Formulations of ion channel modulators and methods of preparation and use of ion channel modulators

Abstract

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

Description

1 / 129 Descriptive Report of the Invention Patent for ION CHANNEL MODULATOR FORMULATIONS AND METHODS OF PREPARATION AND USE OF ION CHANNEL MODULATORS. CROSS-REFERENCE TO RELATED REQUESTS

[001] This application claims the benefit of the Patent Application. Provisional Patent Application US No. 62 / 941,322, filed November 27, 2019; Provisional Patent Application US No. 62 / 941,319, filed November 27, 2019; Provisional Patent Application US No. 63 / 001,906, filed March 30, 2020; Provisional Patent Application US No. 63 / 001,801, filed March 30, 2020; Provisional Patent Application US No. 63 / 028,229, filed May 21, 2020; Provisional Patent Application US No. 63 / 082,864, filed September 24, 2020; and Provisional Patent Application US No. 63 / 082,857, filed on September 24, 2020, the entire content of each of which is incorporated by reference herein. BACKGROUND

[002] Sodium (Na+) ion channels open primarily in a transient manner and are rapidly inactivated, thus generating a fast Na+ current to initiate the action potential. The delayed or persistent sodium current (INaL) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, which contributes to the pathogenesis of electrical and contractile dysfunction in mammals (see, for example, Pharmacol Ther (2008) 119:326-339). Consequently, pharmaceutical compositions or dosage forms comprising compounds that selectively modulate sodium channel activity, for example, abnormal INaL, are useful in the treatment of such disease states. Petition 870230103657, dated 11 / 24 / 2023, page 5 / 151 2 / 129 SUMMARY

[003] This document describes compositions or dosage forms useful for preventing and / or treating a disease, disorder or condition, for example, a disease, disorder or condition related to the aberrant function of a sodium ion channel, for example, abnormal late sodium current (ALNI). This description also includes methods for modulating sodium channel activity using a compound, composition or dosage form described in this document. A method for preparing ion channel modulators is also provided in this document.

[004] In one aspect, the present description provides a dosage form comprising: from about 0.1 mg to about 500 mg (for example, from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg) of Compound 1; and a pharmaceutically acceptable excipient.

[005] In another aspect, the present description 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 (for example, 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).

[006] In one aspect, the present description provides a composition in a dosage form comprising: from about 0.1 mg to about 500 mg (for example, from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg) of Compound 1; and a pharmaceutically acceptable excipient.

[007] In another aspect, the present description provides a composition in a dosage form comprising: a plurality Petition 870230103657, dated 11 / 24 / 2023, p. 6 / 151 3 / 129 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 (for example, 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, a method of treating a condition related to the aberrant function of a sodium ion channel in an individual in need is provided in this document, comprising administering to the individual a dosage form disclosed in this document. A method of treating a condition related to the aberrant function of a sodium ion channel in an individual in need is also provided in this document, comprising administering to the individual about 2.5 mg to about 90 mg of Compound 1. In some embodiments, the condition is a neurological or psychiatric disorder. In some forms, the condition is epilepsy or an epilepsy syndrome.In some forms, the condition is a genetic epilepsy or a genetic epilepsy syndrome. In some forms, the condition is a pediatric epilepsy or a pediatric epilepsy syndrome. In some forms, the condition is epileptic encephalopathy. In some forms, the condition is developmental. In some forms, epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome. In other modalities, epilepsy or an epilepsy syndrome includes epileptic encephalopathy, epileptic encephalopathy with mutations in SCN1A, SCN2A, SCN8A, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable epilepsy in children with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, and associated epileptic encephalopathy. Petition 870230103657, dated 11 / 24 / 2023, page 7 / 151 4 / 129 to the SCN2A gene, focal epilepsy with SCN3A mutation, pediatric cryptogenic partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migratory partial seizures of childhood, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. In some forms, the condition is cancer.

[008] This document also provides a method for treating a psychiatric disorder in an individual in need, wherein the method comprises administering to the individual the oral dosage form disclosed in this document.

[009] The description provides, in part, a method of treating pain in an individual in need, wherein the method comprises administering to the individual the oral dosage form disclosed in this document.

[0010] The methods contemplated include a method of treating cancer in an individual in need, wherein the method comprises administering to the individual a dosage form disclosed in this document.

[0011] In another aspect, a method of treatment or prevention of trigeminal autonomic headache (TAC) in an individual in need is provided in this document, comprising administering to the individual a therapeutically effective amount of a dosage form disclosed in this document.

[0012] Also provided in this document is a method for treating or preventing trigeminal autonomic headache (TAC) in an individual in need, comprising administering to the individual a therapeutically effective amount of Compound 1, for example, from about 2.5 mg to about 90 mg of Compound 1. Petition 870230103657, dated 11 / 24 / 2023, page 8 / 151 5 / 129

[0013] In another aspect, a method of treatment or prevention of migraine in an individual in need is provided in this document, wherein the method comprises administering to the individual a therapeutically effective amount of a dosage form disclosed in this document.

[0014] This document provides, in part, a method for treating or preventing migraine in an individual in need, comprising administering to the individual a therapeutically effective amount of Compound 1, for example, from about 2.5 mg to about 90 mg of Compound 1.

[0015] In another aspect, a method is provided for the treatment or prevention of cortical spreading depression (CSD) in an individual in need, comprising administering to the individual a therapeutically effective amount of a dosage form disclosed in this document.

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

[0017] Also provided in this document is a method of treating or preventing one or more cranial neuropathies in an individual in need, comprising administering to the individual a therapeutically effective amount of a dosage form described in this document.

[0018] In another aspect, a method of treating or preventing one or more cranial neuropathies in an individual in need, comprising administering to the individual a therapeutically effective amount of Compound 1, for example, from 2.5 mg to about 90 mg of Compound 1. Petition 870230103657, dated 11 / 24 / 2023, page 9 / 151 6 / 129

[0019] In another aspect, the present description provides a method for producing Compound 1: or a pharmaceutically acceptable salt thereof, the method characterized by the fact that it comprises the steps of: (i) bringing a solution of 2,2,2-trifluoroethanol into contact with 5-bromo-2,3-difluoropyridine, thereby providing a compound of formula (II): F Br(II); (ii) bring the compound of formula (II) into contact with a palladium and bis(pinacolate)diboron catalyst, thus providing a compound of formula (III): (III); (iii) bring the compound of formula (III) into contact with a palladium and 2-bromo-5-chloro-pyrazine catalyst, thus providing a compound of formula (IV): F CI(IV); (iv) placing the compound of formula (IV) in contact with hydrazine, thus providing a compound of formula (V): Petition 870230103657, dated 11 / 24 / 2023, page 10 / 151 7 / 129 n'NH2 H(V); (v) bring the compound of formula (V) into contact with 2-bromo-2,2-difluoroacetyl chloride, thus providing a compound of formula (VI): FF θ (VI); (vi) placing the compound of formula (VI) in contact with an acid, thus providing a compound of formula (VII): (VII); and (vii) bring the compound of formula (VII) into contact with a silver and ethanol catalyst, thereby providing Compound 1 or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present description provides a method for producing Compound 1: or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is provided by contact with the compound of formula (VII): Petition 870230103657, dated 11 / 24 / 2023, page 11 / 151 8 / 129 (VII) with a silver and ethanol catalyst.

[0021] Other objects and advantages will become apparent to those skilled in the art from a consideration of the Brief Description of the Figures, Detailed Description, Examples, and subsequent Claims. BRIEF DESCRIPTION OF THE FIGURES

[0022] FIG. 1 shows the XRPD pattern of the raw material of Compound 1 and Compound 1 after jet milling.

[0023] FIG. 2 shows the result of dissolving ASD in capsules (2.5 mg and 10 mg active).

[0024] FIG. 3 shows the result of dissolving the mixture of 1:10 with MCC in capsule form (1 and 10 mg of active ingredient).

[0025] FIG. 4 shows the result of dissolving the mixture of 1:10 with MCC in capsule form (2.5 mg of active ingredient with 2% surfactant). DETAILED DESCRIPTION

[0026] As generally described in this document, the present description provides, in part, compounds, compositions and dosages or dosage forms useful for preventing and / or treating a disease, disorder or condition described in this document, for example, a disease, disorder or condition related to the aberrant function of a sodium ion channel, such as abnormal late sodium current (ALNI). Exemplary diseases, disorders or conditions include a neurological disorder (e.g., epilepsy or an epilepsy syndrome, a neurodevelopmental disorder or a neuromuscular disorder), a psychiatric disorder, pain, a gastrointestinal disorder, trigeminal autonomic headache (TAC), migraine, cranial neuropathy or neuropa Petition 870230103657, dated 11 / 24 / 2023, page 12 / 151 9 / 129 multiple cranial dysplasia and cortical spreading depression (CSD). Methods for preparing ion channel modulators are also provided in this document. Definitions

[0027] As used in this document, a pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described in this document include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.

[0028] As used in this document, a pharmaceutically acceptable salt refers to those salts that are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are proportionate to a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from acids and ba Petition 870230103657, dated 11 / 24 / 2023, page 13 / 151 10 / 129 suitable inorganic and organic salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by use of other methods used in the art, such as ion exchange.Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glycoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, and propionate salts. Stearate, succinate, sulfate, tartrate, thiocyanate, ptoluenesulfonate, undecanoate, valerate salts and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N+(C1—4alkyl)4 salts.Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0029] As used in this document, an individual to whom administration is contemplated includes, but is not limited to, human beings (i.e., a man or woman of any age range, for example, a pediatric individual (e.g., infant, child, adolescent) Petition 870230103657, dated 11 / 24 / 2023, page 14 / 151 11 / 129 cente) or adult individual (e.g., young adult, middle-aged adult, or elderly adult) and / or a non-human animal, for example, a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the individual is a human. In certain embodiments, the individual is a non-human animal. The terms human, patient, and individual are used interchangeably in this document.

[0030] Disease, disorder, and condition are used interchangeably in this document.

[0031] As used in this document, and unless otherwise specified, the terms treat, treating, and treatment encompass an action that occurs while an individual suffers from the specified disease, disorder, or condition, that reduces the severity of the disease, disorder, or condition, or slows or decreases the rate of progression of the disease, disorder, or condition (also therapeutic treatment).

[0032] As used in this document, the effective amount of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention may vary depending on factors such as the desired biological outcome, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, weight, health, and condition of the individual. An effective amount encompasses both therapeutic and prophylactic treatment.

[0033] As used in this document, and unless otherwise specified, a therapeutically effective amount of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to slow or minimize one or more symptoms associated with the disease. Petition 870230103657, dated 11 / 24 / 2023, page 15 / 151 12 / 129 disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term therapeutically effective amount may encompass an amount that improves overall therapy, reduces or prevents symptoms or causes of disease or condition, or increases the therapeutic effectiveness of another therapeutic agent.

[0034] As used in this document, the term amorphous refers to a solid in a non-crystalline state. Amorphous solids generally have a crystal-like short-range molecular arrangement, but no long-range order of molecular packing as found in crystalline solids. The solid-state form of a solid can be determined by polarized optical microscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or other standard techniques known to those skilled in the art.

[0035] As used in this document, crystalline refers to a solid with a highly regular chemical structure, that is, with long-range structural order in the crystal lattice. The molecules are arranged in a regular and periodic manner in the three-dimensional space of the lattice. In particular, a crystalline form can be produced as one or more unique crystalline forms.

[0036] The term peaks when referring to peaks in a pattern XRPD of a crystalline form of Compound 1 refers to a collection of certain peaks whose 2Θ values ​​over a range of 0°-40° are, as a whole, exclusively attributed to one of the crystalline forms of Compound 1.

[0037] As used in this document, the phrase amorphous solid dispersion refers to a solid comprising a substance Petition 870230103657, dated 11 / 24 / 2023, p. 16 / 151 13 / 129 pharmacological (e.g., Compound 1) and a dispersion polymer.

[0038] The term dispersion polymer refers to a polymer that allows the pharmaceutical substance (e.g., Compound 1) to be dispersed along such a way that a solid dispersion can be formed. The dispersion polymer may contain a mixture of two or more polymers. Examples of dispersion polymers include, but are not limited to, vinyl polymers and copolymers, vinylpyrrolidine vinylacetate copolymer (PVP-VA), polyvinyl alcohols, polyvinyl acetate copolymers with polyvinyl alcohol, polyvinylpyrrolidine (PVP), acrylate and methacrylate copolymers, methacrylic acid methacrylate copolymer (such as Eudragit®), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers (also referred to as poloxamers), polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate composite graft copolymer (such as Soluplus®), cellulosic polymers,such as hydroxypropyl methyl cellulose acetate (HPMCA), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), carboxymethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and carboxymethyl cellulose acetate butyrate (CMCAB), and the like.

[0039] As used in this document, the terms stable and stability refer to meaning that the evolution of the pharmacological substance (e.g., Compound 1) over time and / or under conditions Petition 870230103657, dated 11 / 24 / 2023, page 17 / 151 14 / 129 Specific environmental conditions (e.g., temperature, humidity, etc.) do not have significant effects on its quality, safety, and / or efficacy over a given period of time. This can be measured by the formation of degradation products (impurities), pH variation, appearance, microbial growth, and / or color, as exemplified in the experimental section. Typically, the compositions according to the invention are considered stable if at least 95% of the initial concentration of each of the pharmacological substances is found after 4 weeks at 25°C and / or if no substantial change in the appearance of the solution is observed during such a period of time and under such temperature conditions. Stability can be evaluated under a range of relative humidity (RH) conditions, typically between 60 and 75% RH.

[0040] As used in this document, the term particle size is defined as the diameter of a particle as determined by the Sympatec particle size analyzer. Compounds

[0041] This document describes pharmaceutical compositions or dosage forms comprising compounds that are useful for preventing and / or treating a disease, disorder or condition, for example, a disease, disorder or condition related to the aberrant function of a sodium ion channel, for example, abnormal late sodium current (INaL).

[0042] In one aspect, the present description is directed to a dosage form comprising Compound 1 represented by: and a pharmaceutically acceptable excipient. In some forms Petition 870230103657, dated 11 / 24 / 2023, page 18 / 151 15 / 129 des, Compound 1 is crystalline. In some embodiments, the crystalline form exhibits a powder method x-ray diffraction pattern comprising peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2. In some embodiments, the crystalline form exhibits a powder method x-ray diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.2. In some embodiments, the crystalline form exhibits a powder X-ray diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2 and 22.6±0.2. In some embodiments, the crystalline form exhibits a powder X-ray diffraction pattern substantially similar to that shown in FIG. 1.

[0043] In some embodiments, Compound 1 is amorphous. Dosage Forms and Compositions

[0044] In one aspect, the present description presents dosage forms or compositions useful for preventing and / or treating a disease, disorder or condition described in this document, for example, a disease, disorder or condition related to the aberrant function of a sodium ion channel, such as abnormal late sodium current (INaL).

[0045] This invention provides pharmaceutical compositions containing, as the active ingredient, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared Petition 870230103657, dated 11 / 24 / 2023, p. 19 / 151 16 / 129 in a manner well known in pharmaceutical technique (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.)

[0046] The pharmaceutical compositions may be administered in single or multiple doses by any of the accepted modes of administration of agents with similar uses, for example, as described in these patents and patent applications incorporated by reference, including rectally, buccally, intranasally and transdermally, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, by means of an impregnated or coated device, such as a stent, for example, or a cylindrical polymer inserted into the artery.

[0047] One mode of administration is parenteral, particularly by injection. Forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oily suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or a sterile aqueous solution and similar pharmaceutical carriers. Aqueous solutions in saline solution are also conventionally used for injection, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol and the like (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. Adequate fluidity may be maintained, for example, by the use of a coating, such as lecithin, by maintaining the required particle size in the case of dispersion and by the use of surfactants.The prevention of microorganism activity can be achieved through various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and others. Petition 870230103657, dated 11 / 24 / 2023, p. 20 / 151 17 / 129 similar.

[0048] Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required quantity into the appropriate solvent with various other ingredients, as enumerated above, as necessary, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the other necessary ingredients of those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously filtered solution thereof.

[0049] Oral administration is another route for administering compounds according to the invention. Administration may be via capsules or tablets, or the like. When producing pharmaceutical compositions that include at least one compound described in this document, the active ingredient is generally diluted by an excipient and / or enclosed within such a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier, or medium for the active ingredient.Therefore, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, packs, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0050] Some examples of suitable excipients include lacto Petition 870230103657, dated 11 / 24 / 2023, page 21 / 151 18 / 129 se, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulations may additionally include: lubricating agents, such as talc, magnesium stearate and mineral oil; humectants; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweetening agents; and flavorings.

[0051] The compositions of the invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to the patient through the use of 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 drugpolymer matrix formulations. Examples of controlled-release systems are given in US Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention uses transdermal delivery devices (patches). These 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 the delivery of pharmaceutical agents is well known in the art.See, for example, US Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​These patches can be designed for continuous, pulsed, or on-demand delivery of pharmaceutical agents.

[0052] The compositions are preferably formulated in a unit dosage form. The term unit dosage forms refers to physically discrete units suitable as unit dosages for human and other mammalian individuals, each unit Petition 870230103657, dated 11 / 24 / 2023, page 22 / 151 19 / 129 containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of a compound described in this document and for parenteral administration, preferably 0.1 to 700 mg of a compound described in this document. It will be understood, however, that the amount of the compound actually administered will generally be determined by a physician in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms and the like.

[0053] To prepare solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is understood that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0054] The tablets or pills of the present invention may be coated or otherwise composed to provide a dosage form that offers the advantage of prolonged action, or to protect against acidic stomach conditions. For example, the tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope relative to the former. The two components may be separated Petition 870230103657, dated 11 / 24 / 2023, page 23 / 151 20 / 129 of these are provided by an enteric coating that serves to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or be delayed in its release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0055] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. Preferably, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized using inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a tent-type face mask or intermittent positive pressure breathing apparatus. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation appropriately.

[0056] In one aspect, a dosage form or a composition in a dosage form comprising: from about 0.1 mg to about 500 mg (for example, from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg) of Compound 1 is provided in this document; and a pharmaceutically acceptable excipient.

[0057] In some embodiments, the dosage form or a composition in a dosage form comprises about 2.5 Petition 870230103657, dated 11 / 24 / 2023, p. 24 / 151 21 / 129 mg to about 150 mg (for example, from about 10 mg to about 150 mg, from about 20 mg to about 150 mg, from about 40 mg to about 150 mg, from about 60 mg to about 150 mg, from about 80 mg to about 150 mg, from about 100 mg to about 150 mg, from about 10 mg to about 120 mg, from about 20 mg to about 120 mg, from about 40 mg to about 120 mg, from about 60 mg to about 120 mg, from about 80 mg to about 120 mg, from about 100 mg to about 120 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 40 mg to about 100 mg, from about 60 mg to about 100 mg, from about 80 mg to about 100 mg, from about 10 mg to about 80 mg, from about 20 mg to about 80 mg, from about 40 mg to about 80 mg, from about 60 mg to about 80 mg, from about 10 mg to about 60 mg, from about 20 mg to about 60 mg, from about 40 mg to about 60 mg, from about 70 mg to about 120 mg, from about 70 mg to about 100 mg,from about 50 mg to about 120 mg, from about 50 mg to about 90 mg, from about 30 mg to about 120 mg, from about 30 mg to about 60 mg, from about 30 mg to about 80 mg, from about 30 mg to about 100 mg) of Compound 1.

[0058] In some embodiments, the dosage form or a composition in a dosage form comprises from about 1 mg to about 100 mg (for example, 1 of about 1 mg to about 80 mg, from about 1 mg to about 50 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about mg, from about 5 mg to about 100 mg, from about 5 mg to about 80 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg) of Compound 1.

[0059] In some embodiments, the dosage forms or a composition in a dosage form comprises approximately 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 Petition 870230103657, dated 11 / 24 / 2023, page 25 / 151 22 / 129 mg, 110 mg, 100 mg, approximately 99 mg, approximately 98 mg, approximately 97 mg, approximately 96 mg, approximately 95 mg, approximately 94 mg, approximately 93 mg, approximately 92 mg, approximately 80 mg, approximately 68 mg, approximately 64 mg, approximately 60 mg, approximately 56 mg, approximately 52 mg, approximately 40 mg, approximately 91 mg, approximately 90 mg, approximately 75 mg, approximately 70 mg, approximately 67 mg, approximately 66 mg, approximately 63 mg, approximately 62 mg, approximately 59 mg, approximately 58 mg, approximately 55 mg, approximately 54 mg, approximately 51 mg, approximately 50 mg, approximately 35 mg, approximately 30 mg, approximately 85 mg, approximately 69 mg, approximately 65 mg, approximately 61 mg mg, about 57mg mg, about 53mg mg, about 45mg mg, about 25mg about 20mg, about 15mg, about 10mg, about 7mg, about 5mg, about 2.5mg, about 2mg, about 1.5mg, or about 1mg of Compound 1.

[0060] In another aspect, the present description provides a dosage form or a composition in a dosage form comprising: a plurality of particles of Compound 1; and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of Compound 1 in the dosage form is from about 0.1 mg to about 500 mg (for example, 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).

[0061] In some forms, the plurality of particles of Compound 1 in dosage form or composition is from about 2.5 mg to about 150 mg (e.g., from about 10 mg to about 150 mg, from about 20 mg to about 150 mg, from about 70 mg to about 120 mg, from about 30 mg to about 60 mg, about 100 mg, about 50 mg).

[0062] In certain embodiments, 10% of the particle plurality of Compound 1 have a particle size smaller than about 1 μm. In other embodiments, 50% of the particle plurality of Compound 1 have a particle size smaller than about 1 μm. Petition 870230103657, dated 11 / 24 / 2023, page 26 / 151 23 / 129 to 1 have a particle size smaller than about 4 μm. In some embodiments, 50% of the plurality of particles of Compound 1 have a particle size smaller than about 2 μm. In certain embodiments, 90% of the plurality of particles of Compound 1 have a particle size smaller than about 30 μm (e.g., smaller than about 15 μM). In other embodiments, 90% of the plurality of particles of Compound 1 have a particle size smaller 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.

[0063] In some embodiments, 10% of the plurality of particles of Compound 1 have a particle size less than about 1 μm, 50% of the plurality of particles of Compound 1 have a particle size less than about 4 μm, and 90% of the plurality of particles of Compound 1 have a particle size less than about 30 μm.

[0064] In some embodiments, the dosage form or composition is configured for oral administration.

[0065] In some embodiments, the dosage form is a solid form.

[0066] In some forms, the dosage is in the form of a capsule.

[0067] In some embodiments, the pharmaceutical excipient in the capsule is a filler (e.g., cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starches and partially pregelatinized starches), anhydrous lactose, lactose monohydrate, sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0068] In some forms, the ratio between Composite 1 and the filling is approximately 1:10. In some forms, the ratio between Composite 1 and the filling is approximately 1:10. In some Petition 870230103657, dated 11 / 24 / 2023, p. 27 / 151 24 / 129 but modalities, the ratio between Composite 1 and the filling is approximately 1:5. In some modalities, the ratio between Composite 1 and the filling is approximately 1:4. In some modalities, the ratio between Composite 1 and the filling is approximately 1:3. In some modalities, the ratio between Composite 1 and the filling is approximately 1:2.

[0069] In some embodiments, the capsule also comprises a lubricant (for example, magnesium stearate, calcium stearate, stearic acid, talc, silica and fats).

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

[0071] In some embodiments, the pharmaceutical excipient in the mixture is a filler (e.g., microcrystalline cellulose or starch). In some embodiments, the ratio between Compound 1 and the filler is about 1:1. In some embodiments, the ratio between Compound 1 and the filler is about 1:10. In some embodiments, the ratio between Compound 1 and the filler is about 1:5. In some embodiments, the ratio between Compound 1 and the filler is about 1:4. In some embodiments, the ratio between Compound 1 and the filler is about 1:3. In some embodiments, the ratio between Compound 1 and the filler is about 1:2.

[0072] In some embodiments, the dosage form is a liquid form.

[0073] In some forms, the dosage is in the form of a solution.

[0074] In some embodiments, the pharmaceutical excipient in the solution is selected from the group consisting of a filler (e.g., polymer (e.g., PEG 400)), an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40), Petition 870230103657, dated 11 / 24 / 2023, page 28 / 151 25 / 129 a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS), a vitamin derivative (e.g., Vitamin ETPGS)), a solvent (e.g., propylene glycol, ethanol, diethylene glycol monoethyl ether (or Transcutol HP)).

[0075] In some embodiments, the concentration of Compound 1 in the solution is from about 0.1 mg / mL to about 10 mg / mL (for example, from about 0.5 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 8 mg / mL, from about 1 mg / mL to about 8 mg / mL, from about 2 mg / mL to about 8 mg / mL, from about 3 mg / mL to about 8 mg / mL, from about 4 mg / mL to about 8 mg / mL, from about 5 mg / mL to about 8 mg / mL, from about 6 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 6 mg / mL, from about 1 mg / mL to about 6 mg / mL, from about 2 mg / mL to about 6 mg / mL, from about 3 mg / mL to about 6 mg / mL, from about 4 mg / mL to about 6 mg / mL, from about 0.5 mg / mL to about 4 mg / mL,from about 1 mg / mL to about 4 mg / mL, or from about 2 mg / mL to about 4 mg / mL).

[0076] 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.

[0077] In some embodiments, the dosage form or composition comprises: from about 20% to about 60% (e.g., from about 25% to about 55%, from about 30% to about 50%, from about Petition 870230103657, dated 11 / 24 / 2023, p. 29 / 151 26 / 129 35% to about 45%, from about 37% to about 42%, or about 40% by weight, of a filler (for example, a polymer (for example, PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 6000, or PEG 8000)); from about 3% to about 25% (for example, from about 3% to about 20%, from about 5% to about 13%, from about 8% to about 13%, from about 5% to about 15%, or about 10%) by weight of an emulsifier (for example, a castor oil derivative (e.g., Kolliphor RH40, macrogol 25 cetostearyl ether (e.g., Cremophor® A25), macrogol 6 cetostearyl ether (e.g., Cremophor® A6), macrogol 35 glycerol ricinoleate (e.g., Cremophor® EL), macrogol 40 glycerol hydroxystearate (e.g., Cremophor® RH 40)); and from about 30% to about 70% (e.g., from about 35% to about 65%, from about 40% to about 60%, from about 45% to about 55%, or about 50% by weight of water; where the concentration of Compound 1 is approximately 0.5 mg / mL or approximately 0.25 mg / mL.

[0078] In certain embodiments, the dosage form or composition comprises: from about 35% to about 45% by weight of a filler (e.g., a polymer (e.g., PEG 400)); from about 5% to about 15% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40)); and from 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.

[0079] In some embodiments, the dosage form or composition comprises: from about 40% to about 75% (e.g., from about 45% to about 70%, from about 50% to about 65%, from about Petition 870230103657, dated 11 / 24 / 2023, p. 30 / 151 27 / 129 55% to about 60%, or about 58%) by weight of an emulsifier (for example, a castor oil derivative (e.g., Kolliphor RH40), a macrogol 25 cetostearyl ether (e.g., Cremophor® A25), a macrogol 6 cetostearyl ether (e.g., Cremophor® A6), a macrogol 35 glycerol rhinoleate (e.g., Cremophor® EL), a macrogol 40 glycerol hydroxystearate (e.g., Cremophor® RH 40)); from about 10% to about 35% (for example, from about 10% to about 30%, from about 10% to about 25%, from about 15% to about 25%, or from about 15% to about 20%) by weight of a surfactant (for example, a glyceride (e.g., Labrafil M2125 CS), caprylcaproyl macrogolglycerides (e.g., Labrasol), natural triglyceride-based oil (e.g., olive oil, sesame oil, coconut oil, palm kernel oil)); from about 3% to about 20% (for example, from about 3% to about 15%, from about 5% to about 15%, or from about 5% to about 10%) by weight of propylene glycol; and 10% to about 35% (e.g., from about 10% to about 30%, from about 10% to about 25%, from about 15% to about 25%, or from about 15% to about 20%) by weight of ethanol; where the concentration of Compound 1 is from about 5 mg / mL to about 10 mg / mL (for example, about 5 mg / mL, about 7.5 mg / mL, or about 10 mg / mL) or from about 2.5 mg to about 5 mg / mL.

[0080] In certain embodiments, the dosage form or composition comprises: from about 55% to about 60% by weight of an emulsifier (for example, a castor oil derivative (e.g., Kolliphor RH40); from about 15% to about 20% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS); from about 5% to about 10% by weight of propylene glycol; and of Petition 870230103657, dated 11 / 24 / 2023, page 31 / 151 28 / 129 approximately 15% to approximately 20% by weight of ethanol; wherein the concentration of Compound 1 is approximately 5 mg / mL to approximately 10 mg / mL or approximately 2.5 mg to approximately 5 mg / mL.

[0081] In some embodiments, the dosage form comprises: from about 50% to about 85% (for example, from about 55% to about 80%, from about 60% to about 75%, or from about 65% to about 70%) by weight of an emulsifier (for example, a castor oil derivative (e.g., Kolliphor RH40), macrogol 25 cetostearyl ether (e.g., Cremophor® A25), macrogol 6 cetostearyl ether (e.g., Cremophor® A6), macrogol 35 glycerol rhinoleate (e.g., Cremophor® EL), macrogol 40 glycerol hydroxystearate (e.g., Cremophor® RH 40)); from about 10% to about 30% (for example, from about 10% to about 25%, from about 15% to about 25%, or from about 18% to about 23%) by weight of a surfactant (for example, a glyceride (e.g., Labrafil M2125 CS), caprylcaproyl macrogolglycerides (e.g., Labrasasol), natural triglyceride-based oil (e.g., olive oil, sesame oil, coconut oil, palm kernel oil)); and from about 3% to about 20% (for example, from about 3% to about 15%, from about 5% to about 15%, from about 5% to about 12%, or from about 7% to about 12%) by weight of propylene glycol; where the concentration of Compound 1 is from about 1 mg / mL to about 10 mg / mL (for example, 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.

[0082] In certain embodiments, the dosage form or composition comprises: from about 65% to about 70% by weight of a Petition 870230103657, dated 11 / 24 / 2023, p. 32 / 151 29 / 129 emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); from about 18% to about 23% by weight of a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS); and from about 7% to about 12% by weight of propylene glycol; wherein the concentration of Compound 1 is from about 1 mg / mL to about 10 mg / mL or from 0.5 mg / mL to about 5 mg / mL.

[0083] In some embodiments, the dosage form or composition comprises: from about 20% to about 60% (for example, from about 25% to about 55%, from about 30% to about 50%, 35% to about 45%, about 35%, about 40% or about 45%) by weight of diethylene glycol monoethyl ether (for example, Transcutol HP); from about 1% to about 20% (for example, from about 3% to about 18%, from about 5% to about 18%, from about 5% to about 15%, from about 8% to about 12%, or about 10%) by weight of a surfactant (for example, a vitamin derivative (e.g., vitamin ETPGS)); and from about 20% to about 80% (for example, from about 25% to about 75%, from about 30% to about 70%, from about 35% to about 55%, from about 40% to about 60%, or from about 45% to about 55%) by weight of water; wherein the concentration of Compound 1 is from about 1 mg / mL to about 5 mg / mL (for example, 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.

[0084] In certain embodiments, the dosage form or composition comprises: from about 35% to about 45% by weight of diethylene glycol monoethyl ether (Transcutol HP); from about 5% to about 15% by weight of a surfactant (e.g., a glyceride (e.g., a vitamin derivative (e.g., vitamin ETPGS)); and Petition 870230103657, dated 11 / 24 / 2023, p. 33 / 151 30 / 129 of about 40% to about 60% by weight of water; where 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.

[0085] In some embodiments, the dosage form or composition comprises: from about 30% to about 40% by weight of an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40); from about 40% to about 50% by weight of a surfactant (e.g., a glyceride (e.g., Capmul MCM C8); from about 5% to about 15% by weight of a plasticizer (e.g., triethyl citrate); and from about 5% to about 15% by weight of a solvent (e.g., ethanol).

[0086] In other embodiments, the dosage form or composition comprises: from about 35% to about 45% by weight of a propylene glycol monocaprylate (e.g., Capryol 90); from about 15% to about 25% by weight of a glyceride (e.g., caprylocaproyl macrogolglycerides (e.g., Labrasol)) and from about 35% to 45% by weight of diethylene glycol monoethyl ether (e.g., Transcutol HP).

[0087] In certain forms, the dosage is in the form of a suspension.

[0088] In some embodiments, the concentration of Compound 1 in the suspension is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25mg / mL.

[0089] In some embodiments, the disclosed suspension may be further diluted with a solvent (e.g., water), wherein the concentration Petition 870230103657, dated 11 / 24 / 2023, p. 34 / 151 31 / 129 The tensile strength of the diluted solution is approximately 50% to approximately 90% of the solution before dilution.

[0090] In some embodiments, the concentration of Compound 1 in the suspension is from about 0.1 mg / mL to about 10 mg / mL (for example, from about 0.5 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 8 mg / mL, from about 1 mg / mL to about 8 mg / mL, from about 2 mg / mL to about 8 mg / mL, from about 3 mg / mL to about 8 mg / mL, from about 4 mg / mL to about 8 mg / mL, from about 5 mg / mL to about 8 mg / mL, from about 6 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 6 mg / mL, from about 1 mg / mL to about 6 mg / mL, from about 2 mg / mL to about 6 mg / mL, from about 3 mg / mL to about 6 mg / mL, from about 4 mg / mL to about 6 mg / mL, from about 0.5 mg / mL to about 4 mg / mL,from about 1 mg / mL to about 4 mg / mL, or from about 2 mg / mL to about 4 mg / mL).

[0091] In some embodiments, the pharmaceutical excipient in the suspension comprises: from about 0.1% to about 5% (for example, from about 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, about 0.1%, about 0.3%, about 0.5%, about 1%, about 2%, or about 3%) by weight of a filler (for example, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium hydroxypropylmethylcellulose, methylcellulose (e.g., 400 cP MC), methylethylcellulose, sodium carboxymethylcellulose, Aerosil (silicon dioxide), alcohol Petition 870230103657, dated 11 / 24 / 2023, page 35 / 151 32 / 129 cetostearyl alcohol, cetyl alcohol, stearyl alcohol, Gelucires 33 / 01, 39 / 01 and 43 / 01, glyceryl behenate (Compritol 888 A TO), glyceryl palmitostearate (Precirol AT05), Softisans 100, 142, 378 and 649, stearyl alcohol carbomer, xanthan gum, maltodextrin, acacia, tragacanth, povidone, or polyvinyl alcohol); and from about 0.1% to about 3% (for example, from about 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.2% to about 2%, from about 0.2% to about 1%, from about 0.2% to about 0.5%, from about 0.1% to about 0.3%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, or about 1%) by weight of an emulsifier (for example, polyethylene sorbate (e.g., Tween®), long-chain carboxylic acid esters of sorbitan (e.g., Span®), ethylene block copolymers or propylene oxide (Pluronic®), polyglycolized glycerides Labrasol®, Labrafil® and Labrafac®),Sorbitan esters of oleate, stearate, laurate or other long-chain carboxylic acids, polyethylene-polypropylene glycol block copolymers (e.g., Poloxamer 188), other long-chain carboxylic acid esters of sorbitan or sucrose, mono- and diglycerides, PEG derivatives of caprylic / capric triglycerides.

[0092] In certain embodiments, the pharmaceutical excipient comprises: about 0.5% by weight of a filler (e.g., methylcellulose, e.g., 400 cP MC); and about 0.2% by weight of an emulsifier (e.g., Tween, e.g., Tween 80, e.g., Poloxamer 188).

[0093] In some embodiments, the pharmaceutical excipient further comprises about 1% by weight of a preservative solution (e.g., paraben solution).

[0094] In some forms, the dosage form is in Petition 870230103657, dated 11 / 24 / 2023, page 36 / 151 33 / 129 amorphous solid dispersion form.

[0095] In some embodiments, the pharmaceutical excipient in the amorphous solid dispersion is a polymer (e.g., Soluplus, Eudragit, HPMCASMF, PVP-VA, methyl methacrylate copolymer of methylacrylic acid, HPMCP, CAP, HPMCAS, HPMCP H-55).

[0096] In some embodiments, the dosage form or composition is stable (e.g., chemically stable) at 25°C and 60% RH for 7 days, 14 days, 21 days, 28 days, 1 month, 3 months, 5 months, 6 months, 12 months, 24 months or 36 months.

[0097] 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, for 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). Methods for Manufacturing Dosage Forms

[0098] In another aspect, the present description provides methods for producing dosage forms, as disclosed in this document. Such methods are, for example, described in the Example section. In some embodiments, the dosage forms contemplated may be in the form of a capsule, mixture (mixture), solution, suspension or ASD. Methods of use

[0099] The formulations described in this document are generally useful for modulating sodium channel activity and are useful in treating conditions related to aberrant sodium channel ion channel function, for example, abnormal late sodium current (INaL). In some embodiments, a formulation comprising Compound 1, as provided by this description, is effective in treating epilepsy or an epilepsy syndrome, a Petition 870230103657, dated 11 / 24 / 2023, page 37 / 151 34 / 129 neurodevelopmental disorder, pain, or a neuromuscular disorder. A supplied formulation comprising Compound 1, or a pharmaceutically acceptable salt thereof, may also modulate all sodium ion channels, or may be specific to only one or a plurality of sodium ion channels, for example, NaV 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 and / or 1.9.

[00100] In one aspect, the present invention provides a method of treating a condition related to the aberrant function of a sodium ion channel in an individual in need, comprising administering to the individual a therapeutically effective amount of Compound 1, for example, from about 2.5 mg to about 90 mg of Compound 1. Epilepsy Syndromes and Epilepsy

[00101] The formulations described in this document (e.g., a dosage form, a composition in a dosage form comprising Compound 1) are useful in the treatment of epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which the activity of nerve cells in the brain is altered, causing seizures or periods of unusual behavior, sensations, and sometimes loss of consciousness. Seizure symptoms vary widely, from a simple blank stare for a few seconds to repeated contractions of the arms or legs during a seizure.

[00102] Epilepsy can involve a generalized seizure or a partial or focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may scream or make some sound, become rigid for several seconds to a minute, and then make rhythmic movements of their arms and legs. The eyes are usually open, the person may appear not to be breathing and may even turn blue. The return to consciousness is gradual, and the person may be confused for minutes. Petition 870230103657, dated 11 / 24 / 2023, page 38 / 151 35 / 129 hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In a partial or focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain that shows abnormal electrical activity, the symptoms may vary.

[00103] Epilepsy, as described in this document, includes generalized, partial, complex partial, tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[00104] The formulations described in this document (e.g., a dosage form, a composition in a dosage form comprising Compound 1) may also be useful in the treatment of epilepsy syndromes. Severe syndromes caused by diffuse brain dysfunction, at least in part due to some aspect of epilepsy, are also referred to as epileptic encephalopathies. They are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for example, West syndrome.

[00105] In some forms, epilepsy syndrome includes epileptic and developmental encephalopathy (EDE), Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[00106] In some forms, epilepsy syndrome or epilepsy is a genetic epilepsy or a genetic epilepsy syndrome. In some forms, epilepsy or an epilepsy syndrome comprises epileptic encephalopathy, epileptic and developmental encephalopathy, epileptic encephalopathy with SCN1A mutations, Petition 870230103657, dated 11 / 24 / 2023, page 39 / 151 36 / 129 SCN2A, SCN8A, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable epilepsy in children with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A gene-associated epileptic encephalopathy, focal epilepsy with SCN3A mutation, pediatric cryptogenic partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migratory partial seizures of childhood, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[00107] In some embodiments, the methods described in this document further comprise the identification of an individual who has epilepsy or an epileptic syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable epilepsy in children with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A gene-associated epileptic encephalopathy, focal epilepsy with SCN3A mutation, pediatric cryptogenic partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of childhood, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP),Epileptic encephalopathy KCNQ2 and epileptic encephalopathy KCNT1) before administering a formulation described in this document.

[00108] In one aspect, the present invention provides a method Petition 870230103657, dated 11 / 24 / 2023, p. 40 / 151 37 / 129 treatment of epilepsy or epilepsy syndrome (e.g., epileptic encephalopathy, epileptic and developmental encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable epilepsy in children with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal / infantile seizures, SCN2A gene-associated epileptic encephalopathy, focal epilepsy with SCN3A mutation, pediatric cryptogenic partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of childhood, autosomal dominant nocturnal frontal lobe epilepsy, death sudden unexpected seizure in epilepsy (SUDEP)Epileptic encephalopathy KCNQ2 and epileptic encephalopathy KCNT1) comprising administering to an individual in need a formulation described in this document.

[00109] A formulation of the present invention (for example, a dosage form, a composition in a dosage form comprising Compound 1) can also be used to treat epilepsy or an epilepsy syndrome (for example, epileptic encephalopathy) in which the individual has a mutation 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, GA-BRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, Petition 870230103657, dated 11 / 24 / 2023, p. 41 / 151 38 / 129 STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[00110] In some embodiments, the methods described in this document further comprise the identification of an individual with a mutation 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, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX before administering a formulation described in this document.

[00111] A formulation of the present invention can also be used to treat epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy) in which the individual has a mutation 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, SNAP25, COL4A3BP, GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRD, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, ABAT, ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ANK2, ANK3, DISC1, DLC1, DLC2, DNAI1, FGF13, GABARAP, GABARAPL1, GABARAPL2, GABBR1, GAD1, GAD2, GLS, GLS2, GLUL, GNAI1, Petition 870230103657, dated 11 / 24 / 2023, page 42 / 151 39 / 129 GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GPHN, HAP1, KCNB2, KCNC2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, PRKACB, PRKACG, PRKCA, PRKCB, PRKCG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5, SLC6A11, SLC6A13, SRC, TRAK1, TRAK2, CHRNA1, CHRNA10, CHRNA3, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB3, CHRNB4, CHRND, CHRNE, CHRNG, GRIA1, GRIA2, GRIA3, GRIA4, GRIK1, GRIK2, GRIK3, GRIK4, GRIK5, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRID1, GRID2, SCN10A, SCN11A, SCN2B, SCN3B, SCN4A, SCN4B, SCN5A, SCN7A, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, KCNA1, KCNA10, KCNA3, KCNA4, KCNA5, KCNA6,KCNA7, KCNAB1, KCNAB2, KCNAB3, KCNB2, KCNC2, KCNC3, 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.

[00112] In some embodiments, the methods described in this document further comprise identifying an individual having a mutation 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, SNAP25, COL4A3BP, Petition 870230103657, dated 11 / 24 / 2023, page 43 / 151 40 / 129 GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRD, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, ABAT, ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ANK2, ANK3, DISC1, DLC1, DLC2, DNAI1, FGF13, GABARAP, GABARAPL1, GABARAPL2, GABBR1, GAD1, GAD2, GLS, GLS2, GLUL, GNAI1, GNAI2, GNAI3, GNB1, GNB2, GNB3, GNB4, GNB5, GNG10, GNG11, GNG12, GNG13, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GPHN, HAP1, KCNB2, KCNC2, KCNC3, KCNJ6, KIF5A, KIF5B, KIF5C, MAGI, MKLN1, MYO5A, NLGN2, NRXN1, NSF, PFN1, PLCL1, PRKACA, PRKACB, PRKACG, PRKCA, PRKCB, PRKCG, RAFT1, RDX, SCN2B, SCN3A, SEMA4D, SLC12A2, SLC12A5, SLC32A1, SLC38A1, SLC38A2, SLC38A3, SLC38A5 SLC6A11, SLC6A13, SRC, TRAK1, TRAK2, CHRNA1, CHRNA10, CHRNA3, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB3, CHRNB4, CHRND, CHRNE, CHRNG, GRIA1, GRIA2, GRIA3, GRIA4, GRIK1, GRIK2, GRIK3, GRIK4, GRIK5, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRID1, GRID2, SCN10A, SCN11A, SCN2B, SCN3B, SCN4A, SCN4B, SCN5A, SCN7A, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, KCNA1, KCNA10, KCNA3, KCNA4, KCNA5, KCNA6,KCNA7, KCNAB1, KCNAB2, KCNAB3, KCNB2, KCNC2, KCNC3, 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 before administering a formulation described in this document. Petition 870230103657, dated 11 / 24 / 2023, page 44 / 151 41 / 129 Neurodevelopmental Disorders

[00113] The formulations described in this document (for example, a dosage form, a composition in a dosage form comprising Compound 1) may be useful in the treatment of a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder comprises autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy. In some modalities, the methods described in this document also include the identification of an individual with a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13 deletion syndrome).3, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) before administration of a formulation described in this document.

[00114] In one aspect, the present invention provides a method of treating a neurodevelopmental disorder (for example, autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) comprising administering to an individual in need thereof a formulation described herein (for example, a dosage form, a composition in a dosage form comprising Compound 1). Pain Petition 870230103657, dated 11 / 24 / 2023, page 45 / 151 42 / 129

[00115] The formulations described in this document (for example, a dosage form, a composition in a dosage form comprising Compound 1) may be useful in the treatment of pain. In some modalities, pain comprises neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or a headache-related disorder.In some embodiments, the methods described in this document further comprise identifying an individual with pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or a related headache disorder) prior to administration of a formulation described in this document (e.g., dosage form, dosage composition, a composition in a dosage form comprising Compound 1).

[00116] In one aspect, the present invention provides a method of treating pain (for example, neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia or a headache-related disorder) comprising administering to an individual in need thereof a formulation described in this document (for example, a dosage form, a composition in a dosage form comprising Compound 1). Neuromuscular Disorders

[00117] The formulations described in this document (for example, a dosage form, a composition in a dosage form comprising Compound 1) may be useful in the treatment of a neuromuscular disorder. In some modalities, the neuro disorder Petition 870230103657, dated 11 / 24 / 2023, page 46 / 151 43 / 129 muscular includes amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation. In some embodiments, the methods described in this document further comprise the identification of an individual with a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) prior to administration of a formulation described in this document.

[00118] In one aspect, the present invention provides a method of treating a neuromuscular disorder (for example, amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-enhanced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) comprising administering to an individual in need of a formulation described in this document (for example, a composition in a dosage form comprising Compound 1). Other Disorders

[00119] In some embodiments, a formulation of the present invention (for example, a dosage form, a composition in a dosage form comprising Compound 1) may have appropriate pharmacokinetic properties such that it may be active with respect to the central and / or peripheral nervous system. In some embodiments, the formulations provided herein (for example, a dosage form, a composition in a dosage form comprising Compound 1) are used to treat one of the Petition 870230103657, dated 11 / 24 / 2023, page 47 / 151 44 / 129 Cardiovascular disease, such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's angina (variant), stable angina, unstable angina, ischemia and reperfusion injury in the kidney, liver and brain, exercise-induced angina, pulmonary hypertension, congestive heart disease, including diastolic and systolic heart failure, recurrent ischemia, cerebral ischemia, stroke, renal ischemia, organ transplant-associated ischemia, acute coronary syndrome, peripheral arterial disease, intermittent claudication, and myocardial infarction.

[00120] In some embodiments, the formulations provided in this document (for example, a dosage form, a composition in a dosage form comprising Compound 1) may be used in the treatment of diseases affecting the neuromuscular system, resulting in itching, convulsions or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and diabetes-related disease states such as diabetic peripheral neuropathy. In some embodiments, a disclosed method comprises administering the pharmaceutical composition.

[00121] In some embodiments, a method of treatment for a neurological disorder or a psychiatric disorder is provided in this document, wherein the method comprises administering to an individual in need a formulation disclosed in this document (for example, a dosage form, a composition in a dosage form comprising Compound 1). Oncology

[00122] In one aspect, the present description provides a method of treating a cancer, wherein the method comprises administering to the individual in need an oral dosage form or composition in a dosage form disclosed in the present description. Petition 870230103657, dated 11 / 24 / 2023, page 48 / 151 45 / 129 Trigeminal-Autonomic Headache

[00123] The compounds, dosage forms, and compositions described in this document (e.g., Compound 1, a dosage form, or a composition comprising Compound 1) are useful in the treatment of trigeminal autonomic cephalalgias (TACs). TACs are a group of primary headaches characterized by unilateral pain, a relatively short duration of symptoms, and associated ipsilateral cranial autonomic signs. TACs may include cluster headache (CH), paroxysmal hemicrania (PH), hemicrania continua (HC), unilateral short-duration neuralgiform headache with conjunctival and lacrimal hyperemia (SUNCT), unilateral short-duration neuralgiform headache with cranial autonomic symptoms (SUNA), and long-duration autonomic symptoms with hemicrania (LASH). Despite their common elements, trigeminal autonomic cephalalgias differ, for example, in the duration and frequency of the attack and in the response to therapy.

[00124] In some embodiments, the present invention provides a method of treating PH, HC, SUNCT, SUNA, and / or LASH using a dosage form described in this document. In some embodiments, the present invention provides a method of treating SUNCT using a compound, dosage form, or composition described in this document (e.g., Compound 1, a dosage form, or a composition comprising Compound 1). In some embodiments, the present invention provides a method of treating SUNA using a provided compound, a dosage form, or a composition described in this document (e.g., Compound 1, a dosage form, or a composition comprising Compound 1). In another aspect, a method of treating or preventing trigeminal autonomic cephalalgia (TAC) in an individual in need is provided in this document, comprising Petition 870230103657, dated 11 / 24 / 2023, page 49 / 151 46 / 129 administer to the individual a therapeutically effective amount of a compound, dosage form or composition disclosed in this document (for example, Compound 1, a dosage form or a composition comprising Compound 1).

[00125] In another aspect, the present invention provides a method of treating or preventing trigeminal autonomic headache (TAC) in an individual in need, comprising administering to the individual a therapeutically effective amount of Compound 1, for example, from 2.5 mg to 90 mg of Compound 1.

[00126] In some modalities, TAC is selected from the group consisting of paroxysmal hemicrania, continuous hemicrania, attacks of short-duration unilateral neuralgiform headache with conjunctival injection and lacrimation (SUNCT), attacks of short-duration unilateral neuralgiform headache with cranial autonomic symptoms (SUNA), and long-duration autonomic symptoms with hemicrania.

[00127] In other modalities, TAC is a unilateral neuralgiform headache attack of short duration.

[00128] In certain sports, the TAC is SUNCT. In some sports, the TAC is SUNA.

[00129] In other modalities, the individual has an inadequate response to at least one medication used to treat a TAC. Migraines

[00130] The compounds, dosage forms and compositions described in this document (for example, Compound 1, a dosage form or a composition comprising Compound 1) are useful in the treatment of migraines. Migraine is a primary headache disorder characterized by recurrent headaches that are moderate to severe. As described in this document, a migraine can be migraine without aura, migraine with aura, migraine. Petition 870230103657, dated 11 / 24 / 2023, p. 50 / 151 47 / 129 hemiplegic pain, familial hemiplegic migraine (FHM), familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 3 (FHM3), familial hemiplegic migraine type 4 (FHM4) and sporadic hemiplegic migraine (SHM).

[00131] In some embodiments, the present invention provides a method of treating migraine without aura, migraine with aura, hemiplegic migraine, FHM, FHM1, FHM2, FHM3, FHM4 and / or SHM using a provided compound. In some embodiments, the present invention provides a method of treating migraine without aura, migraine with aura, FHM1, FHM2, FHM4 and / or SHM using a provided compound, dosage form or composition (for example, Compound 1, a dosage form or a composition comprising Compound 1). In some embodiments, the present invention provides a method of treating migraine without aura using a provided compound. In some embodiments, the present invention provides a method of treating migraine with aura using a provided compound, dosage form or composition (for example, Compound 1, a dosage form or a composition comprising Compound 1).In some embodiments, the present invention provides a method for treating FHM1, FHM2, and / or FHM4 using a provided compound. In some embodiments, the present invention provides a method for treating SHM using a provided compound, dosage form, or composition (e.g., Compound 1, a dosage form, or a composition comprising Compound 1).

[00132] In another aspect, a method of treating or preventing migraine in an individual in need is provided in this document, comprising administering to the individual a therapeutically effective amount of a compound, a dosage form, Petition 870230103657, dated 11 / 24 / 2023, page 51 / 151 48 / 129 a composition disclosed in this document (for example, Compound 1, a dosage form or a composition comprising Compound 1).

[00133] In another aspect, the present invention provides a method of treating or preventing a migraine in an individual in need, comprising administering to the individual a therapeutically effective amount of Compound 1, for example, from about 2.5 mg to about 90 mg of Compound 1.

[00134] In some modalities, the migraine is selected from the group consisting of migraine without aura, migraine with aura, familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM); in other modalities, the migraine is migraine without aura. In certain modalities, the migraine is migraine with aura. In some modalities, the migraine is FHM1. In some modalities, the migraine is FHM2. In other modalities, the migraine is FHM4. In certain modalities, the migraine is SHM. In some modalities, the individual has an inadequate response to at least one medication used to treat a migraine. Cortical spreading depression

[00135] The compounds, dosage forms and compositions described in this document (e.g., Compound 1, a dosage form or a composition comprising Compound 1) are useful in the treatment of cortical spreading depression (CSD). CSD is a sustained wave of depolarization (neuronal inactivation) that spreads through intact brain tissue and is involved, for example, in cerebral ischemia, migraine aura and seizures.

[00136] In another aspect, a method of treatment or prevention of cortical spreading depression (CSD) is provided in an individual Petition 870230103657, dated 11 / 24 / 2023, p. 52 / 151 49 / 129 individual in need, comprising administering to the individual a therapeutically effective amount of a compound, a dosage form or a composition disclosed in this document (for example, Compound 1, a dosage form or a composition comprising Compound 1).

[00137] In another aspect, a method of treating or preventing cortical spreading depression (CSD) in an individual in need is provided in this document, comprising administering to the individual a therapeutically effective amount of Compound 1, for example, from about 2.5 mg to about 90 mg of Compound 1. Cranial neuropathy

[00138] The compounds, dosage forms, and compositions described in this document (e.g., Compound 1, a dosage form, or a composition comprising Compound 1) are useful in the treatment of cranial neuropathy. Neuropathy is a nerve injury disorder that affects the ability to feel and move. When the nerves in the brain or brainstem are affected, it is called cranial neuropathy. Cranial nerves are those that arise directly from the brain or brainstem and often affect areas such as the face and eyes. Cranial neuropathies include Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, and sixth nerve palsy. When several different cranial nerves are affected, it is called multiple cranial neuropathies (MCN).

[00139] Also provided in this document is a method of treating or preventing one or more cranial neuropathies in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound, a dosage form or a composition described in this document (e.g., Compound 1, a dosage form). Petition 870230103657, dated 11 / 24 / 2023, page 53 / 151 50 / 129 or a composition comprising Compound 1).

[00140] In another aspect, a method of treating or preventing cranial neuropathy or multiple cranial neuropathy in an individual in need is provided in this document, comprising administering to the individual a therapeutically effective amount of Compound 1, for example, from about 2.5 mg to about 90 mg of Compound 1.

[00141] In some modalities, cranial neuropathy is selected from the group consisting of sinoatrial palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, and sixth nerve palsy. In other modalities, the dosage form is administered orally. In certain modalities, the dosage form is a capsule. In some modalities, the patient is between 18 and 65 years of age. I stopped at page 32. Combined Therapy.

[00142] A formulation described in this document (for example, a dosage form or a composition comprising Compound 1), for example, for use in modulating a sodium ion channel, for example, delayed sodium current (INaL)) may be administered in combination with another agent or therapy. An individual to be administered a formulation disclosed in this document may have a disease, disorder or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. Such diseases or conditions may relate to epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain or a neuromuscular disorder. Antiepileptic Agents

[00143] Antiepileptic agents include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrichosis Petition 870230103657, dated 11 / 24 / 2023, page 54 / 151 51 / 129 gina, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide and cannabidiol. Combined Therapy with Cardiovascular Agent

[00144] Related cardiovascular diseases or conditions that may benefit from combined treatment with the sodium channel blockers of the invention with other therapeutic agents include, without limitation, angina, including stable angina, unstable angina (UA), exercise-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction, including non-STEMI myocardial infarction, pulmonary hypertension, including pulmonary arterial hypertension, heart failure, including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.

[00145] Suitable therapeutic agents for treating related cardiovascular diseases or conditions include antianginal agents, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid-lowering agents.

[00146] Co-administration of the sodium channel blockers of the invention with suitable therapeutic agents for the treatment of related cardiovascular conditions allows for enhancement of the standard treatment therapy that the patient is currently receiving. Antianginal drugs

[00147] Antianginal drugs include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the heart's oxygen demand, reducing its workload, resulting in a decreased heart rate and less vigorous cardiac contraction. Examples of beta-blockers include Petition 870230103657, dated 11 / 24 / 2023, page 55 / 151 52 / 129 acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

[00148] 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.

[00149] Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels, causing the blood vessels to relax, thus increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine. Agents for Heart Failure

[00150] Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluid in the tissues and circulation, thus relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

[00151] Angiotensin-converting enzyme (ACE) inhibitors reduce the workload on the heart by widening blood vessels and decreasing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Priminivil, Zestril), Petition 870230103657, dated 11 / 24 / 2023, p. 56 / 151 53 / 129 moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altacel) and trandolapril (Mavik).

[00152] Vasodilators reduce pressure in blood vessels, causing them to relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

[00153] Cardiac glycosides are compounds that increase the strength of heart contractions. These compounds strengthen the heart's pumping capacity and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin. Antithrombotic agents

[00154] Antithrombotic agents inhibit the blood's ability to clot. There are three main types of antithrombotic agents: platelet-blocking agents, anticoagulants, and thrombolytic agents.

[00155] Platelet inhibitors inhibit the clotting activity of platelets, thus reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (Plavix), dipyridamole, cilostazol, persantine, sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb / IIIa inhibitors such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta-blockers and calcium channel blockers also have a platelet-inhibiting effect. Anticoagulants prevent blood clots from growing and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

[00156] Thrombolytic agents work to break down a clot. Petition 870230103657, dated 11 / 24 / 2023, page 57 / 151 54 / 129 existing blood. Examples of thrombolytic agents include streptokinase, urokinase and tenecteplase (TNK) and tissue plasminogen activator (t-PA). Antiarrhythmic agents

[00157] 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.

[00158] Combinations with amiodarone and dronedarone are of particular interest, given the recently observed synergistic effects of the sodium channel blocker ranolazine and amiodarone and dronedarone. Antihypertensive agents

[00159] Antihypertensive agents are used to treat hypertension, a condition in which blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clotting disease.Examples of antihypertensive agents include alpha-1-adrenergic antagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizida), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken); Central alpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenz acetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); combined alpha / beta-adrenergic antagonists, such as labetalol (Normodyne, ...). Petition 870230103657, dated 11 / 24 / 2023, page 58 / 151 55 / 129 Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, such as guanethidine (Ismelina), reserpine (Serpasil); central nervous system antihypertensives, such as clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin); antiangiotensin II agents; ACE inhibitors, such as perindopril (Aceon), captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin II receptor antagonists, such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), valsartan (Diovan); calcium channel blockers, such as verapamil (Calan, Isoptina), diltiazem (Cardizem), nifedipine (Adalat, Procardia); diuretics; Direct vasodilators, such as nitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), verapamil; and potassium channel activators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil and pinacidil. Lipid-Reducing Agents

[00160] Lipid-lowering agents are used to reduce the amounts 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).

[00161] In this invention, a patient presenting with an acute coronary heart disease event frequently suffers from secondary medical conditions, such as one or more metabolic disorders, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder. Such patients may benefit from treatment with a combination therapy comprising administering ranolazine to the patient in combination with at least one other therapeutic agent. Petition 870230103657, dated 11 / 24 / 2023, page 59 / 151 56 / 129 Combination Therapy for Pulmonary Disorders

[00162] Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

[00163] Examples of therapeutic agents used to treat pulmonary disorders include bronchodilators, including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium. Combination Therapy for Metabolic Disorders

[00164] Examples of metabolic disorders include, but are not limited to, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[00165] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents, as described in the Combination Therapy with Cardiovascular Agents section above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics. Combination Therapy for Peripheral Vascular Disorders

[00166] Peripheral vascular disorders are disorders related to blood vessels (arteries and veins) located outside the heart and brain, including, for example, peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to internal organs, arms, and legs become completely blocked. Petition 870230103657, dated 11 / 24 / 2023, page 60 / 151 57 / 129 mentally or partially blocked as a result of atherosclerosis. Combined Therapy for Gastrointestinal Disorders

[00167] Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis, peptic ulcer, and pancreatitis.

[00168] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, such as misoprostol (Cytotec); sucralfate; and antacids. Combined therapy with antibiotics, analgesics, antidepressants, and anxiolytics.

[00169] Patients presenting with an acute coronary artery disease event may exhibit conditions that benefit from the administration of therapeutic agents such as antibiotics, analgesics, antidepressants, and anxiolytics in combination with ranolazine. Antibiotics

[00170] Antibiotics are therapeutic agents that kill or stop the growth of microorganisms, including bacteria and fungi. Examples of antibiotic agents include beta-lactam antibiotics, including penicillins (amoxicillin), cephalosporins such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cefradine (Velosef), cefaclor (Ceclor), cefuroxime axetil (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), ceftriaxone Petition 870230103657, dated 11 / 24 / 2023, page 61 / 151 58 / 129 (Rocephin), carbapenems and monobactams; tetracyclines, such as tetracycline; macrolide antibiotics, such as erythromycin; aminoglycosides, such as gentamicin, tobramycin, amikacin; quinolones, such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramins, polymyxins; lincosamides, such as clindamycin; oxazolidinones, such as linezolid; and sulfa antibiotics, such as sulfisoxazole. Painkillers

[00171] Analgesics are therapeutic agents that are used to relieve pain. Examples of analgesics include opioids and morphine mimetics, such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors. Given the ability of the sodium channel blockers of the invention to treat neuropathic pain by inhibiting NaV 1,7 and 1,8 sodium channels, combination with analgesics is particularly ideal. See US Patent Application Publication 20090203707. Antidepressant and Anxiolytic Agents

[00172] Antidepressant and anxiolytic agents include those agents used to treat anxiety disorders, depression, and those used as sedatives and tranquilizers. Examples of antidepressant and anxiolytic agents include benzodiazepines, such as diazepam, lorazepam, and midazolam; benzodiazepines; barbiturates; glutethimide; chloride hydrate; meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Fluctina, Fontex, Prodep, Fludep, Lovan); venlafaxine (Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexano); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban). Antidepressant and anxiolytic agents may include neuroactive steroids and ketamine and NMDA receptor antagonists. Petition 870230103657, dated 11 / 24 / 2023, page 62 / 151 59 / 129 born.

[00173] Consequently, one aspect of the invention provides a composition comprising the sodium channel blockers of the invention and at least one therapeutic agent. In an alternative embodiment, the composition comprises the sodium channel blockers of the invention and at least two therapeutic agents. In other alternative embodiments, the composition comprises the sodium channel blockers of the invention and at least three therapeutic agents, the sodium channel blockers of the invention and at least four therapeutic agents, or the sodium channel blockers of the invention and at least five therapeutic agents.

[00174] Combination therapy methods include co-administration of a single formulation containing the sodium channel blockers of the invention and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the sodium channel blocker of the invention and therapeutic agent or agents, and consecutive administration of a sodium channel blocker of the invention and therapeutic agent or agents, in any order, wherein preferably there is a period of time in which the sodium channel blocker of the invention and the therapeutic agent or agents simultaneously exert their therapeutic effect. Preparation Methods

[00175] Methods for preparing compounds useful for preventing and / or treating a disease, disorder or condition described herein are provided in this document, for example, a disease, disorder or condition related to the aberrant function of a sodium ion channel, such as abnormal late sodium current (INaL).

[00176] In one aspect, the present description provides a method for producing Compound 1: Petition 870230103657, dated 11 / 24 / 2023, page 63 / 151 60 / 129 or a pharmaceutically acceptable salt thereof, the method characterized by the fact that it comprises the steps of: (i) bringing a solution of 2,2,2-trifluoroethanol into contact with 5-bromo-2,3-difluoropyridine, thereby providing a compound of formula (II): (ii) bring the compound of formula (II) into contact with a palladium and bis(pinacolate)diboron catalyst, thus providing a compound of formula (III): (III); (iii) bring the compound of formula (III) into contact with a palladium and 2-bromo-5-chloro-pyrazine catalyst, thus providing a compound of formula (IV): ci(IV); (iv) placing the compound of formula (IV) in contact with hydrazine, thus providing a compound of formula (V): Petition 870230103657, dated 11 / 24 / 2023, page 64 / 151 61 / 129 (v) bring the compound of formula (V) into contact with 2-bromo-2,2-difluoroacetyl chloride, thus providing a compound of formula (VI): (vi) placing the compound of formula (VI) in contact with an acid, thus providing a compound of formula (VII): (vii) bring the compound of formula (VII) into contact with a silver and ethanol catalyst, thereby providing Compound 1 or a pharmaceutically acceptable salt thereof.

[00177] In some embodiments, the palladium catalyst in step (ii) or (iii) is [1,1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride. In certain embodiments, the silver catalyst in step (vii) is silver tetrafluoroborate. In other embodiments, the acid in step (vi) is p-toluenesulfonic acid.

[00178] In another aspect, the present description provides a method for producing Compound 1: Petition 870230103657, dated 11 / 24 / 2023, page 65 / 151 62 / 129 or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is provided by contact with the compound of formula (VII): (VII) with a silver and ethanol catalyst.

[00179] In some embodiments, the compound of formula (VII) is provided by contact with the compound of Formula (VI): FF 0(VI) with an acid.

[00180] In other embodiments, the compound of formula (VI) is provided by contact with the compound of Formula (V): FF N n^An,nh2H(V) with 2-bromo-2,2-difluoroacetyl chloride.

[00181] In certain embodiments, the compound of formula (V) is provided by contact with the compound of formula (IV): Petition 870230103657, dated 11 / 24 / 2023, p. 66 / 151 63 / 129 with hydrazine.

[00182] In some embodiments, the compound of formula (IV) is provided by contact with the compound of formula (III): with a palladium and 2-bromo-5-chloropyrazine catalyst.

[00183] In other embodiments, the compound of formula (III) is provided by contact of the compound of formula (I): Br(H) with a palladium and bis(pinacolate)diboron catalyst.

[00184] In certain embodiments, the compound of formula (II) is provided by contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine. In other embodiments, the silver catalyst is silver tetrafluoroborate. In some embodiments, the acid is p-toluenesulfonic acid. In other embodiments, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. EXEMPLIFICATION

[00185] The following representative examples are intended to help illustrate the invention and are not intended to, nor should they be construed as, limiting the scope of the invention. PSD Particle size distribution XRPD Powder X-ray Diffraction Petition 870230103657, dated 11 / 24 / 2023, p. 67 / 151 64 / 129 NRM Nuclear magnetic resonance LCMS Liquid chromatography-mass spectrometry PEG Polyethylene glycol HPLC High-performance liquid chromatography MC Methylcellulose UR Relative humidity ASD Amorphous solid dispersion PLM Polarized optical microscopy mDSC Modulated differential scanning calorimetry FaSSIF Simulated bowel fluid in a fasting state UPLC Ultra-high performance liquid chromatography API Active pharmaceutical ingredient PVP Polyvinylpyrrolidone HPMC Hydroxypropylmethylcellulose SDS Sodium dodecyl sulfate USP United States Pharmacopeia TFA Trifluoroacetic acid ACN Acetonitrile PK Pharmacokinetics MCC Microcrystalline cellulose MgSt Magnesium stearate rpm RSD Relative standard deviation HG Hard gelatin capsule SLS Sodium laureth sulfate AUC Area under the curve Cmax Maximum observed concentration HPMCAS Hydroxypropylmethylcellulose acetate succinate PG Propylene glycol EA Adverse event Petition 870230103657, dated 11 / 24 / 2023, page 68 / 151 65 / 129 ECG electrocardiogram C-SSRS Columbia Suicide Severity Rating Scale T max Time to maximum observed concentration t1 / 2 Apparent terminal elimination half-life AUC0-last area under the concentration-time curve from time zero to the last measurable concentration AUCc-inf area under the concentration-drug curve from time zero to infinity CL / F clearance Vd / F volume of distribution Clr actual clearance fe fraction of the dose excreted unchanged in urine Ae0-72 Amount excreted unchanged over 72 hours EEG electroencephalogram PD pharmacodynamics Rac (AUC) time to steady-state accumulation ratio based on AUC Rac (Cmax) SAD accumulation ratio based on Cmax Single ascending dose QTcF QT interval with Fridericia correction method OTC over-the-counter BLQ below the quantification level CV% coefficient of variation Example 1. Preparation and characterization of ground Compound 1

[00186] Compound 1 was milled by hand milling or jet milling to reduce particle size. For hand milling, Compound 1 was weighed in a ceramic mill and milled gently for ~5 minutes. The particle size distribution (PSD) of Compound 1 indicated D90 = 77.82 μm and D90 = 28.27 μm before and after milling. Petition 870230103657, dated 11 / 24 / 2023, page 69 / 151 66 / 129 manual action of Compound 1. The PSD through the dry method was conducted by the Sympatec HELOS particle size analyzer, and the dispersion and pressure system were RODOS and 0.5 bar, respectively. Table 1. Changes in particle size after manual grinding. Compound 1 Before After manual grinding D10 1.8 pm 0.8 pm D50 22.2 pm 3.6 pm D90 77.8 pm 28.3 pm

[00187] For jet milling, Compound 1 was micronized by jet milling with a yield of ~90%. The particle size of the jet milled material was reduced to a D90 range of 4.7 to 13.5 μm. Table 2. Changes in particle size after jet milling. Compound 1, Batch 1 Before After jet milling (51 g scale) D10 1.8 pm 0.7 pm D50 15.4 pm 1.8 pm D90 80.9 pm 4.7 pm Compound 1, Batch 2 Before After jet milling (95 g scale) D10 13.2 pm 1.1 pm D50 67.3 pm 3.7 pm D90 162.1 pm 8.3 pm Compound 1, Batch 3 Before After jet milling (104 g scale) D10 14.6 pm 0.87 pm D50 56.8 pm 5.58 pm D90 104 pm 13.5 pm

[00188] X-ray powder diffraction (XRPD) data were collected using a Bruker D8 powder diffractometer. Petition 870230103657, dated 11 / 24 / 2023, pp. 70 / 151 67 / 129 Advance. The samples were irradiated with copper K-alpha X-rays (λ = 1.54179 Å) with the generator operating at 40 kV / 40 mA. The samples were scanned in continuous mode from 3° to 40° (2 θ) with a sample rotation speed of 15 rpm and a scan rate of 10° / min. FIG. 1 shows the XRPD pattern of raw material and jet-milled material, indicating that there is no physical shape change of Compound 1 after jet milling.

[00189] Proton NMR (1H-NMR), Fluorine NMR (19F-NMR) and LC-MS analyses were also performed on Compound 1 before and after jet milling. Both NMR and LC-MS results indicate that no chemical or structural changes were observed in Compound 1 due to jet milling. Example 2. Preparation and stability of formulations comprising Compound 1 Solution formulations 1) Prototype 1: 40% PEG 400 / 10% Cremophor RH40 / 50% water

[00190] 2400 μL of PEG 400 were added to an 8 mL glass vial along with 3 mg of Compound 1 and mixed by vortex and sonicated for 5 min. Then, 600 μL of Cremophor RH40 were added to the container, mixed by vortex and sonicated for 5 min. Then, 3000 μL of water were added to the container, mixed by vortex and sonicated for 5 min. The compound was completely dissolved (0.5 mg / mL). 2) Prototype 2a: 58.1% Cremophor RH40 + 16.9% Labrafil M2125 CS + 8.3% Propylene Glycol + 16.7% Ethanol

[00191] Vehicle preparation: 11.62 mL of Cremophor RH40, 3.38 mL of Labrafil M2125 CS, 1.66 mL of Propylene Glycol and 3.34 mL of Ethanol were mixed to obtain the vehicle for Prototype 2a.

[00192] Approximately 15 mg of the compound were weighed into an 8 mL glass container, and then 2 mL of Prototype 2a were added. Petition 870230103657, dated 11 / 24 / 2023, page 71 / 151 68 / 129 added to the glass container. The contents were mixed by vortex and sonication for 5 min. Compound 1 in Prototype 2a at 7.5 mg / mL was a clear solution. 3) Prototype 2b: 69.74% Cremophor RH40 + 20.28% Labrafil M2125 CS + 9.98% Propylene Glycol.

[00193] Preparation: 11.62 mL of Cremophor RH40, 3.38 mL of Labrafil M2125 CS and 1.66 mL of propylene glycol were mixed to obtain the vehicle for Prototype 2b.

[00194] Approximately 15 mg of the compound were weighed into an 8 mL glass container, then 2 mL of Prototype 2b were added to the container and mixed together by vortexing and sonicating for 5 min. Compound 2 in Prototype 2b at 7.5 mg / mL was unclear. Then, another 140 μL vehicle of Prototype 2b was added to the container and mixed by vortexing and sonicating for 5 min. Prototype 2b at 7 mg / mL was a clear solution. 4) Prototype 3: 40% Transcutol HP / 10% vitamin ETPGS / 50% water

[00195] 600 μL of PEG 400 were added to a 4 mL glass vial along with 3 mg of Compound 1 and mixed by vortex and sonicated for 5 min. Then, 150 μL of Cremophor RH40 were added to the container and mixed by vortex and sonicated for 5 min. Then, 750 μL of water were added to the container and mixed by vortex and sonicated for 5 min. The compound was completely dissolved (2 mg / mL). 5) Prototype 4: 36% Cremophor RH40 + 45% Capmul MCM C8 + 9% Triethyl citrate + 10% Ethanol

[00196] Cremophor RH40, Capmul MCM C8, Triethyl citrate, and Ethanol were added on a weight basis to a glass container and mixed to form a solution mixture. Increasing amounts of Compound 1 were then added to the mixture and vortexed and Petition 870230103657, dated 11 / 24 / 2023, page 72 / 151 69 / 129 were sonicated to form a clear solution. Additional Compound 1 was added with vortexing and sonication until Compound 1 was no longer soluble. The resulting maximum solubility was visually determined to be between 25 and 50 mg / mL. 6) Prototype 5: 40% Capryol 90 + 20% Labrasol + 40% Transcutol HP

[00197] Capryol 90, Labrasol, and Transcutol HP were added on a volumetric basis to a glass container and mixed to form a solution mixture. Increasing amounts of Compound 1 were then added to the mixture and vortexed and sonicated to form a clear solution. Additional Compound 1 was added with 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.

[00198] Table 3 summarizes the prototypes used to prepare solution formulations of Compound 1 with their respective stability. Table 4 shows the detailed stability results. Table 3. Solution formulations comprising Compound 1 Formulation of the solution Target Concentration of Compound 1 (mg / mL) Stability observation (storage at room temperature) Prototype 1 (40% PEG 400 / 10% Kolliphor RH40 / 50% water) 0.5 Stable for 7 days Prototype 2a (58.1% KolliphorRH40 + 16.9% Labrafil M2125 CS + 8.3% Propylene Glycol + 16.7% Ethanol) 7.5 Stable for 7 days Prototype 2b 7 Stable for 7 days (69.74% KolliphorRH40 + 20.28% Labrafil M2125 CS + 9.98% Propylene Glycol 2.3 (diluted in water 3 times) Stable for 7 days Prototype 3 (40% Transcutol HP / 10% Vitamin ETPGS / 50% water) 2 Stable for 7 days Petition 870230103657, dated 11 / 24 / 2023, page 73 / 151 70 / 129

[00199] For the stability and purity test of Compound 1, a high-performance liquid chromatography (HPLC) method was developed. The HPLC method used for the chemical stability and purity test was as follows: Column: Agilent Pursuit XRs C18 column (150 mm * 4.6 mm * 3 μm) Wavelength: 245 nm Column oven temperature: 45 °C Flow rate: 1.0 mL / min Injection volume: 2 μL Mobile Phases: A: 0.1% TFA in water (v / v) B: MeOH: ACN (80:20; v / v) Gradient Program Time (min) A% B% 0.00 50 50 30.0 20 80 35.0 20 80 35.1 50 50 40.0 50 50 Re-equilibration time: 5 min Run time: 40 min Needle wash solvent: ACN: Water (50:50; v / v) Diluent: ACN: Water (90:10; v / v) Table 4. Detailed stability test data for Prototypes 1, 2a and 3 (storage was at room temperature, 1525°C). Target Concentration (mg / mL) Sample Prototype 1 Time Appearance Concentration (mg / mL) Purity (%) 0.5 1 hr clear 0.53 98.58 4 hours clear 0.52 98.58 7 days clear 0.43 97.78 Target Concentration (mg / mL) Sample Prototype 2a Time Appearance Concentration (mg / mL) Purity (%) Petition 870230103657, dated 11 / 24 / 2023, page 74 / 151 71 / 129 Target Concentration (mg / mL) Sample Prototype 1 Time Appearance Concentration (mg / mL) Purity (%) 7.5 1 hr clear 7.36 96.64 4 hours clear 7.31 96.45 7 days clear 7.17 97.28 Target Concentration (mg / mL) Sample Prototype 3 Time Appearance Concentration (mg / mL) Purity (%) 1.0 1 hr clear 1.11 96.87 4 hours clear 1.11 97.01 7 days clear 1.06 97.59

[00200] Approximately 24 mg of compound 1 was added to an 8 mL glass vial and dissolved by prototype 2b, then sonicated for 10 min to obtain a clear solution with a concentration of 7 mg / mL. After that, the solution was diluted 3 times with water for stability testing. The results are as shown in Table 5 below. Table 5: Detailed stability test data for Prototype 2b Sample Time Appearance Target Concentration (mg / mL) Concentration (mg / mL) Purity (%) Prototype 2b diluted in water 3 times Initial clear 2.33 - - 24 hours clear 2.19 99.56 72 hours clear 2.23 99.83 7 days clear 2.45 99.65

[00201] Based on HPLC results and appearance, Prototype formulations 1, 2a, 2b, and 3 comprising Compound 1 were stable under ambient conditions for at least 7 days. Suspension Formulations

[00202] To prepare the suspension formulations of Compound 1, approximately 0.5 mg, 5 mg, and 10 mg of Compound 1 were weighed into separate vials, and 1 mL of 0.5% MC 400 cP / 0.2% Tween 80 was added to each vial. The materials were mixed by vortex and Petition 870230103657, dated 11 / 24 / 2023, page 75 / 151 72 / 129 were stirred at room temperature overnight (24 hours). 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.

[00203] To prepare a suspension formulation comprising jet-ground Compound 1, 15 mg of jet-ground Compound 1 were weighed into a glass vial, and then 10 mL of vehicle (0.5% MC 400 cP / 0.2% Tween 80) was added to disperse it to achieve a Compound 1 concentration of 1.5 mg / mL. The suspension was thoroughly dispersed by homogenization for ~30 seconds. The stability of the suspension was assessed by HPLC and particle size distribution (PSD), and the results are summarized in Table 7. Based on HPLC and PSD, the suspension formulation comprising jet-ground Compound 1 was stable under ambient conditions for 28 days. Table 6. Stability of suspension formulations of Compound 1 in 0.5% MC 400 cP / 0.2% Tween 80. Target Concentration (mg / ml) Time Point Concentration (mg / mL) Purity (%) 10 1 hr 9.69 96.86 4 hours 9.79 97.12 7 days 9.72 96.71 5 1 hr Not available 97.60 4 hours 4.72 97.84 7 days 5.06 96.95 0.5 1 hr 0.58 97.46 4 hours 0.45 96.65 7 days 0.49 97.85 1.5* 1 day 1.44 99.4 6 days 1.43 99.5 Compound 1 not milled unless otherwise indicated. Petition 870230103657, dated 11 / 24 / 2023, page 76 / 151 73 / 129 * designates jet-ground material. Table 7. Stability of the suspension formulation in 0.5% MC 400 cP / 0.2% Tween 80 comprising jet-milled Compound 1. Concentration, target (mg / mL) Time point at TA (day) Appearance Concentration (mg / mL) Purity (%) PSD (D90, µm) 1.5 Initial Homogeneous suspension 1.61 99.43 - 1 Homogeneous suspension 1.44 99.44 - 2 Homogeneous suspension 1.38 99.52 - 3 Homogeneous suspension 1.58 99.49 - 6 Homogeneous suspension 1.43 99.51 - 7 Homogeneous suspension 1.61 99.55 - 14 Homogeneous suspension 1.61 99.36 - 21 Homogeneous suspension 1.56 99.58 6.97 28 Homogeneous suspension 1.64 98.96 6.80

[00204] As shown in Tables 8-11, several suspension formulations were tested for stability under different conditions.

[00205] To prepare a suspension, weigh the required amount of ground Compound 1 into a glass container and add the corresponding volume of vehicle. Thoroughly disperse the compound into a homogeneous suspension using a mixer suspended at the target final concentration. Concentrations were prepared at 0.1 mg / mL and 10 mg / mL. The suspended products were physically evaluated for visual appearance, concentration, purity, and PSD.

[00206] The vehicles are prepared by dissolving 0.5% by weight of 400 cP methylcellulose or 4000 cP methylcellulose and 0.2% Poloxamer 188. Petition 870230103657, dated 11 / 24 / 2023, page 77 / 151 74 / 129 For the preserved suspensions, an additional 1.0% by volume of paraben preservative solution was dissolved in vehicle using a suspension 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, mixing with a stirring bar at room temperature for 1 hour. Table 8. Visual Stability Assessment of Suspension Formulations Comprising Compound 1 after 1, 4, and 24 hours at room temperature. Vehicle Target Concentration (mg / ml) Hours at Room Temperature Visual Appearance (see reference key) 0.5% 400 cP MC, 0.2% Poloxamer 188 and 1.0% paraben preservative solution 0.1 1 * 4 * 24 * 10 1 * 4 * 24 * 0.5% 4000 cP MC, 0.2% Poloxamer 188 and 1.0% paraben preservative solution 0.1 1 # 4 # 24 # 10 1 # 4 # 24 # 0.5% 400 cP MC, 0.2% Poloxamer 188 0.1 1 * 4 * 24 * 10 1 * 4 * 24 * 0.5% 4000 cP MC, 0.2% Poloxamer 188 0.1 1 # 4 # 24 # 10 1 # 4 # 24 # Initially a homogeneous suspension, sedimentation occurred along the way. Petition 870230103657, dated 11 / 24 / 2023, page 78 / 151 75 / 129 hours of time and returned to homogeneous after gentle agitation # initially a viscous homogeneous suspension, sedimentation occurred over time and returned to homogeneous after gentle agitation Table 9. Stability of suspension formulations comprising Compound 1 after 96 hours at room temperature Vehicle Concentration, Target (mg / mL) Hours at Room Temperature Visual Appearance 0.5% 400 cP MC, 0.2% Poloxamer 188 and 1.0% paraben preservative solution 0.1 96 * 10 96 * 0.5% 4000 cP MC, 0.2% Poloxamer 188 and 1.0% paraben preservative solution 0.1 96 # 10 96 # 0.5% 400 cP MC, 0.2% Poloxamer 188 0.1 96 * 10 96 * 0.5% 4000 cP MC, 0.2% Poloxamer 188 0.1 96 # 10 96 # * Initially a homogeneous suspension, sedimentation occurred over time and it returned to homogeneous after gentle agitation for ~1 min. # Initially a viscous homogeneous suspension, sedimentation occurred over time and it returned to homogeneous after gentle agitation for ~2 minutes. Table 10. Stability of suspension formulations comprising Compound 1 at 2-8°C Vehicle Concentration, Target (mg / mL) Time Point at 2-8 °C Appearance Concentration (mg / mL) Purity (%) PSD (D90, μη) 0.5% 400 cP MC, 0.2% Poloxamer 0.1 0 * 0.11 100 19.9 7D * 0.12 100 18.2 14D * 0.11 100 14.2 28D * 0.11 100 15.4 Petition 870230103657, dated 11 / 24 / 2023, page 79 / 151 76 / 129 Vehicle Concentration, Target (mg / mL) Time Point at 2-8 °C Appearance Concentration (mg / mL) Purity (%) PSD (D90, pm) 188 2M * 0.11 95.87 9.1 3M * 0.11 93.20 12.7 10 0 * 10.04 99.83 5.6 7D * 10.18 99.83 6.4 14D * 10.66 99.83 5.4 28D * 10.56 99.83 3.8 2M * 10.99 99.83 4.0 3M * 10.13 99.83 3.6 * Initially a homogeneous suspension, sedimentation occurred over time and returned to homogeneous after gentle agitation for ~1 min. Table 11. Stability of suspension formulations comprising Compound 1 at 25°C / 60% RH Vehicle Concentration, Target (mg / mL) Point in Time at 25°C / 60%RH Appearance Concentration (mg / mL) Purity (%) PSD (D90, pm) 0.5% 400 cP MC, 0.2% Poloxamer 188 0.1 0 * 0.11 100.0 19.9 7D * 0.11 100.0 19.9 14D * 0.11 100 12.9 28D * 0.10 100 8.7 2M * 0.11 95.87 8.6 3M * 0.11 93.20 11.1 10 0 * 10.04 99.83 5.6 7D * 10.48 99.83 6.3 14D * 9.85 99.83 5.2 28D * 10.00 99.83 4.6 2M * 10.47 99.83 4.3 3M * 10.16 99.83 3.5 * initially a homogeneous suspension, sedimentation occurred along Petition 870230103657, dated 11 / 24 / 2023, page 80 / 151 77 / 129 go of time and returned to homogeneous after gentle stirring for ~ 1 min Amorphous solid dispersion (ASD)

[00207] An amorphous solid dispersion including Compound 1 was prepared with a mixture of Compound 1 and polymer. Nine ASD formulations were prepared using 9 different polymers as the solid dispersant (PVPK30, PVPVA64, Soluplus, HPMC E5, HPMC ASMG, HPMC ASMF, HPMC ASHG, Eudragit EPO, Eudragit L100). Approximately 10 mg of Compound 1 and 40 mg of the corresponding polymer were weighed into 40 mL glass vials and dissolved in 1 mL of MeOH / DCM (1:1, v / v) to prepare the stock solution. The resulting clear solutions were stored at 70°C for rapid evaporation to produce a solid dispersion. The product after evaporation was dried under vacuum at 30°C overnight and further characterized by appearance, PLM, XRPD, and mDSC.

[00208] The nine ASD formulations were tested for kinetic solubility in FaSSIF at a concentration of 2 mg / mL. The experiment was run at 37°C with a spin rate of 450 rpm. 0.5 mL of the mixture was taken at each time point and centrifuged before running UPLC (a shortened run time version of the HPLC method described was used to determine the levels of Compound 1). The results are listed in Table 12. Increased solubility was observed for most polymers, especially for Eudragit EPO. Table 12. Summary of the kinetic solubility of ASDs Formulation No. SD Kinetic Solubility in FaSSIF (fog / mL) Final pH 15 min 30 min 60 min 120 min 0 API Crystalline (API = Compound 1) 5.7 8.1 7.1 11.6 6.54 Petition 870230103657, dated 11 / 24 / 2023, page 81 / 151 78 / 129 Formulation No. Solubility (in FaSSIF fog / mL) Final pH 15 min 30 min 60 min 120 min 1 API+ PVP K30 4.9 6.0 5.8 6.7 6.55 2 API+ PVP VA64 4.8 5.7 5.2 5.2 6.54 3 API+ Soluplus 12.9 19.1 17.5 18.7 6.56 4 API+ HPMC E5 8.8 8.2 7.9 7.6 6.57 5 API+ HPMC ASMG 21.7 24.7 26.9 22.1 5.92 6 API+ HPMC ASMF 20.3 26.2 24.4 31.4 5.96 7 API+ HPMC ASHG 28.4 24.2 21.9 20.9 6.49 8 API+ Eudragit EPO 111.0 207.0 273.3 327.2 7.21 9 API+ Eudragit L100 19.2 16.2 19.6 26.6 5.59

[00209] Based on the kinetic solubility assessment of the prototype ASD formulation. Three prototype ASD formulations were then prepared for further evaluation using Soluplus, Eudragit L100 or HPMC ASMF and are summarized in Table 13. The stability test results of the selected ASD formulations are shown in Tables 14 and 15. Table 13. Summary of selected ASD formulations Compound 1 ASD + Soluplus ASD + Eudragit L100 ASD + HPMC ASMF Appearance White powder White powder White powder PLM No birefringence and spherical shape XRPD Amorphous Amorphous Amorphous Tg per mDSC (°C) 91.65 90.83 91.34 Petition 870230103657, dated 11 / 24 / 2023, page 82 / 151 79 / 129 HPLC Test Drug Loading (% p) 18.9 19.3 18.1 Purity (A %) 99.01 98.71 97.61 Kinetic solution Kinetic solution in FASSIF (µg / mL) in 120 min 19 21 31 Table 14. Stability results after 1 week of selected ASD formulations SD Formulation Initial Drug Load (%) Initial Purity (%) Storage Condition After 1 week XRPD HPLC Results Drug Load (%) Purity (%) ASD_Sol uplus 18.9 98.68 25°C / 60%RH, open Partially crystalline 20.80 96.40 40°C / 75%RH, open Partially crystalline 19.82 95.81 18.86 97.81 25°C / 60%RH, closed Partially crystalline 18.69 97.49 60°C, closed Partially crystalline 18.65 96.86 ASD_Eu dragit L100 19.1 97.58 25°C / 60%RH, open Amorphous 19.86 96.79 40°C / 75%RH, open Amorphous 20.00 96.35 19.12 97.31 25°C / 60%RH, closed Amorphous 18.62 96.86 60°C, closed Amorphous 18.63 96.48 Petition 870230103657, dated 11 / 24 / 2023, page 83 / 151 80 / 129 SD Formulation Initial Drug Load (%) Initial Purity (%) Storage Condition After 1 week XRPD HPLC Results Drug Load (%) Purity (%) ASD_HP MC ASMF 18.1 96.42 25°C / 60%RH, open Amorphous 17.44 94.40 40°C / 75%RH, open Partially crystalline 17.33 94.74 17.81 95.17 25°C / 60%RH, closed Amorphous 17.32 95.44 60°C, closed Amorphous 17.38 94.93 Table 15. Stability results after 2 weeks SD Formulation Initial Drug Load (%) Initial Purity (%) Storage Condition After 2 weeks XRPD HPLC Results Drug Load (%) Purity (%) ASD_Sol uplus 18.9 98.68 25°C / 60%RH, open Partially crystalline 21.29 97.24 40°C / 75%RH, open Partially crystalline 20.43 95.23 18.86 97.81 25°C / 60%RH, closed Partially crystalline 17.92 94.01 60°C, closed Partially crystalline 18.69 93.41 Petition 870230103657, dated 11 / 24 / 2023, page 84 / 151 81 / 129 SD Formulation Initial Drug Load (%) Initial Purity (%) Storage Condition After 2 weeks XRPD HPLC Results Drug Load (%) Purity (%) ASD_Eu dragit L100 19.1 97.58 25°C / 60%RH, open Amorphous 19.57 97.21 40°C / 75%RH, open Amorphous 19.99 95.84 19.12 97.31 25°C / 60%RH, closed Amorphous 18.89 96.53 60°C, closed Partially crystalline 18.54 96.09 ASD_HP MC ASMF 18.1 96.42 25°C / 60%RH, open Amorphous 17.69 94.32 40°C / 75%RH, open Partially crystalline 17.77 95.70 17.81 95.17 25°C / 60%RH, closed Amorphous 17.93 94.01 60°C, closed Partially crystalline 17.33 94.54 zxpansão de três ASDs com um secar por pulveriza

[00210] Preparation of ASD-1: Approximately 300 mg of Compound 1 and approximately 1200 mg of Soluplus were weighed into a 250 mL glass container, then 150 mL of acetone were added to produce 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).

[00211] Preparation of ASD-2: Approximately 300 mg of Compound 1 and approximately 1200 mg of Eudragit L100 were weighed into a 250 mL glass container, then 150 mL of acetone were added to produce Petition 870230103657, dated 11 / 24 / 2023, page 85 / 151 82 / 129 a transparent solution before spray drying. After spray drying, the powder was collected and dried under vacuum conditions at 30°C for 12 hours (yield of 74.5%).

[00212] Preparation of ASD-3: Approximately 300 mg of Compound 1 and approximately 1200 mg of HPMC ASMF were weighed into a 250 mL glass container, then 150 mL of acetone were added to produce 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).

[00213] The ASD-3 prototype was also evaluated in an in vitro dissolution study. The spray-dried ASD-3 powder that was collected was manually weighed on an analytical balance directly into size 4 hard gelatin capsules at two dose potencies: 2.5 and 10 mg of active (13.7 and 54.8 mg of ASD).

[00214] The dissolution method used the following conditions: Instrument Configuration Parameters: Agilent 708-DS Instrument; Medium: 0.1 N HCl with 2% SDS; Equipment: USP 2 apparatus (paddles); Rotation speed: 75 rpm (200 rpm for infinite rotation); Medium volume: 900 mL; Temperature: 37.0 ±0.5°C; Sampling time point: 15, 30, 45, 60 min and infinity at 120 min.

[00215] For the dissolution analysis, an HPLC method was used to quantify the levels of Compound 1 in the dissolution medium. The same HPLC method was used for dissolution and content uniformity tests. The HPLC method used is as follows: Petition 870230103657, dated 11 / 24 / 2023, page 86 / 151 83 / 129 Column: Agilent Pursuit XRs C18 column (150 mm * 4.6 mm * 3 μm) Wavelength: 245 nm Column oven temperature: 45°C Flow rate: 1.0 mL / min Injection volume: 2 pL Mobile Phases: A: 0.1% TFA in water (v / v) B: MeOH: ACN (80:20; v / v) Gradient Program Time (min) A% B% 0.00 70 30 10.00 0 100 Re-equilibration time: 2 min Run time: 10 min Needle wash solvent: ACN: Water (50:50; v / v) Diluent: ACN: Water (90:10; v / v)

[00216] Dissolution results are shown in Figure 2, where the release of two dose potencies was 29.76% and 17.64% for the dose potencies of 2.5 mg and 10 mg, respectively.

[00217] The ASD-3 prototype was also evaluated in a pharmacokinetic (PK) study in cynomolgus monkeys using a crossover study design. The spray-dried ASD-3 powder that was collected was manually weighed on an analytical balance directly into size 4 hard gelatin capsules. Three male monkeys were orally given 0.5 mg / kg body weight in a fasting state, and plasma samples were analyzed for Compound 1 levels. Capsule formulations

[00218] Exemplary capsule formulations include 2.5 mg, 10 mg, or 100 mg of Compound 1 per capsule. For the 2.5 mg dose capsule, one formulation includes a 1:10 mixture of Compound 1 to Petition 870230103657, dated 11 / 24 / 2023, page 87 / 151 84 / 129 microcrystalline cellulose (MCC) with 2% magnesium stearate (MgSt) in a gelatin capsule, and another formulation includes 2.5 mg of pure Compound 1 in a gelatin capsule (without additional excipients).

[00219] The ground Compound 1 and the filler (MCC or starch) were weighed separately and mixed for 15 minutes to obtain a homogeneous mixture. A required amount of magnesium stearate was added and mixed. The mixture was manually filled into appropriately sized hard gelatin capsules. The samples were then subjected to stability testing under different conditions and analyzed for appearance, assay at different time points. Mixture formulations Mixture 1 and 2 (1:10 mixture)

[00220] 1 g of ground Compound 1 and 9 g of MCC or starch were weighed into a container. The two components were mixed by turbulation for approximately 15 minutes at a speed of 36 rpm to obtain a homogeneous phase. 0.2 g of MgSt was added and mixed for a further 3 minutes to obtain homogeneous mixture 1 (Table 16). Dose uniformity was assessed by measuring the 10-capsule assay (Tables 18 and 19). Table 16. Composition of mixtures 1 and 2 Mixture 1 Components Function Percentage (% w / w) Compound 1 Active 10 MCC Filler 90 MgSt Lubricant 2 Combination 2 Components Function Percentage (% w / w) Compound 1 Active 10 Starch Filler 90 MgSt Lubricant 2 Petition 870230103657, dated 11 / 24 / 2023, page 88 / 151 85 / 129 Mixture 3 and 4 (1:1 mixture)

[00221] 5 g of ground Compound 1 and 5 g of MCC or starch were weighed into a container. The two components were mixed by turbulation for approximately 15 minutes at a speed of 36 rpm to obtain a homogeneous phase. 0.2 g of MgSt was added and mixed for a further 3 minutes to obtain homogeneous mixture 1 (Table 17). Dose uniformity was assessed by measuring the 10-capsule assay (Tables 20 and 21). Table 17. Composition of mixtures 3 and 4 3-Component Mixture Function Percentage (% w / w) Compound 1 Active 50 MCC Filler 50 MgSt Lubricant 2 4-Component Mixture Function Percentage (% w / w) Compound 1 Active 50 Starch Filler 50 MgSt Lubricant 2

[00222] Tables 18-21 summarize the mixture uniformity results for 4 exemplary mixtures (mixtures 1-4 as described above) comprising Compound 1. Table 18. Uniformity results of the 1:10 mixture. Sampling location Sample weight (mg) Label statement (%) Average (%) RSD (%) Top-1 7.79 97.95 94.18 3.97 Top-2 7.36 92.36 Top-3 9.16 95.09 Middle-1 7.89 86.96 Petition 870230103657, dated 11 / 24 / 2023, page 89 / 151 86 / 129 Sampling location Sample weight (mg) Label statement (%) Average (%) RSD (%) Middle-2 10.69 88.58 Middle-3 7.58 96.55 Middle-4 6.79 94.81 Bottom-1 7.86 96.96 Bottom-2 7.62 95.47 Bottom-3 6.62 97.1 Table 19. Uniformity results of the 1:10 mixture Sampling location Sample weight (mg) Label statement (%) Average (%+6) RSD (%) Top-1 11.83 88.66 93.21 4.34 Top-2 11.47 96.28 Top-3 6.91 93.45 Middle-1 8.51 94.50 Middle-2 7.66 96.34 Middle-3 11.95 91.53 Middle-4 8.54 87.87 Bottom-1 10.45 99.85 Bottom-2 8.49 88.20 Bottom-3 11.13 95.44 Table 20. Uniformity results of the 1:1 mixture of mixture 3 Sampling location Sample weight (mg) Label statement (%) Average (%) RSD (%) Top-1 15.15 93.46 93.88 3.13 Top-2 15.05 94.84 Top-3 16.92 99.64 Middle-1 12.89 89.67 Middle-2 14.96 94.61 Petition 870230103657, dated 11 / 24 / 2023, pp. 90 / 151 87 / 129 Sampling location Sample weight (mg) Label statement (%) Average (%) RSD (%) Middle-3 16.38 91.61 Middle-4 17.46 92.68 Bottom-1 18.32 95.81 Bottom-2 16.61 90.56 Bottom-3 16.63 95.89 Table 21. Uniformity results of the 1:1 mixture of mixture 4 Sampling location Sample weight (mg) Label statement (%) Average (%) RSD (%) Top-1 20.62 95.48 94.26 3.83 Top-2 18.01 95.94 Top-3 22.95 87.41 Middle-1 14.98 88.62 Middle-2 21.74 95.24 Middle-3 17.47 92.89 Middle-4 14.34 94.80 Bottom-1 17.35 96.73 Bottom-2 15.16 98.25 Bottom-3 22.29 97.25

[00223] Tables 21.1, 21.2, 21.3 and 21.4 show the stability results of capsules from mixture 1 and capsules from mixture 2 at dose strengths of 1 mg per capsule (mixing ratio of 1:10), 10 mg per capsule (mixing ratio of 1:10 and 50:50) and 100 mg per capsule (mixing ratio of 50:50). Table 21.1: Stability of the active mixture of 1 mg in a capsule at 25°C / 60%RH Petition 870230103657, dated 11 / 24 / 2023, pp. 91 / 151 88 / 129 Dose of 1 mg in mixture 1 of 1:10 (MCC) at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size #0 HG 0 Mixture in opaque white capsule 100.00 99.83 7D Mixture in opaque white capsule 98.50 99.83 14D Mixture in opaque white capsule 99.00 99.83 28D Mixture in opaque white capsule 102.76 99.83 2M Mixture in opaque white capsule 100.69 99.83 3M Mixture in opaque white capsule 100.58 99.83 Dose of 1 mg in mixture 2 of 1:10 (Starch) at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size #0 HG 0 Mixture in opaque white capsule 100.00 99.83 7D Mixture in opaque white capsule 99.78 99.83 14D Mixture in opaque white capsule 97.60 99.83 28D Mixture in opaque white capsule 98.56 99.83 2M Mixture in opaque white capsule 98.50 99.83 3M Mixture in opaque white capsule 97.97 99.83 Table 21.2: Stability of a 1:10 mixture of 10 mg active ingredient in capsules at 25°C / 60%RH Dose of 10 mg in mixture 1 of 1:10 (MCC) at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size #0 HG 0 Mixture in opaque white capsule 100.00 99.83 7D Mixture in opaque white capsule 99.70 99.83 14D Mixture in opaque white capsule 96.58 99.83 28D Mixture in opaque white capsule 101.47 99.83 2M Mixture in opaque white capsule 99.14 99.83 3M Mixture in opaque white capsule 102.19 99.83 Dose of 10 mg in mixture 2 of 1:10 (Starch) at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size #0 0 Mixture in opaque white capsule 100.00 99.83 Petition 870230103657, dated 11 / 24 / 2023, page 92 / 151 89 / 129 HG 7D Mixture in opaque white capsule 99.23 99.83 14D Mixture in opaque white capsule 98.70 99.83 28D Mixture in opaque white capsule 99.45 99.83 2M Mixture in opaque white capsule 100.29 99.83 3M Mixture in opaque white capsule 99.99 99.83 Table 21.3: Stability of a 50:50 mixture of 10 mg active ingredient in capsules at 25°C / 60%RH Dose of 10 mg in mixture 1 of 50:50 (MCC) at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size #0 HG 0 Mixture in opaque white capsule 100.00 99.83 7D Mixture in opaque white capsule 98.90 99.83 14D Mixture in opaque white capsule 101.36 99.83 28D Mixture in opaque white capsule 100.42 99.83 2M Mixture in opaque white capsule 101.94 99.83 3M Mixture in opaque white capsule 100.97 99.83 Dose of 10 mg in mixture 2 of 50:50 (Starch) at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size #0 HG 0 Mixture in opaque white capsule 100.00 99.83 7D Mixture in opaque white capsule 99.78 99.83 14D Mixture in opaque white capsule 98.42 99.83 28D Mixture in opaque white capsule 98.98 99.83 2M Mixture in opaque white capsule 101.14 99.83 3M Mixture in opaque white capsule 102.01 99.83 Table 21.4 Stability of a 50:50 mixture of 100 mg active ingredient in capsules at 25°C / 60%RH Dose of 100 mg in mixture 1 (MCC) 50:50 at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size #0 HG 0 Mixture in opaque white capsule 100.00 99.83 7D Mixture in opaque white capsule 102.11 99.83 14D Mixture in opaque white capsule 101.52 99.83 Petition 870230103657, dated 11 / 24 / 2023, page 93 / 151 90 / 129 28D Mixture in opaque white capsule 99.93 99.83 2M Mixture in opaque white capsule 101.54 99.83 3M Mixture in opaque white capsule 101.33 99.83 Dose of 100 mg in mixture 2 of 50:50 (Starch) at 25°C / 60%RH Capsule Time Appearance Assay (%) Purity (%) Size #0 HG 0 Mixture in opaque white capsule 100.00 99.83 7D Mixture in opaque white capsule 100.70 99.83 14D Mixture in opaque white capsule 102.06 99.83 28D Mixture in opaque white capsule 98.13 99.83 2M Mixture in opaque white capsule 100.85 99.83 3M Mixture in opaque white capsule 103.63 99.83

[00224] The dissolution of mixture 1 at a 1:10 ratio of Compound 1 to MCC in size #0 HG capsules was evaluated at 1 and 10 mg of active ingredient (10 and 100 mg of mixture with MCC, respectively).

[00225] The dissolution method used the following conditions: Instrument Configuration Parameters: Agilent 708-DS Instrument; Medium: 0.1 N HCl with 2% SDS; Equipment: USP 2 apparatus (paddles); Rotation speed: 75 rpm (200 rpm for infinite rotation); Medium volume: 900 mL; Temperature: 37.0 ±0.5°C; Sampling time point: 15, 30, 45, 60 min and infinity at 120 min.

[00226] The results are shown in Figure 3, where 50.3% of the 1 mg dose potency capsule was released after 120 minutes and 20.5% of the 10 mg dose potency capsule was released after 120 minutes.

[00227] A capsule formulation of the additional prototype mixture was prepared to evaluate the effect of adding surfactant to the mixture. Petition 870230103657, dated 11 / 24 / 2023, page 94 / 151 91 / 129 MCC 1:10 capsule size (Mixture 1). A 1:MCC 1:10 compound with 2% SLS (25 mg of mixture and 0.5 mg of SLS) was manually filled into size 4 hard gelatin capsules (dose level was 2.5 mg of active per capsule) for evaluation in a stability study (Table 21.3), a crossover PK study in monkeys, and a dissolution test. Table 21.5 Stability of a 1:10 mixture of 2.5 mg active ingredient with 2% surfactant Dose of 2.5 mg in MCC mixture with 2% SLS at room temperature for the PK study in monkeys Capsule Time (Day) Appearance Assay (%) Purity (%) Size 0 Opaque white capsule mixture 100.00 99.83 #4 HG 7 Opaque white capsule mixture 101.98 99.83 Dose of 2.5 mg in MCC mixture with 2% Poloxamer at room temperature for the PK study in monkeys Capsule Time Appearance Assay (%) Purity (%) Size 0 Opaque white capsule mixture 100.00 99.83 #4 HG 7 Opaque white capsule mixture 97.39 99.83

[00228] Three male monkeys orally received 0.5 mg / kg body weight in a fasting state, and plasma samples were analyzed for Compound 1 levels. The resulting levels of Compound 1 in plasma did not show a significant increase in exposure for the MCC mixture capsule with surfactant (area under the curve from 0 to infinity, AUC[0-inf] = 1,004 ng-h / ml) compared to without surfactant (AUC[0-inf] = 994 ng-h / ml).

[00229] MCC capsules of mixture 1 with and without surfactant were also evaluated in an in vitro dissolution study at a dose potency of 2.5 mg of Compound 1.

[00230] The dissolution method used the following conditions: Petition 870230103657, dated 11 / 24 / 2023, pp. 95 / 151 92 / 129 Parameters Instrument Configuration Agilent 708-DS Medium 0.1 N HCl with 2% SDS Equipment USP 2 apparatus (blades) Rotation speed 75 rpm (200 rpm for infinite rotation) Medium volume 900 mL Temperature 37.0 ±0.5°C Sampling time point 15, 30, 45, 60 min and infinity at 120 min

[00231] Dissolution results are shown in Figure 4, where the addition of 2% SDS to the formulation significantly increased the in vitro dissolution release, from 38% release after 120 minutes with Poloxamer 188 to 54% release after 120 minutes with SLS.

[00232] Table 22 provides other example formulations for mixture capsules (prototypes 1-12). Table 22. Exemplified formulations Ingredient Example of Business (supplier) Function Quantity (weight in grams) in capsule 1 2 3 4 5 6 7 8 9 10 11 12 1:10 Mixture 1:10 Mixture 1:10 Mixture 1:10 Mixture 1:1 Mixture 1:1 Mixture 1:1 Mixture Compound 1 Active Pharmaceutical Active Pharmaceutical 1.0 1.0 10.0 10.0 10.0 10.0 100.0 100.0 1.0 1.0 10.0 100.0 Starch Starch 1500 (Colorcon) Filler, Dispersant 10.0 100.0 10.0 100.0 5.0 2.5 2.5 25.0 Microcrystalline Cellulose (MCC) Avicel (FMC) Filler, Dispersant 10.0 100.0 10.0 100.0 5.0 2.5 2.5 25.0 Petition 870230103657, dated 11 / 24 / 2023, pp. 96 / 151 93 / 129 Ingredient Example Business (supplier) Function Quantity (weight in grams) in capsule 1 2 3 4 5 6 7 8 9 10 11 12 1:10 Mixture 1:10 Mixture 1:10 Mixture 1:10 Mixture 1:1 Mixture 1:1 Mixture 1:1 Mixture Lactose Lactose (FMC) Filler, Dispersant 2.5 2.5 25.0 Mannitol Mannitol (FMC) Filler, Dispersant 2.5 2.5 25.0 Magnesium Stearate Magnesium Stearate (FMC) Lubricant, Flow Aid 0.22 0.22 2.2 2.2 0.40 2.2 2.2 2.2 0.1 0.1 0.2 1.0 Silica Pyrogenic, Slip (special minerals), Lubricant, Flow Aid 0.1 0.1 0.2 1.0 TOTAL 11.22 11.22 112.2 112.2 20.4 22.2 202.2 202.2 11.2 11.2 20.4 202.0

[00233] Examples of excipients that may be used in the preparation of the formulations as disclosed in this application are shown in Table 23. Table 23. Examples of excipients. Pharmaceutical Product Excipient Example of Trade Name (supplier) Function Capsule or tablet Microcrystalline Cellulose Microcrystalline Cellulose, Compendial PH101 (DuPont) Filler, Dispersant Croscarmellose Sodium Croscarmellose Sodium SD-711 (DuPont) Dispersant, disintegrant Crospovidone Crospovidone XL-10 (Ashland) Dispersant, disintegrant Mannitol Mannitol 100SD (Roquette) Filler, Dispersant Petition 870230103657, dated 11 / 24 / 2023, page 97 / 151 94 / 129 Medicinal Product Excipient Example of Trade Name (supplier) Function Magnesium Stearate Magnesium Stearate LIGAMED MF-2-V Lubricant Poloxamer 188 Poloxamer 188 (FMC) Surfactant, dispersant Tween 80 Tween 80 (Chemical Spectrum) Surfactant, dispersant Sodium Lauryl Sulfate Sodium Lauryl Sulfate SLS Fine (BASF) Surfactant, dispersant Colloidal Silicon Dioxide Colloidal Silicon Dioxide Aerosil 200 Pharm (Evonik) Lubricant Starch Starch 1500 Partially Pregelatinized Corn Starch 2001-NEC (Colorcon) Filler, Dispersant Suspension Polysorbate 80 Tween 80 (Chemical Spectrum) Surfactant, Wetting Agent Poloxamer 188 Pluronic F-68 (FMC) Surfactant, Wetting Agent Methyl cellulose (MC) Methyl cellulose, 400 cP, USP (Alpha Chemical) Suspension aid, thickener Methyl cellulose (MC) Methyl cellulose, 4000 cP, USP (Alpha Chemical) Suspension aid,Hydroxypropyl methylcellulose (HPMC) thickener, Hypermellose HPMC E464 (Orison Chemicals), Suspension aid, thickener. Petition 870230103657, dated 11 / 24 / 2023, pp. 98 / 151 95 / 129 Medicinal Product Excipient Example of Trade Name (supplier) Function Methyl Paraben Methyl Paraben (Sigma Chemical) Antimicrobial preservative Propyl Paraben Propyl Paraben (Sigma Chemical) Antimicrobial preservative Propylene Glycol (PG) Propylene Glycol (Sigma Chemical) Solubilizer, Cosolvent ASD Hydroxypropylmethylcellulose acetate succinate (HPMCAS) AquaSolve HPMC-AS (Ashland) Polymer matrix, amorphous dispersant Polyvinyl caprolactam-polyvinyl polyethylene glycol graft copolymer Soluplus (BASF) Polymer matrix, amorphous dispersant Poly(nilycothymidyl acid deoxydioxide) sodium salt Eudragit L100 Polymer matrix, amorphous dispersant Polyethylene Glycol 400 (PEG 400) solution Kollisolv PEG 400 (BASF) Solubilizer, Cosolvent Polyethylene glycol 300 (PEG 300) Kollisolv PEG 300 (BASF) Solubilizer, Cosolvent Petition 870230103657, dated 11 / 24 / 2023, pp. 99 / 151 96 / 129 Pharmaceutical Product Excipient Example of Trade Name (supplier) Function Hydrogenated Castor Oil Kolliphor RH40 (BASF) Solubilizer, Cosolvent Linoleoyl Glycerides Polyoxyl-6 Labrafil M2125 CS (Gattefossé) Solubilizer, Cosolvent Diethylene Glycol Monoethyl Ether Transcutol HP (Gattefossé) Solubilizer, Cosolvent Polyethylene Glycol 1000 d-α-Tocopheryl Succinate Vitamin E TPGS (Parchem) Solubilizer, Cosolvent Ethanol Ethanol (Cargill) Solubilizer, Cosolvent Propylene Glycol (PG) Propylene Glycol (Sigma Chemical) Solubilizer, Cosolvent Example 3. Pharmacokinetic studies of formulations comprising Compound 1

[00234] Pharmacokinetic (PK) studies were performed in animals with formulations as described in Example 2. Compound 1 was formulated to achieve the desired dose (Table 24) and administered to a group of three fasted animals by single oral gavage. A minimum of 7 time points were used to collect blood samples and then prepare plasma samples for bioanalysis. PK parameters were then obtained after non-compartmental pharmacokinetic analysis using Phoenix WinNonlin software (version 6.3, Pharsight, Mountain View, CA). The linear / log trapezoidal rule was applied in obtaining the PK parameters. Nominal dose levels and Petition 870230103657, dated 11 / 24 / 2023, pp. 100 / 151 97 / 129 nominal sampling times were used in the calculation of all pharmacokinetic parameters. Table 24 summarizes the PK data. The results are summarized in the table below. Studies 14-17 were conducted under a crossover design. In the table, the Prototype 2a solution is 58.1% KolliphorRH40 + 16.9% LabrafilM2125 CS + 8.3% Propylene Glycol + 16.7% Ethanol. MC is methyl cellulose 400 cP, Tween 80 is Polyoxyethylene (80)-sorbitan monooleate, HPMCASMF, soluplus and Eudragit are polymers, and Poloxamer is a copolymer. Table 24. Selected PK data from formulations tested in animals Study Dose (mg / kg) Formulation Species Auc0-inf (ng / ml*h) (ng / mL) 1 5 suspension (0.5%MC 400 cP, 0.2% Tween 80) Rat 1094 A 2 5 suspension (0.5%MC 400 cP, 0.2% Tween 80) Rat 3015 B 3 5 Prototype solution 2a Rat 3024* B 4 5 (HPMC-ASMF) - ASD Rat 5534 C 5 5 (Soluplus) - ASD Rat 6728 D 6 5 (Eudragit L100) - ASD Rat 6936 D 7 15 suspension (0.5%MC 400 cP, 0.2% Tween 80) Rat 5172* C 8 15 suspension (0.5%MC 400 cP, 0.2% Tween 80) - ground Rat 13436 D 9 1 suspension (Prototype 2a) Dog 406 A 10 1 suspension (0.5% MC 400 cP, 0.2% Tween 80) Dog 174 A 11 1 suspension (0.5% MC 400 cP, 0.2% Tween 80) - ground Dog 303 A 12 0.5 suspension (0.5% 400 cP MC, 0.2% Poloxamer 188) - ground Monkey C. 997 B 13 0.5 suspension (0.5% MC 400 cP, 0.2% Tween 80) Monkey C. 762 A Petition 870230103657, dated 11 / 24 / 2023, pp. 101 / 151 98 / 129 Study Dose (mg / kg) Formulation Species Auc0-inf (ng / ml*h) (ng / mL) 14 0.5 Hard gelatin capsule size #4 (1:10 mixture with MCC) Monkey C. 994 A 15 0.5 Hard gelatin capsule size #4 (ASD-3 HPMCASMF, Drug loading (p%) = 18.22%) Monkey C. 1358 B 16 0.5 Hard gelatin capsule size #4 (1:10 mixture with MCC and 2% SLS) Monkey C. 1004 A 17 1.0 Hard gelatin capsule size #4 (1:10 mixture with MCC) Monkey C. 1749 B *Auc(0Last)

[00235] For the Cmax values ​​in Table 24, A indicates more than 50 ng / mL and up to 150 ng / mL, B indicates more than 150 ng / mL and up to 300 ng / mL, C indicates more than 300 mg / mL and up to 600 mg / mL, and D indicates more than 600 ng / mL and up to 900 ng / mL.

[00236] In addition, human PK and the effective dose are estimated. Based on calculations, the effective human dose for a neurological disorder (e.g., epilepsy) is approximately 2.5 to 100 mg (e.g., 60 mg) once daily. Example 4. Randomized, Double-Blind, Placebo-Controlled Clinical Study to Evaluate the Safety, Tolerance, and Pharmacokinetics of Single and Multiple Ascending Doses and the Feeding Effect of Compound 1 in Healthy Volunteers

[00237] This is a three-part clinical study to evaluate the safety, tolerability, PK, and dietary effect of Compound 1 in healthy volunteers aged 18 to 55 years, inclusive. The clinical study consists of the following 3 parts: Part A is randomized, double-blind, and controlled by Petition 870230103657, dated 11 / 24 / 2023, pp. 102 / 151 99 / 129 placebo. Part A is designed to investigate the safety and PK of single ascending doses of Compound 1. • Part B is randomized, double-blind, and placebo-controlled. Part B is designed to investigate the safety and PK of multiple ascending doses of Compound 1 (selected based on the results of Part A). • Part C is a randomized, open-label, crossover design to investigate the PK of a single dose of Compound 1 in fasted and fed states. OBJECTIVES AND OUTCOMES: Part A Objective Primary Outcome • To evaluate the safety and tolerability of single oral doses of Compound 1 • Incidence and severity of adverse events (AEs) • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in electrocardiogram (ECG) parameters • The Incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) measured suicidal ideation or behavior Secondary Objective • To evaluate the pharmacokinetics (PK) of single oral doses of Compound 1 The following PK parameters will be calculated: • Observed maximum concentration (Cmax) • Time to observed maximum concentration (tmax) • Apparent terminal elimination half-life (t1 / 2) Petition 870230103657, dated 11 / 24 / 2023, pp. 103 / 151 100 / 129 Objective Outcome • Area under the concentration-time curve from time zero to the last measurable concentration (AUC0-ultimate) • Area under the drug concentration-time curve from time zero to infinity (AUC0-inf) • Clearance (CL / F) • Volume of distribution (Vd / F) • Renal clearance (Clr) • Fraction of dose excreted unchanged in urine (fe) • Amount excreted unchanged over 72 hours (Ae0-72) Exploratory • To evaluate the pharmacodynamic effect (PD) of Compound 1 on stimulated electroencephalography (EEG) outcomes using auditory stimulation • Electroencephalogram (EEG) measurement of auditory evoked responses (e.g., auditory steady-state response (ASSR)) Part B Objective Primary Outcome • To evaluate the safety and tolerability of repeated 7-day oral doses of Compound 1 • Incidence and severity of adverse events • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in electrocardiogram (ECG) parameters • The incidence of C-SSRS measured suicidal ideation or behavior Petition 870230103657, dated 11 / 24 / 2023, pp. 104 / 151 101 / 129 Objective Secondary Outcome • To evaluate the pharmacokinetics (PK) of repeated 7-day oral doses of Compound 1. The following PK parameters will be calculated on Day 1 and Day 7: • Cmax • tmax • AUC0-ultimate • Area under the concentration-time curve from time zero during a dose administration interval (AUCtau) • Time to steady state Accumulation ratio based on AUC (Rac (AUC)) Accumulation ratio based on Cmax (Rac (Cmax)) Exploratory • To evaluate the PD effect of Compound 1 on stimulated EEG outcomes using auditory stimulation. • EEG measurement of auditory evoked responses (e.g., auditory steady-state response (ASSR)) • circulating metabolite profile Part C Objective Primary Outcome • To evaluate the effect of food on the pharmacokinetics (PK) of single oral doses of Compound 1. The following PK parameters, in fasted and fed states, will be calculated: • Cmax • tmax • AUC0-ultimate • AUC0-inf Secondary Objective • To evaluate the safety and tolerability of oral doses of Compound 1 in the following states: • Incidence and severity of adverse events • Changes in vital sign measurements • Changes in clinical laboratory results Petition 870230103657, dated 11 / 24 / 2023, pp. 105 / 151 102 / 129 Objective Outcomes in fasting and fed states • Changes in electrocardiogram (ECG) parameters • The incidence of C-SSRS measured suicidal ideation or behavior

[00238] Based on emerging safety and PK data from Part A, the SRC may select an initial dose for Part B before completion of all dose-level cohorts in Part A. Part C may begin after the last SAD cohort. Parts A and B are double-blind, including participant and investigator; the sponsor is unblinded to facilitate safety analysis. Each part consists of 3 periods: screening, intervention, and safety follow-up. Screening / Initial Assessment Period

[00239] The screening period for the three parties will last up to 27 days (Day-28 to Day-2). Intervention Period

[00240] After confirmation of continued eligibility, participants check in at the clinic on Day -1 (the day before administration of the study drug) and assessments are performed. Participants remain in the unit from the initial assessment (Day -1) until discharge (Day 6 in Part A, Day 12 in Part B, and Day 13 in Part C). Part A

[00241] Healthy volunteers are included to receive single ascending doses of Compound 1 or placebo on Day 1. Dose escalation in Part A is conducted in a total of 6 planned cohorts (Cohorts A1 to A6). Up to 3 additional cohorts may be studied at planned or intermediate dose levels. Eight participants are included in each cohort and will be randomized to receive Compound 1 or placebo (3:1 ratio). Compound 1 is administered Petition 870230103657, dated 11 / 24 / 2023, pp. 106 / 151 103 / 129 to participants in Cohort A1 at an initial dose of 2.5 mg. Dosing in all cohorts is done under fasting conditions.

[00242] Dosing in each dose-level cohort begins with 2 sentinel participants, with one of the 2 participants randomized to receive Compound 1 and the other participant randomized to receive placebo. The safety and tolerability of each sentinel participant are monitored until Day 6 and analyzed before dose administration to the remaining participants in each cohort.

[00243] Cohorts are dosed in ascending order. After each dose cohort in Part A has completed dose administration, the cumulative blinded safety data collected up to Day 6 and the available blinded PK data are analyzed by the Safety Review Committee (SRC) to determine the safety and tolerability of the study drug.

[00244] If the current dose level is determined to be safe and tolerated, the next dose cohort is included and randomized to receive the selected dose of Active Compound 1 or placebo. EEG to assess the effect of Compound 1 on auditory evoked responses may be performed in one or more cohorts, as determined based on safety and PK profile. Dosage regimen for Part A Study Cohort | Dose and Route of Administration | A1 Compound 1 | 2.5 mg, oral, fasting | A2 Compound 1 | Up to 10 mg, oral, fasting | A3 Compound 1 | Up to 30 mg, oral, fasting | A4 Compound 1 | Up to 60 mg, oral, fasting | A5 Compound 1 | Up to 90 mg, oral, fasting | A6 Compound 1 | Up to 120 mg, oral, fasting Part B

[00245] The initial dose level in Part B is determined by the SRC Petition 870230103657, dated 11 / 24 / 2023, pp. 107 / 151 104 / 129 based on safety, tolerability, and PK data obtained in Part A. The SRC may select an initial dose for Part B before completion of all dose-level cohorts in Part A.

[00246] A dose level is evaluated in Part B if it is determined to be safe and tolerable in Part A. It is anticipated that 3 dose levels will be evaluated in Part B across a total of 3 cohorts (Cohorts B1-B3). An additional cohort may be added to repeat a dose level or study an intermediate dose. Eight participants are included in each cohort and randomized to receive Compound 1 or placebo (3:1 ratio).

[00247] The dose levels of Compound 1 to be evaluated in Part B do not exceed the doses studied in Part A. Dosing begins on Day 1 and continues through Day 7. The last dose is administered on the morning of Day 7. Dosing in all cohorts in Part B is in the fasting state. Two sentinel participants are planned for each dose cohort in Part B. Dosage regimen for Part B Cohort | Drug in Study | Daily Dose and Route of Administration | B1 Compound 1 | Up to 60 mg, oral, on an empty stomach | B2 Compound 1 | Up to 90 mg, oral, on an empty stomach | B3 Compound 1 | Up to 120 mg, oral, on an empty stomach

[00248] After each dose cohort in Part B has completed dosing with the study drug, the SRC analyzes blinded safety data (including safety assessments performed on Day 9) and available PK data to determine the safety and tolerability of the study drug, following the same procedures as in Part A.

[00249] EEG to assess the effect of Compound 1 on auditory evoked responses may be performed in one or more cohorts, as determined by the Sponsor based on the safety profile. Petition 870230103657, dated 11 / 24 / 2023, pp. 108 / 151 105 / 129 and PK. Part C

[00250] Part C can begin once safety and PK have been adequately evaluated in the last cohort of Part A. Up to 16 participants receive two doses of Compound 1, one dose after a minimum 10-hour fast and one after consuming a high-fat, high-calorie meal in a randomized crossover design, with a 7-day suspension of use between periods. Up to 3 additional days of suspension of use may be added between fasting and post-food administration based on the half-life observed in Part A.

[00251] The dose to be used in Part C does not exceed that used in Part A and is approved by the SRC based on accumulated safety and PK data. Sentinel dosing may be used in Part C if deemed appropriate by the SRC. Part C is not blinded. Safety Assessments and Monitoring

[00252] Safety and tolerability assessments include vital signs, 12-lead ECGs, physical examinations, clinical laboratory tests, and C-SSRS, as described in the Statement of Assignments. NUMBER OF PARTICIPANTS: • Part A: It is planned to administer Compound 1 or placebo within 72 hours. • Part B: It is planned to administer Compound 1 or placebo within 32 hours. • Part C: It is planned to administer Compound 1 to up to 16 people. Exclusion Criteria

[00253] A participant who meets any of the following criteria, among other things, during screening will be excluded from this clinical study: • Any abnormal ECG finding evaluated as clinical Petition 870230103657, dated 11 / 24 / 2023, pp. 109 / 151 106 / 129 significantly assessed by the investigator, including a QT interval with Fridericia correction method (QTcF) > 450 ms, confirmed with 1 repeat test, as needed, at screening or on day 1. • Use of prescribed systemic medications or over-the-counter (OTC) medications, including multivitamins, and dietary and herbal supplements, within 2 weeks or 5 times the terminal half-lives of the medication before the first dose of the study drug, whichever is longer, and for the duration of the study. PRODUCT UNDER TEST, REFERENCE THERAPY, ADMINISTRATION: • Part A: Capsules of Compound 1 or the corresponding placebo are administered orally. • Part B: Capsules of Compound 1 or the corresponding placebo are administered orally. • Part C: The capsules of Compound 1 are administered orally. STATISTICAL METHODS:

[00254] PK Analyses: A validated bioanalytical method is used for the determination of plasma and urinary concentrations of Compound 1. Plasma and urinary concentrations are summarized by dose group / condition and point in time using descriptive statistics. In addition to the descriptive statistics specified in the General Conditions above, plasma concentrations are also summarized using the number and percentage of concentrations below the level of quantification (BLQ) and coefficient of variation (CV%).

[00255] Pharmacokinetic parameters are estimated from concentration-time data using standard non-compartmental methods. Urine PK parameters are estimated from urine concentration and volume data. The parameters Petition 870230103657, dated 11 / 24 / 2023, pp. 110 / 151 107 / 129 PK parameters are summarized by dose group / condition using descriptive statistics. In addition to the descriptive statistics specified in the General Conditions above, PK parameters are summarized using CV%, geometric mean, and geometric coefficient of variation. PK parameters are evaluated for linearity and dose proportionality using the power model, when feasible. To test for a feeding effect in Part C, the ratio of the geometric mean (transformed ln) of the test treatment (i.e., fed condition) to the reference treatment (i.e., fasted condition) is estimated with the 90% CIs calculated for Cmax and AUC0-inf. The absence of a feeding effect is concluded if the 90% CIs for the Cmax and AUC0-inf ratios are completely contained within the range of 0.80 to 1.25. If there is unexpected difficulty in determining the terminal half-life, the AUC0-ultimate may be used in place of the AUC0-inf. Example 5. Randomized, Double-Blind, Placebo-Controlled Clinical Study to Evaluate the Safety, Tolerance, and Pharmacokinetics of Single and Multiple Ascending Doses and the Feeding Effect of Compound 1 in Healthy Volunteers

[00256] This is a three-part clinical study to evaluate the safety, tolerability, PK, and dietary effect of Compound 1 in healthy volunteers aged 18 to 55 years, inclusive. The clinical study consists of the following 3 parts: • Part A is randomized, double-blind, and placebo-controlled. Part A is designed to investigate the safety, tolerability, and PK of single ascending doses of Compound 1 from 2.5 mg to 90 mg. • Part B is randomized, double-blind, and placebo-controlled. Part B is designed to investigate the safety, tolerability, and PK of multiple ascending doses of Compound 1 (doses selected based on the results of Part A). Petition 870230103657, dated 11 / 24 / 2023, pp. 111 / 151 108 / 129 • Part C is a randomized, open-label, crossover design to investigate the PK, safety, and tolerability of a single dose of Compound 1 in both fasted and fed states (dose selected based on Part A results). OBJECTIVES AND OUTCOMES: Part A Objective Outcome Primary • To assess the safety and tolerability of single oral doses of Compound 1 • Incidence and severity of adverse events (AEs) • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in electrocardiogram (ECG) parameters • The Incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) measured suicidal ideation or behavior Secondary • Evaluate the pharmacokinetics (PK) of single oral doses of Compound 1. The following PK parameters will be calculated: • Observed maximum concentration (Cmax) • Time to observed maximum concentration (tmax) • Apparent terminal elimination half-life (t1 / 2) • Area under the concentration-time curve from time zero to the last measurable concentration (AUCultimate) • Area under the concentration curve of Petition 870230103657, dated 11 / 24 / 2023, pp. 112 / 151 109 / 129 Objective: Drug outcome as a function of time from time zero to infinity (AUCinf) • Clearance (CL / F) • Volume of distribution (Vd / F) • Renal clearance (Clr) • Fraction of dose excreted unchanged in urine (fe) • Amount excreted unchanged over hours (Ae0-72) Exploratory: • To evaluate the pharmacodynamic effect (PD) of Compound 1 on stimulated electroencephalography (EEG) outcomes using auditory stimulation • Electroencephalogram (EEG) measurement of auditory evoked responses (e.g., auditory steady-state response (ASSR)) Part B Objective Primary Outcome • To evaluate the safety and tolerability of repeated 7-day oral doses of Compound 1 • Incidence and severity of adverse events • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in electrocardiogram (ECG) parameters • The incidence of C-SSRS measured suicidal ideation or behavior Secondary Petition 870230103657, dated 11 / 24 / 2023, pp. 113 / 151 110 / 129 • Evaluate the pharmacokinetics (PK) of repeated 7-day oral doses of Compound 1. The following PK parameters will be calculated: • Cmax • tmax • AUCultimate • Area under the concentration-time curve from time zero during a dose administration interval (AUCtau) • Time to steady state • Accumulation ratio based on AUC (Rac (AUC)) • Accumulation ratio based on Cmax (Rac (Cmax)) Exploratory • Evaluate the PD effect of Compound 1 on stimulated EEG outcomes using auditory stimulation. • EEG measurement of auditory evoked responses (e.g., auditory steady-state response (ASSR)) Part C Objective Primary Outcome • To evaluate the effect of food on the pharmacokinetics (PK) of single oral doses of Compound 1. The following PK parameters, in fasted and fed states, will be calculated: • Cmax • tmax • AUCultima • AUCinf Secondary Objective • To evaluate the safety and • Incidence and severity of adverse events Petition 870230103657, dated 11 / 24 / 2023, pp. 114 / 151 111 / 129 Objective: Outcome: Tolerability of oral doses of Compound 1 in fasting and fed states • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in electrocardiogram (ECG) parameters • The incidence of C-SSRS measured suicidal ideation or behavior

[00257] Based on emerging safety and PK data from Part A, the SRC may select an initial dose for Part B before completion of all dose-level cohorts in Part A. Part C may begin after the last SAD cohort. Parts A and B are double-blind, including participant and investigator; the sponsor is unblinded to facilitate safety analysis. Each part consists of 3 periods: screening, intervention, and safety follow-up.

[00258] After confirmation of continued eligibility, participants check in at the clinic on Day -1 (the day before administration of the study drug) and assessments are performed. Participants remain in the unit from the initial assessment (Day -1) until discharge (Day 6 in Part A, Day 12 in Part B and Day 13 in Part C). Part A

[00259] Healthy volunteers are included to receive single ascending doses of Compound 1 or placebo on Day 1. Dose escalation in Part A is conducted in a total of 6 planned cohorts (Cohorts A1 to A6). Up to 3 additional cohorts may be studied at planned or intermediate dose levels. Eight participants are included in each cohort and will be randomized to receive Compound 1 or placebo (3:1 ratio). Compound 1 is administered to participants in Cohort A1 at an initial dose of 2.5 mg. Dosing in all cohorts is done under fasting conditions. Petition 870230103657, dated 11 / 24 / 2023, pp. 115 / 151 112 / 129

[00260] Dosing in each dose-level cohort begins with 2 sentinel participants, with one of the 2 participants randomized to receive Compound 1 and the other participant randomized to receive placebo. The safety and tolerability of each sentinel participant are monitored until Day 6 and analyzed before dose administration to the remaining participants in each cohort.

[00261] Cohorts are dosed in ascending order. After each dose cohort in Part A has completed dose administration, the cumulative blinded safety data collected up to Day 6 and the available blinded PK data are analyzed by the Safety Review Committee (SRC) to determine the safety and tolerability of the study drug.

[00262] If the current dose level is determined to be safe and tolerated, the next dose cohort is included and randomized to receive the selected dose of Active Compound 1 or placebo. EEG to assess the effect of Compound 1 on auditory evoked responses may be performed in one or more cohorts, as determined based on safety and PK profile. Dosage regimen for Part A Cohort | Drug in Study | Dose and Route of Administration | A1 Compound 1 | 2.5 mg, oral, fasting | A2 Compound 1 | Up to 7.5 mg, oral, fasting | A3 Compound 1 | Up to 15 mg, oral, fasting | A4 Compound 1 | Up to 30 mg, oral, fasting | A5 Compound 1 | Up to 60 mg, oral, fasting | A6 Compound 1 | Up to 90 mg, oral, fasting Part B

[00263] The initial dose level in Part B is determined by the SRC based on safety, tolerability, and PK data obtained in Part A. The SRC may select an initial dose for Part B before Petition 870230103657, dated 11 / 24 / 2023, pp. 116 / 151 113 / 129 completion of all dose-level cohorts in Part A.

[00264] A dose level is evaluated in Part B if it is determined to be safe and tolerable in Part A. It is anticipated that 3 dose levels will be evaluated in Part B across a total of 3 cohorts (Cohorts B1-B3). An additional cohort may be added to repeat a dose level or study an intermediate dose. Participants are enrolled in each cohort and randomized to receive Compound 1 or placebo (3:1 ratio).

[00265] The dose levels of Compound 1 to be evaluated in Part B do not exceed the doses studied in Part A. Dosing begins on Day 1 and continues through Day 7. The last dose is administered on the morning of Day 7. Dosing in all cohorts in Part B is in the fasting state. Two sentinel participants are planned for each dose cohort in Part B. Dosage regimen for Part B Cohort Drug in Study Daily Dose and Route of Administration B1 Compound 1 Up to 30 mg, oral, on an empty stomach B2 Compound 1 Up to 60 mg, oral, on an empty stomach B3 Compound 1 Up to 90 mg, oral, on an empty stomach

[00266] After each dose cohort in Part B has completed dosing with the study drug, the SRC analyzes blinded safety data (including safety assessments performed on Day 9) and available PK data to determine the safety and tolerability of the study drug, following the same procedures as in Part A.

[00267] EEG to assess the effect of Compound 1 on auditory evoked responses may be performed in one or more cohorts, as determined by the Sponsor based on the safety profile and PK. Part C Petition 870230103657, dated 11 / 24 / 2023, pp. 117 / 151 114 / 129

[00268] Part C can begin once safety and PK have been adequately evaluated in the last cohort of Part A. Participants receive two doses of Compound 1, one dose after a minimum of 10 hours of fasting and one after consuming a high-fat, high-calorie meal in a randomized crossover design, with a 7-day withdrawal period between periods. Up to 3 additional days of withdrawal may be added between fasting and post-food administration based on the half-life observed in Part A.

[00269] The dose to be used in Part C does not exceed that used in Part A and is approved by the SRC based on accumulated safety and PK data. Sentinel dosing may be used in Part C if deemed appropriate by the SRC. Part C is not blinded. Safety Assessments and Monitoring

[00270] Safety and tolerability assessments include vital signs, 12-lead ECGs, physical examinations, clinical laboratory tests, and the C-SSRS. Exclusion Criteria

[00271] A participant who meets any of the following criteria, among other things, during screening will be excluded from this clinical study: • Any abnormal ECG finding assessed as clinically significant by the investigator, including a QT interval with Fridericia correction method (QTcF) > 450 ms, confirmed with 1 repeat test, as needed, at screening or on day 1. • Use of prescribed systemic medications or over-the-counter (OTC) medications, including multivitamins, and dietary and herbal supplements within 2 weeks or 5 times the terminal half-lives of the medication before the first dose of the study drug, whichever is longer, and for the duration of the study. Petition 870230103657, dated 11 / 24 / 2023, pp. 118 / 151 115 / 129 everything. PRODUCT UNDER TEST, REFERENCE THERAPY, ADMINISTRATION: • Part A: Capsules of Compound 1 or the corresponding placebo are administered orally. • Part B: Capsules of Compound 1 or the corresponding placebo are administered orally. • Part C: The capsules of Compound 1 are administered orally. STATISTICAL METHODS:

[00272] PK Analyses: A validated bioanalytical method (e.g., liquid chromatography-mass spectrometry (LC-MS)) is used to determine plasma and urinary concentrations of Compound 1. Plasma and urinary concentrations are summarized by dose group / condition and point in time using descriptive statistics. In addition to the descriptive statistics specified in the General Conditions above, plasma concentrations are also summarized using the number and percentage of concentrations below the level of quantification (BLQ) and coefficient of variation (CV%).

[00273] Pharmacokinetic parameters are estimated from concentration-time data using standard non-compartmental methods. Urine PK parameters are estimated from urine concentration and volume data. PK parameters are summarized by dose group / condition using descriptive statistics. In addition to the descriptive statistics specified in the General Conditions above, PK parameters are summarized using CV%, geometric mean, and geometric coefficient of variation. PK parameters are assessed for linearity and dose proportionality using the power model, when feasible. To test for a feeding effect in Part C, the geometric mean (transformed ln) ratio of the treatment is used. Petition 870230103657, dated 11 / 24 / 2023, pp. 119 / 151 The ratio of 116 / 129 to the test (i.e., fed condition) relative to the reference treatment (i.e., fasting condition) is estimated using the 90% CIs calculated for Cmax and AUCinf. The absence of a feeding effect is concluded if the 90% CIs for the Cmax and AUCinf ratios are completely contained within the range of 0.80 to 1.25. If there is unexpected difficulty in determining the terminal half-life, the ultimate AUC may be used instead of the AUCinf. Results

[00274] Preliminary analysis of the first four of six planned cohorts in Part A indicates that Compound 1 appears to be well tolerated at the doses tested. Safety data analyzed included adverse events, vital signs, ECG, C-SSRS, physical examination, and laboratory safety data. In the first three cohorts tested, there were no reported serious adverse events, severe adverse events, or any adverse events that led to withdrawal or discontinuation of the study.

[00275] Based on preliminary data, exposure appears to increase proportionally to the dose level, and peak concentrations are reached in 2-3 hours. The terminal elimination half-life averages 114 hours (~4-5 days) across groups. 90% steady state should be achieved in approximately 2 weeks with once-daily dosing. Example 5. A Randomized Double-Blind Comparison of the Efficacy and Safety of Compound 1 versus Placebo for the Acute and Prophylactic Treatment of Chronic SUNCT and SUNA

[00276] This multicenter clinical study will evaluate the efficacy, safety, tolerability, and pharmacokinetics of Compound 1 in participants, for example, aged 18 to 65 years with chronic SUNCT or chronic SUNA syndromes. This is a double-blind, placebo-controlled study. Participants will be randomized to receive 1 of 3 Petition 870230103657, dated 11 / 24 / 2023, pp. 120 / 151 117 / 129 treatments in a blinded manner [High-dose Compound 1, mg orally daily, Low-dose Compound 1, mg orally daily, or placebo daily] at a 1:1:1 ratio. Participants will self-administer the study drug once daily with weekly clinical visits. Participants will also be asked to answer questions in an electronic diary (eDiary), for example, 3 times daily (pre-dose or approximately 24 hours after the previous dose, approximately 4 hours after the dose, and approximately 10 hours after the dose). Objective Primary Outcome • To evaluate the effects of Compound 1 for the treatment of SUNC and SUNA headaches • Change in the average daily frequency of SUNCT and SUNA headache attacks from baseline to Day 21, as recorded by eDiary • Change in the average peak intensity of SUNCT and SUNA headaches from baseline to Day 21, as measured by the Stanford Pain Scale Secondary • To evaluate the effects of Compound 1 in the treatment of SUNC and SUNA headaches • Change in the average daily frequency of attacks from baseline to the average daily frequency throughout the study treatment period, as recorded by eDiary • Change in the average peak intensity of SUNCT and SUNA headaches from baseline throughout the study periodMeasured by the Stanford Pain Scale • Assess the safety and tolerability of Compound 1 in participants • Incidence and severity of adverse events • Changes in vital sign measurements, Petition 870230103657, dated 11 / 24 / 2023, pp. 121 / 151 118 / 129 Objective Outcomes with SUNCT and SUNA • Changes in clinical laboratory results • Changes in ECG parameters • The Incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) measured suicidal ideation or behavior • Characterize the PK profile of Compound 1 in participants with SUNCT and SUNA • Plasma concentrations of Compound 1 and its possible metabolites • Primary PK parameters: Cmax, tmax, and AUCO-tau Exploratory • Evaluate the effects of Compound 1 on other measures associated with SUNCT and SUNA • Change in the duration of SUNCT and SUNA headaches calculated as the number of minutes of pain per day recorded by the eDiary • Change in the average daily frequency of autonomic symptoms, as assessed by the participant • Change in autonomic symptoms,as assessed by facial images • Change in response to triggering factors • Proportion of participants able to perform their usual daily activities • Changes in factor scores and total SF-36 scores • Patient satisfaction with treatment, measured by the visual analog scale (VAS) • Change in disability level from baseline to Day 21 Petition 870230103657, dated 11 / 24 / 2023, pp. 122 / 151 119 / 129 Objective Outcome • Proportion of participants in remission (defined as absence of headache for the observation period) • Duration of remission

[00277] The clinical study consists of 3 periods: initial screening / assessment, intervention, and safety follow-up. An optional discontinuation period is also available for participants using preventive medications. Screening / Initial Assessment Period

[00278] The screening period will be up to, for example, 28 days (Day -28 to Day -1). An optional discontinuation period of up to, for example, 14 days before screening will be allowed for participants who are discontinuing SUNCT or SUNA preventive medications (e.g., carbamazepine, lamotrigine).

[00279] During screening, participants will complete daily entries in the eDiary during, for example, a 14-day observation period to assess the stability, severity, and frequency of SUNCT and SUNA headaches. Intervention Period

[00280] After eligibility is confirmed during screening, participants will complete the initial assessments (Day 1).

[00281] On Day 1, participants will return to the clinic to be randomized into 1 of 3 treatment groups and receive the first dose of the study drug. Participants will remain in a clinical setting under medical observation for at least, for example, 6 hours. Headache records will be completed using the eDiary daily pre-dose (e.g., approximately 24 hours after the previous dose) and, for example, approximately 4 hours and 10 hours post-dose. After the first dose, participants will continue daily administration at home until Day 21. Participants will return to Petition 870230103657, dated 11 / 24 / 2023, pp. 123 / 151 120 / 129 clinical assessments will be conducted on Day 7 (±1 day), Day 14 (±1 day), and Day 21 (±1 day) to complete the assessments. In selected centers, intensive PK sampling will be obtained in the clinic on Day 1, Day 7 (± 1 day), Day 14 (± 1 day), and Day 21 (± 1 day).

[00282] Key safety measures will include clinical laboratory assessments, 12-lead ECG, C-SSRS, and vital signs. Key efficacy assessments will include headache recording via eDiary (see assessment schedule for further details). Blood samples will be obtained for determination of Compound 1 plasma concentrations using a validated bioanalytical method and may also be used for exploratory method development and / or metabolite characterization. Safety Follow-up Period

[00283] The Safety Follow-up Period will take place from Day 22 to Day 36, for example. At the end of the Safety Follow-up Period, participants will return to the clinic on Day 57 (± 1 day) for the end-of-study assessments. During this visit, the following assessments will be performed: vital signs, physical examination, clinical laboratory tests, ECG, C-SSRS assessment, and efficacy assessments.

[00284] Adverse events and the use and procedures of concomitant medication will be monitored from the moment of informed consent until Day 36 (±1 day). At that time, participants will have completed the clinical study. Inclusion / exclusion criteria

[00285] Participants are either male or female, for example, aged 18 to 65 years (inclusive) at screening and have more than, for example, 1 year of history of chronic SUNCT and SUNA headaches with onset before age 50 and have demonstrated a minimum of, for example, 100 SUNCT and SUNA headaches over 14 years. Petition 870230103657, dated 11 / 24 / 2023, pp. 124 / 151 121 / 129 days during the observation period of the clinical study. Product under trial, reference therapy, administration

[00286] High-dose mg Compound 1 capsules, capsules of Compound 1, either a low-dose dose of mg or a placebo, will be administered orally and provided in pre-packaged containers to participants. Dose / Route of Administration / Regimen

[00287] Dose to be determined using PK data. Route of administration will be oral. Statistical Methods

[00288] Safety, tolerability, PK, and efficacy variables will be summarized using descriptive statistics. 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. When appropriate, 95% confidence intervals (CIs) may be reported. Summaries will be presented by time point, when appropriate.

[00289] Standard PK parameters will be estimated using non-compartmental methods based on concentration-time data. These parameters will include, where possible, exploratory analyses of Cmax, tmax, and AUC0-tau examining the relationship between PK and efficacy parameters, which can be performed for the PK analysis set. Primary and Secondary Effectiveness Measures Headache Log completed via eDiary

[00290] An electronic tablet application to collect information about a participant's headache activity before dose administration (or approximately 24 hours after the previous dose) and approximately 4 hours and 10 hours after the dose. The information collected at all times will include the following: frequency of headaches, duration of headaches, and severity of headaches. Petition 870230103657, dated 11 / 24 / 2023, pages 125 / 151 122 / 129 headaches (measured by the Stanford Pain Scale). Information collected 10 hours after the dose will only include the following: types of attacks, associated symptoms and triggering factors, autonomic symptoms. Other information that will be collected via eDiary 10 hours after the dose will include the following: Visual Analogue Scale (VAS), daily activities and level of disability. Stanford Pain Scale

[00291] The Stanford Pain Scale is a comparative pain scale with descriptions assigned to each of the scale's values, ranging from 0 (No pain) to 10 (Unimaginable and indescribable). Pain rated 0 to 3 is considered mild, pain rated 4 to 6 is considered moderate, and pain rated 7 to 10 is considered severe. The Stanford Pain Scale is completed by the participant. Triggering Factors

[00292] Participants will be asked to rate whether their response to triggers (e.g., brushing hair, touching face, chewing, etc.) has changed using a 5-point scale, 0 = no change 1 = slight improvement 2 = moderate improvement 3 = significant improvement 4 = resolution of triggers. Visual Analog Scale

[00293] The visual analog scale will ask participants to rate their satisfaction with the treatment using a Likert scale with categories ranging from 0 = very weak effect to 10 = very good effect. Disability Level

[00294] The participant's level of disability will be measured by the participant using a Goal Achievement Scale with the following categories: 0 = no disability, 1 = mild, 2 = moderate, 3 = severe, 4 = unbearable. 36-Item Abbreviated Health Questionnaire (v2 Acute) Petition 870230103657, dated 11 / 24 / 2023, pp. 126 / 151 123 / 129

[00295] The SF-36 is a 36-item survey that measures a participant's overall health status (McHorney et al., 1994). The SF-36 assesses 8 health concepts. Scores are weighted sums of the questions in each section. Scores range from 0 to 100, where lower scores indicate greater disability. The acute version of the SF-36 will be completed by the participant when indicated in the SoA. The acute version asks participants about their health status in the previous week. Activities of Daily Living

[00296] The participant will be asked to rate the change in their ability to complete activities of daily living. Example 6. Synthesis of (3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine) (Compound 1) 2h

[00297] Synthesis of A2: To a stirred solution of 2,2,2-trifluoroethanol (5.67 g, 56.71 mmol) in THF (200 mL) at 0 °C, NaH (60% in mineral oil, 2.26 g, 56.71 mmol) was added in small portions. The reaction mixture was stirred for 15 min and 5-bromo-2,3-difluoropyridine (10.0 g, 51.55 mmol) was added dropwise. The reaction mixture was heated slowly at room temperature and stirred for 2 hours. The reaction mixture was cooled to 10 °C and treated with ice-cold water (100 mL). The reaction mixture was extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine. Petition 870230103657, dated 11 / 24 / 2023, pp. 127 / 151 124 / 129 (80 mL), dried with anhydrous Na2SÜ4 and concentrated. The crude product was purified by silica gel column chromatography with 2% ethyl acetate / PE to generate 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 pm. Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min.

[00298] Synthesis of A3: To a stirred solution of 5-bromo-3fluoro-2-(2,2,2-trifluoroethoxy)pyridine (3.0 g, 10.95 mmol) and bis(pinacolate)diboron (3.61 g, 14.23 mmol) in 1,4-dioxane (30.0 mL) was added potassium acetate (2.15 g, 21.9 mmol). Pd(dppf)Cl2.DCM (0.89 g, 1.09 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated to 80 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with 15% ethyl acetate / PE to generate 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 pm. Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min.

[00299] Synthesis of A4: A mixture of Pd(dppf)Cl2 (15.13 g, 20.68 mmol), Cs2CO3 (269.49 g, 827.17 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (141.18 g, 439.69 mmol) and 2-bromo-5-chloropyrazine (80 g, 413.59 mmol) in 1,4-Dioxane (1 L) and Water (150 mL) under N2 was stirred at 35°C for 2 hours. After cooling to room temperature, water (300 mL) was added to the mixture and the mixture was filtered through Celite. After separation, the organic phase was washed with brine (300 mL), dried with anhydrous Na2SO4, filtered, and concentrated to yield the crude product. The crude product was redissolved in EA / PE = 1 / 3 (500 mL) and then filtered through a silica gel conveyor belt. The mass was washed with EA / PE = 1 / 3 (500 mL). Petition 870230103657, dated 11 / 24 / 2023, pp. 128 / 151 125 / 129 The combined organic phase was concentrated to generate an oil-like residue. PE (500 mL) was slowly added to the oil, and a small amount of solid was obtained. The solid was collected and oven-dried to yield the product (100 g, 242.4 mmol, 58% yield) as a solid. LCMS Rt = 1.28 min in 2.0 min of chromatography, 10-80AB, MS ESI calculated for C11H7CF4N3O [M+H]+ 308.0, found 307.9.

[00300] Synthesis of A5: A mixture of 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (140 g, 339.36 mmol) and hydrazine hydrate (169.88 g, 3393.6 mmol) in MeCN (1.4 L) was stirred at 100°C for 16 hours. After cooling to room temperature, the mixture was poured into water (4.5 L). A small amount of solid was observed and collected by filtration. The mass was washed with water (500 mL x 2). The solid was redissolved in EtOAc (3 L), washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated to give the crude product (100 g, 329.8 mmol, 97% yield) as a solid. LCMS Rt = 0.74 min in 1.5 min of chromatography, 5-95AB, MS ESI calculated for C11H10F4N5O [M+H]+304.1, 303.9 were found.

[00301] Synthesis of A6: To a solution of 2-bromo-2,2-difluoroacetic acid (87 g, 497.34 mmol) in THF (1 L) was added one drop of DMF and (COCl)2 (50.5 mL, 596.81 mmol). The resulting mixture was stirred at 20°C for 1 hour. The resulting solution was used directly in the next step. To the solution of 2-bromo-2,2-difluoroacetyl chloride (95.66 g, 494.69 mmol) in THF (1 L) was added [5-[5-fluoro6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (100 g, 329.79 mmol). The resulting mixture was stirred at 20°C for 2 hours. Water (1 L) was added to the solution and extracted with EtOAc (1 L x 2). The combined organic phase was washed with brine (500 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated to yield the crude product (150 mg, 326.0 mmol, 98% yield, mixture of mono- and bisalkylated products) as a solid. LCMS Rt = 0.92 min in 1.5 min and chroma Petition 870230103657, dated 11 / 24 / 2023, pp. 129 / 151 126 / 129 Topography, 5-95AB, MS ESI calculated for Ci3H9BrF6N5Ü2 [M+H]+460.1, 459.8 was obtained.

[00302] Synthesis of A7: A solution of 2-bromo-2,2-difluoro-N'-[5[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]acetohydrazide (150 g, 325.99 mmol) and TsOH (16.84 g, 97.8 mmol) in Toluene (1.5 L) was stirred at 130°C for 16 hours. After cooling to room temperature, the mixture was poured into water (2 L), extracted with EtOAc (2 L x 2). The combined organic phase was washed with brine (1 L x 2), dried with anhydrous Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to generate the product (80 g, 181.0 mmol, 55% yield) as an oil. 1H NMR (CDCh, 400MHz) δ·. = 9.60 (d, 1H), 8.55 (d, 1H), 8.45 (s, 1H), 8.09 (dd, 1H), 4.93 (q, 2H).

[00303] Synthesis of Compound 1: A mixture of 3[bromo(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl][1,2,4]triazolo[4,3-a]pyrazine (76 g, 171.9 mmol) and AgBF4 (66.93 g, 343.81 mmol) in Ethanol (760 mL) was stirred at 60°C for 1 hour. After cooling to room temperature, the mixture was poured into saturated aqueous NaCl (1 L) and EtOAc (2 L). The mixture was filtered through Celite. After separation, the aqueous layer was extracted with EtOAc (500 mL x 2). The combined organic phase was washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel flash column chromatography (EtOAc in PE = 0% to 30% to 50%) and then ground from EtOH (50 mL) to yield the product (44.45 g, 109.01 mmol, 63% yield) as a solid. 1H NMR (CDCl3 400MHz) δ·. = 9.52 (d, 1H), 8.49 (dd, 2H), 8.07 (dd, 1H), 4.93 (q, 2H), 4.37 (q, 2H), 1.51 (t, 3H).LCMS Rt = 1.25 min in chromatography of 2.0 min, 10-80AB, MS ESI calculated for C15H12F6N5O2 [M+H]+408.1, en. Petition 870230103657, dated 11 / 24 / 2023, pp. 130 / 151 127 / 129 contracted 408.0. Equivalents and Scope

[00304] In the claims, articles such as a, an, or aeo may mean one or more of a, unless otherwise indicated or otherwise evident from the context. Claims or descriptions that include or are among one or more members of a group are considered satisfied if one, more than one, or all members of the group are present in, used in, or otherwise relevant to a particular product or process, unless otherwise indicated or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present, is used, or is otherwise relevant to a particular product or process. The invention includes embodiments in which more than one, or all members of the group are present, used in, or otherwise relevant to a particular product or process.

[00305] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms of one or more of the listed claims are introduced into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations found in any other claim that depends on the same basic claim. Where elements are displayed as lists, for example, in Markush group format, each subgroup of the elements is also disclosed, and any element(s) may be removed from the group. It should be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist of, or essentially consist of, such elements and / or features. Petition 870230103657, dated 11 / 24 / 2023, pp. 131 / 151 128 / 129 ticas. For simplicity, these embodiments have not been specifically set forth in haec verba in this document. It is also noted that the terms comprising and containing are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are provided, outcomes are included. Furthermore, unless otherwise indicated or evident from the context and understanding of one skilled in the art, the values ​​that are expressed as ranges may assume any specific value or subrange within the ranges indicated in different embodiments of the invention, down to the tenth of a unit of the lower limit of the range, unless the context clearly indicates otherwise.

[00306] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the present descriptive report, the descriptive report shall prevail. Furthermore, any particular embodiment of the present invention that falls within the prior art can be explicitly excluded from any one or more of the claims. Since such embodiments are considered known to one skilled in the art, they can be excluded even if the exclusion is not explicitly stated in this document. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of the prior art.

[00307] Those skilled in the art will recognize or be able to verify the use of no more than routine experimentation of many equivalents to the specific embodiments described in this document. The scope of the present embodiments described in this document is not intended to be limited to the above Description, but is instead as set forth in the appended claims. Those skilled in the art will recognize or be able to verify the use of no more than many equivalents to the specific embodiments described in this document. Petition 870230103657, dated 11 / 24 / 2023, pp. 132 / 151 129 / 129 technical experts will appreciate that various alterations and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims. Petition 870230103657, dated 11 / 24 / 2023, pp. 133 / 151

Claims

1 / 4 CLAIMS 1. Method of preparation of Compound 1: or a pharmaceutically acceptable salt thereof, the method being characterized in that it comprises the steps of: (i) bringing a solution of 2,2,2-trifluoroethanol into contact with 5-bromo-2,3-difluoropyridine, thereby providing a compound of formula (II): Br(II); (ii) bringing the compound of formula (II) into contact with a palladium and bis(pinacolate)diboron catalyst, thereby providing a compound of formula (III): (III); (iii) bringing the compound of formula (III) into contact with a palladium and 2-bromo-5-chloropyrazine catalyst, thereby providing a compound of formula (IV): FCI(IV); (iv) placing the compound of formula (IV) in contact with hydrazine, thereby providing a compound of formula (V): Petition 870260081439, dated 13 / 08 / 2026, page.5 / 20 2 / 4 FF ·Ά N Jk ,NH2 NH (V); (v) place the compound of formula (V) in contact with 2-bromo-2,2-difluoroacetyl chloride, thus providing a compound of formula (VI): FF θ (VI); (vi) place the compound of formula (VI) in contact with an acid, thus providing a compound of formula (VII): (vii) place the compound of formula (VII) in contact with a silver and ethanol catalyst, thus providing Compound 1 or a pharmaceutically acceptable salt thereof.

2. Method according to claim 1, characterized in that the palladium catalyst in step (ii) or (iii) is [1,1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride.

3. Method according to claim 1 or 2, characterized in that the silver catalyst in step (vii) is silver tetrafluoroborate.

4. Method according to any one of claims 1 to 3, characterized in that the acid in step (vi) is ptoluenesulfonic acid. Petition 870260081439, dated 13 / 08 / 2026, page 6 / 20 3 / 4 5. Method of preparation of Compound 1: or a pharmaceutically acceptable salt thereof, characterized in that Compound 1 or a pharmaceutically acceptable salt thereof is provided by contacting the compound of formula (VII): with a silver and ethanol catalyst; wherein the compound of formula (VII) is provided by contacting the compound of formula (VI): with an acid; wherein the compound of formula (VI) is provided by contacting the compound of formula (V): with 2-bromo-2,2-difluoroacetyl chloride; wherein the compound of formula (V) is provided by contacting the compound of formula (IV): Petition 870260081439, dated 13 / 08 / 2026, page 7 / 20 4 / 4 Cl (IV) with hydrazine; wherein the compound of formula (IV) is provided by contacting the compound of formula (III): 1 (UI) with a palladium and 2-bromo-5-chloropyrazine catalyst; wherein the compound of formula (III) is provided by contact with the compound of formula (II): Br(||) with a palladium and bis(pinacolato)diboron catalyst.

6. Method according to claim 5, characterized in that the compound of formula (II) is provided by contacting a solution of 2,2,2-trifluoroethanol with 5-bromo-2,3-difluoropyridine.

7. Method according to claim 5 or 6, characterized in that the silver catalyst is silver tetrafluoroborate.

8. Method according to any one of claims 5 to 7, characterized in that the acid is p-toluenesulfonic acid.

9. Method according to any one of claims 5 to 8, characterized in that the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. Petition 870260081439, dated 13 / 08 / 2026, page 8 / 20

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