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

Abstract

The present invention relates, in part, to compositions or dosage forms comprising fused heteroaryl compounds useful for preventing and / or treating diseases or disorders associated with abnormal function of voltage-gated sodium ion channels, such as abnormal late sodium current / persistent sodium current. Also provided herein are methods of treating diseases or disorders associated with abnormal function of sodium ion channels, including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, neuromuscular disorders, trigeminal autonomic cephalalgias (TACs), migraines, cranial neuropathies or multiple cranial neuropathies, and cortical spreading depression (CSD). In another aspect, the present invention provides methods of making ion channel modulators.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of the following provisional patent applications: 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 provisional patent applications are incorporated herein by reference. Background Technology

[0003] Sodium ion (Na+) channels open primarily in a transient manner and inactivate rapidly, generating a fast Na+ current to initiate action potentials. Late sodium current, or sustained sodium current (INaL), is the sustained component of the fast Na+ current in cardiomyocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, which leads to the pathogenesis of electrical and systolic dysfunctions in mammals (see, for example, Pharmacol Ther (2008) 119:326-339). Therefore, pharmaceutical compositions or dosage forms containing compounds that selectively modulate sodium channel activity (e.g., abnormal INaL) could be used to treat such disease states. Summary of the Invention

[0004] This document describes compositions or dosage forms that can be used to prevent and / or treat diseases, disorders, or conditions, such as those associated with abnormal function of sodium ion channels, such as abnormal late sodium current (INaL). This disclosure also includes methods for modulating sodium channel activity using the compounds, compositions, or dosage forms described herein. Methods for preparing ion channel modulators are also provided herein.

[0005] In one aspect, this disclosure provides a dosage form comprising: compound 1 in amounts 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.

[0006] In another aspect, this disclosure provides a dosage form comprising: a plurality of particles of compound 1; and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of compound 1 in the dosage form is from about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg).

[0007] In one aspect, this disclosure provides a composition in a dosage form comprising: about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of compound 1; and a pharmaceutically acceptable excipient.

[0008] In another aspect, this 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 from about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg). In another aspect, this document provides a method of treating a condition associated with abnormal sodium ion channel function in a subject of need, the method comprising administering to the subject a dosage form disclosed herein. This document also provides a method of treating a condition associated with abnormal sodium ion channel function in a subject of need, the method comprising administering to the subject about 2.5 mg to about 90 mg of compound 1. In some embodiments, the condition is a neurological or psychiatric disorder. In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is hereditary epilepsy or a hereditary epilepsy syndrome. In some embodiments, the condition is pediatric epilepsy or a pediatric epilepsy syndrome. In some embodiments, the condition is epileptic encephalopathy. In some embodiments, the condition is a developmental disorder. In some embodiments, the epileptic encephalopathy is selected from Dravier syndrome, infantile spasms, or Ring-Gordon syndrome. In other embodiments, the condition is selected from epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early infantile epileptic encephalopathy, Dravier syndrome, Dravier syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, sudden death from epilepsy of unknown cause, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. In some embodiments, the condition is cancer.

[0009] This article also provides methods for treating neurological or psychiatric disorders in subjects in need, wherein such methods involve administering the dosage forms disclosed herein to subjects in need.

[0010] This disclosure partially provides a method for treating pain in a subject in need, wherein the method includes administering the dosage form disclosed herein to the subject.

[0011] The envisioned methods include methods for treating cancer in subjects in need, wherein the method includes administering the dosage form disclosed herein to the subject.

[0012] In another aspect, this article provides a method for treating or preventing trigeminal autonomic headache (TAC) in subjects in need, which involves administering to the subject a therapeutically effective amount of the dosage form disclosed herein.

[0013] This article also provides a method for treating or preventing trigeminal autonomic headache (TAC) in subjects in need, comprising administering to the subject a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1.

[0014] In another aspect, this article provides a method for treating or preventing migraines in subjects in need, the method comprising administering to the subject a therapeutically effective amount of the dosage form disclosed herein.

[0015] This article partially provides a method for treating or preventing migraines in subjects in need, which involves administering a therapeutically effective amount of compound 1 to the subject, for example, about 2.5 mg to about 90 mg of compound 1.

[0016] In another aspect, methods are provided for treating or preventing cortical diffusion inhibition (CSD) in subjects in need, the method comprising administering to the subject a therapeutically effective amount of the dosage form disclosed herein.

[0017] It also provides a method for treating or preventing cortical diffusion inhibition (CSD) in subjects in need, the method comprising administering to the subject a therapeutically effective amount of compound 1, for example about 2.5 mg to about 90 mg.

[0018] This article also provides a method for treating or preventing cranial neuropathy or multiple cranial neuropathy in subjects in need, the method comprising administering to the subject a therapeutically effective amount of the dosage form described herein.

[0019] In another aspect, a method for treating or preventing cranial neuropathy or multiple cranial neuropathy in a subject in need, the method comprising administering to the subject a therapeutically effective amount of compound 1, such as 2.5 mg to about 90 mg of compound 1.

[0020] In another aspect, this disclosure provides the preparation of compound 1:

[0021]

[0022] A method using its pharmaceutically acceptable salt or a method comprising the following steps:

[0023] (i) Contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine to provide a compound of formula (II):

[0024]

[0025] (ii) Contacting the compound of formula (II) with a palladium catalyst and bis(pinacolyl)diboron to provide the compound of formula (III):

[0026]

[0027] (iii) Contacting the compound of formula (III) with a palladium catalyst and 2-bromo-5-chloro-pyrazine to provide the compound of formula (IV):

[0028]

[0029] (iv) Contacting the compound of formula (IV) with hydrazine to provide the compound of formula (V):

[0030]

[0031] (v) Contacting the compound of formula (V) with 2-bromo-2,2-difluoroacetyl chloride to provide the compound of formula (VI):

[0032]

[0033] (vi) Contacting the compound of formula (VI) with an acid to provide the compound of formula (VII):

[0034] as well as

[0035] (vii) Contact the compound of formula (VII) with a silver catalyst and ethanol to provide compound 1 or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, this disclosure provides the preparation of compound 1:

[0037]

[0038] Or a pharmaceutically acceptable salt thereof, wherein compound 1 or a pharmaceutically acceptable salt thereof is disposed of by making a compound of formula (VII):

[0039]

[0040] It is provided by contact with silver catalyst and ethanol.

[0041] Other objects and advantages will become apparent to those skilled in the art upon consideration of the following brief description, detailed description, embodiments, and claims. Attached Figure Description

[0042] Figure 1 The XRPD patterns of Compound 1 as raw material and Compound 1 after jet milling are shown.

[0043] Figure 2 The dissolution results of ASD (2.5 mg and 10 mg active substance) in the capsules are shown.

[0044] Figure 3 The dissolution results of the 1:10 blend (1 mg and 10 mg of active substance) with MCC in the capsules are shown.

[0045] Figure 4 The dissolution results of the 1:10 blend with MCC (2.5 mg of active ingredient and 2% surfactant) in the capsule are shown. Detailed Implementation

[0046] As generally described herein, this disclosure provides in part compounds, compositions, and dosage forms for the prevention and / or treatment of the diseases, disorders, or conditions described herein, such as diseases, disorders, or conditions associated with abnormal functioning of sodium ion channels, such as abnormal late sodium current (INaL). Exemplary diseases, disorders, or conditions include neurological disorders (e.g., epilepsy or epilepsy syndromes, neurodevelopmental disorders, or neuromuscular disorders), mental disorders, pain, gastrointestinal disorders, trigeminal autonomic headache (TAC), migraine, cranial neuropathy or multiple cranial neuropathy, and cortical diffusion inhibition (CSD). Methods for preparing ion channel modulators are also provided herein.

[0047] definition

[0048] As used herein, "pharmaceuticalally acceptable carrier" refers to a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or mediators that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0049] As used herein, a “pharmaceutically acceptable salt” means that which, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, p-valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1-4Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, low-carbon alkyl sulfonates, and aryl sulfonates.

[0050] As used herein, the term "subject" considered for administration includes, but is not limited to, humans (i.e., men or women of any age group, such as child subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0051] Disease, symptom, and illness are used interchangeably in this article.

[0052] As used herein, and unless otherwise indicated, the terms “treatment” and “management” envision actions that occur when a subject is suffering from a particular disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow its progression (also referred to as “therapeutic treatment”).

[0053] As used herein, the term "effective amount" of a compound refers to an amount sufficient to induce the desired biological response. Those skilled in the art will understand that the effective amount of the compounds of the present invention can 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. Effective amounts include both therapeutic and prophylactic treatments.

[0054] As used herein, and unless otherwise indicated, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" can also include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effect of another therapeutic agent.

[0055] As used herein, the term "amorphous" refers to an amorphous solid. Amorphous solids generally have a crystalline short-range molecular arrangement but lack the long-range ordered molecular packing found in crystalline solids. The solid-state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art.

[0056] As used herein, "crystalline" refers to a solid with a highly regular chemical structure (i.e., with long-range structural order in the crystal lattice). These molecules are arranged in a regular, periodic manner in the three-dimensional space of the crystal lattice. Specifically, crystal forms can be generated in one or more single crystal forms.

[0057] The term “peak” when referring to peaks in the XRPD pattern of the crystal form of compound 1 refers to a set of peaks whose 2θ values ​​in the range of 0°–40° are uniquely attributed as a whole to one of the crystal forms of compound 1.

[0058] As used herein, the phrase “amorphous solid dispersion” refers to a solid comprising a pharmaceutical substance (e.g., compound 1) and a dispersed polymer.

[0059] The phrase "dispersion polymer" means a polymer that allows a pharmaceutical substance (e.g., compound 1) to be dispersed such that a solid dispersion can be formed. A dispersion polymer may comprise a mixture of two or more polymers. Examples of dispersion polymers include, but are not limited to, vinyl polymers and copolymers, vinylpyrrolidone-vinyl acetate copolymers ("PVP-VA"), polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymers, polyvinylpyrrolidone ("PVP"), acrylate and methacrylate copolymers, methacrylate-methyl methacrylate copolymers (such as... Polyethylene-polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers (also known as poloxamers), and graft copolymers composed of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate (such as...) Cellulose polymers such as hydroxypropyl methylcellulose acetate (“HPMCA”), hydroxypropyl methylcellulose (“HPMC”), hydroxypropyl cellulose (“HPC”), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate and hydroxyethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate (“HPMCAS”), hydroxypropyl methylcellulose phthalate (“HPMCP”), carboxymethyl ethyl cellulose (“CMEC”), cellulose acetate phthalate (“CAP”), cellulose acetate succinate (“CAS”), hydroxypropyl methylcellulose acetate phthalate (“HPMCAP”), cellulose acetate trimellitate (“CAT”), hydroxypropyl methylcellulose acetate trimellitate (“HPMCAT”), and carboxymethyl cellulose acetate butyrate (“CMCAB”), etc.

[0060] As used herein, the terms "stable" and "stability" mean that the evolution of a pharmaceutical substance (e.g., compound 1) over time and / or under specific environmental conditions (e.g., temperature, humidity, etc.) does not significantly affect its quality, safety, and / or efficacy over a given period of time. This can be measured by changes in the formation of degradation products (impurities), pH, appearance, microbial growth, and / or color, as illustrated in the Experimental Section. Generally, a composition according to the invention is considered stable if at least 95% of the initial concentration of each pharmaceutical substance is measured after 4 weeks at 25°C, and / or if no substantial change in the appearance of the solution is observed during such a period of time and at such temperature conditions. Stability can be assessed at a range of relative humidity (RH) conditions (typically between 60% and 75% RH).

[0061] As used herein, the term “particle size” is defined as the diameter of a particle as determined by a Sympatec particle size analyzer.

[0062] compound

[0063] This article describes pharmaceutical compositions or dosage forms that contain compounds that can be used to prevent and / or treat diseases, disorders, or conditions, such as those associated with abnormal function of sodium ion channels, such as abnormal late sodium current (INaL).

[0064] In one aspect, this disclosure relates to a dosage form comprising compound 1 represented by the following formula:

[0065]

[0066] And pharmaceutically acceptable excipients. In some embodiments, compound 1 is crystalline. In some embodiments, the crystalline form 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 form 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 crystal form 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 crystal form exhibits a pattern substantially similar to... Figure 1 The same X-ray powder diffraction pattern depicted in the image.

[0067] In some implementations, compound 1 is amorphous.

[0068] Dosage Forms and Compositions

[0069] In one aspect, this disclosure is characterized by dosage forms or compositions that can be used for the prevention and / or treatment of the diseases, disorders or conditions described herein (e.g., diseases, disorders or conditions associated with abnormal function of sodium ion channels such as abnormal late sodium current (INaL)).

[0070] This invention provides pharmaceutical compositions comprising a compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants. The pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical field (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by G.S. Banker and T. Rhodes).

[0071] The pharmaceutical composition can be administered in single or multiple doses via any acceptable administration modality having similar efficacy, such administration modalities as described in, for example, those patents and patent applications incorporated herein by reference, including transrectal, buccal, intranasal, and percutaneous routes, via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, local administration, as an inhalant, or, for example, via an impregnation or coating device such as a stent, or via arterial insertion of a cylindrical polymer.

[0072] One mode of administration is parenteral, particularly by injection. The novel compositions of the present invention can be incorporated into forms for injection including aqueous or oil 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 mediators. Saline solutions are also commonly used for injection, but are not preferred in the context of this invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Appropriate flowability can be maintained, for example, by using a coating (such as lecithin), by maintaining the desired particle size in the case of a dispersion, and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0073] The sterile injectable solution is prepared by incorporating the required amount of the compound according to the invention, as needed, together with a variety of other components listed above, into a suitable solvent, followed by filtration and sterilization. Generally, a dispersion is prepared by incorporating various sterilized active ingredients into a sterile medium containing an alkaline dispersion medium and other desired components from those listed above. In cases where sterile powder is used to prepare the sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any other desired components from a previously sterile filtered solution.

[0074] Oral administration is another route of administration of the compounds according to the invention. Administration may be via capsules, tablets, or the like. In the manufacture of pharmaceutical compositions comprising at least one of the compounds described herein, the active ingredient is typically diluted with an excipient and / or encapsulated within a carrier, which may be in the form of capsules, pouches, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as described above), acting as a mordant, carrier, or medium for the active ingredient. Therefore, the composition may be in the following forms: tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0075] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulas may also include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners; and flavoring agents.

[0076] The compositions of the present invention can be formulated to provide a rapid, sustained, or delayed release of an 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. Examples of controlled-release systems are given in U.S. Patents 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed to deliver medications continuously, in pulses, or on demand.

[0077] The composition is preferably formulated in unit dosage forms. The term "unit dosage form" refers to a physical discrete unit suitable for use as a unit dose in human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, combined with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmaceutically effective amount. 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 should be understood that the actual amount of the compound administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated; the chosen route of administration; the compound actually administered and its relative activity; the individual patient's age, weight, and response; and the severity of the patient's symptoms.

[0078] To prepare solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compounds of the present invention. When it is mentioned that these preformed compositions are homogeneous, it means that the active ingredient is generally uniformly dispersed throughout the composition so that the composition can be easily further divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0079] The tablets or pills of the present invention can be coated or otherwise formulated to provide a dosage form that has the advantage of a long duration of action or protection against the acidic conditions of the stomach. For example, the tablets or pills may comprise an internal dose component and an external dose component, the latter being coated over the former. The two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to be delivered intact into the duodenum or to be released with a delay. A variety of materials can be used for such an enteric coating or coating, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, hexadecyl alcohol, and cellulose acetate.

[0080] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered via the oral or nasal respiratory route for local or systemic effects. Compositions in preferably pharmaceutically acceptable solvents can be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizer or the nebulizer can be connected to a mask holder or an intermittent positive pressure ventilator. The solution, suspension, or powder composition can preferably be administered orally or nasally from a device for delivering the preparation in a suitable manner.

[0081] In one aspect, this document provides a dosage form or composition thereof comprising: about 0.1 mg to about 500 mg (e.g., about 0.5 mg to about 200 mg, about 1 mg to about 150 mg, about 10 mg to about 120 mg) of compound 1; and a pharmaceutically acceptable excipient.

[0082] In some embodiments, the dosage form or the composition in the dosage form comprises about 2.5 mg to about 150 mg (e.g., about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 40 mg to about 150 mg, about 60 mg to about 150 mg, about 80 mg to about 150 mg, about 100 mg to about 150 mg, about 10 mg to about 120 mg, about 20 mg to about 120 mg, about 40 mg to about 120 mg, about 60 mg to about 120 mg, 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 120 mg, about 40 mg to about 120 mg, about 80 mg to about 120 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 40 mg to about 120 mg, about 1 ...20 mg, about 10 mg to about 100 mg, about 40 mg to about Compound 1 (approximately 10 mg to 100 mg, approximately 60 mg to 100 mg, approximately 80 mg to 100 mg, approximately 10 mg to 80 mg, approximately 20 mg to 80 mg, approximately 40 mg to 80 mg, approximately 60 mg to 80 mg, approximately 10 mg to 60 mg, approximately 20 mg to 60 mg, approximately 40 mg to 60 mg, approximately 70 mg to 120 mg, approximately 70 mg to 100 mg, approximately 50 mg to 120 mg, approximately 50 mg to 90 mg, approximately 30 mg to 120 mg, approximately 30 mg to 60 mg, approximately 30 mg to 80 mg, approximately 30 mg to 100 mg).

[0083] In some embodiments, the dosage form or the composition in the dosage form comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 80 mg, about 1 mg to about 50 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 10 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).

[0084] In some embodiments, the dosage form or composition thereof comprises about 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, 100 mg, about 99 mg, about 98 mg, about 97 mg, about 96 mg, about 95 mg, about 94 mg, about 93 mg, about 92 mg, about 91 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 69 mg, about 68 mg, or about 67 mg. Compound 1, approximately 66 mg, approximately 65 mg, approximately 64 mg, approximately 63 mg, approximately 62 mg, approximately 61 mg, approximately 60 mg, approximately 59 mg, approximately 58 mg, approximately 57 mg, approximately 56 mg, approximately 55 mg, approximately 54 mg, approximately 53 mg, approximately 52 mg, approximately 51 mg, approximately 50 mg, approximately 45 mg, approximately 40 mg, approximately 35 mg, approximately 30 mg, approximately 25 mg, approximately 20 mg, approximately 15 mg, approximately 10 mg, approximately 7 mg, approximately 5 mg, approximately 2.5 mg, approximately 2 mg, approximately 1.5 mg, or approximately 1 mg.

[0085] In another aspect, this disclosure provides a dosage form or composition thereof comprising: a plurality of particles of compound 1; and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of compound 1 in the dosage form is from about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg).

[0086] In some embodiments, the multiple particles of compound 1 in the dosage form or composition are about 2.5 mg to about 150 mg (e.g., about 10 mg to about 150 mg, about 20 mg to about 150 mg, about 70 mg to about 120 mg, about 30 mg to about 60 mg, about 100 mg, about 50 mg).

[0087] In some embodiments, 10% of the plurality of particles of compound 1 have a particle size of less than about 1 μm. In other embodiments, 50% of the plurality of particles of compound 1 have a particle size of less than about 4 μm. In some embodiments, 50% of the plurality of particles of compound 1 have a particle size of less than about 2 μm. In some embodiments, 90% of the plurality of 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 plurality of particles of compound 1 have a particle size of less than about 5 μm. In some embodiments, 90% of the plurality of particles of compound 1 have a particle size of about 4 μm to 15 μM.

[0088] In some embodiments, 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.

[0089] In some embodiments, the dosage form or composition is configured for oral administration.

[0090] In some implementations, the dosage form is a solid form.

[0091] In some implementations, the dosage form is in capsule form.

[0092] 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 pregelatinized starch), anhydrous lactose, lactose monohydrate, and sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0093] In some embodiments, the ratio of compound 1 to filler is about 1:10. In some embodiments, the ratio of compound 1 to filler is about 1:10. In some embodiments, the ratio of compound 1 to filler is about 1:5. In some embodiments, the ratio of compound 1 to filler is about 1:4. In some embodiments, the ratio of compound 1 to filler is about 1:3. In some embodiments, the ratio of compound 1 to filler is about 1:2.

[0094] In some embodiments, the capsule also contains a lubricant (e.g., magnesium stearate, calcium stearate, stearic acid, talc, silica, and fat).

[0095] In some implementations, the dosage form is in the form of a blend.

[0096] In some embodiments, the pharmaceutical excipient in the blend is a filler (e.g., microcrystalline cellulose or starch). In some embodiments, the ratio of compound 1 to filler is about 1:1. In some embodiments, the ratio of compound 1 to filler is about 1:10. In some embodiments, the ratio of compound 1 to filler is about 1:5. In some embodiments, the ratio of compound 1 to filler is about 1:4. In some embodiments, the ratio of compound 1 to filler is about 1:3. In some embodiments, the ratio of compound 1 to filler is about 1:2.

[0097] In some implementations, the dosage form is a liquid.

[0098] In some implementations, the dosage form is in solution form.

[0099] In some embodiments, the pharmaceutical excipients in the solution are selected from fillers (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)).

[0100] In some embodiments, the concentration of compound 1 in the solution is from about 0.1 mg / mL to about 10 mg / mL (e.g., about 0.5 mg / mL to about 10 mg / mL, about 1 mg / mL to about 10 mg / mL, about 2 mg / mL to about 10 mg / mL, about 3 mg / mL to about 10 mg / mL, about 4 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 6 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 8 mg / mL, about 1 mg / mL to about 8 mg / mL). L, about 2 mg / mL to about 8 mg / mL, about 3 mg / mL to about 8 mg / mL, about 4 mg / mL to about 8 mg / mL, about 5 mg / mL to about 8 mg / mL, about 6 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 6 mg / mL, about 2 mg / mL to about 6 mg / mL, about 3 mg / mL to about 6 mg / mL, about 4 mg / mL to about 6 mg / mL, about 0.5 mg / mL to about 4 mg / mL, about 1 mg / mL to about 4 mg / mL or about 2 mg / mL to about 4 mg / mL).

[0101] 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.

[0102] In some embodiments, the dosage form or the composition comprises:

[0103] About 20% to about 60% by weight (e.g., about 25% to about 55% by weight, about 30% to about 50% by weight, about 35% to about 45% by weight, about 37% to about 42% by weight or about 40% by weight) of fillers (e.g., polymers (e.g., PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 6000 or PEG 8000));

[0104] From about 3% to about 25% by weight (e.g., from about 3% to about 20% by weight, from about 5% to about 13% by weight, from about 8% to about 13% by weight, from about 5% to about 15% by weight, or from about 10% by weight) emulsifiers (e.g., castor oil derivatives (e.g., Kolliphor RH40), polyethylene glycol 25 hexadecyl / octadecyl ether (e.g., A25), polyethylene glycol 6 hexadecyl / octadecyl ether (e.g., A6), polyethylene glycol glycerol ricinoleate 35 (e.g., EL), polyethylene glycol glycerol hydroxystearate 40 (e.g., RH 40); and

[0105] About 30% to about 70% by weight (e.g., about 35% to about 65% by weight, about 40% to about 60% by weight, about 45% to about 55% by weight or about 50% by weight) water;

[0106] The concentration of compound 1 is approximately 0.5 mg / mL or approximately 0.25 mg / mL.

[0107] In some embodiments, the dosage form or the composition comprises: about 35% to about 45% by weight of a filler (e.g., a polymer (e.g., PEG 400)); about 5% to about 15% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); 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.

[0108] In some embodiments, the dosage form or the composition comprises:

[0109] About 40% by weight to about 75% by weight (e.g., about 45% by weight to about 70% by weight, about 50% by weight to about 65% by weight, about 55% by weight to about 60% by weight, or about 58% by weight) of emulsifiers (e.g., castor oil derivatives (e.g., Kolliphor RH40), polyethylene glycol 25 hexadecyl / octadecyl ether (e.g., A25), polyethylene glycol 6 hexadecyl / octadecyl ether (e.g., A6), polyethylene glycol glycerol ricinoleate 35 (e.g., EL), polyethylene glycol glycerol hydroxystearate 40 (e.g., RH 40);

[0110] About 10% to about 35% by weight (e.g., about 10% to about 30% by weight, about 10% to about 25% by weight, about 15% to about 25% by weight, or about 15% to about 20% by weight) surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), caprylic / capric glyceride polyethylene glycol glyceride (e.g., Labrasol), natural triglyceride base oils (e.g., olive oil, sesame oil, coconut oil, palm kernel oil));

[0111] Propylene glycol: about 3% to about 20% by weight (e.g., about 3% to about 15% by weight, about 5% to about 15% by weight, or about 5% to about 10% by weight); and

[0112] 10% by weight to about 35% by weight (e.g., about 10% by weight to about 30% by weight, about 10% by weight to about 25% by weight, about 15% by weight to about 25% by weight or about 15% by weight to about 20% by weight) of ethanol;

[0113] The concentration of compound 1 is from about 5 mg / mL to about 10 mg / mL (e.g., about 5 mg / mL, about 7.5 mg / mL or about 10 mg / mL) or from about 2.5 mg to about 5 mg / mL.

[0114] In some embodiments, the dosage form or the composition comprises: about 55% to about 60% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); about 15% to about 20% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS); about 5% to about 10% by weight of propylene glycol; and about 15% to about 20% by weight of ethanol; wherein the concentration of compound 1 is about 5 mg / mL to about 10 mg / mL or about 2.5 mg to about 5 mg / mL.

[0115] In some implementations, the dosage form comprises:

[0116] About 50% to about 85% by weight (e.g., about 55% to about 80% by weight, about 60% to about 75% by weight, or about 65% to about 70% by weight) of emulsifiers (e.g., castor oil derivatives (e.g., Kolliphor RH40), polyethylene glycol 25 hexadecyl / octadecyl ether (e.g., A25), polyethylene glycol 6 hexadecyl / octadecyl ether (e.g., A6), polyethylene glycol glycerol ricinoleate 35 (e.g., EL), polyethylene glycol glycerol hydroxystearate 40 (e.g., RH40);

[0117] About 10% to about 30% by weight (e.g., about 10% to about 25% by weight, about 15% to about 25% by weight, or about 18% to about 23% by weight) of surfactants (e.g., glycerides (e.g., Labrafil M2125 CS), PEGylated caprylic / capric acid (e.g., Labrasol), natural triglyceride base oils (e.g., olive oil, sesame oil, coconut oil, palm kernel oil)); and

[0118] From about 3 wt% to about 20 wt% (e.g., from about 3 wt% to about 15 wt%, from about 5 wt% to about 15 wt%, from about 5 wt% to about 12 wt%, or from about 7 wt% to about 12 wt%) of propylene glycol;

[0119] The concentration of compound 1 is from about 1 mg / mL to about 10 mg / mL (e.g., from about 2 mg / mL to about 8 mg / mL, about 2 mg / mL, about 5 mg / mL, about 7 mg / mL or about 10 mg / mL) or from 0.5 mg / mL to about 5 mg / mL.

[0120] In some embodiments, the dosage form or the composition comprises: about 65% to about 70% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); about 18% to about 23% by weight of a surfactant (e.g., a glycerol ester (e.g., Labrafil M2125 CS); and about 7% to about 12% by weight of propylene glycol; wherein the concentration of compound 1 is about 1 mg / mL to about 10 mg / mL or 0.5 mg / mL to about 5 mg / mL.

[0121] In some embodiments, the dosage form or the composition comprises:

[0122] About 20% to about 60% by weight (e.g., about 25% to about 55% by weight, about 30% to about 50% by weight, 35% to about 45% by weight, about 35% by weight, about 40% by weight or about 45% by weight) of diethylene glycol monoethyl ether (e.g., Transcutol HP);

[0123] From about 1% to about 20% by weight (e.g., from about 3% to about 18% by weight, from about 5% to about 18% by weight, from about 5% to about 15% by weight, from about 8% to about 12% by weight, or from about 10% by weight) of surfactants (e.g., vitamin derivatives (e.g., vitamin ETPGS)); and

[0124] About 20% to about 80% by weight (e.g., about 25% to about 75% by weight, about 30% to about 70% by weight, about 35% to about 55% by weight, about 40% to about 60% by weight, or about 45% to about 55% by weight) water;

[0125] The concentration of compound 1 is from about 1 mg / mL to about 5 mg / mL (e.g., about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg or about 5 mg / mL) or from 0.5 mg / mL to about 2.5 mg / mL.

[0126] In some embodiments, the dosage form or the composition comprises: about 35% to about 45% by weight of diethylene glycol monoethyl ether (Transcutol HP); about 5% to about 15% by weight of a surfactant (e.g., a glyceride (e.g., a vitamin derivative (e.g., vitamin ETPGS)); and about 40% to about 60% by weight of water; wherein the concentration of compound 1 is about 1 mg / mL to about 5 mg / mL or 0.5 mg / mL to about 2.5 mg / mL.

[0127] In some embodiments, the dosage form or the composition comprises: about 30% to about 40% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); about 40% to about 50% by weight of a surfactant (e.g., a glycerol ester (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).

[0128] In other embodiments, the dosage form or the composition comprises: about 35% to about 45% by weight of propylene glycol monooctanoate (e.g., Capryol 90); about 15% to about 25% by weight of glyceride (e.g., polyethylene glycol glyceride caprylate-capric acid ester (e.g., Labrasol)); and about 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP).

[0129] In some implementations, the dosage form is in the form of a suspension.

[0130] In some embodiments, the concentration of compound 1 in the suspension is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL.

[0131] In some embodiments, the disclosed suspension may be further diluted with a solvent (e.g., water), wherein the concentration of the diluted solution is about 50% to about 90% of the original solution.

[0132] In some embodiments, the concentration of compound 1 in the suspension is from about 0.1 mg / mL to about 10 mg / mL (e.g., about 0.5 mg / mL to about 10 mg / mL, about 1 mg / mL to about 10 mg / mL, about 2 mg / mL to about 10 mg / mL, about 3 mg / mL to about 10 mg / mL, about 4 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 6 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 8 mg / mL, about 1 mg / mL to about 8 mg / mL). mL, about 2 mg / mL to about 8 mg / mL, about 3 mg / mL to about 8 mg / mL, about 4 mg / mL to about 8 mg / mL, about 5 mg / mL to about 8 mg / mL, about 6 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 6 mg / mL, about 2 mg / mL to about 6 mg / mL, about 3 mg / mL to about 6 mg / mL, about 4 mg / mL to about 6 mg / mL, about 0.5 mg / mL to about 4 mg / mL, about 1 mg / mL to about 4 mg / mL or about 2 mg / mL to about 4 mg / mL).

[0133] In some embodiments, the drug excipient in the suspension comprises:

[0134] From about 0.1 wt% to about 5 wt% (e.g., from about 0.1 wt% to about 3 wt%, from about 0.1 wt% to about 2 wt%, from about 0.1 wt% to about 1 wt%, from about 0.5 wt% to about 3 wt%, from about 0.5 wt% to about 2 wt%, from about 0.5 wt% to about 1 wt%, from about 0.1 wt%, from about 0.3 wt%, from about 0.5 wt%, from about 1 wt%, from about 2 wt%, or from about 3 wt%) of fillers (e.g., ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium hydroxypropyl methylcellulose, methylcellulose (e.g., 400 cP MC), methylethyl cellulose, sodium carboxymethyl cellulose, Aerosil (silica), octadecyl alcohol, hexadecyl alcohol, octadecyl alcohol, Gelucires 33 / 01, 39 / 01 and 43 / 01, glyceryl docosanoate (Compritol 888ATO), glyceryl palmitoyl stearate (Precirol) AT05), Softisans 100, 142, 378 and 649, stearyl carbomer, xanthan gum, maltodextrin, gum arabic, tragacanth gum, povidone or polyvinyl alcohol); and

[0135] From about 0.1 wt% to about 3 wt% (e.g., from about 0.1 wt% to about 2 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 0.5 wt%, from about 0.2 wt% to about 2 wt%, from about 0.2 wt% to about 1 wt%, from about 0.2 wt% to about 0.5 wt%, from about 0.1 wt% to about 0.3 wt%, from about 0.1 wt%, from about 0.2 wt%, from about 0.3 wt%, from about 0.4 wt%, from about 0.5 wt%, or from about 1 wt%) of emulsifier (e.g., polyoxyethylene sorbate (e.g., ), sorbitan long-chain carboxylic esters (e.g., ), ethylene oxide or propylene oxide block copolymers PEGylated glycerides and Sorbitan esters of oleic acid, stearic acid, lauric acid or other long-chain carboxylic acids, polyethylene-polypropylene glycol block copolymers (e.g., poloxamer 188), other sorbitan or sucrose long-chain carboxylic acid esters, mono- and diglycerides, caprylic / capric triglyceride PEG derivatives).

[0136] In some embodiments, the pharmaceutical excipient comprises: about 0.5% by weight of a filler (e.g., methylcellulose, such as 400 cP MC); and about 0.2% by weight of an emulsifier (e.g., Tween, such as Tween 80, such as poloxamer 188).

[0137] In some embodiments, the pharmaceutical excipient also comprises about 1% by weight of a preservative solution (e.g., a paraben solution).

[0138] In some implementations, the dosage form is in the form of an amorphous solid dispersion.

[0139] 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 H-55).

[0140] In some embodiments, the dosage form or the composition is stable (e.g., chemically stable) at 25°C and 60% RH for 7 days, 14 days, 21 days, 28 days, 1 month, 3 months, 5 months, 6 months, 12 months, 24 months, or 36 months.

[0141] 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).

[0142] Methods for preparing dosage forms

[0143] In another aspect, this disclosure provides methods for preparing dosage forms as disclosed herein. Such methods are described, for example, in the Examples section. In some embodiments, the contemplated dosage forms may be in the form of capsules, blends, solutions, suspensions, or ASD.

[0144] How to use

[0145] The formulations described herein can generally be used to modulate the activity of sodium channels and can be used to treat conditions associated with abnormal sodium channel ion channel function, such as abnormal late sodium (INaL) currents. In some embodiments, formulations comprising compound 1 as provided in this disclosure are effective in treating epilepsy or epilepsy syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders. The formulations provided comprising compound 1 or a pharmaceutically acceptable salt thereof can also modulate all sodium ion channels, or can be specific to only one or more sodium ion channels, such as Na+. V 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 and / or 1.9.

[0146] In one aspect, the present invention provides a method for treating a condition associated with abnormal function of sodium ion channels in a subject in need, the method comprising administering to the subject a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1.

[0147] Epilepsy and Epilepsy Syndromes

[0148] The formulations described herein (e.g., dosage forms containing compound 1, compositions thereof) may be used to treat epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder characterized by seizures or prolonged abnormal behavior, sensation, and sometimes loss of consciousness caused by disruption of nerve cell activity in the brain. Symptoms of epileptic seizures vary widely, ranging from simple blank stares for a few seconds to repetitive twitching of the arms or legs during a seizure.

[0149] Epilepsy can involve generalized seizures or partial or focal seizures. Generalized seizures involve all areas of the brain. A person experiencing a generalized seizure may shout or make some noise, freeze for a few seconds to a minute, and then perform rhythmic movements of the limbs. The eyes are mostly open, and the person may appear unable to breathe and may actually be cyanotic. Recovery of consciousness is gradual, and the person may be confused for several minutes to several hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic 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 the part of the brain with abnormal electrical activity.

[0150] As described in this article, epilepsy includes generalized, partial, complex partial, tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0151] The formulations described herein (e.g., dosage forms containing compound 1, compositions thereof) may also be used to treat epileptic syndromes. Severe syndromes with diffuse brain dysfunction, caused at least in part by certain aspects of epilepsy, are also known as epileptic encephalopathy. These are associated with treatment-resistant, frequent seizures and severe cognitive impairment (e.g., West syndrome).

[0152] In some implementations, epilepsy syndromes include epileptic encephalopathy such as developmental and epileptic encephalopathy (DEE), Draway syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Randall-Cleffner syndrome, Ring-Gordon syndrome, Otahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0153] In some embodiments, the epilepsy or epilepsy syndrome is hereditary epilepsy or a hereditary epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome includes epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early infantile epileptic encephalopathy, Dravier syndrome, Dravier syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in children with SCN3A mutations, SCN8A epileptic encephalopathy, sudden death from epilepsy of unknown cause, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death from epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0154] In some embodiments, the method described herein further includes identifying subjects suffering from epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early epileptic encephalopathy in infancy, Dravier syndrome, Dravier syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory epilepsy in children with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in children with SCN3A mutations, SCN8A epileptic encephalopathy, sudden death from epilepsy of unknown cause, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden death from epilepsy of unknown cause (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) prior to administration of the formulation described herein.

[0155] In one aspect, the present invention is characterized by a method of treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, developmental and epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early epileptic encephalopathy in infancy, Dravier syndrome, Dravier syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory epilepsy in children with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in children with SCN3A mutations, SCN8A epileptic encephalopathy, sudden death from epilepsy of unknown cause, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy), the method comprising administering the formulation described herein to a subject in need.

[0156] The formulations of the present invention (e.g., dosage forms comprising compound 1, compositions thereof) can also be used to treat epilepsy or epileptic syndromes (e.g., epileptic encephalopathy) in subjects who have mutations in one or more of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, K CNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8 A. SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0157] In some embodiments, the method described herein further includes identifying a subject with a mutation in one or more of the following prior to administration of the formulation described herein: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1. , KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9 A. SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0158] The formulations of the present invention can also be used to treat epilepsy or epileptic syndromes (e.g., epileptic encephalopathy) in subjects who have mutations in one or more of the following: HNRNPU, CACNA1A, CASK, FOXG1, GNB1, GPHN, IQSEC2, MBD5, MECP2, PIGA, PURA, SLC6A8, SLC9A6, TSC1, TSC2, UBE3A, WDR45, ZEB2, SLC1A2, GRIN2D, DYRK1A, PURA, WDR45, HNRNPU, SMC1A, FOXG1, ARID1B, ASXL3, KCNH1, GABRB2, NEXMIF, MECP2, SNAP. 25. COL4A3BP, GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRD, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR 3. ABAT, ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ANK2, ANK3, DISC1, DLC1, DLC2, DNAI1, FGF13, GABARAP, GABARAPL1, GABARAPL 2. GABBR1, GAD1, GAD2, GLS, GLS2, GLUL, GNAI1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GPHN, HAP1, KCNB2, KCNC2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, PRKAC B. PRKACG, PRKCA, PRKCB, PRKCG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5, SLC6A11, SLC6A 13. 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, CACN A1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, KCNA1, K CNA10, KCNA3, KCNA4, KCNA5, KCNA6, KCNA7, KCNAB1, KCNAB2, KCNAB3, KCNB2, KCNC2, KCNC3, KCNC4, KCND1, KCND2, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNE4, KCNF1, KCNG1, KCNG2, KCNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4, KCNH5, KCNH6, KCNH7, KCNH8, KCNQ1, KCNQ5, KCNQ4, KCNRG, KCNS1, KCNS2, KCNS3, KCNV1, KCNV2, HCN2, HCN3, and HCN4.

[0159] In some embodiments, the method described herein further includes identifying a subject with a mutation in one or more of the following prior to administration of the formulation described herein: 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, SN AP25, COL4A3BP, GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRD, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GA BRR3, ABAT, ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ANK2, ANK3, DISC1, DLC1, DLC2, DNAI1, FGF13, GABARAP, GABARAPL1, GABAR APL2, GABBR1, GAD1, GAD2, GLS, GLS2, GLUL, GNAI1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, G NG7, GNG8, GNGT1, GNGT2, GPHN, HAP1, KCNB2, KCNC2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, P RKACB, PRKACG, PRKCA, PRKCB, PRKCG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5, SLC6A11, SLC6A13, SRC, TRAK1, TRAK2, CHRNA1, CHRNA10, CHRNA3, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB3, CHRNB4, CHRND, CHRNE, CHRNG, GRIA1, GRIA2,GRIA3, GRIA4, GRIK1, GRIK2, GRIK3, GRIK4, GRIK5, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRID1, GRID2, SCN10A, SCN11A, SCN2B, SCN3B, SCN4A, SCN4B, SCN5A, SCN7A, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, KCNA 1. KCNA10, KCNA3, KCNA4, KCNA5, KCNA6, KCNA7, KCNAB1, KCNAB2, KCNAB3, KCNB2, KCNC2, KCNC3, KCNC4, KCND1, KCND2, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNE4, KCNF1, KCNG1, KCNG2, KCNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4, KCNH5, KCNH6, KCNH7, KCNH8, KCNQ1, KCNQ5, KCNQ4, KCNRG, KCNS1, KCNS2, KCNS3, KCNV1, KCNV2, HCN2, HCN3, and HCN4.

[0160] Neurodevelopmental disorders

[0161] The formulations described herein (e.g., dosage forms comprising Compound 1, compositions thereof) may be used to treat neurodevelopmental disorders. In some embodiments, the neurodevelopmental disorder includes autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angmann syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatofemoral syndrome, Smith-Lemley-Optz syndrome, or neurodevelopmental disorder with epilepsy. In some embodiments, the method described herein further includes identifying a subject with a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angmann syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatofemoral syndrome, Smith-Lemley-Optz syndrome, or neurodevelopmental disorder with epilepsy) prior to administration of the formulations described herein.

[0162] In one aspect, the present invention is characterized by a method of treating neurodevelopmental disorders (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatofacial syndrome, Smith-Limley-Optz syndrome, or neurodevelopmental disorder with epilepsy), the method comprising administering to a subject in need a formulation described herein (e.g., a dosage form comprising compound 1, or a composition thereof).

[0163] pain

[0164] The formulations described herein (e.g., dosage forms containing compound 1, or compositions thereof) may be used to treat pain. In some embodiments, the pain includes neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, type 3 familial hemiplegic migraine, cluster headache, trigeminal neuralgia, or related headache disorders. In some embodiments, the method described herein further includes identifying a subject suffering from pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, type 3 familial hemiplegic migraine, cluster headache, trigeminal neuralgia, or related headache disorders) prior to administration of the formulations described herein (e.g., dosage forms containing compound 1, or compositions thereof).

[0165] In one aspect, the present invention is characterized by a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, type 3 familial hemiplegic migraine, cluster headache, trigeminal neuralgia, or related headache disorders), the method comprising administering to a subject in need a formulation described herein (e.g., a dosage form comprising compound 1, or a composition thereof).

[0166] Neuromuscular disorders

[0167] The formulations described herein (e.g., dosage forms comprising Compound 1, compositions thereof) may be used to treat neuromuscular disorders. In some embodiments, the neuromuscular disorders include amyotrophic lateral sclerosis (ALS), multiple sclerosis, myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with an SCN4A mutation. In some embodiments, the method described herein further includes identifying a subject with a neuromuscular disorder (e.g., ALS, multiple sclerosis, myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with an SCN4A mutation) prior to administration of the formulations described herein.

[0168] In one aspect, the invention is characterized by a method of treating neuromuscular disorders (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with an SCN4A mutation), the method comprising administering to a subject in need a formulation described herein (e.g., a dosage form comprising compound 1, or a composition thereof).

[0169] Other obstacles

[0170] In some embodiments, the formulations of the present invention (e.g., dosage forms comprising compound 1, or compositions thereof) may have suitable pharmacokinetic properties such that they may be active against the central and / or peripheral nervous systems. In some embodiments, the formulations provided herein (e.g., dosage forms comprising compound 1, or compositions thereof) are intended for the treatment of cardiovascular diseases such as atrial and ventricular arrhythmias (including atrial fibrillation), Prevot's (variant) angina, stable angina, unstable angina, ischemic and reperfusion injury of the heart, kidneys, liver, and brain, exercise-induced angina, pulmonary hypertension, congestive heart disease (including diastolic and systolic heart failure), recurrent ischemia, cerebral ischemia, stroke, renal ischemia, organ transplant-related ischemia, acute coronary syndrome, peripheral artery disease, intermittent claudication, and myocardial infarction.

[0171] In some embodiments, the formulations provided herein (e.g., dosage forms comprising compound 1, compositions thereof) may be used to treat diseases affecting the neuromuscular system that cause itching, seizures, or paralysis, or to treat diabetes or decreased insulin sensitivity and diabetes-related disease states such as diabetic peripheral neuropathy. In some embodiments, the disclosed methods include administering the pharmaceutical composition.

[0172] In some embodiments, this document provides methods for treating neurological or mental disorders, wherein the method includes administering to a subject in need a formulation disclosed herein (e.g., a dosage form containing compound 1, or a composition thereof).

[0173] Oncology

[0174] In another aspect, this disclosure provides a method of treating cancer, wherein the method comprises administering to a subject in need a dosage form or a composition thereof disclosed in this disclosure.

[0175] Trigeminal autonomic headache

[0176] The compounds, dosage forms, and compositions described herein (e.g., compound 1, dosage forms, or compositions comprising compound 1) may be used to treat trigeminal autonomic headache (TAC). TAC is a group of primary headaches characterized by unilateral pain, relatively short symptom duration, and associated ipsilateral cranial autonomic symptoms. TAC may include cluster headache (CH), paroxysmal migraine (PH), persistent migraine (HC), brief unilateral neuropathic headache with conjunctival congestion and lacrimation (SUNCT), brief unilateral neuropathic headache with cranial autonomic symptoms (SUNA), and long-term autonomic symptoms with migraine (LASH). These trigeminal autonomic headaches, while sharing common elements, differ in, for example, in the duration and frequency of attacks and in response to treatment.

[0177] 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, dosage forms, or compositions containing 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, dosage forms, or compositions containing compound 1). In another aspect, the present invention provides methods for treating or preventing trigeminal autonomic headache (TAC) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of the compounds, dosage forms, or compositions disclosed herein (e.g., compound 1, dosage forms, or compositions containing compound 1).

[0178] In another aspect, the present invention provides a method for treating or preventing trigeminal autonomic headache (TAC) in a subject in need, the method comprising administering to the subject a therapeutically effective amount of compound 1, for example, 2.5 mg to 90 mg of compound 1.

[0179] In some implementations, TAC is selected from paroxysmal migraine, persistent migraine, transient unilateral neuralgia-like headache with conjunctival congestion and lacrimation (SUNCT), transient unilateral neuralgia-like headache with cranial autonomic symptoms (SUNA), and long-term autonomic symptoms with migraine.

[0180] In other implementations, TAC is a transient, unilateral neuropathic headache episode.

[0181] In some implementations, TAC is SUNCT. In some implementations, TAC is SUNA.

[0182] In other implementations, the subject does not respond adequately to at least one drug used to treat TAC.

[0183] migraine

[0184] The compounds, dosage forms, and compositions described herein (e.g., compound 1, dosage forms, or compositions comprising compound 1) may be used to treat migraine. Migraine is a primary headache disorder characterized by recurrent headaches of moderate to severe severity. As described herein, migraine can be migraine without aura, migraine with aura, hemiplegic migraine, familial hemiplegic migraine (FHM), type 1 familial hemiplegic migraine (FHM1), type 2 familial hemiplegic migraine (FHM2), type 3 familial hemiplegic migraine (FHM3), type 4 familial hemiplegic migraine (FHM4), and sporadic hemiplegic migraine (SHM).

[0185] In some embodiments, the present invention provides methods for treating migraine without aura, migraine with aura, hemiplegic migraine, FHM, FHM1, FHM2, FHM3, FHM4, and / or SHM using the provided compounds. In some embodiments, the present invention provides methods for treating migraine without aura, migraine with aura, FHM1, FHM2, FHM4, and / or SHM using the provided compounds, dosage forms, or compositions (e.g., compound 1, dosage forms, or compositions containing compound 1). In some embodiments, the present invention provides methods for treating migraine without aura using the provided compounds. In some embodiments, the present invention provides methods for treating migraine with aura using the provided compounds, dosage forms, or compositions (e.g., compound 1, dosage forms, or compositions containing compound 1). In some embodiments, the present invention provides methods for treating FHM1, FHM2, and / or FHM4 using the provided compounds. In some embodiments, the present invention provides methods for treating SHM using the provided compounds, dosage forms, or compositions (e.g., compound 1, dosage forms, or compositions containing compound 1).

[0186] In another aspect, this document provides a method for treating or preventing migraines in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compounds, dosage forms, or compositions disclosed herein (e.g., compound 1, dosage forms or compositions comprising compound 1).

[0187] In another aspect, the present invention provides a method for treating or preventing migraines in a subject in need, the method comprising administering to the subject a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1.

[0188] In some embodiments, the migraine is selected from 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 some 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 some embodiments, the migraine is SHM. In some embodiments, the subject has an inadequate response to at least one drug used to treat migraine.

[0189] Cortical diffusion inhibition

[0190] The compounds, dosage forms, and compositions described herein (e.g., compound 1, dosage forms, or compositions comprising compound 1) may be used to treat cortical diffusion inhibition (CSD). CSD is a continuous depolarization (neuronal inactivation) that runs through intact brain tissue and is involved in conditions such as cerebral ischemia, migraine with aura, and seizures.

[0191] In another aspect, methods are provided for treating or preventing cortical diffusion inhibition (CSD) in subjects in need, the method comprising administering to the subject a therapeutically effective amount of the compounds, dosage forms, or compositions disclosed herein (e.g., compound 1, dosage forms, or compositions comprising compound 1).

[0192] In another aspect, this article provides a method for treating or preventing cortical diffusion inhibition (CSD) in subjects in need, the method comprising administering to the subject a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1.

[0193] Cranial nerve lesions

[0194] The compounds, dosage forms, and compositions described herein (e.g., compound 1, dosage forms, or compositions comprising compound 1) may be used to treat cranial nerve disorders. Neuropathy is a disorder of nerve function that impairs sensation and movement. It is called a cranial nerve disorder when nerves in the brain or brainstem are affected. Cranial nerves are those that originate directly in the brain or brainstem and typically affect areas such as the face and eyes. Cranial nerve disorders include Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, and sixth nerve palsy. When several different cranial nerves are affected, it is called multiple cranial nerve disorders (MCN).

[0195] This article also provides a method for treating or preventing cranial nerve lesions or multiple cranial nerve lesions in subjects in need, the method comprising administering to the subject a therapeutically effective amount of the compound, dosage form, or composition described herein (e.g., compound 1, dosage form, or composition comprising compound 1).

[0196] In another aspect, this article provides a method for treating or preventing cranial neuropathy or multiple cranial neuropathy in a subject in need, the method comprising administering to the subject a therapeutically effective amount of compound 1, for example, about 2.5 mg to about 90 mg of compound 1.

[0197] In some embodiments, the cranial nerve lesion is selected from 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 some embodiments, the dosage form is a capsule. In some embodiments, the patient is 18 to 65 years old.

[0198] combination therapy

[0199] For example, formulations described herein (e.g., dosage forms or compositions comprising compound 1) used to modulate sodium ion channels such as late sodium (INaL) currents may be administered in combination with another agent or therapy. Subjects to receive formulations disclosed herein may have a disease, disorder, or condition or symptoms thereof that would benefit from treatment with another agent or therapy. These diseases or conditions may involve epilepsy or epilepsy syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders.

[0200] Antiepileptic drugs

[0201] Antiepileptic drugs include brivaceran, carbamazepine, clonazepam, clonazepam, diazepam, divalproic acid, eslicarbazepine, ethosuximide, ezogababine, felbapentin, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, rufenamide, tiagabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol.

[0202] Cardiovascular drug combination therapy

[0203] Cardiovascular-related diseases or conditions that can benefit from the combination therapy of the sodium channel blockers of the present invention with other therapeutic agents include, but are not limited to, angina pectoris (including stable angina, unstable angina (UA), exercise-induced angina, variant angina), arrhythmias, intermittent claudication, myocardial infarction (including non-ST-segment elevation myocardial infarction (NSTEMI)), pulmonary hypertension (including pulmonary hypertension), heart failure (including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure) or recurrent ischemia.

[0204] Therapeutic agents suitable for treating cardiovascular-related diseases or conditions include antianginal drugs, heart failure drugs, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid-lowering agents.

[0205] The combined administration of the sodium channel blocker of the present invention with a therapeutic agent suitable for treating cardiovascular-related conditions allows for enhancement of the standard care currently being received by the patient.

[0206] Antianginal drugs

[0207] Antianginal medications include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the heart's oxygen demand by decreasing its workload, thus lowering the heart rate and making the heart contract less forcefully. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betalolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), naldolol (Corgard), propranolol (Inderal), sotalolol (Betapace), and timolol (Blocadren).

[0208] Nitrates dilate arteries and veins, thereby increasing coronary blood flow and lowering blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide 5-mononitrate.

[0209] Calcium channel blockers prevent normal calcium flow into the cells of the heart and blood vessels, causing vasodilation and thus increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), benpredil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

[0210] Heart failure medication

[0211] 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 symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metoprazine (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

[0212] Angiotensin-converting enzyme (ACE) inhibitors reduce the workload on the heart by dilating blood vessels and decreasing blood flow resistance. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moxipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandopril (Mavik).

[0213] Vasodilators reduce pressure on blood vessels by causing them to dilate and relax. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

[0214] Cardiac glycosides are compounds that increase the force of cardiac contractility. These compounds enhance the heart's pumping ability and improve irregular heartbeats. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

[0215] Antithrombotic agents

[0216] Antithrombotic agents inhibit the blood's clotting ability. There are three main types of antithrombotic agents: platelet inhibitors, anticoagulants, and thrombolytics.

[0217] Platelet inhibitors suppress the clotting activity of platelets, thereby reducing arterial clotting. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, dipyridamole, sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb / IIIa inhibitors such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta-blockers and calcium channel blockers also have platelet-inhibiting effects. Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaliparin, lepiludine, and argatroban.

[0218] Thrombolytic agents work by breaking down existing blood clots. Examples of thrombolytic agents include streptokinase, urokinase, tenecteplase (TNK), and tissue plasminogen activator (t-PA).

[0219] Antiarrhythmic agents

[0220] Antiarrhythmic agents are used to treat heart rate and rhythm disorders. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta-blockers are also used as antiarrhythmic agents.

[0221] Given the recent discovery of the synergistic effect of the sodium channel blocker ranolazine with amiodarone and dronedarone, its combination with amiodarone and dronedarone has attracted particular attention.

[0222] Antihypertensive drugs

[0223] Antihypertensive agents are used to treat hypertension, a condition in which blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and presumed clot forillance. Examples of antihypertensive agents include alpha-1-adrenergic antagonists such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride, prazosin, minizide, and terazosin hydrochloride (Hytrin); and beta-adrenergic antagonists such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and indoleol (Visken). Central alpha-adrenergic receptor agonists, such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanethidine acetate (Wytensin), guanifaxine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); and compound alpha / β-adrenergic antagonists, such as labetalol (Normodyne, Trandate) and carvedilol (Core). g); adrenergic neuron blockers, such as ismelin and reserpine; antihypertensive drugs acting on the central nervous system, such as clonidine, methyldopa, and guanethidine; antiangiotensin II drugs; ACE inhibitors, such as perindopril, captopril, enalapril, and lisinopril (Prinivil, Zestril); angiotensin II Receptor antagonists, such as candesartan (Atacand), espressan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), and valsartan (Diovan); calcium channel blockers, such as verapamil (Calan, Isoptin), diltiazem (Cardizem), and nifedipine (Adalat, Procardia); diuretics; direct vasodilators, such as nitroprusside (Nipride), diazepine (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), and verapamil; and potassium channel activators, such as alpracalin, bicalin, clocarlin, imacalin, nicorandil, and pinadrodil.

[0224] lipid-lowering agents

[0225] Lipid-lowering agents are used to reduce the amount of cholesterol or fatty sugars present in the blood. Examples of lipid-lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava), pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

[0226] In this invention, patients presenting with acute coronary events often have secondary medical conditions, such as one or more metabolic disorders, pulmonary disorders, peripheral vascular disorders, or gastrointestinal disorders. Such patients may benefit from combination therapy, including administration of ranolazine and at least one other therapeutic agent.

[0227] Combined therapy for lung disorders

[0228] 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.

[0229] Examples of therapeutic agents used to treat pulmonary disorders include bronchodilators (including β2 agonists and anticholinergics), corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), salbutamol (Proventil), salmeterol (Serevent, SereventDiskus), theophylline, ipratropium bromide (Atrovent), tiotropium bromide (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.

[0230] Combination therapy for metabolic disorders

[0231] Examples of metabolic disorders include, but are not limited to, diabetes (including type 1 and type 2 diabetes), metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0232] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents, as described in the "Combined Cardiovascular Therapy" section above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and intestinal hypoglycemic agent analogs.

[0233] Combined therapy for peripheral vascular disorders

[0234] Peripheral vascular disorders are disorders related to blood vessels (arteries and veins) located outside the heart and brain, including, for example, peripheral artery disease (PAD), a condition that occurs when the arteries supplying blood to internal organs, arms, and legs become completely or partially blocked due to atherosclerosis.

[0235] Combined therapy for gastrointestinal disorders

[0236] Gastrointestinal disorders refer to diseases or conditions related to the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis, peptic ulcer disease, and pancreatitis.

[0237] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), and rabeprazole; H2 blockers such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid); prostaglandins such as misoprostol (Cytotec); sucralfate; and antacids.

[0238] Combination therapy of antibiotics, analgesics, antidepressants and anxiolytics

[0239] Patients presenting with acute coronary events may exhibit symptoms that benefit from the combined use of one or more therapeutic agents (such as antibiotics, analgesics, antidepressants, and anxiolytics) with ranolazine.

[0240] antibiotic

[0241] Antibiotics are therapeutic agents that kill microorganisms (including bacteria and fungi) or stop their growth. Examples of antibiotic agents include β-lactam antibiotics, including penicillin (amoxicillin); cephalosporins, such as cefazolin, cefuroxime, cefadroxil (Duricef), cefalexin (Keflex), cefadroxil (Velosef), cefaclor (Ceclor), cefuroxime axetil (Ceftin), cefprozil (Cefzil), chloramphenicol (Lorabid), cefixime (Suprax), and cefpodoxime proxetil (Vantin). Cefbufenoxan, cefdinir, rocephin, carbapenems and monocyclic cyclophosphamides; 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, streptozotocins, and polymyxins; lincosamides, such as clindamycin; oxazolidinones, such as linezolid; and sulfonamide antibiotics, such as sulfamethoxazole.

[0242] Painkillers

[0243] Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opioids and morphine-like substances such as fentanyl and morphine; acetaminophen; NSAIDs and COX-2 inhibitors. Considering that the sodium channel blocker of the present invention inhibits Na+... V The ability to treat neuropathic pain via 1.7 and 1.8 sodium channels is envisioned, particularly in combination with analgesics. See U.S. Patent Application Publication 20090203707.

[0244] Antidepressants and anti-anxiety medications

[0245] Antidepressants and anxiolytics include those used to treat anxiety disorders and depression, as well as those used as sedatives and tranquilizers. Examples of antidepressants and anxiolytics include benzodiazepines such as diazepam, lorazepam, and midazolam; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuroton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Flucttin, Fontex, Prodep, Fludep, Lovan); venlafaxine (Effexor XR, Efexor); citalopram (Celexa, Cipramide, Talohexane); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban). Antidepressants and anxiolytics may include neuroactive steroids and ketamine, as well as related NMDA receptor antagonists.

[0246] Therefore, 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 one alternative embodiment, the composition comprises the sodium channel blocker of the present invention and at least two therapeutic agents. In further alternative embodiments, 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 and at least five therapeutic agents.

[0247] Combination therapy methods include: combined administration of a single formulation comprising the sodium channel blocker of the present invention and one or more therapeutic agents; substantially simultaneous administration of more than one formulation comprising the sodium channel blocker of the present invention and one or more therapeutic agents; and sequential administration of the sodium channel blocker of the present invention and one or more therapeutic agents in any order, wherein preferably there is a period of time during which the sodium channel blocker of the present invention and one or more therapeutic agents exert their therapeutic effects simultaneously.

[0248] Preparation method

[0249] This article provides methods for preparing compounds that can be used to prevent and / or treat the diseases, disorders, or conditions described herein, such as those associated with abnormal function of sodium ion channels, such as abnormal late sodium current (INaL).

[0250] In one aspect, this disclosure provides for the preparation of compound 1:

[0251]

[0252] A method using its pharmaceutically acceptable salt or a method comprising the following steps:

[0253] (i) Contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine to provide a compound of formula (II):

[0254]

[0255] (ii) Contacting the compound of formula (II) with a palladium catalyst and bis(pinacolyl)diboron to provide the compound of formula (III):

[0256]

[0257] (iii) Contacting the compound of formula (III) with a palladium catalyst and 2-bromo-5-chloro-pyrazine to provide the compound of formula (IV):

[0258]

[0259] (iv) Contacting the compound of formula (IV) with hydrazine to provide the compound of formula (V):

[0260]

[0261] (v) Contacting the compound of formula (V) with 2-bromo-2,2-difluoroacetyl chloride to provide the compound of formula (VI):

[0262]

[0263] (vi) Contacting the compound of formula (VI) with an acid to provide the compound of formula (VII):

[0264] as well as

[0265] (vii) Contact the compound of formula (VII) with a silver catalyst and ethanol to provide compound 1 or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, the palladium catalyst in step (ii) or (iii) is [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II). In some embodiments, the silver catalyst in step (vii) is silver tetrafluoroborate. In other embodiments, the acid in step (vi) is p-toluenesulfonic acid.

[0267] In another aspect, this disclosure provides the preparation of compound 1:

[0268]

[0269] Or a pharmaceutically acceptable salt thereof, wherein compound 1 or a pharmaceutically acceptable salt thereof is disposed of by making a compound of formula (VII):

[0270]

[0271] It is provided by contact with silver catalyst and ethanol.

[0272] In some embodiments, the compound of formula (VII) is made by using the compound of formula (VI):

[0273]

[0274] It is provided by contact with acid.

[0275] In other embodiments, the compound of formula (VI) is used by making the compound of formula (V):

[0276]

[0277] Provided by contact with 2-bromo-2,2-difluoroacetyl chloride.

[0278] In some embodiments, the compound of formula (V) is made by reacting the compound of formula (IV):

[0279]

[0280] Provided by contact with hydrazine.

[0281] In some embodiments, the compound of formula (IV) is made by reacting the compound of formula (III):

[0282]

[0283] Provided by contact with palladium catalyst and 2-bromo-5-chloro-pyrazine.

[0284] In other embodiments, the compound of formula (III) is obtained by making the compound of formula (II):

[0285]

[0286] It is provided by contacting a palladium catalyst and bis(pinacol)diboron.

[0287] In some 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(diphenylphosphine)ferrocene]dichloropalladium(II).

[0288] example

[0289] The following representative embodiments are intended to help illustrate the invention and are not intended to limit the scope of the invention, nor should they be construed as limiting the scope of the invention.

[0290] PSD particle size distribution

[0291] XRPD X-ray powder diffraction

[0292] NMR (Nuclear Magnetic Resonance)

[0293] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0294] PEG (Polyethylene Glycol)

[0295] HPLC (High Performance Liquid Chromatography)

[0296] MC methylcellulose

[0297] RH (Relative Humidity)

[0298] ASD Amorphous Solid Dispersions

[0299] PLM polarized light microscopy

[0300] mDSC (modulated differential scanning calorimetry)

[0301] FaSSIF (Fasting State Simulated Intestinal Fluid)

[0302] UPLC (Ultra-High Performance Liquid Chromatography)

[0303] API active pharmaceutical ingredients

[0304] PVP (Polyvinylpyrrolidone)

[0305] HPMC Hydroxypropyl Methylcellulose

[0306] SDS Sodium lauryl sulfate

[0307] USP (United States Pharmacopeia)

[0308] TFA (trifluoroacetic acid)

[0309] ACN Acetonitrile

[0310] PK Pharmacokinetics

[0311] MCC microcrystalline cellulose

[0312] MgSt (Magnesium Stearate)

[0313] rpm (revolutions per minute)

[0314] RSD (Relative Standard Deviation)

[0315] HG Hard Gelatin Capsules

[0316] SLS Sodium Lauryl Ether Sulfate

[0317] Area under the AUC curve

[0318] C max Maximum observed concentration

[0319] HPMCAS Hydroxypropyl methylcellulose acetate succinate

[0320] PG Propylene Glycol

[0321] AE adverse events

[0322] ECG (electrocardiogram)

[0323] C-SSRS (Columbia Suicide Severity Rating Scale)

[0324] T max Time to maximum observed concentration

[0325] t 1 / 2 Apparent terminal elimination half-life

[0326] AUC 0-last Area under the concentration-time curve from time zero to the final measurable concentration.

[0327] AUC 0-inf Area under the drug concentration-time curve from zero to infinity

[0328] CL / F clearance rate

[0329] V d / F Distribution Volume

[0330] Clr actual clearance rate

[0331] The fraction of fe excreted unchanged in urine

[0332] Ae 0-72 The amount excreted unchanged within 72 hours

[0333] EEG

[0334] PD pharmacodynamics

[0335] Rac(AUC) time to steady state and AUC-based cumulative rate

[0336] Rac(C max Based on C max Cumulative rate

[0337] SAD single escalation dose

[0338] QTcF using Fridricia correction method for QT interval

[0339] OTC (over-the-counter)

[0340] BLQ below quantitative level

[0341] CV% Coefficient of Variation

[0342] Example 1. Preparation and characterization of milled compound 1

[0343] Compound 1 was ground to reduce particle size by manual grinding or jet grinding. 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 indicates that D90 = 77.82 μm before manual grinding and D90 = 28.27 μm after manual grinding. The PSD was analyzed by dry method using a Sympatec HELOS particle size analyzer, with the dispersion system and pressure being RODOS and 0.5 bar, respectively.

[0344] Table 1. Particle size change after manual grinding

[0345] D10 1.8μm 0.8μm D50 22.2μm 3.6μm D90 77.8μm 28.3μm

[0346] For jet milling, compound 1 is micronized by jet milling with a yield of approximately 90%. The particle size of the jet-milled material is reduced to the D90 range of 4.7 to 13.5 μm.

[0347] Table 2. Particle size change after jet milling

[0348] D10 1.8μm 0.7μm D50 15.4μm 1.8μm D90 80.9μm 4.7μm Compound 1, Batch 2 Before After jet milling (95g scale) D10 13.2μm 1.1μm D50 67.3μm 3.7μm D90 162.1μm 8.3μm Compound 1, Batch 3 Before After jet milling (104g scale) D10 14.6μm 0.87μm D50 56.8μm 5.58μm D90 104μm 13.5μm

[0349] X-ray powder diffraction (XRPD) data were collected using a Bruker D8 Advance powder diffractometer. Copper K-α X-rays were used with the generator operating at 40 kV / 40 mA. The sample was irradiated. The sample was scanned in a continuous mode from 3° to 40° (2θ) using a sample rotation speed of 15 rpm and a scan rate of 10° / min. Figure 1 The XRPD pattern of the raw material and the jet-milled material is shown, indicating that compound 1 did not undergo any physical morphological change after jet milling.

[0350] Compound 1 was subjected to proton NMR before and after jet milling. 1 H-NMR), fluorine NMR ( 19 Analyses were performed using 1H NMR and LC-MS. Both NMR and LC-MS results indicated that no chemical or structural changes in compound 1 were observed due to jet milling.

[0351] Example 2. Preparation and stability of formulations containing compound 1

[0352] Solution preparations

[0353] 1) Prototype 1: 40% PEG 400 / 10% Cremophor RH40 / 50% Water

[0354] Add 2400 μL of PEG 400 and 3 mg of Compound 1 to an 8 mL glass vial, vortex, and sonicate for 5 min. Then add 600 μL of Cremophor RH40, vortex, and sonicate for 5 min. Next, add 3000 μL of water, vortex, and sonicate for 5 min to allow the compound to dissolve completely (0.5 mg / mL).

[0355] 2) Prototype 2a: 58.1% Cremophor RH40 + 16.9% Labrafil M2125 CS + 8.3% Propylene Glycol + 16.7% Ethanol

[0356] Mediator preparation: 11.62 mL Cremophor RH40, 3.38 mL Labrafil M2125 CS, 1.66 mL propylene glycol and 3.34 mL ethanol were mixed together to obtain the mediator of prototype 2a.

[0357] 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 together by vortexing and sonication for 5 min. Compound 1 in prototype 2a at a concentration of 7.5 mg / mL was a clear solution.

[0358] 3) Prototype 2b: 69.74% Cremophor RH40 + 20.28% Labrafil M2125 CS + 9.98% Propylene Glycol.

[0359] Preparation: 11.62 mL Cremophor RH40, 3.38 mL Labrafil M2125 CS and 1.66 mL propylene glycol were mixed together to obtain the mediator of prototype 2b.

[0360] 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 min. The 7.5 mg / mL prototype 2b solution was not clear. Then, another 140 μL of prototype 2b was added to the container, and the mixture was vortexed and sonicated for 5 min. The 7 mg / mL prototype 2b solution was clear.

[0361] 4) Prototype 3: 40% Transcutol HP / 10% Vitamin ETPGS / 50% Water

[0362] Add 600 μL of PEG 400 and 3 mg of Compound 1 to a 4 mL glass vial, vortex, and sonicate for 5 min. Then add 150 μL of Cremophor RH40, vortex, and sonicate for 5 min. Next, add 750 μL of water, vortex, and sonicate for 5 min to allow the compound to dissolve completely (2 mg / mL).

[0363] 5) Prototype 4: 36% Cremophor RH40 + 45% Capmul MCM C8 + 9% Triethyl Citrate + 10% Ethanol

[0364] Cremophor RH40, Capmul MCM C8, triethyl citrate, and ethanol were added together by weight to a glass container and mixed to form a solution mixture. Then, incremental amounts of Compound 1 were added to the mixture and vortexed and sonicated to form a clear solution. Additional Compound 1 was added under vortexing and sonication until Compound 1 was no longer soluble. The resulting maximum solubility was visually determined to be between 25 and 50 mg / mL.

[0365] 6) Prototype 5: 40% Capryol 90 + 20% Labrasol + 40% Transcutol HP

[0366] Capryol 90, Labrasol, and Transcutol HP were added together by volume to a glass container and mixed to form a solution mixture. Then, incremental 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 under vortexing and sonication until compound 1 was no longer soluble. The resulting maximum solubility was visually determined to be between 60 and 80 mg / mL.

[0367] Table 3 summarizes the prototypes used to prepare solution formulations of compound 1 and their corresponding stability. Table 4 shows detailed stability results.

[0368] Table 3. Solution formulations containing compound 1

[0369]

[0370] A high-performance liquid chromatography (HPLC) method was developed to test the stability and purity of compound 1. The HPLC method used for chemical stability and purity testing is as follows:

[0371]

[0372] Table 4. Detailed stability test data for prototypes 1, 2a and 3 (stored at room temperature, i.e., 15-25°C).

[0373]

[0374] Approximately 24 mg of compound 1 was added to an 8 mL glass vial and dissolved in prototype 2b. The solution was then sonicated for 10 min to obtain a clear solution with a concentration of 7 mg / mL. This solution was then diluted 3-fold with water for stability testing. The results are shown in Table 5 below.

[0375] Table 5: Detailed stability test data for prototype 2b

[0376]

[0377] Based on HPLC results and appearance, formulations of prototypes 1, 2a, 2b and 3 containing compound 1 are stable under ambient conditions for at least 7 days.

[0378] Suspension formulation

[0379] To prepare suspension formulations of compound 1, approximately 0.5 mg, 5 mg, and 10 mg of compound 1 were weighed into individual vials, and 1 mL of 0.5% MC 400 cP / 0.2% Tween 80 was added to each vial. These materials were mixed together by vortexing and stirred overnight (24 hours) at room temperature. The stability of the suspension formulations was measured by quantifying the purity of compound 1 using high-performance liquid chromatography (HPLC). The suspensions remained homogeneous. Table 6 summarizes the stability results.

[0380] To prepare a suspension formulation containing jet-milled compound 1, 15 mg of jet-milled compound 1 was weighed into a glass vial, and then 10 mL of a mediator (0.5% MC 400 cP / 0.2% Tween 80) was added to disperse the compound to achieve a concentration of 1.5 mg / mL. The suspension was thoroughly 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 for 28 days under ambient conditions.

[0381] Table 6. Stability of Compound 1 suspension formulations in 0.5% MC 400cP / 0.2% Tween 80

[0382]

[0383]

[0384] Unless otherwise specified, this is undiluted compound 1.

[0385] *Specify the material for jet milling.

[0386] Table 7. Stability of suspension formulations containing jet-milled compound 1 in 0.5% MC 400cP / 0.2% Tween 80

[0387]

[0388] As shown in Tables 8 to 11, the stability of various suspension formulations under different conditions was tested.

[0389] To prepare the suspension, the required amount of ground compound 1 was weighed into a glass container and the corresponding volume of mediator was added. The compound was thoroughly dispersed into a homogeneous suspension at the final target concentration using an overhead mixer. Concentrations of 0.1 mg / mL and 10 mg / mL were prepared. The visual appearance, concentration, purity, and PSD of the suspension products were physically evaluated.

[0390] The mordant was prepared by dissolving 0.5% by weight of 400 cP or 4000 cP methylcellulose and 0.2% poloxamer 188. To obtain the preservative suspension, a 1.0% by volume paraben preservative solution was additionally dissolved in the mordant using an overhead mixer. The paraben preservative solution was prepared by dissolving 0.10 g of methylparaben and 0.025 g of propylparaben in 9.875 g of propylene glycol (dissolved by mixing with a stir bar at room temperature for 1 hour).

[0391] Table 8. Visual stability evaluation of suspension formulations containing compound 1 after 1, 4 and 24 hours at room temperature.

[0392]

[0393] *Initially a homogeneous suspension, it settles over time and regains its homogeneity upon gentle stirring.

[0394] Initially a viscous, homogeneous suspension, it settled over time and returned to homogeneity after gentle stirring.

[0395] Table 9. Stability of suspension formulations containing compound 1 after 96 hours at room temperature

[0396]

[0397]

[0398] *Initially a homogeneous suspension, it settles over time and regains homogeneity after gentle stirring for about 1 minute.

[0399] #Initially a viscous, homogeneous suspension, it settled over time and returned to homogeneity after gentle stirring for about 2 minutes.

[0400] Table 10. Stability of suspension formulations containing compound 1 at 2-8 °C

[0401]

[0402] *Initially a homogeneous suspension, it settles over time and regains homogeneity after gentle stirring for about 1 minute.

[0403] Table 11. Stability of suspension formulations containing compound 1 at 25°C / 60% RH

[0404]

[0405]

[0406] *Initially a homogeneous suspension, it settles over time and regains homogeneity after gentle stirring for about 1 minute.

[0407] Amorphous solid dispersions (ASD)

[0408] An amorphous solid dispersion containing compound 1 was prepared by mixing compound 1 with a polymer. Nine ASD formulations were prepared to screen nine different polymers (PVPK30, PPVVA64, Soluplus, HPMCCE5, HPMC ASMG, HPMC ASMF, HPMC ASHG, Eudragit EPO, Eudragit L100) as solid dispersants. Approximately 10 mg of compound 1 and 40 mg of the corresponding polymer were weighed into 40 mL glass vials and dissolved in 1 mL of MeOH / DCM (1:1, volume / volume) to prepare a stock solution. The resulting clear solution was stored at 70 °C and rapidly evaporated to obtain the solid dispersion. The evaporated product was vacuum dried overnight at 30 °C and further characterized by appearance, PLM, XRPD, and mDSC.

[0409] The kinetic solubility of the nine ASD formulations at a concentration of 2 mg / mL in FaSSIF was tested. The experiment was run at 37 °C and 450 rpm. 0.5 mL of the mixture was taken at each time point and centrifuged before UPLC (the level of compound 1 was determined using a shortened run time version of the HPLC method described above). The results are listed in Table 12. Increased solubility was observed in most polymers, especially Eudragit EPO.

[0410] Table 12. Summary of ASD kinetic solubility

[0411]

[0412]

[0413] The kinetic solubility of the prototype ASD formulations was evaluated. Three example prototype ASD formulations were then prepared using Soluplus, Eudragit L100, or HPMC ASMF for further evaluation, and these formulations are summarized in Table 13. The stability test results of the selected ASD formulations are shown in Tables 14 and 15.

[0414] Table 13. Summary of the selected ASD formulations

[0415]

[0416] Table 14. Stability results of the selected ASD formulations after 1 week.

[0417]

[0418]

[0419] Table 15. Stability results after 2 weeks

[0420]

[0421]

[0422] Three ASDs were scaled up using a spray dryer.

[0423] Preparation of ASD-1: Approximately 300 mg of compound 1 and approximately 1200 mg of Soluplus were weighed into a 250 mL glass vial, and then 150 mL of acetone was added to obtain a clear solution before spray drying. After spray drying, the powder was collected and dried under vacuum at 30 °C for 12 hours (80.2% yield).

[0424] Preparation of ASD-2: Approximately 300 mg of compound 1 and approximately 1200 mg of Eudragit L100 were weighed into a 250 mL glass vial, and then 150 mL of acetone was added to obtain a clear solution before spray drying. After spray drying, the powder was collected and dried under vacuum at 30 °C for 12 hours (74.5% yield).

[0425] Preparation of ASD-3: Approximately 300 mg of compound 1 and approximately 1200 mg of HPMC ASMF were weighed into a 250 mL glass vial, and then 150 mL of acetone was added to obtain a clear solution before spray drying. After spray drying, the powder was collected and dried under vacuum at 30 °C for 12 hours (70.0% yield).

[0426] The ASD-3 prototype was also evaluated in an in vitro dissolution study. The collected ASD-3 spray-dried powder was manually weighed directly onto a #4 hard gelatin capsule at two different dosage strengths on an analytical balance: 2.5 and 10 mg of active substance (13.7 and 54.8 mg of ASD).

[0427] The dissolution method uses the following conditions:

[0428] instrument Agilent 708-DS medium 0.1N HCl containing 2% SDS equipment USP Equipment 2 (Paddle Method) Rotation speed 75 rpm (200 rpm for infinite rotation) Medium volume 900mL temperature 37.0±0.5℃ Sampling time point Infinity at 15, 30, 45, 60 min and 120 min

[0429] For dissolution analysis, HPLC is used to quantify the level of compound 1 in the dissolution medium. The same HPLC method is used for both dissolution and content uniformity testing. The HPLC method used is as follows:

[0430]

[0431] Dissolution results are shown in Figure 2 In the study, the release rates for 2.5 mg and 10 mg dose intensities were 29.76% and 17.64%, respectively.

[0432] The ASD-3 prototype was also evaluated in a pharmacokinetic (PK) study in cynomolgus monkeys using a crossover study design. The collected spray-dried ASD-3 powder was manually weighed directly onto #4 hard gelatin capsules using an analytical balance. Three male monkeys were orally administered 0.5 mg / kg body weight under fasting conditions, and the levels of compound 1 in plasma samples were analyzed.

[0433] Capsule formulation

[0434] Exemplary capsule formulations contain 2.5 mg, 10 mg, or 100 mg of compound 1 per capsule. For a 2.5 mg dose capsule, the formulation contains a 1:10 blend of compound 1 from a gelatin capsule with microcrystalline cellulose (MCC) and 2% magnesium stearate (MgSt), and another formulation contains 2.5 mg net compound 1 from a gelatin capsule (without additional excipients).

[0435] Weigh and grind Compound 1 and the filler (MCC or starch) separately and mix for 15 min to obtain a homogeneous mixture. Add the required amount of magnesium stearate and mix together. Manually fill the blend into appropriately sized hard gelatin capsules. Then, perform stability tests on the samples under different conditions and analyze the appearance at different time points.

[0436] Blend formulations

[0437] Blends 1 and 2 (1:10 blend)

[0438] 1 g of ground compound 1 and 9 g of MCC or starch were weighed into a container. The two components were blended by Turbula at 36 rpm for about 15 min to obtain a homogeneous phase. 0.2 g of MgSt was added and the mixture was mixed for another 3 min to obtain homogeneous blend 1 (Table 16). Dosage uniformity was evaluated by measuring 10 capsules (Tables 18 and 19).

[0439] Table 16. Composition of blends 1 and 2

[0440]

[0441] Blends 3 and 4 (1:1 blend)

[0442] 5 g of ground compound 1 and 5 g of MCC or starch were weighed into a container. The two components were mixed by Turbula at 36 rpm for about 15 min to obtain a homogeneous phase. 0.2 g of MgSt was added and mixed for another 3 min to obtain homogeneous blend 1 (Table 17). Dosage uniformity was evaluated by measuring 10 capsules (Tables 20 and 21).

[0443] Table 17. Composition of blends 3 and 4

[0444]

[0445] Tables 18-21 summarize the blending uniformity results for four exemplary blends containing compound 1 (blends 1-4 as described above).

[0446] Table 18. Results of homogeneity of 1:10 blending of blend 1

[0447]

[0448] Table 19. Results of homogeneity of 1:10 blending of blend 2

[0449]

[0450] Table 20. Results of 1:1 blending homogeneity of blend 3

[0451]

[0452] Table 21. Results of 1:1 blending homogeneity of blend 4

[0453]

[0454] Tables 21.1, 21.2, 21.3 and 21.4 show the stability results of blend 1 capsule and blend 2 capsule at dose intensities of 1 mg / capsule (1:10 blend ratio), 10 mg / capsule (1:10 and 50:50 blend ratios), and 100 mg / capsule (50:50 blend ratio).

[0455] Table 21.1: Stability of 1 mg active ingredient blend in capsules at 25°C / 60% RH

[0456]

[0457] Table 21.2: Stability of 10 mg active ingredient 1:10 blend in capsules at 25°C / 60% RH

[0458]

[0459] Table 21.3: Stability of 50:50 blend of 10 mg active ingredient in capsules at 25°C / 60% RH

[0460]

[0461] Table 21.4 Stability of 50:50 blend of 100 mg active ingredient in capsules at 25°C / 60% RH

[0462]

[0463] The dissolution of blend 1, which was a 1:10 ratio of compound 1 to MCC in specification #0HG capsules, was evaluated at 1 and 10 mg of active substance (10 and 100 mg of the blend with MCC, respectively).

[0464] The dissolution method uses the following conditions:

[0465] instrument Agilent 708-DS medium 0.1N HCl containing 2% SDS equipment USP Equipment 2 (Paddle Method) Rotation speed 75 rpm (200 rpm for infinite rotation) Medium volume 900mL temperature 37.0±0.5℃ Sampling time point Infinity at 15, 30, 45, 60 min and 120 min

[0466] The results are shown in Figure 3 Of the 1 mg dose strength capsules, 50.3% were released after 120 minutes, and 20.5% were released after 120 minutes.

[0467] Another prototype blend capsule formulation was prepared to evaluate the effect of adding surfactant to a 1:10 MCC capsule blend (blend 1). 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 (dose level of 2.5 mg active substance / capsule) for evaluation in stability studies (Table 21.3), cross-monkey PK studies, and dissolution tests.

[0468] Table 21.5 Stability of 1:10 blends of 2.5 mg active ingredient containing 2% surfactant

[0469]

[0470] Three male monkeys were orally administered 0.5 mg / kg body weight of compound 1 under fasting conditions, and the levels of compound 1 in plasma samples were analyzed. The resulting levels of compound 1 in plasma showed no significant increase in exposure to the surfactant-containing MCC blend capsules compared to the surfactant-free setting (AUC[0-inf] = 1,004 ng-h / mL, area under the curve from 0 to infinity, AUC[0-inf] = 994 ng-h / mL).

[0471] In an in vitro dissolution study, blends of 1MCC capsules with and without surfactants were evaluated at a dose strength of 2.5 mg of compound 1.

[0472] The dissolution method uses the following conditions:

[0473] instrument Agilent 708-DS medium 0.1N HCl containing 2% SDS equipment USP Equipment 2 (Paddle Method) Rotation speed 75 rpm (200 rpm for infinite rotation) Medium volume 900mL temperature 37.0±0.5℃ Sampling time point Infinity at 15, 30, 45, 60 min and 120 min

[0474] Dissolution results are shown in Figure 4 In this study, adding 2% SDS to the formulation significantly increased in vitro dissolution release, from 38% after 120 minutes when containing poloxamer 188 to 54% after 120 minutes when containing SLS.

[0475] Table 22 provides other illustrative formulations (prototypes 1-12) for use in blend capsules.

[0476] Table 22. Examples of ingredients

[0477]

[0478] Examples of excipients that can be used to prepare formulations as disclosed in this application are shown in Table 23.

[0479] Table 23. Examples of excipients

[0480]

[0481]

[0482] Example 3. Pharmacokinetic study of formulations containing compound 1

[0483] Pharmacokinetic (PK) studies were performed on animals using the formulations described in Example 2. Compound 1 was formulated to achieve the desired dose (Table 24) and administered to a group of three fasted animals via a single oral feeding. Blood samples were collected at at least seven time points, and plasma samples were prepared for bioanalysis. PK parameters were then obtained after non-compartmental pharmacokinetic analysis using PhoenixWinNonlin software (version 6.3, Phasight, Mountain View, CA). A linear / logarithmic trapezoidal rule was applied in obtaining 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 table below. Studies were conducted according to a crossover design 14-17. In this table, the prototype 2a solution was 58.1% Kolliphor RH40 + 16.9% Labrafil M2125CS + 8.3% propylene glycol + 16.7% ethanol. MC is methylcellulose 400cP, Tween 80 is polyoxyethylene (80) sorbitan monooleate, HPMC-ASMF, soluplus and Eudragit are polymers, and poloxamer is a copolymer.

[0484] Table 24. Selected PK data for formulations tested in animals

[0485]

[0486] *Auc(0-Last)

[0487] For the Cmax values ​​in Table 24, A indicates greater than 50 ng / mL and up to 150 ng / mL, B indicates greater than 150 ng / mL and up to 300 ng / mL, C indicates greater than 300 mg / mL and up to 600 mg / mL, and D indicates greater than 600 ng / mL and up to 900 ng / mL.

[0488] In addition, human pharmacokinetic (PK) and effective dose were estimated. Based on calculations, the effective dose for people with neurological disorders (e.g., epilepsy) is approximately 2.5 to 100 mg (e.g., 60 mg) once daily.

[0489] Example 4. A randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability, pharmacokinetics, and food effects of compound 1 in healthy volunteers with single and multiple escalation doses.

[0490] This is a three-part clinical trial evaluating the safety, tolerability, pharmacokinetic (PK) response, and food effects of compound 1 in healthy volunteers aged 18 to 55 years. The clinical trial consists of the following three parts:

[0491] Part A was randomized, double-blind, and placebo-controlled. Part A was designed to investigate the safety and pharmacokinetic profile of a single escalation dose of compound 1.

[0492] Part B was randomized, double-blind, and placebo-controlled. Part B was designed to investigate the safety and pharmacokinetic profile of compound 1 at multiple escalation doses (selected based on results from Part A).

[0493] Part C is a randomized, open-label, crossover design that studies the pharmacokinetic (PK) of a single dose of compound 1 under fasting and feeding conditions.

[0494] Goals and endpoints:

[0495] Part A

[0496]

[0497]

[0498] Part B

[0499]

[0500] Part C

[0501]

[0502] Based on the new safety and PK data in Part A, the SRC can select the starting dose for Part B before completing all dose level cohorts in Part A. Part C can begin after the last SAD cohort. Parts A and B are double-blinded, including blinding for participants and investigators; the sponsor is not blinded to facilitate safety review. Each part consists of three phases: screening, intervention, and safety follow-up.

[0503] Screening / Baseline Period

[0504] The screening period for all three parts will last up to 27 days (from day -28 to day -2).

[0505] Intervention

[0506] After confirming continued eligibility, participants registered and underwent assessment at the clinic on day -1 (the day before administration of the study drug). Participants remained in the clinic from baseline (day -1) until discharge (day 6 in part A, day 12 in part B, and day 13 in part C).

[0507] Part A

[0508] Healthy volunteers were recruited to receive either a single escalation dose of compound 1 or a placebo on day 1. Dose escalation was conducted in part A across a total of six planned cohorts (cohorts A1 through A6). Up to three additional cohorts may be studied at planned or intermediate dose levels. Eight participants were recruited in each cohort and were randomly assigned to receive either compound 1 or a placebo (ratio 3:1). Compound 1 was administered to participants in cohort A1 at an initial dose of 2.5 mg. Dosing was performed in all cohorts under fasting conditions.

[0509] Dosing in each dose level cohort began with two sentinel participants, one of whom was randomly assigned to receive compound 1 and the other to receive placebo. Safety and tolerability were monitored in each sentinel participant until day 6 and were reviewed before dosing the remaining participants in each cohort.

[0510] The cohorts were administered in ascending order. After each dose cohort in Part A had been administered, the blinded cumulative safety data collected up to day 6 and the available blinded PK data were reviewed by the Safety Review Committee (SRC) to determine the safety and tolerability of the investigational drug.

[0511] If the current dose level is determined to be safe and tolerable, the next dose cohort is recruited and randomly assigned to receive either the selected dose of active compound 1 or placebo. EEG to assess the effect of compound 1 on auditory evoked responses may be performed in one or more cohorts (e.g., determined based on safety and PK profiles).

[0512] Partial A dosing regimen

[0513] A1 Compound 1 2.5mg, orally, on an empty stomach. A2 Compound 1 Up to 10 mg, orally, on an empty stomach. A3 Compound 1 Up to 30mg, orally, without food. A4 Compound 1 Up to 60mg, orally, without food. A5 Compound 1 Up to 90mg, orally, without food. A6 Compound 1 Up to 120 mg, orally, without food.

[0514] Part B

[0515] The SRC determines the starting dose level in Part B based on the safety, tolerability, and PK data obtained in Part A. The SRC may select the starting dose for Part B before completing the dose level cohort in Part A.

[0516] If a dose level is determined to be safe and tolerable in Part A, that dose level will be evaluated in Part B. It is anticipated that three dose levels will be evaluated in a total of three cohorts (cohorts B1–B3) in Part B. An additional cohort may be added to replicate the dose level or investigate intermediate doses. Eight participants were recruited in each cohort, and these participants were randomly assigned to receive either compound 1 or a placebo (ratio 3:1).

[0517] The dose level of compound 1 to be evaluated in Part B shall not exceed the dose studied in Part A. Dosing shall begin on Day 1 and continue until Day 7. The last dose shall be administered on the morning of Day 7. Dosing in all cohorts in Part B shall be performed under fasting conditions. Two sentinel participants shall be planned for each dose cohort in Part B.

[0518] Partial B dosing regimen

[0519]

[0520]

[0521] After each dose cohort in Part B has completed administration of the study drug, the SRC reviews the blinded safety data (including the safety assessment performed on day 9) and available PK data according to the same procedure in Part A to determine the safety and tolerability of the study drug.

[0522] EEG for evaluating the effect of compound 1 on auditory evoked responses can be performed in one or more cohorts (as determined by the sponsor based on safety and PK spectra).

[0523] Part C

[0524] Once safety and pharmacokinetic profiles have been adequately evaluated in the final cohort of Part A, Part C can begin. Up to 16 participants will receive two doses of compound 1 in a randomized crossover design: one dose after a minimum 10-hour fast and one dose after a high-fat, high-calorie diet, with a 7-day washout period between the doses. Up to an additional 3-day washout period may be added between the fasting and dietary administration based on the observed half-life in Part A.

[0525] The doses used in Part C should not exceed those used in Part A and are approved by the SRC based on cumulative safety and PK data. Sentinel dosing may be used in Part C if the SRC deems it appropriate. Part C is not blinded.

[0526] Safety assessment and monitoring

[0527] Safety and tolerability assessments include vital signs, 12-lead ECG, physical examination, clinical laboratory tests, and C-SSRS, as outlined in SoAs.

[0528] Number of participants:

[0529] • Part A: The plan is to administer compound 1 or a placebo to up to 72 participants.

[0530] Part B: The plan is to administer compound 1 or a placebo to up to 32 participants.

[0531] • Part C: Plans to administer compound 1 to up to 16 individuals.

[0532] Exclusion criteria

[0533] Participants who meet any of the following criteria during screening will be excluded from this clinical trial:

[0534] • Any abnormal ECG result assessed by the investigator as clinically significant, including a QT interval (QTcF) >450 ms using the Fridricia correction method, and confirmed by a repeat test on screening or day 1 if necessary.

[0535] • Use of systemic prescription or over-the-counter (OTC) medications, including multivitamins and dietary and herbal supplements, within 2 weeks prior to the first dose of the study drug or within 5 times the drug's terminal half-life (whichever is longer) and throughout the duration of the study.

[0536] Test products, reference therapies, and application:

[0537] Part A: Oral administration of compound 1 capsules or a matched placebo.

[0538] Part B: Oral administration of compound 1 capsules or a matching placebo.

[0539] Part C: Oral administration of compound 1 capsules.

[0540] Statistical methods:

[0541] PK analysis: Plasma and urine concentrations of compound 1 were determined using validated bioanalytical methods. Plasma and urine concentrations were summarized by dose group / condition and time point using descriptive statistics. In addition to the descriptive statistics specified in the general conditions above, plasma concentrations were summarized using the number and percentage of concentrations below the quantitation level (BLQ) and the coefficient of variation (CV%).

[0542] Pharmacokinetic parameters were estimated from concentration-time data using standard non-compartmental methods. Urinary PK parameters were estimated from urine concentration and volume data. PK parameters were summarized by dose group / condition using descriptive statistics. In addition to the descriptive statistics specified in the general conditions above, PK parameters were summarized using CV%, geometric mean, and geometric coefficient of variation. Power models were used to assess the linearity and dose-proportionality of PK parameters where feasible. To test the food effect in a partial C, for C... max and AUC 0-inf The calculated 90% CI estimates the geometric mean ratio (ln transform) of the test treatment (i.e., feeding condition) relative to the reference treatment (i.e., fasting condition). If C max and AUC 0-inf If the 90% CI of the ratio is entirely contained within the range of 0.80 to 1.25, then it can be inferred that there is no food effect. If unexpected difficulties arise in determining the terminal half-life, the AUC can be used. 0-last Replace AUC 0-inf .

[0543] Example 5. A randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability, pharmacokinetics, and food effects of compound 1 in healthy volunteers with single and multiple escalation doses.

[0544] This is a three-part clinical trial evaluating the safety, tolerability, pharmacokinetic (PK) response, and food effects of compound 1 in healthy volunteers aged 18 to 55 years. The clinical trial consists of the following three parts:

[0545] Part A was randomized, double-blind, and placebo-controlled. Part A was designed to investigate the safety, tolerability, and pharmacokinetics of compound 1 at single escalation doses from 2.5 mg to 90 mg.

[0546] Part B was randomized, double-blind, and placebo-controlled. Part B was designed to investigate the safety, tolerability, and pharmacokinetics of compound 1 at multiple escalation doses (selected based on the results from Part A).

[0547] Part C is a randomized, open-label, crossover design that studies the pharmacokinetic, safety, and tolerability of a single dose of compound 1 (selected based on the results from Part A) under fasting and feeding conditions.

[0548] Goals and endpoints:

[0549] Part A

[0550]

[0551] Part B

[0552]

[0553]

[0554] Part C

[0555]

[0556] Based on the new safety and PK data in Part A, the SRC can select the starting dose for Part B before completing all dose level cohorts in Part A. Part C can begin after the last SAD cohort. Parts A and B are double-blinded, including blinding for participants and investigators; the sponsor is not blinded to facilitate safety review. Each part consists of three phases: screening, intervention, and safety follow-up.

[0557] After confirming continued eligibility, participants registered and underwent assessment at the clinic on day -1 (the day before administration of the study drug). Participants remained in the clinic from baseline (day -1) until discharge (day 6 in part A, day 12 in part B, and day 13 in part C).

[0558] Part A

[0559] Healthy volunteers were recruited to receive either a single escalation dose of compound 1 or a placebo on day 1. Dose escalation was conducted in part A across a total of six planned cohorts (cohorts A1 through A6). Up to three additional cohorts may be studied at planned or intermediate dose levels. Eight participants were recruited in each cohort and were randomly assigned to receive either compound 1 or a placebo (ratio 3:1). Compound 1 was administered to participants in cohort A1 at an initial dose of 2.5 mg. Dosing was performed in all cohorts under fasting conditions.

[0560] Dosing in each dose level cohort began with two sentinel participants, one of whom was randomly assigned to receive compound 1 and the other to receive placebo. Safety and tolerability were monitored in each sentinel participant until day 6 and were reviewed before dosing the remaining participants in each cohort.

[0561] The cohorts were administered in ascending order. After each dose cohort in Part A had been administered, the blinded cumulative safety data collected up to day 6 and the available blinded PK data were reviewed by the Safety Review Committee (SRC) to determine the safety and tolerability of the investigational drug.

[0562] If the current dose level is determined to be safe and tolerable, the next dose cohort is recruited and randomly assigned to receive either the selected dose of active compound 1 or placebo. EEG to assess the effect of compound 1 on auditory evoked responses may be performed in one or more cohorts (e.g., determined based on safety and PK profiles).

[0563] Partial A dosing regimen

[0564] A1 Compound 1 2.5mg, orally, on an empty stomach. A2 Compound 1 Maximum 7.5 mg, orally, on an empty stomach. A3 Compound 1 Up to 15mg, orally, on an empty stomach. A4 Compound 1 Up to 30mg, orally, without food. A5 Compound 1 Up to 60mg, orally, without food. A6 Compound 1 Up to 90mg, orally, without food.

[0565] Part B

[0566] The SRC determines the starting dose level in Part B based on the safety, tolerability, and PK data obtained in Part A. The SRC may select the starting dose for Part B before completing the dose level cohort in Part A.

[0567] If a dose level is determined to be safe and tolerable in Part A, that dose level will be evaluated in Part B. It is anticipated that three dose levels will be evaluated in a total of three cohorts (cohorts B1–B3) in Part B. An additional cohort may be added to replicate the dose level or study intermediate doses. Participants were recruited in each cohort and were randomly assigned to receive either compound 1 or a placebo (ratio 3:1).

[0568] The dose level of compound 1 to be evaluated in Part B shall not exceed the dose studied in Part A. Dosing shall begin on Day 1 and continue until Day 7. The last dose shall be administered on the morning of Day 7. Dosing in all cohorts in Part B shall be performed under fasting conditions. Two sentinel participants shall be planned for each dose cohort in Part B.

[0569] Partial B dosing regimen

[0570] B1 Compound 1 Up to 30mg, orally, without food. B2 Compound 1 Up to 60mg, orally, without food. B3 Compound 1 Up to 90mg, orally, without food.

[0571] After each dose cohort in Part B has completed administration of the study drug, the SRC reviews the blinded safety data (including the safety assessment performed on day 9) and available PK data according to the same procedure in Part A to determine the safety and tolerability of the study drug.

[0572] EEG for evaluating the effect of compound 1 on auditory evoked responses can be performed in one or more cohorts (as determined by the sponsor based on safety and PK spectra).

[0573] Part C

[0574] Once safety and pharmacokinetic profiles have been adequately evaluated in the final cohort of Part A, Part C can begin. Participants will receive two doses of compound 1 in a randomized crossover design: one dose after a minimum 10-hour fast and one dose after consuming a high-fat, high-calorie diet, with a 7-day washout period between each dose. Up to an additional 3-day washout period may be added between fasting and dietary administration based on the observed half-life in Part A.

[0575] The doses used in Part C should not exceed those used in Part A and are approved by the SRC based on cumulative safety and PK data. Sentinel dosing may be used in Part C if the SRC deems it appropriate. Part C is not blinded.

[0576] Safety assessment and monitoring

[0577] Safety and tolerability assessments included vital signs, 12-lead ECG, physical examination, clinical laboratory tests, and C-SSRS.

[0578] Exclusion criteria

[0579] Participants who meet any of the following criteria during screening will be excluded from this clinical trial:

[0580] • Any abnormal ECG result assessed by the investigator as clinically significant, including a QT interval (QTcF) >450 ms using the Fridricia correction method, and confirmed by a repeat test on screening or day 1 if necessary.

[0581] • Use of systemic prescription or over-the-counter (OTC) medications, including multivitamins and dietary and herbal supplements, within 2 weeks prior to the first dose of the study drug or within 5 times the drug's terminal half-life (whichever is longer) and throughout the duration of the study.

[0582] Test products, reference therapies, and application:

[0583] Part A: Oral administration of compound 1 capsules or a matched placebo.

[0584] Part B: Oral administration of compound 1 capsules or a matching placebo.

[0585] Part C: Oral administration of compound 1 capsules.

[0586] Statistical methods:

[0587] PK analysis: Plasma and urine concentrations of compound 1 were determined using a validated bioanalytical method (e.g., liquid chromatography-mass spectrometry (LC-MS)). Plasma and urine concentrations were summarized by dose group / condition and time point using descriptive statistics. In addition to the descriptive statistics specified in the general conditions above, plasma concentrations were summarized using the number and percentage of concentrations below the level of quantitation (BLQ) and the coefficient of variation (CV%).

[0588] Pharmacokinetic parameters were estimated from concentration-time data using standard non-compartmental methods. Urinary PK parameters were estimated from urine concentration and volume data. PK parameters were summarized by dose group / condition using descriptive statistics. In addition to the descriptive statistics specified in the general conditions above, PK parameters were summarized using CV%, geometric mean, and geometric coefficient of variation. Power models were used to assess the linearity and dose-proportionality of PK parameters where feasible. To test the food effect in a partial C, for C... max and AUC inf The calculated 90% CI estimates the geometric mean ratio (ln transform) of the test treatment (i.e., feeding condition) relative to the reference treatment (i.e., fasting condition). If C max and AUC inf If the 90% CI of the ratio is entirely contained within the range of 0.80 to 1.25, then it can be inferred that there is no food effect. If unexpected difficulties arise in determining the terminal half-life, the AUC can be used. last Replace AUC inf .

[0589] result

[0590] Preliminary analyses of the first four of the six planned cohorts in Part A of the study indicated that compound 1 was well tolerated at the tested doses. Reviewed safety data included adverse events, vital signs, ECG, C-SSRS, physical examination, and safety laboratory data. No serious adverse events, severe adverse events, or any adverse events leading to study withdrawal or termination were reported in the first three cohorts tested.

[0591] Based on these preliminary data, exposure appears to increase proportionally with dose level and reach maximum concentrations within 2–3 hours. The terminal elimination half-life averaged 114 hours (approximately 4–5 days) across all groups. Steady-state of 90% should be achieved within approximately 2 weeks with once-daily dosing.

[0592] Example 5. Randomized, double-blind comparison of the efficacy and safety of compound 1 versus placebo in the emergency and prophylactic treatment of chronic SUNCT and SUNA.

[0593] This multicenter clinical trial will evaluate the efficacy, safety, tolerability, and pharmacokinetics of compound 1 in participants aged 18 to 65 years with chronic SUNCT or chronic SUNA. It is a double-blind, placebo-controlled study. Participants will be randomized in a 1:1:1 ratio to receive one of three blinded treatments [daily oral high dose of compound 1 mg, daily oral low dose of compound 1 mg, or daily placebo]. Participants will self-administer the study drug once daily and have weekly clinic visits. Participants will also be asked to answer questions in an electronic diary, for example, three times daily (before or approximately 24 hours after the previous dose, approximately 4 hours after the first dose, and approximately 10 hours after the first dose).

[0594]

[0595] This clinical trial consists of three phases: screening / baseline, intervention, and safety follow-up. An optional washout period can also be used for participants taking preventative medication.

[0596] Screening / Baseline Period

[0597] The screening period will be as long as, for example, 28 days (from day -28 to day -1). Participants who have discontinued SUNCT or SUNA prophylactic medications (e.g., carbamazepine, lamotrigine) will be allowed an optional washout period of up to, for example, 14 days before screening.

[0598] During the screening period, participants will complete daily eDiary entries during, for example, a 14-day observation period to assess the stability, severity, and frequency of SUNCT and SUNA headaches.

[0599] Intervention

[0600] Once eligibility is confirmed during the screening period, participants will complete a baseline assessment (Day 1).

[0601] On Day 1, participants will return to the clinic to be randomly assigned to one of three treatment groups and receive the first dose of the study drug. Participants will remain in the clinical setting for medical observation for at least, for example, 6 hours. A headache log will be completed via eDiary before daily administration (e.g., approximately 24 hours after the previous administration) and, for example, approximately 4 hours and 10 hours after administration. After the first dose, participants will continue once-daily administration at home until Day 21. Participants will return to the clinic for assessment, for example, on Day 7 (±1 day), Day 14 (±1 day), and Day 21 (±1 day). Intensive PK sampling will be performed at the clinic at selected sites, for example, on Day 1, Day 7 (±1 day), Day 14 (±1 day), and Day 21 (±1 day).

[0602] Key safety endpoints will include clinical laboratory evaluation, 12-lead ECG, C-SSRS, and vital signs. Key efficacy assessments will include a headache log recorded via eDiary (see assessment timeline for more details). Blood samples will be obtained to determine plasma concentrations of compound 1 using validated bioanalytical methods, and these blood samples may also be used for exploratory method development and / or metabolite characterization.

[0603] Safety follow-up period

[0604] The safety follow-up period will last from, for example, day 22 to, for example, day 36. At the end of the safety follow-up period, participants will return to the clinic for study termination assessment, for example, day 57 (±1 day). During this visit, the following assessments will be performed: vital signs, physical examination, clinical laboratory tests, ECG, C-SSRS assessment, and efficacy assessment.

[0605] Adverse events, concomitant medications, and procedures will be monitored from the date of informed consent until day 36 (±1 day). By this time, participants will have completed the clinical trial.

[0606] Inclusion / Exclusion Criteria

[0607] Participants were, for example, women or men aged 18 to 65 years at screening time who had a history of chronic SUNCT and SUNA headaches for more than one year, with onset before age 50, and who exhibited at least 100 SUNCT and SUNA headaches within 14 days during the clinical trial observation period.

[0608] Test products, reference therapies, application

[0609] High-dose mg compound 1 capsules, low-dose mg compound 1 capsules, or placebo will be administered orally and provided to participants in pre-packaged containers.

[0610] Dosage / Route / Regimen

[0611] Dosage and pharmacokinetic (PK) data are pending. The route of administration will be oral.

[0612] Statistical methods

[0613] Descriptive statistics will be used to summarize safety, tolerability, pharmacokinetic (PK), and power variables. Descriptive summaries of categorical variables will include counts and percentages. Descriptive summaries of continuous variables will include the number of participants (n), mean, standard deviation (SD), median, minimum, and maximum. 95% confidence intervals (CIs) may be reported where appropriate. Summaries will be presented at time points where appropriate.

[0614] Standard PK parameters will be estimated using non-compartmental methods based on concentration-time data. Where possible, these parameters will include Cmax, tmax, and AUC0-tau. Exploratory analyses examining the relationship between PK and efficacy parameters can be performed on the PK analysis set.

[0615] Primary and secondary efficacy indicators

[0616] Headache log completed via eDiary

[0617] An electronic tablet application is used to collect information about participants' headache activity before administration (or approximately 24 hours after the previous dose) and approximately 4 and 10 hours after administration. Information collected at all time points will include: headache frequency, headache duration, and headache severity (measured using the Stanford Pain Scale). Information collected only at 10 hours after administration will include: attack type, associated symptoms and triggers, and autonomic symptoms. Additional information collected via eDiary at 10 hours after administration will include: Visual Analogue Scale (VAS), activities of daily living, and degree of disability.

[0618] Stanford Pain Scale

[0619] The Stanford Pain Scale is a comparative pain scale with descriptions assigned to each scale value, ranging from 0 (no pain) to 10 (indescribable, unimaginable). Pain on a scale of 0 to 3 is considered "mild," pain on a scale of 4 to 6 is considered "moderate," and pain on a scale of 7 to 10 is considered "severe." The Stanford Pain Scale is completed by participants.

[0620] Triggering factors

[0621] Participants will be asked to use a 5-point scale to rate whether their response to triggers (e.g., combing hair, touching face, chewing, etc.) has changed, with 0 = no change, 1 = slight improvement, 2 = moderate improvement, 3 = significant improvement, and 4 = triggers have disappeared.

[0622] Visual Analogue Scale

[0623] The Visual Analogue Scale will ask participants to use a Likert scale to rate their satisfaction with the treatment, with categories ranging from 0 = very poor outcome to 10 = excellent outcome.

[0624] degree of disability

[0625] The participants will use a goal achievement scale with the following categories to measure the participants' disability level: 0 = no disability, 1 = mild, 2 = moderate, 3 = severe, 4 = intolerable.

[0626] 36-Item Health Survey Summary (2nd Edition, Acute Phase)

[0627] 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. Scores are a weighted sum of the questions in each section. Scores range from 0 to 100, with lower scores indicating a greater degree of disability. In cases indicated in the SoA, the acute phase version of the SF-36 will be completed by the participant. This acute phase version asks the participant about their health status in the previous week.

[0628] Daily life activities

[0629] Participants will be asked to assess changes in their ability to perform daily living activities.

[0630] Example 6. Synthesis of (3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine) (Compound 1)

[0631]

[0632] Synthesis of A2: NaH (60% from mineral oil, 2.26 g, 56.71 mmol) was added dropwise to a stirred solution of 2,2,2-trifluoroethanol (5.67 g, 56.71 mmol) in THF (200 mL) at 0 °C. The reaction mixture was stirred for 15 min, and 5-bromo-2,3-difluoropyridine (10.0 g, 51.55 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 2 h. The reaction mixture was cooled to 10 °C and treated with ice water (100 mL). The reaction mixture was extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by column chromatography on silica gel using 2% ethyl acetate / PE to give the product (10.5 g, 38.1 mmol, 73% yield). LCMS: 273.9 (M+H) and 276.0 (M+2+H), Rt 2.53 min; Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH aqueous solution: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0633] 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(pinacol)diboron (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 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 15% ethyl acetate / PE to give the product (2.0 g, 6.2 mmol, 56% yield). LCMS: 322.1 (M+H), Rt 2.97 min; Column: Atlantis dC18 (50 x 4.6 mm), 5 μm; Mobile phase: A: 0.1% HCOOH aqueous solution: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0634] Synthesis of A4: A mixture of 1,4-dioxane (1 L) and water (150 mL) containing 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-dioxacyclopentaborane-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (141.18 g, 439.69 mmol), and 2-bromo-5-chloropyrazine (80 g, 413.59 mmol) was stirred at 35 °C under N2 for 2 h. After cooling to room temperature, water (300 mL) was added to the mixture, and the mixture was filtered through diatomaceous earth. After separation, the organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was redissolved in EA / PE = 1 / 3 (500 mL) and then filtered through a silica gel pad. The filter cake was washed with EA / PE = 1 / 3 (500 mL). The combined organic phases were concentrated to give an oily residue. PE (500 mL) was slowly added to this oil, and some solid was obtained. The solid was collected and dried in an oven to give the product in solid form (100 g, 242.4 mmol, 58% yield). LCMS R t = 1.28 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 11 H7ClF4N3O[M+H] + The calculated MS ESI value is 308.0, and the measured value is 307.9.

[0635] 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 h. After cooling to room temperature, the mixture was poured into water (4.5 L). Some solids were observed and collected by filtration. The filter cake was washed with water (500 mL x 2). The solids were redissolved in EtOAc (3 L), washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product in solid form (100 g, 329.8 mmol, 97% yield). LCMS R t =0.74 min (in a 1.5 min chromatogram), 5-95AB, C 11 H 10 F4N5O[M+H] + The calculated MS ESI value is 304.1, and the measured value is 303.9.

[0636] Synthesis of A6: One drop of DMF and (COCl)₂ (50.5 mL, 596.81 mmol) were added to a solution of 2-bromo-2,2-difluoro-acetic acid (87 g, 497.34 mmol) in THF (1 L). The resulting mixture was stirred at 20 °C for 1 hour. The resulting solution was used directly in the next step. [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (100 g, 329.79 mmol) was added to a solution of 2-bromo-2,2-difluoro-acetyl chloride (95.66 g, 494.69 mmol) in THF (1 L). The resulting mixture was stirred at 20 °C for 2 hours. Water (1 L) was added to this solution, and the mixture was extracted with EtOAc (1 L x 2). The combined organic phases were washed with brine (500 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product in solid form (150 g, 326.0 mmol, 98% yield, a mixture of monoalkylated and dialkylated products). LCMS R t =0.92 min (in a 1.5 min chromatogram), 5-95AB, C 13 H9BrF6N5O2[M+H] + The calculated MS ESI value is 460.1, and the measured value is 459.8.

[0637] Synthesis of A7: A solution of 2-bromo-2,2-difluoro-N'-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]acetylhydrazine (150 g, 325.99 mmol) and TsOH (16.84 g, 97.8 mmol) in toluene (1.5 L) was stirred at 130 °C for 16 h. After cooling to room temperature, the mixture was poured into water (2 L) and extracted with EtOAc (2 L x 2). The combined organic phases were washed with brine (1 L x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc / PE = 0% to 15% to 30%) to give the product in oil form (80 g, 181.0 mmol, 55% yield). 1 H 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).

[0638] Synthesis of Compound 1: A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (76 g, 171.9 mmol) and AgBF4 (66.93 g, 343.81 mmol) in ethanol (760 mL) was stirred at 60 °C for 1 hour. After cooling to room temperature, the mixture was poured into a saturated aqueous solution of NaCl (1 L) and EtOAc (2 L). The mixture was filtered through diatomaceous earth. After separation, the aqueous layer was extracted with EtOAc (500 mL x 2). The combined organic phases were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by passing it through a rapid column chromatography on silica gel (EtOAc / PE = 0% to 30% to 50%), and then ground with EtOH (50 mL) to give the product in solid form (44.45 g, 109.01 mmol, 63% yield). 1 H NMR (CDCl3 400MHz) 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). LCMSR t = 1.25 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 15 H 12 F6N5O2[M+H] + The calculated MS ESI value is 408.1, and the measured value is 408.0.

[0639] Equivalents and scope

[0640] In the claims, articles such as “a,” “an,” and “the” can refer to one or more species unless the contrary is indicated or otherwise apparent from the context. A claim or description including “or” among one or more members of a group is considered to satisfy the requirement that one or more members of the group are present in, used in, or otherwise associated with the specified product or process, unless the contrary is indicated or otherwise apparent from the context. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise associated with a given product or method. The invention includes embodiments in which more than one or all members of the group are present in, used in, or otherwise associated with a given product or method.

[0641] Furthermore, this invention covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are incorporated 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. Where elements are presented as a list, for example in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that, generally, when an invention or aspect thereof is referred to as comprising a particular element and / or feature, certain embodiments of the invention or aspect thereof consist of or are substantially composed of such elements and / or features. For simplicity, those embodiments are not specifically described herein in such language. It should also be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. Where a scope is given, endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and understanding of one of ordinary skill in the art, values ​​expressed as ranges may be assumed in different embodiments of the invention to be any specific value or subrange within the range, accurate to one-tenth of the lower limit unit of the range, unless the context clearly indicates otherwise.

[0642] This application relates to various granted patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, the specification shall prevail. Furthermore, any particular embodiment of the invention falling within the prior art may be expressly excluded from any one or more claims. Because such embodiments are considered known to those skilled in the art, they may be excluded even if not expressly stated herein. For any reason, whether or not related to the existence of prior art, any particular embodiment of the invention may be excluded from any claim.

[0643] Those skilled in the art will recognize or be able to determine many equivalent embodiments of the specific implementation described herein using no more than routine experiments. The scope of the embodiments described herein is not intended to be limited to the above description, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the appended claims.

Claims

1. A method for preparing compound 1: , A method using a pharmaceutically acceptable salt thereof, said method comprising the following steps: (i) Contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine to provide a compound of formula (II): (II); (ii) Contacting the compound of formula (II) with a palladium catalyst and bis(pinacol)diboron to provide the compound of formula (III): (III); (iii) Contacting the compound of formula (III) with a palladium catalyst and 2-bromo-5-chloro-pyrazine to provide the compound of formula (IV): (IV); (iv) Contacting the compound of formula (IV) with hydrazine to provide the compound of formula (V): (V)； (v) Contacting the compound of formula (V) with 2-bromo-2,2-difluoroacetyl chloride to provide the compound of formula (VI): (WE); (vi) Contacting the compound of formula (VI) with an acid to provide the compound of formula (VII): (VII); and (vii) Contact the compound of formula (VII) with a silver catalyst and ethanol to provide compound 1 or a pharmaceutically acceptable salt thereof.

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

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

4. The method according to any one of claims 1 to 2, wherein the acid in step (vi) is p-toluenesulfonic acid.

5. A method for preparing compound 1: (I) Or a pharmaceutically acceptable salt thereof, wherein: (i) Compound 1 or a pharmaceutically acceptable salt thereof, by making a compound of formula (VII): (VII) Provided by contact with silver catalyst and ethanol; (ii) wherein the compound of formula (VII) is obtained by making the compound of formula (VI): (WE) Provided through contact with acid; (iii) wherein the compound of formula (VI) is obtained by making the compound of formula (V): (V) Provided by contact with 2-bromo-2,2-difluoroacetyl chloride; (iv) wherein the compound of formula (V) is obtained by making the compound of formula (IV): (IV) Provided by contact with hydrazine; (v) wherein the compound of formula (IV) is obtained by making the compound of formula (III): (III) Provided by contact with palladium catalyst and 2-bromo-5-chloro-pyrazine; as well as (vi) wherein the compound of formula (III) is obtained by making the compound of formula (II): (II) It is provided by contacting a palladium catalyst and bis(pinacol)diboron.

6. The method of claim 5, wherein the silver catalyst in step (i) is silver tetrafluoroborate.

7. The method according to any one of claims 5 to 6, wherein the acid in step (ii) is p-toluenesulfonic acid.

8. The method according to any one of claims 5 to 6, wherein the palladium catalyst in step (v) or (vi) is [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride.

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