FORMULATIONS OF ION CHANNEL MODULATORS AND METHODS OF PREPARATION AND USE OF ION CHANNEL MODULATORS

Abstract

The present invention relates, in part, to compositions or dosage forms comprising fused heteroaryl compounds useful for preventing and / or treating a disease or condition related to the abnormal function of a voltage-sensitive sodium ion channel, for example, abnormal late / constant sodium current. Methods for treating a disease or condition related to the abnormal function of a sodium ion channel, including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, neuromuscular disorders, trigeminal autonomic cephalalgia (TAC), migraine, cranial neuropathy or multiple cranial neuropathy, and cortical spreading depression (CDS), are also provided herein. In another aspect, the present invention provides a method for manufacturing ion channel modulators.

Description

ION CHANNEL MODULATOR FORMULATIONS AND METHODS OF PREPARATION AND USE OF ION CHANNEL MODULATORS zcfrQnn / zznz / E / YiAi 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 by reference into this disclosure. BACKGROUND Sodium ion (Na+) channels open primarily transiently and inactivate rapidly, thereby generating a rapid Na+ current to initiate the action potential. The delayed or persistent sodium current (INaL) is a sustained component of the rapid Na+ current in cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal enhancement of INaL, contributing to the pathogenesis of electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther (2008) 119:326–339). Accordingly, pharmaceutical compounds or dosage forms comprising compounds that selectively modulate sodium channel activity, e.g., abnormal INaL, are useful for treating such disease states. COMPENDIUM Described herein are compounds or dosage forms useful for preventing and / or treating a disease, disorder, or condition, e.g., a disease, disorder, or condition related to abnormal function of a sodium ion channel, e.g., abnormal late sodium current (INaL). The present disclosure also encompasses methods of modulating sodium channel activity using a compound, composition, or dosage form described herein. Also provided herein is a method of preparing ion channel modulators. In one aspect, the present disclosure provides 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. In another aspect, the present disclosure provides a dosage form comprising: a plurality of particles of Composition 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). In one aspect, the present disclosure provides a composition in a dosage form comprising: 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) of Compound 1; and a pharmaceutically acceptable excipient. In another aspect, the present disclosure provides a composition in a dosage form comprising: a plurality of particles of Composition 1; and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of Compound 1 in the composition 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). In another aspect, provided herein is a method of treating a condition related to abnormal sodium ion channel function in a subject in need thereof, comprising administering to the subject a dosage form described herein.Also provided herein is a method of treating a condition related to abnormal sodium ion channel function in a subject in need thereof, comprising administering to the subject from 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 a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is a pediatric epilepsy or a pediatric epilepsy syndrome. In some embodiments, the condition is 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 modalities, the condition is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable epilepsy in infancy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden death expected in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy and KCNT1 epileptic encephalopathy. In some forms, the condition is a cancer. zcfrQnn / zznz / E / YiAi Also provided herein is a method of treating a neurological disorder or a psychiatric disorder in a subject in need thereof, wherein the method comprises administering to a subject in need thereof a dosage form described herein. The present disclosure provides, in part, a method for treating pain in a subject in need thereof, wherein the method comprises administering to the subject a dosage form described in the present disclosure. Contemplated methods include a method of treating a cancer in a subject in need thereof, wherein the method comprises administering to the subject a dosage form described herein. In another aspect, provided in the present disclosure is 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 a dosage form described in the present disclosure. Also 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 Compound 1, e.g., about 2.5 mg to about 90 mg of Compound 1. In another aspect, provided in the present disclosure is a method for treating or preventing a migraine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dosage form described in the present disclosure. Provided herein, in part, is a method of treating or preventing a migraine 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. In another aspect, there is provided 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 a dosage form described herein. Also provided is a method of 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, e.g., about 2.5 mg to about 90 mg. Also provided herein is a method of treating or preventing a cranial neuropathy or multiple cranial neuropathies in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dosage form described herein. In another aspect, a method of treating or preventing cranial neuropathy or multiple cranial neuropathies in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, e.g., from 2.5 mg to about 90 mg of Compound 1. In another aspect, the present disclosure provides a method of manufacturing Compound 1: zcfronn / zznz / E / YiAi zcfrQnn / zznz / E / YiAi or a pharmaceutically acceptable salt thereof, the method comprising the steps of: (i) contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoro-pyridine, thereby providing a compound of formula (II): FF (i) contacting the compound of formula (II) with a palladium and bis(pinacolato)diboron catalyst thereby providing a compound of formula (III): (iii) contacting the compound of formula (III) with a palladium catalyst and 2-bromo-5-chloro-pyrazine thereby providing a compound of formula (IV): (iv) contacting the compound of formula (IV) with hydrazine thereby providing a compound of formula (V): (v) contacting the compound of formula (V) with 2-bromo-2,2-difluoro-acetyl chloride thereby providing a compound of formula (VI): zcfrQnn / zznz / E / YiAi (vi) contacting the compound of formula (VI) with an acid thereby providing a compound of formula (Vil): (vii) contacting the compound of formula (VII) with a silver catalyst and ethanol thereby providing Compound 1 or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method of manufacturing Compound 1: or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is provided by contacting the compound of formula (VII): with a silver and ethanol catalyst. Other objects and advantages will be apparent to those skilled in the art from a consideration of the Brief Description of the Figures, Detailed Description, Examples and Claims that follow. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the XRPD pattern of the raw material of Compound 1 and Compound 1 after jet milling. Figure 2 shows the result of dissolving ASD in the capsule (2.5 mg and 10 mg of active). Figure 3 shows the dissolution result of a 1:10 mixture with MCC in the capsule (1 and 10 mg of active). Figure 4 shows the dissolution result of the 1:10 mixture with MCC in the capsule (2.5 mg of active with 2% surfactant). DETAILED DESCRIPTION As generally described herein, the present disclosure provides, in part, compounds, compositions, and dosage forms or doses useful for preventing and / or treating a disease, disorder, or condition described herein, e.g., a disease, disorder, or condition related to abnormal function of a sodium ion channel, such as a late abnormal sodium current (INaL). Illustrative diseases, disorders, or conditions include a neurological disorder (e.g., epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, or a neuromuscular disorder), a psychiatric disorder, pain, a gastrointestinal disorder, trigeminal autonomic cephalalgia (TAC), migraine, cranial neuropathy or multiple cranial neuropathy, and cortical spreading depression (CSD). Also provided herein are methods of preparing ion channel modulators. Definitions 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 with which it is formulated.Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial mixtures of glycerides 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylenepolyoxypropylene block polymers, polyethylene glycol and wool fat. As used herein, “pharmaceutically acceptable salt” refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are 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 this invention include those derived from suitable organic and inorganic bases and acids.Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group 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 the use of other methods used in the art such as ion exchange.Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorale, camphorulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4 alkyl)4 salts.Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed by the use of counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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. Disease, disorder, and condition are used interchangeably in this description. As used herein, and unless otherwise specified, the terms “treat,” “treating,” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder, or condition, that reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition (also “therapeutic treatment”). As used herein, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses both therapeutic and prophylactic treatment. 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 the 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 the disease, disorder, or condition. The term “therapeutically effective amount” may encompass an amount that improves overall therapy, reduces or prevents symptoms or causes of the disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. As used herein, the term “amorphous” refers to a solid in a non-crystalline state. Amorphous solids generally possess a crystal-like short-range molecular arrangement, but not the long-range molecular close-packed order found in crystalline solids. The solid state form of a solid can be determined by polarized optical microscopy, X-ray powder diffraction (“XRPD”), differential scanning calorimetry (“DSC”), or other standard techniques known to those skilled in the art. As used herein, "crystalline" refers to a solid that has a highly regular chemical structure, that is, a long-range structural order in the crystal lattice. Molecules are arranged periodically and regularly in the three-dimensional space of the lattice. In particular, a crystalline form can occur as one or more single crystalline forms. The term “peaks” when referring to peaks in an XRPD pattern of a crystal form of Compound 1 refers to a collection of certain peaks whose 2Θ values ​​in an interval of 0 or 40° are, in general, assigned exclusively to one of the crystal forms of Compound 1. As used herein, the phrase “solid amorphous dispersion” refers to a solid comprising an active ingredient (e.g., Compound 1) and a dispersion polymer. The phrase “dispersion polymer” means a polymer that allows the active ingredient (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-vinylacetate copolymer (“PVP-VA”), polyvinyl alcohols, polyvinyl alcohol-polyvinyl acetate copolymers, polyvinyl pyrrolidine (“PVP”), acrylate-methacrylate copolymers, methylacrylic acid-methyl methacrylate copolymer (such as Eudragit®), polyethylene-polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers (also referred to as poloxamers), graft copolymer composed of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate (such as Soluplus®), cellulosic polymers,such as hydroxypropyl methylcellulose acetate (“HPMCA”), hydroxypropyl methylcellulose (“HPMC”), hydroxypropyl cellulose (“HPC”), methylcellulose, hydroxyethyl methylcellulose, hydroxyethylcellulose, hydroxyethylcellulose acetate, and hydroxyethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate (“HPMCAS”), hydroxypropyl methylcellulose phthalate (“HPMCP”), carboxymethyl ethylcellulose (“CMEC”), cellulose acetate phthalate (“CAP”), cellulose acetate succinate (“CAS”), hydroxypropyl methylcellulose acetate phthalate (“HPMCAP”), cellulose acetate trimellitates (“CAT”), hydroxypropyl methylcellulose acetate trimellitates (“HPMCAT”), and carboxymethylcellulose acetate butyrate (“CMCAB”), and the like. zcfrQnn / zznz / E / YiAi As used herein, the terms “stable” and “stability” refer to the fact that the evolution of the active ingredient (e.g., Compound 1) over time and / or under specific environmental conditions (e.g., temperature, humidity, etc.) does not have significant effects on its quality, safety and / or efficacy over a given period of time. It can be measured through the formation of degradation products (impurities), pH variation, appearance, microbial growth and / or color, as exemplified in the experimental section. Typically, the compositions according to the invention are considered stable if at least 95% of the initial concentration of each of the active ingredients is found after 4 weeks at 25 ° C, and / or if no substantial change in the appearance of the solution is observed during said period of time and under said temperature conditions.Stability can be evaluated over a range of relative humidity (RH) conditions, typically between 60 and 75%RH. As used herein, the term “particle size” is defined as the diameter of a particle as determined by the Sympatec particle size analyzer. Compounds Described herein are dosage forms and pharmaceutical compositions comprising compounds that are useful for preventing and / or treating a disease, disorder, or condition, e.g., a disease, disorder, or condition related to abnormal function of a sodium ion channel, e.g., abnormal late sodium current (ALC). In one aspect, the present disclosure is directed to a dosage form comprising Compound 1 represented by: zcfrQnn / zznz / E / YiAi 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 (26): 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 exhibits an X-ray powder diffraction pattern substantially the same as that depicted in Figure 1. In some embodiments, Compound 1 is amorphous. Dosage forms and compositions In one aspect, the present 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 related to abnormal function of a sodium ion channel, such as abnormal late sodium current (INaL). This invention provides pharmaceutical compositions containing, as the 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 solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker and C.T. Rhodes, Eds.) The pharmaceutical compositions may be administered in single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example, as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical injection, as an inhalant, or through an impregnated or coated device, such as a stent, for example, or a cylindrical polymer inserted into an artery. One mode of administration is parenteral, particularly by injection. Forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical carriers. Aqueous solutions in saline are also conventionally used for injections, 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 may also be employed.Adequate fluidity can be maintained, for example, by using a coating, such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants. Various antibacterial and antifungal agents can prevent the action of microorganisms, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with the various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients in a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which produce a powder of the active ingredient plus any additional desired ingredients from a pre-filtered solution thereof. Oral administration is another route for administering compounds according to the invention. Administration may be by capsule or tablet, or the like. In manufacturing pharmaceutical compositions that include at least one compound described herein, the active ingredient is generally diluted by an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as indicated above), which acts as a vehicle, carrier, or medium for the active ingredient.Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and powders in sterile packaging. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may also include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.The compositions of the invention may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to the patient by employing methods known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or polymer matrix formulations of drugs. Examples of controlled-release systems are provided 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 employs transdermal delivery devices (“patches”). Such transdermal patches may 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 the delivery of pharmaceutical agents are well known in the art. See, e.g., 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. The compositions are preferably formulated in unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a 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.It will be understood, however, that the amount of the compound actually administered will generally be determined by a physician, in view of relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. The tablets or pills of the present invention may 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 tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of a sachet over the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or delay release. A variety of materials may be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable solvents, aqueous or organic, or mixtures thereof, and powders. The 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 a local or systemic effect. The compositions preferably in pharmaceutically acceptable solvents may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be coupled to a mask tent, or to an intermittent positive pressure breathing machine. The solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices that administer the formulation in a suitable manner. 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. zcfrQnn / zznz / E / YiAi In some embodiments, the dosage form or a composition in a dosage form comprises from about 2.5 mg to about 150 mg (e.g., from about 10 mg to about 150 mg, from about 20 mg to about 150 mg, from about 40 mg to about 150 mg, from about 60 mg to about 150 mg, from about 80 mg to about 150 mg, from about 100 mg to about 150 mg, from about 10 mg to about 120 mg, from about 20 mg to about 120 mg, from about 40 mg to about 120 mg, from about 60 mg to about 120 mg, from about 80 mg to about 120 mg, from about 100 mg to about 120 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 40 mg to about 120 mg). mg to about 100 mg, from about 60 mg to about 100 mg,from about 80 mg to about 100 mg, from about 10 mg to about 80 mg, from about 20 mg to about 80 mg, from about 40 mg to about 80 mg, from about 60 mg to about 80 mg, from about 10 mg to about 60 mg, from about 20 mg to about 60 mg, from about 40 mg to about 60 mg, from about 70 mg to about 120 mg, from about 70 mg to about 100 mg, from about 50 mg to about 120 mg, from about 50 mg to 90 mg, from about 30 mg to about 120 mg, from about 30 mg to about 60 mg, from about 30 mg to about 80 mg, from about 30 mg to about 100 mg) of Compound 1., In some embodiments, the dosage form or a composition in a dosage form comprises from about 1 mg to about 100 mg (e.g., from about 1 mg to about 80 mg, from about 1 mg to about 50 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about mg, from about 5 mg to about 100 mg, from about 5 mg to about 80 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg) of Compound 1. In some embodiments, the dosage form or a composition in a dosage form comprises about 200 mg, about 190 mg, about 180 mg, about 170 mg, about 160 mg, about 150 mg, about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 99 mg, about 98 mg, about 97 mg, about 96 mg, about 95 mg, about 94 mg, about 93 mg, about 100 mg, about 91 mg, about 90 mg, about 85 mg, about 100 mg, about 75 mg, about 70 mg, about 69 mg, about 67 mg, about 66 mg, about 65 mg, about 63 mg, about 62 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 10 59 mg, approximately 58 mg, approximately 57 mg,about mg, about 55 mg, about 54 mg, about 53 mg, about mg, about 51 mg, about 50 mg, about 45 mg, about mg, about 35 mg, about 30 mg, about 25 mg, about 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., 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). In some embodiments, the plurality of Compound 1 particles in the dosage form or composition is 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 70 mg to about 120 mg, from about 30 mg to about 60 mg, about 100 mg, about 50 mg). In certain embodiments, 10% of the plurality of Compound 1 particles have a particle size of less than about 1 pm. In other embodiments, 50% of the plurality of Compound 1 particles have a particle size of less than about 4 pm. In some embodiments, 50% of the plurality of Compound 1 particles have a particle size of less than about 2 pm. In certain embodiments, 90% of the plurality of Compound 1 particles have a particle size of less than about 30 pm (e.g., less than about 15 pm). In other embodiments, 90% of the plurality of Compound 1 particles have a particle size of less than about 5 pm. In some embodiments, 90% of the plurality of Compound 1 particles have a particle size of about 4 pm to 15 pm. In some embodiments, 10% of the plurality of Compound 1 particles have a particle size of less than about 1 pm, 50% of the plurality of Compound 1 particles have a particle size of less than about 4 pm, and 90% of the plurality of Compound 1 particles have a particle size of less than about 30 pm. In some embodiments, the dosage form or composition is configured for oral administration. In some embodiments, the dosage form is a solid form. In some embodiments, the dosage form is in the form of a capsule. In some embodiments, the pharmaceutical excipient in the capsule is a filler (e.g., cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starches, and partially pregelatinized starches), anhydrous lactose, lactose monohydrate, sugar alcohols (e.g., sorbitol, xylitol, and mannitol). In some embodiments, the ratio of Compound 1 to filler is approximately zcfrQnn / zznz / E / YiAi 1:10. 1:10. In some embodiments, the ratio of Compound 1 In some embodiments, the ratio of Compound 1 to the filler is approximately with respect to the filler is approximately 1:5. 1:4. 1:3. In some embodiments, the ratio of the Compound to the filler is about 0.5% to about 0.5%, and the ratio of the Compound to the filler is about 0.5% to about 0.5%. In some embodiments, the ratio of the Compound to the filler is about 0.5% to about 0.5%. 1:2. In some embodiments, the capsule further comprises a lubricant (e.g., magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats). In some embodiments, the dosage form is in the form of a mixture. In some embodiments, the pharmaceutical excipient in the mixture is a filler (e.g., microcrystalline cellulose or starch). In some embodiments, the ratio of Compound 1 to the filler is about 1:1. In some embodiments, the ratio of Compound 1 to the filler is about 1:10. In some embodiments, the ratio of Compound 1 to about about about 1:5. 1:4. 1:3. In some embodiments, the ratio of the Compound to the filler is about 1:2. In some embodiments, the dosage form is a liquid form. In some embodiments, the dosage form is in the form of a solution. In some embodiments, the pharmaceutical excipient in the solution is selected from the group consisting of a filler (e.g., polymer (e.g., PEG 400)), an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40), a surfactant (e.g., Labrafil M2125 CS), a vitamin derivative (e.g., Vitamin ETPGS)), a solvent (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)). 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 2 mg / ml). 0.1 mg / ml, mg / ml mg / ml, mg / ml mg / ml, from approximately 3 to approximately 10 of approximately approximately approximately mg / ml mg / ml, mg / ml mg / ml, mg / ml to approximately 10 of approximately 5 of approximately approximately approximately mg / ml, mg / ml mg / ml, 0.5 mg / ml mg / ml, from approximately 2 mg / ml to approximately 8 mg / ml, from approximately 3 mg / ml to approximately 8 mg / ml, from approximately 4 mg / ml to approximately 8 mg / ml, from approximately 5 mg / ml to approximately 8 mg / ml, from approximately 6 mg / ml to approximately 8 mg / ml, from approximately 0.5 mg / ml to approximately 6 mg / ml, from approximately 1 mg / ml to approximately 6 mg / ml, from approximately 2 mg / ml to approximately 6 mg / ml, from approximately 3 mg / ml to approximately 6 mg / ml, from approximately 4 mg / ml to approximately 6 mg / ml, from approximately 0.5 mg / ml to approximately 4 mg / ml, from approximately 1 mg / ml to approximately 4 mg / ml, or from approximately 2 mg / ml to approximately 4 mg / ml). 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. In some embodiments, the dosage form or composition comprises: from about 20% to about 60% (e.g., from about 25% to about 55%, from about 30% to about 50%, from about 35% to about 45%, from about 37% to about 42%, or about 40%) by weight of a filler (e.g., a polymer (e.g., PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 6000, or PEG 8000)); from about 3% to about 25% (e.g., from about 3% to about 20%, from about 5% to about 13%, from about 8% to about 13%, from about 5% to about 15%, or about 10%) by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40, macrogol cetostearyl ether 25 (e.g., Cremophor® A25), macrogol 6 cetostearyl ether (e.g., Cremophor® A6), macrogol 35 glycerol ricinoleate (e.g., Cremophor® EL), macrogol 40 glycerol hydroxystearate (e.g., Cremophor® RH 40)); 35% to approximately 65%, approximately 40% to about 60%, about 45% to about 55%, 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. In certain embodiments, the dosage form or 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); and about 40% to about 60% by weight of water; wherein the concentration of Compound 1 is about 0.5 mg / ml or about 0.25 mg / ml. In some embodiments, the dosage form or composition comprises: de aproximadamente 40 % a aproximadamente 75 % (p. ej., de aproximadamente 45 % a aproximadamente 70 %, de aproximadamente 50 % a aproximadamente 65 %, de aproximadamente 55 % a aproximadamente 60 %, o aproximadamente 58 %) en peso de un emulsifier (p. ej., un derivado de zcfrQnn / zznz / E / YiAi aceite de ricino (p. ej., Kolliphor RH40, éter cetoestearílico macrogol 25 (p. ej., Cremophor® A25), éter cetoestearílico macrogol 6 (p. ej., Cremophor® A6), ricinoleato de glicerol macrogol 35 (p. ej., Cremophor® EL), hidroxiestearate de glycerol macrogol 40 (e.g., Cremophor® RH 40)); from about 10% to about 35% (e.g., from about 10% to about 30%, from about 10% to about 25%, from about 15% to about 25%, or from about 15% to about 20%) by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS), caprylocaproyl macrogolglycerides (e.g., Labrasol), oil based on natural triglyceride (e.g., olive oil, sesame oil, cologne oil, palm kernel oil)); from about 3% to about 20% (e.g., from about 3% to about 15%, from about 5% to about 15%, or from about 5% to about 10%) by weight of propylene glycol; and % to about 35% (e.g., from about 10% to about 30%, from about 10% to about 25%, from about 15% to about 25%, or from about 15% to about 20%) by weight of ethanol; wherein the concentration of Compound 1 is from about 5 mg / ml to about 10 mg / ml (e.g., about 5 mg / ml, about 7.5 mg / ml, or about 10 mg / ml) or from about 2.5 mg to about 5 mg / ml. In certain embodiments, the dosage form or composition comprises: from about 55% to about 60% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); from about 15% to about 20% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS); from about 5% to about 10% by weight of propylene glycol; and from about 15% by weight to about 20% by weight of ethanol; wherein the concentration of Compound 1 is from about 5 mg / ml to about 10 mg / ml or from about 2.5 mg to about 5 mg / ml. In some embodiments, the dosage form comprises: de aproximadamente 50 % a aproximadamente 85 % (p. ej., de aproximadamente 55 % a aproximadamente 80 %, de aproximadamente 60 % a aproximadamente 75 %, o de aproximadamente 65 % a aproximadamente 70 %) en peso de un emulsificatore (p. ej., un derivado de aceite de ricino (p. ej., Kolliphor RH40) éter cetoestearílico macrogol 25 (p. ej., Cremophor® A25), éter cetoestearílico macrogol 6 (p. ej., Cremophor® A6), ricinoleato de glicerol macrogol 35 (p. ej., Cremophor® EL), hidroxiestearato de glicerol macrogol 40 (p. ej..Cremophor® RH 40)); from about 10% to about 30% (e.g., from about 10% to about 25%, from about 15% to about 25%, or from about 18% to about 23%) by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS), caprylocaproyl macrogolglycerides (e.g., Labrasol), natural triglyceride-based oil (e.g., olive oil, sesame oil, cologne oil, palm kernel oil)); and from about 3% to about 20% (e.g., from about 3% to about 15%, from about 5% to about 15%, from about 5% to about 12%, or from about 7% to about 12%) by weight of propylene glycol; wherein the concentration of Compound 1 is from about 1 mg / ml to about 10 mg / ml (e.g., from 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 from 0.5 mg / ml to about 5 mg / ml. 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; wherein the concentration of Compound 1 is from about 1 mg / ml to about 10 mg / ml or from 0.5 mg / ml to about 5 mg / ml. In some embodiments, the dosage form or composition comprises: from about 20% to about 60% (e.g., from about 25% to about 55%, from about 30% to about 50%, 35% to about 45%, about 35%, about 40%, or about 45%) by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP); from about 1% to about 20% (e.g., from about 3% to about 18%, from about 5% to about 18%, from about 5% to about 15%, from about 8% to about 12%, or about 10%) by weight of a surfactant (e.g., a vitamin derivative (e.g., vitamin ETPGS)); and from about 20% to about 80% (e.g., from about 25% to about 75%, from about 30% to about 70%, from about 35% to about 55%, from about 40% to about 60%, or from about 45% to about 55%) by weight of water; wherein the concentration of Compound 1 is from about 1 mg / ml to about 5 mg / ml (e.g., about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg, or about 5 mg / ml) or from 0.5 mg / ml to about 2.5 mg / ml. 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; wherein the concentration of Compound 1 is from about 1 mg / ml to about 5 mg / ml or from 0.5 mg / ml to about 2.5 mg / ml. 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). In other embodiments, the dosage form or composition comprises: about 35% to about 45% by weight of a propylene glycol monocaprylyl ether (e.g., Capryol 90); about 15% to about 25% by weight of a glyceride (e.g., caprylocaproyl macrogolglycerides (e.g., Labrasol)); and about 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutor HP). In certain embodiments, the dosage form is in the form of a suspension. 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, about 25 mg / ml. In some embodiments, the described suspension may be further diluted with a solvent (e.g., water), wherein the concentration of the diluted solution is about 50% to about 90% of the solution before dilution. 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, from about 2 mg / ml to about 8 mg / ml, from about 3 mg / ml to about 8 mg / ml, from about 4 mg / ml to about 8 mg / ml). mg / ml, from about 5 mg / ml to about 8 mg / ml, from about 6 mg / ml to about 8 mg / ml, from about 0.5 mg / ml to about 6 mg / ml, from about 1 mg / ml to about 6 mg / ml, from about 2 mg / ml to about 6 mg / ml, from about 3 mg / ml to about 6 mg / ml, from about 4 mg / ml to about 6 mg / ml, from about 0.5 mg / ml to about 4 mg / ml, from about 1 mg / ml to about 4 mg / ml, or from about 2 mg / ml to about 4 mg / ml)., In some embodiments, the pharmaceutical excipient in the suspension comprises: zcfrQnn / zznz / E / YiAi from about 0.1% to about 5% (e.g., from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, about 0.1%, about 0.3%, about 0.5%, about 1%, about 2%, or about 3%) by weight of a filler (e.g., ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium hydroxypropylmethylcellulose, methylcellulose (e.g.,, 400 cP MC), methylethylcellulose, sodium carboxymethylcellulose, 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), Softisans 100, 142, 378 and 649, stearyl alcohol carbomer, xanthan gum, maltodextrin, acacia, tragacanth, povidone, or polyvinyl alcohol); and from about 0.1% to about 3% (e.g., from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.2% to about 2%, from about 0.2% to about 1%, from about 0.2% to about 0.5%, from about 0.1% to about 0.3%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, or about 1%) by weight of an emulsifier (e.g.,, polyoxyethylene sorbate (e.g., Tween®), long chain carboxylic acid esters of sorbitan (e.g., Span®), block copolymers of ethylene or propylene oxide (Pluronic®), polyglycolyzed glycerides (Labrasol®, Labrafil®, and Labrafac®), sorbitan esters of oleate, stearate, laurate, or other long chain carboxylic acids, polyethylene-polypropylene glycol block copolymers (e.g., Poloxamer 188), other long chain carboxylic acid esters of sorbitan or sucrose, mono- and diglycerides, PEG derivatives of caprylic / capric triglycerides). In certain embodiments, the pharmaceutical excipient comprises: about 0.5% by weight of a filler (e.g., methylcellulose, e.g., 400 cP MC); and about 0.2% by weight of an emulsifier (e.g., Tween, e.g., Tween 80, e.g., Poloxamer 188). In some embodiments, the pharmaceutical excipient further comprises about 1% by weight of a preservative solution (e.g., paraben solution). In some embodiments, the dosage form is in the form of a solid amorphous dispersion. In some embodiments, the pharmaceutical excipient in the solid amorphous dispersion is a polymer (e.g., Soluplus, Eudragit, HPMCASMF, PVP-VA, methyl methacrylate and methacrylate acid copolymer, HPMCP, CAP, HPMCAS, HPMCP H-55). 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. 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, at least 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). Manufacturing methods of dosage forms In another aspect, the present disclosure provides methods for manufacturing dosage forms as described herein. Such methods are described, for example, in the Examples section. In some embodiments, contemplated dosage forms may be in the form of a capsule, mixture, solution, suspension, or ASD. Methods of use The formulations described herein are generally useful for modulating sodium channel activity and are useful for treating conditions related to abnormal function of a sodium ion channel, e.g., abnormal late sodium current (INaL). In some embodiments, a formulation comprising Compound 1 as provided herein is effective in treating epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder. A provided formulation comprising Compound 1, or a pharmaceutically acceptable salt thereof, may also modulate all sodium ion channels, or may be specific for only one or a plurality of sodium ion channels, e.g., Nav 1,1, 1,2, 1,3, 1,4, 1,5, 1,6, 1,7, 1,8, and / or 1,9. In one aspect, the present invention provides a method of treating a condition related to abnormal sodium ion channel function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, e.g., from about 2.5 mg to about 90 mg of Compound 1. Epilepsy and epilepsy syndromes The formulations described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1) are useful in the treatment of epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cell activity in the brain is disrupted, resulting in seizures or periods of unusual behavior, sensations, and sometimes loss of consciousness. Symptoms of seizures will vary widely, from simply staring blankly for a few seconds to repeated twitching of the arms or legs during a seizure. Epilepsy can involve a generalized seizure or a partial or focal seizure. All areas of the brain participate in a generalized seizure. A person experiencing a generalized seizure may cry or make some sound, become rigid for several seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are usually open, the person may not appear to be breathing, and may actually turn blue. The return to consciousness is gradual, and the person may become confused for minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic. In a partial or focal seizure, only one part of the brain is affected, so only one part of the body is affected. Depending on which part of the brain has abnormal electrical activity, symptoms can vary. Epilepsy, as described herein, includes generalized seizure, partial seizure, complex partial seizure, tonic-clonic seizure, clonic seizure, tonic seizure, refractory seizure, status epilepticus, absence seizure, febrile seizure, or temporal lobe epilepsy. The formulations described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1) may also be useful in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least in part, by some aspect of epilepsy are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and with severe cognitive dysfunction, e.g., West syndrome. In some embodiments, the epilepsy syndrome comprises an epileptic encephalopathy, such as congenital epileptic encephalopathy (EED), 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 Glutl deficiency. In some forms, epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome.In some embodiments, epilepsy or an epileptic syndrome comprises epileptic encephalopathy, congenital epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable epilepsy in infancy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migrating partial seizures of infancy, nocturnal epilepsy of the autosomal dominant frontal lobe, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy or KCNT1 epileptic encephalopathy. In some embodiments, the methods described herein further comprise identifying a subject having epilepsy or an epileptic syndrome (e.g., epileptic encephalopathy, congenital epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable epilepsy in infancy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, partial seizures malignant migratory disorders of childhood, autosomal dominant nocturnal frontal lobe epilepsy,sudden unexpected death in epilepsy (SUDEP), epileptic encephalopathy KCNQ2 or epileptic encephalopathy KCNT1) prior to administration of a formulation described herein. In one aspect, the present invention features a method of treating epilepsy or an epileptic syndrome (e.g., epileptic encephalopathy, congenital epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable epilepsy in infancy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migrating partial seizures of infancy, Autosomal dominant nocturnal frontal lobe epilepsy, sudden death expected in epilepsy (SUDEP),KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy) comprising administering to a subject in need thereof a composition described herein., A formulation of the present invention (e.g., a dosage form, a composition in a dosage form comprising Compound 1) may also be used to treat an epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy), wherein the subject has a mutation in one or more of 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, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1 A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1 B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1 D24 and WWOX. In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of 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, 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, STX1 B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX prior to administration of a formulation described herein. A formulation of the present invention may also be used to treat an epilepsy or epilepsy syndrome (e.g., epileptic encephalopathy), wherein the subject has a mutation in one or more of HNRNPU, CACNA1 A, 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, zcfrQnn / zznz / E / YiAi GABRA2, GABRA3, GABRA4, 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, GNAI1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GPHN, HAP1, KCNB2, KCNC2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, PRKACB, PRKACG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5, SLC6A11, SLC6A13, SRC, TRAK1, TRAK2, CHRNA1, CHRNA10, CHRNA3, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNA1, CHRNA3 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,CACNA1 A, CACNA1B, CACNA1C, CACNA1 D, CACNA1 E, CACNA1F, CACNA1G, CACNA1H, CACNA11, 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 y HCN4., In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of HNRNPU, CACNA1 A, 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, GABRA4, 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, GNAI1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GPHN, PAH1, KCNB2, KCNC2, 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, 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, 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, zcfrQnn / zznz / E / YiAi, 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 prior to administration of a formulation described herein. Neurodevelopmental disorders The formulations described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1) may be useful in the treatment of a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder comprises autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy. In some embodiments, the methods described herein further comprise identifying a subject having a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13 deletion syndrome.3, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) prior to administration of a formulation described herein. In one aspect, the present invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) comprising administering to a subject in need thereof a formulation described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1). Pain The formulations described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1) may be useful in the treatment of 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 as having 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.,, a dosage form, a composition in a dosage form comprising Compound 1). zcfrQnn / zznz / E / YiAi In one aspect, the present 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 described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1). Neuromuscular disorders The formulations described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1) may be useful in the treatment of a neuromuscular disorder. In some embodiments, the neuromuscular disorder comprises amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or SCN4A-mutated laryngospasm.In some embodiments, the methods described herein further comprise identifying a subject as having a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or SCN4A-mutated laryngospasm) prior to administering a formulation described herein. In one aspect, the present disclosure features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or SCN4A-mutated laryngospasm) comprising administering to a subject in need thereof a formulation described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1). Other disorders In some embodiments, a formulation of the present invention (e.g., a dosage form, a composition in a dosage form comprising Compound 1) may have suitable pharmacokinetic properties such that it may be active with respect to the central and / or peripheral nervous system. In some embodiments, the formulations provided herein (e.g.,, a dosage form, a composition in a dosage form comprising Compound 1) are used to treat a cardiovascular disease such as atrial and ventricular arrhythmias including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury of the heart, kidney, liver and brain, exercise-induced 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. zcfrQnn / zznz / E / YiAi In some embodiments, the formulations provided herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1) can be used in the treatment of diseases affecting the neuromuscular system resulting in itching, seizures, or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and pathological conditions related to diabetes, such as diabetic peripheral neuropathy. In some embodiments, a disclosed method comprises administering the pharmaceutical composition. In some embodiments, provided herein is a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a formulation described herein (e.g., a dosage form, a composition in a dosage form comprising Compound 1). In another aspect, the present disclosure provides a method for treating a cancer, wherein the method comprises administering to a subject in need thereof a dosage form or a composition in the dosage form described in the present disclosure. Trigeminal autonomic headache! The compounds, dosage forms, and compositions described herein (e.g., Compound 1, a dosage form, or a composition comprising Compound 1) are useful in the treatment of trigeminal autonomic cephalalgias (TACs). TACs are a group of primary headache disorders characterized by unilateral pain, relatively short symptom duration, and associated ipsilateral cranial autonomic signs. TACs can include cluster headaches (CHs), paroxysmal hemicrania (PH), hemicrania continua (HCs), short-term unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCTs), short-term unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNAs), and long-term autonomic symptoms with hemicrania (LASHs). Despite their common elements, trigeminal autonomic cephalalgias differ, e.g.,, in the duration and frequency of the attack and in the response to therapy. In some embodiments, the present invention provides a method of treating PH, HC, SUNCT, SUNA, and / or LASH using a dosage form described herein. In some embodiments, the present invention provides a method of treating SUNCT using a compound, dosage form, or composition described herein (e.g., Compound 1, a dosage form, or a composition comprising Compound 1). In some embodiments, the present invention provides a method of treating SUNA using a provided compound, dosage form, or composition described herein (e.g., Compound 1, a dosage form, or a composition 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 described herein (e.g., Compound 1, a dosage form, or a composition comprising Compound 1). In another aspect, the present invention provides 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 Compound 1, e.g., 2.5 mg to 90 mg of Compound 1. In some modalities, TACs are selected from the group consisting of paroxysmal hemicrania, hemicrania continua, short-term unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-term unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and long-term autonomic symptoms with hemicrania. In other modalities, TAC is a short-lasting unilateral neuralgiform headache attack. In certain modalities, the CT scan is SUNCT. In some modalities, the CT scan is SUNA. In other modalities, the subject has an inadequate response to at least one medication used for the treatment of a TAC. Migraines The compounds, dosage forms, and compositions described herein (e.g., Compound 1, a dosage form, or a composition comprising Compound 1) are useful in the treatment of migraine headaches. Migraine is a primary headache disorder characterized by recurrent moderate to severe headaches. As described herein, a 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), semiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM). In some embodiments, the present invention provides a method for treating migraine without aura, migraine with aura, hemiplegic migraine, FHM, FHM1, FHM2, FHM3, FHM4, and / or SHM using a provided compound. In some embodiments, the present invention provides a method for treating migraine without aura, migraine with aura, FHM1, FHM2, FHM4, and / or SHM using a provided compound, dosage form, or composition (e.g., Compound 1, a dosage form, or a composition comprising Compound 1). In some embodiments, the present invention provides a method for treating migraine without aura using a provided compound. In some embodiments, the present invention provides a method for treating migraine with aura using a provided compound, dosage form, or disclosed composition (e.g., Compound 1, a dosage form, or a composition comprising Compound 1).In some embodiments, the present invention provides a method for treating FHM1, FHM2, and / or FHM4 using a provided compound. In some embodiments, the present invention provides a method for treating SHM using a provided compound, dosage form, or disclosed composition (e.g., Compound 1, a dosage form, or a composition comprising Compound 1). zcfrQnn / zznz / E / YiAi In another aspect, provided in the present disclosure is a method for treating or preventing a migraine 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 a composition comprising Compound 1). In another aspect, the present invention provides a method of treating or preventing a migraine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, e.g., from about 2.5 mg to about 90 mg of Compound 1. In some modalities, 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 modalities, the migraine is migraine without aura. In certain modalities, the migraine is migraine with aura. In some modalities, the migraine is FHM1. In some modalities, the migraine is FHM2. In other modalities, the migraine is FHM4. In certain modalities, the migraine is SHM. In some modalities, the subject has an inadequate response to at least one medication used for the treatment of a migraine. Spreading cortical depression The compounds, dosage forms, and compositions described herein (e.g., Compound 1, a dosage form or a composition comprising Compound 1) are useful in the treatment of cortical spreading depression (CSD). CSD is a wave of sustained depolarization (neuronal inactivation) that moves through intact brain tissue and is involved in, for example, cerebral ischemia, migraine with aura, and seizures. In another aspect, there is provided 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 a compound, dosage form, or composition described herein (e.g., Compound 1, a dosage form or composition comprising Compound 1). In another aspect, provided herein is a method of 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, e.g., about 2.5 mg to about 90 mg of Compound 1. Cranial neuropathy The compounds, dosage forms, and compositions described herein (e.g., Compound 1, a dosage form, or a composition comprising Compound 1) are useful in the treatment of cranial neuropathy. Neuropathy is a disorder of nerve damage and affects the ability to feel and move. When nerves in the brain or brainstem are affected, it is called cranial neuropathy. Cranial nerves are those that arise directly from the brain or brainstem and often affect areas such as the face and eyes. Cranial neuropathies include 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 neuropathies (MCN). Also provided herein is a method of treating or preventing cranial neuropathy or multiple cranial neuropathies 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). In another aspect, provided herein is a method of treating or preventing cranial neuropathy or multiple cranial neuropathy 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. In some modalities, cranial neuropathy 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 modalities, the dosage form is administered orally. In certain modalities, the dosage form is a capsule. In some modalities, the patient is between 18 and 65 years of age. Polytherapy A formulation described herein (e.g., a dosage form or composition comprising Compound 1), e.g., for use in modulating a sodium ion channel, e.g., late sodium current (INaL), may be administered in combination with another agent or therapy. A subject to be administered a formulation described herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. Such diseases or conditions may be related to epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder. Antiepileptic agents Los agente antiepilepticos incluyen brivaracetam, carbamazepina, clobazam, clonazepam, diazepam, divalproex, eslicarbazepina, etosuximida, ezogabina, felbamato, gabapentina, lacosamida, lamotrigina, levetiracetam, lorazepam, oxcarbezepina, permpanel, fenobarbital, phenitoína, pregabalina, primidona, rufinamida, tigabina, topiramato,ácido valproico, vigabatrin, zonisamiday cannabidiol. Combination therapy of cardiovascular agents Diseases or conditions relating to the cardiovascular system that may benefit from combination therapy of the sodium channel blockers of the invention with other therapeutic agents include, but are not limited to, angina, including stable angina, unstable angina (UA), exercise-induced 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. Suitable therapeutic agents for treating cardiovascular diseases or conditions include antianginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid-lowering agents. Co-administration of the sodium channel blockers of the invention with therapeutic agents suitable for treating conditions related to the cardiovascular system allows for the improvement of the standard therapy that the patient is currently receiving. Antianginal Antianginals include beta blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload, resulting in a slower heart rate and less forceful heart contraction. Examples of beta blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Zlac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren). Nitrates dilate arteries and veins, increasing coronary artery blood flow and lowering blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate. Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels, causing the blood vessels to relax 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), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine. Agents for heart failure Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics remove excess fluid from the tissues and circulation, which relieves many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra). Angiotensin-converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding blood vessels and decreasing resistance to blood flow. Some 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). zcfrQnn / zznz / E / YiAi Vasodilators reduce pressure on blood vessels by causing them to relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators. Cardiac glycosides are compounds that increase the strength of the heart's contractions. These compounds strengthen the heart's pumping capacity and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin. Antithrombotic agents Antithrombotics inhibit the blood's ability to clot. There are three main types of antithrombotics: platelet inhibitors, anticoagulants, and thrombolytic agents. Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries. Examples of platelet inhibitors include aspirin, ticlopidine, clopidogrel (Plavix), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb / IIIa inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta-blockers and calcium channel blockers also have a platelet-inhibiting effect. Anticoagulants prevent blood clots from getting bigger and prevent new clots from forming. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low-molecular-weight heparin, danaparoid, lepirudin, and argatroban. Thrombolytic agents work to break down an existing blood clot. Examples of thrombolytic agents include streptokinase, urokinase, tenecteplase (TNK), and tissue plasminogen activator (t-PA). Antiarrhythmic agents Antiarrhythmic agents 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 agents. Combinations with amiodarone and dronedarone are of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amioarone and dronedarone. Antihypertensive agents Antihypertensive agents 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 clotting. Examples of antihypertensive agents include alpha-1 adrenergic antagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken);Central alpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenzo acetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); combined alpha / beta-adrenoceptor antagonists, such as labetalol (Normodyne, Trandate), carvedilol (Coreg); adrenergic neuron blocking agents, such as guanethidine (Ismeline), reserpine (Serpasil); centrally acting antihypertensives, such as clonidine (Catapres), methyldopa (Aldomet), guanabenzo (Wytensin); antiangiotensin II agents; GAS inhibitors, such as perindopril (Aceon) captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril);angiotensin II receptor antagonists, such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), valsartan (Diovan); calcium channel blockers, such as verapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat, Procardia); diuretics; direct vasodilators, such as nitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), verapamil; and potassium channel activators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil. Lipid-lowering agents Lipid-lowering agents are used to reduce the amount of cholesterol, or fatty sugars, in the blood. Examples of lipid-lowering agents 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). In this invention, the patient experiencing an acute coronary artery disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder. Such patients may benefit from treatment with a combination therapy comprising administering ranolazine to the patient in combination with at least one other therapeutic agent. Combination therapy for lung disorders Pulmonary disorder refers to any disease or condition related to the lungs. Examples of lung disorders include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema. Examples of therapeutic agents used to treat lung disorders include bronchodilators, including beta2 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. zcfrQnn / zznz / E / YiAi Combination therapy for metabolic disorders Some examples of metabolic disorders include, but are not limited to, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides. Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents, as described in the “Combination Therapy of Cardiovascular Agents” section above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics. Combination therapy for peripheral vascular disorders Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain. These include, for example, peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis. Combination therapy for gastrointestinal disorders Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Some examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis. Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid); nizatidine (Axid); prostaglandins, such as misoprostol (Cytotec); sucralfate; and antacids. Combination therapy of antibiotics, analgesics, antidepressants and anxiolytics Patients presenting with an acute coronary artery disease event may have conditions that benefit from the administration of therapeutic agents or agents that are antibiotics, analgesics, antidepressants, and anxiolytics in combination with ranolazine. Antibiotics Antibiotics are therapeutic agents that kill or stop the growth of microorganisms, including bacteria and fungi. Examples of antibiotics include beta-lactam antibiotics, including penicillins (amoxicillin); cephalosporins, such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), and cephradine (Velosef); cefaclor (Ceclor), cefuroxime axetil (Ceftina), cefprozil (Cefzil), loracarbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), ceftriaxone (Rocephin); carbapenems, and monobactams; tetracyclines, such as tetracycline; macrolide antibiotics, 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; oxazolidines such as linezolid; and sulfa antibiotics such as sulfisoxazole. Painkillers Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opiates and morphoinomimetics, such as fentanyl and morphine; acetaminophen; NSAIDs; and COX-2 inhibitors. Given the ability of the sodium channel blockers of the invention to treat neuropathic pain by inhibiting the Nav1,7 and Nav1,8 sodium channels, combination with analgesics is particularly envisioned. See U.S. patent application publication 20090203707. Antidepressants and anxiolytics Antidepressants and anxiolytics include those used to treat anxiety disorders, depression, and those used as sedatives and tranquilizers. Examples of antidepressants and anxiolytics include benzodiazepines, such as diazepam, lorazepam, and midazolam; benzodiazepines; barbiturates; glutethimide; doral hydrate; meprobamate; sertraline (Zoloft, Lustral, ApoSertral, Asentra, Gladem, Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep., Fludep, Lovan); venlafaxine (Effexor XR, Efexor); citalopram (Celexa, Cipramil, talohexane); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban). Antidepressant and anxiolytic agents may include neuroactive corticosteroids and ketamine, and related NMDA receptor antagonists. Accordingly, one aspect of the invention provides a composition comprising the sodium channel blockers of the invention and at least one therapeutic agent. In an alternative embodiment, the composition comprises the sodium channel blockers of the invention and at least two therapeutic agents. In further alternative embodiments, the composition comprises the sodium channel blockers of the invention and at least three therapeutic agents, the sodium channel blockers of the invention and at least four therapeutic agents, or the sodium channel blockers of the invention and at least five therapeutic agents. Combination therapy methods include co-administration of a single formulation containing the sodium channel blockers of the invention and therapeutic agent(s), substantially contemporaneous administration of more than one formulation comprising the sodium channel blocker of the invention and therapeutic agent(s), and consecutive administration of a sodium channel blocker of the invention and therapeutic agent(s), in any order, wherein preferably there is a period of time where the sodium channel blocker of the invention and therapeutic agent(s) simultaneously exert their therapeutic effect. zcfrQnn / zznz / E / YiAi Preparation methods Provided herein are methods for preparing compounds useful for preventing and / or treating a disease, disorder, or condition described herein, e.g., a disease, disorder, or condition related to abnormal function of a sodium ion channel, such as late abnormal sodium current (LASC). In one aspect, the present disclosure provides a method of manufacturing Compound 1: zcfronn / zznz / E / YiAi or a pharmaceutically acceptable salt thereof, the method comprising the steps of: (i) contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoro-pyridine, thereby providing a compound of formula (II): F F F Br(ll); (i) contacting the compound of formula (II) with a palladium and bis(pinacolato)diboron catalyst thereby providing a compound of formula (III): (iii) contacting the compound of formula (III) with a palladium catalyst and 2-bromo-5-chloro-pyrazine thereby providing a compound of formula (IV): F F CI(IV); (iv) contacting the compound of formula (IV) with hydrazine thereby providing a compound of formula (V): F F zcfrQnn / zznz / E / YiAi ,NH2 N2 H (V); (v) contacting the compound of formula (V) with 2-bromo-2,2-difluoro-acetyl chloride thereby providing a compound of formula (VI): F F H NH Br O (VI); (vi) contacting the compound of formula (VI) with an acid thereby providing a compound of formula (VII): F F Br (Vil); and (vil) contacting the compound of formula (Vil) with a silver catalyst and ethanol thereby providing Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the palladium catalyst in step (i) 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. In another aspect, the present disclosure provides a method of manufacturing Compound 1: or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is provided by contacting the compound of formula (VII): FF zcfrQnn / zznz / E / YiAi with a silver catalyst and ethanol. In some embodiments, the compound of formula (VII) is provided by contacting the compound of formula (VI): FF ° (VI) with an acid. In some embodiments, the compound of formula (VI) is provided by contacting the compound of formula (V): FF N Jk ,NH2 Η (V) with 2-bromo-2,2-difluoro-acetyl chloride. In some embodiments, the compound of formula (V) is provided by contacting the compound of formula (IV): FF with hydrazine. In some embodiments, the compound of formula (IV) is provided by contacting the compound of formula (III): > u NCNNCC σ u N with a palladium catalyst and 2-bromo-5-chloro-pyrazine. In some embodiments, the compound of formula (III) is provided by contacting the compound of formula (II): FF with a palladium and bis(pinacolato)boron catalyst. 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-pindina. 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. EXEMPLIFICATION The following representative examples are intended to help illustrate the invention, and are not intended to limit the scope of the invention, nor should they be construed as such. PSD Particle size distribution XRPD X-ray powder diffraction NMR Nuclear magnetic resonance LC-MS Liquid chromatography-mass spectrometry PEG Polyethylene glycol HPLC High-performance liquid chromatography MC Methylcellulose HR Relative humidity ASD Amorphous solid dispersion PLM Polarized light microscopy mDSC Modulated differential calorimetry FaSSIF Simulated fasting intestinal fluid UPLC Ultra-performance liquid chromatography API Active pharmaceutical ingredient PVP Polyvinylpyrrolidone HPMC Hydroxypropyl methylcellulose SDS sodium dodecyl sulfate USP United States Pharmacopeia TFA trifluoroacetic acid ACN acetonitrile PK pharmacokinetics MCC microcrystalline cellulose MgSt magnesium stearate rpm RSD revolutions per minute relative standard deviation HG hard gelatin capsule SLS sodium lauryl sulfate AUC area under the curve Cmax maximum observed concentration HPMCAS hydroxypropyl methylcellulose acetate succinate PG propylene glycol AE adverse event ECG electrocardiogram C-SSRS Columbia University Suicide Risk Scale Tmax time to maximum observed concentration tl / 2 apparent terminal elimination half-life AUCo last area under the concentration-time curve from time zero to last half-life AUCo ¡nf area under the drug concentration-time curve from time zero to infinity CL / F clearance Vd / F volume of distribution Clr actual clearance f e fraction of dose excreted unchanged in urine Aeo-72 amount excreted unchanged over 72hours EEG and ectroe nceph alogra phy PD pharmacodynamics Rae (AUC) time to steady-state accumulation quotient based on AUC RaC (Cmax) SAD accumulation ratio based on Cmax single ascending dose QTcF QT interval with Fridericia's correction method OTC over-the-counter BLQ below level of quantification CV% coefficient of variation zcfrQnn / zznz / E / YiAi Example 1. Preparation and characterization of ground Compound 1 Compound 1 was milled by hand milling or jet milling to reduce particle size. For hand milling, Compound 1 was weighed into a ceramic motor and gently milled for ~5 min. The particle size distribution (PSD) of Compound 1 indicated D90 = 77.82 pm and D90 = 28.27 pm before and after hand milling of Compound 1. The PSD was performed by dry method using Sympatec HELOS particle size analyzer, and the dispersion system and pressure were RODOS and 0.5 bar, respectively. zcfrQnn / zznz / E / YiAi Table 1. Changes in particle size after manual grinding Compound 1 Before After manual grinding D10 1.8 pm 0.8 pm D50 22.2 pm 3.6 pm D90 77.8 pm 28.3 pm For jet milling, Compound 1 was micronized by jet milling with a yield of ~90%. The particle size of the jet-milled material was reduced to a D90 range of 4.7 to 13.5 pm. Table 2. Changes in particle size after jet milling Compound 1, Batch 1 Before After Jet Milling (51g Scale) D10 1.8 pm 0.7 pm D50 15.4 pm 1.8 pm D90 80.9 pm 4.7 pm Compound 1, Batch 2 Before After Jet Milling (95g Scale) D10 13.2 pm 1.1 pm D50 67.3 pm 3.7 pm D90 162.1 pm 8.3 pm Compound 1, Batch 3 Before After Jet Milling (104g Scale) D10 14.6 pm 0.87 pm D50 56.8 pm 5.58 pm D90 104 pm 13.5 pm 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 A) with the generator operating at 40 kV / 40 mA. Samples were scanned in continuous mode from 3° to 40° (28) with a sample rotation speed of 15 rpm and a scan rate of 10 s / min. Figure shows the XRPD pattern of the raw material and the jet-milled material, indicating no change in the physical form of Compound 1 after jet-milling. Proton NMR (1H-NMR), Florin NMR (19F-NMR), and LC-MS analyses were also performed on Compound 1 before and after jet milling. Both the NMR and LC-MS results indicate that no chemical or structural changes were observed in Compound 1 due to jet milling. Example 2. Preparation and stability of formulations comprising Compound 1 Solution formulations 1) Prototype 1:40% PEG 400 / 10% Cremophor RH40 / 50% water 2400 µL of PEG 400 was added to an 8 mL glass vial along with 3 mg of Compound 1 and mixed by vortexing and sonicated for 5 min. Then, 600 µL of Cremophor RH40 was added to the vessel, mixed together by vortexing and sonicated for 5 min. Then, 3000 µL of water was added to the vessel, mixed by vortexing and sonicated for 5 min. The compound was completely dissolved (0.5 mg / mL). 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 to obtain the vehicle of prototype 2a. Approximately 15 mg of compound was weighed into an 8 mL glass vessel, and then 2 mL of Prototype 2a was added to the glass vessel. The contents were mixed by vortex mixing and sonication for 5 min. Compound 1 in Prototype 2a at 7.5 mg / mL was a clear solution. 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 to obtain the vehicle of Prototype 2b. Approximately 15 mg of compound was weighed into 8 mL glass vessels, then 2 mL of prototype 2b was added to the vessel and vortexed and sonicated for 5 min. Compound 2 in prototype 2b at 7.5 mg / mL was not clear. Another 140 μL of prototype 2b vehicle was then added to the vessel and vortexed and sonicated for 5 min. Prototype 2b at 7 mg / mL was a clear solution. 4) Prototype 3: 40% Transcutol HP / 10% Vitamin ETPGS / 50% Water 600 pL of PEG 400 was added to a 4 mL glass vial along with 3 mg of Compound 1 and mixed by vortexing and sonicated for 5 min. Then, 150 pL of Cremophor RH40 was added to the vessel and mixed by vortexing and sonicated for 5 min. Then, 750 pL of water was added to the vessel and mixed by vortexing and sonicated for 5 min. The compound was completely dissolved (2 mg / mL). 5) Prototype 4: 36% Cremophor RH40 + 45% Capmul MCM C8 + 9% triethylcitrate + 10% ethanol zcfrQnn / zznz / E / YiAi Cremophor RH40, Capmul MCM 08, Triethylcitrate, and Ethanol were added together on a weight basis to a glass container and mixed together to form a solution mixture. Increasing amounts of Compound 1 were then added to the mixture and vortexed and sonicated to form a clear solution. Additional Compound 1 was added by vortexing and sonication until Compound 1 was no longer soluble. The resulting maximum solubility was visually determined to be between 25 and 50 mg / mL. 6) Prototype 5: 40% Capryol 90 + 20% Labrasol + 40% Transcutol HP Capryol 90, Labrasol, and Transcutol HP were added together volumetrically to a glass container and mixed to form a solution mixture. Increasing amounts of Compound 1 were then added to the mixture and vortexed and sonicated to form a clear solution. Additional Compound 1 was added by vortexing and sonication until Compound 1 was no longer soluble. The resulting maximum solubility was determined visually to be between 60 and 80 mg / mL. Table 3 summarizes the prototypes used to prepare solution formulations of Compound 1 with their respective stability. Table 4 shows the detailed stability results. zcfrQnn / zznz / E / YiAi Table 3.Solution formulations comprising Compound 1 Solution formulation Target concentration of compound 1 (mg / ml) Stability observation (storage at room temperature) Prototype 1 (40% PEG 400 / 10% Kolliphor RH40 / 50% water) 0.5 Stable for 7 days Prototype 2a (58.1% KolliphorRH40 + 16.9% Labrafil M2125 CS + 8.3% propylene glycol + 16.7% ethanol) 7.5 Stable for 7 days Prototype 2b (69.74% KolliphorRH40 + 20.28% Labrafil M2125 CS + 9.98% propylene glycol) 7 Stable for 7 days 2.3 (diluted in water 3 times) Stable for 7 days Prototype 3 (40% Transcutol HP / 10% vitamin ETPGS / 50% water) 2 Stable for 7 days A high-performance liquid chromatography (HPLC) method was developed for stability and purity testing of Compound 1. The HPLC method used for chemical stability and purity testing was as follows: Column Agilent Pursuit XRs C18 Column (150 mm* 4.6 mm* 3 pm) Wavelength 245 nm Column Oven Temp. 45 °C Flow Rate 1.0 mL / min Injection Volume 2 pL Mobile Phases A: 0.1% TFA in Water (v / v) B:MeOH:ACN (80:20; v / v) Gradient Program Time (min) A% B% 0.00 50 50 30.0 20 80 35.0 20 80 35.1 50 50 40.0 50 50 Reequilibration Time 5 min Run Time 40 min Needle Wash Solvent ACN:Water (50:50; v / v) ACN:Water Diluent (90:10; v / v) zcfrQnn / zznz / E / YiAi Table 4. Detailed stability test data for prototypes 1, 2a and 3 (storage was carried out at room temperature, 15-25 °C). Target Conc. (mg / ml) Sample Prototype 1 Time Appearance Conc. (mg / ml) Purity (%) 0.5 1 h clear 0.53 98.58 4 h clear 0.52 98.58 7 days clear 0.43 97.78 Target Conc. (mg / ml) Sample Prototype 2a Time Appearance Conc. (mg / ml) Purity (%) 7.5 1 h clear 7.36 96.64 4 h clear 7.31 96.45 7 days clear 7.17 97.28 Target Conc. (mg / ml) Sample Prototype 3 Time Appearance Conc. (mg / ml) Purity (%) 1.0 1 h clear 1.11 96.87 4 h clear 1.11 97.01 7 days transparent 1.06 97.59 Approximately 24 mg of Compound 1 was added to an 8 mL glass bottle and dissolved using prototype 2b. It was then sonicated for 10 min to obtain a clear solution with a concentration of 7 mg / mL. The solution was then diluted 3-fold with water for stability testing. The results are shown in Table 5 below. zcfrQnn / zznz / E / YiAi Table 5: Detailed stability test data for prototype 2b Sample Time 0 Appearance Target conc. (mg / ml) Conc. (mg / ml) Purity (%) Prototype 2b diluted in water 3 times initial transparent 2.33 - - 24 h transparent 2.19 99.56 72 h transparent 2.23 99.83 7 days transparent 2.45 99.65 Based on the HPLC results and appearance, Prototype formulations 1, 2a, 2b, and 3 comprising Compound 1 were stable under ambient conditions for at least 7 days. Suspension formulations 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 400 cP / 0.2% Tween 80 was added to each vial. The materials were mixed together by vortexing and stirred at room temperature overnight (24 h). The stability of the suspension formulations was measured by quantifying the purity of Compound 1 using high-pressure liquid chromatography (HPLC). The suspensions remained homogeneous. Table 6 summarizes the stability results. To prepare a suspension formulation comprising jet-milled Compound 1, 15 mg of jet-milled Compound 1 was weighed into a glass vial and then 10 mL of vehicle (0.5% MC 400 cP / 0.2% Tween 80) was added to disperse it and achieve a Compound 1 concentration of 1.5 mg / mL. The suspension was completely dispersed by homogenization for ~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 comprising jet-milled Compound 1 was stable under ambient conditions for 28 days. Table 6. Stability of Compound 1 suspension formulations in 0.5% MC 400 cP / 0.2% of Tween 80. Target Concentration (mg / mL) Time Point Concentration (ng / mL) Purity (%) 10 1 h 9.69 96.86 4 hrs 9.79 97.12 7 days 9.72 96.71 5 1 h Not Available 97.60 4 hrs 4.72 97.84 7 days 5.06 96.95 0.5 1 h 0.58 97.46 4 hrs 0.45 96.65 7 days 0.49 97.85 1.5* 1 day 1.44 99.4 6 days 1.43 99.5 Compound 1 not ground unless otherwise indicated. * designates jet-ground material. zcfrQnn / zznz / E / YiAi Table 7. Stability of suspension formulation in 0.5% MC 400 cP / 0.2% Tween 80 comprising jet-milled Compound 1 Target Conc. (mg / ml) Time Point at RT (day) Appearance Conc. (mg / ml) Purity (%) DEP (D90, um) 1.5 Initial Homogeneous Suspension 1.61 99.43 - 1 Homogeneous Suspension 1.44 99.44 - 2 Homogeneous Suspension 1.38 99.52 - 3 Homogeneous Suspension 1.58 99.49 - 6 Homogeneous Suspension 1.43 99.51 - 7 Homogeneous Suspension 1.61 99.55 - 14 Homogeneous suspension 1.61 99.36 - 21 Homogeneous suspension 1.56 99.58 6.97 28 Homogeneous suspension 1.64 98.96 6.80 zcfronn / zznz / E / YiAi As shown in Tables 8-11, the suspension formulations were tested for stability under different conditions. To prepare a suspension, weigh the required amount of ground Compound 1 into a glass container and add the corresponding volume of vehicle. Disperse the compound thoroughly into a homogeneous suspension using an overhead mixer to the final concentration target. Concentrations were prepared at 0.1 mg / mL and 10 mg / mL. The suspension products were physically evaluated for visual appearance, concentration, purity, and PSD. The vehicles are prepared by dissolving 0.5% by weight of 400 cP methylcellulose or 4000 cP methylcellulose and 0.2% poloxamer 188. For preserved suspensions, 1.0% by volume of paraben preservative solution was additionally dissolved in the vehicle using an overhead mixer. The paraben preservative solution was prepared by dissolving 0.10 g of methylparaben, 0.025 g of propylparaben in 9.875 g of propylene glycol dissolved by mixing with a stir bar at room temperature for 1 hour. Table 8.Evaluation of the visual stability of suspension formulations comprising Compound 1 after 1, 4 and 24 hours at room temperature Vehicle Target Concentration (mg / ml) Hours at RT Visual Appearance (see reference legend) 0.5% 400 cP MC, 0.2% Poloxamer 188 and 1.0% paraben preservative solution 0.1 1 ★ 4 ★ 24 * 10 1 * 4 ★ 24 ★ 0.5% 4000 cP MC, 0.2% Poloxamer 188 and 1.0% paraben preservative solution 0.1 1 # 4 # 24 # 10 1 # 4 # 24 # 0.5% 400 cP MC, 0.27o Poloxamer 188 0.1 1 ★ 4 * 24 * 10 1 ★ 4 ★ 24 ★ 0.57o 4000 cP MC, 0.27o Poloxamer 188 0.1 1 # 4 # 24 # 10 1 # 4# 24# * initially homogeneous suspension, sedimentation occurred over time and became homogeneous again after gentle stirring zcfrQnn / zznz / E / YiAi # initially homogeneous viscous suspension, sedimentation occurred over time and became homogeneous again after gentle stirring Table 9. Stability of suspension formulations comprising Compound 1 after 96 hours at room temperature Vehicle Target Conc. (mg / ml) Hours at RT Visual Appearance 0.57o 400 cP MC, 0.27o Poloxamer 188 and 1.07o paraben preservative solution 0.1 96 * 10 96 ★ 0.57o 4000 cP MC, 0.27o Poloxamer 188 and 1.07o paraben preservative solution 0.1 96 # 10 96 # 0.57o 400 cP MC, 0.27o Poloxamer 188 0.1 96 * 10 96 * 0.57o 4000 cP MC, 0.27o Poloxamer 188 0.1 96 # 10 96 # * Initially homogeneous suspension, sedimentation occurred over time and became homogeneous again after gentle stirring for ~1 min # Initially homogeneous viscous suspension, sedimentation occurred over time and became homogeneous again after gentle stirring for ~2 min Table 10. Stability of suspension formulations comprising Compound 1 at 2-8 °C Vehicle Target Conc. (mg / ml) Time point at 2-8 °C Aspect Conc. (mg / ml) Purity (%) DEP (D90, pm) 0.5% 400 CP MC, 0.27o Poloxamer 188 0.1 0 ★ 0.11 100 19.9 7D ★ 0.12 100 18.2 14D ★ 0.11 100 14.2 28 D ★ 0.11 100 15.4 2M * 0.11 95.87 9.1 3M * 0.11 93.20 12.7 10 0 ★ 10.04 99.83 5.6 7D ★ 10.18 99.83 6.4 14D ★ 10.66 99.83 5.4 28 D ★ 10.56 99.83 3.8 2M * 10.99 99.83 4.0 3M * 10.13 99.83 3.6 * Initially homogeneous suspension, sedimentation occurred over time and became homogeneous again after gentle shaking for ~1 min Table 11. Stability of suspension formulations comprising Compound 1 at 25 °C / 60% RH zcfrQnn / zznz / E / YiAi Vehicle Target Conc. (mg / ml) Time Point at 25°C / 60 7o RH Aspect Conc. (mg / ml) Purity (%) DEP (D90, pm) 0.57o 400 CP MC, 0.27o Poloxamer 188 0.1 0 ★ 0.11 100.0 19.9 7D ★ 0.11 100.0 19.9 14D ★ 0.11 100 12.9 28 D ★ 0.10 100 8.7 2M * 0.11 95.87 8.6 3M * 0.11 93.20 11.1 10 0 ★ 10.04 99.83 5.6 7D ★ 10.48 99.83 6.3 14D ★ 9.85 99.83 5.2 28 D * 10.00 99.83 4.6 2M * 10.47 99.83 4.3 3M * 10.16 99.83 3.5 * Initially homogeneous suspension, sedimentation occurred over time and became homogeneous again after gentle shaking for ~1 min Amorphous solid dispersion (ASD) The amorphous solid dispersion including Compound 1 was prepared with a mixture of Compound 1 and the polymer. Nine ASD formulations were prepared using a selection of 9 different polymers as the solid dispersant (PVPK30, PVPVA64, Soluplus, HPMC E5, HPMC ASMG, HPMC ASMF, HPMC ASHG, Eudragit EPO, Eudragit L100). Approximately 10 mg of Compound 1 and 40 mg of the corresponding polymer were weighed into 40-mL glass vials, and dissolved in 1 mL of MeOH / DCM (1:1, v / v) to prepare the stock solution. The obtained clear solutions were stored at 70°C to rapidly evaporate and yield a solid dispersion. The product after evaporation was dried under vacuum at 30°C overnight and further characterized by appearance, PLM, XRPD, and mDSC. The nine ASD formulations were tested for kinetic solubility in FaSSIF at a concentration of 2 mg / mL. The experiment was run at 37 °C with a speed of 450 rpm. At each time point, 0.5 mL of the mixture was removed and centrifuged prior to UPLC (a shortened runtime version of the HPLC method described was used to determine Compound 1 levels). The results are listed in Table 12. Improved solubility was observed for most polymers, especially for Eudragit EPO. Table 12. Summary of the kinetic solubility of the ASDs zcfrQnn / zznz / E / YiAi No. Formulation SD Kinetic Solubility in FaSSIF (pg / ml) Final pH 15 min 30 min 60 min 120 min 0 Crystalline API (API Compound 1) 5.7 8.1 7.1 11.6 6.54 1 API+ PVP K30 4.9 6.0 5.8 6.7 6.55 2 API+ PVP VA64 4.8 5.7 5.2 5.2 6.54 3 API+ Soluplus 12.9 19.1 17.5 18.7 6.56 4 API+ HPMC E5 8.8 8.2 7.9 7.6 6.57 5 API+ HPMC ASMG 21.7 24.7 26.9 22.1 5.92 6 API+ HPMC ASMF 20.3 26.2 24.4 31.4 5.96 7 API+ HPMC ASHG 28.4 24.2 21.9 20.9 6.49 8 API+ Eudragit EPO 111.0 207.0 273.3 327.2 7.21 9 API+ Eudragit L100 19.2 16.2 19.6 26.6 5.59 Based on the kinetic solubility evaluation of the ASD prototype formulation, three ASD prototype formulations were then prepared for further evaluation using Soluplus, Eudragit L100, or HPMC ASMF and are summarized in Table 13. The stability testing results of the selected ASD formulations are shown in Tables 14 and 15. zcfrQnn / zznz / E / YiAi Table 13. Summary of selected ASD formulations Compound 1 ASD + Soluplus ASD + Eudragit L100 ASD + HPMC ASMF Appearance White powder White powder White powder PLM No birefringence and spherical shape XRPD Amorphous Amorphous Amorphous Tg by mDSC (SC) 91.65 90.83 91.34 HPLC Assay Drug Loading (w%) 18.9 19.3 18.1 Purity (% A) 99.01 98.71 97.61 Sol. kineticsSol. kinetics in FASSIF (ug / ml) at 120 min 19 21 31 Table 14. Stability results after 1 week of selected ASD formulations SD Formulation Initial Drug Loading (%) Initial Purity (%) Storage Condition After 1 Week XRPD HPLC Results Drug Loading (%) Purity (%) ASD_Soluplus 18.9 98.68 25 SC / 60% RH, opened Partially crystalline 20.80 96.40 40 SC / 75% RH, opened Partially crystalline 19.82 95.81 18.86 97.81 25 SC / 60% RH, closed Partially crystalline 18.69 97.49 60 2C, closed Partially crystalline 18.65 96.86 ASD_Eudragit L100 19.1 97.58 25 SC / 60% RH, open Amorphous 19.86 96.79 40 SC / 75% RH, open Amorphous 20.00 96.35 19.12 97.31 25 SC / 60% RH, closed Amorphous 18.62 96.86 60 SC, closed Amorphous 18.63 96.48 ASDHPMC ASMF 18.1 96.42 25 SC / 60% RH, open Amorphous 17.44 94.40 40 BC / 75 % RH, open Partially crystalline 17.33 94.74 17.81 95.17 25 BC / 60 % RH, closed Amorphous 17.32 95.44 60 SC, closed Amorphous 17.38 94.93 zcfrQnn / zznz / E / YiAi Table 15. Stability results after 2 weeks SD Formulation Initial Drug Loading (%) Initial Purity (%) Storage Condition After 2 Weeks XRPD HPLC Results Drug Loading (%) Purity (%) ASD_Soluplus 18.9 98.68 25 SC / 60% RH, open Partially crystalline 21.29 97.24 40 BC / 75% RH, open Partially crystalline 20.43 95.23 18.86 97.81 25 BC / 60% RH, closed Partially crystalline 17.92 94.01 60 BC, closed Partially crystalline 18.69 93.41 ASDEudragit L100 19.1 97.58 25 SC / 60% RH, open Amorphous 19.57 97.21 40 SC / 75% RH, open Amorphous 19.99 95.84 19.12 97.31 25 SC / 60% RH, closed Amorphous 18.89 96.53 60 SC, closed Partially crystalline 18.54 96.09 ASDHPMC ASMF 18.1 96.42 25 2C / 60% RH, open Amorphous 17.69 94.32 40 SC / 75 7o RH, open Partially crystalline 17.77 95.70 17.81 95.17 25 SC / 60 7o RH, closed Amorphous 17.93 94.01 60 SC, closed Partially crystalline 17.33 94.54 zcfrQnn / zznz / E / YiAi Three ASD scale with a spray dryer Preparation of ASD-1: Approximately 300 mg of Compound 1 and approximately 1200 mg of Soluplus were weighed into a 250 ml glass flask, then 150 ml of acetone was added to make a clear solution before spray drying. After spray drying, the powder was collected and dried under vacuum at 30 °C for 12 hours (80.2% yield). Preparation of ASD-2: Approximately 300 mg of Compound 1 and approximately 1200 mg of Eudragit L100 were weighed into a 250 ml glass flask, then 150 ml of acetone was added to make a clear solution before spray drying. After spray drying, the powder was collected and dried under vacuum at 30 °C for 12 hours (74.5% yield). Preparation of ASD-3: About 300 mg of Compound 1 and about 1200 mg of HPMC ASMF were weighed into a 250 ml glass flask, then 150 ml of acetone was added to make a clear solution before spray drying. After spray drying, the powder was collected and dried under vacuum at 30 °C for 12 hours (yield 70.0%). The ASD-3 prototype was also evaluated in an in vitro dissolution study. The collected spray-dried ASD-3 powder was weighed by hand on an analytical balance directly into size 4 hard gelatin capsules at two dosage strengths: 2.5 and 10 mg of active (13.7 and 54.8 mg of ASD). The dissolution method used the following conditions: Configuration Parameters Agilent 708-DS Instrument Media 0.1 N HCl with 2% SDS Apparatus USP Apparatus 2 (paddle) Rotational Speed ​​75 rpm (200 rpm for infinite rotation) Media Volume 900 mL Temperature 37.0 ±0.5 °C Sampling Time Point 15, 30, 45, 60 minutes, and infinity at 120 minutes zcfrQnn / zznz / E / YiAi For dissolution analysis, an HPLC method was used to quantify the levels of Compound 1 in the dissolution media. The same HPLC method was used for the dissolution and content uniformity tests. The HPLC method used is as follows: Column Agilent Pursuit XRs C18 Column (150 mm* 4.6 mm* 3 pm) Wavelength 245 nm Column Oven Temp. 45 °C Flow Rate 1.0 mL / min Injection Volume 2 pL Mobile Phases A: 0.1% TFA in Water (v / v) B:MeOH:ACN (80:20; v / v) Gradient Program Time (min) A% B% 0.00 70 30 10.00 0 100 Reequilibration Time 2 min Run Time 10 min Needle Wash Solvent ACN:Water (50:50; v / v) Diluent ACN:Water (90:10; v / v) The dissolution results are shown in Figure 2, where the release of two dose concentrations was 29.76% and 17.64% for the 2.5 mg and 10 mg dose concentrations, respectively. The ASD-3 prototype was also evaluated in a pharmacokinetic (PK) study in cynomolgus monkeys using a crossover design. The collected spray-dried ASD-3 powder was weighed by hand on an analytical balance directly into size 4 hard gelatin capsules. Three male monkeys were orally administered 0.5 mg / kg of body weight under fasting conditions, and plasma samples were analyzed for Compound 1 levels. Capsule formulations Illustrative capsule formulations include 2.5 mg, 10 mg, or 100 mg of Compound 1 per capsule. For the 2.5 mg dose capsule, one formulation includes a 1:10 blend of Compound 1 to microcrystalline cellulose (MCC) with 2% magnesium stearate (MgSt) in a gelatin capsule, and another formulation includes 2.5 mg of pure Compound 1 in a gelatin capsule (with no additional excipients). Ground compound 1 and the filler (MCC or starch) were weighed separately and mixed for 15 minutes to obtain a homogeneous mixture. A required amount of magnesium stearate was added and mixed. The mixture was hand-filled into appropriately sized hard gelatin capsules. Samples were then subjected to stability testing under various conditions and analyzed for appearance and titration at different time points. Mixture formulations Mix 1 and 2 (1:10 mix) One g of ground Compound 1 and 9 g of MCC or starch were weighed into a container. The two components were mixed by Turbula for approximately 15 minutes at a speed of 36 rpm to obtain a homogeneous phase. 0.2 g of MgSt was added and mixed for another 3 minutes to obtain homogeneous mixture 1 (Table 16). Dose uniformity was assessed by measuring the 10-capsule assay (Tables 18 and 19). zcfrQnn / zznz / E / YiAi Table 16. Composition of mixtures 1 and 2 Combination 1 Components Function Percentage (w / w %) Compound 1 Active 10 MCC Filler 90 MgSt Lubricant 2 Combination 2 Components Function Percentage (w / w %) Compound 1 Active 10 Starch Filler 90 MgSt Lubricant 2 Mix 3 and 4 (1:1 mix) 5 g of ground Compound 1 and 5 g of MCC or starch were weighed into a container. The two components were mixed by Turbula for approximately 15 minutes at a speed of 36 rpm to obtain a homogeneous phase. 0.2 g of MgSt was added and mixed for another 3 minutes to obtain homogeneous mixture 1 (Table 17). Dose uniformity was assessed by measuring the 10-capsule assay (Tables 20 and 21). Table 17. Composition of mixtures 3 and 4 Combination 3 Components Function Percentage (w / w %) Compound 1 Active 50 MCC Filler 50 MgSt Lubricant 2 Combination 4 Components Function Percentage (w / w %) Compound 1 Active 50 Starch Filler 50 MgSt Lubricant 2 zcfrQnn / zznz / E / YiAi Tables 18-21 summarize the mix uniformity results for 4 illustrative mixes (mixes 1-4 as described above) comprising Compound 1. Table 18. 1:10 mix uniformity results of mix 1 Sample Collection Location Sample Weight (mg) Label Statement (%) Average (%) RSD (%) Upper-I 7.79 97.95 94.18 3.97 Upper-2 7.36 92.36 Upper-3 9.16 95.09 Middle-1 7.89 86.96 Middle-2 10.69 88.58 Middle-3 7.58 96.55 Middle-4 6.79 94.81 Lower-1 7.86 96.96 Lower-2 7.62 95.47 Lower-3 6.62 97.1 Table 19. 1:10 mix uniformity results of mix 2 Sample Collection Location Sample Weight (mg) Label Declaration (%) Average (%) RSD (%) 5 Top-1 11.83 88.66 93.21 4.34 Top-2 11.47 96.28 Top-3 6.91 93.45 Middle-1 8.51 94.50 Middle-2 7.66 96.34 Middle-3 11.95 91.53 Middle-4 8.54 87.87 10 Bottom-1 10.45 99.85 Bottom-2 8.49 88.20 Bottom-3 11.13 95.44 15 Table 20. 1:1 Blend Uniformity Results for Blend 3 Sampling Location Sample Weight (mg) Label Claim (%) Average (%) RSD (%) Top-1 15.15 93.46 93.88 3.13 20 Upper-2 15.05 94.84 Upper-3 16.92 99.64 Medium-1 12.89 89.67 Medium-2 14.96 94.61 25 Medium-3 16.38 91.61 Medium-4 17.46 92.68 Lower-1 18.32 95.81 Lower-2 16.61 90.56 30 Lower-3 16.63 95.89 zcfrQnn / zznz / E / YiAi Table 21. 1:1 mix uniformity results of mix 4 Sample Collection Location Sample Weight (mg) Label Claim (%) Average (%) RSD (%) Top-1 20.62 95.48 94.26 3.83 Top-2 18.01 95.94 Upper-3 22.95 87.41 Middle-1 14.98 88.62 Middle-2 21.74 95.24 Middle-3 17.47 92.89 Middle-4 14.34 94.80 Lower-1 17.35 96.73 Lower-2 15.16 98.25 Lower-3 22.29 97.25 zcfrQnn / zznz / E / YiAi Tables 21.1, 21.2, 21.3 and 21.4 show the stability results of Mixture 1 capsules and Mixture 2 capsules at dose strengths of 1 mg per capsule (mixing ratio of 1:10), 10 mg per capsule (mixing ratios of 1:10 and 50:50) and 100 mg per capsule (mixing ratio of 50:50). Table 21.1: Stability of 1 mg of active mixture in capsule at 25 °C / 60 % RH 1 mg dose in 1:10 mix 1 (MCC) at 25C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size No. 0 HG 0 Mix in white opaque capsule 100.00 99.83 7D Mix in white opaque capsule 98.50 99.83 14D Mix in white opaque capsule 99.00 99.83 28 D Mix in white opaque capsule 102.76 99.83 2M Mix in white opaque capsule 100.69 99.83 3M Mix in white opaque capsule 100.58 99.83 1 mg dose in 1:10 mix 2 (starch) at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size No. 0 HG 0 White Opaque Capsule Mixture 100.00 99.83 7D White Opaque Capsule Mixture 99.78 99.83 14D White Opaque Capsule Mixture 97.60 99.83 28D White Opaque Capsule Mixture 98.56 99.83 2M White Opaque Capsule Mixture 98.50 99.83 3M White Opaque Capsule Mixture 97.97 99.83 Table 21.2: Stability of 10 mg of 1:10 active mixture in capsule at 25 °C / 60 % RH 10 mg dose in 1:10 mixture (MCC) at 25 °C / 60% RH Capsule Time Appearance Assay(%) Purity(%) Size No. 0 HG 0 Blend in white opaque capsule 100.00 99.83 7D Blend in white opaque capsule 99.70 99.83 14D Blend in white opaque capsule 96.58 99.83 28D Blend in white opaque capsule 101.47 99.83 2M Blend in white opaque capsule 99.14 99.83 3M Blend in white opaque capsule 102.19 99.83 10 mg dose in 1:10 mix 2 (starch) at 25°C / 60% RH Capsule Time Appearance Assay(%) Purity(%) Size No. 0 HG 0 Blend in white opaque capsule 100.00 99.83 7D Blend in white opaque capsule 99.23 99.83 14D White opaque capsule mix 98.70 99.83 28D White opaque capsule mix 99.45 99.83 2M White opaque capsule mix 100.29 99.83 3M White opaque capsule mix 99.99 99.83 zcfronn / zznz / E / YiAi Table 21.3: Stability of 10 mg of 50:50 active mixture in capsule at 25 °C / 60% RH 10 mg dose in 50:50 blend 1 (MCC) at 25°C / 60% RH Capsule Time Appearance Assay (%) Purity (%) Size No. 0 HG 0 Blend in white opaque capsule 100.00 99.83 7D Blend in white opaque capsule 98.90 99.83 14D Blend in white opaque capsule 101.36 99.83 28D Blend in white opaque capsule 100.42 99.83 2M Blend in white opaque capsule 101.94 99.83 3M Blend in white opaque capsule 100.97 99.83 10 mg dose in 50:50 blend 2 (starch) at 25°C / 60% RH Capsule Time Appearance Assay (%) Purity (%) Size No. 0 HG 0 White Opaque Capsule Mixture 100.00 99.83 7D White Opaque Capsule Mixture 99.78 99.83 14D White Opaque Capsule Mixture 98.42 99.83 28D White Opaque Capsule Mixture 98.98 99.83 2M White Opaque Capsule Mixture 101.14 99.83 3M White Opaque Capsule Mixture 102.01 99.83 Table 21.4 Stability of 100 mg of 50:50 active mixture in the capsule at 25 °C / 60% RH 100 mg dose in 50:50 blend 1 (MCC) at 25°C / 60% RH Capsule Time Appearance Assay (%) Purity (%) Size No. 0 HG 0 Blend in white opaque capsule 100.00 99.83 7D Blend in white opaque capsule 102.11 99.83 14D Blend in white opaque capsule 101.52 99.83 28D Blend in white opaque capsule 99.93 99.83 2M Blend in white opaque capsule 101.54 99.83 3M Blend in white opaque capsule 101.33 99.83 100 mg dose in 50:50 blend 2 (starch) at 25°C / 60% RH Capsule Time Appearance Assay (%) Purity (%) Size No. 0 HG 0 White Opaque Capsule Mixture 100.00 99.83 7D White Opaque Capsule Mixture 100.70 99.83 14D White Opaque Capsule Mixture 102.06 99.83 28D White Opaque Capsule Mixture 98.13 99.83 2M White Opaque Capsule Mixture 100.85 99.83 3M White Opaque Capsule Mixture 103.63 99.83 zcfrQnn / zznz / E / YiAi The dissolution of mixture 1 in the 1:10 ratio of Compound 1 to MCC in HG capsule size #0 was evaluated at both 1 and 10 mg of active (10 and 100 mg of mixture with MCC, respectively). The dissolution method used the following conditions: Parameters Setup Instrument Agilent 708-DS Media 0.1 N HCl with 2% SDS Apparatus USP Apparatus 2 (paddle) Rotation speed 75 rpm (200 rpm for infinite rotation) Media volume 900 mL Temperature 37.0 ±0.5 °C Sample collection time point 15, 30, 45, 60 minutes, and infinity at 120 minutes 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. Another prototype mix capsule formulation was prepared to evaluate the effect of adding surfactant to the 1:10 MCC capsule mix (Mix 1). A 1:10 Compound 1:MCC with 2% SLS (25 mg of mix and 0.5 mg of SLS) was hand-filled into size 4 hard gelatin capsules (dose level was 2.5 mg of active per capsule) for evaluation in a stability study (Table 21.3), a monkey crossover PK study, and a dissolution test. zcfrQnn / zznz / E / YiAi Table 21.5 Stability of 2.5 mg of 1:10 active mixture with 2% surfactant 2.5 mg dose in MCC mixture with 2% SLS at RT for monkey PK study Capsule Time (day) Appearance Assay(%) Purity(%) Size #4 HG 0 Mixture in white opaque capsule 100.00 99.83 7 Mixture in white opaque capsule 101.98 99.83 2.5 mg dose in MCC mixture with 2% Poloxamer 188 at RT for monkey PK study Capsule Time Appearance Assay(%) Purity(%) Size #4 HG 0 Mixture in white opaque capsule 100.00 99.83 7 Mixture in white opaque capsule 97.39 99.83 Three male monkeys were orally administered 0.5 mg / kg of body weight in a fasted state and plasma samples were analyzed for Compound 1 levels. The resulting plasma levels of Compound 1 did not show a significant increase in exposure for the MCC mixture capsule with surfactant (area under the curve from 0 to infinity, AUC[0-inf] = 1.004 ng-h / ml) compared to without surfactant (AUC[0-inf] = 994 ng-h / ml). MCC capsules of Blend 1 with and without surfactant were also evaluated in an in vitro dissolution study at a dose concentration of 2.5 mg of Compound 1. The dissolution method used the following conditions: Parameters Setup Instrument Agilent 708-DS Media 0.1 N HCl with 2% SDS Apparatus USP Apparatus 2 (paddle) Rotation speed 75 rpm (200 rpm for infinite rotation) Media volume 900 mL Temperature 37.0 ±0.5 °C Sample collection time point 15, 30, 45, 60 minutes, and infinity at 120 minutes The dissolution results are shown in Figure 4, where 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. zcfrQnn / zznz / E / YiAi Table 22 provides other exemplified formulations for the mixing capsules (prototypes 1-12). Table 22. Exemplified formulations Ingredient Operation example (supplier) Function Quantity (weight in grams) in capsule 1 2 3 4 5 6 7 8 9 10 11 12 Me zel a 1:1 0 Me zel a 1:1 0 Me zel a 1:1 0 Me zel a 1:1 0 Co m bi nat ion 1:1 Co m bi nat ion 1:1 Co m bi nat ion 1:1 Co m bi nat ion 1:1 Compound 1 Pharmaceutical active Pharmaceutical active 1.0 1.0 10. 0 10. 0 10. 0 10. 0 10 0.0 10 0.0 1. 0 1. 0 10 .0 10 0.0 Starch Starch 1500 (Colored) Filler, dispersant 10. 0 10 0.0 10. 0 10 0.0 5. 0 2. 5 2. 5 25. 0 Microcrystalline Cellulose (MCC) Avicel (FMC) Filler, dispersant 10. 0 10 0.0 10. 0 10 0.0 5. 0 2. 5 2. 5 25. 0 Lactose Lactose (FMC) Filler, dispersant 2. 5 2. 5 25. 0 Mannitol Mannitol (FMC) Filler, dispersant 2. 5 2. 5 25. 0 Magnesium Stearate Magnesium Stearate (FMC) Lubricant, flow aid 0.2 2 0.2 2 2.2 2.2 0.4 0 2.2 2.2 2.2 0. 1 0. 1 0. 2 1.0 Fused silica Glidant (minerals Lubricant, flow aid 0. 1 0. 1 0. 2 1.0 specialized s) 11. 11. 11 11 20. 22. 20 20 11 11 20 20 TOTAL 22 22 2.2 2.2 4 2 2.2 2.2 .2 .2 .4 2.0 zcfrQnn / zznz / E / YiAi Examples of excipients that may be used in the preparation of the formulations as described in this application are shown in Table 23. Table 23. Exemplified excipients Drug Excipient Example of trade name (Supplier) Function Capsule or tablet Suspension Cellulose, microcrystalline Cellulose, microcrystalline, pharmacopoeial PH101 (DuPont) Filler, dispersant Croscarmellose sodium Croscarmellose sodium SD-711 (DuPont) Dispersant, disintegrant Crospovidone Crospovidone XL-10 (Ashland) Dispersant, disintegrant Mannitol Mannitol 100SD (Roquette) Filler, dispersant Magnesium stearate Magnesium stearate LIGAMED MF2-V Lubricant Poloxamer 188 Poloxamer 188 (FMC) Surfactant, dispersant Tween 80 Tween 80 (Spectrum Chemical) Surfactant, dispersant Sodium lauryl sulfate Sodium lauryl sulfate SLS fine (BASF) Surfactant, dispersant Dioxide Colloidal silicon dioxide Aerosil 200 Pharm (Evonik) Lubricant Starch Starch 1500 Partially pregelatinized corn starch 2001 NEC (Colorcon) Filler, dispersant Polysorbate 80 Tween 80 (Spectrum Chemical) Surfactant,wetting agent Poloxamer 188 Pluronic Acid F-68 (FMC) Surfactant, wetting agent, Methylcellulose (MC) Methylcellulose, 400 cP, USP (Alpha Chemical) Suspending aid, thickener Methylcellulose (MC) Methylcellulose, 4000 cP, USP (Alpha Chemical) Suspending aid, thickener Hydroxypropyl methylcellulose (HPMC) Hypermellose HPMC E-464 (Orison Chemicals) Suspending aid, thickener Methyl Paraben Methylparaben (Sigma Chemical) Antimicrobial preservative Propylparaben Propylparaben (Sigma Chemical) Antimicrobial preservative Propylene glycol (PG) Propylene glycol (Sigma Chemical) Solubilizer, cosolvent ASD Hydroxypropyl methylcellulose acetate succinate (HPMCAS) AquaSolve HPMC-AS (Ashland) Polymer matrix, amorphous dispersant Polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer Soluplus (BASF) Polymer matrix, amorphous dispersant Poly(deoxyadenylocthymidylic acid) sodium salt Eudragit L100 Polymer matrix, amorphous dispersant Solution Polyethylene glycol 400 (PEG 400) PEG 400 from Kollisolv (BASF) Solubilizer,cosolvent Polyethylene glycol 300 (PEG 300) PEG 300 from Kollisolv (BASF) Solubilizer, cosolvent Hydrogenated castor oil Kolliphor RH40 (BASF) Solubilizer, cosolvent Linoleoyl Polyoxyl-6 glycerides Labrafil M2125 CS (Gattefossé) Solubilizer, cosolvent Diethylene glycol monoethyl ether Transcutol HP (Gattefossé) Solubilizer, cosolvent, zcfrQnn / zznz / E / YiAi da-Tocopheryl polyethylene glycol 1000 succinate Vitamin E TPGS (Parchem) Solubilizer, cosolvent Ethanol Ethanol (Cargill) Solubilizer, cosolvent Propylene glycol (PG) Propylene glycol (Sigma Chemical) Solubilizer, cosolvent zcfrQnn / zznz / E / YiAi Example 3. Pharmacokinetic studies of formulations comprising Compound 1 Pharmacokinetic (PK) studies were conducted in animals with formulations as described in Example 2. Compound 1 was formulated to achieve the desired dose (Table 24) and administered to a group of three fasted animals by a single oral overfeed. A minimum of 7 time points were used to draw blood samples and then prepare plasma samples for bioanalysis. PK parameters were obtained after non-compartmental pharmacokinetic analysis using Phoenix WinNonlin software (version 6.3, Pharsight, Mountain View, CA). The linear / logarithmic trapezoidal rule was applied to obtain PK parameters. Nominal dose levels and nominal sampling times were used in the calculation of all pharmacokinetic parameters. Table 24 summarizes the PK data. The results are summarized in the following table. Studies 14-17 were conducted under a crossover design.In the table, prototype solution 2a is 58.1% KolliphorRH40 + 16.9% LabrafilM2125 CS + 8.3 7o propylene glycol + 16.7 7o ethanol. MC is methylcellulose 400 cP, Tween 80 is polyoxyethylene (80) sorbitan monooleate, HPMC-ASMF, soluplus, and Eudragit are polymers, and Poloxamer is copolymer. Table 24. Selected PK data of formulations evaluated in animals Study Dose (mg / kg) Formulation Species AucO-inf (ng / ml*h) (ng / ml) 1 5 (0.5 7oMC 400 cP, 0.2 7o Tween 80) suspension Rat 1094 A 2 5 (0.5 7oMC 400 cP, 0.2 7o Tween 80) suspension Rat 3015 B 3 5 Prototype solution 2a Rat 3024* B 4 5 (HPMC-ASMF) - ASD Rat 5534 C 5 5 (Soluplus) - ASD Rat 6728 D 6 5 (Eudragit L100) - ASD Rat 6936 D 7 15 (0.5 7oMC 400 cP, 0.2 7o Tween 80) suspension Rat 5172* C 8 15 (0.5 7oMC 400 cP, 0.2 7o Tween 80) suspension - milled Rata 13436 D 9 1 66 (Prototype 2a) solution Dog 406 A 10 1 (0.5%MC 400 cP, 0.2% Tween 80) suspension Dog 174 A 11 1 (0.5%MC 400 cP, 0.2% Tween 80) suspension - milled Dog 303 A 12 0.5 (0.5% 400 cP MC, 0.2% Poloxamer 188) suspension - milled Monkey C. 997 B 13 0.5 (0.5%MC 400 cP, 0.2% Tween 80) suspension Monkey C. 762 A 14 0.5 Hard gelatin capsule size 4 (1:10 mix with MCC) Monkey C. 994 A 15 0.5 Gelatin capsule hard size 4 (ASD-3 HPMCASMF, drug loading (w%)= 18.22%) Mono C. 1358 B 16 0.5 Hard gelatin capsule size 4 (1:10 mix with MCC and 2% SLS) Mono C. 1004 A 17 1.0 Hard gelatin capsule size 4 (1:10 mix with MCC) Mono C. 1749 B zcfrQnn / zznz / E / YiAi *Auc(0-Last For the Cmax values ​​in Table 24, A indicates greater than 50 ng / ml and up to 150 ng / ml, B indicates greater than 150 ng / ml and up to 300 ng / ml, C indicates greater than 300 mg / ml and up to 600 mg / ml, and D indicates greater than 600 ng / ml and up to 900 ng / ml. In addition, human PK and effective dose are estimated. Based on these calculations, the effective human dose for a neurological disorder (e.g., epilepsy) is approximately 2.5–100 mg (e.g., 60 mg) once daily. Example 4. Randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending doses and the effect of food of Compound 1 in healthy volunteers This is a three-part clinical trial to evaluate the safety, tolerability, PK, and food-related effects of Compound 1 in healthy volunteers aged 18 to 55 years, inclusive. The clinical trial consists of the following three parts: • Part A is randomized, double-blind, and 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, and placebo-controlled. Part B is designed to investigate the safety and PK of multiple ascending doses of Compound 1 (selected based on the results of 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. OBJECTIVES AND EVALUATION CRITERIA: Part A zcfrQnn / zznz / E / YiAi Objective Endpoint Primary • To evaluate the safety and tolerability of single oral doses of Compound 1 • Incidence and severity of adverse events (AEs) • Changes in vital sign measurements • Changes in clinical laboratory findings • Changes in electrocardiogram (ECG) parameters • Incidence of suicidal behavior or ideation as measured by the Columbia University Suicide Risk Rating Scale (C-SSRS) Secondary • To evaluate the pharmacokinetics (PK) of single oral doses of Compound 1 The following PK parameters will be calculated: • Maximum observed concentration (Cmax) • Time to maximum observed concentration (tmax) • Apparent terminal elimination half-life (ti / 2) • Area under the concentration-time curve from time of zero to the last measurable concentration (AUC)) • Area under the drug concentration-time curve from time zero to infinity (ABCo ¡nt) • Clearance (CL / F) • Volume of distribution (Vd / F) • Renal clearance (Clr) • Fraction of the dose excreted unchanged in urine (fe) • Amount excreted unchanged over 72 hours (Aeo 72). Exploratory • To assess the pharmacodynamic (PD) effect of Compound 1 on stimulated electroencephalography (EEG) endpoints using auditory stimulation • EEG measurement of auditory evoked responses (e.g., auditory steady-state response (ASSR)) 7ChQnn / 77n7 / B / YIAI Part B Objective Endpoint Primary • To evaluate the safety and tolerability of 7-day repeat oral doses of Compound 1 • Incidence and severity of AEs • Changes in vital sign measurements • Changes in clinical laboratory findings • Changes in electrocardiogram (ECG) parameters • Incidence of suicidal ideation or behavior as measured by the C-SSRS Secondary • To evaluate the pharmacokinetics (PK) of 7-day repeat oral doses of Compound 1. The following PK parameters will be calculated on Day 1 and Day 7: • Cmax • tmax • AUCo-uit • Area under the concentration-time curve from time zero during a dosing interval (AUCtau) • Time to steady-state • Accumulation ratio versus AUC (Rae(AUC)) • Accumulation ratio versus Cmax (Rae(Cmax)) Exploratory • To assess the PD effect of Compound 1 on EEG endpoints stimulated using auditory stimulation.• EEG measurement of auditory evoked responses (e.g., auditory steady-state response (ASSR)). • circulating metabolite profile zcfrQnn / zznz / E / YiAi Part C Objective Endpoint Primary • To evaluate the effect of food on the pharmacokinetics (PK) of single oral doses of Compound 1. The following PK parameters will be estimated, both in the fasted and fed states: • Cmax • tmax • AUCo-it, • AUCo-inf Secondary • To evaluate the safety and tolerability of oral doses of Compound 1 in the fasted and fed states • Incidence and severity of AEs • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in electrocardiogram (ECG) parameters • Incidence of suicidal ideation or behavior as measured by the C-SSRS Based on emerging safety and PK data from Part A, the SRC may select a starting dose for Part B before completing all dose-level cohorts in Part A. Part C may begin after the last SAD cohort. Parts A and B are double-blind, including the participant and investigator; the sponsor is unblinded to facilitate safety review. Each part consists of three periods: Screening, Intervention, and Safety Follow-up. Screening / Lead Period The selection period for all three parts will last up to 27 days (Day-28 to Day-2). Intervention period After confirmation of continued eligibility, participants enter the clinic on Day -1 (the day before study drug administration) and undergo assessments. Participants remain in the unit from baseline (Day -1) until hospital discharge (Day 6 in Part A, Day 12 in Part B, and Day 13 in Part C). Part A Healthy volunteers are enrolled to receive single ascending doses of Compound 1 or placebo on Day 1. Dose escalation in Part A is performed in a total of 6 planned cohorts (Cohorts A1 to A6). Up to 3 additional cohorts may be studied at planned or intermediate dose levels. Eight participants are enrolled in each cohort and will be randomized to receive Compound 1 or placebo (3:1 ratio). Compound 1 is administered to participants in Cohort A1 at the starting dose of 2.5 mg. Dosing in all cohorts is performed under fasting conditions. Dosing in each dose-level cohort begins with two vigilant participants, with one randomized to receive Compound 1 and the other randomized to receive placebo. The safety and tolerability of each vigilant participant is monitored through Day 6 and reviewed prior to dosing the remaining participants in each cohort. Cohorts are dosed in ascending order. After each dose cohort in Part A has completed dosing, the Safety Review Committee (SRC) reviews the blinded cumulative safety data collected through Day 6 and any available blinded PK data to determine the safety and tolerability of the study drug. If the current dose level is determined to be safe and tolerated, 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. zcfrQnn / zznz / E / YiAi Part A Dosing Regimen Cohort Study Drug Dose and Route of Administration A1 Compound 1 2.5 mg, oral, fasting A2 Compound 1 Up to 10 mg, oral, fasting A3 Compound 1 Up to 30 mg, oral, fasting A4 Compound 1 Up to 60 mg, oral, fasting A5 Compound 1 Up to 90 mg, oral, fasting A6 Compound 1 Up to 120 mg, oral, fasting Part B The SRC determines the starting dose level in Part B based on the safety, tolerability, and PK data obtained in Part A. The SRC may select a starting dose for Part B before completing all dose level cohorts in Part A. A dose level is evaluated in Part B if it is determined to be safe and tolerable in Part A. Three dose levels are planned to be evaluated in Part B in a total of three cohorts (Cohorts B1-B3). An additional cohort may be added to repeat a dose level or study an intermediate dose. Eight participants are enrolled in each cohort and randomized to receive Compound 1 or placebo (3:1 ratio). The dose levels of Compound 1 to be evaluated in Part B do not exceed the doses studied in Part A. Dosing begins on Day 1 and continues through Day 7. The last dose is administered on the morning of Day 7. Dosing in all cohorts in Part B is performed under fasting conditions. Two vigilant participants are planned for each dose cohort in Part B. zcfrQnn / zznz / E / YiAi Part B Dosing Regimen Cohort Study Drug Daily Dose and Route of Administration B1 Compound 1 Up to 60 mg, oral, fasting B2 Compound 1 Up to 90 mg, oral, fasting B3 Compound 1 Up to 120 mg, oral, fasting After each dose cohort in Part B has completed study drug administration, the SRC evaluates blinded safety data (including safety assessments conducted on Day 9) and available PK data to determine the safety and tolerability of the study drug, following the same procedures as in Part A. 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. Part C Part C may begin once safety and PK have been adequately evaluated in the final cohort of Part A. Up to 16 participants receive two doses of Compound 1, one dose after a minimum of 10 hours of fasting and one after consumption of a high-fat, high-calorie meal in a randomized crossover design, with a 7-day washout period between periods. Up to 3 additional days of washout may be added between fasted and fed dosing based on the observed half-life in Part A. The dose to be used in Part C does not exceed that used in Part A and is approved by the SRC based on accumulated safety and PK data. Administration of a surveillance dose may be used in Part C if deemed appropriate by the SRC. Part C is unblinded. Security assessments and monitoring Safety and tolerability assessments include vital signs, 12-lead ECG, physical examinations, clinical laboratory tests, and the C-SSRS, as described in the SoA. NUMBER OF PARTICIPANTS: • Part A: It is planned to administer up to 72 of Compound 1 or placebo. • Part B: It is planned to administer up to 32 doses of Compound 1 or placebo. • Part C: Up to 16 doses of Compound 1 are planned to be administered. Exclusion criteria A participant who meets any of the following criteria, among other things, at screening is excluded from this clinical trial: • Any abnormal ECG finding assessed as clinically significant by the investigator, including a QT interval with Fridericia's correction method (QTcF) >450 ms, confirmed with 1 repeat test as needed, at screening or on day 1. • Use of prescription or over-the-counter (OTC) systemic medications, including multivitamins, dietary, and herbal supplements within 2 weeks or 5 times the terminal half-life of the medication prior to the first dose of study drug, whichever is longer, and throughout the study. TEST PRODUCT, REFERENCE THERAPY, ADMINISTRATION: • Part A: Compound 1 capsules or matching placebo are administered orally. • Part B: Compound 1 capsules or matching placebo are administered orally. • Part C: Compound 1 capsules are administered orally. STATISTICAL METHODS: PK Analysis: A validated bioanalytical method is used for the determination of plasma and urine concentrations of Compound 1. Plasma and urine concentrations are summarized by dose group / condition and time point using descriptive statistics. In addition to the descriptive statistics specified in the General Conditions above, plasma concentrations are also summarized using the amount and percentage of concentrations below the level of quantification (BLQ) and the coefficient of variation (CV%). Pharmacokinetic parameters are estimated from concentration-time data using standard noncompartmental methods. Urine PK parameters are estimated from urine 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 conditions above, PK parameters are summarized using CV%, geometric mean, and geometric coefficient of variation. PK parameters are evaluated for linearity and dose proportionality using the power model when possible. To assess the effect of food in Part C, the ratio of the geometric mean (In-transformed) of the test treatment (i.e., fed) relative to the reference treatment (i.e., fasted) is estimated with 90% CIs calculated for Cmax and AUC or nt.Absence of a food effect is concluded if the 90% CIs for the ratios of Cmax and AUC-inf are entirely within the range of 0.80 to 1.25. If there is unexpected difficulty in determining the terminal half-life, AUC-inf may be used instead of AUC-inf. Example 5. Randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending doses and the effect of food of Compound 1 in healthy volunteers zcfrQnn / zznz / E / YiAi This is a three-part clinical trial to evaluate the safety, tolerability, PK, and food-related effects of Compound 1 in healthy volunteers aged 18 to 55 years, inclusive. The clinical trial consists of the following three parts: • Part A is a randomized, double-blind, placebo-controlled study. Part A is designed to investigate the safety, tolerability, and PK of single ascending doses of Compound 1 from 2.5 to 90 mg. • Part B is a randomized, double-blind, placebo-controlled trial. Part B is designed to investigate the safety, tolerability, and PK of multiple ascending doses of Compound 1 (doses selected based on the results of 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 under fasting and fed conditions (dose selected based on the results of Part A). zcfrQnn / zznz / E / YiAi OBJECTIVES AND EVALUATION CRITERIA: Part A Objective Endpoint Primary • To evaluate the safety and tolerability of single oral doses of Compound 1 • Incidence and severity of adverse events (AEs) • Changes in vital sign measurements • Changes in clinical laboratory findings • Changes in electrocardiogram (ECG) parameters • Incidence of suicidal behavior or ideation as measured by the Columbia University Suicide Risk Rating Scale (C-SSRS) Secondary • To evaluate the pharmacokinetics (PK) of single oral doses of Compound 1 The following PK parameters will be calculated: • Maximum observed concentration (Cmax) • Time to maximum observed concentration (tmax) • Apparent terminal elimination half-life (ti / 2) • Area under the concentration-time curve from time of zero to last mean concentration (AUC) • Area under the drug concentration-time curve from time zero to infinity (AUCinf) • Clearance (CL / F) • Volume of distribution (Vd / F) • Renal clearance (Clr) • Fraction of dose excreted unchanged in urine (fe) • Amount excreted unchanged over hours (Aeo-72) Exploratory • To assess the pharmacodynamic (PD) effect of Compound 1 on paced electroencephalography (EEG) endpoints using auditory stimulation • EEG measurement of auditory evoked responses (e.g., auditory steady-state response (ASSR)) 7ChQnn / 77n7 / B / YIAI Part B Objective Endpoint Primary • To evaluate the safety and tolerability of repeated 7-day oral doses of Compound 1 • Incidence and severity of AEs • Changes in vital sign measurements • Changes in clinical laboratory findings • Changes in electrocardiogram (ECG) parameters • Incidence of suicidal ideation or behavior as measured by the C-SSRS Secondary • To evaluate the pharmacokinetics (PK) of repeated 7-day oral doses of Compound 1 The following PK parameters will be calculated: • Cmax • tmax • AUCut • Area under the concentration-time curve from time zero over a dosing interval (AUCtau) • Time to steady state • Accumulation ratio based on AUC (Rae (AUC)) • Accumulation ratio based on Cmax (RaC. (Cmax)) Exploratory • To evaluate the PD effect of Compound 1 on stimulated EEG endpoints using auditory stimulation. • EEG measurement of auditory evoked responses (e.g., auditory steady-state response (ASSR)) zcfrQnn / zznz / E / YiAi Part C Objective Endpoint Primary • To evaluate the effect of food on the pharmacokinetics (PK) of single oral doses of Compound 1. The following PK parameters will be estimated, both in the fasted and fed states: • Cmax • tmax • AUCit • AUCinf Secondary • To evaluate the safety and tolerability of oral doses of Compound 1 in the fasted and fed states • Incidence and severity of AEs • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in electrocardiogram (ECG) parameters • Incidence of suicidal ideation or behavior as measured by the C-SSRS Based on emerging safety and PK data from Part A, the SRC may select a starting dose for Part B before completing all dose-level cohorts in Part A. Part C may begin after the final SAD cohort. Parts A and B are double-blinded, including the participant and investigator; the sponsor is unblinded to facilitate safety review. Each part consists of three periods: Screening, Intervention, and Safety Follow-up. After confirmation of continued eligibility, participants enter the clinic on Day -1 (the day before study drug administration) and undergo assessments. Participants remain in the unit from baseline (Day -1) until hospital discharge (Day 6 in Part A, Day 12 in Part B, and Day 13 in Part C). Part A Healthy volunteers are enrolled to receive single ascending doses of Compound 1 or placebo on Day 1. Dose escalation in Part A is performed in a total of 6 planned cohorts (Cohorts A1 to A6). Up to 3 additional cohorts may be studied at planned or intermediate dose levels. Eight participants are enrolled in each cohort and will be randomized to receive Compound 1 or placebo (3:1 ratio). Compound 1 is administered to participants in Cohort A1 at the starting dose of 2.5 mg. Dosing in all cohorts is performed under fasting conditions. Dosing in each dose-level cohort begins with two vigilant participants, with one randomized to receive Compound 1 and the other randomized to receive placebo. The safety and tolerability of each vigilant participant is monitored through Day 6 and reviewed prior to dosing the remaining participants in each cohort. Cohorts are dosed in ascending order. After each dose cohort in Part A has completed dosing, the Safety Review Committee (SRC) reviews the blinded cumulative safety data collected through Day 6 and any available blinded PK data to determine the safety and tolerability of the study drug. If the current dose level is determined to be safe and tolerated, 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. zcfrQnn / zznz / E / YiAi Part A Dosing Regimen Cohort Study Drug Dose and Route of Administration A1 Compound 1 2.5 mg, oral, fasting A2 Compound 1 Up to 7.5 mg, oral, fasting A3 Compound 1 Up to 15 mg, oral, fasting A4 Compound 1 Up to 30 mg, oral, fasting A5 Compound 1 Up to 60 mg, oral, fasting A6 Compound 1 Up to 90 mg, oral, fasting Part B The SRC determines the starting dose level in Part B based on the safety, tolerability, and PK data obtained in Part A. The SRC may select a starting dose for Part B before completing all dose-level cohorts in Part A. A dose level is evaluated in Part B if it is determined to be safe and tolerable in Part A. It is anticipated that 3 dose levels will be evaluated in Part B in a total of 3 cohorts (Cohorts B1-B3). An additional cohort may be added to repeat a dose level or study an intermediate dose. Participants are enrolled in each cohort and randomized to receive Compound 1 or placebo (3:1 ratio). The dose levels of Compound 1 to be evaluated in Part B do not exceed the doses studied in Part A. Dosing begins on Day 1 and continues through Day 7. The last dose is administered on the morning of Day 7. Dosing in all cohorts in Part B is performed under fasting conditions. Two vigilant participants are planned for each dose cohort in Part B. zcfrQnn / zznz / E / YiAi Part B Dosing Regimen Cohort Study Drug Daily Dose and Route of Administration B1 Compound 1 Up to 30 mg, oral, fasting B2 Compound 1 Up to 60 mg, oral, fasting B3 Compound 1 Up to 90 mg, oral, fasting After each dose cohort in Part B has completed study drug administration, the SRC evaluates blinded safety data (including safety assessments conducted on Day 9) and available PK data to determine the safety and tolerability of the study drug, following the same procedures as in Part A. 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. Part C Part C may begin once safety and PK have been adequately evaluated in the final cohort of Part A. Participants receive two doses of Compound 1, one dose after a minimum of 10 hours of fasting and one after consumption of a high-fat, high-calorie meal in a randomized crossover design, with a 7-day washout period between periods. Up to 3 additional days of washout may be added between fasted and fed dosing based on the observed half-life in Part A. The dose to be used in Part C does not exceed that used in Part A and is approved by the SRC based on accumulated safety and PK data. Administration of a surveillance dose may be used in Part C if deemed appropriate by the SRC. Part C is unblinded. Security assessments and monitoring Safety and tolerability assessments include vital signs, 12-lead ECG, physical examinations, clinical laboratory tests, and the C-SSRS. Exclusion criteria A participant who meets any of the following criteria, among other things, at screening is excluded from this clinical trial: • Any abnormal ECG finding assessed as clinically significant by the investigator, including a QT interval with Fridericia's correction method (QTcF) >450 ms, confirmed with 1 repeat test as needed, at screening or on day 1. • Use of prescription or over-the-counter (OTC) systemic medications, including multivitamins, dietary, and herbal supplements within 2 weeks or 5 times the terminal half-life of the medication prior to the first dose of study drug, whichever is longer, and throughout the study. TEST PRODUCT, REFERENCE THERAPY, ADMINISTRATION: • Part A: Compound 1 capsules or matching placebo are administered orally. • Part B: Compound 1 capsules or matching placebo are administered orally. • Part C: Compound 1 capsules are administered orally. STATISTICAL METHODS: PK Analysis: A validated bioanalytical method (e.g., liquid chromatography-mass spectrometry (LC-MS)) is used for the determination of plasma and urine concentrations of Compound 1. Plasma and urine concentrations are summarized by dose group / condition and time point using descriptive statistics. In addition to the descriptive statistics specified in the General Conditions above, plasma concentrations are also summarized using the amount and percentage of concentrations below the level of quantification (BLQ) and the coefficient of variation (CV%).Pharmacokinetic parameters are estimated from concentration-time data using standard noncompartmental methods. Urine PK parameters are estimated from urine 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 conditions above, PK parameters are summarized using CV%, geometric mean, and geometric coefficient of variation. PK parameters are evaluated for linearity and dose proportionality using the power model when possible. To assess the effect of food in Part C, the ratio of the geometric mean (In-transformed) of the test treatment (i.e., fed) relative to the reference treatment (i.e., fasted) is estimated with 90% CIs calculated for Cmax and AUCint.The absence of a food effect is concluded if the 90% CIs for the ratios of Cmax and AUCint are entirely within the range of 0.80 to 1.25. If there is unexpected difficulty in determining the terminal half-life, AUCuh may be used instead of AUCinf. Results Preliminary analysis of the first four of the six planned cohorts of the Part A study indicates that Compound 1 appears to be well tolerated at the doses evaluated. 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 any adverse events leading to withdrawal or discontinuation from the study were reported in the first three cohorts evaluated. Based on preliminary data, exposure appears to increase proportionally with dose level, with peak concentrations reached within 2–3 hours. The terminal elimination half-life averages 114 hours (~4–5 days) across all groups. Steady state should be achieved within approximately 2 weeks with once-daily dosing. Example 5. A randomized, double-blind comparison of the efficacy and safety of Compound 1 with 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, e.g., 18 to 65 years of age with chronic SUNCT or chronic SUNA. This is a double-blind, placebo-controlled study. Participants will be randomized to receive 1 of 3 blinded treatments [high-dose Compound 1 1 mg orally daily, low-dose Compound 1 1 mg orally daily, or placebo daily] in a 1:1:1 ratio. Participants will self-administer the study drug once daily with weekly clinic visits. Participants will also be asked to answer questions in an electronic diary (eDiary), e.g., 3 times daily (pre-dose or approximately 24 hours after the previous dose, approximately 4 hours post-dose, and approximately 10 hours post-dose). zcfrQnn / zznz / E / YiAi Objective Primary Endpoint To assess the effects of Compound 1 for the treatment of SUNCT and SUNA headaches • Change in average daily frequency of SUNCT and SUNA headache attacks from baseline to Day 21, as recorded by electronic diary • Change in average maximum intensity of SUNCT and SUNA headache severity from baseline to Day 21, as measured by the Stanford Pain Scale Secondary • To assess the effects of Compound 1 on the treatment of SUNCT and SUNA headaches • Change in average daily attack frequency from baseline to the average daily frequency throughout the study treatment period, as recorded in the electronic diary • Change in average maximum intensity of SUNCT and SUNA headache severity from baseline throughout the study period,as measured by the Stanford Pain Scale • To evaluate the safety and tolerability of Compound 1 in participants with SUNCT and SUNA • Incidence and severity of adverse events • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in ECG parameters • Incidence of suicidal behavior or ideation as measured by the Columbia Scale for Suicide Risk (CSSRS) • To characterize the PK profile of Compound 1 in participants with SUNCT and SUNA • Plasma concentrations of Compound 1 and its potential metabolites • Major PK parameters: Cmax, tmax,and ABCO-tau Exploratory • To assess the effects of Compound 1 on other measures associated with SUNCT and SUNA • Change in headache duration by SUNCT and SUNA calculated as the number of minutes of pain per day recorded in the electronic diary • Change in average daily frequency of autonomic symptoms as assessed by the participant • Change in autonomic symptoms, zcfrQnn / zznz / E / YiAi as assessed by facial imaging • Change in response to trigger factors • Proportion of participants able to perform their usual daily activities • Changes in SF-36 total and factor scores • Patient satisfaction with treatment as measured by the visual analogue scale (VAS) • Change in disability level from baseline to day 21 • Proportion of patients in remission (defined as absence of headache for the observation interval) • Duration of remission The clinical trial consists of three periods: screening / baseline, intervention, and safety follow-up. An optional washout period is also available for participants receiving preventive medications. Selection / initial period The screening period will be up to, e.g., 28 days (Day -28 to Day -1). An optional washout period of up to, e.g., 14 days before screening will be allowed for participants discontinuing SUNCT or SUNA preventative medications (e.g., carbamazepine, lamotrigine). During screening, participants will complete daily electronic diary entries for, e.g., a 14-day observation period to assess the stability, severity, and frequency of SUNCT and SUNA headaches. Intervention period After eligibility is confirmed during screening, participants will complete initial screening (Day 1). On Day 1, participants will return to the clinic to be randomized to 1 of 3 treatment groups and receive the first dose of study drug. Participants will remain in a clinical setting under medical observation for at least, e.g., 6 hours. Headache logs will be completed via electronic diary daily predose (e.g., approximately 24 hours after the previous dose) and, e.g., approximately 4 hours and 10 hours postdose. After the first dose, participants will continue daily home dosing through Day 21. Participants will return to the clinic, e.g., on Day 7 (±1 day), Day 14 (±1 day), and Day 21 (±1 day) to complete assessments. At selected centers, samples for intensive PK will be obtained in the clinic, e.g., at 14 days. e.g., day 1, day 7 (±1 day), day 14 (±1 day), and day 21 (±1 day). Key safety measures will include clinical laboratory assessments, 12-lead ECG, C-SSRS, and vital signs. Key efficacy assessments will include headache recording via electronic diary (see assessment schedule for additional details). Blood samples will be obtained for determination of Compound 1 plasma concentrations using a validated bioanalytical method and may also be used for exploratory method development and / or metabolite characterization. Safety monitoring period The safety follow-up period will occur from, for example, day 22 to, for example, day 36. At the end of the safety follow-up period, participants will return to the clinic, for example, on day 57 (±1 day) for end-of-study assessments. During this visit, the following assessments will be performed: vital signs, physical examination, clinical laboratory tests, ECG, C-SSRS assessment, and efficacy assessments. Adverse events, concomitant procedures, and medication use will be monitored from the time of informed consent through day 36 (±1 day). At that point, participants will have completed the clinical trial. Inclusion / exclusion criteria Participants are female or male, e.g., 18 to 65 years of age (inclusive) at screening and have more than, e.g., 1 year history of chronic SUNCT and SUNA headache with onset before age 50 years and demonstrated a minimum of, e.g., 100 SUNCT and SUNA headaches per 14 days during the observation period of the clinical trial. Test product, reference therapy, administration High-mg Compound 1 capsules, low-mg Compound 1 capsules, or placebo will be administered orally and provided in prepackaged containers to participants. Dose / route / regimen Dose to be determined with PK data. The route of administration will be oral. 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 (CIs) may be reported where appropriate. Summaries will be presented by time point, where appropriate. Standard PK parameters will be estimated using noncompartmental methods based on concentration-time data. These parameters will include, where possible, exploratory analyses zcfrQnn / zznz / E / YiAi of Cmax, tmax, and AUCO-tau that examine the relationship between PK parameters and efficacy that can be performed for the PK analysis suite. Primary and secondary efficacy measures Headache log completed via electronic diary An electronic tablet application will be used to collect information on a participant's headache activity prior to dosing (or approximately 24 hours after the previous dose) and approximately 4 hours and 10 hours postdose. Information collected at all time points will include the following: headache frequency, headache duration, and headache severity (as measured by the Stanford Pain Scale). Information collected 10 hours postdose will include only the following: attack types, associated symptoms and triggers, and autonomic symptoms. Other information collected via electronic diary 10 hours postdose will include: Visual Analog Scale (VAS), activities of daily living, and disability level. Stanford Pain Scale The Stanford Pain Scale is a comparative pain scale with descriptions assigned to each of the scale values, ranging from 0 (no pain) to 10 (unimaginable and undignified). Pain rated 0 to 3 is considered “minor,” pain rated 4 to 6 is considered “moderate,” and pain rated 7 to 10 is considered “severe.” The participant completes the Stanford Pain Scale. Triggering factors Participants will be asked to rate whether their response to triggers (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 4=resolution of triggers. Visual analog scale The visual analog scale will ask participants to rate their satisfaction with the treatment using a Likert scale with categories ranging from 0 = very bad effect to 10 = very good effect. Disability level The participant's disability level will be measured by the participant using a goal achievement scale with the following categories: 0 = no disability, 1 = mild, 2 = moderate, 3 = severe, 4 = unbearable. 36-Item Health Questionnaire Short Form (v2 Acute) The SF-36 is a 36-item survey that measures a participant's general health status (McHorney et al., 1994). The SF-36 assesses eight health concepts. Scores are weighted sums of the questions in each section. Scores range from 0 to 100, with lower scores indicating greater disability. The acute version of the SF-36 will be completed by the participant when indicated in the SoA. The acute version asks participants about their health status in the past week. Activities of Daily Living zcfrQnn / zznz / E / YiAi The participant will be asked to rate the change in their ability to complete activities of daily living. Example 6. Synthesis of (3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2!2,2-trifluoroethoxy)-3zcfrQnn / zznz / E / YiAi pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine) (Compound 1) A6 A7 Synthesis A2: To a stirred solution of 2,2,2-trifluoroethanol (5.67 g, 56.71 mmol) in THF (200 mL) at 0 °C was added NaH (60% in mineral oil, 2.26 g, 56.71 mmol) in small portions. The reaction mixture was stirred for 15 min, and 5-bromo-2,3-difluoropyridine (10.0 g, 51.55 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to 10 SC, and treated with ice-water (100 mL). The reaction mixture was extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by column chromatography on silica gel with 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), 2.53 min column temp.Environment: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 ml / min. Synthesis 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)Cl2DCM (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 with 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 mm x 4.6 mm), 5 pm mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min. Synthesis of A4: A mixture of Pd(dppf)Cl2 (15.13 g, 20.68 mmol), CS2CO3 (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 ml) and water (150 ml) under N2 was stirred at 35 °C for 2 hours. After cooling to room temperature, water (300 ml) was added 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 pad. The cake was washed with EA / PE = 1 / 3 (500 ml). The combined organic phase was concentrated to give a residue as an oil. PE (500 ml) was added slowly to the oil, and some solid was obtained.The solid was collected and oven dried to give the product (100 g, 242.4 mmol, 58% yield) as a solid. LCMS Rt = 1.28 min on 2.0 min chromatography, 10-80AB, MS ESI calcd for C11H7CIF4N3O [M+H]+ [M+H]+308.0, found 307.9. Synthesis 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) was stirred in MeCN (1.4 L) at 100 °C for 16 h. After cooling to room temperature, the mixture was poured into water (4.5 L). Some solid was observed and the solid was collected by filter. The cake was washed with water (500 ml x 2). The solid was redissolved in EtOAc (3 L), washed with brine (500 mL x 2), dried over anhydrous NaSO4, filtered, and concentrated to give the crude product (100 g, 329.8 mmol, 97% yield) as a solid. LCMS Rt = 0.74 min on 1.5 min chromatography, 5-95AB, MS ESI calcd for C11H10F4N5O [M+H]+304.1, found 303.9. 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 one drop of DMF and (COCl)2 (50.5 mL, 596.81 mmol). The resulting mixture was stirred at 20 °C for 1 hour.The resulting solution was used in the next step directly. 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 hours. To the solution was added water (1 L), extracted with EtOAc (1 L x 2). The combined organic phase was washed with brine (500 x ml x 2), dried over anhydrous Na2SO4, filtered and concentrated to afford the product (150 g, 326.0 mmol, 98% yield, mixture of mono- and bisalkylated products) as a solid. LCMS Rt = 0.92 min on 1.5 min chromatography, 5-95AB, MS ESI calcd for Ci3HgBrF6N5O2 [M+H]+460.1, found 459.8. Synthesis A7: A solution of 2-bromo-2,2-difluoro-N'-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrrolidine-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 hours. After cooling to room temperature, the mixture was poured into water (2 L), extracted with EtOAc (2 L x 2). The combined organic phase was washed with brine (1 L x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give a 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.1H NMR (CDCI3, 400MHz) óh = 9.60 (d, 1H), 8.55 (d, 1H), 8.45 (s, 1H), 8.09 (dd, 1H), 4.93 (q, 2H). 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 AgBF4 (66.93 g, 343.81 mmol) in ethanol (760 mL) was stirred at 60 °C for 1 hour. 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 x 2). The combined organic phase was washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by silica gel flash chromatography (EtOAc in PE = 0% to 30% to 50%) and triturated from EtOH (50 mL) to give the product (44.45 g, 109.01 mmol, 63% yield) as a solid.1H NMR (CDCh 400MHz) δΗ=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 Rt = 1.25 min on 2.0 min chromatography, 10-80AB, MS ESI calcd for C15H12F6N5O2 [M+H]+408.1, found 408.0. Equivalents and scope In the claims, terms such as “a,” “an,” “the,” and “an” may mean one or more unless otherwise indicated or otherwise evident from the context. Claims or descriptions that include “or” among one or more members of a group are considered satisfied if one, more than one, or all of the members of the group are present, employed, or otherwise relevant to a given product or process, unless otherwise indicated or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present, employed, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all, of the members of the group are present, employed, or otherwise relevant to a given product or process. Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms of one or more of the recited claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also described, and any element may be deleted from the group. It should be understood that, in general, where the invention, or aspects of the invention, are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist of, or consist essentially of, such elements and / or features.For the sake of simplicity, these embodiments have not been specifically set forth in haec verba in the present description. It is also noted that the terms "comprising" and "containing" are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Furthermore, unless indicated or otherwise evident from the context and understanding of one skilled in the art, values ​​expressed as ranges may assume any specific value or subrange within the ranges established in different embodiments of the invention, down to the tenth unit of the lower limit of the range, unless the context clearly indicates otherwise. This application refers to various issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. zcfrQnn / zznz / E / YiAi If there is a conflict between any of the incorporated references and the specification in question, the specification shall govern. Furthermore, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from one or more of the claims. Since such embodiments are considered to be known to one skilled in the art, they may be excluded even if the exclusion is not explicitly set forth in this description. Any particular embodiment of the invention may be excluded from any claim, for any reason, whether or not related to the existence of the prior art. Those skilled in the art will recognize or be able to determine, without further routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the foregoing description, but is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications may be made to this description without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

1. A dosage form comprising: from approximately 0.1 mg to approximately 500 mg (e.g., from approximately 0.5 mg to approximately 200 mg, from approximately 1 mg to approximately 150 mg, from approximately 10 mg to approximately 120 mg) of Compound 1; and a pharmaceutically acceptable excipient.

2. The dosage form of claim 1, wherein the dosage form comprises from approximately 2.5 mg to 150 mg (e.g., from approximately 10 mg to approximately 150 mg, from approximately 20 mg to approximately 150 mg, from approximately 70 mg to approximately 120 mg, from approximately 30 mg to approximately 60 mg, approximately 100 mg, approximately 50 mg) of Compound 1.

3. 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 approximately 0.1 mg to approximately 500 mg (e.g., from approximately 0.5 mg to approximately 200 mg, from approximately 1 mg to approximately 150 mg, from approximately 10 mg to approximately 120 mg).

4. The dosage form of claim 3, wherein the plurality of particles of Compound 1 in the dosage form is from approximately 2.5 mg to approximately 150 mg (e.g., from approximately 10 mg to approximately 150 mg, from approximately 20 mg to approximately 150 mg, from approximately 70 mg to approximately 120 mg, from approximately 30 mg to approximately 60 mg, approximately 100 mg, approximately 50 mg).

5. The dosage form of claim 3 or 4, wherein 10% of the plurality of particles of Compound 1 have a particle size of less than approximately 1 pm.

6. The dosage form of any one of claims 3-5, wherein 50% of the plurality of particles of Compound 1 have a particle size of less than approximately 4 pm.

7. The dosage form of claim 6, wherein 50% of the plurality of particles of Compound 1 have a particle size of less than approximately 2 pm.

8. The dosage form of any one of claims 3-7, wherein 90% of the plurality of particles of Compound 1 have a particle size of less than approximately 30 pm (e.g., less than approximately 15 pM).

9. The dosage form of claim 8, wherein 90% of the plurality of particles of Compound 1 have a particle size of less than approximately 5 pm.

10. The dosage form of claim 9, wherein 10% of the plurality of particles of Compound 1 have a particle size of less than approximately 1 pm, 50% of the plurality of particles of Compound 1 have a particle size of less than approximately 4 pm, and 90% of the plurality of particles of Compound 1 have a particle size of less than approximately 30 pm.

11. The dosage form of any one of claims 1-10, wherein the dosage form is for oral administration.

12. The dosage form of any one of claims 1-11, wherein the dosage form is a solid form.

13. The dosage form of any one of claims 1-12, wherein Compound 1 is crystalline.

14. The dosage form of any one of claims 1-13, wherein the crystalline form exhibits a powder X-ray diffraction pattern comprising peaks at the following diffraction angles (2Θ): 12.6±0.2, 15.8±0.2 and 18.6±0.

2.

15. The dosage form of any one of claims 1-14, wherein the crystalline form exhibits a powder X-ray diffraction pattern comprising peaks at the following diffraction angles (29): 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.

16. The dosage form of any one of claims 1-15, wherein the crystalline form exhibits a powder X-ray diffraction pattern comprising peaks at the following diffraction angles (29): 19.7±9.2, 12.3±9.2, 12.6±9.2, 14.9±9.2, 15.8±9.2, 16.6±9.2, 16.8±9.2, 18.6±9.2, 21.9±9.2 and 22.6±9.

2.

17. The dosage form of any one of claims 1-16, wherein the crystalline form exhibits a powder X-ray diffraction pattern substantially the same as that depicted in Figure 1.

18. The dosage form of any one of claims 1-17, wherein the dosage form is in the form of a capsule.

19. The dosage form of any one of claims 1-18, wherein the dosage form is in the form of a mixture.

29. The dosage form of claim 18 or 19, wherein the pharmaceutical excipient is a filler (e.g., microcrystalline cellulose or starch).

21. The dosage form of any one of claims 18-29, wherein the ratio of Compound 1 to the filler is approximately 1:

1.

22. The dosage form of any one of claims 18-29, wherein the ratio of Compound 1 to the filler is approximately 1:

19.

23. The dosage form of any one of claims 18-29, wherein the pharmaceutical excipient is a filler or a lubricant.

24. The dosage form of any one of claims 18-23,wherein the dosage form comprises: from approximately 59% to 99% by weight fill and from 9% to approximately 5% by weight of lubricant.

25. The dosage form of any one of claims 18-23, wherein the dosage form comprises: from approximately 1% to approximately 50% by weight of Compound 1; from approximately 50% to approximately 90% by weight fill; and from 0% to approximately 4% by weight of lubricant.

26. The dosage form of any one of claims 1, 2, and 11, wherein the dosage form is a liquid form.

27. The dosage form of claim 26, wherein the dosage form is a solution form.

28. The dosage form of claim 27, wherein the pharmaceutical excipient is selected from the group consisting of a cosolubilizer / cosolvent (e.g., polymer (e.g., PEG 400)), an emulsifier (e.g., a castor oil derivative, e.g.,1. Compound 1 (Kolliphor RH40), a surfactant (e.g., glyceride (e.g., Labrafil M2125 CS), a vitamin derivative (e.g., Vitamin ETPGS)), a solvent (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutor HP)).

29. The dosage form of any one of claims 26-28, wherein the concentration of Compound 1 is from approximately 0.1 mg / ml to approximately 10 mg / ml.

30. The dosage form of any one of claims 26-28, wherein the dosage form comprises: from approximately 35% to approximately 45% by weight of a filler (e.g., a polymer (e.g., PEG 400)); of approximately 5% to approximately 15% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); and of approximately 40% to approximately 60% by weight of water; wherein the concentration of Compound 1 is approximately 0.5 mg / ml or approximately 0.25 mg / ml.

31. The dosage form of any one of claims 26-28, wherein the dosage form comprises: approximately 55% to approximately 60% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); approximately 15% to approximately 20% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS)); approximately 5% to approximately 10% by weight of propylene glycol; and approximately 15% to approximately 20% by weight of ethanol; wherein the concentration of Compound 1 is approximately 5 mg / ml to approximately 10 mg / ml, or approximately 2.5 mg / ml to approximately 5 mg / ml.

32. The dosage form of any one of claims 26-28, wherein the dosage form comprises: zcfrQnn / zznz / E / YiAi from about 65% to about 70% by weight of an emulsifier (e.g., a castor oil derivative (e.g.,Kolliphor RH40); of approximately 18% to approximately 23% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS); and of approximately 7% to approximately 12% by weight of propylene glycol; wherein the concentration of Compound 1 is of approximately 1 mg / ml to approximately 10 mg / ml, or of approximately 0.5 mg / ml to approximately 5 mg / ml.

33. The dosage form of any one of claims 26-28, wherein the dosage form comprises: of approximately 35% to approximately 45% by weight of diethylene glycol monoethyl ether (Transcutol HP); of approximately 5% to approximately 15% by weight of a surfactant (e.g., a glyceride (e.g., a vitamin derivative (e.g., Vitamin ETPGS)); and of approximately 40% to approximately 60% by weight of water; wherein the The concentration of Compound 1 is approximately 1 mg / ml to approximately 5 mg / ml, or approximately 0.5 mg / ml to approximately 2,5 mg / ml.

34. The dosage form of any one of claims 26-28, wherein the dosage form comprises: approximately 30% to approximately 40% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); approximately 40% to approximately 50% by weight of a surfactant (e.g., a glyceride (e.g., Capmul MCM C8)); approximately 5% to 15% by weight of a plasticizer (e.g., triethyl citrate); and approximately 5% to approximately 15% by weight of a solvent (e.g., ethanol).

35. The dosage form of any one of claims 26-28, wherein the dosage form comprises: approximately 35% to approximately 45% by weight of a propylene glycol monocaprylate (e.g., Capryol). 90); from about 15% to about 25% by weight of a glyceride (e.g., caprylocaproyl macrogolglycerides (e.g.,Labrasol)) and approximately 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP).

34. The dosage form of any one of claims 26-33, wherein the solution may be further diluted with a solvent (e.g., water), wherein the concentration of the diluted solution is approximately 50% to approximately 90% of the solution before dilution.

36. The dosage form of any one of claims 1, 2, 11 and 26, wherein the dosage form is in the form of a suspension. zcfrQnn / zznz / E / YiAi 37. The dosage form of claim 35, wherein the concentration of Compound 1 is approximately 0.1 mg / ml, approximately 0.5 mg, approximately 1 mg / ml, approximately 5 mg / ml, approximately 10 mg / ml, or approximately 15 mg / ml of Compound 1.

38. The dosage form of claim 36 or 37, wherein the pharmaceutical excipient comprises: approximately 0,5% by weight of a filler (e.g., methylcellulose, e.g., 400 cP MC); and approximately 0.2% by weight of an emulsifier (e.g., Tween 80, e.g., Poloxamer 188).

39. The dosage form of claim 38, wherein the pharmaceutical excipient further comprises approximately 1% by weight of a preservative solution (e.g., paraben solution).

40. The dosage form of any one of claims 1, 2, and 11, wherein Compound 1 is amorphous.

41. The dosage form of any one of claims 1, 2, 11, and 40, wherein the dosage form is in the form of an amorphous solid dispersion.

42. The dosage form of claim 41, wherein the pharmaceutical excipient is a polymer (e.g., Soluplus, Eudragit, and HPMC ASMF).

43. The dosage form of any one of claims 1-42, 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.

44. A composition in a dosage form comprising: from approximately 0.1 mg to approximately 500 mg (e.g., from approximately 0.5 mg to approximately 200 mg, from approximately 1 mg to approximately 150 mg, from approximately 10 mg to approximately 120 mg) of Compound 1; and a pharmaceutically acceptable excipient.

45. The composition of claim 44, wherein the composition comprises from approximately 2.5 mg to 150 mg (e.g., from approximately 10 mg to approximately 150 mg, from approximately 20 mg to approximately 150 mg, from approximately 70 mg to approximately 120 mg, from approximately 30 mg to approximately 60 mg, approximately 100 mg, approximately 50 mg) of Compound 1.

46. 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 from approximately 0.1 mg to approximately 500 mg (e.g., from approximately 0.5 mg to approximately 200 mg, from approximately 1 mg to approximately 150 mg, from approximately 10 mg to approximately 120 mg). zcfrQnn / zznz / E / YiAi 47. The composition of claim 46, wherein the plurality of particles of Compound 1 in the composition is from approximately 2.5 mg to approximately 150 mg (e.g., from approximately 10 mg to approximately 150 mg, from approximately 20 mg to approximately 150 mg, from approximately 70 mg to approximately 120 mg, from approximately 30 mg to approximately 60 mg, approximately 100 mg, approximately 50 mg).

48. The composition of claim 46 or 47, wherein 10% of the plurality of particles of Compound 1 have a particle size of less than approximately 1 pm.

49. The composition of any one of claims 46-48,wherein 50% of the plurality of particles of Compound 1 have a particle size of less than approximately 4 pm.

50. The composition of claim 49, wherein 50% of the plurality of particles of Compound 1 have a particle size of less than approximately 2 pm.

51. The composition of any one of claims 46-50, wherein 90% of the plurality of particles of Compound 1 have a particle size of less than approximately 30 pm (e.g., less than approximately 15 pm).

52. The composition of claim 511, wherein 90% of the plurality of particles of Compound 1 have a particle size of less than approximately 5 pm.

53. The composition of claim 52, wherein 10% of the plurality of particles of Compound 1 have a particle size of less than approximately 1 pm.50% of the plurality of particles of Compound 1 have a particle size of less than approximately 4 pm and 90% of the plurality of particles of Compound 1 have a particle size of less than approximately 30 pm.

54. The composition according to any one of claims 44-53, wherein the composition is for oral administration.

55. The composition of any one of claims 44-54, wherein the dosage form is in solid form.

56. The composition of any one of claims 44-55, wherein Compound 1 is crystalline.

57. The composition of any one of claims 44-56, wherein the crystalline form exhibits a powder X-ray diffraction pattern comprising peaks at the following diffraction angles (26): 12.6±0.2, 15.8±0.2, and 18.6±0.

2.

58. The composition of any one of claims 44-57,where the crystalline form exhibits a powder X-ray diffraction pattern comprising peaks at the following diffraction angles (26): 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.

59. The composition of any one of claims 44-58, wherein the crystalline form exhibits a powder X-ray diffraction pattern comprising peaks at the following diffraction angles (26): 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. zcfrQnn / zznz / E / YiAi 60. The composition of any one of claims 44-59, wherein the crystalline form exhibits a powder X-ray diffraction pattern substantially the same as that depicted in Figure 1.

61. The composition of any one of claims 44-60, wherein the dosage form is in the form of a capsule.

62. The composition of any one of claims 44-61,62. The composition of claim 61 or 62, wherein the dosage form is in the form of a mixture.

63. The composition of claim 61 or 62, wherein the pharmaceutical excipient is a filler (e.g., microcrystalline cellulose or starch).

64. The composition of any one of claims 61-63, wherein the ratio of Compound 1 to the filler is approximately 1:

1.

65. The composition of any one of claims 61-63, wherein the ratio of Compound 1 to the filler is approximately 1:

10.

66. The composition of any one of claims 61-63, wherein the pharmaceutical excipient is a filler or a lubricant.

67. The composition of any one of claims 61-66, wherein the composition comprises approximately 50% to 90% by weight of filler and 0% to approximately 5% by weight of lubricant.

68. The composition of any one of claims 61-67,wherein the composition comprises: from approximately 1% to approximately 50% by weight of Compound 1; from approximately 50% to approximately 90% by weight filler; and from 0% to approximately 4% by weight of lubricant.

69. The composition of any one of claims 44, 45, or 54, wherein the dosage form is in liquid form.

70. The composition of claim 69, wherein the dosage form is a solution.

71. The composition of claim 70, wherein the pharmaceutical excipient is selected from the group consisting of a cosolubilizer / cosolvent (e.g., polymer (e.g., PEG 400)), an emulsifier (e.g., a castor oil derivative, e.g., Kolliphor RH40), a surfactant (e.g., glyceride (e.g., Labrafil M2125 OS), a vitamin derivative (e.g., Vitamin ETPGS)), a solvent (e.g., propylene glycol, ethanol,diethylene glycol monoethyl ether (or Transcutor HP)).

72. The composition of any one of claims 69-71, wherein the concentration of Compound 1 is from approximately 0.1 mg / ml to approximately 10 mg / ml.

73. The composition of any one of claims 69-71, wherein the composition comprises: zcfrQnn / zznz / E / YiAi from approximately 35% to approximately 45% by weight of a filler (e.g., a polymer (e.g., PEG 400)); from approximately 5% to approximately 15% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); and from approximately 40% to approximately 60% by weight of water; wherein the concentration of Compound 1 is approximately 0.5 mg / ml or approximately 0.25 mg / ml.

74. The composition of any one of claims 69-71, wherein the composition comprises: from approximately 55% to approximately 60% by weight of an emulsifier (e.g., a castor oil derivative (e.g.,Kolliphor RH40); from approximately 15% to approximately 20% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS); from approximately 5% to approximately 10% by weight of propylene glycol; and from approximately 15% to approximately 20% by weight of ethanol; wherein the concentration of Compound 1 is from approximately 5 mg / ml to approximately 10 mg / ml, or from approximately 2.5 mg / ml to approximately 5 mg / ml.

75. The composition of any one of claims 69-71, wherein the composition comprises: from approximately 65% ​​to approximately 70% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); from approximately 18% to approximately 23% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS); and from approximately 7% to approximately 12% by weight of propylene glycol; wherein the concentration of Compound 1 is from approximately 1 mg / ml to approximately 10 mg / ml,or from approximately 0.5 mg / ml to approximately 5 mg / ml.

76. The composition of any one of claims 69-71, wherein the composition comprises: from approximately 35% to approximately 45% by weight of diethylene glycol monoethyl ether (Transcutol HR); of approximately 5% to approximately 15% by weight of a surfactant (e.g., a glyceride (e.g., a vitamin derivative (e.g., Vitamin ETPGS)); and of approximately 40% to approximately 60% by weight of water; wherein the concentration of Compound 1 is of approximately 1 mg / ml to approximately 5 mg / ml, or of approximately 0.5 mg / ml to approximately 2.5 mg / ml.

77. The composition of any one of claims 69-71, wherein the composition comprises: of approximately 30% to approximately 40% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); of approximately 40% to approximately 50% by weight of a surfactant (e.g.,a glyceride (e.g., Capmul MCM C8); approximately 5% to 15% by weight of a plasticizer (e.g., triethyl citrate); and approximately 5% to approximately 15% by weight of a solvent (e.g., ethanol).

78. The composition of any one of claims 69-71, wherein the composition comprises: approximately 35% to approximately 45% by weight of a propylene glycol monocaprylate (e.g., Capryol 90); approximately 15% to approximately 25% by weight of a glyceride (e.g., caprylocaproyl macrogolglycerides (e.g., Labrasol)); and approximately 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP).

79. The composition of any one of claims 44, 45, 54 and 69, wherein the dosage form is in the form of a suspension.

80. The composition of claim 79, wherein the concentration of Compound 1 is approximately 0.1 mg / ml, approximately 0.5 mg, approximately 1 mg / ml,81. The composition of claim 79 or 80, wherein the pharmaceutical excipient comprises: approximately 0.5 wt% of a filler (e.g., methylcellulose, e.g., 400 cP MC); and approximately 0.2 wt% of an emulsifier (e.g., Tween 80, e.g., Poloxamer 188).

82. The composition of claim 81, wherein the pharmaceutical excipient further comprises approximately 1 wt% of a preservative solution (e.g., paraben solution).

83. The composition of any one of claims 44, 45, and 54, wherein Compound 1 is amorphous.

84. The composition of any one of claims 44, 45, 54 and 83, wherein the dosage form is in the form of an amorphous solid dispersion.

85. The composition of claim 84, wherein the pharmaceutical excipient is a polymer (e.g., Soluplus, Eudragit,and HPMC ASMF).

86. The composition of any one of claims 44-85, wherein the 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, or 6 months.

87. A method for treating a condition related to the abnormal function of a sodium ion channel in a subject in need thereof, comprising administering to the subject a dosage form or composition of any one of claims 1-86. zcfrQnn / zznz / E / YiAi 88. A method for treating a condition related to the abnormal function of a sodium ion channel in a subject in need thereof, comprising administering to the subject from approximately 2.5 mg to approximately 90 mg of Compound 1.

89. The method of claim 87 or 88, wherein the condition is a neurological or psychiatric disorder.

90. The method of any one of claims 87-89,91. The method of any one of claims 87-90, wherein the condition is epilepsy or an epilepsy syndrome.

92. The method of any one of claims 87-91, wherein the condition is pediatric epilepsy or a pediatric epilepsy syndrome.

93. The method of any one of claims 87-92, wherein the condition is epileptic or congenital encephalopathy.

94. The method of claim 93, wherein the epileptic or congenital encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.

95. The method of any one of claims 87-94, wherein the condition is selected from the group consisting of epileptic encephalopathy, congenital epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome,Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migratory partial seizures of childhood, autosomal dominant frontal lobe nocturnal epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

96. The method of any one of claims 87-89, wherein the condition is cancer.

97. A method for treating a neurological or psychiatric disorder in a subject in need thereof.wherein the method comprises administering to a subject in need a dosage form described in any one of claims 1-86.

98. A method for treating pain in a subject in need, wherein the method comprises administering to the subject a dosage form or composition of any one of claims 1-86.

99. A method for treating cancer in a subject in need, wherein the method comprises administering to the subject a dosage form or composition of any one of claims 1-86.

100. A method for treating or preventing trigeminal autonomic cephalalgia (TAC) in a subject in need, comprising administering to the subject a therapeutically effective amount of a dosage form or composition of any one of claims 1-86.

101. A method for treating or preventing trigeminal autonomic cephalalgia (TAC) in a subject in need,comprising administering to the subject a therapeutically effective amount of Compound 1, e.g., from 2.5 mg to 90 mg of Compound 1.

102. The method of claim 100 or 101, wherein the CATs are selected from the group consisting of cluster headache (CH), paroxysmal hemicrania (PH), continuous hemicrania (HC), short-duration unilateral neuralgiform headache attack with conjunctival injection and lacrimation (SUNCT), short-duration unilateral neuralgiform headache attack with cranial autonomic symptoms (SUNA), and long-duration autonomic symptoms with hemicrania.

103. The method of claim 102, wherein the CAT is a short-duration unilateral neuralgiform headache attack.

104. The method of claim 102, wherein the CAT is a SUNCT.

105. The method of claim 102, wherein TAC is a SUNA.

106. The method of any one of claims 100-105,where the subject has an inadequate response to at least one drug used for the treatment of a TAC.

107. A method for treating or preventing a headache in a subject in need, comprising administering to the subject a therapeutically effective amount of a dosage form or composition of any one of claims 1-86.

108. A method for treating or preventing a migraine in a subject in need, comprising administering to the subject a therapeutically effective amount of Compound 1, p. e.g., from approximately 2.5 mg to approximately 90 mg of Compound 1.

109. The method of claim 107 or 108, wherein the migraine is selected from a 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).

110. The method of claim 109,111. The method of claim 109, wherein the migraine is migraine without aura.

112. The method of claim 109, wherein the migraine is migraine with aura.

113. The method of claim 109, wherein the migraine is FHM1.

114. The method of claim 109, wherein the migraine is FHM2.

115. The method of claim 109, wherein the migraine is FHM4.

116. The method of claim 109, wherein the migraine is SHM.

117. The method of any one of claims 107-115, wherein the subject has an inadequate response to at least one drug used for the treatment of migraine.

117. A method for treating or preventing cortical spreading depression (CSD) in a subject in need, comprising administering to the subject a therapeutically effective amount of a dosage form or composition of any one of claims 1-86. zcfrQnn / zznz / E / YiAi 118. A method for treating or preventing cortical spreading depression (CSD) in a subject in need,comprising administering to the subject a therapeutically effective amount of Compound 1, e.g., from approximately 2.5 mg to approximately 90 mg of Compound 1.

119. A method for treating or preventing cranial neuropathy or multiple cranial neuropathy in a subject in need, comprising administering to the subject a therapeutically effective amount of a dosage form or composition of any one of claims 1-86.

120. A method for treating or preventing cranial neuropathy or multiple cranial neuropathy in a subject in need, comprising administering to the subject a therapeutically effective amount of Compound 1, e.g., from approximately 2.5 mg to approximately 90 mg of Compound 1.

121. The method of claim 119 or 120, wherein the cranial neuropathy is selected from the group consisting of Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy,and sixth nerve palsy.

122. The method of any one of claims 87-121, wherein the dosage form is administered orally.

123. The method of any one of claims 87-122, wherein the dosage form is a capsule.

124. The method of any one of claims 87-123, wherein the subject is between 18 and 65 years of age.

125. A method for manufacturing Compound 1: zcfrQnn / zznz / E / YiAi or a pharmaceutically acceptable salt thereof, the method comprising the steps of: (i) contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine,thus providing a compound of formula (II): Br(H); (i) contacting the compound of formula (II) with a palladium and bis(pinacolato)diboron catalyst, thus providing a compound of formula (III): 100; (iii) contacting the compound of formula (III) with a palladium and 2-bromo-5-chloropyrazine catalyst, thus providing a compound of formula (IV): FF zcfrQnn / zznz / E / YiAi; (iv) contacting the compound of formula (IV) with hydrazine, thus providing a compound of formula (V): FF H (V); (v) contacting the compound of formula (V) with 2-bromo-2 chloride,2-difluoroacetyl, thus providing a compound of formula (VI): FF °(VI); (vi) contacting the compound of formula (VI) with an acid, thus providing a compound of formula (VI): FF; (vii) contacting the compound of formula (VI) with a silver and ethanol catalyst, thus providing Compound 1 or a pharmaceutically acceptable salt thereof.

126. The method of claim 125, wherein the palladium catalyst in step (i) or (iii) is [1,T-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

127. The method of claim 125 or 126, wherein the silver catalyst in step (vii) is silver tetrafluoroborate.

128. The method of any one of claims 125-127, wherein the acid in step (vi) is p-toluenesulfonic acid. 101 129. A method for manufacturing Compound 1: zcfrQnn / zznz / E / YiAi or a pharmaceutically acceptable salt thereof,wherein Compound 1 or a pharmaceutically acceptable salt thereof is provided by contacting the compound of formula (VI):

130. The method of claim 129, wherein the compound of formula (VI) is provided by contacting the compound of formula (VI): FF 0 (VI) with an acid.

131. The method of claim 130, wherein the compound of formula (VI) is provided by contacting the compound of formula (V): FFH (V) with 2-bromo-2,2-difluoroacetyl chloride.

132. The method of claim 131, wherein the compound of formula (V) is provided by contacting the compound of formula (IV): 102 zcfrQnn / zznz / E / YiAi with hydrazine.

133. The method of claim 132, wherein the compound of formula (IV) is provided by contacting the compound of formula (III) with a palladium and 2-bromo-5-chloropyrazine catalyst.

134. The method of claim 133,wherein the compound of formula (III) is provided by contacting the compound of formula (II): FF with a palladium and bis(pinacolate)diboron catalyst.

135. The method of claim 134, wherein the compound of formula (II) is provided by contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine.

136. The method of any one of claims 125-135, wherein the silver catalyst is silver tetrafluoroborate.

137. The method of any one of claims 125-136, wherein the acid is p-toluenesulfonic acid.

138. The method of any one of claims 125-137, wherein the palladium catalyst is [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride.