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

Abstract

We provide formulations of ion channel modulators. [Solution] The present invention partially relates to compositions or dosage forms comprising condensed heteroaryl compounds useful for preventing and / or treating diseases or conditions associated with abnormal function of voltage-gated sodium ion channels, such as abnormal delayed / persistent sodium currents. Methods for treating diseases or conditions associated with abnormal function of sodium ion channels, including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, neuromuscular disorders, trigeminal-autonomic headache (TAC), migraines, cranial nerve disorders or polycranial nerve disorders, and cortical spreading depression (CSD), are also provided herein. In another aspect, the present invention provides methods for producing ion channel modulators.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests 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 these applications are incorporated herein by reference. [Background technology]

[0002] Sodium ion (Na+) channels open primarily transiently and are rapidly inactivated, thereby generating a fast Na+ current and initiating an action potential. Delayed or sustained sodium currents (INaL) are the sustained components of fast Na+ currents in cardiomyocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther (2008) 119:326-339). Therefore, pharmaceutical compositions or dosage forms containing compounds that selectively modulate sodium channel activity, such as abnormal INaL, are useful in treating such conditions. [Overview of the project]

[0003] This specification describes compositions or dosage forms useful for preventing and / or treating diseases, disorders, or conditions, such as abnormal function of sodium ion channels, such as diseases, disorders, or conditions associated with abnormal delayed sodium current (INaL). This disclosure also includes methods for modulating sodium channel activity using the compounds, compositions, or dosage forms described herein. Furthermore, this specification provides methods for preparing ion channel modulators.

[0004] In one embodiment, the present disclosure provides a pharmaceutical composition comprising compound 1 in an amount of about 0.1 mg to about 500 mg (for example, about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) and a pharmaceutically acceptable excipient.

[0005] In another embodiment, the disclosure provides a dosage form comprising a plurality of particles of compound 1 and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of compound 1 in the dosage form is 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).

[0006] In one embodiment, the present disclosure provides a composition in a dosage form comprising compound 1 in an amount of 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) and a pharmaceutically acceptable excipient.

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

[0008] This specification also provides methods for treating mental disorders in subjects requiring treatment, the methods including administering the dosage forms disclosed herein to the subject.

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

[0010] The contemplated methods include a method of treating cancer in a subject that requires treatment thereof, the method comprising administering to the subject a dosage form disclosed herein.

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

[0012] Also provided herein is a method of treating or preventing trigeminal autonomic cephalgia (TAC) in a subject that requires treatment or prevention thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1, such as from about 2.5 mg to about 90 mg of Compound 1.

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

[0014] Provided herein is, in part, a method of treating or preventing migraine in a subject that requires treatment or prevention thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1, such as from about 2.5 mg to about 90 mg of Compound 1.

[0015] Provided herein is a method of treating or preventing cortical spreading depression (CSD) in a subject that requires treatment or prevention thereof, the method comprising administering to the subject a therapeutically effective amount of a dosage form disclosed herein thereof.

[0016] A method of treating or preventing cortical spreading depression (CSD) in a subject needing such treatment or prevention, the method comprising administering to the subject a therapeutically effective amount of Compound 1, for example, from about 2.5 mg to about 90 mg, is also provided.

[0017] Also provided herein is a method of treating or preventing a cranial nerve disorder or a polyneuropathy in a subject needing such treatment or prevention, the method comprising administering to the subject a therapeutically effective amount of the dosage form described herein.

[0018] In another aspect, there is provided a method of treating or preventing a cranial nerve disorder or a polyneuropathy in a subject needing such treatment or prevention, the method comprising administering to the subject a therapeutically effective amount of Compound 1, for example, from about 2.5 mg to about 90 mg of Compound 1.

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

[0020] In another aspect, this disclosure relates to compound 1, [ka] or a method for preparing a pharmaceutically acceptable salt thereof, wherein compound 1 or its pharmaceutically acceptable salt is of formula (VII): [ka] A method is provided which involves contacting the compound with a silver catalyst and ethanol.

[0021] Other purposes and advantages will become apparent to those skilled in the art by considering the following brief description of the drawings, the modes for carrying out the invention, the examples, and the claims. [Brief explanation of the drawing]

[0022] [Figure 1] The raw materials for compound 1 after jet pulverization and the XRPD pattern of compound 1 are shown. [Figure 2] The dissolution results of ASD in capsules (2.5 mg and 10 mg of active ingredient) are shown. [Figure 3] The dissolution results of a 1:10 blend with MCC in capsules (1 and 10 mg of active ingredient) are shown. [Figure 4] The dissolution results of a 1:10 blend of MCC in a capsule (containing 2.5 mg of active ingredient with 2% surfactant) are shown. [Modes for carrying out the invention]

[0023] As generally described herein, this disclosure provides, in part, compounds, compositions, and dosages or formulations useful for preventing and / or treating diseases, disorders, or conditions described herein, such as diseases, disorders, or conditions related to abnormal function of sodium ion channels, such as abnormal delayed sodium current (INaL). Exemplary diseases, disorders, or conditions include neurological disorders (e.g., epilepsy or epileptic syndromes, neurodevelopmental disorders, or neuromuscular disorders), psychiatric disorders, pain, gastrointestinal disorders, trigeminal-autonomic headache (TAC), migraines, cranial nerve disorders or polycranial nerve disorders, and cortical spreading depression (CSD). Methods for preparing ion channel modulators are also provided herein.

[0024] definition As used herein, “pharmaceutically acceptable carrier” means a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound into 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, e.g., human serum albumin, buffers, e.g., phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolinic tallow.

[0025] As used herein, “pharmaceutically acceptable salt” refers to a salt that, within reasonable medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that balances 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. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfonates, benzoates, bisulfates, and boron. Examples include salts, butyrates, camphorates, camphor sulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptonates, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfons, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrinates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates. pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 Examples include alkyl)4 salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons, where appropriate.

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

[0027] Diseases, disorders, and conditions are used interchangeably in this specification.

[0028] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to an action that occurs while the subject is suffering from a specified disease, disorder, or condition, and that reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition (including “therapeutic treatment”).

[0029] As used herein, “effective dose” of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective dose of a compound in the present 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. The effective dose encompasses both therapeutic and prophylactic treatments.

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

[0031] As used herein, the term "amorphous" refers to a solid in a non-crystalline state. Amorphous solids generally have a crystalline-like short-range molecular arrangement, but unlike crystalline solids, they do not have the molecular packing seen in crystalline solids. There is no long-range order. The solid-state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or other standard techniques known to those skilled in the art.

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

[0033] When referring to peaks in the XRPD pattern of the crystalline form of compound 1, the term "peak" refers to a specific set of peaks whose 2θ values, collectively, are uniquely assigned to one of the crystalline forms of compound 1, over a range of 0° to 40°.

[0034] As used herein, the phrase “amorphous solid dispersion” refers to a solid comprising the active pharmaceutical ingredient (e.g., Compound 1) and the dispersion polymer.

[0035] The phrase “dispersion polymer” means a polymer that enables the active pharmaceutical ingredient (e.g., Compound 1) to be dispersed throughout so that a solid dispersion can be formed. The dispersion polymer may contain a mixture of two or more polymers. Examples of dispersion polymers, but are not limited to, vinyl polymers and copolymers, vinylpyrrolidine vinyl acetate copolymer (PVP-VA), polyvinyl alcohol, polyvinyl alcohol polyvinyl acetate copolymer, polyvinylpyrrolidine ("PVP"), acrylate and methacrylate copolymers, methyl methacrylate copolymer (Eudragit®), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer (also known as poloxamer), polyethylene glycol, graft copolymers composed of polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus®), cellulosic polymers, e.g., hydroxypropyl methylcellulose acetate ("HPMCA"), hydroxypropyl methylcellulose ("HP") Examples include methylcellulose ("MC"), hydroxypropylcellulose ("HPC"), methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose acetate, and hydroxyethylethylcellulose, hydroxypropylmethylcellulose acetate succinate ("HPMCAS"), hydroxypropylmethylcellulose phthalate ("HPMCP"), carboxymethylethylcellulose ("CMEC"), cellulose acetate phthalate ("CAP"), cellulose acetate succinate ("CAS"), hydroxypropylmethylcellulose acetate phthalate ("HPMCAP"), cellulose acetate trimellitate ("CAT"), hydroxypropylmethylcellulose acetate trimellitate ("HPMCAT"), and carboxymethylcellulose acetate butyrate ("CMCAB").

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

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

[0038] compound This specification describes pharmaceutical compositions and dosage forms comprising compounds useful for preventing and / or treating diseases, disorders, or conditions related to abnormal function of sodium ion channels, such as abnormal delayed sodium current (INaL).

[0039] In one embodiment, this disclosure relates to compound 1, represented by: [ka] The present invention relates to dosage forms comprising compound 1 and a pharmaceutically acceptable excipient. In some embodiments, compound 1 is crystalline. In some embodiments, the crystalline morphology exhibits an X-ray powder diffraction pattern with 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 morphology exhibits an X-ray powder diffraction pattern with 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 morphology exhibits an X-ray powder diffraction pattern with peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2, and 22.6±0.2. In some embodiments, the crystalline morphology has an X-ray powder diffraction pattern substantially identical to that shown in Figure 1.

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

[0041] Dosage and composition In one embodiment, the present disclosure features dosage forms or compositions useful for preventing and / or treating diseases, disorders, or conditions described herein, such as diseases, disorders, or conditions related to abnormal function of sodium ion channels, such as abnormal delayed sodium current (INaL).

[0042] The present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof, a carrier comprising one or more pharmaceutically acceptable excipients, an inert solid diluent and a packing agent, a diluent comprising a sterile aqueous solution and various organic solvents, an osmotic enhancer, a solubilizer and an adjuvant. The pharmaceutical composition may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in ways well known in the pharmaceutical art (e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (see GSBanker & CTRhodes, Eds.)).

[0043] Pharmaceutical compositions are administered, for example, as inhalants, by intra-arterial injection, intravenous injection, intraperitoneal injection, parenteral injection, intramuscular injection, subcutaneous injection, oral injection, topical injection, or by other means, including rectal injection, oral injection, intranasal injection, and transdermal injection routes. For example, the drug may be administered in single or multiple doses by any of the acceptable modes of administration having similar utility to those described in the patents and patent applications incorporated by reference, via an impregnated or coated device such as a stent or an arterial insertion cylindrical polymer.

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

[0045] Sterile injectable solutions are prepared by incorporating the required amount of the compound according to the present invention into a suitable solvent containing, if necessary, various other components listed above, and then sterilizing by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. In the case of sterile powders for preparing sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying techniques to obtain powders of the active ingredients and any additional desired components from the sterile solution that has been pre-sterilized and filtered.

[0046] Oral administration is another route for administering the compounds according to the present invention. Administration may be via capsules or tablets, etc. In the preparation of a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or encapsulated in such a carrier, which may be in the form of a capsule, pouch, paper, or other container. When the excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material (as described above) acting as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, licks, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound.

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

[0048] The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug polymer matrix formulations. An example of a controlled-release system is U.S. Patent No. 3,845,770. This is described in U.S. Patents No. 4,326,525, No. 4,902,514, and No. 5,616,345. Another formulation for use in the method of the present invention utilizes a transdermal delivery device ("patch"). Such a transdermal patch may be used to provide a continuous or discontinuous infusion of the compound of the present invention in a controlled amount. The configuration and use of transdermal patches for delivering pharmaceuticals are well known in the art. See, for example, U.S. Patents No. 5,023,252, No. 4,992,445, and No. 5,001,139. ​​Such patches may be constructed for continuous, pulsed, or on-demand delivery of pharmaceuticals.

[0049] The composition is preferably formulated in unit dosage forms. The term “unit dosage form” refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in relation to a suitable pharmaceutically effective excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmaceutically effective dose. Preferably, for oral administration, each dose unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of the compound described herein. However, it will be understood that the actual amount of compound administered will usually be determined by a physician in consideration of relevant circumstances, including the condition being treated, the route of administration selected, the actual compound administered and its relative activity, the individual patient’s age, weight, and response, and the severity of the patient’s symptoms.

[0050] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present invention. When these preliminary formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, thereby allowing the composition to be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0051] The tablets or pills of the present invention may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-term action or to protect from the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dosage component and an outer dosage component, the latter in the form of a coating covering the former. The two components may be separated by an enteric coating that functions to withstand disintegration in the stomach and allow the inner component to pass through the duodenum intact or be released with delayed release. A variety of materials may be used for such enteric coatings or coatings, including many polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0052] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. Compositions in preferably pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spray device, or the spray device may be attached to a face mask tent or an intermittent positive pressure respirator. The solution, suspension, or powder composition may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0053] In one embodiment, this specification provides a dosage form or composition in a dosage form comprising about 0.1 mg to about 500 mg (for example, about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of compound 1 and a pharmaceutically acceptable excipient.

[0054] In some embodiments, the dosage form or the composition in the dosage form is approximately 2.5 mg to approximately 150 mg (for example, approximately 10 mg to approximately 150 mg, approximately 20 mg to approximately 150 mg, approximately 40 mg to approximately 15 mg) 0mg, about 60mg to about 150mg, about 80mg to about 150mg, about 100mg to about 150mg, about 10mg to about 120mg, about 20mg to about 120mg, about 40mg to about 120mg, about 60mg to about 120mg , about 80 mg to about 120 mg, about 100 mg to about 120 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 40 mg to about 100 mg, about 60 mg to about 100 mg, about 80 mg to about 100 mg, about 1 It contains compound 1 in the following amounts: 0mg to approximately 80mg, approximately 20mg to approximately 80mg, approximately 40mg to approximately 80mg, approximately 60mg to approximately 80mg, approximately 10mg to approximately 60mg, approximately 20mg to approximately 60mg, approximately 40mg to approximately 60mg, approximately 70mg to approximately 120mg, approximately 70mg to approximately 100mg, approximately 50mg to approximately 120mg, approximately 50mg to approximately 90mg, approximately 30mg to approximately 120mg, approximately 30mg to approximately 60mg, approximately 30mg to approximately 80mg, and approximately 30mg to approximately 100mg.

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

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

[0057] In another aspect, the Disclosure provides a dosage form or 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 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).

[0058] In some embodiments, the number of particles of compound 1 in the dosage form or composition is about 2.5 mg to 150 mg (for example, about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, about 50 mg).

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

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

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

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

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

[0064] In some embodiments, the pharmaceutical excipients in the capsule are fillers (e.g., cellulose derivatives (e.g., microcrystalline cellulose), starch (e.g., hydrolyzed starch and partially gelatinized starch), anhydrous lactose, lactose monohydrate, and sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

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

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

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

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

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

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

[0071] In some embodiments, the pharmaceutical excipients in solution include fillers (e.g., polymers (e.g., PEG400)), emulsifiers (e.g., castor oil derivatives (e.g., Kolliphor)), and The solvent is selected from the group consisting of RH40), surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), vitamin derivatives (e.g., Vitamin ETPGS)), and solvents (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)).

[0072] In some embodiments, the concentration of compound 1 in the solution ranges from approximately 0.1 mg / mL to approximately 10 mg / mL (for example, approximately 0.5 mg / mL to approximately 10 mg / mL, approximately 1 mg / mL to approximately 10 mg / mL, approximately 2 mg / mL to approximately 10 mg / mL, approximately 3 mg / mL to approximately 10 mg / mL, approximately 4 mg / mL to approximately 10 mg / mL, approximately 5 mg / mL to approximately 10 mg / mL, approximately 6 mg / mL to approximately 10 mg / mL, approximately 0.1 mg / mL to approximately 8 mg / mL, approximately 0.5 mg / mL to approximately 8 mg / mL, approximately 1 mg / mL to approximately 8 mg / mL). L is approximately 2 mg / mL to 8 mg / mL, approximately 3 mg / mL to 8 mg / mL, approximately 4 mg / mL to 8 mg / mL, approximately 5 mg / mL to 8 mg / mL, approximately 6 mg / mL to 8 mg / mL, approximately 0.5 mg / mL to 6 mg / mL, approximately 1 mg / mL to 6 mg / mL, approximately 2 mg / mL to 6 mg / mL, approximately 3 mg / mL to 6 mg / mL, approximately 4 mg / mL to 6 mg / mL, approximately 0.5 mg / mL to 4 mg / mL, approximately 1 mg / mL to 4 mg / mL, or approximately 2 mg / mL to 4 mg / mL). .

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

[0074] In some embodiments, the dosage form or composition, Fillers of approximately 20% to 60% by weight (e.g., approximately 25% to 55% by weight, approximately 30% to 50% by weight, approximately 35% to 45% by weight, approximately 37% to 42% by weight, or approximately 40% by weight) (e.g., polymers (e.g., PEG 200, PEG 300, PEG (PEG-400, PEG-600, PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-6000 or PEG-8000), Approximately 3% to 25% by weight (for example, approximately 3% to 20% by weight, approximately 5% to 13% by weight, approximately 8% to 13% by weight, approximately 5% to 15% by weight, or approximately 10% by weight) of emulsifiers (for example, castor oil derivatives (for example, Kolliphor RH40, macrogol 25 cetostearyl ether (for example, Cremophor® A25), macrogol 6 cetostearyl ether (for example, Cremophor® A6), macrogol glycerol ricinolate 35 (for example, Cremophor® EL), macrogol-glycerol hydroxystearate 40 (for example, Cremophor® RH40)) and, Approximately 30% to 70% by weight of water (for example, approximately 35% to 65% by weight, approximately 40% to 60% by weight, approximately 45% to 55% by weight, or approximately 50% by weight) and It contains, and the concentration of compound 1 is approximately 0.5 mg / mL or approximately 0.25 mg / mL.

[0075] 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., PEG400)), 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.

[0076] In some embodiments, the dosage form or composition, Approximately 40% to 75% by weight (for example, approximately 45% to 70% by weight, approximately 50% to 65% by weight, approximately 55% to 60% by weight, or approximately 58% by weight) of emulsifiers (for example, castor oil derivatives (e.g., Kolliphor RH40), macrogol 25 cetostearyl ether (e.g., Cremophor® A25), macrogol 6 cetostearyl ether (e.g., Cremophor® A6), macrogol glycerol ricinolate 35 (e.g., Cremophor® EL), macrogol-glycerol hydroxystearate 40 (e.g., Cremophor® RH40)), Surfactants in approximately 10% to 35% by weight (for example, approximately 10% to 30% by weight, approximately 10% to 25% by weight, approximately 15% to 25% by weight, or approximately 15% to 20% by weight) (e.g., glycerides (e.g., Labrafil M2125 CS), caprylocaproyl macrogol glycerides (e.g., Labrasol), natural triglyceride-based oils (e.g., olive oil, sesame oil, coconut oil, palm kernel oil)) and Approximately 3% to 20% by weight of propylene glycol (for example, approximately 3% to 15% by weight, approximately 5% to 15% by weight, or approximately 5% to 10% by weight), It contains ethanol in an amount of 10% to approximately 35% by weight (for example, approximately 10% to approximately 30% by weight, approximately 10% to approximately 25% by weight, approximately 15% to approximately 25% by weight, or approximately 15% to approximately 20% by weight), The concentration of compound 1 is approximately 5 mg / mL to approximately 10 mg / mL (for example, approximately 5 mg / mL, approximately 7.5 mg / mL, or approximately 10 mg / mL), or approximately 2.5 mg to approximately 5 mg / mL.

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

[0078] In some embodiments, the dosage form is Approximately 50% to approximately 85% by weight (for example, approximately 55% to approximately 80% by weight, approximately 60% to approximately 75% by weight, or approximately 65% ​​to approximately 70% by weight) of emulsifiers (for example, castor oil derivatives (for example, Kolliphor RH40), macrogol 25 cetostearyl ether (for example, Cremophor® A25), macrogol 6 cetostearyl ether (for example, Cremophor® A6), macrogol glycerol ricinolate 35 (for example, Cremophor® EL), macrogol-glycerol hydroxystearate 40 (for example, Cremophor® RH40)), and Surfactants in approximately 10% to 30% by weight (for example, approximately 10% to 25% by weight, approximately 15% to 25% by weight, or approximately 18% to 23% by weight) (e.g., glycerides (e.g., Labrafil M2125 CS), caprylocaproyl macrogol glycerides (e.g., Labrasol), natural triglyceride-based oils (e.g., olive oil, sesame oil, coconut oil, palm kernel oil)) and It contains approximately 3% to 20% by weight of propylene glycol (for example, approximately 3% to 15% by weight, approximately 5% to 15% by weight, approximately 5% to 12% by weight, or approximately 7% to 12% by weight), The concentration of compound 1 is approximately 1 mg / mL to approximately 10 mg / mL (for example, approximately 2 mg / mL to approximately 8 mg / mL, approximately 2 mg / mL, approximately 5 mg / mL, approximately 7 mg / mL, or approximately 10 mg / mL), or 0.5 mg / mL to approximately 5 mg / mL.

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

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

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

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

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

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

[0085] In some embodiments, the concentrations of compound 1 in the suspension are approximately 0.1 mg / mL, approximately 0.5 mg / mL, approximately 1 mg / mL, approximately 1.5 mg / mL, approximately 2 mg / mL, approximately 2.5 mg / mL, approximately 3 mg / mL, approximately 3.5 mg / mL, approximately 4 mg / mL, approximately 4.5 mg / mL, approximately 5 mg / mL, approximately 6 mg / mL, approximately 7 mg / mL, approximately 8 mg / mL, approximately 9 mg / mL, approximately 10 mg / mL, approximately 11 mg / mL, approximately 12 mg / mL, approximately 13 mg / mL, approximately 14 mg / mL, approximately 15 mg / mL, approximately 20 mg / mL, and approximately 25 mg / mL.

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

[0087] In some embodiments, the concentration of compound 1 in the suspension is approximately 0.1 mg / mL to approximately 10 mg / mL (for example, approximately 0.5 mg / mL to approximately 10 mg / mL, approximately 1 mg / mL to approximately 10 mg / mL, approximately 2 mg / mL to approximately 10 mg / mL, approximately 3 mg / mL to approximately 10 mg / mL, approximately 4 mg / mL to approximately 10 mg / mL, approximately 5 mg / mL to approximately 10 mg / mL, approximately 6 mg / mL to approximately 10 mg / mL, approximately 0.1 mg / mL to approximately 8 mg / mL, approximately 0.5 mg / mL to approximately 8 mg / mL, approximately 1 mg / mL to approximately 8 mg / mL). L is approximately 2 mg / mL to 8 mg / mL, approximately 3 mg / mL to 8 mg / mL, approximately 4 mg / mL to 8 mg / mL, approximately 5 mg / mL to 8 mg / mL, approximately 6 mg / mL to 8 mg / mL, approximately 0.5 mg / mL to 6 mg / mL, approximately 1 mg / mL to 6 mg / mL, approximately 2 mg / mL to 6 mg / mL, approximately 3 mg / mL to 6 mg / mL, approximately 4 mg / mL to 6 mg / mL, approximately 0.5 mg / mL to 4 mg / mL, approximately 1 mg / mL to 4 mg / mL, or approximately 2 mg / mL to 4 mg / mL).

[0088] In some embodiments, the pharmaceutical excipients in the suspension are Approximately 0.1% to approximately 5% (for example, approximately 0.1% by weight to approximately 3% by weight, approximately 0.1% by weight to approximately 2% by weight) Fillers in amounts of % (approximately 0.1% to 1% by weight, approximately 0.5% to 3% by weight, approximately 0.5% to 2% by weight, approximately 0.5% to 1% by weight, approximately 0.1% by weight, approximately 0.3% by weight, approximately 0.5% by weight, approximately 1% by weight, approximately 2% by weight, or approximately 3% by weight) (e.g., ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, caboxymethylcellulose, sodium hydroxypropylmethylcellulose, methylcellulose (e.g., 400cP 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), Softisan 100, 142, 378 and 649, stearyl alcohol carbomer, xanthan gum, maltodextrin, acacia, tragacanth, povidone, or polyvinyl alcohol) and An emulsifier (e.g., polyoxyethylene sorbate (e.g., Tween®), sorbitan long-chain carboxylic acid ester (e.g., Span®), ethylene or propylene oxide dobro) in an amount of approximately 0.1% to approximately 3% by weight (e.g., approximately 0.1% to approximately 2%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 0.5%, approximately 0.1% to approximately 0.3%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, or approximately 1%). It comprises block copolymers (Pluronic®), polyglycolyzed glycerides (Labrasol®, Labrafil®, and Labrafac®), sorbitan esters of oleic acid, stearic acid, lauric acid, or other long-chain carboxylic acids, polyethylene-polypropylene glycol block copolymers (e.g., poloxamer 188), other sorbitan or sucrose long-chain carboxylic acid esters, monoglycerides and diglycerides, and PEG derivatives of caprylic / capric triglyceride.

[0089] 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).

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

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

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

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

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

[0095] Method for preparing dosage forms In another embodiment, the Disclosure provides a method for preparing the dosage forms disclosed herein. Such a method is described, for example, in the Examples section. In some embodiments, the intended dosage form may be in the form of a capsule, a blend, a solution, a suspension, or an ASD.

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

[0097] In one embodiment, the present invention provides a method for treating a condition in a subject requiring treatment for a condition related to abnormal function of sodium ion channels, comprising administering a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1 to the subject.

[0098] Epilepsy and epileptic syndromes The formulations described herein (e.g., dosage forms, compositions in dosage forms containing compound 1) are useful for the treatment of epilepsy and epileptic syndromes. Epilepsy is a CNS disorder in which the activity of nerve cells in the brain is disrupted, resulting in seizures or periods of abnormal behavior, sensation, and sometimes loss of consciousness. Seizure symptoms vary greatly, from simple, expressionless stares lasting a few seconds to recurrent short contractions of the arms or legs during a seizure.

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

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

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

[0102] In some embodiments, epileptic syndromes include epileptic encephalopathy, such as developmental and epileptic encephalopathy (DEE), Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile seizures, West syndrome, juvenile myoclonic epilepsy, and Landau syndrome. This includes Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0103] In some embodiments, epilepsy or epileptic syndrome is hereditary epilepsy or hereditary epileptic syndrome. In some embodiments, epilepsy or epileptic syndrome includes epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infant epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, infantile malignant shift-focus partial seizures, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0104] In some embodiments, the method described herein involves administering the formulation described herein to the patient with epilepsy or epileptic syndrome (e.g., epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infant epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile convulsions, benign familial neoplasia) before administration of the formulation described herein. This further includes identifying subjects with live-birth-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, infantile malignant shift-focus partial seizures, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0105] In one embodiment, the present invention relates to epilepsy or epileptic syndromes (e.g., epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infant epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation) A method for treating (sexual epilepsy, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, infantile malignant shift-focus partial seizures, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy), characterized by a method comprising administering the formulation described herein to a subject in need of such treatment.

[0106] The formulations of the present invention (e.g., dosage forms containing compound 1, compositions within the dosage forms) also target 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, IER3IP 1, 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 It may also be used to treat epilepsy or epileptic syndromes (epileptic encephalopathy) with mutations in one or more of the following: SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

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

[0108] The formulations of the present invention also target HNRNPU, CACNA1A, CASK, FOXG1, GNB1, GPHN, IQSEC2, MBD5, MECP2, PIGA, PURA, SLC6A8, SLC9A6, TSC1, TSC2, UBE3A, WDR45, ZEB2, SLC1A2, GRIN2D, DYRK1A, PURA, WDR45, HNRNPU, SMC1A, FOXG1, ARID1B, ASXL3, KCNH1, GABRB2, NEXMIF, MECP2, SNAP25, COL4A3BP, GABRA1, GABRA2, GABRA3, GABR A4, GABRA5, GABRA6, GABRB1, GABRB2, GABRD, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, ABAT, ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ANK2, ANK3, DISC1, DLC1, DLC2, DNAI1, FGF13, GABARAP, GABARAPL1, GABARAPL2, GABBR1, GAD1, GAD2, GLS, GLS2, GLUL, GNAI 1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GPHN, HAP1, KCNB2, KCNC 2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, PRKACB, PRKACG, PRKCA, PRKCB, PRKCG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5, SLC6A11, SLC6A13, SRC, TRAK1, TRAK2, CHRNA1, CHRNA10, CHR NA3, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB3, CHRNB4, CHRND, CHRNE, CHRNG, GRIA1, GRIA2, GRIA3, GRIA4, GRIK1, GRIK2, GRIK3, GRIK4, GRIK5,GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRID1, GRID2, SCN10A, SCN11A, SCN2B, SCN3B, SCN4A, SCN4B, SCN5A, SCN7A, CACNA1A, CA CNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CA, CNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, KCNA1, KCNA10, KCNA3, KCNA4, KCNA5, KCNA6, KCNA7, KCNAB1, KCNAB2, KCN AB3, KCNB2, KCNC2, KCNC3, KCNC4, KCND1, KCND2, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNE4, KCNF1, KCNG1, KCNG2, K It may also be used to treat epilepsy or epileptic syndromes (e.g., epileptic encephalopathy) that have mutations in one or more of the following: CNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4, KCNH5, KCNH6, KCNH7, KCNH8, KCNQ1, KCNQ5, KCNQ4, KCNRG, KCNS1, KCNS2, KCNS3, KCNV1, KCNV2, HCN2, HCN3, and HCN4.

[0109] In some embodiments, the method described herein involves administering HNRNPU, CACNA1A, CASK, FOXG1, GNB1, GPHN, IQSEC2, MBD5, MECP2, PIGA, PURA, SLC6A8, SLC9A6, TSC1, TSC2, UBE3A, WDR45, ZEB2, SLC1A2, GRIN2D, DYRK1A, PURA, WDR45, HNRNPU, SMC1A, FOXG1, ARID1B, ASXL3, KCNH1, GABRB2, NEXMIF, MECP2, SNAP25, COL4A before administering the formulation described herein. 3BP, GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRD, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, ABAT, A DCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ANK2, ANK3, DISC1, DLC1, DLC2, DNAI1, FGF13, GABARAP, GABARAPL1, GABARAPL2, GABBR1 , GAD1, GAD2, GLS, GLS2, GLUL, GNAI1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GN GT1, GNGT2, GPHN, HAP1, KCNB2, KCNC2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, PRKACB, PRKAC G, PRKCA, PRKCB, PRKCG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5, SLC6A11, SLC6A13, SRC, TRAK1, TRAK2, CHRNA1, CHRNA10, CHRNA3, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB3, CHRNB4, CHRND, CHRNE, CHRNG, GRIA1, GRIA2, GRIA3, GRIA4,GRIK1, GRIK2, GRIK3, GRIK4, GRIK5, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRID1, GRID2, SCN10A, SCN11A, SCN2B, SCN3B, SCN4A, SCN4B, SCN5A, SCN7A, CACNA1A, CACNA1B, CACN A1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, KCNA1, KCNA10, KCNA 3. Mutation in one or more of the following: KCNA4, KCNA5, KCNA6, KCNA7, KCNAB1, KCNAB2, KCNAB3, KCNB2, KCNC2, KCNC3, KCNC4, KCND1, KCND2, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNE4, KCNF1, KCNG1, KCNG2, KCNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4, KCNH5, KCNH6, KCNH7, KCNH8, KCNQ1, KCNQ5, KCNQ4, KCNRG, KCNS1, KCNS2, KCNS3, KCNV1, KCNV2, HCN2, HCN3, and HCN4, This further includes identifying the object possessing it.

[0110] Neurodevelopmental disorders The formulations described herein (e.g., dosage forms containing Compound 1, compositions in dosage forms) may be useful for the treatment of neurodevelopmental disorders. In some embodiments, the neurodevelopmental disorders include autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palothocardiofacial syndrome, Smith-Lemle-Oppitz syndrome, or neurodevelopmental disorders with epilepsy. In some embodiments, the methods described herein further include identifying subjects having 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, palothocardiofacial syndrome, Smith-Lemle-Oppitz syndrome, or neurodevelopmental disorders with epilepsy) before administering the formulations described herein.

[0111] In one embodiment, the present invention relates to a method for 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, palatocardiafacial syndrome, Smith-Lemle-Oppitz syndrome, or neurodevelopmental disorder with epilepsy), characterized by a method comprising administering a formulation described herein (e.g., a dosage form containing compound 1, a composition in the dosage form) to a subject in need of such treatment.

[0112] pain The formulations described herein (e.g., dosage forms containing Compound 1, compositions in the dosage forms) may be useful for the treatment of pain. In some embodiments, the pain includes neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or related headache disorders. In some embodiments, the methods described herein further include identifying a subject having pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or related headache disorders) before administering the formulations described herein (e.g., dosage forms containing Compound 1, compositions in the dosage forms).

[0113] In one embodiment, the present invention relates to a method for treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or related headache disorders), characterized by a method comprising administering a formulation described herein (e.g., a dosage form containing compound 1, a composition in the dosage form) to a subject in need of such treatment.

[0114] Neuromuscular disorders The formulations described herein (e.g., dosage forms containing Compound 1, compositions in the dosage forms) may be useful for the treatment of neuromuscular disorders. In some embodiments, the neuromuscular disorders include amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutations. In some embodiments, the methods described herein further include identifying subjects having a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutations) before administering the formulations described herein.

[0115] In one embodiment, the present invention relates to neuromuscular disorders (e.g., amyotrophic lateral sclerosis, multiple sclerosis) A method for treating myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutation, characterized by a method comprising administering a formulation described herein (e.g., a dosage form containing compound 1, a composition in the dosage form) to a subject in need of such treatment.

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

[0117] In some embodiments, the formulations provided herein (e.g., dosage forms containing compound 1, compositions in dosage forms) may be used for the treatment of diseases affecting the neuromuscular system that cause itching, seizures, or paralysis, or for the treatment of diabetes or decreased insulin sensitivity, as well as for diabetes-related conditions such as diabetic peripheral neuropathy. In some embodiments, the disclosed methods include administering the pharmaceutical composition.

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

[0119] Oncology In another aspect, the Disclosure provides a method for treating cancer, the method comprising administering a dosage form or composition contained in a dosage form disclosed in the Disclosure to a subject in need of such treatment.

[0120] Trigeminal autonomic headache The compounds, dosage forms, and compositions described herein (e.g., Compound 1, dosage forms or compositions comprising Compound 1) are useful for the treatment of trigeminal autonomic headache (TAC). TAC is a group of primary headaches characterized by unilateral pain, relatively short duration of symptoms, and associated ipsitemporal autonomic symptoms. TAC may include cluster headache (CH), paroxysmal hemigraine (PH), persistent hemigraine (HC), short-duration persistent unilateral neuralgia-like headache attacks with conjunctival hyperemia and lacrimation (SUNCT), short-duration persistent unilateral neuralgia-like headache attacks with cranial autonomic symptoms (SUNA), and long-duration persistent autonomic symptoms with hemigraine (LASH). Despite their common elements, trigeminal autonomic headaches differ, for example, in attack duration and frequency, and in response to treatment.

[0121] In some embodiments, the present invention provides methods for treating PH, HC, SUNCT, SUNA, and / or LASH using the dosage forms described herein. In some embodiments, the present invention provides methods for treating SUNCT using the compounds, dosage forms, or compositions described herein (e.g., Compound 1, a dosage form or composition comprising Compound 1). In some embodiments, the present invention provides methods for treating SUNA using the compounds, dosage forms, or compositions provided herein (e.g., Compound 1, a dosage form or composition comprising Compound 1). In another embodiment, the present invention provides methods for treating or preventing trigeminal autonomic headache (TAC) in subjects requiring treatment or prevention. The provided method involves administering a therapeutically effective dose of one of the compounds, dosage forms, or compositions disclosed herein (e.g., Compound 1, a dosage form or composition comprising Compound 1) to a target.

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

[0123] In some embodiments, TAC is selected from the group consisting of paroxysmal hemiparoxysmal headache, persistent hemiparoxysmal headache, short-duration persistent hemineuralgia-like headache (SUNCT) with conjunctival congestion and lacrimation, short-duration persistent hemineuralgia-like headache (SUNA) with autonomic symptoms in the head, and prolonged persistent autonomic symptoms with hemiparoxysmal headache.

[0124] In other embodiments, TAC is a short-duration, persistent, unilateral neuralgia-like headache attack.

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

[0126] In other embodiments, the subject has an insufficient response to at least one drug used to treat TAC.

[0127] Migraine The compounds, dosage forms, and compositions described herein (e.g., Compound 1, dosage forms or compositions comprising Compound 1) are useful for the treatment of migraine. Migraine is a primary headache disorder characterized by moderate to severe recurrent headaches. As described herein, migraine may be aura-free migraine, aura-present migraine, hemiplegic migraine, familial hemiplegic migraine (FHM), familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 3 (FHM3), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM).

[0128] In some embodiments, the present invention provides 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, dosage form or composition containing 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 composition (e.g., compound 1, dosage form or composition containing 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 composition (e.g., compound 1, a dosage form or composition comprising compound 1).

[0129] In another embodiment, the Specified provides a method for treating or preventing migraine in a subject requiring treatment or prevention of migraine, comprising administering a therapeutically effective amount of one of the compounds, dosage forms, or compositions disclosed herein (e.g., Compound 1, a dosage form or composition comprising Compound 1) to the subject.

[0130] In another aspect, the present invention provides a method for treating or preventing migraines in a subject requiring treatment or prevention, comprising administering a therapeutically effective amount of compound 1, for example, 2.5 mg to 90 mg of compound 1, to the subject.

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

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

[0133] In another embodiment, the present invention provides a method for treating or preventing cortical spreading depression (CSD) in a subject requiring treatment or prevention, comprising administering a therapeutically effective amount of one of the compounds, dosage forms, or compositions disclosed herein (e.g., Compound 1, a dosage form or composition comprising Compound 1) to the subject.

[0134] The present invention provides a method for treating or preventing cortical spreading depression (CSD) in subjects requiring treatment or prevention, comprising administering a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1, to the subject.

[0135] Neurological disorders The compounds, dosage forms, and compositions described herein (e.g., Compound 1, dosage forms or compositions comprising Compound 1) are useful for the treatment of cranial nerve disorders. Nerve disorders are diseases of nerve damage that affect the ability to feel and move. When nerves in the brain or brainstem are affected, it is called a cranial nerve disorder. Cranial nerves are nerves that originate directly from the brain or brainstem and often affect areas such as the face and eyes. Cranial nerve disorders include Bell's palsy, microvascular cranial nerve palsy, 3rd nerve palsy, 4th nerve palsy, and 6th nerve palsy. When several different cranial nerves are affected, it is called multiple cranial nerve disorders (MCNs).

[0136] Furthermore, this specification provides a method for treating or preventing cranial nerve disorders or polyneuropathy in subjects requiring treatment or prevention of such disorders, comprising administering a therapeutically effective amount of a compound, dosage form, or composition described herein (e.g., Compound 1, a dosage form or composition containing Compound 1) to the subject.

[0137] In another embodiment, the Specified Publicly Provided Methods for Treating or Preventing a Subject Requiring Treatment or Prevention of a Cranial Neuropathy or Polyneuropathy, comprising administering a therapeutically effective amount of Compound 1, for example, about 2.5 mg to about 90 mg of Compound 1, to the subject.

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

[0139] Combination therapy The formulations described herein (e.g., dosage forms or compositions comprising Compound 1) may be administered in combination with other agents or therapies used, for example, to modulate sodium ion channels (e.g., delayed sodium (INaL) currents). Subjects to whom the formulations disclosed herein should be administered may have diseases, disorders, conditions, or symptoms thereof that would benefit from treatment with other agents or therapies. These diseases or conditions may be related to epilepsy or epileptic syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders.

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

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

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

[0143] By administering the sodium channel blocker of the present invention simultaneously with therapeutic agents suitable for treating cardiovascular-related conditions, it becomes possible to enhance the standard treatment the patient is currently receiving.

[0144] Antiangin medication Antianginal drugs include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the amount of oxygen the heart needs by reducing the workload on the heart, resulting in a lower heart rate and less vigorous contractions. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trendate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

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

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

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

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

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

[0150] Cardiac glycosides are compounds that increase the contractile force of the heart. These compounds enhance the heart's pumping capacity and improve irregular heart rate. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

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

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

[0153] Thrombolytic drugs work by breaking down existing blood clots. An example of a thrombolytic drug is Strep. Examples include tokinase, urokinase, and tenecteplase (TNK), as well as tissue plasminogen activator (t-PA).

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

[0155] Considering the synergistic effects of the recently discovered sodium channel blocker lanolazine, amioarone, and doronedarone, the combination of amiodarone and doronedarone is particularly interesting.

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

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

[0158] In this invention, patients presenting with acute coronary artery disease events often suffer from secondary medical conditions such as metabolic disorders, pulmonary disorders, peripheral vascular disorders, or gastrointestinal disorders, one or more of which are present. These patients may benefit from combination therapy, which includes administering lanolazine in combination with at least one therapeutic agent.

[0159] Combination therapy for lung injury Lung disorders refer 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.

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

[0161] Combination therapy for dysphagia Examples of metabolic disorders include, but are not limited to, diabetes mellitus, including type 1 and type 2 diabetes, metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0162] Examples of medications used to treat metabolic disorders include antihypertensives and lipid-lowering drugs, as described in the "Combination Therapy with Cardiovascular Agents" section above. Additional medications used to treat metabolic disorders include insulin, sulfonylurea, biguanides, alpha-glucosidase inhibitors, and incretin mimetic compounds.

[0163] 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, and include, for example, peripheral artery disease (PAD), a condition that occurs when the arteries that supply blood to the internal organs, arms, and legs are completely or partially blocked as a result of atherosclerosis.

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

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

[0166] Combination therapy with antibiotics, analgesics, antidepressants, and anti-anxiety medications. Patients presenting with acute coronary artery disease events may benefit from the administration of lanolazine in combination with antibiotics, analgesics, antidepressants, and anxiolytics.

[0167] antibiotics Antibiotics are therapeutic drugs that kill or stop the growth of microorganisms, including both bacteria and fungi. Examples of antibiotics include penicillin (amoxicillin), cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cefradin (Velosef), cefaclor (Ceclor), and cefuroxime axel (cefuroxime). Examples include β-lactam antibiotics such as cephalosporins, carbapenems, and monobactams, including axtel (Ceftin), cefprodil (Cefzil), loracarbef, cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), and ceftriaxone (Rocephin); 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, streptogramin, and polymyxin; lincosamides such as clindamycin; oxazolidinoees such as linezolid; and sulfonamides such as sulfisoxazole.

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

[0169] Antidepressants and anti-anxiety drugs Antidepressants and anxiolytics include medications used to treat anxiety disorders and depression, as well as medications used as sedatives and tranquilizers. Examples of antidepressants and anxiolytics include benzodiazepines (e.g., diazepam, lorazepam, and midazolam), benzodiazepines, barbiturates, glutethimide, chloral hydrate, meprobamate, sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan), and venlafaxine (Effexor). Examples include XR (Efexor), citalopram (Celexa, Cipramil, Talohexane), paroxetine (Paxil, Seroxat, Aropax), trazodone (Desyrel), amitriptyline (Elavil), and bupropion (Wellbutrin, Zyban). Antidepressants and anxiolytics may include neurostimulant steroids and ketamine, as well as related NMDA receptor antagonists.

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

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

[0172] Preparation method This specification provides methods for preparing compounds useful for preventing and / or treating diseases, disorders, or conditions described herein, such as diseases, disorders, or conditions related to abnormal function of sodium ion channels, such as abnormal delayed sodium current (INaL).

[0173] In one embodiment, the present disclosure relates to a compound of formula 1, [ka] or a method for preparing a pharmaceutically acceptable salt thereof, wherein the method is (i) A step of providing a compound of formula (II) by contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine, [ka] (ii) A step of providing a compound of formula (III) by contacting a compound of formula (II) with a palladium catalyst and bis(pinacolate)diborone, [ka] (iii) A step of providing a compound of formula (IV) by contacting a compound of formula (III) with a palladium catalyst and 2-bromo-5-chloropyrazine, [ka] (iv) By contacting the compound of formula (IV) with hydrazine, the compound of formula (V) is obtained. The steps of providing goods, [ka] (v) A step of providing a compound of formula (VI) by contacting a compound of formula (V) with 2-bromo-2,2-difluoroacetyl chloride, [ka] (vi) A step of providing a compound of formula (VII) by contacting a compound of formula (VI) with an acid, [ka] (vii) A method is provided comprising the step of providing compound 1 or a pharmaceutically acceptable salt thereof by contacting a compound of formula (VII) with a silver catalyst and ethanol.

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

[0175] In another aspect, this disclosure relates to compound 1, [ka] or a method for preparing a pharmaceutically acceptable salt thereof, wherein compound 1 or its pharmaceutically acceptable salt is of formula (VII): [ka] The present invention provides a method, which involves contacting a compound with a silver catalyst and ethanol.

[0176] In some embodiments, the compound of formula (VII) is formula (VI): [ka] The compound is provided by contacting it with an acid.

[0177] In other embodiments, the compound of formula (VI) is formula (V): [ka] The compound is provided by contacting it with 2-bromo-2,2-difluoroacetyl chloride.

[0178] In certain embodiments, the compound of formula (V) is formula (IV): [ka] The compound is provided by contacting it with hydrazine.

[0179] In some embodiments, the compound of formula (IV) is formula (III): [ka] The compound is provided by contacting it with a palladium catalyst and 2-bromo-5-chloropyrazine.

[0180] In other embodiments, the compound of formula (III) is formula (II): [ka] The compound is provided by contacting it with a palladium catalyst and bis(pinacolate)diboron.

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

[0182] Examples The following representative examples are intended to illustrate the present invention and are not intended to limit the scope of the invention, nor should they be construed as such. [Table 1] TIFF2026086664000026.tif21170

[0183] Example 1. Preparation and characterization of pulverized compound 1 Compound 1 was ground by manual or jet grinding to reduce its particle size. For manual grinding, compound 1 was weighed into a ceramic motor and gently ground for approximately 5 minutes. The particle size distribution (PSD) of compound 1 showed D90 = 77.82 μm and D90 = 28.27 μm before and after manual grinding. The PSD obtained by the dry method was measured by Sympatec The analysis was performed using a HELOS particle size analyzer, with the dispersion system and pressure set to RODOS and 0.5 bar, respectively. [Table 2]

[0184] In the case of jet pulverization, compound 1 was pulverized by jet pulverization with a yield of approximately 90%. The particle size of the jet-pulverized material was reduced to a range of 4.7–13.5 μm (D90). [Table 3]

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

[0186] For compound 1 before and after jet pulverization, proton NMR ( 1 H-NMR, fluorine NMR ( 19 1F-NMR and LC-MS analysis were also performed. Both the NMR and LC-MS results were used to determine the chemical or structural properties of compound 1 obtained by jet pulverization. This indicates that no significant changes were observed.

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

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

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

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

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

[0192] 4) Prototype 3: 40% Transcutol HP / 10% Vitamin ETPGS / 50% Water 600 μL of PEG400 was added to a 4 mL glass vial along with 3 mg of compound 1, mixed together using a vortex mixer, and sonicated for 5 minutes. Next, 150 μL of Cremophor RH40 was added to the vial, mixed together using a vortex mixer, and sonicated for 5 minutes. Then, 750 μL of water was added to the vial, mixed together using a vortex mixer, and sonicated for 5 minutes. The compound was completely dissolved (2 mg / mL).

[0193] 5) Prototype 4: 36% Cremophore RH40 + 45% Capmul MCM C8 + 9% Triethyl citrate + 10% Ethanol Cremophore RH40, Capmul MCM C8, triethyl citrate, and ethanol were added together by weight in a glass container and mixed to form a solution mixture. Then, increasing amounts of compound 1 were added to the mixture and vortexed and sonicated to form a clear solution. Additional compound 1 was added while vortexing and sonicating until compound 1 was no longer soluble. The maximum solubility obtained was 25-50 mg / It was visually determined to be mL.

[0194] 6) Prototype 5: 40% Capryol 90 + 20% Labrasol + 40% Transcutol HP Capryol 90, Labrasol, and Transcutol HP were added together by volume in a glass container and mixed to form a solution mixture. Then, increasing amounts of compound 1 were added to the mixture, and the mixture was vortexed and sonicated to form a clear solution. Additional compound 1 was added while vortexing and sonicating until compound 1 was no longer soluble. The maximum solubility obtained was visually determined to be 60–80 mg / mL.

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

[0196] For the stability and purity tests of Compound 1, a high-performance liquid chromatography (HPLC) method was developed. The HPLC method used for the chemical stability and purity tests was as follows. [Table 5] [Table 6]

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

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

[0199] Suspension formulation To prepare the suspension formulation 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 Vortex and stirred at room temperature overnight (24 hours). The stability of the suspension formulation was measured by quantifying the purity of Compound 1 using high-performance liquid chromatography (HPLC). The suspension remained a homogeneous suspension. Table 6 summarizes the stability results.

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

Table 8

Table 9

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

[0202] To prepare the suspension, the required amount of milled Compound 1 is weighed into a glass container and the corresponding volume of vehicle is added. Using an overhead mixer at the final concentration target, the compound is completely dispersed into a homogeneous suspension. Concentrations were prepared at 0.1 mg / mL and 10 mg / mL. The suspension product was physically evaluated for appearance, concentration, purity, and PSD.

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

Table 10

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

[0205] Nine ASD formulations were tested for kinetic solubility in FaSSIF at a concentration of 2 mg / mL. The experiment was conducted at 37°C and a speed of 450 rpm. At each time point, 0.5 mL of the mixture was taken out and centrifuged before running ULC (the level of compound 1 was determined using the shortened runtime version of the HPLC method described). The results are shown in Table 12. Improved solubility was observed for most polymers, particularly Eudragit EPO. [Table 14]

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

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

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

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

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

[0211] The following conditions were used for the elution method. [Table 18]

[0212] For elution analysis, the compound level in the elution medium was quantified using HPLC. The same HPLC method was used for both the elution test and the content uniformity test. The HPLC method used is as follows: [Table 19]

[0213] The dissolution results are shown in Figure 2. At dose intensities of 2.5 mg and 10 mg, the release rates for the two dose intensities were 29.76% and 17.64%, respectively.

[0214] The ASD-3 prototype was also evaluated in a pharmacokinetic (PK) study in cynomolgus monkeys using a crossover study design. The collected ASD-3 spray-dried powder was manually weighed directly into size #4 hard gelatin capsules using an analytical balance. Three male monkeys were orally administered 0.5 mg per kg of body weight under fasting conditions, and plasma samples were analyzed for compound level 1.

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

[0216] The pulverized compound 1 and the filler (MCC or starch) were weighed separately and blended for 15 minutes to obtain a homogeneous mixture. The required amount of magnesium stearate was added and blended together. The blend was manually filled into appropriately sized hard gelatin capsules. The samples were then kept stable under various conditions and analyzed for the appearance of the assay at various time points.

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

[0218] Blends 3 and 4 (1:1 blend) 5 g of pulverized compound 1 and 5 g of MCC or starch were weighed into a container. The two components were mixed using a Turbula at a speed of 36 rpm for approximately 15 minutes to obtain a homogeneous phase. 0.2 g of MgSt was added and mixed for a further 3 minutes to obtain homogeneous blend 1 (Table 17). Dose uniformity was evaluated by measuring a 10-capsule assay (Tables 20 and 21). [Table 21]

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

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

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

[0222] The following conditions were used for the elution method. [Table 30]

[0223] The results are shown in Figure 3, where 50.3% of the 1 mg dose-intensity capsules were released after 120 minutes, and 20.5% of the 10 mg dose-intensity capsules were released after 120 minutes.

[0224] To evaluate the effect of adding a surfactant to the 1:10 MCC capsule blend (Blend 1), further prototype blend capsule formulations were prepared. For evaluation in stability tests (Table 21.3), crossover PK tests, and dissolution tests, a 1:10 compound 1:MCC (25 mg blend and 0.5 mg SLS) containing 2% SLS was manually filled into size #4 hard gelatin capsules (the dose level was 2.5 mg of active ingredient per capsule). [Table 31]

[0225] Three male monkeys were orally administered 0.5 mg per kg of body weight while fasted, and plasma samples were analyzed for compound 1 levels. The levels of compound 1 in the obtained plasma did not show a significant increase with exposure to the MCC blend capsule containing the surfactant (AUC[0-inf] = 1,004 ng-hours / mL) compared to the case without the surfactant (area under the curve from 0 hours to infinity, AUC[0-inf] = 994 ng-hours / mL).

[0226] Blend 1 MCC capsules, both containing and without the surfactant, were also evaluated in in vitro dissolution tests at a dose intensity of 2.5 mg of compound 1.

[0227] The following conditions were used for the elution method. [Table 32]

[0228] The dissolution results are shown in Figure 4. When 2% SDS was added to the formulation, the in vitro dissolution and release significantly increased, from 38% release after 120 minutes with Poloxamer 188 to 54% release after 120 minutes with SLS.

[0229] Table 22 presents other exemplary formulations of the blend capsules (prototypes 1-12). [Table 33]

[0230] Table 23 shows examples of excipients that may be used in the preparation of the formulations disclosed in this application. [Table 34] TIFF2026086664000060.tif121170

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

[0232] Regarding the Cmax values ​​in Table 24, A represents values ​​greater than 50 ng / mL and a maximum of 150 ng / mL, B represents values ​​greater than 150 ng / mL and a maximum of 300 ng / mL, C represents values ​​greater than 300 mg / mL and a maximum of 600 mg / mL, and D represents values ​​greater than 600 ng / mL and a maximum of 900 ng / mL.

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

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

[0235] Objectives and evaluation criteria: [Table 36] [Table 37] [Table 38]

[0236] Based on new safety and PK data from Part A, the SRC may select the starting dose for Part B before completion of all dose-level cohorts in Part A. Part C may be initiated after the last SAD cohort. Parts A and B are double-blinded, including participants and investigators, while the sponsor is not blinded to facilitate safety review. Each part consists of three periods: screening, intervention, and safety follow-up.

[0237] Screening / Baseline Period The screening period for all three parts is a maximum of 27 days (-28th day to -2nd day). That is the case.

[0238] Intervention period Following continuous eligibility checks, participants check in to the clinic on day -1 (the day before investigational drug administration) for evaluation. Participants remain in the unit from baseline (day -1) until discharge (day 6 of Part A, day 12 of Part B, and day 13 of Part C).

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

[0240] In each dose level cohort, administration was initiated with two sentinel participants, one of whom was randomized to receive compound 1 and the other to receive placebo. Safety and tolerability for each sentinel participant were monitored until day 6 and reviewed before administration to the remaining participants in each cohort.

[0241] The cohorts will be administered in an escalating manner. After each dose cohort in Part A has completed administration, blinded cumulative safety data and available blinded PK data collected up to day 6 will be reviewed by the Safety Review Board (SRC) to determine the safety and tolerability of the investigational drug.

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

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

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

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

[0246] In each dose cohort of Part B, after the completion of investigational drug administration, the SRC will review blinded safety data (including safety assessments conducted on day 9) and available PK data, following the same procedure as in Part A, to determine the safety and tolerability of the investigational drug.

[0247] EEG to evaluate the effect of compound 1 on auditory-induced responses may be performed in one or more cohorts determined by the sponsor based on safety and PK profiles.

[0248] Part C Part C can be initiated once safety and PK have been adequately assessed in the final cohort of Part A. Up to 16 participants will receive two doses of compound 1, one after fasting for at least 10 hours and the other after a high-fat, high-calorie meal in a randomized crossover design, with a 7-day washout period. Based on the half-lives observed in Part A, an additional washout of up to 3 days may be added between the fasting and feeding doses.

[0249] The dose used in Part C shall not exceed the dose used in Part A and shall be approved by the SRC based on the safety and PK data obtained. Sentinel administration may be used in Part C if deemed appropriate by the SRC. Part C is not blinded.

[0250] Safety assessment and monitoring Safety and tolerability assessments include vital signs, 12-lead ECG, physical examination, clinical laboratory tests, and the C-SSRS outlined in SoAs.

[0251] Number of participants: ● Part A: Up to 72 people are scheduled to receive either compound 1 or a placebo. ● Part B: Up to 32 people are scheduled to receive either compound 1 or a placebo. ● Part C: Compound 1 is scheduled to be administered to a maximum of 16 people.

[0252] Exclusion criteria During screening, participants who meet any of the following criteria will be excluded from this clinical trial: ●ECG abnormalities, including a QT interval >450 milliseconds using the Fridericia correction method (QTcF), confirmed by a single repeated test as needed at the time of screening or on day 1, and evaluated as clinically significant by the principal investigator. ●Two weeks prior to the first dose of the investigational drug or five times the terminal half-life of the drug, whichever is longer. Use of multivitamins, as well as nutritional and herbal supplements, during the clinical trial period, in systemic prescription drugs or over-the-counter (OTC) drugs.

[0253] Test product, reference therapy, administration: ● Part A: Capsules of Compound 1 or corresponding placebo are administered orally. ● Part B: Capsules of Compound 1 or corresponding placebo are administered orally. ● Part C: Capsules of Compound 1 are administered orally.

[0254] Statistical methods: PK analysis: For the determination of the plasma and urine concentrations of Compound 1, validated biological analytical methods are utilized. Plasma and urine concentrations are summarized by dose group / condition and time point using descriptive statistics. In addition to the descriptive statistics specified under the general conditions described above, plasma concentrations are also summarized using the number and percentage of concentrations below the quantification level (BLQ) and coefficient of variation (CV%).

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

[0256] Example 5. A randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and pharmacokinetics of single and multiple dose escalations of Compound 1 and the effects of food in healthy volunteers. This is a three-part clinical trial to evaluate the safety, tolerability, pharmacokinetics, and dietary effects of compound 1 in healthy volunteers aged 18–55 years. The trial consists of the following three parts: ● Part A is randomized, double-blind, and placebo-controlled. Part A is designed to investigate the safety, tolerability, and pharmacokinetics of a single escalating dose of Compound 1 ranging from 2.5 mg to 90 mg. ● Part B will be randomized, double-blind, and placebo-controlled. Part B is designed to investigate the safety, tolerability, and pharmacokinetics of multiple escalating doses of compound 1 (dosages selected based on the results from Part A). ● Part C is a randomized, open-label, crossover design to investigate the pharmacokinetics, safety, and tolerability of a single dose of Compound 1 (a dose selected based on the results from Part A) in fasted and fed states.

[0257] Objectives and evaluation criteria: [Table 41] [Table 42] [Table 43]

[0258] Based on new safety and PK data from Part A, the SRC may select the starting dose for Part B before completion of all dose-level cohorts in Part A. Part C may be initiated after the last SAD cohort. Parts A and B are double-blinded, including participants and investigators, while the sponsor is not blinded to facilitate safety review. Each part consists of three periods: screening, intervention, and safety follow-up.

[0259] After continuous eligibility checks, participants check in to the clinic on day -1 (the day before investigational drug administration) for evaluation. Participants will be monitored from baseline (day -1) until discharge (part Remain in the unit on day 6 of Part A, day 12 of Part B, and day 13 of Part C.

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

[0261] In each dose level cohort, administration was initiated with two sentinel participants, one of whom was randomized to receive compound 1 and the other to receive placebo. Safety and tolerability for each sentinel participant were monitored until day 6 and reviewed before administration to the remaining participants in each cohort.

[0262] The cohorts will be administered in an escalating manner. After each dose cohort in Part A has completed administration, blinded cumulative safety data and available blinded PK data collected up to day 6 will be reviewed by the Safety Review Board (SRC) to determine the safety and tolerability of the investigational drug.

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

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

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

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

[0267] In each dose cohort of Part B, after the completion of investigational drug administration, the SRC will review blinded safety data (including safety assessments conducted on day 9) and available PK data, following the same procedure as in Part A, to determine the safety and tolerability of the investigational drug.

[0268] EEG to evaluate the effect of compound 1 on auditory-induced responses may be performed in one or more cohorts determined by the sponsor based on safety and PK profiles.

[0269] Part C Part C can be initiated once safety and PK have been adequately assessed in the final cohort of Part A. Participants will receive two doses of compound 1, one after fasting for at least 10 hours and the other after consuming a high-fat, high-calorie meal in a randomized crossover design, with a 7-day washout period. Based on the half-lives observed in Part A, an additional washout of up to 3 days may be added between the fasting and feeding doses.

[0270] The dose used in Part C shall not exceed the dose used in Part A and shall be approved by the SRC based on the safety and PK data obtained. Sentinel administration may be used in Part C if deemed appropriate by the SRC. Part C is not blinded.

[0271] Safety assessment and monitoring Safety and tolerability assessments include vital signs, 12-lead ECG, physical examination, clinical tests, and C-SSRS.

[0272] Exclusion criteria During screening, participants who meet any of the following criteria will be excluded from this clinical trial: ●ECG abnormalities, including a QT interval >450 milliseconds using the Fridericia correction method (QTcF), confirmed by a single repeated test as needed at the time of screening or on day 1, and evaluated as clinically significant by the principal investigator. ● Use of systemic prescription or over-the-counter (OTC) medications, including multivitamins and nutritional and herbal supplements, during the two weeks prior to the first dose of the investigational drug or five times the drug's terminal half-life, whichever is longer, and during the trial period.

[0273] Test product, reference therapy, dosage: ● Part A: A capsule of compound 1 or the corresponding placebo is administered orally. ● Part B: A capsule of compound 1 or the corresponding placebo is administered orally. ● Part C: A capsule of compound 1 is administered orally.

[0274] Statistical methods: PK Analysis: Validated biological analytical methods (e.g., liquid chromatography-mass spectrometry (LC-MS)) are used to determine the plasma and urinary concentrations of compound 1. Plasma and urinary concentrations are summarized by dose group / condition and time point using descriptive statistics. (See above for general information.) In addition to descriptive statistics identified by the conditions, plasma concentrations are also summarized using the number and percentage of concentrations below the level of quantification (BLQ) and coefficient of variation (CV%).

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

[0276] result Preliminary analyses of the first four of the six planned cohorts in Part A of the trial indicate that compound 1 appears to be well tolerable at the tested dose. Reviewed safety data included adverse events, vital signs, ECG, C-SSRS, physical examination, and safety laboratory data. No serious, severe, or adverse events leading to discontinuation or termination of the trial were reported in the first three cohorts tested.

[0277] Based on preliminary data, exposure appears to increase proportionally with dose levels, with peak concentrations reached in 2–3 hours. The terminal elimination half-life averages 114 hours (approximately 4–5 days) across the entire group. 90% of steady-state individuals should be reached in about two weeks with once-daily administration.

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

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

[0280] Screening / Baseline Period The screening period will be, for example, 28 days (-28th day to -1st day). For participants discontinuing SUNCT or SUNA prophylactic medications (e.g., carbamazepine, lamotrigine), an optional washout period is permitted, for example, up to 14 days prior to screening.

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

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

[0283] On day 1, participants return to the clinic and are randomized to one of three treatment groups to receive their first dose of the investigational drug. Participants remain in the clinical setting under medical observation for at least, for example, 6 hours. Headache logs are completed via eDiary daily before administration (e.g., approximately 24 hours after the previous dose) and, for example, approximately 4 and 10 hours after administration. After the first dose, participants continue daily administration at home until day 21. Participants return to the clinic to complete evaluations, for example, on day 7 (±1 day), day 14 (±1 day), and day 21 (±1 day). At selected sites, intensive PK sample collection is taken at the clinic, for example, on day 1, day 7 (±1 day), day 14 (±1 day), and day 21 (±1 day).

[0284] Key safety measures include clinical laboratory evaluation, 12-lead ECG, C-SSRS, and vital signs. Key efficacy evaluations include headache logging via eDiary (see evaluation schedule for details). Blood samples are obtained to measure plasma concentrations of compound 1 using validated bioanalytical methods and may also be used for exploratory method development and / or metabolite characterization.

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

[0286] Adverse events and the use and procedures of concomitant medications are monitored from the time of informed consent until day 36 (±1 day). At that point, the participant is considered to have completed the clinical trial.

[0287] Selection / Exclusion Criteria Participants are, for example, women or men aged 18-65 years (inclusive) at the time of screening, with a history of chronic SUNCT and SUNA headaches that began before age 50 and lasted for, for example, more than one year, and who experience at least, for example, 100 episodes of SUNCT and SUNA headache over a 14-day period during the observation period of the clinical trial.

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

[0289] Dosage / route / regime The dosage is determined by PK data. The route of administration is oral.

[0290] statistical methods Safety, tolerability, PK, and efficacy variables are summarized using descriptive statistics. Descriptive summaries of categorical variables include counts and percentages. Descriptive summaries of continuous variables include the number of participants (n), mean, standard deviation (SD), median, minimum, and maximum. Where appropriate, 95% confidence intervals (CIs) may be reported. Summaries are not required. It will be presented as needed, at each stage.

[0291] Standard PK parameters are estimated using a non-compartmental method based on concentration-time data. These parameters, where possible, include Cmax, tmax, and AUC0-tau, and exploratory analyses can be performed to examine the relationship between PK and efficacy parameters for the PK analysis population.

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

[0293] Stanford Pain Scale The Stanford Pain Scale is a comparative pain scale with a corresponding explanation for each scale value ranging from 0 (no pain) to 10 (unspeakable pain). Pain rated between 0 and 3 is considered "mild," pain rated between 4 and 6 is considered "moderate," and pain rated between 7 and 10 is considered "severe." The Stanford Pain Scale is completed by the participant.

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

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

[0296] Level of disability Participants' disability levels are measured by the participants themselves using the following goal achievement scale categories: 0 = no disability, 1 = mild, 2 = moderate, 3 = severe, 4 = unbearable.

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

[0298] activities of daily living Participants will be asked to assess changes in their ability to perform activities of daily living.

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

[0300] Synthesis of A2: To a stirred solution of 2,2,2-trifluoroethanol (5.67 g, 56.71 mmol) in 200 mL of THF at 0°C, NaH (60% in mineral oil, 2.26 g, 56.71 mmol) was added in small amounts. The reaction mixture was stirred for 15 minutes, 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 hours. The reaction mixture was cooled to 10°C and treated with ice water (100 mL). The mixture was extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silica gel using 2% ethyl acetate / PE to obtain the product (10.5 g, 38.1 mmol, yield 73%). LCMS: 273.9 (M+H) and 276.0 (M+2+H), Rt 2.53 min. Column: ZORBAX XDB C-18 (50 × 4.6 mm), 3.5 μm. Mobile phase: A: Water: 0.1% HCOOH in ACN (95:5), B: ACN, flow rate: 1.5 mL / min.

[0301] Synthesis of A3: Potassium acetate (2.15 g, 21.9 mmol) was added to a stirred solution of 5-bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine (3.0 g, 10.95 mmol) and bis(pinacolate)diborone (3.61 g, 14.23 mmol) in 1,4-dioxane (30.0 mL). Pd(dppf)Cl2 . DCM (0.89 g, 1.09 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 15% ethyl acetate / PE to obtain the product (2.0 g, 6.2 mmol, yield 56%). LCMS: 322.1 (M+H), Rt 2.97 min. Column: Atlantis dC18 (50 × 4.6 mm), 5 μm. Mobile phase: A: Water: 0.1% HCOOH in ACN (95:5), B: ACN, flow rate: 1.5 mL / min.

[0302] 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 L) and water (150 mL) was stirred under N2 at 35°C for 2 hours. After cooling to room temperature, water (300 mL) was added to the mixture, and the mixture was filtered through Celite. After separation, the organic phase was washed with brine (300 mL) and dried over anhydrous Na2SO4. The mixture was filtered and concentrated to obtain the crude product. The crude product was redissolved in EA / PE=1 / 3 (500 mL) and then filtered through a silica gel mat. The cake was washed with EA / PE=1 / 3 (500 mL). The combined organic phase was concentrated to obtain an oily residue. PE (500 mL) was slowly added to this oily residue to obtain some solid. The solid was collected and dried in an oven to obtain the product (100 g, 242.4 mmol, yield 58%) as a solid. LCMS R t = 1.28 min chromatography in 2.0 min, 10⁻⁸ AB, MS ESI C 11 H7ClF4N3O[M+H] + The calculated value for this is 308.0, and the measured value is 307.9.

[0303] Synthesis of A5: A mixture of 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (140 g, 339.36 mmol) and hydrazine hydrate (169.88 g, 3393.6 mmol) in MeCN (1.4 L) was stirred at 100°C for 16 hours. After cooling to room temperature, the mixture was poured into water (4.5 L). Some solid was observed and collected by filtration. The cake was washed with water (500 mL x 2). The solid was redissolved in RINKAN (3 L), washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (100 g, 329.8 mmol, yield 97%) as a solid. LCMS R t = 0.74 min chromatography at 1.5 min, 5-95AB, MS ESI C 11 H 10 F4N5O[M+H] + The calculated value for this is 304.1, and the measured value is 303.9.

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

[0305] Synthesis of A7: A solution of 2-bromo-2,2-difluoro-N'-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine-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) and extracted with ethyl acetate (2 L x 2). The combined organic phase was washed with brine (1 L x 2), dried over anhydrous sodium 2 SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0%~15%~30%) to obtain the product (80 g, 181.0 mmol, yield 55%) as an oil. 1 1H NMR (CDCl3, 400MHz) δ H =9.60(d,1H),8.55(d,1H),8.45(s,1H),8.09(dd,1H),4.93(q,2H).

[0306] Synthesis of Compound 1: A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (76 g, 171.9 mmol) and AgBF4 (66.93 g, 343.81 mmol) in ethanol (760 mL) was stirred at 60°C for 1 hour. The mixture was cooled to room temperature, then poured into saturated NaCl aqueous solution (1 L) and  (2 L). The mixture was filtered through Celite. After separation, the aqueous layer was extracted with  (500 mL x 2). The combined organic phases were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel ( in PE = 0%~30%~50%), and then polished with EtOH (50 mL) to obtain the product (44.45 g, 109.01 mmol, yield 63%) as a solid. 11H NMR (CDCl 3400MHz) δ H =9.52(d,1H),8.49(dd,2H),8.07(dd,1H),4.93(q,2H),4.37(q,2H),1.51(t,3H). LCMS R t = 1.25 min chromatography for 2.0 min, 10⁻⁸ AB, MS ESI C 15 H 12 F6N5O2[M+H] + The calculated value for this is 408.1, and the measured value is 408.0.

[0307] Even and range In the claims, articles such as “a,” “an,” and “the” may mean one or more unless otherwise indicated or evident from the context. A claim or statement containing “or” between one or more elements of a group is deemed satisfied if one, two or more, or all, of the elements of the group are present in, used in, or related to a given product or process, unless otherwise indicated or evident from the context. An invention includes an embodiment in which exactly one element of the group is present in, used in, or related to a given product or process. An invention includes an embodiment in which two or more, or all, elements of the group are present in, used in, or related to a given product or process.

[0308] Furthermore, the invention encompasses all variations, combinations, and permutations, and one or more limitations, elements, sections, and terms described from one or more of the enumerated claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. If elements are presented as a list, for example in Markush group form, each subgroup of elements is also disclosed, and any element may be removed from this group. In general, where an invention or aspect of an invention is considered to include certain elements and / or features, it should be understood that certain embodiments or aspects of the invention consist of, or essentially consist of, such elements and / or features. For the sake of brevity, those embodiments are not specifically described verbatim in this specification. It should also be noted that the terms “including” and “containing” are intended to be open and may allow for the inclusion of additional elements or steps. Where a scope is given, endpoints are included. Furthermore, unless otherwise indicated or is evident from the context and the understanding of those skilled in the art, any value expressed as a range may be considered, unless the context explicitly indicates otherwise, to any specific value or subrange within the range described in different embodiments of the invention, up to one-tenth of the lower limit unit of the range.

[0309] This application references various issued patents, published patent applications, scholarly articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any of the incorporated references and this specification, this specification shall prevail. In addition, any particular embodiment of the Invention within the scope of the prior art may be clearly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not clearly stated herein, as they are considered to be known to those skilled in the art. Any particular embodiment of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the prior art.

[0310] Those skilled in the art can use only ordinary experiments to determine many of the specific embodiments described herein. It will be possible to recognize or confirm the equivalents. The scope of the embodiments described herein is not intended to be limited to embodiments for carrying out the above invention, but rather as described in the appended claims. Those skilled in the art will understand that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims.

Claims

1. It is a dosage form, Compound 1 in amounts ranging from approximately 0.1 mg to approximately 500 mg (for example, approximately 0.5 mg to approximately 200 mg, approximately 1 mg to approximately 150 mg, approximately 10 mg to approximately 120 mg), A dosage form containing pharmaceutically acceptable excipients.

2. The dosage form according to claim 1, wherein the dosage form contains compound 1 in an amount of about 2.5 mg to about 150 mg (for example, about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, about 50 mg).

3. It is a dosage form, Multiple particles of compound 1, It contains pharmaceutically acceptable excipients, A dosage form in which the amount of multiple particles of compound 1 in the dosage form is about 0.1 mg to about 500 mg (for example, about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg).

4. The dosage form according to claim 3, wherein the plurality of particles of compound 1 in the dosage form are approximately 2.5 mg to approximately 150 mg (for example, approximately 10 mg to approximately 150 mg, approximately 20 mg to approximately 150 mg, approximately 70 mg to approximately 120 mg, approximately 30 mg to approximately 60 mg, approximately 100 mg, and approximately 50 mg).

5. The dosage form according to claim 3 or 4, wherein 10% of the plurality of particles of compound 1 have a particle size of less than about 1 μm.

6. The dosage form according to any one of claims 3 to 5, wherein 50% of the plurality of particles of compound 1 have a particle size of less than about 4 μm.

7. The dosage form according to claim 6, wherein 50% of the plurality of particles of compound 1 have a particle size of less than about 2 μm.

8. The dosage form according to any one of claims 3 to 7, wherein 90% of the plurality of particles of compound 1 have a particle size of less than about 30 μm (for example, less than about 15 μm).

9. The dosage form according to claim 8, wherein 90% of the plurality of particles of compound 1 have a particle size of less than about 5 μm.

10. The dosage form according to claim 9, wherein 10% of the plurality of particles of compound 1 have a particle size of less than about 1 μm, 50% of the plurality of particles of compound 1 have a particle size of less than about 4 μm, and 90% of the plurality of particles of compound 1 have a particle size of less than about 30 μm.

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

12. The dosage form according to any one of claims 1 to 11, wherein the dosage form is in solid form.

13. The dosage form according to any one of claims 1 to 12, wherein compound 1 is crystalline.

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

2.

15. The dosage form according to any one of claims 1 to 14, wherein the crystalline form exhibits an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.

2.

16. The dosage form according to any one of claims 1 to 15, wherein the crystalline form exhibits an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 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.

17. The dosage form according to any one of claims 1 to 16, wherein the crystalline form has substantially the same X-ray powder diffraction pattern as that shown in Figure 1.

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

19. The dosage form according to any one of claims 1 to 18, wherein the dosage form is in the form of a blend.

20. The dosage form according to claim 18 or 19, wherein the pharmaceutical excipient is a filler (for example, microcrystalline cellulose or starch).

21. The dosage form according to any one of claims 18 to 20, wherein the ratio of compound to filler is approximately 1:

1.

22. The dosage form according to any one of claims 18 to 20, wherein the ratio of the compound to the filler is about 1:

10.

23. The dosage form according to any one of claims 18 to 20, wherein the pharmaceutical excipient is a filler or a lubricant.

24. The aforementioned dosage form is Approximately 50% to 90% by weight of filler, A dosage form according to any one of claims 18 to 23, comprising 0% to about 5% by weight of a lubricant.

25. The aforementioned dosage form is Compound 1 in an amount of approximately 1% to approximately 50% by weight, Approximately 50% to 90% by weight of filler, A dosage form according to any one of claims 18 to 23, comprising 0% to about 4% by weight of a lubricant.

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

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

28. The aforementioned pharmaceutical excipients include co-solubilizers / co-solvents (e.g., polymers (e.g., PEG400)), emulsifiers (e.g., castor oil derivatives, e.g., Kolliphor RH40), surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), vitamin derivatives (e.g., Vitamin ETPGS)), and solvents (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcu)). The dosage form according to claim 27, selected from the group consisting of (tol HP).

29. The dosage form according to any one of claims 26 to 28, wherein the concentration of compound 1 is about 0.1 mg / mL to about 10 mg / mL.

30. The aforementioned dosage form is Approximately 35% to 45% by weight of filler (e.g., polymer (e.g., PEG400)), Approximately 5% to 15% by weight of an emulsifier (for example, a castor oil derivative (for example, Kolliphor RH40)) It contains approximately 40% to 60% by weight of water, The dosage form according to any one of claims 26 to 28, wherein the concentration of compound 1 is about 0.5 mg / mL or about 0.25 mg / mL.

31. The aforementioned dosage form is Approximately 55% to 60% by weight of an emulsifier (for example, a castor oil derivative (for example, Kolliphor RH40)), Approximately 15% to 20% by weight of surfactant (for example, glycerides (for example, Labrafil M2125 CS)), Approximately 5% to 10% by weight of propylene glycol, It contains approximately 15% to 20% by weight of ethanol, The dosage form according to any one of claims 26 to 28, wherein the concentration of compound 1 is about 5 mg / mL to about 10 mg / mL, or about 2.5 mg / mL to about 5 mg / mL.

32. The aforementioned dosage form is Approximately 65% ​​to 70% by weight of an emulsifier (for example, a castor oil derivative (for example, Kolliphor RH40)) Approximately 18% to approximately 23% by weight of surfactants (for example, glycerides (for example, Labrafil M2125 CS)), It contains approximately 7% to 12% by weight of propylene glycol, The dosage form according to any one of claims 26 to 28, wherein the concentration of compound 1 is about 1 mg / mL to about 10 mg / mL, or about 0.5 mg / mL to about 5 mg / mL.

33. The aforementioned dosage form is Approximately 35% to 45% by weight of diethylene glycol monoethyl ether (Transcutol HP), Approximately 5% to 15% by weight of surfactants (e.g., glycerides (e.g., vitamin derivatives (e.g., vitamin ETPGS))) It contains approximately 40% to 60% by weight of water, The dosage form according to any one of claims 26 to 28, wherein the concentration of compound 1 is about 1 mg / mL to about 5 mg / mL, or about 0.5 mg / mL to about 2.5 mg / mL.

34. The aforementioned dosage form is Approximately 30% to 40% by weight of an emulsifier (for example, a castor oil derivative (for example, Kolliphor RH40)) Approximately 40% to 50% by weight of surfactant (e.g., glycerides (e.g., Capmul MCM C8)), Approximately 5% to 15% by weight of a plasticizer (e.g., triethyl citrate), A dosage form according to any one of claims 26 to 28, comprising approximately 5% to approximately 15% by weight of a solvent (e.g., ethanol).

35. The aforementioned dosage form is Approximately 35% to 45% by weight of propylene glycol monocaprylate (e.g., Capryol 90), Approximately 15% to 25% by weight of glycerides (e.g., caprylocaproyl macrogol glyceride (e.g., Labrasol)) and A dosage form according to any one of claims 26 to 28, comprising approximately 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP).

34. The dosage form according to any one of claims 26 to 33, wherein the solution may be further diluted with a solvent (for example, water), and the concentration of the diluted solution is about 50% to about 90% of the concentration of the solution before dilution.

36. The dosage form according to any one of claims 1, 2, 11, and 26, wherein the dosage form is in the form of a suspension.

37. The dosage form according to claim 35, wherein the concentration of compound 1 is about 0.1 mg / mL, about 0.5 mg, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, or about 15 mg / mL.

38. The aforementioned pharmaceutical excipients Approximately 0.5% by weight of a filler (e.g., methylcellulose, e.g., 400 cP MC), Approximately 0.2% by weight of an emulsifier (e.g., Tween 80, e.g., Poloxamer) 188) The dosage form according to claim 36 or 37, comprising

39. The dosage form according to claim 38, wherein the pharmaceutical excipient further comprises about 1% by weight of a preservative solution (for example, a paraben solution).

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

41. The dosage form according to 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 according to claim 41, wherein the pharmaceutically active ingredient is a polymer (e.g., soluplus, Eudragit, and HPMC ASMF).

43. The dosage form according to any one of claims 1 to 42, wherein the dosage form is stable (e.g., chemically stable) for 7 days, 14 days, 21 days, 28 days, 1 month, 3 months, or 6 months at 25°C and 60% RH.

44. A composition in a dosage form, Compound 1 in amounts ranging from approximately 0.1 mg to approximately 500 mg (for example, approximately 0.5 mg to approximately 200 mg, approximately 1 mg to approximately 150 mg, approximately 10 mg to approximately 120 mg), A composition comprising a pharmaceutically acceptable excipient.

45. The composition according to claim 44, wherein the composition comprises about 2.5 mg to about 150 mg of compound 1 (for example, about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, about 50 mg).

46. A composition in a dosage form, Multiple particles of compound 1, It contains pharmaceutically acceptable excipients, A composition in which the amount of a plurality of particles of compound 1 in the composition is about 0.1 mg to about 500 mg (for example, about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg).

47. The composition according to claim 46, wherein the plurality of particles of compound 1 in the composition amount to about 2.5 mg to about 150 mg (for example, about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, about 50 mg).

48. The composition according to claim 46 or 47, wherein 10% of the plurality of particles of compound 1 have a particle size of less than about 1 μm.

49. The composition according to any one of claims 46 to 48, wherein 50% of the plurality of particles of compound 1 have a particle size of less than about 4 μm.

50. The composition according to claim 49, wherein 50% of the plurality of particles of compound 1 have a particle size of less than about 2 μm.

51. The composition according to any one of claims 46 to 50, wherein 90% of the plurality of particles of compound 1 have a particle size of less than about 30 μm (for example, less than about 15 μm).

52. The composition according to claim 51, wherein 90% of the plurality of particles of compound 1 have a particle size of less than about 5 μm.

53. The composition according to claim 52, wherein 10% of the plurality of particles of compound 1 have a particle size of less than about 1 μm, 50% of the plurality of particles of compound 1 have a particle size of less than about 4 μm, and 90% of the plurality of particles of compound 1 have a particle size of less than about 30 μm.

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

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

56. The composition according to any one of claims 44 to 55, wherein compound 1 is crystalline.

57. The composition according to any one of claims 44 to 56, wherein the crystalline form exhibits an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.

2.

58. The composition according to any one of claims 44 to 57, wherein the crystalline form exhibits an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.

2.

59. The composition according to any one of claims 44 to 58, wherein the crystalline form exhibits an X-ray powder diffraction pattern including peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 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.

60. The composition according to any one of claims 44 to 59, wherein the crystalline form has substantially the same X-ray powder diffraction pattern as shown in Figure 1.

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

62. The composition according to any one of claims 44 to 61, wherein the dosage form is in the form of a blend.

63. The composition according to claim 61 or 62, wherein the pharmaceutical excipient is a filler (for example, microcrystalline cellulose or starch).

64. The composition according to any one of claims 61 to 63, wherein the ratio of compound to filler is about 1:

1.

65. The composition according to any one of claims 61 to 63, wherein the ratio of the compound to the filler is about 1:

10.

66. The composition according to any one of claims 61 to 63, wherein the pharmaceutically acceptable excipient is a filler or a lubricant.

67. The composition form is Approximately 50% to 90% by weight of filler, A composition according to any one of claims 61 to 66, comprising 0% to about 5% by weight of a lubricant.

68. The composition is Compound 1 in an amount of approximately 1% to approximately 50% by weight, Approximately 50% to 90% by weight of filler, A composition according to any one of claims 61 to 67, comprising 0% to about 4% by weight of a lubricant.

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

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

71. The composition according to claim 70, wherein the pharmaceutically acceptable excipient is selected from the group consisting of cosolubilizers / cosolvents (e.g., polymers (e.g., PEG400)), emulsifiers (e.g., castor oil derivatives, e.g., Kolliphor RH40), surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), vitamin derivatives (e.g., Vitamin ETPGS)), and solvents (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)).

72. The composition according to any one of claims 69 to 71, wherein the concentration of compound 1 is about 0.1 mg / mL to about 10 mg / mL.

73. The composition is Approximately 35% to 45% by weight of filler (e.g., polymer (e.g., PEG400)) )and, Approximately 5% to 15% by weight of an emulsifier (for example, a castor oil derivative (for example, Kolliphor RH40)) It contains approximately 40% to 60% by weight of water, The composition according to any one of claims 69 to 71, wherein the concentration of compound 1 is about 0.5 mg / mL or about 0.25 mg / mL.

74. The composition is Approximately 55% to 60% by weight of an emulsifier (for example, a castor oil derivative (for example, Kolliphor RH40)), Approximately 15% to 20% by weight of surfactant (for example, glycerides (for example, Labrafil M2125 CS)), Approximately 5% to 10% by weight of propylene glycol, It contains approximately 15% to 20% by weight of ethanol, The composition according to any one of claims 69 to 71, wherein the concentration of compound 1 is about 5 mg / mL to about 10 mg / mL, or about 2.5 mg / mL to about 5 mg / mL.

75. The composition is Approximately 65% ​​to 70% by weight of an emulsifier (for example, a castor oil derivative (for example, Kolliphor RH40)) Approximately 18% to approximately 23% by weight of surfactants (for example, glycerides (for example, Labrafil M2125 CS)), Contains approximately 7% to 12% by weight of propylene glycol, The composition according to any one of claims 69 to 71, wherein the concentration of compound 1 is about 1 mg / mL to about 10 mg / mL, or about 0.5 mg / mL to about 5 mg / mL.

76. The composition is Approximately 35% to 45% by weight of diethylene glycol monoethyl ether (Transcutol HP), Approximately 5% to 15% by weight of surfactants (e.g., glycerides (e.g., vitamin derivatives (e.g., vitamin ETPGS))) It contains approximately 40% to 60% by weight of water, The composition according to any one of claims 69 to 71, wherein the concentration of compound 1 is about 1 mg / mL to about 5 mg / mL, or about 0.5 mg / mL to about 2.5 mg / mL.

77. The composition is Approximately 30% to 40% by weight of an emulsifier (for example, a castor oil derivative (for example, Kolliphor RH40)) Approximately 40% to 50% by weight of surfactant (e.g., glycerides (e.g., Capmul MCM C8)), Approximately 5% to 15% by weight of a plasticizer (e.g., triethyl citrate), A composition according to any one of claims 69 to 71, comprising about 5% to about 15% by weight of a solvent (for example, ethanol).

78. The composition is Approximately 35% to 45% by weight of propylene glycol monocaprylate (e.g., Capryol 90), Approximately 15% to 25% by weight of glycerides (e.g., caprylocaproyl macrogol glyceride (e.g., Labrasol)) and Approximately 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Tra A composition according to any one of claims 69 to 71, comprising nscutol HP.

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

80. The composition according to claim 79, wherein the concentration of compound 1 is about 0.1 mg / mL, about 0.5 mg, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, or about 15 mg / mL.

81. The aforementioned pharmaceutical excipients Approximately 0.5% by weight of a filler (e.g., methylcellulose, e.g., 400 cP MC), Approximately 0.2% by weight of an emulsifier (e.g., Tween 80, e.g., Poloxamer) The composition according to claim 79 or 80, comprising 188) and

82. The composition according to claim 81, wherein the pharmaceutical excipient further comprises about 1% by weight of a preservative solution (for example, a paraben solution).

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

84. The composition according to 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 according to claim 84, wherein the pharmaceutically active ingredient is a polymer (e.g., soluplus, Eudragit, and HPMC ASMF).

86. The composition according to any one of claims 44 to 85, wherein the composition is stable (e.g., chemically stable) for 7 days, 14 days, 21 days, 28 days, 1 month, 3 months, or 6 months at 25°C and 60% RH.

87. A method for treating a condition in a subject requiring treatment for a condition related to abnormal function of sodium ion channels, comprising administering to the subject a dosage form or composition according to any one of claims 1 to 86.

88. A method for treating a condition related to abnormal function of sodium ion channels in a subject requiring treatment, comprising administering compound 1 in an amount of about 2.5 mg to about 90 mg to the subject.

89. The method according to claim 87 or 88, wherein the condition is a neurological disorder or a mental disorder.

90. The method according to any one of claims 87 to 89, wherein the condition is epilepsy or an epileptic syndrome.

91. The method according to any one of claims 87 to 90, wherein the condition is hereditary epilepsy or hereditary epilepsy syndrome.

92. The method according to any one of claims 87 to 91, wherein the condition is childhood epilepsy or childhood epileptic syndrome.

93. The method according to any one of claims 87 to 92, wherein the condition is developmental or epileptic encephalopathy.

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

95. The aforementioned conditions include epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, and SCN8A mutations, early infant epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, and focal epilepsy with SCN3A mutation. The method according to any one of claims 87 to 94, selected from the group consisting of epilepsy, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, infantile malignant shift-focus partial seizures, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

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

97. A method for treating a neurological or mental disorder in a person requiring treatment, wherein the method comprises administering a dosage form according to any one of claims 1 to 86 to the person requiring treatment.

98. A method for treating pain in a subject requiring treatment, the method comprising administering to the subject a dosage form or composition according to any one of claims 1 to 86.

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

100. A method for treating or preventing trigeminal autonomic headache (TAC) in a subject requiring treatment or prevention, comprising administering a dosage form or composition according to any one of claims 1 to 86 to the subject.

101. A method for treating or preventing trigeminal autonomic headache (TAC) in a subject requiring treatment or prevention, comprising administering a therapeutically effective amount of compound 1, for example, 2.5 mg to 90 mg of compound 1, to the subject.

102. The method according to claim 100 or 101, wherein the TAC is selected from the group consisting of paroxysmal hemiparoxysmal headache, persistent hemiparoxysmal headache, short-duration persistent hemineuralgia-like headache attacks with conjunctival congestion and lacrimation (SUNCT), short-duration persistent hemineuralgia-like headache attacks with cephaloautonomic symptoms (SUNA), and prolonged persistent autonomic symptoms with hemiparoxysmal headache.

103. The method according to claim 102, wherein the TAC is a short-duration, persistent hemigupathic headache attack.

104. The method according to claim 102, wherein the TAC is SUNCT.

105. The method according to claim 102, wherein the TAC is SUNA.

106. The method according to any one of claims 100 to 105, wherein the subject has an insufficient response to at least one agent used to treat the TAC.

107. A method for treating or preventing migraine in a person requiring treatment or prevention of migraine, comprising administering to the person a therapeutically effective amount of a dosage form or composition according to any one of claims 1 to 86.

108. A method for treating or preventing migraine in a person requiring treatment or prevention, comprising administering a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1, to the person.

109. The method according to claim 107 or 108, wherein the migraine is selected from the group consisting of migraine without aura, migraine with aura, familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM).

110. The method according to claim 109, wherein the migraine is a migraine without aura.

111. The method according to claim 109, wherein the migraine is a migraine with aura.

112. The method according to claim 109, wherein the migraine is FHM1.

113. The method according to claim 109, wherein the migraine is FHM2.

114. The method according to claim 109, wherein the migraine is FHM4.

115. The method according to claim 109, wherein the migraine is SHM.

116. The method according to any one of claims 107 to 115, wherein the subject has an insufficient response to at least one drug used to treat the migraine.

117. A method for treating or preventing cortical spreading depression (CSD) in a subject requiring treatment or prevention, comprising administering to the subject a therapeutically effective amount of the dosage form or composition described in any one of claims 1 to 86.

118. A method for treating or preventing cortical spreading depression (CSD) in a subject requiring treatment or prevention, comprising administering a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1, to the subject.

119. A method for treating or preventing a neurological disorder or multiple neurological disorder in a subject requiring treatment or prevention, comprising administering to the subject a therapeutically effective amount of the dosage form or composition described in any one of claims 1 to 86.

120. A method for treating or preventing a subject who requires treatment or prevention of a cranial nerve disorder or multiple cranial nerve disorder, comprising administering a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1, to the subject.

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

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

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

124. The method according to any one of claims 87 to 123, wherein the subject is 18 to 65 years of age.

125. Compound 1, 【Chemistry 1】 or a method for preparing a pharmaceutically acceptable salt thereof, wherein the method is (i) A step of providing a compound of formula (II) by contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine, 【Chemistry 2】 (ii) The step of providing a compound of formula (III) by contacting the compound of formula (II) with a palladium catalyst and bis(pinacolate)diboron, 【Transformation 3】 (iii) The step of providing a compound of formula (IV) by contacting the compound of formula (III) with a palladium catalyst and 2-bromo-5-chloropyrazine, 【Chemistry 4】 (iv) The step of providing a compound of formula (V) by contacting the compound of formula (IV) with hydrazine, 【Transformation 5】 (v) The step of providing a compound of formula (VI) by contacting the compound of formula (V) with 2-bromo-2,2-difluoroacetyl chloride, 【Transformation 6】 (vi) The step of providing a compound of formula (VII) by contacting the compound of formula (VI) with an acid, 【Transformation 7】 (vii) A method comprising the step of contacting a compound of formula (VII) with a silver catalyst and ethanol to provide compound 1 or a pharmaceutically acceptable salt thereof.

126. The method according to claim 125, wherein the palladium catalyst in step (ii) or (iii) is [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

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

128. The method according to any one of claims 125 to 127, wherein the acid in step (vi) is p-toluenesulfonic acid.

129. Compound 1, 【Transformation 8】 or a method for preparing a pharmaceutically acceptable salt thereof, wherein compound 1 or its pharmaceutically acceptable salt is of formula (VII): 【Chemistry 9】 A method provided by contacting a compound with a silver catalyst and ethanol.

130. The compound of formula (VII) is the compound of formula (VI): 【Chemistry 10】 The method according to claim 129, provided by contacting the compound with an acid.

131. The compound of formula (VI) is the compound of formula (V): 【Chemistry 11】 The method according to claim 130, provided by contacting the compound with 2-bromo-2,2-difluoroacetyl chloride.

132. The compound of formula (V) is the compound of formula (IV): 【Chemistry 12】 The method according to claim 131, provided by contacting the compound with hydrazine.

133. The compound of formula (IV) is the compound of formula (III): 【Chemistry 13】 The method according to claim 132, provided by contacting the compound with a palladium catalyst and 2-bromo-5-chloropyrazine.

134. The compound of formula (III) is the compound of formula (II): 【Chemistry 14】 The method according to claim 133, provided by contacting the compound with a palladium catalyst and bis(pinacolate)diboron.

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

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

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

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