No. 63 / 082,857, filed September 24, 2020, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Sodium ion (Na+) channels primarily open transiently and are rapidly inactivated, generating fast Na+ currents that initiate action potentials. The delayed or persistent sodium current (INaL) is a persistent component of fast Na+ currents in cardiomyocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL augmentation, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther (2008) 119:326-339). Therefore, pharmaceutical compositions or dosage forms containing compounds that selectively modulate sodium channel activity, such as abnormal INaL, are useful for treating such conditions. Summary of the Invention

[0003] Described herein are compositions or dosage forms useful for preventing and / or treating diseases, disorders, or conditions, e.g., diseases, disorders, or conditions associated with abnormal sodium ion channel function, e.g., abnormal late sodium current (INaL). The disclosure also includes methods for modulating sodium channel activity using the compounds, compositions, or dosage forms described herein. Also provided herein are methods for preparing ion channel modulators.

[0004] In one aspect, the present disclosure provides a pharmaceutical composition comprising about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of Compound 1 and a pharmaceutically acceptable excipient.

[0005] In another aspect, the present disclosure provides a dosage form comprising a plurality of particles of Compound 1 and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of Compound 1 in the dosage form is from about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg).

[0006] In one aspect, the present disclosure provides a composition in a dosage form comprising about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of Compound 1 and a pharmaceutically acceptable excipient.

[0007] In another aspect, the present disclosure provides a composition in a dosage form comprising a plurality of particles of Compound 1 and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of Compound 1 in the composition is about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg). In another aspect, provided herein is a method of treating a condition associated with abnormal sodium ion channel function in a subject in need thereof, the method comprising administering to the subject a dosage form disclosed herein. Also provided herein is a method of treating a condition associated with abnormal sodium ion channel function in a subject in need thereof, the method comprising administering to the subject about 2.5 mg to about 90 mg of Compound 1. In some embodiments, the condition is a neurological or psychiatric disorder. In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is childhood epilepsy or a childhood epilepsy syndrome. In some embodiments, the condition is an epileptic encephalopathy. In some embodiments, the condition is developmental. In some embodiments, the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome. In other embodiments, the condition is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. In some embodiments, the condition is cancer.

[0008] Also provided herein is a method of treating a psychiatric disorder in a subject in need thereof, the method comprising administering to the subject a dosage form disclosed herein.

[0009] The present disclosure provides, in part, a method of treating pain in a subject in need thereof, the method comprising administering to the subject a dosage form disclosed herein.

[0010] Contemplated methods include methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a dosage form disclosed herein.

[0011] In another aspect, provided herein is a method of treating or preventing trigeminal autonomic headache (TAC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dosage form disclosed herein.

[0012] Also provided herein is a method for treating or preventing trigeminal autonomic headache (TAC) in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg of Compound 1, to the subject.

[0013] In another aspect, provided herein is a method of treating or preventing migraine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dosage form disclosed herein.

[0014] Provided herein, in part, is a method for treating or preventing migraine in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1, e.g., about 2.5 mg to about 90 mg of Compound 1.

[0015] Provided herein are methods for treating or preventing cortical spreading depression (CSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dosage form disclosed herein.

[0016] Also provided is a method for treating or preventing cortical growth suppression (CSD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg.

[0017] Also provided herein are methods for treating or preventing cranial neuropathy or cranial polyneuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dosage form described herein.

[0018] In another aspect, a method for treating or preventing cranial neuropathy or cranial polyneuropathy in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg of Compound 1, to the subject.

[0019] In another aspect, the present disclosure provides a compound 1, [ka] or a pharmaceutically acceptable salt thereof, comprising: (i) contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoro-pyridine to provide a compound of formula (II); [ka] (ii) contacting a compound of formula (II) with a palladium catalyst and bis(pinacolato)diboron to provide a compound of formula (III); [ka] (iii) contacting the compound of formula (III) with a palladium catalyst and 2-bromo-5-chloro-pyrazine to provide a compound of formula (IV); [ka] (iv) contacting a compound of formula (IV) with hydrazine to provide a compound of formula (V); [ka] (v) contacting the compound of formula (V) with 2-bromo-2,2-difluoro-acetyl chloride to provide a compound of formula (VI); [ka] (vi) contacting a compound of formula (VI) with an acid to provide a compound of formula (VII); [ka] (vii) contacting the compound of formula (VII) with a silver catalyst and ethanol to provide Compound 1 or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present disclosure provides a compound 1, [ka] or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is a compound represented by formula (VII): [ka] with a silver catalyst and ethanol.

[0021] Other objects and advantages will become apparent to those skilled in the art upon consideration of the following brief description of the drawings, detailed description, examples, and claims. [Brief explanation of the drawings]

[0022] [Figure 1] 1 shows the XRPD patterns of Compound 1 raw material and Compound 1 after jet milling. [Figure 2] The dissolution results of ASD in capsules (2.5 mg and 10 mg active ingredient) are shown. [Figure 3] Figure 1 shows dissolution results of a 1:10 blend with MCC in capsules (1 and 10 mg active ingredient). [Figure 4] Figure 1 shows dissolution results of a 1:10 blend with MCC in capsules (2.5 mg active ingredient with 2% surfactant). DETAILED DESCRIPTION OF THE INVENTION

[0023] As generally described herein, the present disclosure provides, in part, compounds, compositions, and dosages or formulations useful for preventing and / or treating the diseases, disorders, or conditions described herein, e.g., diseases, disorders, or conditions associated with abnormal function of sodium ion channels, such as abnormal late sodium current (INaL). Exemplary diseases, disorders, or conditions include neurological disorders (e.g., epilepsy or epilepsy syndromes, neurodevelopmental disorders, or neuromuscular disorders), psychiatric disorders, pain, gastrointestinal disorders, trigeminal autonomic headache (TAC), migraine, cranial neuropathy or cranial polyneuropathy, and cortical spreading depression (CSD). Also provided herein are methods for preparing ion channel modulators.

[0024] definition As used herein, " pharmaceutically acceptable carrier " refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound that it is formulated with.The pharmaceutically acceptable carrier, adjuvant, or vehicle that can be used in the compositions described herein includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and wool fat.

[0025] As used herein, "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0026] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0027] Disease, disorder, and condition are used interchangeably herein.

[0028] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with the specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition (also "therapeutic treatment").

[0029] As used herein, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health and condition of the subject.The effective amount includes therapeutic and prophylactic treatment.

[0030] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0031] As used herein, the term "amorphous" refers to a solid in a non-crystalline state. Amorphous solids generally have crystalline-like short-range molecular arrangements, but lack the long-range order of molecular packing seen in crystalline solids. The solid state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or other standard techniques known to those skilled in the art.

[0032] As used herein, "crystalline" refers to a solid having a highly regular chemical structure, i.e., a solid having long-range structural order in a crystal lattice. The molecules are arranged in a regular, periodic manner in the three-dimensional space of the lattice. In particular, crystalline forms can be produced as one or more single crystal forms.

[0033] The term "peaks," when referring to peaks in an XRPD pattern of a crystalline form of Compound 1, refers to a particular collection of peaks whose values ​​of 2θ, spanning the range of 0° to 40°, are collectively uniquely assigned to one of the crystalline forms of Compound 1.

[0034] As used herein, the phrase "amorphous solid dispersion" refers to a solid comprising a drug substance (e.g., Compound 1) and a dispersion polymer.

[0035] The phrase "dispersion polymer" refers to a polymer that allows a drug substance (e.g., Compound 1) to be dispersed throughout such that a solid dispersion can be formed. The dispersion polymer may contain a mixture of two or more polymers. Examples of dispersion polymers include, but are not limited to, vinyl polymers and copolymers, vinylpyrrolidine-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymer, polyvinylpyrrolidine ("PVP"), acrylate and methacrylate copolymers, methyl acrylate-methyl methacrylate copolymers (such as Eudragit®), polyethylene-polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers (also called poloxamers), polyethylene glycol, graft copolymers composed of polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus®), cellulosic polymers such as hydroxypropyl methylcellulose acetate ("HPMCA"), hydroxypropyl methylcellulose ("HPMCA"). MC"), hydroxypropyl cellulose ("HPC"), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate ("HPMCAS"), hydroxypropyl methyl cellulose phthalate ("HPMCP"), carboxymethyl ethyl cellulose ("CMEC"), cellulose acetate phthalate ("CAP"), cellulose acetate succinate ("CAS"), hydroxypropyl methyl cellulose acetate phthalate ("HPMCAP"), cellulose acetate trimellitate ("CAT"), hydroxypropyl methyl cellulose acetate trimellitate ("HPMCAT"), and carboxymethyl cellulose acetate butyrate ("CMCAB").

[0036] As used herein, the terms "stable" and "stability" mean that the evolution of a drug substance (e.g., Compound 1) over time and / or under specific environmental conditions (e.g., temperature, humidity, etc.) does not significantly affect its quality, safety, and / or efficacy over a given period of time. This can be measured via the formation of degradation products (impurities), pH fluctuations, appearance, microbial growth, and / or color, as exemplified in the experimental section. Typically, a composition according to the present invention is considered stable if at least 95% of the initial concentration of each drug substance is found after 4 weeks at 25°C, and / or if no substantial change in the appearance of the solution is observed during such time and under such temperature conditions. Stability can be assessed over a range of relative humidity (RH) conditions, typically 60-75% RH.

[0037] As used herein, the term "particle size" is defined as the diameter of a particle as determined by a Sympatec particle size analyzer.

[0038] compound Described herein are pharmaceutical compositions and dosage forms comprising compounds useful for preventing and / or treating diseases, disorders, or conditions, e.g., diseases, disorders, or conditions associated with abnormal function of sodium ion channels, e.g., abnormal late sodium current (INaL).

[0039] In one aspect, the present disclosure provides Compound 1, represented by: [ka] and a pharmaceutically acceptable excipient. In some embodiments, Compound 1 is crystalline. In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2. In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.2. In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2, and 22.6±0.2. In some embodiments, the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0040] In some embodiments, Compound 1 is amorphous.

[0041] Dosage Forms and Compositions In one aspect, the disclosure features dosage forms or compositions useful for preventing and / or treating a disease, disorder, or condition described herein, e.g., a disease, disorder, or condition associated with abnormal function of a sodium ion channel, such as an abnormal late sodium current (INaL).

[0042] The present invention provides pharmaceutical compositions containing, as an active ingredient, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical arts (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0043] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration for drugs, for example, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, including rectal, buccal, intranasal, and transdermal routes, as an inhalant, or via an impregnated or coated device such as, for example, a stent or an arterially inserted cylindrical polymer, with utilities similar to those described in those patents and patent applications incorporated by reference.

[0044] One mode of administration is parenteral, particularly by injection. Forms in which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0045] Sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount in a suitable solvent, which contains various other components as listed above, as needed, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other components as listed above.For the preparation of sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains powder of active ingredient and any additional desired components from the sterile solution that has been previously sterilized and filtered.

[0046] Oral administration is another route for administering the compounds of the present invention. Administration can be via capsules or tablets, etc. In preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed in such a carrier, which can be in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, the excipient can be in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0047] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propylhydroxy-benzoates, sweeteners, and flavoring agents.

[0048] The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are described in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present invention uses transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for delivering pharmaceuticals is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0049] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will typically be determined by a physician in light of relevant circumstances, including the condition being treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0050] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0051] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating covering the former.The two components can be separated by an enteric layer that functions to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed-released.A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0052] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0053] In one aspect, provided herein is a dosage form or composition in a dosage form comprising about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of Compound 1 and a pharmaceutically acceptable excipient.

[0054] In some embodiments, the dosage form or the composition in the dosage form contains from about 2.5 mg to about 150 mg (e.g., from about 10 mg to about 150 mg, from about 20 mg to about 150 mg, from about 40 mg to about 150 mg, from about 60 mg to about 150 mg, from about 80 mg to about 150 mg, from about 100 mg to about 150 mg, from about 10 mg to about 120 mg, from about 20 mg to about 120 mg, from about 40 mg to about 120 mg, from about 60 mg to about 120 mg, from about 80 mg to about 120 mg, from about 100 mg to about 120 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 4 The compound 1 may comprise 0 mg to about 100 mg, about 60 mg to about 100 mg, about 80 mg to about 100 mg, about 10 mg to about 80 mg, about 20 mg to about 80 mg, about 40 mg to about 80 mg, about 60 mg to about 80 mg, about 10 mg to about 60 mg, about 20 mg to about 60 mg, about 40 mg to about 60 mg, about 70 mg to about 120 mg, about 70 mg to about 100 mg, about 50 mg to about 120 mg, about 50 mg to 90 mg, about 30 mg to about 120 mg, about 30 mg to about 60 mg, about 30 mg to about 80 mg, or about 30 mg to about 100 mg.

[0055] In some embodiments, the dosage form or composition in the dosage form contains about 1 mg to about 100 mg (e.g., about 1 mg to about 80 mg, about 1 mg to about 50 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 50 mg, about 5 mg to about 100 mg, about 5 mg to about 80 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg) of Compound 1.

[0056] In some embodiments, the dosage form or the composition in the dosage form contains about 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, 100 mg, about 99 mg, about 98 mg, about 97 mg, about 96 mg, about 95 mg, about 94 mg, about 93 mg, about 92 mg, about 91 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 69 mg, about 68 mg, about 67 mg, Contains about 66 mg, about 65 mg, about 64 mg, about 63 mg, about 62 mg, about 61 mg, about 60 mg, about 59 mg, about 58 mg, about 57 mg, about 56 mg, about 55 mg, about 54 mg, about 53 mg, about 52 mg, about 51 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 7 mg, about 5 mg, about 2.5 mg, about 2 mg, about 1.5 mg, or about 1 mg of Compound 1.

[0057] In another aspect, the present disclosure provides a dosage form or a composition in a dosage form comprising a plurality of particles of Compound 1 and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of Compound 1 in the dosage form is from about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg).

[0058] In some embodiments, the plurality of particles of Compound 1 in the dosage form or composition is between about 2.5 mg and 150 mg (e.g., between about 10 mg and about 150 mg, between about 20 mg and about 150 mg, between about 70 mg and about 120 mg, between about 30 mg and about 60 mg, about 100 mg, about 50 mg).

[0059] In certain embodiments, 10% of the particles of Compound 1 have a particle size of less than about 1 μm. In other embodiments, 50% of the particles of Compound 1 have a particle size of less than about 4 μm. In some embodiments, 50% of the particles of Compound 1 have a particle size of less than about 2 μm. In certain embodiments, 90% of the particles of Compound 1 have a particle size of less than about 30 μm (e.g., less than about 15 μm). In other embodiments, 90% of the particles of Compound 1 have a particle size of less than about 5 μm. In some embodiments, 90% of the particles of Compound 1 have a particle size of between about 4 μm and 15 μm.

[0060] In some embodiments, 10% of the particles of Compound 1 have a particle size of less than about 1 μm, 50% of the particles of Compound 1 have a particle size of less than about 4 μm, and 90% of the particles of Compound 1 have a particle size of less than about 30 μm.

[0061] In some embodiments, the dosage form or composition is adapted for oral administration.

[0062] In some embodiments, the dosage form is a solid form.

[0063] In some embodiments, the dosage form is in the form of a capsule.

[0064] In some embodiments, the pharmaceutical excipient in the capsule is a filler (e.g., a cellulose derivative (e.g., microcrystalline cellulose), a starch (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, a sugar alcohol (e.g., sorbitol, xylitol, and mannitol).

[0065] In some embodiments, the ratio of Compound 1 to filler is about 1:10. In some embodiments, the ratio of Compound 1 to filler is about 1:10. In some embodiments, the ratio of Compound 1 to filler is about 1:5. In some embodiments, the ratio of Compound 1 to filler is about 1:4. In some embodiments, the ratio of Compound 1 to filler is about 1:3. In some embodiments, the ratio of Compound 1 to filler is about 1:2.

[0066] In some embodiments, the capsule further comprises a lubricant (e.g., magnesium stearate, calcium stearate, stearic acid, talc, silica, and fat).

[0067] In some embodiments, the dosage form is in the form of a blend.

[0068] In some embodiments, the pharmaceutical excipient in the blend is a filler (e.g., microcrystalline cellulose or starch). In some embodiments, the ratio of Compound 1 to filler is about 1:1. In some embodiments, the ratio of Compound 1 to filler is about 1:10. In some embodiments, the ratio of Compound 1 to filler is about 1:5. In some embodiments, the ratio of Compound 1 to filler is about 1:4. In some embodiments, the ratio of Compound 1 to filler is about 1:3. In some embodiments, the ratio of Compound 1 to filler is about 1:2.

[0069] In some embodiments, the dosage form is in liquid form.

[0070] In some embodiments, the dosage form is in the form of a solution.

[0071] In some embodiments, the pharmaceutical excipient in the solution is selected from the group consisting of a bulking agent (e.g., a polymer (e.g., PEG400)), an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40), a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS), a vitamin derivative (e.g., Vitamin ETPGS)), or a solvent (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)).

[0072] In some embodiments, the concentration of Compound 1 in the solution is from about 0.1 mg / mL to about 10 mg / mL (e.g., from about 0.5 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 8 mg / mL, from about 1 mg / mL to about 8 mg / mL) , about 2 mg / mL to about 8 mg / mL, about 3 mg / mL to about 8 mg / mL, about 4 mg / mL to about 8 mg / mL, about 5 mg / mL to about 8 mg / mL, about 6 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 6 mg / mL, about 2 mg / mL to about 6 mg / mL, about 3 mg / mL to about 6 mg / mL, about 4 mg / mL to about 6 mg / mL, about 0.5 mg / mL to about 4 mg / mL, about 1 mg / mL to about 4 mg / mL, or about 2 mg / mL to about 4 mg / mL).

[0073] In some embodiments, the concentration of Compound 1 in the solution is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, or about 10 mg / mL.

[0074] In some embodiments, the dosage form or composition comprises: about 20% to about 60% by weight (e.g., about 25% to about 55% by weight, about 30% to about 50% by weight, about 35% to about 45% by weight, about 37% to about 42% by weight, or about 40% by weight) of a filler (e.g., a polymer (e.g., PEG 200, PEG 300, PEG 400, PEG 6000, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 6000, or PEG 8000)); about 3% by weight to about 25% by weight (e.g., about 3% by weight to about 20% by weight, about 5% by weight to about 13% by weight, about 8% by weight to about 13% by weight, about 5% by weight to about 15% by weight, or about 10% by weight) of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40, macrogol 25 cetostearyl ether (e.g., Cremophor® A25), macrogol 6 cetostearyl ether (e.g., Cremophor® A6), macrogol glycerol ricinoleate 35 (e.g., Cremophor® EL), macrogol-glycerol hydroxystearate 40 (e.g., Cremophor® RH40)); about 30% by weight to about 70% by weight (e.g., about 35% by weight to about 65% by weight, about 40% by weight to about 60% by weight, about 45% by weight to about 55% by weight, or about 50% by weight) of water; wherein the concentration of Compound 1 is about 0.5 mg / mL or about 0.25 mg / mL.

[0075] In certain embodiments, the dosage form or composition comprises about 35% to about 45% by weight of a bulking agent (e.g., a polymer (e.g., PEG 400)), about 5% to about 15% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)), and about 40% to about 60% by weight of water, and has a concentration of Compound 1 of about 0.5 mg / mL or about 0.25 mg / mL.

[0076] In some embodiments, the dosage form or composition comprises: about 40% by weight to about 75% by weight (e.g., about 45% by weight to about 70% by weight, about 50% by weight to about 65% by weight, about 55% by weight to about 60% by weight, or about 58% by weight) of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40), macrogol 25 cetostearyl ether (e.g., Cremophor® A25), macrogol 6 cetostearyl ether (e.g., Cremophor® A6), macrogol glycerol ricinoleate 35 (e.g., Cremophor® EL), macrogol-glycerol hydroxystearate 40 (e.g., Cremophor® RH40)); About 10% to about 35% by weight (e.g., about 10% to about 30% by weight, about 10% to about 25% by weight, about 15% to about 25% by weight, or about 15% to about 20% by weight) of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS), caprylocaproyl macrogolglyceride (e.g., Labrasol), a natural triglyceride-based oil (e.g., olive oil, sesame oil, coconut oil, palm kernel oil)), about 3% to about 20% by weight (e.g., about 3% to about 15% by weight, about 5% to about 15% by weight, or about 5% to about 10% by weight) of propylene glycol; 10% to about 35% by weight (e.g., about 10% to about 30% by weight, about 10% to about 25% by weight, about 15% to about 25% by weight, or about 15% to about 20% by weight) of ethanol, The concentration of Compound 1 is about 5 mg / mL to about 10 mg / mL (for example, about 5 mg / mL, about 7.5 mg / mL, or about 10 mg / mL), or about 2.5 mg to about 5 mg / mL.

[0077] In certain embodiments, the dosage form or composition comprises about 55% to about 60% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)), about 15% to about 20% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS)), about 5% to about 10% by weight of propylene glycol, and about 15% to about 20% by weight of ethanol, and has a concentration of Compound 1 of about 5 mg / mL to about 10 mg / mL, or about 2.5 mg to about 5 mg / mL.

[0078] In some embodiments, the dosage form comprises: About 50% by weight to about 85% by weight (e.g., about 55% by weight to about 80% by weight, about 60% by weight to about 75% by weight, or about 65% by weight to about 70% by weight) of an emulsifier (e.g., castor oil derivatives (e.g., Kolliphor RH40), macrogol 25 cetostearyl ether (e.g., Cremophor® A25), macrogol 6 cetostearyl ether (e.g., Cremophor® A6), macrogol glycerol ricinoleate 35 (e.g., Cremophor® EL), macrogol-glycerol hydroxystearate 40 (e.g., Cremophor® RH40))); About 10% to about 30% by weight (e.g., about 10% to about 25% by weight, about 15% to about 25% by weight, or about 18% to about 23% by weight) of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS), caprylocaproyl macrogolglyceride (e.g., Labrasol), a natural triglyceride-based oil (e.g., olive oil, sesame oil, coconut oil, palm kernel oil)), about 3% to about 20% by weight (e.g., about 3% to about 15% by weight, about 5% to about 15% by weight, about 5% to about 12% by weight, or about 7% to about 12% by weight) of propylene glycol; The concentration of Compound 1 is about 1 mg / mL to about 10 mg / mL (e.g., about 2 mg / mL to about 8 mg / mL, about 2 mg / mL, about 5 mg / mL, about 7 mg / mL, or about 10 mg / mL), or 0.5 mg / mL to about 5 mg / mL.

[0079] In certain embodiments, the dosage form or composition comprises about 65% to about 70% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)), about 18% to about 23% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS)), and about 7% to about 12% by weight of propylene glycol, and has a concentration of Compound 1 of about 1 mg / mL to about 10 mg / mL, or 0.5 mg / mL to about 5 mg / mL.

[0080] In some embodiments, the dosage form or composition comprises: about 20% by weight to about 60% by weight (e.g., about 25% by weight to about 55% by weight, about 30% by weight to about 50% by weight, 35% by weight to about 45% by weight, about 35% by weight, about 40% by weight, or about 45% by weight) of diethylene glycol monoethyl ether (e.g., Transcutol HP); About 1% by weight to about 20% by weight (e.g., about 3% by weight to about 18% by weight, about 5% by weight to about 18% by weight, about 5% by weight to about 15% by weight, about 8% by weight to about 12% by weight, or about 10% by weight) of a surfactant (e.g., a vitamin derivative (e.g., Vitamin ETPGS)), about 20% by weight to about 80% by weight (e.g., about 25% by weight to about 75% by weight, about 30% by weight to about 70% by weight, about 35% by weight to about 55% by weight, about 40% by weight to about 60% by weight, or about 45% by weight to about 55% by weight) of water, The concentration of Compound 1 is about 1 mg / mL to about 5 mg / mL (for example, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg, or about 5 mg / mL), or 0.5 mg / mL to about 2.5 mg / mL.

[0081] In certain embodiments, the dosage form or composition comprises about 35% to about 45% by weight of diethylene glycol monoethyl ether (Transcutol HP), about 5% to about 15% by weight of a surfactant (e.g., a glyceride (e.g., a vitamin derivative (e.g., Vitamin ETPGS)), and about 40% to about 60% by weight of water, and has a concentration of Compound 1 of about 1 mg / mL to about 5 mg / mL or 0.5 mg / mL to about 2.5 mg / mL.

[0082] In some embodiments, the dosage form or composition comprises about 30% to about 40% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40), about 40% to about 50% by weight of a surfactant (e.g., a glyceride (e.g., Capmul MCM C8)), about 5% to 15% by weight of a plasticizer (e.g., triethyl citrate), and about 5% to about 15% by weight of a solvent (e.g., ethanol).

[0083] In other embodiments, the dosage form or composition comprises about 35% to about 45% by weight of propylene glycol monocaprylate (e.g., Capryol 90), about 15% to about 25% by weight of a glyceride (e.g., caprylocaproyl macrogolglyceride (e.g., Labrasol)), and about 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP).

[0084] In some embodiments, the dosage form is a suspension.

[0085] In some embodiments, the concentration of Compound 1 in the suspension is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL.

[0086] In some embodiments, the disclosed suspensions may be further diluted with a solvent (e.g., water), with the concentration of the diluted solution being about 50% to about 90% of the concentration of the solution before dilution.

[0087] In some embodiments, the concentration of Compound 1 in the suspension is from about 0.1 mg / mL to about 10 mg / mL (e.g., from about 0.5 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 8 mg / mL, from about 1 mg / mL to about 8 mg / mL). L, about 2 mg / mL to about 8 mg / mL, about 3 mg / mL to about 8 mg / mL, about 4 mg / mL to about 8 mg / mL, about 5 mg / mL to about 8 mg / mL, about 6 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 6 mg / mL, about 2 mg / mL to about 6 mg / mL, about 3 mg / mL to about 6 mg / mL, about 4 mg / mL to about 6 mg / mL, about 0.5 mg / mL to about 4 mg / mL, about 1 mg / mL to about 4 mg / mL, or about 2 mg / mL to about 4 mg / mL).

[0088] In some embodiments, the pharmaceutical excipients in the suspension include: about 0.1% to about 5% (e.g., about 0.1% to about 3% by weight, about 0.1% to about 2% by weight, about 0.1% to about 1% by weight, about 0.5% to about 3% by weight, about 0.5% to about 2% by weight, about 0.5% to about 1% by weight, about 0.1% by weight, about 0.3% by weight, about 0.5% by weight, about 1% by weight, about 2% by weight, or about 3% by weight) of filler (e.g., ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium hydroxypropyl methylcellulose, methylcellulose (e.g., 400 cP MC), methyl ethyl cellulose, sodium carboxymethyl cellulose, Aerosil (silicon dioxide), cetostearyl alcohol, cetyl alcohol, stearyl alcohol, Gelucires 33 / 01, 39 / 01, and 43 / 01, glyceryl behenate (Compritol 888 A) TO), glyceryl palmitostearate (Precirol AT05), Softisan 100, 142, 378 and 649, stearyl alcohol carbomer, xanthan gum, maltodextrin, acacia, tragacanth, povidone, or polyvinyl alcohol) and about 0.1 wt % to about 3 wt % (e.g., about 0.1 wt % to about 2 wt %, about 0.1 wt % to about 1 wt %, about 0.1 wt % to about 0.5 wt %, about 0.2 wt % to about 2 wt %, about 0.2 wt % to about 1 wt %, about 0.2 wt % to about 0.5 wt %, about 0.1 wt % to about 0.3 wt %, about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %, or about 1 wt %) of an emulsifier (e.g., polyoxyethylene sorbate (e.g., Tween®), sorbitan long-chain carboxylic acid ester (e.g., Span®), ethylene or propylene oxide bromine, Examples of suitable sorbitan esters include sorbitan copolymers (Pluronic®), polyglycolyzed glycerides (Labrasol®, Labrafil®, and Labrafac®), sorbitan esters of oleic acid, stearic acid, lauric acid, or other long-chain carboxylic acids, polyethylene-polypropylene glycol block copolymers (e.g., Poloxamer 188), other sorbitan or sucrose long-chain carboxylic acid esters, mono- and diglycerides, and PEG derivatives of caprylic / capric triglyceride.

[0089] In certain embodiments, the pharmaceutical excipient comprises about 0.5% by weight of a bulking agent (e.g., methylcellulose, e.g., 400cP MC) and about 0.2% by weight of an emulsifier (e.g., Tween, e.g., Tween 80, e.g., Poloxamer 188).

[0090] In some embodiments, the pharmaceutical excipient further comprises about 1% by weight of a preservative solution (eg, a paraben solution).

[0091] In some embodiments, the dosage form is in the form of an amorphous solid dispersion.

[0092] In some embodiments, the pharmaceutical excipient in the amorphous solid dispersion is a polymer (e.g., Soluplus, Eudragit, HPMCASMF, PVP-VA, methyl acrylate methyl methacrylate copolymer, HPMCP, CAP, HPMCAS, HPMCP H-55).

[0093] In some embodiments, the dosage form or composition is stable (e.g., chemically stable) at 25°C and 60% RH for 7 days, 14 days, 21 days, 28 days, 1 month, 3 months, 5 months, 6 months, 12 months, 24 months, or 36 months.

[0094] In some embodiments, the dosage form or composition is stable (e.g., chemically stable) at 25°C and 60% RH for at least 7 days (e.g., at least 14 days, 21 days, at least 28 days, at least 1 month, at least 2 months, at least 3 months, at least 5 months, at least 6 months, at least 12 months, at least 24 months, or at least 36 months).

[0095] Dosage Form Preparation Method In another aspect, the present disclosure provides methods for making the dosage forms disclosed herein. Such methods are described, for example, in the Examples section. In some embodiments, the intended dosage form may be in the form of a capsule, blend, solution, suspension, or ASD.

[0096] How to use The formulations described herein are generally useful for modulating sodium channel activity and are useful for treating conditions associated with abnormal function of sodium channel ion channels, such as abnormal slow sodium (INaL) currents. In some embodiments, formulations comprising Compound 1 provided by the present disclosure are effective for treating epilepsy or epilepsy syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders. The provided formulations may also modulate all sodium ion channels or may modulate one or more sodium ion channels, such as Na VIt may be specific only to 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and / or 1.9.

[0097] In one aspect, the present invention provides a method for treating a condition associated with abnormal function of a sodium ion channel in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, e.g., about 2.5 mg to about 90 mg of Compound 1.

[0098] Epilepsy and epilepsy syndromes The formulations (e.g., dosage forms, compositions in dosage forms comprising Compound 1) described herein are useful for treating epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which neuronal activity in the brain is disrupted, resulting in seizures or periods of abnormal behavior, sensations, and sometimes loss of consciousness. Seizure symptoms vary widely, from a simple blank stare for a few seconds to repetitive twitching of the arms or legs during a seizure.

[0099] Epilepsy can include generalized seizures or partial or focal seizures. All areas of the brain are involved in generalized seizures. A person experiencing a generalized seizure may scream or make some noise, stiffen for a few seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are typically open, and the person may not appear to be breathing and may actually turn blue. Consciousness gradually returns, and the person may be confused for several minutes to several hours. There are six main types of generalized seizures: tonic-clonic, tonic-clonic, myoclonic, absence, and atonic. Partial or focal seizures involve only part of the brain, so only part of the body is affected. Symptoms may vary depending on the part of the brain with abnormal electrical activity.

[0100] Epilepsy as referred to herein includes generalized, partial, complex partial, tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0101] The formulations described herein (e.g., dosage forms, compositions in dosage forms containing Compound 1) can also be useful for treating epilepsy syndromes.Severe syndromes accompanied by diffuse brain dysfunction, at least partially caused by some aspects of epilepsy, are also called epileptic encephalopathy.These are associated with frequent seizures that are resistant to treatment and severe cognitive impairment, such as West syndrome.

[0102] In some embodiments, the epilepsy syndrome comprises an epileptic encephalopathy, e.g., developmental and epileptic encephalopathy (DEE), Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0103] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome comprises epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0104] In some embodiments, the methods described herein include, prior to administration of the formulations described herein, administering to a patient suffering from epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neoplasia, encephalopathy ... The method further includes identifying a subject with: live-born infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with an SCN3A mutation, cryptogenic childhood partial epilepsy with an SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0105] In one aspect, the present invention provides a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathies, developmental and epileptic encephalopathies, epileptic encephalopathies with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, ... In some embodiments, the present invention features a method for treating a condition known as epilepsy, including but not limited to: epilepsy, cryptogenic childhood partial epilepsy with an SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy, comprising administering a formulation described herein to a subject in need of such treatment.

[0106] Formulations of the invention (e.g., dosage forms, compositions in dosage forms comprising Compound 1) also may be used when a subject is taking any of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, It may also be used to treat epilepsy or epilepsy syndromes (epileptic encephalopathies) with mutations in one or more of NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0107] In some embodiments, the methods described herein include administering to a subject an additional 20 mg or more of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KC and identifying subjects with a mutation in one or more of TD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0108] The formulations of the present invention may also be used to treat conditions in which a subject is taking one or more of the following: HNRNPU, CACNA1A, CASK, FOXG1, GNB1, GPHN, IQSEC2, MBD5, MECP2, PIGA, PURA, SLC6A8, SLC9A6, TSC1, TSC2, UBE3A, WDR45, ZEB2, SLC1A2, GRIN2D, DYRK1A, PURA, WDR45, HNRNPU, SMC1A, FOXG1, ARID1B, ASXL3, KCNH1, GABRB2, NEXMIF, MECP2, SNAP25, COL4A3BP, GABRA1, GABRA2, GABRA3, GABR A4, GABRA5, GABRA6, GABRB1, GABRB2, GABRD, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, ABAT, ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ANK2, ANK3, DISC1, DLC1, DLC2, DNAI1, FGF13, GABARAP, GABARAPL1, GABARAPL2, GABBR1, GAD1, GAD2, GLS, GLS2, GLUL, GNAI 1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GPHN, HAP1, KCNB2, KCNC 2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, PRKACB, PRKACG, PRKCA, PRKCB, PRKCG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5, SLC6A11, SLC6A13, SRC, TRAK1, TRAK2, CHRNA1, CHRNA10, CHR NA3, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB3, CHRNB4, CHRND, CHRNE, CHRNG, GRIA1, GRIA2, GRIA3, GRIA4, GRIK1, GRIK2, GRIK3, GRIK4, GRIK5,GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRID1, GRID2, SCN10A, SCN11A, SCN2B, SCN3B, SCN4A, SCN4B, SCN5A, SCN7A, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G , CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, KCNA1, KCNA10, KCNA3, KCNA4, KCNA5, KCNA6, KCNA7, KCNAB1, KCNAB2 , KCNAB3, KCNB2, KCNC2, KCNC3, KCNC4, KCND1, KCND2, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNE4, KCNF1, KCNG1, KCNG2, KCNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4, KCNH5, KCNH6, KCNH7, KCNH8, KCNQ1, KCNQ5, KCNQ4, KCNRG, KCNS1, KCNS2, KCNS3, KCNV1, KCNV2, HCN2, HCN3, and HCN4.

[0109] In some embodiments, the methods described herein can involve administering to a subject an additional 20 mg or more of the following: HNRNPU, CACNA1A, CASK, FOXG1, GNB1, GPHN, IQSEC2, MBD5, MECP2, PIGA, PURA, SLC6A8, SLC9A6, TSC1, TSC2, UBE3A, WDR45, ZEB2, SLC1A2, GRIN2D, DYRK1A, PURA, WDR45, HNRNPU, SMC1A, FOXG1, ARID1B, ASXL3, KCNH1, GABRB2, NEXMIF, MECP2, SNAP25, COL4A prior to administration of the formulations described herein. 3BP, GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRD, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, ABAT, A DCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ANK2, ANK3, DISC1, DLC1, DLC2, DNAI1, FGF13, GABARAP, GABARAPL1, GABARAPL2, GABBR1 , GAD1, GAD2, GLS, GLS2, GLUL, GNAI1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GN GT1, GNGT2, GPHN, HAP1, KCNB2, KCNC2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, PRKACB, PRKAC G, PRKCA, PRKCB, PRKCG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5, SLC6A11, SLC6A13, SRC, TRAK1, TRAK2, CHRNA1, CHRNA10, CHRNA3, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB3, CHRNB4, CHRND, CHRNE, CHRNG, GRIA1, GRIA2, GRIA3, GRIA4,GRIK1, GRIK2, GRIK3, GRIK4, GRIK5, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRID1, GRID2, SCN10A, SCN11A, SCN2B, SCN3B, SCN4A, SCN4B, SCN5A, SCN7A, CACNA1A, CACNA1B, CACNA1C, C ACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, KCNA1, KCNA10, KCNA3, KCNA4, K The method further includes identifying subjects with a mutation in one or more of CNA5, KCNA6, KCNA7, KCNAB1, KCNAB2, KCNAB3, KCNB2, KCNC2, KCNC3, KCNC4, KCND1, KCND2, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNE4, KCNF1, KCNG1, KCNG2, KCNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4, KCNH5, KCNH6, KCNH7, KCNH8, KCNQ1, KCNQ5, KCNQ4, KCNRG, KCNS1, KCNS2, KCNS3, KCNV1, KCNV2, HCN2, HCN3, and HCN4.

[0110] Neurodevelopmental disorders Formulations described herein (e.g., dosage forms, compositions in dosage forms comprising Compound 1) can be useful for treating neurodevelopmental disorders. In some embodiments, the neurodevelopmental disorder comprises autism, autism with epilepsy, tuberous sclerosis complex, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorder with epilepsy. In some embodiments, the methods described herein further comprise identifying a subject with a neurodevelopmental disorder (e.g., autism with epilepsy, tuberous sclerosis complex, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorder with epilepsy) prior to administration of a formulation described herein.

[0111] In one aspect, the invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis complex, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental with epilepsy), the method comprising administering to a subject in need thereof a formulation (e.g., a dosage form, a composition in a dosage form, comprising Compound 1) described herein.

[0112] pain The formulations described herein (e.g., dosage forms, compositions in dosage forms comprising Compound 1) can be useful for treating pain. In some embodiments, the pain comprises neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or a related headache disorder. In some embodiments, the methods described herein further comprise identifying a subject with pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or a related headache disorder) prior to administration of a formulation described herein (e.g., dosage form, compositions in dosage forms comprising Compound 1).

[0113] In one aspect, the invention features a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or a related headache disorder) comprising administering to a subject in need thereof a formulation (e.g., a dosage form, a composition in a dosage form, comprising Compound 1) described herein.

[0114] Neuromuscular disorders The formulations described herein (e.g., dosage forms, compositions in dosage forms comprising Compound 1) can be useful for treating neuromuscular disorders. In some embodiments, the neuromuscular disorder includes amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutations. In some embodiments, the methods described herein further include identifying a subject with a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutations) prior to administration of a formulation described herein.

[0115] In one aspect, the invention features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with an SCN4A mutation), the method comprising administering to a subject in need thereof a formulation (e.g., a dosage form, a composition in a dosage form, comprising Compound 1) described herein.

[0116] Other disorders In some embodiments, the formulations of the present invention (e.g., dosage forms, compositions in dosage forms comprising Compound 1) may have suitable pharmacokinetic properties so that they may be active with respect to the central nervous system and / or peripheral nervous system. In some embodiments, the formulations provided herein (e.g., dosage forms, compositions in dosage forms comprising Compound 1) are used to treat cardiovascular diseases such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in the heart, kidney, liver, and brain, exertional angina, pulmonary hypertension, congestive heart disease, including diastolic and systolic heart failure, recurrent ischemia, cerebral ischemia, stroke, renal ischemia, ischemia associated with organ transplantation, acute coronary syndrome, peripheral arterial disease, intermittent claudication, and myocardial infarction.

[0117] In some embodiments, the formulations provided herein (e.g., dosage forms, compositions in dosage forms comprising Compound 1) can be used to treat diseases affecting the neuromuscular system that result in itching, seizures, or paralysis, or to treat diabetes or decreased insulin sensitivity, as well as conditions associated with diabetes, such as diabetic peripheral neuropathy. In some embodiments, the disclosed methods comprise administering a pharmaceutical composition.

[0118] In some embodiments, provided herein are methods for treating a neurological or psychiatric disorder, the methods comprising administering a formulation disclosed herein (e.g., a dosage form, a composition in a dosage form, comprising Compound 1) to a subject in need of such treatment.

[0119] Oncology In another aspect, the present disclosure provides a method of treating cancer, the method comprising administering to a subject in need thereof a dosage form or a composition in a dosage form disclosed in the present disclosure.

[0120] Trigeminal autonomic headache The compounds, dosage forms, and compositions described herein (e.g., Compound 1, dosage forms or compositions containing Compound 1) are useful for treating trigeminal autonomic headaches (TAC). TAC is a group of primary headaches characterized by unilateral pain, a relatively short duration of symptoms, and associated ipsilateral autonomic symptoms. TAC can include cluster headache (CH), paroxysmal hemicrania (PH), hemicrania continua (HC), short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA), and long-lasting unilateral headache with hemicrania (LASH). Despite their common elements, trigeminal autonomic headaches differ, for example, in attack duration and frequency and response to treatment.

[0121] In some embodiments, the present invention provides methods of treating PH, HC, SUNCT, SUNA, and / or LASH using the dosage forms described herein. In some embodiments, the present invention provides methods of treating SUNCT using the compounds, dosage forms, or compositions described herein (e.g., Compound 1, dosage forms or compositions comprising Compound 1). In some embodiments, the present invention provides methods of treating SUNA using the provided compounds, dosage forms, or compositions described herein (e.g., Compound 1, dosage forms or compositions comprising Compound 1). In another aspect, provided herein is a method of treating or preventing trigeminal autonomic headache (TAC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, dosage form, or composition disclosed herein (e.g., Compound 1, dosage forms or compositions comprising Compound 1).

[0122] In another aspect, the present invention provides a method for treating or preventing trigeminal autonomic headache (TAC) in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, for example, 2.5 mg to 90 mg of Compound 1, to the subject.

[0123] In some embodiments, the TAC is selected from the group consisting of paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA), and long-lasting hemicrania with autonomic symptoms.

[0124] In another embodiment, the TAC is a short-lasting unilateral neuralgiform headache attack.

[0125] In certain embodiments, the TAC is SUNCT. In some embodiments, the TAC is SUNA.

[0126] In other embodiments, the subject has an inadequate response to at least one agent used in the treatment of TAC.

[0127] Migraine The compounds, dosage forms, and compositions described herein (e.g., Compound 1, dosage forms or compositions comprising Compound 1) are useful for treating migraine. Migraine is a primary headache disorder characterized by moderate to severe recurrent headaches. As described herein, migraine can be migraine without aura, migraine with aura, hemiplegic migraine, familial hemiplegic migraine (FHM), familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 3 (FHM3), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM).

[0128] In some embodiments, the present invention provides methods for treating migraine without aura, migraine with aura, hemiplegic migraine, FHM, FHM1, FHM2, FHM3, FHM4, and / or SHM using provided compounds. In some embodiments, the present invention provides methods for treating migraine without aura, migraine with aura, FHM1, FHM2, FHM4, and / or SHM using provided compounds, dosage forms, or compositions (e.g., Compound 1, dosage forms or compositions comprising Compound 1). In some embodiments, the present invention provides methods for treating migraine without aura using provided compounds. In some embodiments, the present invention provides methods for treating migraine with aura using provided compounds, dosage forms, or compositions (e.g., Compound 1, dosage forms or compositions comprising Compound 1). In some embodiments, the present invention provides methods for treating FHM1, FHM2, and / or FHM4 using provided compounds. In some embodiments, the present invention provides methods of treating SHM using a provided compound, dosage form, or composition (e.g., Compound 1, a dosage form or composition comprising Compound 1).

[0129] In another aspect, provided herein is a method of treating or preventing migraine in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, dosage form, or composition disclosed herein (e.g., Compound 1, a dosage form or composition comprising Compound 1).

[0130] In another aspect, the present invention provides a method for treating or preventing migraine in a subject in need thereof, comprising administering a therapeutically effective amount of Compound 1, e.g., 2.5 mg to 90 mg of Compound 1, to the subject.

[0131] In some embodiments, the migraine is selected from the group consisting of migraine without aura, migraine with aura, familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM). In other embodiments, the migraine is migraine without aura. In certain embodiments, the migraine is migraine with aura. In some embodiments, the migraine is FHM1. In some embodiments, the migraine is FHM2. In other embodiments, the migraine is FHM4. In certain embodiments, the migraine is SHM. In some embodiments, the subject has an inadequate response to at least one medication used to treat migraine.

[0132] Cortical spreading inhibition The compounds, dosage forms, and compositions described herein (e.g., Compound 1, dosage forms or compositions comprising Compound 1) are useful for treating cortical spreading depression (CSD), which is a sustained wave of depolarization (neuronal deactivation) that travels through intact brain tissue and is involved in, for example, cerebral ischemia, migraine aura, and seizures.

[0133] In another aspect, there is provided a method for treating or preventing cortical spreading depression (CSD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, dosage form, or composition disclosed herein (e.g., Compound 1, a dosage form or composition comprising Compound 1).

[0134] Provided is a method for treating or preventing cortical spreading depression (CSD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg of Compound 1, to the subject.

[0135] Cranial nerve disorders The compounds, dosage forms, and compositions described herein (e.g., Compound 1, dosage forms or compositions containing Compound 1) are useful for treating cranial neuropathy. Neuropathy is a disease of nerve damage that affects the ability to feel and move. When nerves in the brain or brainstem are affected, it is called a cranial neuropathy. Cranial nerves are nerves that arise directly from the brain or brainstem and often affect areas such as the face and eyes. Cranial neuropathy includes Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, and sixth nerve palsy. When several different cranial nerves are affected, it is called multiple cranial neuropathy (MCN).

[0136] Also provided herein are methods for treating or preventing cranial neuropathy or cranial polyneuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, dosage form, or composition described herein (e.g., Compound 1, a dosage form or composition comprising Compound 1).

[0137] In another aspect, provided herein is a method for treating or preventing cranial neuropathy or cranial polyneuropathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg of Compound 1.

[0138] In some embodiments, the cranial nerve disorder is selected from the group consisting of Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, and sixth nerve palsy. In other embodiments, the dosage form is administered orally. In certain embodiments, the dosage form is a capsule. In some embodiments, the patient is between 18 and 65 years of age.

[0139] Combination therapy The formulations described herein (e.g., dosage forms or compositions comprising Compound 1) can be administered in combination with another drug or therapy, for example, for use in modulating sodium ion channels, e.g., late sodium (INaL) current. The subject to whom the formulations disclosed herein are to be administered can have a disease, disorder, or condition, or symptoms thereof, that would benefit from treatment with another drug or therapy. These diseases or conditions can be related to epilepsy or epilepsy syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders.

[0140] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol.

[0141] Combination cardiovascular therapy Cardiovascular-related diseases or conditions that may benefit from combination therapy of the sodium channel blockers of the present invention with other therapeutic agents include, but are not limited to, angina pectoris, including stable angina, unstable angina (UA), exertional angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction, including non-STE myocardial infarction (NSTEMI), pulmonary hypertension, including pulmonary arterial hypertension, heart failure, including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.

[0142] Suitable therapeutic agents for treating cardiovascular-related diseases or conditions include antianginal agents, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid-lowering agents.

[0143] Co-administration of the sodium channel blockers of the present invention with therapeutic agents suitable for treating cardiovascular-related conditions allows for the augmentation of the standard of care therapy currently being received by the patient.

[0144] Antianginal drugs Antianginal medications include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the heart's workload, thereby reducing its oxygen demands, resulting in a slower heart rate and less forceful contractions. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

[0145] Nitrates dilate arteries and veins, thereby increasing coronary blood flow and lowering blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide 5-nitrate.

[0146] Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels, relaxing the blood vessels and thereby increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisolodipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

[0147] Heart failure drugs Medications used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics remove excess fluid from tissues and the circulation, thereby alleviating many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

[0148] Angiotensin-converting enzyme (ACE) inhibitors reduce the heart's workload by dilating blood vessels and decreasing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).

[0149] Vasodilators reduce pressure on blood vessels by relaxing and dilating them. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

[0150] Cardiac glycosides are compounds that increase the force of cardiac contraction. These compounds strengthen the heart's pumping ability and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

[0151] Antithrombotic drugs Antithrombotic drugs inhibit the blood's ability to clot. There are three main types of antithrombotic drugs: antiplatelet drugs, anticoagulants, and thrombolytic drugs.

[0152] Antiplatelet drugs inhibit the coagulation activity of platelets, thereby reducing arterial clotting. Examples of antiplatelet drugs include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantinsulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb / IIIa inhibitors such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta-blockers and calcium channel blockers also have platelet-inhibiting effects. Anticoagulants prevent clots from growing and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low-molecular-weight heparin, danaparoid, lepirudin, and argatroban.

[0153] Thrombolytic drugs work by breaking down existing clots. Examples of thrombolytic drugs include streptokinase, urokinase, and tenecteplase (TNK), as well as tissue plasminogen activator (t-PA).

[0154] Antiarrhythmic drugs Antiarrhythmic drugs are used to treat heart rate and rhythm disorders. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta-blockers are also used as antiarrhythmic drugs.

[0155] The combination of amiodarone with dronedarone is of particular interest given the recently discovered synergistic effects of amiodarone with the sodium channel blocker ranolazine.

[0156] Antihypertensive drugs Antihypertensive drugs are used to treat hypertension, a condition in which blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and by implication, blood clots. Examples of antihypertensive drugs include alpha-1-adrenergic blockers, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic blockers, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken). central alpha-adrenergic receptor agonists such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenzacetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); labetalol (Normodyne, Trandate), carbezole combined alpha / beta-adrenergic blocking drugs such as fluprexol (Coreg); adrenergic neuron blockers such as guanethidine (ismelin) and reserpine (Serpasil); centrally acting antihypertensive drugs such as clonidine (Catapres), methyldopa (Aldomet), and guanabenz (Wytensin); antiangiotensin II drugs; perindopril (Aceon), captopril (Capoten), enalapril (Vasotec), and lisinopril ACE inhibitors such as (Prinivil, Zestril); angiotensin II receptor antagonists such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), and valsartan (Diovan); calcium channel blockers such as verapamil (Calan, Isoptin), diltiazem (Cardizem), and nifedipine (Adalat, Procardia); diuretics;Direct vasodilators such as nitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), and verapamil; and potassium channel activators such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

[0157] Lipid-lowering drugs Lipid-lowering drugs are used to reduce the amount of cholesterol or fatty acids present in the blood. Examples of lipid-lowering drugs include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava), pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

[0158] In the present invention, patients presenting with an acute coronary artery disease event often suffer from secondary medical conditions, such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder, and such patients may benefit from combination therapy treatment comprising administering to the patient ranolazine in combination with at least one therapeutic agent.

[0159] Combination therapy for lung disorders Pulmonary disorders refer to any disease or condition related to the lungs. Examples of pulmonary disorders include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

[0160] Examples of therapeutic agents used to treat lung disorders include bronchodilators, including beta-2 agonists and anticholinergics, corticosteroids, and electrolyte supplements.Specific examples of therapeutic agents used to treat lung disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.

[0161] Combination Therapy for Metabolic Disorders Examples of metabolic disorders include, but are not limited to, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0162] Examples of therapeutic agents used to treat metabolic disorders include antihypertensives and lipid-lowering agents, such as those described in the "Combined Cardiovascular Therapy" section above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.

[0163] Peripheral vascular disease combination therapy Peripheral vascular disorders are disorders related to blood vessels (arteries and veins) located outside the heart and brain, and include, for example, peripheral arterial disease (PAD), a condition that occurs when the arteries that supply blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis.

[0164] Combination therapy for gastrointestinal disorders Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.

[0165] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), and rabeprazole; H2 blockers such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid); prostaglandins such as misoprostol (Cytotec); sucralfate; and antacids.

[0166] Combination therapy with antibiotics, analgesics, antidepressants, and anti-anxiety medications Patients presenting with an acute coronary artery disease event may present a condition that would benefit from the administration of therapeutic agent(s) that are antibiotics, analgesics, antidepressants, and anti-anxiety agents in combination with ranolazine.

[0167] antibiotics Antibiotics are therapeutic drugs that kill or stop the growth of microorganisms, including both bacteria and fungi. Examples of antibiotics include penicillin (amoxicillin), cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor), cefuroxime Axtel (cefuroxime beta-lactam antibiotics, including cephalosporins, carbapenems, and monobactams, such as cephalosporins (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), and ceftriaxone (Rocephin); tetracyclines, such as tetracycline; macrolides, such as erythromycin; aminoglycosides, such as gentamicin, tobramycin, and amikacin; quinolones, such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramins, and polymyxins; lincosamides, such as clindamycin; oxazolidinones, such as linezolid; and sulfa antibiotics, such as sulfisoxazole.

[0168] painkillers Analgesics are therapeutic drugs used to relieve pain. Examples of analgesics include sedatives and morphine-like drugs such as fentanyl and morphine, paracetamol, NSAIDs, and COX-2 inhibitors. V Given the ability of the sodium channel blockers of the present invention to treat neuropathic pain via 1.7 and 1.8 sodium channel inhibition, combination with analgesics is particularly contemplated. See U.S. Application Publication No. 2009 / 0203707.

[0169] Antidepressants and anti-anxiety drugs Antidepressants and anti-anxiety medications include medications used to treat anxiety disorders, depression, and medications used as sedatives and tranquilizers. Examples of antidepressants and anti-anxiety medications include benzodiazepines (e.g., diazepam, lorazepam, and midazolam), benzodiazepines, barbiturates, glutethimide, chloral hydrate, meprobamate, sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan), venlafaxine (Effexor), and the like. Antidepressants and anxiolytics include neurostimulant steroids and ketamine, as well as related NMDA receptor antagonists.

[0170] Thus, one aspect of the present invention provides a composition comprising a sodium channel blocker of the present invention and at least one therapeutic agent. In an alternative embodiment, the composition comprises a sodium channel blocker of the present invention and at least two therapeutic agents. In further alternative embodiments, the composition comprises a sodium channel blocker of the present invention and at least three therapeutic agents, a sodium channel blocker of the present invention and at least four therapeutic agents, or a sodium channel blocker of the present invention and at least five therapeutic agents.

[0171] Methods of combination therapy include simultaneous administration of a single formulation containing a sodium channel blocker of the present invention and a therapeutic agent(s), essentially simultaneous administration of multiple formulations comprising a sodium channel blocker of the present invention and a therapeutic agent(s), and sequential administration of a sodium channel blocker of the present invention and a therapeutic agent(s) in any order, preferably during which there is a period of time during which the sodium channel blocker of the present invention and a therapeutic agent(s) simultaneously exert their therapeutic effects.

[0172] Preparation method Provided herein are methods for preparing compounds useful for preventing and / or treating the diseases, disorders, or conditions described herein, e.g., diseases, disorders, or conditions associated with abnormal function of sodium ion channels, such as abnormal late sodium current (INaL).

[0173] In one aspect, the present disclosure provides a compound of formula 1: [ka] or a pharmaceutically acceptable salt thereof, the method comprising: (i) contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoro-pyridine to provide a compound of formula (II); [ka] (ii) contacting a compound of formula (II) with a palladium catalyst and bis(pinacolato)diboron to provide a compound of formula (III); [ka] (iii) contacting the compound of formula (III) with a palladium catalyst and 2-bromo-5-chloro-pyrazine to provide a compound of formula (IV); [ka] (iv) contacting a compound of formula (IV) with hydrazine to provide a compound of formula (V); [ka] (v) contacting the compound of formula (V) with 2-bromo-2,2-difluoro-acetyl chloride to provide a compound of formula (VI); [ka] (vi) contacting a compound of formula (VI) with an acid to provide a compound of formula (VII); [ka] (vii) contacting the compound of formula (VII) with a silver catalyst and ethanol to provide Compound 1 or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the palladium catalyst in step (ii) or (iii) is [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. In certain embodiments, the silver catalyst in step (vii) is silver tetrafluoroborate. In other embodiments, the acid in step (vi) is p-toluenesulfonic acid.

[0175] In another aspect, the present disclosure provides a compound 1, [ka] or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is a compound represented by formula (VII): [ka] with a silver catalyst and ethanol.

[0176] In some embodiments, the compound of formula (VII) has formula (VI): [ka] with an acid.

[0177] In other embodiments, the compound of formula (VI) has formula (V): [ka] with 2-bromo-2,2-difluoro-acetyl chloride.

[0178] In certain embodiments, the compound of formula (V) has formula (IV): [ka] with hydrazine.

[0179] In some embodiments, the compound of formula (IV) has formula (III): [ka] with a palladium catalyst and 2-bromo-5-chloro-pyrazine to provide:

[0180] In other embodiments, the compound of formula (III) has formula (II): [ka] with a palladium catalyst and bis(pinacolato)diboron to provide:

[0181] In certain embodiments, the compound of Formula (II) is provided by contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoro-pyridine. In other embodiments, the silver catalyst is silver tetrafluoroborate. In some embodiments, the acid is p-toluenesulfonic acid. In other embodiments, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

[0182] Example The following representative examples are intended to serve to illustrate the present invention and are not intended, nor should they be construed, to limit the scope of the invention. [Table 1] TIFF0007822621000026.tif21170

[0183] Example 1. Preparation and Characterization of Milled Compound 1 Compound 1 was milled by manual milling or jet milling to reduce particle size. For manual milling, Compound 1 was weighed into a ceramic mill and gently milled for approximately 5 minutes. The particle size distribution (PSD) of Compound 1 showed D90 = 77.82 μm and D90 = 28.27 μm before and after manual milling of Compound 1. PSD by the dry method was performed using a Sympatec HELOS particle size analyzer, and the dispersion system and pressure were RODOS and 0.5 bar, respectively. [Table 2]

[0184] In the case of jet milling, compound 1 was micronized by jet milling in approximately 90% yield. The particle size of the jet milled material was reduced to a D90 range of 4.7-13.5 μm. [Table 3]

[0185] X-ray powder diffraction (XRPD) data were collected using a Bruker D8 Advance powder diffractometer. Samples were irradiated with copper K-alpha X-rays (λ = 1.54179 Å) using a generator operating at 40 kV / 40 mA. Samples were scanned in continuous mode from 3° to 40° (2θ) with a sample rotation rate of 15 rpm and a scan rate of 10° / min. Figure 1 shows the XRPD patterns of the raw and jet-milled material, indicating no change in the physical form of compound 1 after jet-milling.

[0186] Compound 1 before and after jet milling was analyzed by proton NMR ( 1 H-NMR), Fluorine NMR ( 19 F-NMR, and LC-MS analyses were also performed. Both the NMR and LC-MS results indicate that no chemical or structural changes to compound 1 were observed upon jet milling.

[0187] Example 2. Preparation and stability of formulations containing Compound 1 Solution preparation 1) Prototype 1: 40% PEG 400 / 10% Cremophor RH40 / 50% water 2400 μL of PEG400 was added to an 8 mL glass vial with 3 mg of Compound 1, and the mixture was mixed together using a vortex and sonicated for 5 minutes. Next, 600 μL of Cremophor RH40 was added to the vial, and the mixture was mixed together using a vortex and sonicated for 5 minutes. Next, 3000 μL of water was added to the vial, and the mixture was mixed together using a vortex and sonicated for 5 minutes. The compound was completely dissolved (0.5 mg / mL).

[0188] 2) Prototype 2a: 58.1% Cremophor RH40 + 16.9% Labrafil M2125 CS + 8.3% propylene glycol + 16.7% ethanol Vehicle Preparation: 11.62 mL of Cremophor RH40, 3.38 mL of Labrafil M2125 CS, 1.66 mL of propylene glycol, and 3.34 mL of ethanol were mixed together to obtain the prototype 2a vehicle.

[0189] Approximately 15 mg of compound 1 was weighed into an 8 mL glass container, and then 2 mL of prototype 2a was added to the glass container. The contents were mixed by vortexing and sonication for 5 minutes. 7.5 mg / mL of prototype 2a compound 1 was a clear solution.

[0190] 3) Prototype 2b: 69.74% Cremophor RH40 + 20.28% Labrafil M2125 CS + 9.98% Propylene Glycol. Preparation: 11.62 mL of Cremophor RH40, 3.38 mL of Labrafil M2125 CS and 1.66 mL of propylene glycol were mixed together to provide the vehicle for prototype 2b.

[0191] Approximately 15 mg of compound was weighed into an 8 mL glass container, and then 2 mL of prototype 2b was added to the container, mixed together by vortexing, and sonicated for 5 minutes. Compound 2 in 7.5 mg / mL prototype 2b was not clear. Next, another 140 μL of prototype 2b vehicle was added to the container, mixed together by vortexing, and sonicated for 5 minutes. The 7 mg / mL prototype 2b was a clear solution.

[0192] 4) Prototype 3: 40% Transcutol HP / 10% Vitamin ETPGS / 50% water 600 μL of PEG400 is added to a 4 mL glass vial together with 3 mg of compound 1, and the mixture is mixed by vortexing, and ultrasonicated for 5 minutes.Then, 150 μL of Cremophor RH40 is added to the vial, and the mixture is mixed by vortexing, and ultrasonicated for 5 minutes.Then, 750 μL of water is added to the vial, and the mixture is mixed by vortexing, and ultrasonicated for 5 minutes.Compound is completely dissolved (2 mg / mL).

[0193] 5) Prototype 4: 36% Cremophor RH40 + 45% Capmul MCM C8 + 9% triethyl citrate + 10% ethanol Cremophor RH40, Capmul MCM C8, triethyl citrate, and ethanol were added together by weight to a glass container and mixed together to form a solution mixture. Increasing amounts of Compound 1 were then added to the mixture, vortexed, and sonicated to form a clear solution. Additional Compound 1 was added with vortexing and sonication until Compound 1 was no longer soluble. The maximum solubility achieved was visually determined to be 25-50 mg / mL.

[0194] 6) Prototype 5: 40% Capryol 90 + 20% Labrasol + 40% Transcutol HP Capryol 90, Labrasol, and Transcutol HP were added together by volume to a glass container and mixed together to form a solution mixture. Increasing amounts of Compound 1 were then added to the mixture, vortexed, and sonicated to form a clear solution. Additional Compound 1 was added with vortexing and sonication until Compound 1 was no longer soluble. The maximum solubility achieved was visually determined to be 60-80 mg / mL.

[0195] Table 3 summarizes the prototypes and their respective stability used to prepare solution formulations of Compound 1. Table 4 shows the detailed stability results. [Table 4]

[0196] A high performance liquid chromatography (HPLC) method was developed for the stability and purity testing of Compound 1. The HPLC method used for chemical stability and purity testing was as follows: [Table 5] [Table 6]

[0197] Approximately 24 mg of compound 1 was added to an 8 mL glass bottle, dissolved by Prototype 2b, and then sonicated for 10 minutes to obtain a clear solution with a concentration of 7 mg / mL.Then, the solution was diluted with water three times for stability testing.The results are shown in Table 5 below. [Table 7]

[0198] Based on HPLC results and appearance, formulations of prototypes 1, 2a, 2b and 3 containing compound 1 were stable at ambient conditions for at least 7 days.

[0199] Suspension formulation To prepare suspension formulations of Compound 1, approximately 0.5 mg, 5 mg, and 10 mg of Compound 1 were weighed into separate vials, and 1 mL of 0.5% MC 400cP / 0.2% Tween 80 was added to each vial. The materials were mixed together using a vortex and stirred overnight (24 hours) at room temperature. The stability of the suspension formulations was determined by quantifying the purity of Compound 1 using high-pressure liquid chromatography (HPLC). The suspensions remained homogeneous. Table 6 summarizes the stability results.

[0200] To prepare the suspension formulation containing jet-milled Compound 1, 15 mg of jet-milled Compound 1 was weighed into a glass vial and then dispersed in 10 mL of vehicle (0.5% MC 400 cP / 0.2% Tween 80) to achieve a Compound 1 concentration of 1.5 mg / mL. The suspension was completely dispersed by homogenization for approximately 30 seconds. The stability of the suspension was evaluated by HPLC and particle size distribution (PSD), and the results are summarized in Table 7. Based on HPLC and PSD, the suspension formulation containing jet-milled Compound 1 was stable under ambient conditions for 28 days. [Table 8] [Table 9]

[0201] As shown in Tables 8-11, various suspension formulations were tested for stability under different conditions.

[0202] To prepare the suspension, weigh the required amount of ground Compound 1 into a glass container and add the corresponding volume of vehicle. Use an overhead mixer to thoroughly disperse the compound into a homogenous suspension at the final concentration target. Concentrations were prepared at 0.1 mg / mL and 10 mg / mL. The suspension product was physically evaluated for appearance, concentration, purity, and PSD.

[0203] The vehicle was prepared by dissolving 0.5% by weight of either 400 cP or 4000 cP methylcellulose and 0.2% Poloxamer 188. For the stock suspension, an additional 1.0% by volume of paraben stock solution was dissolved in the vehicle using an overhead mixer. The paraben stock solution was prepared by dissolving 0.10 g of methylparaben, 0.025 g of propylparaben in 9.875 g of propylene glycol and mixing with a stir bar for 1 hour at room temperature. [Table 10] [Table 11] [Table 12] [Table 13]

[0204] Amorphous Solid Dispersions (ASD) Amorphous solid dispersions containing Compound 1 were prepared using a mixture of Compound 1 and a polymer. Nine different polymers (PVPK30, PVPVA64, Soluplus, HPMC E5, HPMC ASMG, HPMC ASMF, HPMC ASHG, Eudragit EPO, and Eudragit L100) were used to screen for solid dispersion agents, and nine ASD formulations were prepared. Approximately 10 mg of Compound 1 and 40 mg of the corresponding polymer were weighed into a 40-mL glass vial and dissolved in 1 mL of MeOH / DCM (1:1, v / v) to prepare a stock solution. The resulting clear solution was stored at 70 °C and rapidly evaporated to obtain the solid dispersion. The evaporated product was dried under vacuum at 30 °C overnight and further characterized by appearance, PLM, XRPD, and mDSC.

[0205] Nine ASD formulations were tested for kinetic solubility in FaSSIF at a concentration of 2 mg / mL. Experiments were performed at 37°C and a speed of 450 rpm. At each time point, 0.5 mL of the mixture was removed and centrifuged before running UPLC (a shortened runtime version of the HPLC method described was used to determine the levels of Compound 1). The results are shown in Table 12. Enhanced solubility was observed for most polymers, especially Eudragit EPO. [Table 14]

[0206] Based on the kinetic solubility evaluation of the prototype ASD formulations, three exemplary prototype ASD formulations were then prepared for further evaluation using Soluplus, Eudragit L100, or HPMC ASMF, as summarized in Table 13. Stability testing results for selected ASD formulations are shown in Tables 14 and 15. [Table 15] [Table 16] [Table 17]

[0207] Scale-up of three ASDs using a spray dryer ASD-1 Preparation: Approximately 300 mg of Compound 1 and approximately 1200 mg of Soluplus were weighed into a 250 mL glass, and then 150 mL of acetone was added to form a clear solution, which was then spray-dried. After spray-drying, the powder was collected and dried under vacuum at 30°C for 12 hours (yield 80.2%).

[0208] ASD-2 Preparation: Approximately 300 mg of Compound 1 and approximately 1200 mg of Eudragit L100 were weighed into a 250 mL glass, and then 150 mL of acetone was added to form a clear solution, which was then spray-dried. After spray-drying, the powder was collected and dried under vacuum at 30°C for 12 hours (yield 74.5%).

[0209] ASD-3 Preparation: Approximately 300 mg of Compound 1 and approximately 1200 mg of HPMC ASMF were weighed into a 250 mL glass, and then 150 mL of acetone was added to form a clear solution, which was then spray-dried. After spray-drying, the powder was collected and dried under vacuum at 30°C for 12 hours (yield 70.0%).

[0210] The ASD-3 prototype was also evaluated in an in vitro dissolution test. The collected ASD-3 spray-dried powder was hand-weighed directly into size #4 hard gelatin capsules using an analytical balance in two dosage strengths: 2.5 and 10 mg of active ingredient (13.7 and 54.8 mg of ASD).

[0211] The elution method was carried out under the following conditions: [Table 18]

[0212] For dissolution analysis, an HPLC method was used to quantify Compound 1 levels in the dissolution medium. The same HPLC method was used for both the dissolution test and the content uniformity test. The HPLC method used is as follows: [Table 19]

[0213] The dissolution results are shown in Figure 2, where the release for the two dose strengths was 29.76% and 17.64%, respectively, for 2.5 mg and 10 mg dose strengths.

[0214] The ASD-3 prototype was also evaluated in a pharmacokinetic (PK) study in cynomolgus monkeys using a crossover study design. Collected ASD-3 spray-dried powder was manually weighed directly into size #4 hard gelatin capsules using an analytical balance. Three male monkeys were orally administered 0.5 mg / kg body weight in the fasted state, and plasma samples were analyzed for Compound 1 levels.

[0215] Capsule formulation Exemplary capsule formulations contain 2.5 mg, 10 mg, or 100 mg per capsule of Compound 1. For the 2.5 mg dose capsule, the formulation contains a 1:10 blend of Compound 1 to microcrystalline cellulose (MCC) with 2% magnesium stearate (MgSt) in a gelatin capsule, while another formulation contains 2.5 mg of pure Compound 1 (without additional excipients) in a gelatin capsule.

[0216] The ground Compound 1 and filler (MCC or starch) were weighed separately and blended for 15 minutes to obtain a homogeneous mixture. The required amount of magnesium stearate was added and blended together. The blend was manually filled into hard gelatin capsules of appropriate size. The samples were then subjected to stability under various conditions and analyzed for assay appearance at various time points.

[0217] Blended formulation Blends 1 and 2 (1:10 blend) 1 g of ground Compound 1 and 9 g of MCC or starch were weighed into a container. The two components were mixed in a Turbula at 36 rpm for approximately 15 minutes to obtain a homogeneous phase. 0.2 g of MgSt was added and mixed for an additional 3 minutes to obtain a homogeneous Blend 1 (Table 16). Dose uniformity was evaluated by measuring a 10-capsule assay (Tables 18 and 19). [Table 20]

[0218] Blends 3 and 4 (1:1 blends) 5g of ground Compound 1 and 5g of MCC or starch were weighed into a container. The two components were mixed in a Turbula at 36 rpm for about 15 minutes to obtain a homogeneous phase. 0.2g of MgSt was added and mixed for an additional 3 minutes to obtain a homogeneous Blend 1 (Table 17). Dose uniformity was evaluated by measuring a 10-capsule assay (Tables 20 and 21). [Table 21]

[0219] Tables 18-21 summarize the blend uniformity results for four exemplary blends containing Compound 1 (Blends 1-4 above). [Table 22] [Table 23] [Table 24] [Table 25]

[0220] Tables 21.1, 21.2, 21.3, and 21.4 show the stability results for Blend 1 and Blend 2 capsules at dose strengths of 1 mg per capsule (1:10 blend ratio), 10 mg per capsule (1:10 and 50:50 blend ratios), and 100 mg per capsule (50:50 blend ratio). [Table 26] [Table 27] [Table 28] [Table 29]

[0221] Dissolution of Blend 1 at a 1:10 ratio of Compound 1 to MCC in size #0 HG capsules was evaluated at both 1 mg and 10 mg of active ingredient (10 mg and 100 mg blends with MCC, respectively).

[0222] The elution method was carried out under the following conditions: [Table 30]

[0223] The results are shown in Figure 3, where 50.3% of the 1 mg dose strength capsule was released after 120 minutes and 20.5% of the 10 mg dose strength capsule was released after 120 minutes.

[0224] Further prototype blend capsule formulations were prepared to evaluate the effect of adding surfactant to the 1:10 MCC capsule blend (Blend 1). 1:10 Compound 1:MCC (25 mg blend and 0.5 mg SLS) with 2% SLS was hand-filled into size #4 hard gelatin capsules (dose level was 2.5 mg active ingredient per capsule) for evaluation in stability studies (Table 21.3), crossover monkey PK studies, and dissolution studies. [Table 31]

[0225] Three male monkeys were orally administered 0.5 mg / kg body weight in the fasted state, and plasma samples were analyzed for Compound 1 levels. The resulting plasma Compound 1 levels showed no significant increase in exposure from surfactant-containing MCC blend capsules (AUC[0-inf] = 1,004 ng-hr / mL) compared with no surfactant (area under the curve from time 0 to infinity, AUC[0-inf] = 994 ng-hr / mL).

[0226] Blend 1 MCC capsules with and without surfactant were also evaluated in an in vitro dissolution test at a dose strength of 2.5 mg Compound 1.

[0227] The elution method was carried out under the following conditions: [Table 32]

[0228] Dissolution results are shown in Figure 4 and show that the addition of 2% SDS to the formulation significantly increased the in vitro dissolution release, from 38% release after 120 minutes with Poloxamer 188 to 54% release after 120 minutes with SLS.

[0229] Table 22 presents other exemplary formulations of blended capsules (Prototypes 1-12). [Table 33]

[0230] Examples of excipients that may be used in preparing the formulations disclosed in this application are provided in Table 23. [Table 34] TIFF0007822621000060.tif121170

[0231] Example 3. Pharmacokinetic study of formulations containing Compound 1 Pharmacokinetic (PK) studies were conducted in animals using the formulations described in Example 2. Compound 1 was formulated to achieve the desired dose (Table 24) and administered to groups of three fasted animals by single oral gavage. A minimum of seven time points were used to collect blood samples, and plasma samples were then prepared for bioanalysis. PK parameters were then obtained after non-compartmental pharmacokinetic analysis using Phoenix WinNonlin software (version 6.3, Pharsight, Mountain View, CA). A linear / logarithmic trapezoidal rule was applied to obtain PK parameters. Nominal dose levels and nominal sample collection times were used to calculate all pharmacokinetic parameters. PK data are summarized in Table 24. The results are summarized in the following table. Studies 14 to 17 were conducted under a crossover design. In the table, Prototype 2a solution is 58.1% Kolliphor RH40 + 16.9% Labrafil M2125 CS + 8.3% propylene glycol + 16.7% ethanol. MC is methylcellulose 400cP, Tween 80 is polyoxyethylene (80) sorbitan monooleate, HPMC-ASMF, Soluplus, and Eudragit are polymers, and Poloxamer is a copolymer. [Table 35]

[0232] For the Cmax values ​​in Table 24, A indicates more than 50 ng / mL and up to 150 ng / mL, B indicates more than 150 ng / mL and up to 300 ng / mL, C indicates more than 300 mg / mL and up to 600 mg / mL, and D indicates more than 600 ng / mL and up to 900 ng / mL.

[0233] Furthermore, human PK and effective doses are estimated. Based on calculations, the human effective dose for neurological disorders (e.g., epilepsy) is approximately 2.5 to 100 mg (e.g., 60 mg) once daily.

[0234] Example 4. A randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of Compound 1 and the effect of food in healthy volunteers This is a three-part clinical trial to evaluate the safety, tolerability, PK, and food effects of Compound 1 in healthy volunteers aged 18-55 years. The trial consists of three parts: Part A is randomized, double-blind, placebo-controlled. Part A is designed to investigate the safety and PK of single ascending doses of Compound 1. Part B is randomized, double-blind, placebo-controlled, and designed to investigate the safety and PK of multiple ascending doses of Compound 1 (selected based on the results from Part A). Part C is a randomized, open-label, crossover design to investigate the PK of a single dose of Compound 1 in the fasted and fed states.

[0235] Objectives and Evaluation Items: [Table 36] [Table 37] [Table 38]

[0236] Based on emerging safety and PK data from Part A, the SRC may select the starting dose for Part B before the completion of all dose-level cohorts in Part A. Part C may begin after the last SAD cohort. Parts A and B are double-blind, including participants and investigators, and the sponsor is unblinded to facilitate safety review. Each part consists of three periods: screening, intervention, and safety follow-up.

[0237] Screening / Baseline Period The screening period for all three parts will last a maximum of 27 days (days -28 to -2).

[0238] Intervention period After confirmation of continued eligibility, participants will check in to the clinic on Day -1 (the day before study drug administration) and undergo assessments. Participants will remain on the unit from baseline (Day -1) until discharge (Day 6 for Part A, Day 12 for Part B, and Day 13 for Part C).

[0239] Part A Healthy volunteers will be enrolled to receive a single ascending dose of Compound 1 or placebo on Day 1. Dose escalation in Part A will be conducted in a total of six planned cohorts (Cohorts A1-A6). Up to three additional cohorts may be tested at the planned dose levels or intermediate dose levels. Eight participants will be enrolled in each cohort and randomized (3:1 ratio) to receive either Compound 1 or placebo. Compound 1 will be administered to Cohort A1 participants at a starting dose of 2.5 mg. Dosing in all cohorts will be under fasting conditions.

[0240] Dosing in each dose-level cohort will begin with two sentinel participants, one of whom will be randomized to receive Compound 1 and the other randomized to receive placebo. Safety and tolerability in each sentinel participant will be monitored through Day 6 and reviewed prior to dosing of the remaining participants in each cohort.

[0241] Cohorts will be dosed in an escalating fashion. After each dose cohort in Part A completes dosing, the blinded cumulative safety data collected through Day 6 and any available blinded PK data will be reviewed by a Safety Review Committee (SRC) to determine the safety and tolerability of the investigational drug.

[0242] If the current dose level is determined to be safe and tolerable, the next dose cohort will be enrolled and randomized to receive the selected dose of active Compound 1 or placebo. EEG to assess the effect of Compound 1 on auditory-evoked responses may be performed in one or more cohorts, as determined based on the safety and PK profile. [Table 39]

[0243] Part B The starting dose level for Part B will be determined by the SRC based on the safety, tolerability, and PK data obtained in Part A. The SRC may select the starting dose for Part B prior to the completion of all dose-level cohorts in Part A.

[0244] If Part A is deemed safe and tolerable, dose levels will be evaluated in Part B. Three dose levels are expected to be evaluated in Part B, across a total of three cohorts (Cohorts B1-B3). One additional cohort may be added to repeat dose levels or test intermediate doses. Eight participants will be enrolled in each cohort and randomized to receive either Compound 1 or placebo (ratio 3:1).

[0245] The dose levels of Compound 1 evaluated in Part B will not exceed the doses tested in Part A. Dosing will begin on Day 1 and continue through Day 7. The final dose will be administered on the morning of Day 7. Dosing in all cohorts in Part B will be under fasting conditions. Two sentinel participants are planned for each dose cohort in Part B. [Table 40]

[0246] After dosing of the investigational drug is completed for each dose cohort in Part B, the SRC will review the blinded safety data (including the safety assessment performed on Day 9) and available PK data, following the same procedures as in Part A, to determine the safety and tolerability of the investigational drug.

[0247] EEG to assess the effect of Compound 1 on auditory-evoked responses may be performed in one or more cohorts as determined by the sponsor based on the safety and PK profile.

[0248] Part C Part C can begin once safety and PK have been adequately evaluated in the final cohort of Part A. Up to 16 participants will receive two doses of Compound 1, one after a 10-hour fast and one after a high-fat, high-calorie meal in a randomized crossover design with a 7-day washout period. Based on the half-life observed in Part A, up to a 3-day washout period may be added between fasted and fed doses.

[0249] The dose used in Part C will not exceed the dose used in Part A and will be approved by the SRC based on the safety and PK data generated. Sentinel dosing may be used in Part C if deemed appropriate by the SRC. Part C is unblinded.

[0250] Safety Assessment and Monitoring Safety and tolerability assessments will include vital signs, 12-lead ECG, physical examination, laboratory tests, and the C-SSRS as outlined in the SoAs.

[0251] Number of participants: Part A: Up to 72 people will receive Compound 1 or a placebo. ●Part B: Up to 32 people will be administered Compound 1 or placebo. ●Part C: Up to 16 people will be administered Compound 1.

[0252] Exclusion criteria At screening, participants who meet any of the following criteria, among others, will be excluded from this clinical trial: Abnormal ECG findings assessed by the investigator as clinically significant, including a QT interval with Fridericia correction (QTcF) of >450 milliseconds, confirmed by a single repeat test if necessary, at screening or Day 1. Use of systemic prescription or over-the-counter (OTC) medications, including multivitamins, and nutritional and herbal supplements, for 2 weeks prior to the first dose of the study drug or 5 times the drug's terminal half-life, whichever is longer, and throughout the study period.

[0253] Test product, reference therapy, and administration: Part A: Compound 1 capsules or matching placebo will be administered orally. Part B: Compound 1 capsules or matching placebo will be administered orally. Part C: Compound 1 capsules are administered orally.

[0254] Statistical methods: PK Analysis: Validated bioanalytical methods will be utilized to determine plasma and urine concentrations of Compound 1. Plasma and urine concentrations will be summarized by dose group / condition and time point using descriptive statistics. In addition to the descriptive statistics specified in the general terms above, plasma concentrations will also be summarized using the number and percentage of concentrations below the level of quantitation (BLQ) and coefficient of variation (CV%).

[0255] Pharmacokinetic parameters are estimated from concentration-time data using standard non-compartmental methods. Urinary PK parameters are estimated from urinary concentration and volume data. PK parameters are summarized by dose group / condition using descriptive statistics. In addition to the descriptive statistics specified in the general terms above, PK parameters are summarized using CV%, geometric mean, and geometric coefficient of variation. PK parameters are assessed for linearity and dose-proportionality using power models, where possible. To test the effect of food in Part C, the geometric mean ratio (ln-transformed) of the test treatment (i.e., fed condition) to the reference treatment (i.e., fasted condition) is defined as C max and AUC 0-inf Estimates are based on the 90% CI calculated for C max and AUC 0-inf If the 90% CI of both ratios is completely contained within the interval 0.80 to 1.25, it can be concluded that there is no food effect. If there are unexpected difficulties in determining the terminal half-life, the AUC 0-last AUC 0-inf may be used instead of

[0256] Example 5. A randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of Compound 1 and the effect of food in healthy volunteers This is a three-part clinical trial to evaluate the safety, tolerability, PK, and food effects of Compound 1 in healthy volunteers aged 18-55 years. The trial consists of three parts: Part A is a randomized, double-blind, placebo-controlled study designed to investigate the safety, tolerability, and PK of single ascending doses of Compound 1 from 2.5 mg to 90 mg. Part B is randomized, double-blind, placebo-controlled, and designed to investigate the safety, tolerability, and PK of multiple ascending doses of Compound 1 (doses selected based on the results from Part A). Part C is a randomized, open-label, crossover design to investigate the PK, safety, and tolerability of a single dose of Compound 1 (at a dose selected based on the results from Part A) under fasted and fed conditions.

[0257] Objectives and Evaluation Items: [Table 41] [Table 42] [Table 43]

[0258] Based on emerging safety and PK data from Part A, the SRC may select the starting dose for Part B before the completion of all dose-level cohorts in Part A. Part C may begin after the last SAD cohort. Parts A and B are double-blind, including participants and investigators, and the sponsor is unblinded to facilitate safety review. Each part consists of three periods: screening, intervention, and safety follow-up.

[0259] After confirmation of continued eligibility, participants will check in to the clinic on Day -1 (the day before study drug administration) and undergo assessments. Participants will remain on the unit from baseline (Day -1) until discharge (Day 6 for Part A, Day 12 for Part B, and Day 13 for Part C).

[0260] Part A Healthy volunteers will be enrolled to receive a single ascending dose of Compound 1 or placebo on Day 1. Dose escalation in Part A will be conducted in a total of six planned cohorts (Cohorts A1-A6). Up to three additional cohorts may be tested at the planned dose levels or intermediate dose levels. Eight participants will be enrolled in each cohort and randomized (3:1 ratio) to receive either Compound 1 or placebo. Compound 1 will be administered to Cohort A1 participants at a starting dose of 2.5 mg. Dosing in all cohorts will be under fasting conditions.

[0261] Dosing in each dose-level cohort will begin with two sentinel participants, one of whom will be randomized to receive Compound 1 and the other randomized to receive placebo. Safety and tolerability in each sentinel participant will be monitored through Day 6 and reviewed prior to dosing of the remaining participants in each cohort.

[0262] Cohorts will be dosed in an escalating fashion. After each dose cohort in Part A completes dosing, the blinded cumulative safety data collected through Day 6 and any available blinded PK data will be reviewed by a Safety Review Committee (SRC) to determine the safety and tolerability of the investigational drug.

[0263] If the current dose level is determined to be safe and tolerable, the next dose cohort will be enrolled and randomized to receive the selected dose of active Compound 1 or placebo. EEG to assess the effect of Compound 1 on auditory-evoked responses may be performed in one or more cohorts, as determined based on the safety and PK profile. [Table 44]

[0264] Part B The starting dose level for Part B will be determined by the SRC based on the safety, tolerability, and PK data obtained in Part A. The SRC may select the starting dose for Part B prior to the completion of all dose-level cohorts in Part A.

[0265] If Part A is deemed safe and tolerable, dose levels will be evaluated in Part B. Three dose levels are expected to be evaluated in Part B, across a total of three cohorts (Cohorts B1-B3). One additional cohort may be added to repeat dose levels or test intermediate doses. Participants will be enrolled in each cohort and randomized to receive either Compound 1 or placebo (3:1 ratio).

[0266] The dose levels of Compound 1 evaluated in Part B will not exceed the doses tested in Part A. Dosing will begin on Day 1 and continue through Day 7. The final dose will be administered on the morning of Day 7. Dosing in all cohorts in Part B will be under fasting conditions. Two sentinel participants are planned for each dose cohort in Part B. [Table 45]

[0267] After dosing of the investigational drug is completed for each dose cohort in Part B, the SRC will review the blinded safety data (including the safety assessment performed on Day 9) and available PK data, following the same procedures as in Part A, to determine the safety and tolerability of the investigational drug.

[0268] EEG to assess the effect of Compound 1 on auditory-evoked responses may be performed in one or more cohorts as determined by the sponsor based on the safety and PK profile.

[0269] Part C Part C can begin once safety and PK have been adequately evaluated in the final cohort of Part A. Participants will receive two doses of Compound 1, one after a 10-hour fast and one after a high-fat, high-calorie meal in a randomized crossover design, with a 7-day washout period. Based on the half-life observed in Part A, up to a 3-day washout period may be added between fasted and fed doses.

[0270] The dose used in Part C will not exceed the dose used in Part A and will be approved by the SRC based on the safety and PK data generated. Sentinel dosing may be used in Part C if deemed appropriate by the SRC. Part C is unblinded.

[0271] Safety Assessment and Monitoring Safety and tolerability assessments included vital signs, 12-lead ECG, physical examination, laboratory tests, and C-SSRS.

[0272] Exclusion criteria At screening, participants who meet any of the following criteria, among others, will be excluded from this clinical trial: Abnormal ECG findings assessed by the investigator as clinically significant, including a QT interval with Fridericia correction (QTcF) of >450 milliseconds, confirmed by a single repeat test if necessary, at screening or Day 1. Use of systemic prescription or over-the-counter (OTC) medications, including multivitamins, and nutritional and herbal supplements, for 2 weeks prior to the first dose of the study drug or 5 times the drug's terminal half-life, whichever is longer, and throughout the study period.

[0273] Test product, reference therapy, and administration: Part A: Compound 1 capsules or matching placebo will be administered orally. Part B: Compound 1 capsules or matching placebo will be administered orally. Part C: Compound 1 capsules are administered orally.

[0274] Statistical methods: PK Analysis: Validated bioanalytical methods (e.g., liquid chromatography-mass spectrometry (LC-MS)) will be utilized to determine plasma and urine concentrations of Compound 1. Plasma and urine concentrations will be summarized by dose group / condition and time point using descriptive statistics. In addition to the descriptive statistics specified in the general terms above, plasma concentrations will also be summarized using the number and percentage of concentrations below the level of quantitation (BLQ) and coefficient of variation (CV%).

[0275] Pharmacokinetic parameters are estimated from concentration-time data using standard non-compartmental methods. Urinary PK parameters are estimated from urinary concentration and volume data. PK parameters are summarized by dose group / condition using descriptive statistics. In addition to the descriptive statistics specified in the general terms above, PK parameters are summarized using CV%, geometric mean, and geometric coefficient of variation. PK parameters are assessed for linearity and dose-proportionality using power models, where possible. To test the effect of food in Part C, the geometric mean ratio (ln-transformed) of the test treatment (i.e., fed condition) to the reference treatment (i.e., fasted condition) is defined as C max and AUC inf Estimates are based on the 90% CI calculated for C max and AUC inf If the 90% CI of both ratios is completely contained within the interval 0.80 to 1.25, it can be concluded that there is no food effect. If there are unexpected difficulties in determining the terminal half-life, the AUC last is the AUC inf can be used instead of

[0276] result Preliminary analyses of the first four of the six planned cohorts in Part A of the study indicate that Compound 1 appears to be well tolerated at the doses tested. Safety data reviewed included adverse events, vital signs, ECG, C-SSRS, physical examination, and safety laboratory data. No serious adverse events, severe adverse events, or adverse events leading to study discontinuation or interruption were reported in the first three cohorts tested.

[0277] Based on preliminary data, exposure appears to increase proportionally with dose level, with maximum concentrations achieved in 2-3 hours. The terminal elimination half-life averaged 114 hours (approximately 4-5 days) across groups. 90% of steady state should be achieved in approximately 2 weeks with once-daily dosing.

[0278] Example 5. Randomized, double-blind comparison of the efficacy and safety of Compound 1 versus placebo for the acute and prophylactic treatment of chronic SUNCT and SUNA. This multicenter clinical trial will evaluate the efficacy, safety, tolerability, and pharmacokinetics of Compound 1 in participants aged 18 to 65 years with chronic SUNCT or chronic SUNA. This is a double-blind, placebo-controlled study. Participants will be randomized in a 1:1:1 ratio to receive one of three blinded treatments: a high dose of Compound 1 administered orally daily in mg doses, a low dose of Compound 1 administered orally daily in mg doses, or a placebo administered daily. Participants will self-administer the study drug once daily at weekly clinic visits. Participants will be asked to complete questionnaires in an electronic diary (eDiary) three times daily (approximately 24 hours before or after the previous dose, approximately 4 hours after, and approximately 10 hours after the dose). [Table 46]

[0279] The clinical trial will consist of three periods: screening / baseline, intervention, and safety follow-up. An optional washout period will also be available for participants receiving prophylactic medication.

[0280] Screening / Baseline Period The screening period will be, for example, up to 28 days (days -28 to -1). For participants who discontinue SUNCT or SUNA prophylactic medications (e.g., carbamazepine, lamotrigine), an optional washout period will be allowed, for example, up to 14 days before screening.

[0281] During screening, participants will complete daily eDiary entries to assess the stability, severity, and frequency of SUNCT and SUNA headaches, for example, during the 14-day observation period.

[0282] Intervention period After confirmation of eligibility during screening, participants will complete a baseline assessment (Day 1).

[0283] On Day 1, participants return to the clinic, are randomized to one of three treatment groups, and receive their first dose of study medication. Participants remain at the clinic under medical observation for at least 6 hours. Headache logs are completed via eDiary before each dose (e.g., approximately 24 hours after the previous dose) and approximately 4 and 10 hours after each dose. After the first dose, participants continue daily dosing at home until Day 21. Participants return to the clinic to complete assessments, e.g., on Days 7 (± 1 day), 14 (± 1 day), and 21 (± 1 day). At select sites, centralized PK sampling is obtained at the clinic, e.g., on Days 1, 7 (± 1 day), 14 (± 1 day), and 21 (± 1 day).

[0284] Key safety measures will include clinical laboratory assessments, 12-lead ECG, C-SSRS, and vital signs. Primary efficacy assessments will include a headache log via eDiary (see Assessment Schedule for details). Blood samples will be obtained to measure plasma concentrations of Compound 1 using a validated bioanalytical method and may also be used for exploratory method development and / or metabolite characterization.

[0285] Safety follow-up period The safety follow-up period is conducted, for example, from day 22 to, for example, day 36. At the end of the safety follow-up period, participants return to the clinic, for example, on day 57 (± 1 day) for an end-of-study assessment. During this visit, the following assessments are performed: vital signs, physical examination, clinical lab tests, ECG, C-SSRS assessment, and efficacy assessment.

[0286] Adverse events and concomitant medication and procedure use will be monitored from the time of informed consent until Day 36 (± 1 day), at which point participants will have completed the trial.

[0287] Inclusion / Exclusion Criteria Participants were women or men aged 18–65 years (inclusive) at screening, with a history of chronic SUNCT and SUNA headaches lasting for at least one year, with onset before age 50, and a minimum of 100 SUNCT and SUNA headaches over a 14-day period during the clinical trial observation period.

[0288] Test product, reference therapy, and administration One high-dose mg capsule of the compound, one low-dose mg capsule of the compound, or placebo will be administered orally and provided to participants in pre-packaged containers.

[0289] Dose / Route / Regimen The dose will be determined by PK data. The route of administration will be oral.

[0290] statistical methods Safety, tolerability, PK, and efficacy variables will be summarized using descriptive statistics. Descriptive summaries for categorical variables will include counts and percentages. Descriptive summaries for continuous variables will include the number of participants (n), mean, standard deviation (SD), median, minimum, and maximum. 95% confidence intervals (CI) may be reported where appropriate. Summaries will be presented by time point, as appropriate.

[0291] Standard PK parameters are estimated using non-compartmental methods based on concentration-time data. These parameters include Cmax, tmax, and AUC0-tau, when available, and exploratory analyses examining the relationship between PK and efficacy parameters can be performed on the PK population.

[0292] Primary and secondary efficacy measures Headache log completed via eDiary An electronic tablet application to collect information about participants' headache activity pre-dose (or approximately 24 hours after the previous dose) and approximately 4 and 10 hours post-dose. Information collected at all time points includes headache frequency, headache duration, and headache severity (measured by the Stanford Pain Scale). Information collected only at 10 hours post-dose includes the following: attack type, accompanying symptoms, and trigger factors, and autonomic symptoms. Additional information collected via the eDiary at 10 hours post-dose includes visual analog scale (VAS), activities of daily living, and level of disability.

[0293] Stanford Pain Scale The Stanford Pain Scale is a comparative pain scale in which a description is assigned to each scale value, ranging from 0 (no pain) to 10 (unimaginable, indescribable). Pain rated between 0 and 3 is considered "mild," pain rated between 4 and 6 is considered "moderate," and pain rated between 7 and 10 is considered "severe." The Stanford Pain Scale is completed by the participant.

[0294] Trigger Factor Participants are asked to rate whether their response to trigger factors (e.g., brushing hair, touching face, chewing, etc.) has changed using a 5-point scale: 0 = no change, 1 = slight improvement, 2 = moderate improvement, 3 = significant improvement, and 4 = resolution of trigger factors.

[0295] Visual Analogue Scale The visual analogue scale asks participants to rate their satisfaction with the treatment using a Likert scale with categories ranging from 0 = very low effect to 10 = very high effect.

[0296] Level of disability The level of disability will be measured by the participant using a goal attainment scale with the following categories: 0 = no disability, 1 = mild, 2 = moderate, 3 = severe, 4 = intolerable.

[0297] 36-Item Short Form Health Survey (v2 Acute) The SF-36 is a 36-item survey that measures participants' overall health status (McHorney et al., 1994). The SF-36 assesses eight health concepts. The score is a weighted sum of the questions in each section. The score ranges from 0 to 100, with lower scores indicating greater disability. The acute version of the SF-36 is completed by participants if indicated in the SoA. The acute version asks participants about their health over the past week.

[0298] activities of daily living Participants are asked to rate the change in their ability to perform activities of daily living.

[0299] Example 6. Synthesis of (3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine) (Compound 1) [ka]

[0300] Synthesis of A2: To a stirred solution of 2,2,2-trifluoroethanol (5.67 g, 56.71 mmol) in THF (200 mL) at 0 °C, NaH (60% in mineral oil, 2.26 g, 56.71 mmol) was added portionwise. The reaction mixture was stirred for 15 minutes, and 5-bromo-2,3-difluoro-pyridine (10.0 g, 51.55 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 10 °C and treated with ice water (100 mL). The mixture was extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with brine (80 mL), dried over anhydrous NaSO, and concentrated. The crude compound was purified by column chromatography on silica gel using 2% ethyl acetate / PE to give the product (10.5 g, 38.1 mmol, 73% yield). LCMS: 273.9 (M+H) and 276.0 (M+2+H), Rt 2.53 min. Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN. Flow rate: 1.5 mL / min.

[0301] Synthesis of A3: To a stirred solution of 5-bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine (3.0 g, 10.95 mmol) and bis(pinacolato)diboron (3.61 g, 14.23 mmol) in 1,4-dioxane (30.0 mL) was added potassium acetate (2.15 g, 21.9 mmol). Pd(dppf)Cl . DCM (0.89 g, 1.09 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 15% ethyl acetate / PE to give the product (2.0 g, 6.2 mmol, 56% yield). LCMS: 322.1 (M+H), Rt 2.97 min. Column: Atlantis dC18 (50×4.6 mm), 5 μm. Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN. Flow rate: 1.5 mL / min.

[0302] Synthesis of A4: A mixture of Pd(dppf)Cl (15.13 g, 20.68 mmol), CsCO (269.49 g, 827.17 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (141.18 g, 439.69 mmol), and 2-bromo-5-chloropyrazine (80 g, 413.59 mmol) in 1,4-dioxane (1 L) and water (150 mL) was stirred under N at 35 °C for 2 h. After cooling to room temperature, water (300 mL) was added to the mixture, and the mixture was filtered through Celite. After separation, the organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was redissolved in EA / PE=1 / 3 (500 mL) and then filtered through a silica gel mat. The cake was washed with EA / PE=1 / 3 (500 mL). The combined organic phase was concentrated to give the residue as an oil. To this oil, PE (500 mL) was slowly added to give some solid. The solid was collected and dried in an oven to give the product (100 g, 242.4 mmol, 58% yield) as a solid. LCMS R t = 2.0 min chromatography at 1.28 min, 10-80AB, MS ESI C 11 H7ClF4N3O[M+H] + The calculated value was 308.0 and the measured value was 307.9.

[0303] Synthesis of A5: A mixture of 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (140 g, 339.36 mmol) and hydrazine hydrate (169.88 g, 3393.6 mmol) in MeCN (1.4 L) was stirred at 100° C. for 16 hours. After cooling to room temperature, the mixture was poured into water (4.5 L). Some solid was observed, and the solid was collected by filtration. The cake was washed with water (500 mL×2). The solid was redissolved in EtOAc (3 L), washed with brine (500 mL×2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (100 g, 329.8 mmol, 97% yield) as a solid. LCMS Rt = 0.74 min in 1.5 min chromatography, 5-95AB, MS ESI C 11 H 10 F4N5O[M+H] + The calculated value was 304.1 and the measured value was 303.9.

[0304] Synthesis of A6: To a solution of 2-bromo-2,2-difluoro-acetic acid (87 g, 497.34 mmol) in THF (1 L) was added 1 drop of DMF and (COCl)2 (50.5 mL, 596.81 mmol). The resulting mixture was stirred at 20 °C for 1 h. The resulting solution was used directly in the next step. To a solution of 2-bromo-2,2-difluoro-acetyl chloride (95.66 g, 494.69 mmol) in THF (1 L) was added [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (100 g, 329.79 mmol). The resulting mixture was stirred at 20 °C for 2 h. Water (1 L) was added to the solution and extracted with EtOAc (1 L × 2). The combined organic phase was washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product (150 g, 326.0 mmol, 98% yield, mixture of mono- and bis-alkylated products) as a solid. LCMS R t = 0.92 min in 1.5 min chromatography, 5-95AB, MS ESI C 13 H9BrF6N5O2[M+H] + The calculated value was 460.1 and the measured value was 459.8.

[0305] Synthesis of A7: A solution of 2-bromo-2,2-difluoro-N'-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]acetohydrazide (150 g, 325.99 mmol) and TsOH (16.84 g, 97.8 mmol) in toluene (1.5 L) was stirred at 130 °C for 16 h. After cooling to room temperature, the mixture was poured into water (2 L) and extracted with EtOAc (2 L × 2). The combined organic phase was washed with brine (1 L × 2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (80 g, 181.0 mmol, 55% yield) as an oil. 1 H NMR (CDCl3, 400 MHz) δ H =9.60(d,1H),8.55(d,1H),8.45(s,1H),8.09(dd,1H),4.93(q,2H).

[0306] Synthesis of Compound 1: A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (76 g, 171.9 mmol) and AgBF (66.93 g, 343.81 mmol) in ethanol (760 mL) was stirred at 60 °C for 1 h. After cooling to room temperature, the mixture was poured into saturated aqueous NaCl (1 L) and EtOAc (2 L). The mixture was filtered through Celite. After separation, the aqueous layer was extracted with EtOAc (500 mL × 2). The combined organic phase was washed with brine (500 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) and then triturated from EtOH (50 mL) to give the product (44.45 g, 109.01 mmol, 63% yield) as a solid. 1 H NMR (CDCl3 400 MHz) δ H=9.52(d,1H),8.49(dd,2H),8.07(dd,1H),4.93(q,2H),4.37(q,2H),1.51(t,3H). LCMS R t = 2.0 min chromatography, 1.25 min, 10-80AB, MS ESI C 15 H 12 F6N5O2[M+H] + The calculated value was 408.1 and the measured value was 408.0.

[0307] Equality and scope In the claims, articles such as "a," "an," and "the" can mean one or more, unless otherwise indicated to the contrary or clear from the context. A claim or description including "or" between one or more elements of a group is considered to be satisfied if one, more than one, or all of the group elements are present in, employed in, or relevant to a given product or process, unless otherwise indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one element of a group is present in, employed in, or relevant to a given product or process. The invention includes embodiments in which two or more, or all, group elements are present in, employed in, or relevant to a given product or process.

[0308] Furthermore, the invention encompasses all variations, combinations, and permutations, including the introduction into another claim of one or more limitations, elements, clauses, and recited terms from one or more of the enumerated claims. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. Generally, when an invention, or an aspect of an invention, is described as including certain elements and / or features, it should be understood that a particular embodiment of the invention or aspect of the invention consists of, or consists essentially of, such elements and / or features. For purposes of brevity, those embodiments have not been specifically described verbatim herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and permit the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can be considered to be any specific value or subrange within the stated range of different embodiments of the invention, to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0309] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the invention within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed to be known to those of ordinary skill in the art. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0310] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above detailed description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the present invention, as defined in the following claims. This specification includes, for example, the subject matter described in the following sections: Section 1. A dosage form comprising: about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of Compound 1; and a pharmaceutically acceptable excipient. Section 2. Item 1. The dosage form according to Item 1, wherein the dosage form contains about 2.5 mg to about 150 mg (e.g., about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, or about 50 mg) of Compound 1. Section 3. A dosage form comprising: a plurality of particles of Compound 1; and a pharmaceutically acceptable excipient, A dosage form, wherein the amount of the plurality of particles of Compound 1 in the dosage form is about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg). Section 4. Item 4. The dosage form according to Item 3, wherein the plurality of particles of Compound 1 in the dosage form is about 2.5 mg to about 150 mg (e.g., about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, or about 50 mg). Section 5. Item 3 or 4, wherein 10% of the particles of Compound 1 have a particle size of less than about 1 μm. Section 6. Item 6. The dosage form according to any one of Items 3 to 5, wherein 50% of the plurality of particles of Compound 1 have a particle size of less than about 4 μm. Section 7. Item 7. The dosage form of item 6, wherein 50% of the particles of Compound 1 have a particle size of less than about 2 μm. Section 8. Item 8. The dosage form according to any one of items 3 to 7, wherein 90% of the plurality of particles of Compound 1 have a particle size of less than about 30 μm (eg, less than about 15 μm). Section 9. Item 9. The dosage form of item 8, wherein 90% of the particles of Compound 1 have a particle size of less than about 5 μm. Section 10. Item 10% of the particles of Compound 1 have a particle size of less than about 1 μm, 50% of the particles of Compound 1 have a particle size of less than about 4 μm, and 90% of the particles of Compound 1 have a particle size of less than about 30 μm. Section 11. Item 11. The dosage form according to any one of Items 1 to 10, wherein the dosage form is for oral administration. Section 12. Item 12. The dosage form according to any one of items 1 to 11, wherein the dosage form is a solid form. Section 13. Item 13. The dosage form according to any one of Items 1 to 12, wherein Compound 1 is crystalline. Section 14. Item 14. The dosage form of any one of items 1 to 13, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2. Section 15. Item 15. The dosage form of any one of items 1 to 14, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7 ± 0.2, 12.3 ± 0.2, 12.6 ± 0.2, 15.8 ± 0.2, 18.6 ± 0.2, and 22.6 ± 0.2. Section 16. Item 16. The dosage form of any one of items 1 to 15, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7 ± 0.2, 12.3 ± 0.2, 12.6 ± 0.2, 14.9 ± 0.2, 15.8 ± 0.2, 16.6 ± 0.2, 16.8 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2. Section 17. Item 17. The dosage form of any one of items 1 to 16, wherein the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1. Section 18. Item 18. The dosage form according to any one of Items 1 to 17, wherein the dosage form is in the form of a capsule. Section 19. Item 19. The dosage form according to any one of items 1 to 18, wherein the dosage form is in the form of a blend. Section 20. 20. The dosage form of claim 18 or 19, wherein the pharmaceutical excipient is a filler (e.g., microcrystalline cellulose or starch). Section 21. 21. The dosage form according to any one of items 18 to 20, wherein the ratio of compound 1 to said filler is about 1:1. Section 22. 21. The dosage form according to any one of items 18 to 20, wherein the ratio of the compound 1 to the filler is about 1:10. Section 23. Item 21. The dosage form according to any one of Items 18 to 20, wherein the pharmaceutical excipient is a filler or a lubricant. Section 24. The dosage form comprises: Approximately 50% to 90% by weight of a filler; 24. The dosage form according to any one of items 18 to 23, comprising 0% to about 5% by weight of a lubricant. Section 25. The dosage form comprises: about 1 wt % to about 50 wt % of Compound 1; about 50% to about 90% by weight of a filler; 24. The dosage form according to any one of items 18 to 23, comprising 0% to about 4% by weight of a lubricant. Section 26. Item 12. The dosage form of any one of items 1, 2, and 11, wherein the dosage form is in liquid form. Section 27. Item 27. The dosage form according to Item 26, wherein the dosage form is in the form of a solution. Section 28. Item 28. The dosage form of item 27, wherein the pharmaceutical excipient is selected from the group consisting of co-solvents (e.g., polymers (e.g., PEG400)), emulsifiers (e.g., castor oil derivatives, e.g., Kolliphor RH40), surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), vitamin derivatives (e.g., Vitamin ETPGS)), and solvents (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)). Section 29. 29. The dosage form according to any one of items 26 to 28, wherein the concentration of compound 1 is about 0.1 mg / mL to about 10 mg / mL. Section 30. The dosage form comprises: About 35% to about 45% by weight of a filler (e.g., a polymer (e.g., PEG 400)); About 5% to about 15% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); about 40% to about 60% by weight of water, Item 29. The dosage form according to any one of Items 26 to 28, wherein the concentration of Compound 1 is about 0.5 mg / mL or about 0.25 mg / mL. Section 31. The dosage form comprises: about 55% to about 60% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); About 15% to about 20% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS)); about 5% to about 10% by weight of propylene glycol; about 15% to about 20% by weight of ethanol; 29. The dosage form according to any one of items 26 to 28, wherein the concentration of Compound 1 is about 5 mg / mL to about 10 mg / mL, or about 2.5 mg / mL to about 5 mg / mL. Section 32. The dosage form comprises: About 65% to about 70% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); About 18% to about 23% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS)); about 7% to about 12% by weight of propylene glycol; Item 29. The dosage form according to any one of Items 26 to 28, wherein the concentration of Compound 1 is about 1 mg / mL to about 10 mg / mL, or about 0.5 mg / mL to about 5 mg / mL. Section 33. The dosage form comprises: about 35% to about 45% by weight of diethylene glycol monoethyl ether (Transcutol HP); About 5% by weight to about 15% by weight of a surfactant (e.g., a glyceride (e.g., a vitamin derivative (e.g., vitamin ETPGS)), about 40% to about 60% by weight of water, Item 29. The dosage form according to any one of Items 26 to 28, wherein the concentration of Compound 1 is about 1 mg / mL to about 5 mg / mL, or about 0.5 mg / mL to about 2.5 mg / mL. Section 34. The dosage form comprises: About 30% to about 40% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); About 40% to about 50% by weight of a surfactant (e.g., a glyceride (e.g., Capmul MCM C8)); about 5% to 15% by weight of a plasticizer (e.g., triethyl citrate); 29. The dosage form according to any one of items 26 to 28, comprising about 5% by weight to about 15% by weight of a solvent (e.g., ethanol). Section 35. The dosage form comprises: about 35% to about 45% by weight of propylene glycol monocaprylate (e.g., Capryol 90); about 15% to about 25% by weight of a glyceride (e.g., caprylocaproyl macrogolglyceride (e.g., Labrasol)); 29. The dosage form according to any one of items 26 to 28, comprising about 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP). Section 34. Item 34. The dosage form according to any one of Items 26 to 33, wherein the solution may be further diluted with a solvent (e.g., water), and the concentration of the diluted solution is about 50% to about 90% of the concentration of the solution before dilution. Section 36. Item 27. The dosage form of any one of items 1, 2, 11, and 26, wherein the dosage form is in the form of a suspension. Section 37. Item 36. The dosage form of item 35, wherein the concentration of Compound 1 is about 0.1 mg / mL, about 0.5 mg, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, or about 15 mg / mL of Compound 1. Section 38. The pharmaceutical excipient is about 0.5 wt. % of a filler (e.g., methylcellulose, e.g., 400 cP MC); Item 38. The dosage form of item 36 or 37, comprising about 0.2% by weight of an emulsifier (e.g., Tween 80, e.g., Poloxamer 188). Section 39. Item 39. The dosage form of Item 38, wherein the pharmaceutical excipient further comprises about 1% by weight of a preservative solution (e.g., a paraben solution). Section 40. Item 12. The dosage form of any one of items 1, 2, and 11, wherein Compound 1 is amorphous. Section 41. 41. The dosage form of any one of paragraphs 1, 2, 11, and 40, wherein the dosage form is in the form of an amorphous solid dispersion. Section 42. Item 42. The dosage form of item 41, wherein the pharmaceutical excipient is a polymer (e.g., soluplus, Eudragit, and HPMC ASMF). Section 43. Item 43. The dosage form according to any one of items 1 to 42, wherein the dosage form is stable (e.g., chemically stable) at 25°C and 60% RH for 7 days, 14 days, 21 days, 28 days, 1 month, 3 months, or 6 months. Section 44. 1. A composition in a dosage form comprising: about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of Compound 1; and a pharmaceutically acceptable excipient. Section 45. Item 45. The composition according to Item 44, wherein the composition contains about 2.5 mg to about 150 mg (e.g., about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, or about 50 mg) of Compound 1. Section 46. 1. A composition in a dosage form comprising: a plurality of particles of Compound 1; and a pharmaceutically acceptable excipient, The composition, wherein the amount of the plurality of particles of Compound 1 in the composition is about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg). Section 47. Item 47. The composition according to Item 46, wherein the plurality of particles of Compound 1 in the composition is about 2.5 mg to about 150 mg (e.g., about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, or about 50 mg). Section 48. Item 46 or 47, wherein 10% of the particles of Compound 1 have a particle size of less than about 1 μm. Section 49. Item 49. The composition according to any one of items 46 to 48, wherein 50% of the plurality of particles of Compound 1 have a particle size of less than about 4 μm. Section 50. Item 50. The composition of item 49, wherein 50% of the plurality of particles of Compound 1 have a particle size of less than about 2 μm. Section 51. Item 51. The composition according to any one of items 46 to 50, wherein 90% of the plurality of particles of Compound 1 have a particle size of less than about 30 μm (eg, less than about 15 μm). Section 52. Item 52. The composition of item 51, wherein 90% of the particles of Compound 1 have a particle size of less than about 5 μm. Section 53. Item 53. The composition of claim 52, wherein 10% of the particles of Compound 1 have a particle size of less than about 1 μm, 50% of the particles of Compound 1 have a particle size of less than about 4 μm, and 90% of the particles of Compound 1 have a particle size of less than about 30 μm. Section 54. Item 54. The composition according to any one of Items 44 to 53, wherein the composition is for oral administration. Section 55. Item 55. The composition according to any one of items 44 to 54, wherein the dosage form is a solid form. Section 56. Item 56. The composition according to any one of Items 44 to 55, wherein Compound 1 is crystalline. Section 57. 57. The composition of any one of items 44 to 56, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2. Section 58. Item 44 to 57, wherein the crystalline form exhibits an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 10.7 ± 0.2, 12.3 ± 0.2, 12.6 ± 0.2, 15.8 ± 0.2, 18.6 ± 0.2, and 22.6 ± 0.2. The composition of any one of items 44 to 57. Section 59. Item 44 to 58, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7 ± 0.2, 12.3 ± 0.2, 12.6 ± 0.2, 14.9 ± 0.2, 15.8 ± 0.2, 16.6 ± 0.2, 16.8 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2. The composition of any one of items 44 to 58. Section 60. Item 44 to 59, the composition of any one of items 44 to 59, wherein the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1. Section 61. Item 61. The composition according to any one of items 44 to 60, wherein the dosage form is a capsule. Section 62. Item 44 to 61, wherein the dosage form is a blend. Section 63. Item 63. The composition of item 61 or 62, wherein the pharmaceutical excipient is a filler (e.g., microcrystalline cellulose or starch). Section 64. Item 64. The composition according to any one of items 61 to 63, wherein the ratio of compound 1 to the filler is about 1:1. Section 65. Item 64. The composition according to any one of items 61 to 63, wherein the ratio of the compound to the filler is about 1:10. Section 66. Item 64. The composition according to any one of items 61 to 63, wherein the pharmaceutical excipient is a filler or a lubricant. Section 67. The composition form is Approximately 50% to 90% by weight of a filler; Item 67. The composition according to any one of Items 61 to 66, comprising 0% to about 5% by weight of a lubricant. Section 68. The composition comprises: about 1 wt % to about 50 wt % of Compound 1; about 50% to about 90% by weight of a filler; Item 68. The composition according to any one of Items 61 to 67, comprising 0% to about 4% by weight of a lubricant. Section 69. Item 44, 45, and 54, wherein the composition is in liquid form. Section 70. Item 70. The composition according to item 69, wherein the dosage form is in the form of a solution. Section 71. Item 70. The composition of claim 70, wherein the pharmaceutical excipient is selected from the group consisting of co-solvents (e.g., polymers (e.g., PEG400)), emulsifiers (e.g., castor oil derivatives, e.g., Kolliphor RH40), surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), vitamin derivatives (e.g., Vitamin ETPGS)), and solvents (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)). Section 72. Item 72. The composition according to any one of Items 69 to 71, wherein the concentration of Compound 1 is about 0.1 mg / mL to about 10 mg / mL. Section 73. The composition comprises: About 35% to about 45% by weight of a filler (e.g., a polymer (e.g., PEG 400)); About 5% to about 15% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); about 40% to about 60% by weight of water, Item 72. The composition according to any one of items 69 to 71, wherein the concentration of compound 1 is about 0.5 mg / mL or about 0.25 mg / mL. Section 74. The composition comprises: about 55% to about 60% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); About 15% to about 20% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS)); about 5% to about 10% by weight of propylene glycol; about 15% to about 20% by weight of ethanol; Item 72. The composition according to any one of Items 69 to 71, wherein the concentration of Compound 1 is about 5 mg / mL to about 10 mg / mL, or about 2.5 mg / mL to about 5 mg / mL. Section 75. The composition comprises: About 65% to about 70% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); About 18% to about 23% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS)); about 7% to about 12% by weight of propylene glycol; Item 72. The composition according to any one of Items 69 to 71, wherein the concentration of Compound 1 is about 1 mg / mL to about 10 mg / mL, or about 0.5 mg / mL to about 5 mg / mL. Section 76. The composition comprises: about 35% to about 45% by weight of diethylene glycol monoethyl ether (Transcutol HP); About 5% by weight to about 15% by weight of a surfactant (e.g., a glyceride (e.g., a vitamin derivative (e.g., vitamin ETPGS)), about 40% to about 60% by weight of water, Item 72. The composition according to any one of Items 69 to 71, wherein the concentration of Compound 1 is about 1 mg / mL to about 5 mg / mL, or about 0.5 mg / mL to about 2.5 mg / mL. Section 77. The composition comprises: About 30% to about 40% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); About 40% to about 50% by weight of a surfactant (e.g., a glyceride (e.g., Capmul MCM C8)); about 5% to 15% by weight of a plasticizer (e.g., triethyl citrate); Item 72. The composition according to any one of items 69 to 71, comprising about 5% by weight to about 15% by weight of a solvent (e.g., ethanol). Section 78. The composition comprises: about 35% to about 45% by weight of propylene glycol monocaprylate (e.g., Capryol 90); about 15% to about 25% by weight of a glyceride (e.g., caprylocaproyl macrogolglyceride (e.g., Labrasol)); Item 72. The composition of any one of items 69 to 71, comprising about 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP). Section 79. Item 44, 45, 54, and 69, wherein the dosage form is a suspension. Section 80. 80. The composition of claim 79, wherein the concentration of Compound 1 is about 0.1 mg / mL, about 0.5 mg, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, or about 15 mg / mL of Compound 1. Section 81. The pharmaceutical excipient is about 0.5 wt. % of a filler (e.g., methylcellulose, e.g., 400 cP MC); Item 81. The composition of item 79 or 80, comprising about 0.2% by weight of an emulsifier (e.g., Tween 80, e.g., Poloxamer 188). Section 82. Item 82. The composition of item 81, wherein the pharmaceutical excipient further comprises about 1% by weight of a preservative solution (e.g., a paraben solution). Section 83. 55. The composition of any one of paragraphs 44, 45, and 54, wherein Compound 1 is amorphous. Section 84. Item 44, 45, 54, and 83, wherein the dosage form is in the form of an amorphous solid dispersion. Section 85. Item 85. The composition of item 84, wherein the pharmaceutical excipient is a polymer (e.g., soluplus, Eudragit, and HPMC ASMF). Section 86. Item 86. The composition according to any one of Items 44 to 85, wherein the composition is stable (e.g., chemically stable) for 7 days, 14 days, 21 days, 28 days, 1 month, 3 months, or 6 months at 25°C and 60% RH. Section 87. 87. A method for treating a condition associated with abnormal function of a sodium ion channel in a subject in need thereof, comprising administering to said subject a dosage form or composition according to any one of paragraphs 1 to 86. Section 88. A method for treating a condition associated with abnormal function of a sodium ion channel in a subject in need thereof, comprising administering to the subject about 2.5 mg to about 90 mg of Compound 1. Section 89. 89. The method of paragraph 87 or 88, wherein the condition is a neurological or psychiatric disorder. Section 90. Item 89. The method of any one of items 87 to 89, wherein the condition is epilepsy or an epilepsy syndrome. Section 91. 91. The method of any one of paragraphs 87 to 90, wherein the condition is a genetic epilepsy or a genetic epilepsy syndrome. Section 92. 92. The method of any one of paragraphs 87 to 91, wherein the condition is childhood epilepsy or a childhood epilepsy syndrome. Section 93. Item 93. The method of any one of items 87 to 92, wherein the condition is a developmental or epileptic encephalopathy. Section 94. 94. The method of clause 93, wherein the developmental or epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome. Section 95. The condition is selected from the group consisting of epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epileptic encephalopathy with SCN3A mutations, 95. The method of any one of items 87 to 94, wherein the target gene is selected from the group consisting of epilepsy, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. Section 96. Item 89. The method of any one of items 87 to 89, wherein the condition is cancer. Section 97. 87. A method for treating a neurological or psychiatric disorder in a subject in need thereof, the method comprising administering to a subject in need thereof a dosage form according to any one of paragraphs 1 to 86. Section 98. 87. A method for treating pain in a subject in need thereof, the method comprising administering to the subject a dosage form or composition according to any one of paragraphs 1 to 86. Section 99. 87. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a dosage form or composition according to any one of paragraphs 1 to 86. Section 100. A method for treating or preventing trigeminal autonomic headache (TAC) in a subject in need thereof, comprising administering to the subject a dosage form or composition described in any one of paragraphs 1 to 86. Section 101. A method for treating or preventing trigeminal autonomic headache (TAC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, for example, 2.5 mg to 90 mg of Compound 1. Section 102. 102. The method of clause 100 or 101, wherein the TAC is selected from the group consisting of paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA), and long-lasting hemicrania with autonomic symptoms. Section 103. Item 103. The method of item 102, wherein the TAC is a short-lasting unilateral neuralgiform headache attack. Section 104. Item 103. The method of item 102, wherein the TAC is SUNCT. Section 105. Item 103. The method of item 102, wherein the TAC is SUNA. Section 106. Item 106. The method of any one of items 100 to 105, wherein the subject has an inadequate response to at least one agent used to treat the TAC. Section 107. A method for treating or preventing migraine in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a dosage form or composition according to any one of paragraphs 1 to 86. Section 108. A method for treating or preventing migraine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg of Compound 1. Section 109. 109. The method of claim 107 or 108, wherein the migraine is selected from the group consisting of migraine without aura, migraine with aura, familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM). Section 110. Item 109. The method of paragraph 109, wherein the migraine is migraine without aura. Section 111. Item 109. The method of claim 109, wherein the migraine is a migraine with aura. Section 112. Item 109. The method of item 109, wherein the migraine is FHM1. Section 113. Item 109. The method of item 109, wherein the migraine is FHM2. Section 114. Item 109. The method of item 109, wherein the migraine is FHM4. Section 115. Item 109. The method of item 109, wherein the migraine is SHM. Section 116. 116. The method of any one of paragraphs 107 to 115, wherein the subject has an inadequate response to at least one drug used to treat the migraine. Section 117. 87. A method for treating or preventing cortical spreading depression (CSD) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a dosage form or composition according to any one of paragraphs 1 to 86. Section 118. A method for treating or preventing cortical spreading depression (CSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg of Compound 1. Section 119. A method for treating or preventing cranial nerve disorder or cranial polyneuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the dosage form or composition according to any one of items 1 to 86. Section 120. A method for treating or preventing cranial nerve disorder or cranial multiple nerve disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg of Compound 1. Section 121. 121. The method of paragraph 119 or 120, wherein the cranial nerve disorder is selected from the group consisting of Bell's palsy, microvascular cranial nerve palsy, cranial nerve 3 palsy, cranial nerve 4 palsy, and cranial nerve 6 palsy. Section 122. Item 122. The method of any one of items 87 to 121, wherein the dosage form is administered orally. Section 123. Item 87 to 122, wherein the dosage form is a capsule. Section 124. Item 87-123, wherein the subject is 18 to 65 years old. Section 125. compound 1,

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Claims

1. Compound 1, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, said method comprising: (i) contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoro-pyridine to provide a compound of formula (II); 【Chemistry 2】 (ii) contacting said compound of formula (II) with a palladium catalyst and bis(pinacolato)diboron to provide a compound of formula (III); 【Transformation 3】 (iii) contacting said compound of formula (III) with a palladium catalyst and 2-bromo-5-chloro-pyrazine to provide a compound of formula (IV); 【Chemistry 4】 (iv) contacting said compound of formula (IV) with hydrazine to provide a compound of formula (V); 【Transformation 5】 (v) contacting said compound of formula (V) with 2-bromo-2,2-difluoro-acetyl chloride to provide a compound of formula (VI); 【Transformation 6】 (vi) contacting said compound of formula (VI) with an acid to provide a compound of formula (VII); 【Transformation 7】 (vii) contacting the compound of formula (VII) with a silver catalyst and ethanol to provide Compound 1 or a pharmaceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the palladium catalyst in step (ii) or (iii) is [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

3. 3. The method of claim 1 or 2, wherein the silver catalyst in step (vii) is silver tetrafluoroborate.

4. 4. The method of any one of claims 1 to 3, wherein the acid in step (vi) is p-toluenesulfonic acid.

5. Compound 1, 【Transformation 8】 or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is a compound of formula (VII): 【Chemistry 9】 with a silver catalyst and ethanol.

6. The compound of formula (VII) is a compound of formula (VI): 【Chemistry 10】 6. The method of claim 5, wherein the compound is provided by contacting the compound of formula (I) with an acid.

7. The compound of formula (VI) is represented by formula (V): 【Chemistry 11】 7. The method of claim 6, wherein the compound of formula (I) is provided by contacting the compound of formula (I) with 2-bromo-2,2-difluoro-acetyl chloride.

8. The compound of formula (V) is represented by formula (IV): 【Chemistry 12】 8. The method of claim 7, wherein the compound is provided by contacting the compound of formula (I) with hydrazine.

9. The compound of formula (IV) is a compound of formula (III): 【Chemistry 13】 with a palladium catalyst and 2-bromo-5-chloro-pyrazine.

10. The compound of formula (III) is represented by formula (II): 【Chemistry 14】 with a palladium catalyst and bis(pinacolato)diboron.

11. 11. The method of claim 10, wherein the compound of formula (II) is provided by contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoro-pyridine.

12. The method of any one of claims 5 to 11, wherein the silver catalyst is silver tetrafluoroborate.

13. The method of any one of claims 6 to 12, wherein the acid is p-toluenesulfonic acid.

14. The method according to any one of claims 9 to 13, wherein the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

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