Pharmaceutical preparations and their uses

Abstract

A pharmaceutical formulation, particularly a solid oral dosage form (e.g., tablet), is disclosed, and its use is also disclosed, which includes (i) a compound of Formula I in an amount of about 40 wt% to about 70 wt%, (ii) a filler, (iii) a disintegrant, (iv) and a lubricant. Pharmaceutical formulations suitable for treating viral infections, such as coronavirus infections, pneumoviridae virus infections, picornaviridae virus infections, flaviviridae virus infections, orthomyxovirus infections, and paramyxoviridae virus infections, are provided.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 381,272, filed October 27, 2022, and U.S. Provisional Patent Application No. 63 / 508,567, filed June 16, 2023, each of which is incorporated by reference in its entirety for all purposes.

[0002] FIELD OF THE INVENTION Pharmaceutical formulations suitable for treating viral infections, such as coronavirus infections, pneumoviridae virus infections, picornaviridae virus infections, flaviviridae virus infections, orthomyxoviridae virus infections, and paramyxoviridae virus infections, are provided. In particular, solid oral dosage forms comprising a compound of Formula I and uses thereof are provided. [Background technology]

[0003] The compounds of formula I are antiviral agents. [ka]

[0004] The compound of formula I, its preparation method, and its salts and polymorphic forms are described in WO 2022 / 047065 (Compound 15). Chinese Patent No. 114869893 describes a solid dosage form of the compound of formula I, particularly a tablet. The solid dosage form disclosed in Chinese Patent No. 114869893 is obtained by a wet granulation process and is characterized by a low loading (24.4%) of the compound of formula I. The issue of low dose loading, i.e., the content percentage of formula I in the formulation, is not addressed in Chinese Patent No. 114869893.

[0005] Therefore, there is a need to develop a solid dosage form (for example, a tablet / capsule dosage form) that contains a high loading of the compound of Formula I. A high drug loading allows the tablet / capsule to have a suitable size, so that patients can easily swallow the tablet / capsule. A higher drug loading also helps minimize the number of tablets / capsules required per dose, which can lead to better patient compliance.

[0006] The overall physical properties and manufacturability of low drug load formulations are primarily determined by the inactive ingredients or excipients in the formulation. However, at high drug loads, the contribution of the physical properties of the active pharmaceutical ingredient ("API") to the manufacturability of the formulation becomes dominant. Not all APIs have the necessary properties with respect to compressibility required to obtain high-load tablets using a dry granulation process. In general, most small molecule APIs can be formulated in low-dose forms because the physical properties of the excipients utilized in the formulation, rather than the physical properties of the API itself, govern the properties of the solid composition. As drug loading increases, the physicochemical properties of the drug substance become increasingly dominant in the tablet manufacturing process. It is common to include filler excipients with brittle properties and others with ductile / plastic properties in a single formulation. The combination of brittle and plastic materials in a given formulation is important to the "manufacturability" of that formulation. However, because APIs can have a full spectrum of physical properties and are not selected based on these physical properties, it is not expected that a particular API will have physical properties that contribute favorably to the overall formulation in terms of manufacturability and stability. In fact, it is not uncommon for the physical properties of the API to actually present the greatest obstacle to creating a viable formulation. Therefore, it is surprising and unexpected to find that APIs can be formulated in dry granulation manufacturing processes with drug loadings exceeding 40%. As described below, the ability to prepare tablets of Formula I with drug loadings of greater than 40%, using, for example, a dry granulation process, is a surprising observation. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2022 / 047065 [Patent Document 2] Chinese Patent No. 114869893 Summary of the Invention [Means for solving the problem]

[0008] In one aspect, the disclosure provides a pharmaceutical formulation comprising: (i) a compound represented by Formula I: [ka] or a pharmaceutically acceptable salt thereof; (ii) a filler; (iii) a disintegrant; and (iv) a lubricant, wherein the compound of Formula I is present in an amount of about 40 wt% to about 70 wt%. In some embodiments, the pharmaceutical formulation comprises the filler in an amount of about 20 wt% to about 60 wt%; the disintegrant in an amount of about 1 wt% to about 10 wt%; and the lubricant in an amount of about 0.5 wt% to about 5% wt%. In some embodiments, the pharmaceutical formulation comprises the filler in an amount of about 40 wt% to about 50 wt%; the disintegrant in an amount of about 1 wt% to about 10 wt%; and the lubricant in an amount of about 0.5 wt% to about 5 wt%. In some embodiments, the pharmaceutical formulation comprises (i) a compound of Formula I in an amount of about 45 wt% to about 55 wt%; (ii) a filler in an amount of about 44 wt% to about 46 wt%; (iii) a disintegrant in an amount of about 3 wt% to about 5 wt%; and (iv) a lubricant in an amount of about 0.5 wt% to about 2 wt%. In some embodiments, the pharmaceutical formulation comprises (i) a compound of Formula I in an amount of about 50 wt%; (ii) a filler in an amount of about 44 wt% to about 46 wt%; (iii) a disintegrant in an amount of about 3 wt% to about 5 wt%; and (iv) a lubricant in an amount of about 0.5 wt% to about 2 wt%. In some embodiments, the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the disintegrant is starch, pregelatinized starch, hydroxypropyl starch, cellulose, cross-linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium. In some embodiments, the disintegrant is crospovidone. In some embodiments, the lubricant is stearic acid, sodium stearyl fumarate, or magnesium stearate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the pharmaceutical formulation comprises about 100 mg to about 700 mg of the compound of Formula I. In some embodiments, the pharmaceutical formulation comprises about 100 mg of the compound of Formula I. In some embodiments, the pharmaceutical formulation comprises about 350 mg of the compound of Formula I. In some embodiments, the pharmaceutical formulation comprises about 500 mg of the compound of Formula I.

[0009] In one aspect, the disclosure provides a pharmaceutical tablet formulation comprising: (i) a compound of Formula I or a pharmaceutically acceptable salt thereof; (ii) a filler; (iii) a disintegrant; and (iv) a lubricant; wherein the compound of Formula I is present in an amount of about 40% to about 70% by weight. In some embodiments, the tablet comprises the filler in an amount of about 20% to about 60% by weight, the disintegrant in an amount of about 1% to about 10% by weight, and the lubricant in an amount of about 0.5% to about 5% by weight. In some embodiments, the tablet comprises the filler in an amount of about 40% to about 50% by weight, the disintegrant in an amount of about 1% to about 10% by weight, and the lubricant in an amount of about 0.5% to about 5% by weight. In some embodiments, the tablet comprises (i) a compound of Formula I in an amount of about 45 wt% to about 55 wt%, (ii) a filler in an amount of about 44 wt% to about 46 wt%, (iii) a disintegrant in an amount of about 3 wt% to about 5 wt%, and (iv) a lubricant in an amount of about 0.5 wt% to about 2 wt%. In some embodiments, the tablet comprises (i) a compound of Formula I in an amount of about 50 wt%, (ii) a filler in an amount of about 44 wt% to about 46 wt%, (iii) a disintegrant in an amount of about 3 wt% to about 5 wt%, and (iv) a lubricant in an amount of about 0.5 wt% to about 2 wt%. In some embodiments, the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the disintegrant is starch, pregelatinized starch, hydroxypropyl starch, cellulose, cross-linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium. In some embodiments, the disintegrant is crospovidone. In some embodiments, the lubricant is stearic acid, sodium stearyl fumarate, magnesium stearate, or a combination thereof. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the tablet comprises about 100 mg to about 700 mg of the compound of Formula I. In some embodiments, the tablet comprises about 100 mg of the compound of Formula I. In some embodiments, the tablet comprises about 350 mg of the compound of Formula I. In some embodiments, the tablet comprises about 500 mg of the compound of Formula I.

[0010] In one aspect, the present disclosure provides a tablet comprising: (i) a compound of Formula I in an amount of about 50 to 700 mg; (ii) microcrystalline cellulose in an amount of about 50 to 500 mg; (iii) crospovidone in an amount of about 5 to 50 mg; and (iv) magnesium stearate in an amount of about 1 to 20 mg. In some embodiments, the tablet comprises: (i) a compound of Formula I in an amount of about 100 mg; (ii) microcrystalline cellulose in an amount of about 89 mg; (iii) crospovidone in an amount of about 8 mg; and (iv) magnesium stearate in an amount of about 3 mg. In some embodiments, the tablet comprises: (i) a compound of Formula I in an amount of about 500 mg; (ii) microcrystalline cellulose in an amount of about 445 mg; (iii) crospovidone in an amount of about 40 mg; and (iv) magnesium stearate in an amount of about 10 mg. In some embodiments, the tablet comprises (i) the compound of formula I in an amount of about 350 mg, (ii) microcrystalline cellulose in an amount of about 315 mg, (iii) crospovidone in an amount of about 28 mg, and (iv) magnesium stearate in an amount of about 7 mg.

[0011] In one aspect, the present disclosure provides a tablet comprising (a) a tablet core and (b) a film coat, wherein the tablet core comprises (i) a compound of Formula I or a pharmaceutically acceptable salt thereof, (ii) a filler, (iii) a disintegrant, and (iv) a lubricant; and the compound of Formula I is present in an amount of about 40 wt% to about 70 wt%. In some embodiments, the tablet comprises the filler in an amount of about 20 wt% to about 60 wt%; the disintegrant in an amount of about 1 wt% to about 10 wt%; and the lubricant in an amount of about 0.5 wt% to about 5 wt%. In some embodiments, the tablet core comprises the filler in an amount of about 40 wt% to about 50 wt%, the disintegrant in an amount of about 1 wt% to about 10 wt% (wt%), and the lubricant in an amount of about 0.5 wt% to about 5 wt% (wt%). In some embodiments, the tablet core comprises (i) a compound of Formula I in an amount of about 45-55 wt%, (ii) a filler in an amount of about 44 wt% to about 46 wt%, (iii) a disintegrant in an amount of about 3 wt% to about 5 wt%, and (iii) a lubricant in an amount of about 0.5 wt% to about 2 wt%. In some embodiments, the tablet core comprises (i) a compound of Formula I in an amount of about 50 wt%, (ii) a filler in an amount of about 44 wt% to about 46 wt%, (iii) a disintegrant in an amount of about 3 wt% to about 5 wt%, and (iv) a lubricant in an amount of about 0.5 wt% to about 2 wt%. In some embodiments, the film coat comprises Opadry® II. In some embodiments, the film coat comprises Opadry® QX. In some embodiments, the film coat comprises Opadry® II Purple. In some embodiments, the film coat comprises Opadry® II Yellow. In some embodiments, the film coat comprises Opadry® QX Yellow. In some embodiments, the film coat comprises a titanium-free variant of Opadry®. In some embodiments, the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the disintegrant is starch, pregelatinized starch, hydroxypropyl starch, cellulose, cross-linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium.In some embodiments, the disintegrant is crospovidone. In some embodiments, the lubricant is stearic acid, sodium stearyl fumarate, or magnesium stearate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the tablet contains about 100 mg to about 700 mg of the compound of formula I. In some embodiments, about 100 mg of the compound of formula I. In some embodiments, the tablet contains about 350 mg of the compound of formula I. In some embodiments, the tablet contains about 500 mg of the compound of formula I.

[0012] In one aspect, the present disclosure provides a method of treating a viral infection in a human in need thereof, comprising administering to the human a pharmaceutical formulation or tablet provided herein. In some embodiments, the method comprises administering to the human at least one additional therapeutic or prophylactic agent. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a zoonotic coronavirus infection. In some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is selected from the group consisting of 229E viral infection, NL63 viral infection, OC43 viral infection, and HKU1 viral infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID-19). In some embodiments, the viral infection is a SARS-CoV viral infection. In some embodiments, the viral infection is a MERS-CoV viral infection. In some embodiments, the viral infection is a Pneumoviridae viral infection.In some embodiments, the pneumoviridae viral infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviridae viral infection is a human metapneumovirus infection. In some embodiments, the viral infection is a picornaviridae viral infection. In some embodiments, the viral infection is an enterovirus infection. In some embodiments, the viral infection is selected from the group consisting of a coxsackie A virus infection, a coxsackie A virus infection, an enterovirus D68 infection, an enterovirus B69 infection, an enterovirus D70 infection, an enterovirus A71 infection, and a poliovirus infection. In some embodiments, the picornaviridae viral infection is a human rhinovirus infection (HRV). In some embodiments, the picornaviridae viral infection is an HRV-A, HRV-B, or HRV-C infection. In some embodiments, the viral infection is a flaviviridae viral infection. In some embodiments, the Flaviviridae virus infection is Dengue virus infection, Yellow Fever virus infection, West Nile virus infection, Tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, Bovine viral diarrhea, Zika virus infection, or HCV infection. In some embodiments, the viral infection is a Filoviridae virus infection. In some embodiments, the Filoviridae virus infection is Ebola virus infection or Marburg virus infection. In some embodiments, the viral infection is an Orthomyxoviridae virus infection. In some embodiments, the viral infection is an Influenza virus infection. In some embodiments, the viral infection is an Influenza virus A or Influenza virus B infection. In some embodiments, the viral infection is a Paramyxoviridae virus infection.In some embodiments, the viral infection is a human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection.

[0013] In one aspect, the present disclosure provides a method for the manufacture of a medicament for treating or preventing a viral infection in a human in need thereof, wherein a pharmaceutical formulation provided herein is used.

[0014] In one aspect, the present disclosure provides a use of a pharmaceutical formulation provided herein for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof. In some embodiments, the medicament is used in combination with at least one additional therapeutic or prophylactic agent.

[0015] In one aspect, the present disclosure provides a pharmaceutical formulation or tablet as disclosed herein for use in treating or preventing a viral infection in a human in need thereof. In some embodiments, the pharmaceutical formulation or tablet is for use in combination with at least one additional therapeutic agent. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows a flow diagram illustrating an exemplary preparation of a solid oral dosage form disclosed herein.

[0017] [Figure 2] 1 shows the results of stability studies performed on exemplary formulations disclosed herein.

[0018] [Figure 3] 1 shows the results of stability studies performed on exemplary formulations disclosed herein.

[0019] [Figure 4] 1 shows the results of stability studies performed on Formulation 8.

[0020] [Figure 5] 1 shows the results of stability studies performed on Formulation 8.

[0021] [Figure 6] 1 shows the results of stability studies performed on Formulation 8. DETAILED DESCRIPTION OF THE INVENTION

[0022] Described herein are pharmaceutical formulations, particularly solid dosage forms (e.g., tablets and capsules), of compounds of Formula I: [ka]

[0023] The compound of formula I is disclosed in WO 2022 / 047065 as compound 15. The IUPAC name of the compound of formula I is ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate. Its CAS registry number is 2647441-36-7.

[0024] The compounds described herein, exemplified by Formula I, have chiral centers, e.g., chiral carbons. Accordingly, pharmaceutical formulations, e.g., solid oral dosage forms (e.g., tablets), disclosed herein include embodiments in which the compound having the chemical structure of Formula I is present as a racemic mixture of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Additionally, pharmaceutical formulations, e.g., solid oral dosage forms (e.g., tablets), disclosed herein include embodiments in which the compound of Formula I is an enriched or resolved optical isomer at any or all asymmetric, chiral atoms. In other words, chiral centers apparent from the depiction are provided as chiral isomers or racemic mixtures. Racemic and diastereomeric mixtures, as well as pharmaceutical formulations, e.g., solid oral dosage forms (e.g., tablets), containing isolated or synthesized individual optical isomers substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the present invention. Racemic mixtures can be separated into their individual substantially optically pure isomers by suitable techniques, such as, for example, separation of diastereomeric salts formed with optically active auxiliaries, e.g., acids or bases, followed by conversion back to optically active materials. In some embodiments, the compounds of Formula I are substantially pure enantiomers.

[0025] Stereochemical definitions and rules used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the indication of rotation of plane-polarized light by the compound; S, (-), or 1 means that the compound is levorotatory, while compounds with the prefix R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0026] The compounds of Formula I may also exist as tautomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the present invention. For example, ene-amine tautomers may exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all of their possible tautomers are within the scope of the present invention.

[0027] Any formula or structure given herein, including compounds of Formula I, is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure include, but are not limited to, 3 H, 13 C and 14 and those into which a radioactive isotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in the radiotherapy of patients.

[0028] Pharmaceutical formulations, e.g., solid oral dosage forms (e.g., tablets), of the present disclosure also include embodiments in which the pharmaceutical formulation comprises a compound of the chemical structure of Formula I, but in which 1 to n hydrogens bonded to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the compound of Formula I. Such compounds may exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of compounds of Formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). In light of the present disclosure, such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium. Thus, in some embodiments, the pharmaceutical formulations disclosed herein comprise a compound of the formula [ka] This includes compounds of the formula:

[0029] Deuterium-labeled or substituted therapeutic compounds used in pharmaceutical formulations, e.g., solid oral dosage forms (e.g., tablets) disclosed herein, may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0030] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0031] "X-ray powder diffraction pattern" or "XRPD pattern" as used herein preferably refers to an X-ray powder diffraction pattern obtained using CuKα radiation.

[0032] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or lessening the severity of the disease or condition), b) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0033] "Prevention" or "preventing" means any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0034] As used herein, the term "excipient(s)" is intended to refer to, among others, basifying agents, solubilizing agents, glidants, fillers, binders, lubricants, diluents, preservatives, surfactants, dispersing agents, etc. The term also includes agents such as sweeteners, flavoring agents, coloring agents, preservatives, and coating agents. Such components are generally present in admixture within solid oral dosage forms (e.g., tablets).

[0035] As used herein, "mild renal impairment" in reference to a patient means that the patient has mild kidney damage. Mild renal impairment may also be referred to as "mild CKD." A patient may be classified as having mild renal impairment using known methods, such as determining the patient's eGFR (e.g., using a formula appropriate for the patient population) and comparing the eGFR to appropriate guidelines (e.g., a given eGFR formula and / or current medical guidelines for the patient population). For example, a patient with a blood glucose level of at least 60 mL / min / 1.73 m 2 ~90mL / min / 1.73m 2 An eGFR less than 100mg / kg may indicate mild renal dysfunction.

[0036] As used herein, "moderate renal impairment" in reference to a patient means that the patient has moderate kidney damage. Moderate renal impairment may also be referred to as "moderate CKD." A patient may be classified as having moderate renal impairment using known methods, such as determining the patient's eGFR (e.g., using a formula appropriate for the patient population) and comparing the eGFR to appropriate guidelines (e.g., a given eGFR formula and / or current medical guidelines for the patient population). For example, a patient with an eGFR of at least 30 mL / min / 1.73 m 2 ~60mL / min / 1.73m 2An eGFR less than 100 mg / kg can indicate moderate renal impairment.

[0037] As used herein, "severe renal impairment" in reference to a patient means that the patient has severe kidney damage. Severe renal impairment may also be referred to as "severe CKD." A patient may be classified as having severe renal impairment using known methods, such as determining the patient's eGFR (e.g., using a formula appropriate for the patient population) and comparing the eGFR to appropriate guidelines (e.g., a given eGFR formula and / or current medical guidelines for the patient population). For example, a patient with an eGFR of at least 15 mL / min / 1.73 m 2 ~30mL / min / 1.73m 2 An eGFR below 100kJ / day can indicate severe renal dysfunction.

[0038] As used herein, "d n " refers to the particle size distribution by volume where n is between 0 and 100. For example, d less than 800 μm 90 means that 90% of the particle volume is less than 800 μm. Pharmaceutical preparations

[0039] All pharmaceutical formulations described herein comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical formulations disclosed herein comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more components selected from a filler, a lubricant, and a disintegrant. In some embodiments, the pharmaceutical formulations disclosed herein comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, (ii) a filler, (iii) a lubricant, and (iv) a disintegrant.

[0040] In some embodiments, the pharmaceutical formulations disclosed herein are solid dosage forms. The solid dosage forms disclosed herein contain one or more excipients. The excipients must be compatible with the other components of the formulation and physiologically harmless to the recipient. Examples of suitable excipients can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[0041] The pharmaceutical formulations disclosed herein are for oral administration to a subject (e.g., a human). Accordingly, provided herein are solid dosage forms of the compound of Formula I for oral administration ("solid oral dosage forms"). In some embodiments, the solid oral dosage forms disclosed herein comprise one or more excipients selected from (i) a filler, (ii) a disintegrant, and (iii) a lubricant. In some embodiments, the solid oral dosage forms disclosed herein comprise (i) a filler, (ii) a disintegrant, and (iii) a lubricant.

[0042] Typically, a pharmaceutical composition may have desirable properties for medical or pharmaceutical use. Such properties include manufacturability (e.g., compressibility, ease of handling, ability to consistently prepare doses of the same strength, etc.), physical stability (e.g., thermal stability, shelf life, etc.), chemical stability, drug loading, dissolution rate (e.g., bioavailability), and process control. Thus, the pharmaceutical composition (e.g., tablet) may provide advantages such as improving the manufacturing process of the compound, improving the stability or storage of the drug product form of the compound, or improving the drug loading of the compound. Compounds of Formula I

[0043] The solid oral dosage forms disclosed herein can include any suitable amount of a compound of Formula I, for example, about 0.1 mg to about 1000 mg of a compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein include about 10 mg to about 800 mg, about 10 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 10 mg to about 50 mg, about 10 mg to about 30 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 mg to about 10 ... g ~ about 600 mg, about 50 mg - about 400 mg, about 50 mg - about 200 mg, about 50 mg - about 100 mg, about 100 mg - about 1000 mg, about 100 mg - about 800 mg, about 100 mg ~ about 600mg, about 100mg - about 400mg, about 100mg - about 200mg, about 200mg - about 1000mg, about 200mg - about 800mg, about 200mg - about 600mg, about 200mg to about 400mg, about 300mg to about 1000mg, about 300mg to about 800mg, about 300mg to about 600mg, about 300mg to about 400mg, about 400mg to about 100 0mg, about 400mg to about 800mg, about 400mg to about 600mg, about 400mg to about 500mg, about 500mg to about 1000mg, about 500mg to about 800mg, about 500mg to The solid oral dosage forms disclosed herein contain about 600 mg, about 600 mg to about 1000 mg, about 600 mg to about 900 mg, about 600 mg to about 800 mg, about 600 mg to about 700 mg, about 700 mg to about 1000 mg, about 700 mg to about 900 mg, about 700 mg to about 800 mg, about 800 mg to about 1000 mg, about 800 mg to about 900 mg, or about 900 mg to about 1000 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein contain about 50 to about 800 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein contain about 100 to about 700 mg of the compound of Formula I, e.g., about 100 mg, about 350 mg, about 500 mg, or about 700 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 100 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 350 mg of the compound of Formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 500 mg of the compound of Formula I.In some embodiments, the solid oral dosage forms disclosed herein comprise about 700 mg of the compound of formula I. In some embodiments, the solid oral dosage forms disclosed herein comprise about 175 mg of the compound of formula I.

[0044] The solid oral dosage forms disclosed herein can contain any suitable amount of a compound of formula I, for example, from about 1 mg to about 1000 mg of a compound of formula I.

[0045] The compound of formula I can be used in any suitable form. For example, the compound of formula I can be amorphous or crystalline. In some embodiments, the compound of formula I is amorphous. In some embodiments, the compound of formula I is crystalline. In some embodiments, the compound of formula I is in free base form.

[0046] Crystalline forms of the compound of Formula I useful in the formulations and methods of the present disclosure are described, for example, in International Patent Application Publication No. WO 2022 / 047065. For example, the compound of Formula I can be crystalline free base Form I, free base Form II, free base Form III, xinafoate salt Material A, HCl salt Form I, HCl salt Material A, HCl salt Material B, HCl salt Material C, or a combination thereof, as described in WO 2022 / 047065. In some embodiments, the compound of Formula I is crystalline. Unless otherwise specifically stated, when a pharmaceutically acceptable salt of the compound of Formula I is used in the pharmaceutical formulations described herein, the % wt of Formula I is adjusted accordingly based on a salt correction factor.

[0047] The salt correction factor is calculated by taking the molar mass of the pharmaceutically acceptable salt of the compound of Formula I and dividing it by the molar mass of the free base form of the compound of Formula I. For example, for the hydrochloride salt of the compound of Formula I, the salt correction factor is 1.10. Therefore, the % wt of the hydrochloride salt of Formula I is 1.10 multiplied by the % wt specified for the compound of Formula I.

[0048] In some embodiments, the compound of Formula I is the crystalline free base Form III described in International Patent Application Publication No. WO 2022 / 047065. In some embodiments, the crystalline compound of Formula I is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2θ reflection angles of 9.8°, 16.0°, and 25.4° (2θ + / − 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern comprising one, two, or three of 2θ reflection angles of 9.8°, 16.0°, and 25.4° (2θ + / − 0.2 degrees), and 10.2°, 19.1°, and 26.9° (2θ + / − 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern comprising one or two of the following reflection angles: 9.8°, 16.0°, and 25.4° 2θ (2θ + / − 0.2 degrees), and 10.2°, 19.1°, and 26.9° 2θ (2θ + / − 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern comprising one of the following reflection angles: 9.8°, 16.0°, and 25.4° 2θ (2θ + / − 0.2 degrees), and 10.2°, 19.1°, and 26.9° 2θ (2θ + / − 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern that includes two of the following 2θ reflection angles: 9.8°, 16.0°, and 25.4° (2θ + / - 0.2 degrees), and 10.2°, 19.1°, and 26.9° (2θ + / - 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern that includes two of the following 2θ reflection angles: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (2θ + / - 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern that includes any three of the following 2θ reflection angles: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (2θ + / - 0.2 degrees).

[0049] In some embodiments, the crystalline compound of Formula I has an XRPD pattern that includes one, two, or three of the following 2-theta reflection angles: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (2-theta + / - 0.2 degrees), and 10.4°, 19.8°, and 20.7° (2-theta + / - 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern that includes one or two of the following 2-theta reflection angles: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (2-theta + / - 0.2 degrees), and 10.4°, 19.8°, and 20.7° (2-theta + / - 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern comprising one of the following 2-theta reflection angles: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (2-theta + / - 0.2 degrees), and 10.4°, 19.8°, and 20.7° (2-theta + / - 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern comprising two of the following 2-theta reflection angles: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (2-theta + / - 0.2 degrees), and 10.4°, 19.8°, and 20.7° (2-theta + / - 0.2 degrees). In some embodiments, the crystalline compound of Formula I has an XRPD pattern comprising the following 2θ reflection angles (2θ + / − 0.2 degrees): 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9°. In some embodiments, the crystalline compound of Formula I has an XRPD pattern comprising any three of the following 2θ reflection angles (2θ + / − 0.2 degrees): 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9°.

[0050] The compound of Formula I can have any suitable purity. For example, the compound of Formula I can have a purity of at least about 90%, or at least about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or at least about 99.9%. In some embodiments, the compound of Formula I has a purity of at least about 99.1%. In some embodiments, the compound of Formula I has a purity of at least about 99.3%. In some embodiments, the compound of Formula I has a purity of at least about 99.5%. In some embodiments, the compound of Formula I has a purity of at least about 99.7%. In some embodiments, the compound of Formula I has a purity of at least about 99.5%. In some embodiments, the compound of formula I has a purity of at least about 99.9%.

[0051] In some embodiments, the compound of formula I has a d of less than about 800 μm. 90 For example, the morphology has a diameter of less than about 750 μm, about 700 μm, about 650 μm, about 600 μm, about 550 μm, about 500 μm, about 450 μm, about 400 μm, about 350 μm, about 300 μm, about 250 μm, about 200 μm, about 150 μm, about 100 μm, about 50 μm, about 40 μm, about 30 μm, about 20 μm, or about 10 μm. 90 In some embodiments, the shape is about 10 μm to 500 μm, e.g., about 10 μm to 450 μm, about 10 μm to 400 μm, about 10 μm to 350 μm, about 10 μm to 300 μm, about 10 μm to 250 μm, about 10 μm to 200 μm, about 10 μm to 150 μm, about 10 μm to 100 μm, about 40 μm to 800 μm, about 40 μm to 750 μm, about 40 μm to 800 μm, about 40 μm to 950 μm, about 40 μm to 950 μm, about 40 μm to 1000 μm, about 40 μm to 1200 μm, about 40 μm to 150 ...200 μm, about 40 μm to 1500 μm, about 40 μm to 1000 μm, about 4 μm~700μm, approx. 40μm~650μm, approx. 40μm~600μm, approx. 40μm~550μm, approx. 40μm~500μm, approx. 40μm~450μm, approx. 40μm~400 μm, about 40 μm to 350 μm, about 40 μm to 300 μm, about 40 μm to 250 μm, about 40 μm to 200 μm, about 40 μm to 150 μm, or about 40 μm to 100 μm d 90In some embodiments, the morphology has a d of about 10 μm to 500 μm, e.g., about 40 μm to 500 μm, or about 100 μm to 500 μm. 90 It has.

[0052] In some embodiments, the compound of formula I has a d of less than about 300 μm. 50 For example, compounds of Formula I have a d of less than about 250 μm, about 200 μm, about 150 μm, about 100 μm, about 90 μm, about 80 μm, about 70 μm, about 60 μm, about 50 μm, about 40 μm, about 35 μm, about 30 μm, about 25 μm, about 20 μm, about 15 μm, about 10 μm, about 9 μm, about 8 μm, about 7 μm, about 6 μm, about 5 μm, about 4 μm, about 3 μm, about 2 μm, or about 1 μm. 50 In some embodiments, the compound of formula I has a d of about 0.1 μm to 300 μm. 50 In some embodiments, the morphology has a d of about 1 μm to 300 μm. 50 In some embodiments, the compound of formula I has a d of about 10 μm to 300 μm. 50 In some embodiments, the morphology has a d of about 10 μm to 2500 μm. 50 It has.

[0053] In some embodiments, the compound of formula I has a d of less than about 100 μm. 10 For example, compounds of Formula I have a d of less than 95 μm, 90 μm, 85 μm, 80 μm, 75 μm, 70 μm, 65 μm, 60 μm, 55 μm, 50 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm, 0.5 μm, 0.4 μm, 0.3 μm, 0.2 μm, or 0.1 μm. 10In some embodiments, the morphology is about 0.1 μm to 90 μm, e.g., about 1 μm to 90 μm, 1 μm to 80 μm, 1 μm to 70 μm, 1 μm to 60 μm, 1 μm to 50 μm, 1 μm to 40 μm, 1 μm to 30 μm, about 1 μm to 20 μm, 1 μm to 15 μm, 1 μm to 10 μm, 1 μm to 9 μm, 1 μm to 8 μm, 1 μm to 7 μm, 1 μm ~6μm, 1μm~5μm, 1μm~4μm, 1μm~3μm, 1μm~2μm, 0.1μm~15μm, 0.1μm~10μm, 0.1μm~9μm, 0.1μm~8 μm, 0.1μm~7μm, 0.1μm~6μm, 0.1μm~5μm, 0.1μm~4μm, 0.1μm~3μm, 0.1μm~2μm, or 0.1μm~1μm d 10 In some embodiments, the morphology has a d of about 1 μm to 60 μm. 10 It has.

[0054] In some embodiments, the compound of formula I is micronized. lubricant

[0055] Examples of lubricants that can be used in the solid oral dosage forms disclosed herein include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide, carnauba wax, polyethylene glycol, and talc powder. In some embodiments, the lubricant is selected from the group consisting of stearic acid, sodium stearyl fumarate, magnesium stearate, and combinations thereof. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate.

[0056] The amount of lubricant in the solid oral dosage forms disclosed herein is generally about 0.5 to about 5% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 4.5% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 4.0% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 3.5% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 3.0% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 2.5% by weight. In some embodiments, the amount of lubricant is about 0.5 to about 2.0% by weight. In some embodiments, the amount of lubricant is about 0.5% by weight. In some embodiments, the amount of lubricant is about 1.0% by weight. In some embodiments, the amount of lubricant is about 1.5% by weight. In some embodiments, the amount of lubricant is about 2% by weight. In some embodiments, the amount of lubricant is about 2.5% by weight. In some embodiments, the amount of lubricant is about 3.0% by weight. In some embodiments, the amount of lubricant is about 3.5% by weight. In some embodiments, the amount of lubricant is about 4.0% by weight. In some embodiments, the amount of lubricant is about 4.5% by weight. In some embodiments, the amount of lubricant is about 5.0% by weight. In some embodiments, the amount of lubricant in the tablet is about 1.0% to about 1.5% by weight. In some embodiments, the amount of lubricant in the tablet is about 1.0% by weight. In some embodiments, the amount of lubricant in the tablet is about 1.5% by weight.

[0057] In some embodiments, the solid oral dosage form contains less than about 100 mg of lubricant. For example, the solid oral dosage form contains about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, or less than about 10 mg of lubricant. In some embodiments, the solid oral dosage form contains about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg of lubricant, or about 1 mg to about 60 mg of lubricant. In some embodiments, the solid oral dosage form contains about 1 mg to about 50 mg of lubricant, about 1 mg to about 40 mg, 1 mg to about 30 mg, 1 mg to about 20 mg, or about 1 mg to about 10 mg of lubricant. In some embodiments, the tablet contains about 1 mg to about 20 mg of lubricant.

[0058] In some embodiments, the solid oral dosage form disclosed herein comprises magnesium stearate. In some embodiments, the amount of magnesium stearate in the solid oral dosage form is about 1.0% to about 1.5% by weight. In some embodiments, the amount of magnesium stearate in the solid oral dosage form is about 1.0% by weight. In some embodiments, the amount of magnesium stearate in the solid oral dosage form is about 1.5% by weight. In some embodiments, the solid oral dosage form comprises less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, or less than about 10 mg of magnesium stearate. In some embodiments, the solid oral dosage form comprises from about 1 mg to about 50 mg of lubricant, or from about 1 mg to about 40 mg, 1 mg to about 30 mg, 1 mg to about 20 mg, or about 1 mg to about 10 mg of magnesium stearate. In some embodiments, the solid oral dosage form comprises from about 1 mg to about 20 mg of magnesium stearate.

[0059] In some embodiments, the solid oral dosage form comprises 100 mg of the compound of Formula I and about 0.5 mg to about 5 mg of a lubricant. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 0.5 mg to about 5 mg of a lubricant. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 1 to about 4 mg of a lubricant. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 3 mg of a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet.

[0060] In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 1.8 mg to about 18 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 5 mg to about 10 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 6 mg to about 8 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 7 mg of lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet.

[0061] In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 2.5 mg to about 25 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 5 mg to about 15 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 1 to about 8 mg to about 12 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 10 mg of lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet.

[0062] In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 3.6 mg to about 36 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 10 mg to about 20 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 12 mg to about 16 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 14 mg of lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet.

[0063] In some embodiments, the solid oral dosage form comprises 175 mg of the compound of Formula I and about 0.5 mg to about 5 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 2 to about 4 mg of lubricant. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 3.5 mg of lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the solid oral dosage form is a tablet. Disintegrating agent (disintegrant)

[0064] Examples of disintegrants that can be used in the solid oral dosage forms described herein include, but are not limited to, starch, pregelatinized starch, hydroxypropyl starch, cellulose (e.g., microcrystalline cellulose and low-substituted hydroxypropyl cellulose), cross-linked PVP (crospovidone), sodium starch glycolate, croscarmellose sodium, and the like. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is starch. In some embodiments, the disintegrant is pregelatinized starch. In some embodiments, the disintegrant is cellulose. In some embodiments, the disintegrant is microcrystalline cellulose. In some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose. In some embodiments, the disintegrant is cross-linked PVP (crospovidone). In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the disintegrant is croscarmellose sodium.

[0065] In some embodiments, the lubricant is magnesium stearate and the disintegrant is crospovidone.

[0066] In some embodiments, the disintegrant is Polyplasdone™ xl-10 crospovidone.

[0067] In some embodiments, the amount of disintegrant in the solid oral dosage form is from about 1% to about 10% by weight. In some embodiments, the amount of disintegrant in the tablet is about 1% to about 9% by weight, about 1% to about 8% by weight, about 1% to about 7% by weight, about 1% to about 6% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, about 1% to about 3% by weight, about 1% to about 2% by weight, about 2% to about 10% by weight, 2% to about 9% by weight, about 2% to about 8% by weight, about 2% to about 7% by weight, about 2% to about 6% by weight, about 2% to about 5% by weight, about 2% to about 4% by weight, about 2% to about 3% by weight, about 3% to about 10% by weight, about 3% to about 9% by weight, about 3% to about 8% by weight, about 3% to about 7% by weight, about 3% to about 6% by weight, or about 3% by weight. about 5% by weight, about 3% by weight to about 4% by weight, about 4% by weight to about 10% by weight, about 4% by weight to about 9% by weight, about 4% by weight to about 8% by weight, about 4% by weight to about 7% by weight, about 4% by weight to about 6% by weight, about 4% by weight to about 5% by weight, about 5% by weight to about 10% by weight, about 5% by weight to about 9% by weight, about 5% by weight to about 8% by weight, about 5% by weight to about 7% by weight, about 5% by weight to about 6% by weight, about 6% by weight to about 10% by weight, about 6% by weight to about 9% by weight, about 6% by weight to about 8% by weight, about 6% by weight to about 7% by weight, about 7% by weight to about 10% by weight, about 7% by weight to about 9% by weight, about 7% by weight to about 8% by weight, about 8% by weight to about 10% by weight, about 8% by weight to about 9% by weight, or about 9% by weight to about 10% by weight. In some embodiments, the amount of disintegrant in the solid oral dosage form is from about 3% to about 5% by weight.

[0068] In some embodiments, the solid oral dosage form comprises from about 5 mg to about 200 mg of disintegrant. In some embodiments, the solid oral dosage form comprises from about 5 mg to about 190 mg, 5 mg to about 180 mg, 5 mg to about 170 mg, 5 mg to about 160 mg, 5 mg to about 150 mg, 5 mg to about 140 mg, 5 mg to about 130 mg, 5 mg to about 120 mg, 5 mg to about 110 mg, 5 mg to about 100 mg, 5 mg to about 90 mg, 5 mg to about 80 mg, 5 mg to about 70 mg, or 5 mg to about 60 mg , 5 mg to about 50 mg, 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 50 mg, or about 30 mg to about 40 mg of disintegrant. In some embodiments, the solid oral dosage form contains about 5 mg to about 50 mg of disintegrant. In some embodiments, the solid oral dosage form contains about 40 mg to about 50 mg of disintegrant.

[0069] In some embodiments, the disintegrant is crospovidone. In some embodiments, the amount of crospovidone in the solid oral dosage form is from about 1% to about 10% by weight. In some embodiments, the amount of crospovidone in the solid oral dosage form is from about 1% to about 9% by weight, from about 1% to about 8% by weight, from about 1% to about 7% by weight, from about 1% to about 6% by weight, from about 1% to about 5% by weight, from about 1% to about 4% by weight, from about 1% to about 3% by weight, from about 1% to about 2% by weight, from about 2% to about 10%, from 2% to about 9% by weight, from about 2% to about 8% by weight, from about 2% to about 7% by weight, from about 2% to about 6% by weight, from about 2% to about 5% by weight, from about 2% to about 4% by weight, from about 2% to about 3% by weight, from about 3% to about 10% by weight, from about 3% to about 9% by weight, from about 3% to about 8% by weight, from about 3% to about 7% by weight, from about 3% to about 6% by weight, from about 3% to about 6% by weight, from about 3% to about 7% by weight, from about 3% to about 6% by weight, from about 3% to about 8% by weight, from about 3% to about 6% by weight, from about 3% to about 9% by weight, from about 3% to about 8% by weight, from about 3% to about 7% by weight, from about 3% to about 6 ...3% by weight, from about 3% to about 3% by weight, from about 3% to about 3% by weight % by weight to about 5% by weight, about 3% by weight to about 4% by weight, about 4% by weight to about 10% by weight, about 4% by weight to about 9% by weight, about 4% by weight to about 8% by weight, about 4% by weight to about 7% by weight, about 4% by weight to about 6% by weight, about 4% by weight to about 5% by weight, about 5% by weight to about 10% by weight, about 5% by weight to about 9% by weight, about 5% by weight to about 8% by weight, about 5% by weight to about 7% by weight, about 5% by weight to about 6% by weight, about 6% by weight to about 10% by weight, about 6% by weight to about 9% by weight, about 6% by weight to about 8% by weight, about 6% by weight to about 7% by weight, about 7% by weight to about 10% by weight, about 7% by weight to about 9% by weight, about 7% by weight to about 8% by weight, about 8% by weight to about 10% by weight, about 8% by weight to about 9% by weight, or about 9% by weight to about 10% by weight. In some embodiments, the amount of crospovidone in the solid oral dosage form is about 3% to about 5%. In some embodiments, the solid oral dosage form is a tablet.

[0070] In some embodiments, the solid oral dosage form contains about 5 mg to about 50 mg of crospovidone. In some embodiments, the solid oral dosage form contains about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, or about 40 mg to about 50 mg of crospovidone. In some embodiments, the solid oral dosage form is a tablet.

[0071] In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 1 to about 10 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 5 to about 10 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 8 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 1 to about 10 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 5 to about 10 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 100 mg of the compound of Formula I and about 8 mg of crospovidone. In some embodiments, the solid oral dosage form is a tablet.

[0072] In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 5 to about 50 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 25 to about 50 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 40 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 5 to about 50 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 25 to about 50 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 500 mg of the compound of Formula I and about 40 mg of crospovidone. In some embodiments, the solid oral dosage form is a tablet.

[0073] In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 3.5 to about 35 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 18 to about 35 mg of disintegrant. In some embodiments, the solid oral dosage form comprises 350 mg of the compound of Formula I and about 28 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 3.5 to about 35 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 18 to about 35 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 350 mg of the compound of Formula I and about 28 mg of crospovidone. In some embodiments, the solid oral dosage form is a tablet. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 7 to about 70 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of formula I and about 36 to about 70 mg of disintegrant. In some embodiments, the solid oral dosage form comprises 700 mg of the compound of formula I and about 56 mg of disintegrant.

[0074] In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 7 to about 70 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 36 to about 70 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 700 mg of the compound of Formula I and about 56 mg of crospovidone. In some embodiments, the solid oral dosage form is a tablet.

[0075] In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 2 to about 18 mg of disintegrant. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 9 to about 18 mg of disintegrant. In some embodiments, the solid oral dosage form comprises 175 mg of the compound of Formula I and about 14 mg of disintegrant.

[0076] In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 2 to about 18 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 9 to about 18 mg of crospovidone. In some embodiments, the solid oral dosage form comprises about 175 mg of the compound of Formula I and about 14 mg of crospovidone. In some embodiments, the solid oral dosage form is a tablet. Filler

[0077] Examples of fillers (also known as extenders or diluents) that can be used in the solid oral dosage forms disclosed herein include, but are not limited to, starch, maltodextrin, polyols (such as lactose), and cellulose. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler is lactose. In some embodiments, the filler is mannitol. In some embodiments, the filler is dicalcium phosphate.

[0078] In some embodiments, the amount of filler in the solid oral dosage form is about 20% to about 60% by weight, hi some embodiments, the amount of filler in the solid oral dosage form is about 20% to about 50% by weight, about 20% to about 40% by weight, about 20% to about 30% by weight, about 30% to about 60% by weight, about 30% to about 50% by weight, about 30% to about 40% by weight, about 40% to about 60% by weight, or about 40% to about 50% by weight.

[0079] In some embodiments, the amount of filler in the solid oral dosage form is about 40% to about 50% by weight. In some embodiments, the amount of filler in the solid oral dosage form is about 40% to about 48%, about 40% to about 46%, about 40% to about 44%, about 40% to about 42%, about 42% to about 50%, about 42% to about 48%, about 42% to about 46%, about 42% to about 44%, about 44% to about 50%, about 44% to about 48%, about 44% to about 46%, about 46% to about 50%, about 46% to about 48%, or about 48% to about 50%. In some embodiments, the amount of filler in the solid oral dosage form is about 44% to about 46% by weight.

[0080] In some embodiments, the amount of filler in the solid oral dosage form is about 50 mg to about 1000 mg. In some embodiments, the amount of filler in the solid oral dosage form is about 50 mg to about 950 mg, about 50 mg to about 900 mg, about 50 mg to about 850 mg, about 50 mg to about 800 mg, about 50 mg to about 750 mg, about 50 mg to about 700 mg, about 50 mg to about 650 mg, about 50 mg to about 600 mg, about 50 mg to about 550 mg, about 50 mg to about 500 mg, about 50 mg to about 450 mg, about 50 mg to about 400 mg, about 50 mg to about 35 0mg, about 50mg to about 300mg, about 50mg to about 250mg, about 50mg to about 200mg, about 50mg to about 150mg, about 50mg to about 100mg, about 100mg to about 500mg, about 100mg to about 450mg , about 100mg to about 400mg, about 100mg to about 350mg, about 100mg to about 300mg, about 100mg to about 250mg, about 100mg to about 200mg, about 100mg to about 150mg, about 150mg to about 500m g, about 150mg to about 450mg, about 150mg to about 400mg, about 150mg to about 350mg, about 150mg to about 300mg, about 150mg to about 250mg, about 150mg to about 200mg, about 200mg to about 50 0mg, about 200mg to about 450mg, about 200mg to about 400mg, about 200mg to about 350mg, about 200mg to about 300mg, about 200mg to about 250mg, about 250mg to about 500mg, about 250mg to about In some embodiments, the amount of filler in the solid oral dosage form is about 50 mg to about 500 mg.

[0081] In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the amount of microcrystalline cellulose in the solid dosage form is about 40% to about 50% by weight. In some embodiments, the amount of microcrystalline cellulose in the solid dosage form is about 40% to about 48%, about 40% to about 46%, about 40% to about 44%, about 40% to about 42%, about 42% to about 50%, about 42% to about 48%, about 42% to about 46%, about 42% to about 44%, about 44% to about 50%, about 44% to about 48%, about 44% to about 46%, about 46% to about 50%, about 46% to about 48%, or about 48% to about 50%. In some embodiments, the amount of microcrystalline cellulose in the solid dosage form is about 44% to about 46% by weight.

[0082] In some embodiments, the amount of microcrystalline cellulose in the solid dosage form is about 50 mg to about 1000 mg. In some embodiments, the amount of microcrystalline cellulose in the solid dosage form is about 50 mg to about 950 mg, about 50 mg to about 900 mg, about 50 mg to about 850 mg, about 50 mg to about 800 mg, about 50 mg to about 750 mg, about 50 mg to about 700 mg, about 50 mg to about 650 mg, about 50 mg to about 600 mg, about 50 mg to about 550 mg, about 50 mg to about 500 mg, 50 mg to about 450 mg, about 50 mg to about 400 mg, about 50 mg to about 350mg, about 50mg to about 300mg, about 50mg to about 250mg, about 50mg to about 200mg, about 50mg to about 150mg, about 50mg to about 100mg, about 100mg to about 500mg, about 100mg to about 450 mg, about 100mg to about 400mg, about 100mg to about 350mg, about 100mg to about 300mg, about 100mg to about 250mg, about 100mg to about 200mg, about 100mg to about 150mg, about 150mg to about 50 0mg, about 150mg to about 450mg, about 150mg to about 400mg, about 150mg to about 350mg, about 150mg to about 300mg, about 150mg to about 250mg, about 150mg to about 200mg, about 200mg to about 500mg, about 200mg to about 450mg, about 200mg to about 400mg, about 200mg to about 350mg, about 200mg to about 300mg, about 200mg to about 250mg, about 250mg to about 500mg, about 250mg to about In some embodiments, the amount of microcrystalline cellulose in the solid dosage form is about 450 mg, about 250 mg to about 400 mg, about 250 mg to about 350 mg, about 250 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 450 mg, about 300 mg to about 400 mg, about 300 mg to about 350 mg, about 350 mg to about 500 mg, about 350 mg to about 450 mg, about 350 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 450 mg, or about 450 mg to about 500 mg. In some embodiments, the amount of microcrystalline cellulose in the solid dosage form is about 50 mg to about 500 mg.

[0083] In some embodiments, the solid dosage form comprises about 100 mg of the compound of Formula I and about 40 mg to about 120 mg of filler. In some embodiments, the solid dosage form comprises about 100 mg of the compound of Formula I and about 80 mg to about 100 mg of filler. In some embodiments, the solid dosage form comprises about 100 mg of the compound of Formula I and about 85 mg to about 95 mg of filler. In some embodiments, the solid dosage form comprises about 100 mg of the compound of Formula I and about 89 mg of filler. In some embodiments, the solid dosage form is a tablet.

[0084] In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 200 mg to about 600 mg of a filler. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 400 mg to about 500 mg of a filler. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 425 mg to about 475 mg of a filler. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 450 mg of a filler. In some embodiments, the solid dosage form is a tablet.

[0085] In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 140 mg to about 420 mg of filler. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 280 mg to about 350 mg of filler. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 298 mg to about 333 mg of filler. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 315 mg of filler. In some embodiments, the solid dosage form is a tablet.

[0086] In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 70 mg to about 210 mg of filler. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 140 mg to about 175 mg of filler. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 149 mg to about 167 mg of filler. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 157.5 mg of filler. In some embodiments, the solid dosage form is a tablet.

[0087] In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 280 mg to about 840 mg of filler. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 560 mg to about 700 mg of filler. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 600 mg to about 670 mg of filler. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 630 mg of filler. In some embodiments, the solid dosage form is a tablet.

[0088] In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 100 mg of the compound of Formula I and about 40 mg to about 120 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 100 mg of the compound of Formula I and about 80 mg to about 100 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 100 mg of the compound of Formula I and about 85 mg to about 95 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 100 mg of the compound of Formula I and about 89 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet.

[0089] In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 200 mg to about 600 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 400 mg to about 500 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 425 mg to about 475 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 500 mg of the compound of Formula I and about 450 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet.

[0090] In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 140 mg to about 420 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 280 mg to about 350 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 298 mg to about 333 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 350 mg of the compound of Formula I and about 315 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet.

[0091] In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 280 mg to about 840 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 560 mg to about 700 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 600 mg to about 670 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 700 mg of the compound of Formula I and about 630 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet.

[0092] In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 70 mg to about 210 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 140 mg to about 175 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 150 mg to about 168 mg of microcrystalline cellulose. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 149 mg to about 167 mg of filler. In some embodiments, the solid dosage form comprises about 175 mg of the compound of Formula I and about 157.5 mg of microcrystalline cellulose. In some embodiments, the solid dosage form is a tablet. Film Coating

[0093] In some embodiments, the solid dosage forms (e.g., tablets) provided herein are uncoated. In certain other embodiments, the solid dosage forms (e.g., tablets) provided herein are coated (in which case they include a coating). While uncoated solid dosage forms (e.g., tablets) may be used, it is more common in clinical settings to provide coated solid dosage forms (e.g., tablets), in which case a conventional non-enteric coating may be used. The film coating may be composed of a hydrophilic polymeric material, including but not limited to, polysaccharide materials such as hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), poly(vinyl alcohol-co-ethylene glycol), and other water-soluble polymers. In some embodiments, the water-soluble material included in the film coating of the embodiments disclosed herein comprises a single polymeric material, while in certain other embodiments, it is formed using a mixture of two or more polymers.

[0094] In some embodiments, the coating is yellow or purple. Suitable coatings include, but are not limited to, polymeric film coatings such as polyvinyl alcohol, e.g., "Opadry® II" (comprising partially hydrolyzed PVA, titanium dioxide, macrogol 3350 (PEG), and talc, and optionally containing a colorant such as iron oxide (e.g., iron oxide red or iron oxide black), or indigo carmine, or iron oxide yellow, or FD&C Yellow #6), and Opadry® QX (comprising polyethylene glycol / macrogol polyvinyl alcohol graft copolymer, talc, titanium dioxide, glyceryl mono- and dicaprylocaprate (glyceryl monocaprylocaprate Type I), polyvinyl alcohol, and optionally containing a colorant such as iron oxide (e.g., iron oxide red or iron oxide black), or indigo carmine, or iron oxide yellow, or FD&C Yellow #6). In some embodiments, the film coating is Opadry® II purple or yellow. In some embodiments, the film coating is Opadry® QX yellow. The amount of coating is generally about 2-4% of the tablet core weight, in some embodiments, the amount of coating is about 3% by weight (based on the tablet core weight).

[0095] In some embodiments, the film coating is white. In some embodiments, the coating is Opadry® QX White. The amount of coating is generally about 2-4% of the tablet core weight. In some embodiments, the amount of coating is about 3% by weight (based on the tablet core weight).

[0096] In some embodiments, the film coating does not contain TiO. In some embodiments, the film coating contains CaCO. In some embodiments, the film coating contains a TiO-free variant of Opadry®.

[0097] Unless otherwise stated, if the dosage form is coated, it should be understood that references to weight percent are calculated relative to the tablet core weight.

[0098] The "tablet core weight" calculated herein is the sum of (i) the compound of formula I, (ii) the filler, (iii) the disintegrant, and (iv) the lubricant. The core tablet weight does not include the weight of the film coating.

[0099] The "tablet weight" calculated herein is the sum of (i) the compound of formula I, (ii) the filler, (iii) the disintegrant, (iv) the lubricant, and (v) the film coating.

[0100] In some embodiments, the solid dosage form comprises: [Table 1]

[0101] In some embodiments, the solid dosage form is a tablet comprising: [Table 2]

[0102] In some embodiments, the solid dosage form comprises: [Table 3]

[0103] In some embodiments, the solid dosage form is a tablet comprising: [Table 4]

[0104] In some embodiments, the solid dosage form comprises: [Table 5]

[0105] In some embodiments, the solid oral dosage form is a tablet comprising: [Table 6]

[0106] In some embodiments, the solid dosage form comprises: [Table 7]

[0107] In some embodiments, the solid dosage form is a tablet comprising: [Table 8]

[0108] In some embodiments, the solid dosage form is a tablet comprising: [Table 9]

[0109] In some embodiments, the solid dosage form comprises: [Table 10]

[0110] In some embodiments, the solid dosage form comprises: [Table 11]

[0111] In some embodiments, the solid oral dosage form is a tablet comprising: [Table 12]

[0112] In some embodiments, the solid oral dosage form is a tablet comprising: [Table 13]

[0113] In some embodiments, the solid oral formulation comprises: [Table 14]

[0114] In some embodiments, the solid oral dosage form is a tablet comprising: [Table 15]

[0115] In some embodiments, the tablet comprises: [Table 16]

[0116] In some embodiments, the tablet comprises: [Table 17]

[0117] In some embodiments, the tablet comprises: [Table 18]

[0118] In some embodiments, the tablet comprises: [Table 19]

[0119] In some embodiments, the tablet comprises: [Table 20]

[0120] In some embodiments, the tablet comprises: [Table 21]

[0121] In some embodiments, the tablet comprises: [Table 22]

[0122] In some embodiments, the tablet comprises: [Table 23]

[0123] In some embodiments, the tablet comprises: [Table 24]

[0124] In some embodiments, the tablet comprises: [Table 25]

[0125] In some embodiments, the solid dosage form comprises 175 mg of the compound of formula I, microcrystalline cellulose, crospovidone, magnesium stearate, and a film coat. In some embodiments, the solid dosage form comprises 175 mg of the compound of formula I, microcrystalline cellulose, crospovidone, magnesium stearate, and Opadry® QX White.

[0126] In some embodiments, the solid dosage form comprises 350 mg of the compound of formula I, microcrystalline cellulose, crospovidone, magnesium stearate, and a film coat. In some embodiments, the solid dosage form comprises 350 mg of the compound of formula I, microcrystalline cellulose, crospovidone, magnesium stearate, and Opadry® QX Yellow. Pharmaceutical compositions and tablets

[0127] The present application also provides pharmaceutical compositions, particularly tablets, comprising a compound represented by Formula I or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is present in an amount of about 40 wt% to about 70 wt%. In certain embodiments, the compound is present in an amount of about 45 wt% to about 70 wt%. In certain embodiments, the compound is present in an amount of about 45 wt% to about 55 wt%. In certain embodiments, the compound is present in an amount of about 50 wt%.

[0128] The present application also provides pharmaceutical compositions, particularly tablets, comprising a compound represented by Formula I or a pharmaceutically acceptable salt thereof, wherein the drug load of the compound of Formula I in the pharmaceutical composition (e.g., tablet) is greater than 40%. In certain embodiments, the drug load of the compound of Formula I in the pharmaceutical composition or tablet is 70% or less. In certain embodiments, the drug load of the compound of Formula I in the pharmaceutical composition or tablet is greater than 40% and less than 70%. In certain embodiments, the drug load of the compound of Formula I in the pharmaceutical composition or tablet is 45% or more and less than 70%. In certain embodiments, the drug load of the compound of Formula I in the pharmaceutical composition or tablet is greater than 45%. In certain embodiments, the drug load of the compound of Formula I in the pharmaceutical composition or tablet is 55% or less. In certain embodiments, the drug load of the compound of Formula I in the pharmaceutical composition or tablet is 45% or more and less than 55%. In certain embodiments, the drug load of the compound of Formula I in the pharmaceutical composition or tablet is about 50%.

[0129] In certain embodiments, the compound is the free base form of the compound of Formula I. In particular, in certain embodiments, the compound is a crystalline free base form characterized by an X-ray powder diffraction (XRPD) pattern comprising 2θ reflection angles of 9.8°, 16.0°, and 25.4° (2θ+ / −0.2 degrees).

[0130] The pharmaceutical composition or tablet may further comprise a filler. In certain embodiments, the filler is present in an amount of about 20 to about 60 wt %. In certain embodiments, the filler is present in an amount of about 40 to about 50 wt %. In certain embodiments, the filler is present in an amount of about 44 to about 46 wt %.

[0131] In certain embodiments, the filler is microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount of about 20 to about 60 wt%. In certain embodiments, the microcrystalline cellulose is present in an amount of about 40 to about 50 wt%. In certain embodiments, the microcrystalline cellulose is present in an amount of about 44 to about 46 wt%.

[0132] In certain embodiments, the pharmaceutical composition comprises about 40 wt% to 70 wt% of the compound of Formula I or a pharmaceutically acceptable salt thereof, and about 20 wt% to about 60 wt% of microcrystalline cellulose. Preferably, the pharmaceutical composition comprises about 45 wt% to 70 wt% of the compound of Formula I or a pharmaceutically acceptable salt thereof, and about 20 wt% to about 60 wt% of microcrystalline cellulose. Preferably, the pharmaceutical composition comprises about 45 wt% to 55 wt% of the compound of Formula I or a pharmaceutically acceptable salt thereof, and about 20 wt% to about 60 wt% of microcrystalline cellulose. Preferably, the pharmaceutical composition comprises about 40 wt% to 70 wt% of the compound of Formula I or a pharmaceutically acceptable salt thereof, and about 40 wt% to about 50 wt% of microcrystalline cellulose. Preferably, the pharmaceutical composition comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 45 wt% to about 55 wt% and microcrystalline cellulose in an amount of about 40 wt% to about 50 wt%.

[0133] The pharmaceutical composition or tablet may further comprise a disintegrant. In certain embodiments, the disintegrant is present in an amount of about 1 wt% to about 10 wt%. In certain embodiments, the disintegrant is present in an amount of about 3 wt% to about 5 wt%.

[0134] In certain embodiments, the disintegrant is crospovidone. In certain embodiments, the pharmaceutical composition comprises crospovidone in an amount of about 1 wt% to about 10 wt%. In certain embodiments, the pharmaceutical composition comprises crospovidone in an amount of about 3 wt% to about 5 wt%.

[0135] The pharmaceutical composition or tablet may further comprise a lubricant. In certain embodiments, the lubricant is present in an amount of about 0.5 wt% to about 5 wt%. In certain embodiments, the lubricant is present in an amount of about 0.5 wt% to about 2 wt%.

[0136] In certain embodiments, the lubricant is magnesium stearate. In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.5 wt% to about 5 wt%. In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.5 wt% to about 2 wt%.

[0137] The pharmaceutical composition or tablet may comprise a compound of formula I or a pharmaceutically acceptable salt thereof, a filler, a disintegrant, and a lubricant. In certain embodiments, the filler is microcrystalline cellulose, and the disintegrant is crospovidone. In certain embodiments, the filler is microcrystalline cellulose, and the lubricant is magnesium stearate. In certain embodiments, the disintegrant is crospovidone, and the lubricant is magnesium stearate. In certain embodiments, the filler is microcrystalline cellulose, the disintegrant is crospovidone, and the lubricant is magnesium stearate. In certain embodiments, the compound is the free base form of the compound of formula I, the filler is microcrystalline cellulose, the disintegrant is crospovidone, and the lubricant is magnesium stearate.

[0138] The pharmaceutical composition or tablet may comprise: (i) the compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 40 wt% to about 70 wt%, (ii) microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%, (iii) crospovidone in an amount of about 1 wt% to about 10 wt%; and (iv) magnesium stearate in an amount of about 0.5 wt% to about 5 wt%.

[0139] In certain embodiments, the pharmaceutical composition or tablet may comprise (i) about 45% to about 70% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof, (ii) about 20% to about 60% by weight of microcrystalline cellulose, (iii) about 1% to about 10% by weight of crospovidone, and (iv) about 0.5% to about 5% by weight of magnesium stearate. In certain embodiments, the pharmaceutical composition or tablet may comprise (i) about 45% to about 55% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof, (ii) about 20% to about 60% by weight of microcrystalline cellulose, (iii) about 1% to about 10% by weight of crospovidone, and (iv) about 0.5% to about 5% by weight of magnesium stearate. In certain embodiments, the pharmaceutical composition or tablet may comprise: (i) the compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 50 wt %, (ii) microcrystalline cellulose in an amount of about 20 wt % to about 60 wt %, (iii) crospovidone in an amount of about 1 wt % to about 10 wt %; and (iv) magnesium stearate in an amount of about 0.5 wt % to about 5 wt %.

[0140] In certain embodiments, the pharmaceutical composition or tablet may comprise (i) about 40% to about 70% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof, (ii) about 40% to about 50% by weight of microcrystalline cellulose, (iii) about 1% to about 10% by weight of crospovidone, and (iv) about 0.5% to about 5% by weight of magnesium stearate. In certain embodiments, the pharmaceutical composition or tablet may comprise (i) about 40% to about 70% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof, (ii) about 44% to about 66% by weight of microcrystalline cellulose, (iii) about 1% to about 10% by weight of crospovidone, and (iv) about 0.5% to about 5% by weight of magnesium stearate.

[0141] In certain embodiments, the pharmaceutical composition or tablet may comprise (i) about 40% to about 70% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof, (ii) about 20% to about 60% by weight of microcrystalline cellulose, (iii) about 3% to about 5% by weight of crospovidone, and (iv) about 0.5% to about 5% by weight of magnesium stearate. In certain embodiments, the pharmaceutical composition or tablet may comprise (i) about 40% to about 70% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof, (ii) about 20% to about 60% by weight of microcrystalline cellulose, (iii) about 1% to about 10% by weight of crospovidone, and (iv) about 0.5% to about 2% by weight of magnesium stearate.

[0142] In certain embodiments, the pharmaceutical composition or tablet is manufactured by dry granulation. In certain embodiments, the dry granulation is carried out using a roller compaction process. Administration

[0143] The pharmaceutical preparation described herein is for oral administration.The frequency of the dosage of the compound described herein is determined by the need of individual patient, and can be, for example, once a day, twice a day, or more times a day.The administration of the compound continues as long as it is necessary to treat viral infection.

[0144] In some embodiments, a single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once weekly. A single dose can also be administered once monthly. In some embodiments, a compound described herein is administered once daily in the methods described herein. In some embodiments, a compound described herein is administered twice daily in the methods described herein. In some embodiments, a compound described herein is administered three times daily in the methods described herein. In some embodiments, a pharmaceutical formulation described herein, e.g., a solid dosage form (e.g., a tablet), contains 350 mg of the compound of Formula I and is administered twice daily. In some embodiments, a pharmaceutical formulation described herein, e.g., a solid dosage form (e.g., a tablet), contains 700 mg of a compound of Formula I and is administered once daily. In some embodiments, a pharmaceutical formulation described herein, e.g., a solid dosage form (e.g., a tablet), contains 500 mg of a compound of Formula I and is administered once daily. In some embodiments, a pharmaceutical formulation described herein, e.g., a solid dosage form (e.g., a tablet), contains 175 mg of a compound of Formula I and is administered twice daily.

[0145] In some embodiments, a pharmaceutical formulation described herein, e.g., a solid dosage form (e.g., a tablet), contains 175 mg of a compound of formula I, administered twice daily on day 1, then once daily on days 2, 3, 4, and 5. In some embodiments, a pharmaceutical formulation described herein, e.g., a solid dosage form (e.g., a tablet), contains 350 mg of a compound of formula I, administered once daily on days 1, 2, 3, 4, and 5.

[0146] In some embodiments, the pharmaceutical formulations described herein are administered to a patient, and the patient has mild renal impairment, moderate renal impairment, or severe renal impairment.

[0147] In some embodiments, the patient has mild renal impairment and the pharmaceutical formulation comprises 350 mg of the compound of Formula I, administered twice daily. In some embodiments, the patient has mild renal impairment and the pharmaceutical formulation comprises 350 mg of the compound of Formula I, administered twice daily for 5 days.

[0148] In some embodiments, the patient has moderate renal impairment and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered once daily. In some embodiments, the patient has moderate renal impairment and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered once daily for 5 days.

[0149] In some embodiments, the patient has severe renal impairment and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered once daily. In some embodiments, the patient has severe renal impairment and the pharmaceutical formulation comprises 175 mg of the compound of Formula I and is administered once daily. In some embodiments, the patient has severe renal impairment and the pharmaceutical formulation comprises 350 mg of the compound of Formula I and is administered once daily for one day. In some embodiments, the patient has severe renal impairment and the pharmaceutical formulation comprises 175 mg of the compound of Formula I and is administered once daily for four days. Manufacturing method

[0150] Also provided are methods for producing pharmaceutical formulations, such as solid oral dosage forms (eg, tablets), disclosed herein.

[0151] Tableting methods in general are well known in the pharmaceutical arts, and techniques and formulations generally can be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA), which is incorporated herein by reference in its entirety.

[0152] A tablet can be made by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form, such as powder or granules, optionally mixed with an excipient.

[0153] In some embodiments, the pharmaceutical composition or tablet is manufactured using a method including dry granulation. Dry granulation can be performed by roller compaction. Dry granulation can be performed on a blend of the compound of Formula I, a filler, a disintegrant, and a lubricant. In some embodiments, the composition includes microcrystalline cellulose as a filler, crospovidone as a disintegrant, and magnesium stearate as a lubricant.

[0154] In some embodiments, the manufacturing method comprises the steps of: 1. Blending the compound of formula I, a filler, and a disintegrant; 2. Add lubricant and blend; and 3. The resulting blend is dry granulated.

[0155] Also provided herein is a method of making a tablet, the method comprising: 1. Blending a compound of formula I, a filler, and a disintegrant to form mixture 1; 2. Adding a lubricant to Blend 1 to form Blend 2; 3. Blending Mixture 2 to form Mixture 3; and 3. Dry granulating blend 4 to form tablets.

[0156] In some embodiments, the method comprises blending the drug substance with excipients. In some embodiments, the manufacturing process comprises co-blending and lubricating the compound of Formula I with intragranular excipients. In some embodiments, the method further comprises roller compaction and / or milling. The resulting granules of Formula I are then blended with extragranular excipients. The resulting mixture is then compressed into core tablets. In some embodiments, the tablets are further coated with a film coat. An exemplary manufacturing process is shown in Figure 1. Treatment method

[0157] The pharmaceutical formulations disclosed herein, such as solid oral dosage forms (e.g., tablets), are used to treat viral infections. In some embodiments, the solid oral dosage forms (e.g., tablets) disclosed herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of viral infections.

[0158] Thus, there is provided a method for treating a viral infection in a subject, comprising administering to the subject a solid oral dosage form disclosed herein.Similarly, there is provided a solid oral dosage form for use in such a treatment method.There is also provided the use of the solid oral dosage form in the manufacture of an oral dosage form disclosed herein for treating a viral infection.

[0159] In some embodiments, the solid oral dosage forms disclosed herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of viral infection. Thus, a method for preventing an infectious disease in a subject at risk of an infectious disease is provided, comprising administering a solid oral dosage form disclosed herein to the subject. Similarly, the solid oral dosage forms disclosed herein are provided for use in such treatment methods. The present invention also provides the use of the solid oral dosage forms disclosed herein in the manufacture of oral dosage forms for preventing viral infection in a subject at risk of an infectious disease.

[0160] The methods include administering a solid oral dosage form disclosed herein to a subject, typically a human, and generally include repeated administration, typically once or twice daily. In some embodiments, administration is once daily. In some embodiments, administration is twice daily. Treatment can be prophylactic or therapeutic.

[0161] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Paramyxoviridae infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a solid oral dosage form (particularly a tablet) disclosed herein. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus.

[0162] In some embodiments, the viral infection is a human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection.

[0163] In some embodiments, the viral infection is a Pneumoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (particularly a tablet) provided herein. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviridae virus infection is a human metapneumovirus infection.

[0164] In some embodiments, the present disclosure provides a solid oral dosage form (particularly a tablet) disclosed herein for use in treating a pneumoviridae virus infection in a human in need thereof. In some embodiments, the pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviridae virus infection is a human metapneumovirus infection.

[0165] In some embodiments, the present disclosure provides a method for treating a RSV infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (particularly a tablet) provided herein. In some embodiments, the human is suffering from a chronic respiratory syncytial virus infection. In some embodiments, the human is acutely infected with RSV.

[0166] In some embodiments, a method of inhibiting RSV replication is provided, the method comprising administering a solid oral dosage form (particularly a tablet) disclosed herein to a human in need thereof, wherein the administration is by inhalation.

[0167] In some embodiments, the present disclosure provides a method for reducing the viral load associated with a RSV infection, the method comprising administering a solid oral dosage form (particularly a tablet) disclosed herein to a human infected with RSV.

[0168] In some embodiments, the viral infection is a Picornaviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (particularly a tablet) of the present disclosure. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections, including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic polio-like syndrome, epidemic pleurodynia (an acute, febrile, infectious illness that typically occurs during epidemics), hand, foot, and mouth disease, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the Picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0169] In some embodiments, the viral infection is selected from the group consisting of a Coxsackie A virus infection, a Coxsackie A virus infection, an Enterovirus D68 infection, an Enterovirus B69 infection, an Enterovirus D70 infection, an Enterovirus A71 infection, and a Poliovirus infection.

[0170] In some embodiments, the present disclosure provides a solid oral dosage form (particularly a tablet) for use in treating a Picornaviridae virus infection in a human in need thereof, hi some embodiments, the Picornaviridae virus infection is a human rhinovirus infection.

[0171] In some embodiments, the viral infection is a Flaviviridae virus infection. Accordingly, in some embodiments, the present disclosure provides methods of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (particularly a tablet) described herein. Representative Flaviviridae viruses include, but are not limited to, dengue fever, yellow fever, West Nile, Zika, Japanese encephalitis virus, and hepatitis C (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0172] In some embodiments, the Flaviviridae virus infection is dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

[0173] In some embodiments, the present disclosure provides a use of a solid oral dosage form (e.g., a tablet) disclosed herein for the treatment of a Flaviviridae virus infection in a human in need thereof. In some embodiments, the Flaviviridae virus infection is a Dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow Fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0174] In some embodiments, the viral infection is a Filoviridae virus infection. Accordingly, in some embodiments, provided herein are methods of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (particularly a tablet) disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Tai Forest, or Reston variant) and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0175] In some embodiments, the present disclosure provides a solid oral dosage form (particularly a tablet) for use in treating a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0176] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, provided herein are methods of treating a coronavirus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (particularly a tablet) provided herein. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS-CoV) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or a zoonotic coronavirus (PEDV or HKU CoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0177] In some embodiments, the viral infection is caused by a SARS-CoV-2 variant, such as the B.1.1.7 variant (UK variant), the B.1.351 variant (South African variant), the P.1 variant (Brazilian variant), the B.1.1.7 with the E484K mutation, the B.1.1.207 variant, the B.1.1.317 variant, the B.1.1.318 variant, the B.1.429 variant, the B.1.525 variant, or the P.3 variant. In some embodiments, the viral infection is caused by the B.1.1.7 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the B.1.351 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the P.1 variant of SARS-CoV-2.

[0178] In some embodiments, the present disclosure provides solid oral dosage forms (particularly tablets) for use in treating a coronavirus virus infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or a zoonotic coronavirus (PEDV or HKUCoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0179] In some embodiments, the viral infection is an Arenaviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating an Arenaviridae virus infection in a human in need thereof, the method comprising administering to the human a solid oral dosage form (particularly a tablet) disclosed herein. In some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0180] In some embodiments, the present disclosure provides a compound for use in treating an Arenaviridae virus infection in a human in need thereof, hi some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0181] In some embodiments, the viral infection is an orthomyxovirus infection, such as an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0182] As described more fully herein, the solid oral dosage forms (particularly tablets) described herein can be administered to an individual (e.g., a human) infected with a viral infection along with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected individual simultaneously with the compounds of the present disclosure, or before or after administration of the compounds of the present disclosure. Combination therapy

[0183] Pharmaceutical preparations, such as the solid oral dosage forms described herein, can also be used in combination with one or more additional therapeutic agents. Accordingly, provided herein is a method for treating a viral infection in a subject in need thereof, the method comprising administering to the subject a solid oral dosage form disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents.

[0184] In some embodiments, the additional therapeutic agent comprises an antiviral agent. Any suitable antiviral agent can be used in the methods described herein.

[0185] In some embodiments, the additional therapeutic agent is a 2,5-oligoadenylate synthetase stimulator, 5-HT 2a receptor antagonists, 5-lipoxygenase inhibitors, ABL family tyrosine kinase inhibitors, Abl tyrosine kinase inhibitors, acetaldehyde dehydrogenase inhibitors, acetyl-CoA carboxylase inhibitors, actin antagonists, actin modulators, activity-dependent neuroprotectant modulators, adenosine A3 receptor agonists, adrenergic receptor antagonists, adrenomedullin ligands, adrenomedullin ligand inhibitors, advanced glycation end products receptor antagonists, advanced glycation end products receptor modulators, AKT protein kinase inhibitors, alanine-proline-rich secretory protein stimulators, aldose reductase inhibitors, alkaline phosphatase stimulators, alpha 2 adrenergic receptor antagonists, alpha 2B adrenergic receptor agonists, AMP-activated protein kinase stimulators, AMPA receptor modulators, amyloid protein deposition inhibitors, androgen receptor antagonists, angiotensin II AT-1 receptor antagonists, angiotensin II AT-2 receptor agonists, angiotensin II receptor modulators, angiotensin-converting enzyme 2 inhibitors, angiotensin-converting enzyme 2 modulators, angiotensin-converting enzyme 2 stimulators, angiotensin receptor modulators, annexin A5 stimulators, anoctamin 1 inhibitors, anticoagulants, antihistamines, antihypoxic agents, antithrombotic agents, AP1 transcription factor modulators, apelin receptor agonists, APOA1 gene stimulators, apolipoprotein A1 agonists, apolipoprotein B antagonists, apolipoprotein B modulators -, apolipoprotein C3 antagonists, aryl hydrocarbon receptor agonists, aryl hydrocarbon receptor antagonists, ATP-binding cassette transporter B5 inhibitors, Axl tyrosine kinase receptor inhibitors, bactericidal permeability protein inhibitors, basigin inhibitors, basigin modulators, BCL2 gene inhibitors, BCL2L11 gene stimulators, Bcr protein inhibitors, beta 1 adrenergic receptor modulators, beta 2 adrenergic receptor agonists, beta adrenergic receptor agonists, beta-arrestin stimulators,Blood coagulation modulators, BMP10 gene inhibitors, BMP15 gene inhibitors, bone morphogenetic protein-10 ligand inhibitors, bone morphogenetic protein-15 ligand inhibitors, bradykinin B2 receptor antagonists, brain-derived neurotrophic factor ligands, bromodomain-containing protein 2 inhibitors, bromodomain-containing protein 4 inhibitors, Btk tyrosine kinase inhibitors, C-reactive protein modulators, Ca2+ release-activated Ca2+ channel 1 inhibitors, cadherin 5 modulators, calcium-activated chloride channel inhibitors, calcium channel modulators inhibitors, calpain-I inhibitors, calpain-II inhibitors, calpain-IX inhibitors, cannabinoid CB2 receptor agonists, cannabinoid receptor modulators, casein kinase II inhibitors, CASP8-FADD-like modulator inhibitors, caspase inhibitors, catalase stimulators, CCL26 gene inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, CD11a agonists, CD122 agonists, CD3 antagonists, CD4 agonists, CD40 ligands, CD40 ligand modulators, CD40 ligands ligand receptor agonists, CD40 ligand receptor modulators, CD49d agonists, CD70 antigen modulators, CD73 agonists, CD73 antagonists, CD95 antagonists, CFTR inhibitors, CGRP receptor antagonists, chemokine receptor-like 1 agonists, chloride channel inhibitors, chloride channel modulators, cholera enterotoxin subunit B inhibitors, cholesterol ester transfer protein inhibitors, collagen modulators, complement C1s subcomponent inhibitors, complement C3 inhibitors, complement factor C5 inhibitors inhibitors, complement factor C5a inhibitors, complement factor H stimulators, complement cascade inhibitors, complement factor C2 inhibitors, complement factor D inhibitors, connective tissue growth factor ligand inhibitors, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, COVID19 small envelope membrane protein modulators, COVID19 nonstructural protein 8 modulators, COVID19 nucleoprotein modulators, COVID19 protein 3a inhibitors,COVID19 replicase polyprotein 1a inhibitors, COVID19 replicase polyprotein 1a modulators, COVID19 replicase polyprotein 1ab inhibitors, COVID19 replicase polyprotein 1ab modulators, COVID19 spike glycoprotein inhibitors, COVID19 spike glycoprotein modulators, COVID19 structural glycoprotein modulators, CRF-2 receptor agonists, CSF-1 agonists, CSF-1 antagonists, CX3CR1 chemokine antagonists, CXC10 chemokine ligand inhibitors, CXC5 chemokine ligand inhibitors, CX CL1 gene modulators, CXCL2 gene modulators, CXCL3 gene modulators, CXCR1 chemokine antagonists, CXCR2 chemokine antagonists, CXCR4 chemokine antagonists, cyclin D1 inhibitors, cyclin E inhibitors, cyclin-dependent kinase-1 inhibitors, cyclin-dependent kinase-2 inhibitors, cyclin-dependent kinase-5 inhibitors, cyclin-dependent kinase-7 inhibitors, cyclin-dependent kinase-9 inhibitors, cyclooxygenase-2 inhibitors, cyclooxygenase inhibitors, cyclophilin inhibitors, cysteine ​​protease inhibitors, cytochrome P450 3A4 inhibitors, cytokine receptor antagonists, cytotoxic T lymphocyte protein gene modulators, cytotoxic T lymphocyte protein-4 inhibitors, cytotoxic T lymphocyte protein-4 stimulators, DDX3 inhibitors, dehydrogenase inhibitors, dehydropeptidase-1 modulators, deoxyribonuclease I stimulators, deoxyribonuclease gamma stimulators, deoxyribonuclease stimulators, dihydroceramide delta-4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase I inhibitors, dipeptidyl peptidase III inhibitors, diuretics, DNA binding protein inhibitors, DNA methyltransferase inhibitors, dopamine transporter inhibitors, E-selectin antagonists, Ecto NOX disulfide thiol exchanger 2 inhibitors, EGFR gene inhibitors, elongation factor 1 alpha 2 modulators, endoplasmin modulators, endoribonuclease DICER modulators, endothelin ET-A receptor antagonists,Epidermal growth factor receptor antagonist, E-selectin antagonist, estrogen receptor beta agonist, estrogen receptor modulator, eukaryotic initiation factor 4A-I inhibitor, Exo-alpha sialidase modulator, Exportin 1 inhibitor, factor Ia modulator, factor IIa modulator, factor VII antagonist, factor Xa antagonist, factor XIa antagonist, FGF receptor antagonist, FGF-1 ligand, FGF-1 ligand inhibitor, FGF-2 ligand inhibitor, FGF1 receptor antagonist, FGF2 receptor antagonist, FGF3 receptor antagonist, Flt3 tyrosine kinase inhibitor, Fractalkine ligand inhibitor, free fatty acid receptor 2 agonist, free fatty acid receptor 3 agonist, furin inhibitor, Fyn tyrosine kinase inhibitor, FYVE finger phosphoinositide kinase inhibitor, G protein-coupled bile acid receptor 1 agonist, GABA A receptor modulators, galectin-3 inhibitors, gamma-secretase inhibitors, GDF agonists, gelsolin stimulators, glial neurotrophic factor ligands, glucocorticoid receptor agonists, glutathione peroxidase stimulators, GM-CSF ligand inhibitors, GM-CSF receptor agonists, GM-CSF receptor modulators, Griffithsin modulators, growth regulatory protein alpha ligand inhibitors, Grp78 calcium binding protein inhibitors, heat shock protein HSP90 alpha inhibitors, heat shock protein HSP90 beta inhibitors, heat shock protein inhibitors, heat shock protein stimulators, hemagglutinin modulators, hemoglobin modulators, hemolysin alpha inhibitors, heparanase inhibitors, heparin agonists, hepatitis B structural protein inhibitors, hepatitis C virus NS5B polymerase inhibitors, HIF prolyl hydroxylase inhibitors, HIF prolyl hydroxylase-2 inhibitors, high mobility group protein B1 inhibitors, histamine H1 receptor antagonists, histamine H2 receptor antagonists, histone deacetylase-6 inhibitors, histone inhibitors, HIV protease inhibitors, HIV-1 gp120 protein inhibitors, HIV-1 protease inhibitors, HIV-1 reverse transcriptase inhibitors, HLA class I antigen modulators,HLA class II antigen modulators, host cell factor modulators, Hsp 90 inhibitors, human papillomavirus E6 protein modulators, human papillomavirus E7 protein modulators, hypoxia-inducible factor inhibitor gene inhibitors, hypoxia-inducible factor-2 alpha modulators, I-kappa B kinase inhibitors, I-kappa B kinase modulators, ICAM-1 stimulators, IgG receptor FcRn large subunit p51 modulators, IL-12 receptor antagonists, IL-15 receptor agonists, IL-15 receptor modulators, IL-17 antagonists, IL-18 receptor agonists accessory protein antagonist, IL-2 receptor agonist, IL-22 agonist, IL-23 antagonist, IL-6 receptor agonist, IL-6 receptor antagonist, IL-6 receptor modulator, IL-7 receptor agonist, IL-8 receptor antagonist, IL12 gene stimulator, IL8 gene modulator, immunoglobulin G modulator, immunoglobulin G1 agonist, immunoglobulin G1 modulator, immunoglobulin agonist, immunoglobulin gamma Fc receptor I modulator, immunoglobulin brin kappa modulators, inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, integrin agonists, integrin alpha-4 / beta-7 antagonists, integrin alpha-V / beta-1 antagonists, integrin alpha-V / beta-6 antagonists, interferon agonists, interferon alpha 14 ligands, interferon alpha 2 ligands, interferon alpha 2 ligand modulators, interferon alpha ligands, interferon alpha ligand inhibitors, interferon alpha ligand modulators, interferon beta ligands, interferon gamma ligand inhibitors, interferon gamma receptor agonists, interferon gamma receptor antagonists, interferon receptor modulators, interferon type I receptor agonists, interleukin 17A ligand inhibitors, interleukin 17F ligand inhibitors, interleukin 18 ligand inhibitors, interleukin 22 ligands, interleukin-1 beta ligand inhibitors,Interleukin-1 beta ligand modulator, interleukin-1 ligand inhibitor, interleukin-2 ligand, interleukin-29 ligand, interleukin-6 ligand inhibitor, interleukin-7 ligand, interleukin-8 ligand inhibitor, IRAK-4 protein kinase inhibitor, JA, K tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, Jun N-terminal kinase modulators, kallikrein modulators, Kelch-like ECH-associated protein 1 modulators, Kit tyrosine kinase inhibitors, KLKB1 gene inhibitors, lactoferrin stimulators, lanosterol-14 demethylase inhibitors, Lck tyrosine kinase inhibitors, leukocyte Ig-like receptor A4 modulators, leukocyte elastase inhibitors, leukotriene BLT receptor antagonists, leukotriene D4 antagonists, leukotriene receptor antagonists, listeriolysin stimulators, liver X receptor antagonists, low molecular weight heparins, pulmonary surfactant-associated protein B stimulators, pulmonary surfactant-associated protein D modulators, Lyn tyrosine kinase inhibitors, Lyn tyrosine kinase stimulators, lysine-specific histone demethylase 1 inhibitors, macrophage migration inhibitory factor inhibitors, mannan-binding lectin serine protease inhibitors, mannan-binding lectin serine protease-2 inhibitors, MAO B inhibitors, MAP kinase inhibitors, MAPK gene modulators, matrix metalloproteinase modulators, maxi-K potassium channel inhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitors, melanocortin MC1 receptor agonists, melanocortin MC3 receptor agonists, metalloproteinase-12 inhibitors, METTL3 gene inhibitors, moesin inhibitors, moesin modulators, monocyte chemoattractant protein 1 ligand inhibitors, monocyte differentiation antigen CD14 inhibitors, mRNA cap guanine N7 methyltransferase modulators, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, mTOR inhibitors, mucolipin modulators, muscarinic receptor antagonists, myeloperoxidase,NACHT LRR PYD domain protein 3 inhibitors, NAD synthase modulators, NADPH oxidase inhibitors, neuropilin 2 modulators, neuroplastin inhibitors, NFE2L2 gene stimulators, NK cell receptor agonists, NK1 receptor antagonists, NMDA receptor antagonists, NMDA receptor epsilon 2 subunit inhibitors, non-receptor tyrosine kinase TYK2 antagonists, non-nucleoside reverse transcriptase inhibitors, nuclear erythroid 2-related factor 2 stimulators, nuclear factor kappa B inhibitors, nuclear factor kappa B modulators, nuclease stimulators, nucleolin inhibitors, nuclear protein inhibitors, nuclear protein modulators, nucleoside reverse transcriptase inhibitors, opioid receptor agonists, opioid receptor antagonists, opioid receptor mu modulators, opioid receptor sigma antagonists 1, ornithine decarboxylase inhibitors, outer membrane protein inhibitors, OX40 ligands, p38 MAP kinase alpha inhibitors, p38 MAP kinase inhibitors, p38 MAP kinase modulators, p53 tumor suppressor protein stimulators, palmitoyl protein thioesterase 1 inhibitors, papain inhibitors, PARP inhibitors, PARP modulators, PDE 10 inhibitors, PDE 3 inhibitors, PDE 4 inhibitors, PDGF receptor alpha antagonists, PDGF receptor antagonists, PDGF receptor beta antagonists, peptidyl prolyl cis-trans isomerase A inhibitors, peroxiredoxin 6 modulators, PGD2 antagonists, PGI2 agonists, P-glycoprotein inhibitors, phosphoinositide 3-kinase inhibitors, phosphoinositide-3 kinase delta inhibitors, phosphoinositide-3 kinase gamma inhibitors, phospholipase A2 inhibitors, plasma kallikrein inhibitors, plasminogen activator inhibitor 1 inhibitors, platelet inhibitors, platelet glycoprotein VI inhibitors, polo-like kinase 1 inhibitors, poly ADP-ribose polymerase 1 inhibitors, poly ADP-ribose polymerase 2 inhibitors, polymerase cofactor VP35 inhibitors, PPAR alpha agonists, progesterone receptor agonists, programmed cell death protein 1 modulators, prolyl hydroxylase inhibitors, prostaglandin E synthase-1 inhibitors, protease inhibitors, proteasome inhibitors,Protein arginine deiminase IV inhibitors, protein tyrosine kinase inhibitors, protein tyrosine phosphatase beta inhibitors, protein tyrosine phosphatase-2C inhibitors, proto-oncogene Mas agonists, purinoceptor antagonists, Raf protein kinase inhibitors, RANTES ligands, Ras gene inhibitors, retinoate receptor response protein 2 stimulators, Rev protein modulators, ribonuclease stimulators, RIP-1 kinase inhibitors, RNA helicase inhibitors, RNA polymerase inhibitors, RNA polymerase modulators, S-phase kinase-associated protein 2 inhibitors, SARS coronavirus 3C protease-like inhibitors, serine protease inhibitors, serine-threonine protein kinase ATR inhibitors, serine-threonine protein kinase TBK1 inhibitors, serum amyloid De A protein modulators, signal transducer CD24 stimulators, sodium channel stimulators, sodium glucose transporter-2 inhibitors, sphingosine kinase 1 inhibitors, sphingosine kinase 2 inhibitors, sphingosine kinase inhibitors, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-5 agonists, sphingosine-1-phosphate receptor-5 modulators, spike glycoprotein inhibitors, Src tyrosine kinase inhibitors, STAT-1 modulators, STAT-3 inhibitors, STAT-5 inhibitors, STAT3 gene inhibitors, stem cell antigen-1 inhibitors, stimulators of interferon gene protein stimulators, sulfatase inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, Syk tyrosine kinase inhibitors, T cell immunoreceptor Ig ITIM protein inhibitors, T cell receptor agonists, T cell surface glycoprotein CD28 inhibitors, T cell differentiation antigen CD6 inhibitors, T cell surface glycoprotein CD8 stimulators, T cell transcription factor NFAT modulators, tankyrase-1 inhibitors, tankyrase-2 inhibitors, Tek tyrosine kinase receptor stimulators, telomerase modulators, tetanus toxin modulators, TGF beta receptor antagonists, TGFB2 gene inhibitors, thymosin beta 4 ligands, thyroid hormone receptor beta agonists, tissue factor inhibitors, tissue plasminogen activator modulators,Tissue plasminogen activator stimulators, TLR agonists, TLR modulators, TLR-2 agonists, TLR-2 antagonists, TLR-3 agonists, TLR-4 agonists, TLR-4 antagonists, TLR-6 agonists, TLR-7 agonists, TLR-7 antagonists, TLR-8 antagonists, TLR-9 agonists, TMPRSS2 gene inhibitors, TNF alpha ligand inhibitors, TNF alpha ligand modulators, TNF binders, TNF gene inhibitors, topoisomerase inhibitors, transcription factor EB stimulators, transferrin Phosphomodulators, transketolase inhibitors, translocation-associated protein inhibitors, transmembrane serine protease 2 inhibitors, transthyretin modulators, TREM receptor 1 antagonists, TRP cation channel C1 modulators, TRP cation channel C6 inhibitors, TRP cation channel V6 inhibitors, trypsin 1 inhibitors, trypsin 2 inhibitors, trypsin 3 inhibitors, trypsin inhibitors, tubulin alpha inhibitors, tubulin beta inhibitors, tumor necrosis factor 14 ligand inhibitors, TYK2 gene inhibitors, type I IL-1 receptor antagonists the therapeutic agent is a tyrosine protein kinase ABL1 inhibitor, a ubiquinol cytochrome C reductase 14 kDa inhibitor, a ubiquitin ligase modulator, an unspecified GPCR agonist, an unspecified cytokine receptor modulator, an unspecified enzyme stimulator, an unspecified gene inhibitor, an unspecified receptor modulator, a urokinase plasminogen activator inhibitor, a vascular cell adhesion protein 1 agonist, a vasodilator, a VEGF ligand inhibitor, a VEGF receptor antagonist, a VEGF-1 receptor antagonist, a VEGF-1 receptor modulator, a VEGF-2 receptor antagonist, a VEGF-3 receptor antagonist, a vimentin inhibitor, a vimentin modulator, a VIP receptor agonist, a viral envelope protein inhibitor, a viral protease inhibitor, a viral protease modulator, a viral protein target modulator, a viral ribonuclease inhibitor, a viral structural protein modulator, a vitamin D3 receptor agonist, an X-linked inhibitor of apoptosis protein inhibitor, a xanthine oxidase inhibitor, or a zonulin inhibitor. ,

[0186] In some embodiments, the solid oral dosage forms of the present disclosure may be administered in combination with Sars-Cov-2 treatments such as parenteral fluids (including dextrose saline and lactated Ringer's solution), nutrients, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin / clavulanate, trimethoprim / sulfamethoxazole, R-327 and cephalosporin antibiotics such as ceftriaxone and cefuroxime), antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal agents, vitamin and mineral supplements (including vitamin K, vitamin D, cholecalciferol, vitamin C and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as dexamethasone, methylprednisolone, prednisone, mometasone, immunomodulatory agents (e.g., interferons), vaccines, and analgesics.

[0187] In some embodiments, the additional therapeutic agent is an Abl tyrosine kinase inhibitor (such as, for example, radotinib or imatinib).

[0188] In some embodiments, the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor, such as ADX-629.

[0189] In some embodiments, the additional therapeutic agent is an adenosine A3 receptor agonist, such as piclidenoson.

[0190] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand, such as adrenomedullin.

[0191] In some embodiments, the additional therapeutic agent is a p38 MAPK+PPAR gamma agonist / insulin sensitizer, such as KIN-001.

[0192] In some embodiments, the additional therapeutic agent is a PPAR alpha agonist, such as DWTC-5101 (fenofibrate choline).

[0193] In some embodiments, the additional therapeutic agent is a cyclophilin inhibitor, such as lencofilstat.

[0194] In some embodiments, the additional therapeutic agent is a p38 MAP kinase inhibitor, such as PRX-201 or Gen-1124.

[0195] In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as cafficlestat.

[0196] In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurosin.

[0197] In some embodiments, the additional therapeutic agent is an annexin A5 stimulator, such as AP-01 or SY-005.

[0198] In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064MM.

[0199] In some embodiments, the additional therapeutic agent is an anticoagulant such as heparin (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparinux.

[0200] In some embodiments, the additional therapeutic agent is an androgen receptor antagonist, such as bicalutamide, enzalutamide, or purselutamide (procultamide).

[0201] In some embodiments, the additional therapeutic agent is an antihypoxic agent, such as trans-sodium crocetinate.

[0202] In some embodiments, the additional therapeutic agent is an antithrombotic agent such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tenecteplase.

[0203] In some embodiments, the additional therapeutic agent is an antihistamine such as chloroperastine or clemastine.

[0204] In some embodiments, the additional therapeutic agent is an apolipoprotein A1 agonist, eg, CER-001.

[0205] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as ethyl icosapentate.

[0206] In some embodiments, the additional therapeutic agent is an axl tyrosine kinase receptor inhibitor, such as bemcentinib.

[0207] In some embodiments, the additional therapeutic agent is a corticosteroid / beta 2 adrenergic receptor agonist such as budesonide plus formoterol fumarate.

[0208] In some embodiments, the additional therapeutic agent is a BET bromodomain inhibitor / APOA1 gene stimulator, e.g., apabetalone.

[0209] In some embodiments, the additional therapeutic agent is a blood coagulation modulating agent, such as lanadelumab.

[0210] In some embodiments, the additional therapeutic agent is a bradykinin B2 receptor antagonist, eg, icatiban.

[0211] In some embodiments, the additional therapeutic agent is an EGFR gene inhibitor / Btk tyrosine kinase inhibitor, e.g., abivertinib.

[0212] In some embodiments, the additional therapeutic agent is a Btk tyrosine kinase inhibitor (such as, for example, ibrutinib or zanubrutinib).

[0213] In some embodiments, the additional therapeutic agent is a calpain-I / II / IX inhibitor, eg, BLD-2660.

[0214] In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as Onternaviz or PPP-003.

[0215] In some embodiments, the additional therapeutic agent is a Ca2+ release-activated Ca2+ channel 1 inhibitor, for example, zegoculactin (CM-4620).

[0216] In some embodiments, the additional therapeutic agent is an ATR inhibitor, such as berzosertib.

[0217] In some embodiments, the additional therapeutic agent is a cadherin-5 modulating agent, such as FX-06.

[0218] In some embodiments, the additional therapeutic agent is a casein kinase II inhibitor, such as silmitasertib.

[0219] In some embodiments, the additional therapeutic agent is a caspase inhibitor, such as emricasan.

[0220] In some embodiments, the additional therapeutic agent is a catalase / superoxide dismutase stimulator, such as MP-1032.

[0221] In some embodiments, the additional therapeutic agent is a CCR2 / CCR5 chemokine antagonist (such as, for example, cenicriviroc).

[0222] In some embodiments, the additional therapeutic agent is a CCR5 chemokine antagonist (such as, for example, maraviroc or leronlimab).

[0223] In some embodiments, the additional therapeutic agent is a CD122 agonist / IL-2 receptor agonist, eg, bempegaldeleukin.

[0224] In some embodiments, the additional therapeutic agent is a CD73 agonist / interferon beta ligand (eg, FP-1201).

[0225] In some embodiments, the additional therapeutic agent is a cholesterol ester transfer protein inhibitor, such as dalcetrapib.

[0226] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease / complement C1s subcomponent inhibitor / myeloperoxidase inhibitor, such as RLS-0071.

[0227] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor / leukotriene BLT receptor antagonist, e.g., nomacopan.

[0228] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor, eg, eculizumab, STSA-1002, zilucoplan.

[0229] In some embodiments, the additional therapeutic agent is a CXCR4 chemokine antagonist, such as plerixafor or motixafortide.

[0230] In some embodiments, the additional therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidyl-prolyl cis-trans isomerase A inhibitor, such as alisporivir.

[0231] In some embodiments, the additional therapeutic agent is a cysteine ​​protease inhibitor, such as SLV-213.

[0232] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, brequinar, RP-7214, or emvodostat.

[0233] In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, eg, Metablok.

[0234] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor / IL-17 antagonist, such as bidofurzimus.

[0235] In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.

[0236] In some embodiments, the additional therapeutic agent is a desoxyribonuclease I stimulator, such as GNR-039 or dornase alfa.

[0237] In some embodiments, the additional therapeutic agent is a NET inhibitor, such as NTR-441.

[0238] In some embodiments, the additional therapeutic agent is a dihydroceramide delta 4 desaturase inhibitor / sphingosine kinase 2 inhibitor, e.g., opaganib.

[0239] In some embodiments, the additional therapeutic agent is a DNA methyltransferase inhibitor, for example, azacytidine.

[0240] In some embodiments, the additional therapeutic agent is an LXR antagonist (such as, for example, larscosterol).

[0241] In some embodiments, the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brenosertib.

[0242] In some embodiments, the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044.

[0243] In some embodiments, the additional therapeutic agent is an elongation factor 1 alpha 2 modulator, eg, plitidepsin.

[0244] In some embodiments, the additional therapeutic agent is a eukaryotic initiation factor 4A-I inhibitor, such as zotatifine.

[0245] In some embodiments, the additional therapeutic agent is an exo-alpha sialidase modulator, such as DAS-181.

[0246] In some embodiments, the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor.

[0247] In some embodiments, the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567.

[0248] In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor / IL-12 receptor antagonist / IL-23 antagonist, e.g., apilimod dimesylate.

[0249] In some embodiments, the additional therapeutic agent is a GABA A receptor modulator, such as brexanolone.

[0250] In some embodiments, the additional therapeutic agent is a glucocorticoid receptor agonist, eg, ciclesonide, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005.

[0251] In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim.

[0252] In some embodiments, the additional therapeutic agent is a GPCR agonist, such as esveraprost sodium.

[0253] In some embodiments, the additional therapeutic agent is a Griffithin modulator, eg, Q-Griffithin.

[0254] In some embodiments, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast.

[0255] In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, or levocetirizine dihydrochloride.

[0256] In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine.

[0257] In some embodiments, the additional therapeutic agent is a heat shock protein stimulator such as BGP-15 / insulin sensitizer / PARP inhibitor.

[0258] In some embodiments, the additional therapeutic agent is a histone inhibitor, such as STC-3141.

[0259] In some embodiments, the additional therapeutic agent is a histone deacetylase-6 inhibitor, eg, CKD-506.

[0260] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase-2 inhibitor, eg, desidustat.

[0261] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase inhibitor (such as, for example, vadadustat).

[0262] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist (such as, for example, reparixin).

[0263] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist, such as CYT-107.

[0264] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist / interleukin-7 ligand, eg, efyneptakine alfa.

[0265] In some embodiments, the additional therapeutic agent is an IL-22 agonist, such as efmarodocoquin alfa.

[0266] In some embodiments, the additional therapeutic agent is an IL-22 agonist / interleukin 22 ligand, such as F-652.

[0267] In some embodiments, the additional therapeutic agent targets IL-33 (such as, for example, tozorakimab).

[0268] In some embodiments, the additional therapeutic agent is an IL-15 agonist, such as nogapenkin alfa.

[0269] In some embodiments, the additional therapeutic agent is an integrin alpha-V / beta-1 antagonist / integrin alpha-V / beta-6 antagonist, such as bexotegrast.

[0270] In some embodiments, the additional therapeutic agent is an interferon alpha-2 ligand, eg, interferon alpha-2b or virafin.

[0271] In some embodiments, the additional therapeutic agent is an interferon beta ligand, eg, interferon beta-1a follow-on biologic, interferon beta-1b, or SNG-001.

[0272] In some embodiments, the additional therapeutic agent is an interferon receptor modulator, such as pegylated interferon lambda-1a.

[0273] In some embodiments, the additional therapeutic agent is an interleukin-2 ligand, eg, aldesleukin.

[0274] In some embodiments, the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, eg, dimlobicertib.

[0275] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, jactinib, tofacitinib, or nedulcitinib (TD-0903).

[0276] In some embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor, eg, alberestat.

[0277] In some embodiments, the additional therapeutic agent is a pulmonary surfactant-associated protein D modulator, eg, AT-100.

[0278] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, e.g., donidalorsen.

[0279] In some embodiments, the additional therapeutic agent is a lysine-specific histone demethylase 1 / MAO B inhibitor, such as bafidemstat.

[0280] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease inhibitor, e.g., conestat alfa.

[0281] In some embodiments, the additional therapeutic agent is a maximum K potassium channel inhibitor, such as ENA-001.

[0282] In some embodiments, the additional therapeutic agent is a MEK protein kinase inhibitor (such as, for example, zapnometinib).

[0283] In some embodiments, the additional therapeutic agent is a MEK-1 protein kinase inhibitor / Ras gene inhibitor, eg, antroquinonol.

[0284] In some embodiments, the additional therapeutic agent is a melanocortin MC1 receptor agonist, eg, PL-8177.

[0285] In some embodiments, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, for example, resomeragon acetate.

[0286] In some embodiments, the additional therapeutic agent is a matrix metalloproteinase-12 inhibitor, eg, FP-025.

[0287] In some embodiments, the additional therapeutic agent is a NACHT LRR PYD domain protein 3 inhibitor, such as dapanstril, DFV-890, or ZYIL-1.

[0288] In some embodiments, the additional therapeutic agent is an NADPH oxidase inhibitor, for example, isquinaxib.

[0289] In some embodiments, the additional therapeutic agent is a neuropilin 2 modulator, such as efzofitimod.

[0290] In some embodiments, the additional therapeutic agent is an NK1 receptor antagonist, such as aprepitant or tradipitant.

[0291] In some embodiments, the additional therapeutic agent is an NMDA receptor antagonist, such as translocetin or ifenprodil.

[0292] In some embodiments, the additional therapeutic agent is a nuclear factor kappa B inhibitor / p38 MAP kinase inhibitor (such as, for example, Zenuzolac).

[0293] In some embodiments, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine.

[0294] In some embodiments, the additional therapeutic agent is an opioid receptor sigma antagonist 1, such as MR-309.

[0295] In some embodiments, the additional therapeutic agent is a PGD2 antagonist, e.g., asapiprant.

[0296] In some embodiments, the additional therapeutic agent is a PDGF receptor antagonist / TGFβ receptor antagonist / p38 MAP kinase inhibitor (such as, for example, deupirfenidone).

[0297] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as varespladib methyl.

[0298] In some embodiments, the additional therapeutic agent is a phosphoinositide 3-kinase inhibitor / mTOR complex inhibitor, such as ductolisib.

[0299] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, such as sirolimus.

[0300] In some embodiments, the additional therapeutic agent is a phosphoinositide-3 kinase delta / gamma inhibitor (such as, for example, duvelisib).

[0301] In some embodiments, the additional therapeutic agent is a plasminogen activator inhibitor-1 inhibitor, such as TM-5614.

[0302] In some embodiments, the additional therapeutic agent is a protein tyrosine phosphatase beta inhibitor, e.g., razuprotafib.

[0303] In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor (such as, for example, DNL-758 or SIR-0365).

[0304] In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as obefagimod.

[0305] In some embodiments, the additional therapeutic agent is an S-phase kinase-associated protein 2 inhibitor (such as, for example, niclosamide, SCAI-502, or DWRX-2003).

[0306] In some embodiments, the additional therapeutic agent is a signal transducer CD24 stimulator, such as EXO-CD24.

[0307] In some embodiments, the additional therapeutic agent is a sodium glucose transporter-2 inhibitor, such as dapagliflozin propanediol.

[0308] In some embodiments, the additional therapeutic agent is a calcium channel stimulator, such as solnatide.

[0309] In some embodiments, the additional therapeutic agent is a sphingosine-1-phosphate receptor-1 agonist / sphingosine-1-phosphate receptor-5 agonist, such as ozanimod.

[0310] In some embodiments, the additional therapeutic agent is a nonsteroidal anti-inflammatory drug, such as Ampion.

[0311] In some embodiments, the additional therapeutic agent is a superoxide dismutase stimulator, such as avasopasem manganese.

[0312] In some embodiments, the additional therapeutic agent is a Syk tyrosine kinase inhibitor, such as fostamacitinib sodium hydrate.

[0313] In some embodiments, the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist, such as AV-001.

[0314] In some embodiments, the additional therapeutic agent is a TGFB2 gene inhibitor, e.g., travedersen.

[0315] In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.

[0316] In some embodiments, the additional therapeutic agent is a TLR-3 agonist, such as lintatolimod.

[0317] In some embodiments, the additional therapeutic agent is a TLR-4 antagonist, such as ApTLR-4FT, EB-05, or erythrolan.

[0318] In some embodiments, the additional therapeutic agent is a TLR-7 / 8 antagonist (such as, for example, empatran).

[0319] In some embodiments, the additional therapeutic agent is a TLR-2 / 6 agonist, such as INNA-051.

[0320] In some embodiments, the additional therapeutic agent is a TLR-7 agonist, such as PRTX-007 or APR-002.

[0321] In some embodiments, the additional therapeutic agent is a TLR agonist such as, for example, PUL-042.

[0322] In some embodiments, the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.

[0323] In some embodiments, the additional therapeutic agent is a TLR-2 / 4 antagonist, such as VB-201.

[0324] In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor, such as pezipanelmin.

[0325] In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anakinra.

[0326] In some embodiments, the additional therapeutic agent is a TREM receptor 1 antagonist, eg, nangibotide.

[0327] In some embodiments, the additional therapeutic agent is a trypsin inhibitor, such as urinastatin.

[0328] In some embodiments, the additional therapeutic agent is a tubulin inhibitor such as sabizabrin, CCI-001, PCNT-13, CR-42-24, albendazole, entasobrin, SAR-132885, or ON-24160.

[0329] In some embodiments, the additional therapeutic agent is a VIP receptor agonist, such as aviptadil.

[0330] In some embodiments, the additional therapeutic agent is a xanthine oxidase inhibitor, such as oxypurinol.

[0331] In some embodiments, the additional therapeutic agent is a vasodilator, e.g., iloprost, epoprostenol (VentaProst), zavegepant, TXA-127, USB-002, ambrisentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamole.

[0332] In some embodiments, the additional therapeutic agent is a vitamin D3 receptor agonist, such as cholecalciferol.

[0333] In some embodiments, the additional therapeutic agent is a zonulin inhibitor, such as larazotide acetate.

[0334] In some embodiments, the additional therapeutic agent is a synthetic retinoid derivative, such as fenretinide.

[0335] In some embodiments, the additional therapeutic agent is a glucose metabolism inhibitor (such as, for example, WP-1122 or WP-1096).

[0336] In some embodiments, the additional therapeutic agent is adalimumab, AT-H201, 2-deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer, AZD-1656, belapectin, vitepiramicin, bucillamine, budesonide, CNM-AgZn-17, codevir, CT-38, danicopan, didodecylmethotrexate, DW -2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, Genistein, GLS-1200, hzVSF-v13, Imidazolyl ethanamidopentanedioic acid, IMM-101, MAS-825, MRG-001, Nasitrol, Nylexa, Orbelemtinib, OP-101, OPN-019, Orynotide rhesus theta defensin-1, pyronaridine plus artesunate, dapsone, RPH-104, sodium pyruvate, sulfoladex, tafenoquine, TB-006, telasevec, Tempol, TL-895, thimesol, trimodulin, XC-221, XC-7, duncemtinib, metformin glicinate, lucinactant, EOM-613, mosdipimode, ivermectin, leflunomide, ibudilast, RBT-9, raloxifene, prothion, gemcabene, or idronoxyl.

[0337] In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as AK-119.

[0338] In some embodiments, the additional therapeutic agent is a CD95 protein fusion, such as asnercept.

[0339] In some embodiments, the additional therapeutic agent is a complement factor C2 modulator, eg, ARGX-117.

[0340] In some embodiments, the additional therapeutic agent is a complement C3 inhibitor, such as AMY-101 or NGM-621.

[0341] In some embodiments, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor (such as, for example, EB-06).

[0342] In some embodiments, the additional therapeutic agent is a cytotoxic T-lymphocyte protein-4 fusion protein, such as abatacept.

[0343] In some embodiments, the additional therapeutic agent is an anti- S. aureus antibody (e.g., tosatocumab, etc.).

[0344] In some embodiments, the additional therapeutic agent is an anti-LPS antibody, such as IMM-124-E.

[0345] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand inhibitor (such as, for example, enivalcimab).

[0346] In some embodiments, the additional therapeutic agent is a basigin inhibitor, such as meplasmab.

[0347] In some embodiments, the additional therapeutic agent is a CD3 antagonist, such as foralaumab.

[0348] In some embodiments, the additional therapeutic agent is a connective tissue growth factor ligand inhibitor (e.g., PRS-220, pamrevlumab, etc.).

[0349] In some embodiments, the additional therapeutic agent is a complement factor C5a inhibitor, such as BDB-1 or vilobelimab.

[0350] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor, e.g., ravulizumab.

[0351] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease-2 inhibitor (such as, for example, narsoplimab).

[0352] In some embodiments, the additional therapeutic agent is a GM-CSF modulator such as STSA-1005, gimcilumab, namilumab, prommallimab, otilimab, or lenzilumab.

[0353] In some embodiments, the additional therapeutic agent is a heat shock protein inhibitor / IL-6 receptor antagonist (such as, for example, siltuximab).

[0354] In some embodiments, the additional therapeutic agent is an IL-6 receptor antagonist, such as clazakizumab, revilimab, olokizumab, tocilizumab, or sirukumab.

[0355] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist (such as, for example, BMS-986253).

[0356] In some embodiments, the additional therapeutic agent is an interleukin-1 beta ligand inhibitor, such as canakinumab.

[0357] In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab.

[0358] In some embodiments, the additional therapeutic agent is an anti-ILT7 antibody, such as daxzilimab.

[0359] In some embodiments, the additional therapeutic agent is a monocyte differentiation antigen CD14 inhibitor, such as atibuclimab.

[0360] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as lanadelumab.

[0361] In some embodiments, the additional therapeutic agent is a platelet glycoprotein VI inhibitor (such as, for example, glenzocimab).

[0362] In some embodiments, the additional therapeutic agent is a T-cell differentiation antigen CD6 inhibitor, such as itolizumab.

[0363] In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor / TNF binder (such as, for example, infliximab).

[0364] In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as AVTX-002.

[0365] In some embodiments, the additional therapeutic agent is IMC-2 (valacyclovir plus celecoxib) or AXA-1125.

[0366] In some embodiments, the additional therapeutic agent is COVID-HIG.

[0367] In some embodiments, the solid dosage forms of the present disclosure are co-administered with one or more agents useful in the treatment and / or prevention of COVID-19.

[0368] Non-limiting examples of such agents include corticosteroids, such as dexamethasone, hydrocortisone, methylprednisolone, or prednisone; interleukin-6 (IL-6) receptor blockers, such as tocilizumab or sarilumab; Janus kinase (JAK) inhibitors, such as baricitinib, ruxolitinib, or tofacitinib; and antiviral agents, such as molnupiravir, sotrovimab, or remdesivir.

[0369] In further embodiments, the solid oral dosage forms of the present disclosure are co-administered with two or more drugs useful for the treatment and / or prevention of COVID-19, including, but not limited to, nilmatrervir and ritonavir, casirivimab and imdevimab, or ruxolitinib and tofacitinib.

[0370] In some embodiments, the additional therapeutic agent comprises an antiviral agent. In some embodiments, the antiviral agent is an entry inhibitor. In some embodiments, the antiviral agent is a protease inhibitor. In some embodiments, the antiviral agent is an RNA polymerase inhibitor. In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0371] In some embodiments, the antiviral agent is an angiotensin-converting enzyme 2 inhibitor, an angiotensin-converting enzyme 2 modulator, an angiotensin-converting enzyme 2 stimulator, an angiotensin II AT-2 receptor agonist, an angiotensin II AT-2 receptor antagonist, an angiotensin II receptor modulator, a coronavirus nucleoprotein modulator, a coronavirus small envelope protein modulator, a coronavirus spike glycoprotein inhibitor, a coronavirus spike glycoprotein modulator, a SARS-CoV-2 envelope small membrane protein inhibitor, a SARS-CoV-2 envelope small membrane protein modulator, a SARS-CoV-2 MPro inhibitors, SARS-CoV-2 nonstructural protein 8 modulators, SARS-CoV-2 nucleoprotein inhibitors, SARS-CoV-2 nucleoprotein modulators, SARS-CoV-2 protein 3a inhibitors, SARS-CoV-2 replicase polyprotein 1a inhibitors, SARS-CoV-2 replicase polyprotein 1a modulators, SARS-CoV-2 replicase polyprotein 1ab inhibitors, SARS-CoV-2 replicase polyprotein 1ab modulators, SARS-CoV-2 spike glycoprotein inhibitors, SARS-CoV-2 spike glycoprotein modulators, SARS-CoV-2 structural glycoprotein modulators, papain inhibitors, protease inhibitors, protease modulators, RNA polymerase inhibitors, RNA polymerase modulators, RNA-dependent RNA polymerase (RdRp) inhibitors, SARS coronavirus 3C protease-like inhibitors, SARS-CoV-2 The inhibitor is selected from an nsp14 methyltransferase enzyme inhibitor, a 3CLpro / Mpro inhibitor, a serine protease inhibitor, a transmembrane serine protease 2 inhibitor, a transmembrane serine protease 2 modulator, a viral envelope protein inhibitor, a viral protease inhibitor, a viral protease modulator, a viral protein target modulator, a viral ribonuclease inhibitor, and a viral structural protein modulator.

[0372] In some embodiments, the additional therapeutic agent is an entry inhibitor, e.g., in some embodiments, the additional therapeutic agent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor.

[0373] In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 inhibitor, eg, SBK-001.

[0374] In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 modulator, such as Numifil or JN-2019.

[0375] In some embodiments, the additional therapeutic agent is an entry inhibitor, such as MU-UNMC-1.

[0376] In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 stimulator, such as alnasidase alfa.

[0377] In some embodiments, the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, eg, VP-01.

[0378] In some embodiments, the additional therapeutic agent is an ACE II receptor antagonist, eg, DX-600.

[0379] In some embodiments, the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127.

[0380] In some embodiments, the additional therapeutic agent is a transmembrane serine protease 2 modulator, eg, BC-201.

[0381] In some embodiments, the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004.

[0382] In some embodiments, the additional therapeutic agent is an RNAi agent, such as ARO-COV or SNS-812.

[0383] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, an inactivated vaccine (i.e., an inactivated SARS-CoV-2 vaccine), a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, a viral vector vaccine, a cellular vaccine, or a dendritic cell vaccine.

[0384] In some embodiments, the additional therapeutic agent is selected from the group consisting of Tojinameran, NVX-CoV2373, Elasomeran, KD-414, Ad26.COV2-S, Bakhiszebria, SCB-2019, AKS-452, VLA-2001, HDT-301, S-268019, MVC-COV1901, mRNA-1273.214, mRNA-1273.213, mRNA-1273.222, NVX-CoV2515, Covaxin, BBIBP-CorV, GBP-510, mRNA-127 3.351+mRNA-1273.617 (SARS-CoV-2 multivalent mRNA vaccine, COVID-19), Ad5-nCoV, Omicron-based COVID-19 vaccine (mRNA vaccine, COVID-19), mRNA-1073, mRNA-1273.214, mRNA-1230, mRNA-1283, Omicron-based COVID-19 vaccine, SARS-CoV-2 subunit recombinant, recombinant vaccine, etc., Sputnik M, ZyCoV-D, COVID-19 XWG-03, mRNA-1273.529, mRNA-1010, CoronaVac, AZD-2816, Sputnik V, Inactivated SARS-CoV-2 Vaccine (Verocell, COVID-19), DS-5670, PHH-1V, INO-4800, UB-612, Coronavirus Vaccine (Whole Virion, Inactivated / Purified), ReCOV, MT-2766, ARCT-154, SP-0253, CORBEVAX, mRNA-1273.211, ZF-2001, Sputnik Light, Recombinant Protein Vaccine (COVID-19 / SARS-CoV-2 Infection), VSV Vectored Vaccine Targeting Spike Glycoprotein (COVID-19), VLA-2101, GRT-R912, GRAd-COV2, VPM-1002, COViran Barekat, Ad5-nCoV-IH, ARCoV, Covax-19, Recombinant SARS-CoV-2 Vaccine (Protein Subunit / CHO Cells, COVID-19), BBV-154, RAZI Cov Pars, COVID-19 Vaccine (Inactivated / Vero Cells / Intramuscular, SARS-CoV-2 Infection), COVID-19 Vaccine (Inactivated, Vero Cells / Intramuscular), BNT-162b2s01, BNT-162b4, BNT-162b5, BNT-162b2 Omi, BNT-162b2 bivalent, CIGB-66, mRNA-1273.617, Mycobacterium w, ERUCOV-VAC, AG-0301-COVID19, fakhravac, AV-COVID-19, peptide vaccine (COVID-19), Nanocovax, SARS-CoV-2 vaccine (inactivated / Vero cell / intramuscular, COVID-19), QAZCOVID-IN, S-875670 nasal vaccine, VTP-500, or BNT162b5.

[0385] In some embodiments, the additional therapeutic agent is a protease inhibitor. For example, in some embodiments, the additional therapeutic agent is a 3C-like cysteine ​​protease inhibitor (3CL (also called main protease, M)), a papain-like protease inhibitor (PL), a serine protease inhibitor, or a transmembrane serine protease 2 inhibitor (TMPRSS2).

[0386] In some embodiments, the additional therapeutic agent is a 3CLpro / Mpro inhibitor such as CDI-873, GC-373, GC-376, PBI-0451, UCI-1, voftrervir (FB-2001, DC-402234), DC-402267, GDI-4405, RAY-1216, MPI-8, SH-879, SH-580, EDP-235, VV-993, CDI-988, MI-30, nilmatrervir, ensitrervir, ASC-11, EDDC-2214, SIM-0417, CDI-45205, COR-803, ALG-097111, TJC-642, CVD-0013943, eravacycline, cynarin, or prexasertib.

[0387] In some embodiments, the additional therapeutic agent is a papain-like protease inhibitor (PLpro), e.g., SBFM-PL4 or GRL-0617.

[0388] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp13 inhibitor, such as EIS-4363.

[0389] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp14 inhibitor, such as TO-507.

[0390] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 spike (S) and a protease modulator, e.g., ENU-200.

[0391] In some embodiments, the additional therapeutic agent is a protease inhibitor, such as ALG-097558 or MRX-18.

[0392] In some embodiments, the additional therapeutic agent is a serine protease inhibitor, for example, upamostat, nafamostat, camostat mesylate, nafamostat mesylate, or camstat.

[0393] In some embodiments, the additional therapeutic agent is a 3CLpro / transmembrane serine protease 2 inhibitor, e.g., SNB-01 (pentalandil) or SNB-02.

[0394] In some embodiments, the additional therapeutic agent is a Pan-Corona, Cov-X, or a viral protease inhibitor such as bepridil.

[0395] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, e.g., in some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor or an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0396] In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor, such as remdesivir, NV-CoV-2-R, NV-CoV-1 encapsulated remdesivir, GS-621763, DEP remdesivir, ATV-006, VV-116, LGN-20, CMX-521, and compounds disclosed in WO2022142477, WO2021213288, WO2022047065.

[0397] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, such as molnupiravir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galidesivir.

[0398] In some embodiments, the additional therapeutic agent is a viral entry inhibitor, such as brilacidin.

[0399] In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, e.g., an antibody that binds to SARS or MERS.

[0400] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an antibody against SARS-CoV-2, a neutralizing nanobody, an antibody targeting the SARS-CoV-2 spike protein, a fusion protein, a multispecific antibody, and an antibody capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibody).

[0401] In some embodiments, the additional therapeutic agent is an antibody that targets a specific site on ACE2. In some embodiments, the additional therapeutic agent is a polypeptide that targets the SARS-CoV-2 spike protein (S-protein).

[0402] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 virus antibody.

[0403] In some embodiments, the antibody is ABBV-47D11, COVI-GUARD (STI-1499), C144-LS+C135-LS, DXP-604, JMB-2002, LY-CovMab, bamlanivimab (LY-CoV555), GIGA-2050, IBI-314, S309, SAB-185, etesevimab (CB6), COR-101, JS016, VNAR, VIR-7832 and / or sotrovimab (VIR-7831), casirivimab+imdevimab (REGN-COV2 or REGN 10933+RGN 10987), BAT2020, BAT2019, 47D11, YBSW-015, or PA-001.

[0404] In some embodiments, the additional therapeutic agent is STI-9199 (COVI-SHIELD), STI-9167, or AR-701 (AR-703 and AR-720).

[0405] In some embodiments, the additional therapeutic agent is BRII-196, BRII-198, ADG-10, azintrevimab (ADG-20), ABP-300, BA-7208, BI-767551, BHV-1200, CT-P63, JS-026, sotrovimab (GSK-4182136), tixagevimab + silgavimab (AZD-7442), regdanvimab, SAB-301, AOD-01, putavimab (COVI-AMG), 9MW-3311 (MW-33), DXP-593, BSVEQAb, anti-SARS-CoV-2 IgY, COVID-EIG, CSL-760, F-61, REGN-3048-3051, SARS-CoV-2 monoclonal antibody (COVID-19, ADM-03820), enobuzimab (HFB-30132A), INM-005, SCTA01, TY-027, XAV-19, amvalvimab + romursevimab, SCTA-01, bebuterovimab, veldavimab, IBI-O123, and IGM-6268. FYB-207, FS-2101, RBT-0813, REGN-14256, REGN-14284, SPKM-001, XVR-011, TB202-3, TB181-36, TB339 -031, LMN-301, LQ-050, COVAB-36, MAD-0004J08, STI-2099, TATX-03, TZLS-501, ZCB-11 or ACV-200-17.

[0406] In some embodiments, the additional therapeutic agent is an engineered ACE-2-IgG1-Fc fusion protein that targets the SARS-Cov-2 RBD, such as EU-129, a bivalent ACE2-IgG Fc null fusion protein (SI-F019).

[0407] In some embodiments, the additional therapeutic agent is an ACE2-Fc receptor fusion protein, such as HLX-71.

[0408] In some embodiments, the additional therapeutic agent is ensobibep.

[0409] In some embodiments, the additional therapeutic agent is SYZJ-001.

[0410] In some embodiments, the additional therapeutic agent is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 plus ritonavir) or lopinavir plus ritonavir.

[0411] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor, such as elsulfavirine.

[0412] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as azuvudine.

[0413] In some embodiments, the additional therapeutic agent is Abbv-990, BAT-2022, NED-260, ALG-097431, bardoxolone, delcetravir, ESFAM-289, ENOB-CV-01, ENOB-CV-11, EIS-10700, Beta-521, SIM-0417, molnupiravir, Pan-Corona, Tollovir, nilmatorivir + ritonavir (Paxlovid®), favipiravir, GC-376, upamostat, LeSoleil-01, LeSoleil-02+, benfovir, VV-116 , VV-993, SNB-01, EDP-235, Cov-X, Encitrervir, MPI-8, Mastinib, ALG-097558, ASC-11, PBI-0451, Nafamostat, Nafamostat Mesylate, CDI-45205, COR-803, ALG-097111, BC-201, SH-879, CDI-873, CDI-988, Remdesivir, NV-CoV-2-R, NV-CoV-1 Encapsulated Remdesivir, NA-831 + Remdesivir, DEP Remdesivir, GS-621763, GLS-5310, Bemnifosbuvir, Q LS-1128, ASC-10, SBFM-PL4, camstat mesylate, UCI-1, FB-2001 (DC-402234), ebselen, SH-580, LeSoleil-01, LeSoleil-02+, MRX-18, MXB-9, MI-09, MI-30, SNB-02, SJP-002C, TJC-642, ENU-200, CVD-0013943, bepridil, MXB-004, eravacycline, GRL-0617, camostat, GC-373, nitazoxanide, cynarin, prexasertib, RAY-1216, SACT- COVID-19, MP-18, EIDD-1931, EDDC-2214, nitric oxide, apabetalone, AnQlar, SBK-001, LQ-050, CG-SpikeDown, vanlanivimab, HLX-71, HT-002, HY-209, HY-3000, FYB-207, Ensovibep, SYZJ-001, EU-129, Numifil, JN-2019, AR-701, Bostecil, PLM-402, PJS-539, CTB-ACE2, TB181-36, TB202-3, ABP-300, XVR-011, MSP-008-22,MU-UNMC-1, MU-UNMC-2, alnasidase alfa, VP-01, TRV-027, DX-600, TXA-127, NVX-CoV2515, riamirovir, tosinameran, elasomeran, Ad5-nCoV, BBIBP-CorV, CoronaVac, MVC-COV1901, NVX-CoV2373, sotrovimab, Sputnik V, TEE-001, Tyme-19, Vaxzevria, ZF-2001, or ZyCoV-D.

[0414] The solid oral dosage forms disclosed herein can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. The combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0415] Co-administration of a solid oral form disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a solid oral dosage form disclosed herein with one or more other active therapeutic agents such that therapeutically effective amounts of both the compound of Formula I and the one or more other active therapeutic agents are present in the patient's body.

[0416] Co-administration includes administration of a unit dose of a solid oral dosage form disclosed herein before or after administration of a unit dose of one or more other active therapeutic agents, e.g., administration of a solid oral dosage form disclosed herein within seconds, minutes, or hours of administration of one or more other active therapeutic agents. For example, a unit dose of a solid oral dosage form disclosed herein can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a solid oral dosage form disclosed herein. In some cases, it may be desirable to administer a unit dose of a solid oral dosage form disclosed herein first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of a solid oral dosage form disclosed herein.

[0417] Combination therapy can provide "synergistic" and "synergistic" effects, i.e., effects achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by separate tablets, pills, capsules, or different injections in separate syringes. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect indicates an antiviral effect that is greater than the expected purely additive effect of the individual compounds of the combination. Overview

[0418] The term "pharmaceutically acceptable" with respect to a substance refers to a substance that is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable" with respect to an excipient includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary animals.

[0419] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses (or can be converted into a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion, or a coordination compound with an organic base such as diethanolamine, triethanolamine, N-methylglucamine, and the like. This definition also includes ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are incorporated herein by reference.

[0420] The term "comprise" and its variations, such as "comprises" and "comprising", should be interpreted in an open and inclusive sense, i.e., "including, but not limited to".

[0421] The term "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). For example, in certain non-limiting examples, the term "about" with respect to a numerical value x refers to x ± 5% or x ± 1%.

[0422] "% w / w" or "wt%" refers to the weight of a component as a percentage of the total weight of the dosage form in which the component is present, e.g., a composition comprising "5% w / w of X" refers to a composition in which the weight of component X is 5% of the total weight of the composition. Unless otherwise specified, if the dosage form is coated, it should be understood that references to weight % are calculated with respect to the tablet core weight. When weight % ranges are given for different components of a composition, it will be understood that the total weight % of the components add up to 100%. In particular, when the upper limits of each range, when added together, exceed 100%, it will be understood that the actual amounts of components present in the composition will be selected so that the total weight % does not add up to 100%.

[0423] The "tablet core weight" calculated herein is the sum of (i) the compound of formula I, (ii) the filler, (iii) the disintegrant, and (iv) the lubricant. The core tablet weight does not include the weight of the film coating.

[0424] The "tablet weight" calculated herein is the sum of (i) the compound of formula I, (ii) the filler, (iii) the disintegrant, (iv) the lubricant, and (v) the film coating.

[0425] For example, for a tablet containing 100 mg of the compound of formula I, 89 mg of filler, 8 mg of disintegrant, 3 mg of lubricant, and 6 mg of film coat: The tablet core weight is 100 mg (weight of Formula I) + 89 mg (weight of filler) + 8 mg (weight of disintegrant) + 3 mg (weight of lubricant) = 200 mg. The tablet weight is 100 mg (weight of Formula I) + 89 mg (weight of filler) + 8 mg (weight of disintegrant) + 3 mg (weight of lubricant) + 6 mg (amount of film coat) = 206 mg. The wt% of the compound of formula I is 100 mg (weight of formula I) / 200 mg (weight of tablet core) = 50%. The wt% of filler is 89 mg (weight of filler) / 200 mg (weight of tablet core) = 44.5%. The wt% of the disintegrant is 8 mg (weight of disintegrant) / 200 mg (weight of tablet core) = 4%. The wt% of the lubricant is 3 mg (weight of lubricant) / 200 mg (weight of tablet core) = 1.5%. The wt% of the film coat is 6 mg (weight of lubricant) / 200 mg (weight of tablet core) = 3%. [Example]

[0426] Example 1: Tablets of the compound of formula I Tablets of the compound of Formula I to be evaluated were manufactured using a dry granulation / tablet compression / film coating process train. To minimize exposure of Formula I to moisture during the granulation process, dry granulation by roller compaction was selected as a means of combining Formula I with inert excipients. The overall manufacturing process consisted of co-blending and lubrication of Formula I with intragranular excipients, followed by roller compaction and milling. The resulting granules of Formula I were then blended and lubricated with extragranular magnesium stearate to produce the final powder blend of Formula I, which was compressed into core tablets and subsequently film-coated (using Opadry® II or QX).

[0427] Example 2: Manufacturing Process The manufacturing / packaging procedure for tablets of Formula I is divided into four unit processes: 1. Mixing the drug substance of formula I with intragranular excipients, dry granulating, milling and blending with extragranular magnesium stearate to obtain the final powder blend of formula I; 2. Compress the tablet to obtain the tablet core; 3. Film-coating the tablets to obtain film-coated tablets; and 4. Packaging.

[0428] The manufacturing process steps for producing the final drug product are detailed below. Final Powder Blend of Formula I (Partitioning, Blending, Dry Granulation, Milling, Final Blending) 1. Weigh out the drug substance of Formula I and excipients (microcrystalline cellulose and crospovidone). Adjust the weight of the drug substance of Formula I based on the drug content factor (DCF) and simultaneously adjust the weight of the microcrystalline cellulose. 2. Blend the Formula I drug substance, microcrystalline cellulose, and crospovidone in a tumble blender. 3. Add the intragranular portion of magnesium stearate to a tumble blender and blend. 4. The resulting blend is dry granulated using a roller compactor. 5. Blend the extragranular portion of magnesium stearate. Tableting 6. Compress the final powder blend of Formula I to a target total tablet weight of 200 mg at an appropriate main compression force to achieve a target hardness of 7 kP (range: 3-15 kP), 700 mg at an appropriate main compression force to achieve a target hardness of 16 kP (range: 8-30 kP), or 1000 mg at an appropriate main compression force to achieve a target hardness of 21 kP (range: 10-40 kP). See the table below for formulation hardness. [Table 26] Film Coating 7. Prepare a suspension of Opadry® II or QX. Film coat the tablet cores to achieve a target tablet weight gain of 3% (range 2-4%). Example 3: Stability of tablets of Formula I

[0429] Five film-coated tablets were packaged in a 45 cc white HDPE bottle containing a polyester coil. Each bottle was capped using a white, continuous-thread, child-resistant polypropylene crew cap with an induction-sealed aluminum face liner. Two stability studies were then performed: one at 30°C and 75% relative humidity (RH) for 9 months and one at 40°C and 75% relative humidity (RH) for 6 months.

[0430] The water content of the initial formulation and the formulations after the stability experiments was measured by Karl Fischer titration. The initial impurity content, assay impurities, and impurities after each stability experiment were measured by UPLC. The dissolution percentage at 45 minutes was measured for both the initial formulation and the formulations after the stability experiments using a Type II dissolution apparatus at 37°C.

[0431] The results of the stability studies are summarized in Figure 2. It can be seen that all of the formulations tested exhibited excellent stability and dissolution both before and after the stability study. Trace amounts of degradation were observed over the time course of the stability studies. The dissolution results demonstrate that the release of Formula I was ≧94% at 45 minutes for all experiments.

[0432] The following formulations / lots were tested: [Table 27] IG: intragranular EG: extragranular MCC: Microcrystalline cellulose [Table 28] IG: intragranular EG: extragranular MCC: Microcrystalline cellulose [Table 29] IG: intragranular EG: extragranular MCC: Microcrystalline cellulose [Table 30] IG: intragranular EG: extragranular MCC: Microcrystalline cellulose

[0433] As shown in Figure 2, three of the impurities found in the tested formulations were compound GS 441524 (the parent nucleoside of the compound of Formula I) and compounds A and B. The structures of these compounds are shown below: [ka] Example 4: Stability of tablets of Formula I

[0434] The stability of tablets of Formula I was examined when stored in 6 mil Aclar, non-dried bottles, and open conditions. Stability studies were conducted at 40°C and 75% relative humidity (RH) for 1 or 3 months.

[0435] The appearance of the tablets was recorded both at the beginning and end of the stability experiment. The water content of the initial formulation and the formulations after the stability experiment was measured by Karl Fischer titration. The initial impurity content and impurities after each stability experiment were measured by UPLC. The dissolution percentage at 45 minutes for both the initial formulation and the formulations after the stability experiment was measured as follows: Formulation F5: Dissolution was measured at 75 rpm using a Type 2 apparatus, 900 mL of 20 mM sodium acetate (pH 4.5) containing 0.5% TWEEN® 20. Dissolution was measured at a temperature of 37°C. Formulation F6: Dissolution was measured at 75 rpm using a Type 2 apparatus, 1000 mL of 25 mM sodium acetate (pH 4.5) containing 0.25% SLS. Dissolution was measured at a temperature of 37°C. Formulation F7: Dissolution was measured at 75 rpm using a Type 2 apparatus, 1000 mL of 20 mM sodium acetate (pH 4.5) containing 0.5% TWEEN® 20. Dissolution was measured at a temperature of 37°C.

[0436] The results of the stability experiments are summarized in Figure 3. As can be seen, the Formula I tablets are chemically and physically stable when stored in 6 mil Aclar, non-dried bottles, and open conditions where less than 0.1% degradation is observed. Equilibration to approximately 4.5% moisture content is observed at 75% RH. Dissolution results demonstrate that the Formula I tablets release completely (>97%) by 45 minutes.

[0437] The following formulations / lots were tested: [Table 31] IG: intragranular EG: extragranular MCC: Microcrystalline cellulose [Table 32] EG: extragranular MCC: Microcrystalline cellulose [Table 33] EG: extragranular MCC: Microcrystalline cellulose

[0438] As shown in Figure 3, three of the impurities found in the tested formulations were compound GS 441524 and compounds C and D. The structures of these compounds are shown below: [ka] Example 5: Stability of Formulation F8

[0439] The stability of Formulation F8 was examined when stored at elevated temperatures without a desiccant. The results of the stability experiment are shown in Figures 4-6. Two of the impurities found in the examined formulation were GS-441524 and Compound D. [Table 34] EG: extragranular MCC: Microcrystalline cellulose

[0440] All publications, patents, and patent applications are incorporated herein by reference in their entirety, as if individually incorporated by reference. The invention has been described with reference to various specific preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the disclosure.

Claims

1. 1. A pharmaceutical formulation comprising: (i) a compound represented by formula I or a pharmaceutically acceptable salt thereof; 【Transformation 7】 (ii) fillers; (iii) a disintegrant; and (iv) lubricant Including; A pharmaceutical formulation wherein said compound of formula I is present in an amount of about 40 wt% to about 70 wt%.

2. (i) said filler in an amount of about 20 wt % to about 60 wt %; (ii) the disintegrant in an amount of about 1 wt % to about 10 wt %; and (iii) said lubricant in an amount of about 0.5 wt % to about 5 wt % 2. The pharmaceutical formulation of claim 1, comprising:

3. (i) said filler in an amount of about 40 wt % to about 50 wt %; (ii) the disintegrant in an amount of about 1 wt % to about 10 wt %; and (iii) said lubricant in an amount of about 0.5 wt % to about 5 wt % 3. The pharmaceutical formulation of claim 1 or 2, comprising:

4. (i) the compound of formula I in an amount of about 45 wt % to about 55 wt %; (ii) said filler in an amount of about 44 wt % to about 46 wt %; (iii) the disintegrant in an amount of about 3 wt % to about 5 wt %; and (iv) said lubricant in an amount of about 0.5 wt % to about 2 wt % The pharmaceutical formulation according to any one of claims 1 to 3, comprising:

5. (i) the compound of formula I in an amount of about 50 wt %; (ii) said filler in an amount of about 44 wt % to about 46 wt %; (iii) the disintegrant in an amount of about 3 wt % to about 5 wt %; and (iv) said lubricant in an amount of about 0.5 wt % to about 2 wt % 2. The pharmaceutical formulation of claim 1, comprising:

6. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate.

7. The pharmaceutical formulation according to any one of claims 1 to 6, wherein the filler is microcrystalline cellulose.

8. 8. The pharmaceutical formulation of claim 1, wherein the disintegrant is starch, pregelatinized starch, hydroxypropyl starch, cellulose, cross-linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium.

9. The pharmaceutical formulation according to any one of claims 1 to 8, wherein the disintegrant is crospovidone.

10. 10. The pharmaceutical formulation of any one of claims 1 to 9, wherein the lubricant is stearic acid, sodium stearyl fumarate, or magnesium stearate.

11. The pharmaceutical formulation according to any one of claims 1 to 10, wherein the lubricant is magnesium stearate.

12. 12. The pharmaceutical formulation according to any one of claims 1 to 11, wherein the filler is microcrystalline cellulose and the disintegrant is crospovidone.

13. 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein the filler is microcrystalline cellulose and the lubricant is magnesium stearate.

14. 14. The pharmaceutical formulation according to any one of claims 1 to 13, wherein the disintegrant is crospovidone and the lubricant is magnesium stearate.

15. 15. The pharmaceutical formulation of any one of claims 1 to 14, wherein the filler is microcrystalline cellulose, the disintegrant is crospovidone, and the lubricant is magnesium stearate.

16. 16. The pharmaceutical formulation of any one of claims 1 to 15, comprising from about 100 mg to about 700 mg of the compound of formula I.

17. 17. The pharmaceutical formulation of any one of claims 1 to 16, comprising about 175 mg of the compound of formula I.

18. 17. The pharmaceutical formulation of any one of claims 1 to 16, comprising about 100 mg of the compound of formula I.

19. 17. The pharmaceutical formulation of any one of claims 1 to 16, comprising about 350 mg of the compound of formula I.

20. 17. The pharmaceutical formulation of any one of claims 1 to 16, comprising about 500 mg of the compound of formula I.

21. 21. The pharmaceutical composition of any one of claims 1 to 20, wherein the compound is the free base of Formula I.

22. 22. The pharmaceutical composition of any one of claims 1 to 21, wherein the compound is a crystalline form of the free base of Formula I characterized by an X-ray powder diffraction pattern comprising 2-theta reflection angles of 9.8°, 16.0°, and 25.4° (2-theta + / - 0.2 degrees).

23. 23. The pharmaceutical composition of any one of claims 1 to 22, formed by dry granulation.

24. A tablet, (i) a compound of formula I or a pharmaceutically acceptable salt thereof; 【Transformation 8】 (ii) fillers; (iii) a disintegrant; and (iv) lubricant Including; A tablet wherein said compound of formula I is present in an amount of about 40 wt% to about 70 wt%.

25. (i) said filler in an amount of about 20 wt % to about 60 wt %; (ii) the disintegrant in an amount of about 1 wt % to about 10 wt %; and (iii) said lubricant in an amount of about 0.5 wt % to about 5 wt % 25. The tablet of claim 24, comprising:

26. (i) said filler in an amount of about 40 wt % to about 50 wt %; (ii) the disintegrant in an amount of about 1 wt % to about 10 wt %; and (iii) said lubricant in an amount of about 0.5 wt % to about 5 wt % 26. The tablet of claim 24 or 25, comprising:

27. (i) the compound of formula I in an amount of about 45 wt % to about 55 wt %; (ii) said filler in an amount of about 44 wt % to about 46 wt %; (iii) the disintegrant in an amount of about 3 wt % to about 5 wt %; and (iv) said lubricant in an amount of about 0.5 wt % to about 2 wt % The tablet according to any one of claims 24 to 26, comprising:

28. (i) the compound of formula I in an amount of about 50 wt %; (ii) said filler in an amount of about 44 wt % to about 46 wt %; (iii) the disintegrant in an amount of about 3 wt % to about 5 wt %; and (iv) said lubricant in an amount of about 0.5 wt % to about 2 wt % The tablet according to any one of claims 24 to 27, comprising:

29. 29. The tablet of any one of claims 24 to 28, wherein the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate.

30. 30. The tablet of any one of claims 24 to 29, wherein the filler is microcrystalline cellulose.

31. 31. The tablet of any one of claims 24 to 30, wherein the disintegrant is starch, pregelatinized starch, hydroxypropyl starch, cellulose, cross-linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium.

32. 32. The tablet of any one of claims 24 to 31, wherein the disintegrant is crospovidone.

33. 33. The tablet of any one of claims 24 to 32, wherein the lubricant is stearic acid, sodium stearyl fumarate, magnesium stearate, or a combination thereof.

34. 34. The tablet of any one of claims 24 to 33, wherein the lubricant is magnesium stearate.

35. 35. The tablet of any one of claims 24 to 34, wherein the filler is microcrystalline cellulose and the disintegrant is crospovidone.

36. 36. The tablet of any one of claims 24 to 35, wherein the filler is microcrystalline cellulose and the lubricant is magnesium stearate.

37. 37. The tablet of any one of claims 24 to 36, wherein the disintegrant is crospovidone and the lubricant is magnesium stearate.

38. 38. The tablet of any one of claims 24 to 37, wherein the filler is microcrystalline cellulose, the disintegrant is crospovidone, and the lubricant is magnesium stearate.

39. 39. The tablet of any one of claims 24 to 38, comprising from about 100 mg to about 700 mg of the compound of formula I.

40. 40. The tablet of any one of claims 24 to 39, comprising about 175 mg of the compound of formula I.

41. 40. The tablet of any one of claims 24 to 39, comprising about 100 mg of the compound of formula I.

42. 40. The tablet of any one of claims 24 to 39, comprising about 350 mg of the compound of formula I.

43. 40. The tablet of any one of claims 24 to 39, comprising about 500 mg of the compound of formula I.

44. 44. The tablet of any one of claims 24 to 43, wherein the compound is the free base of formula I.

45. 45. The tablet of any one of claims 24 to 44, wherein the compound is a crystalline form of the free base of Formula I characterized by an X-ray powder diffraction pattern comprising 2θ reflection angles at 9.8°, 16.0°, and 25.4° (2θ+ / −0.2 degrees).

46. 46. ​​The tablet of any one of claims 24 to 45, formed by dry granulation.

47. A tablet, (i) a compound of formula I in an amount of about 50 to 700 mg; 【Chemistry 9】 (ii) microcrystalline cellulose in an amount from about 50 mg to about 500 mg; (iii) crospovidone in an amount of about 5 mg to 50 mg; and (iv) magnesium stearate in an amount from about 1 mg to about 20 mg tablets, including

48. (i) the compound of formula I in an amount of about 175 mg; (ii) microcrystalline cellulose in an amount of about 157.5 mg; (iii) crospovidone in an amount of about 14 mg; and (iv) magnesium stearate in an amount of about 3.5 mg 48. The tablet of claim 47, comprising:

49. (i) the compound of formula I in an amount of about 100 mg; (ii) microcrystalline cellulose in an amount of about 89 mg; (iii) crospovidone in an amount of about 8 mg; and (iv) magnesium stearate in an amount of about 3 mg 48. The tablet of claim 47, comprising:

50. (i) the compound of formula I in an amount of about 500 mg; (ii) microcrystalline cellulose in an amount of about 445 mg; (iii) crospovidone in an amount of about 40 mg; and (iv) magnesium stearate in an amount of about 10 mg 48. The tablet of claim 47, comprising:

51. (i) the compound of formula I in an amount of about 350 mg; (ii) microcrystalline cellulose in an amount of about 315 mg; (iii) crospovidone in an amount of about 28 mg; and (iv) magnesium stearate in an amount of about 7 mg 48. The tablet of claim 47, comprising:

52. 1. A tablet comprising: (a) a tablet core; and (b) a film coat, wherein the tablet core comprises: (i) a compound of formula I or a pharmaceutically acceptable salt thereof; 【Chemistry 10】 (ii) fillers; (iii) a disintegrant; and (iv) lubricant Including; A tablet wherein said compound of formula I is present in an amount of about 40 wt% to about 70 wt%.

53. The tablet core comprises: (i) said filler in an amount of about 20 wt % to about 60 wt %; (ii) the disintegrant in an amount of about 1 wt % to about 10 wt %; and (iii) said lubricant in an amount of about 0.5 wt % to about 5 wt % 53. The tablet of claim 52, comprising:

54. The tablet core comprises: (i) said filler in an amount of about 40% to about 50% by weight; (ii) the disintegrant in an amount of about 1% to about 10% by weight (wt %); and (iii) said lubricant in an amount of about 0.5% to about 5% by weight (wt %) 54. The tablet of claim 52 or 53, comprising:

55. The tablet core comprises: (i) the compound of formula I in an amount of about 45-55 wt %; (ii) said filler in an amount of about 44% to about 46% by weight; (iii) the disintegrant in an amount of about 3% to about 5% by weight (wt %); and (iv) said lubricant in an amount of about 0.5 wt % to about 2 wt % The tablet according to any one of claims 52 to 54, comprising:

56. The tablet core comprises: (i) the compound of formula I in an amount of about 50 wt %; (ii) said filler in an amount of about 44 wt % to about 46 wt %; (iii) the disintegrant in an amount of about 3 wt % to about 5 wt %; and (iv) said lubricant in an amount of about 0.5 wt % to about 2 wt % The tablet according to any one of claims 52 to 55, comprising:

57. 57. The tablet of any one of claims 52 to 56, wherein the film coat comprises Opadry® II.

58. 58. The tablet of any one of claims 52 to 57, wherein the film coat comprises Opadry® II Purple.

59. 58. The tablet of any one of claims 52 to 57, wherein the film coat comprises Opadry® II Yellow.

60. 57. The tablet of any one of claims 52 to 56, wherein the film coat comprises Opadry® QX.

61. 61. The tablet of any one of claims 52 to 56 and 60, wherein the film coat comprises Opadry® QX White.

62. 61. The tablet of any one of claims 52 to 56 and 60, wherein the film coat comprises Opadry QX® Yellow.

63. 63. The tablet of any one of claims 52 to 62, wherein the filler is microcrystalline cellulose, lactose, mannitol, or dicalcium phosphate.

64. 63. The tablet of any one of claims 52 to 62, wherein the filler is microcrystalline cellulose.

65. 65. The tablet of any one of claims 52 to 64, wherein the disintegrant is starch, pregelatinized starch, hydroxypropyl starch, cellulose, cross-linked PVP (crospovidone), sodium starch glycolate, or croscarmellose sodium.

66. 66. The tablet of any one of claims 52 to 65, wherein the disintegrant is crospovidone.

67. 67. The tablet of any one of claims 52 to 66, wherein the lubricant is stearic acid, sodium stearyl fumarate, or magnesium stearate.

68. 67. The tablet of any one of claims 52 to 66, wherein the lubricant is magnesium stearate.

69. 69. The tablet of any one of claims 52 to 68, wherein the filler is microcrystalline cellulose and the disintegrant is crospovidone.

70. 70. The tablet of any one of claims 52 to 69, wherein the filler is microcrystalline cellulose and the lubricant is magnesium stearate.

71. 71. The tablet of any one of claims 52 to 70, wherein the disintegrant is crospovidone and the lubricant is magnesium stearate.

72. 72. The tablet of any one of claims 52 to 71, wherein the filler is microcrystalline cellulose, the disintegrant is crospovidone, and the lubricant is magnesium stearate.

73. 73. The tablet of any one of claims 52 to 72, comprising from about 100 mg to about 700 mg of the compound of formula I.

74. 74. The tablet of any one of claims 52 to 73, comprising about 100 mg of the compound of formula I.

75. 74. The tablet of any one of claims 52 to 73, comprising about 175 mg of the compound of formula I.

76. 74. The tablet of any one of claims 52 to 73, comprising about 350 mg of the compound of formula I.

77. 74. The tablet of any one of claims 52 to 73, comprising about 500 mg of the compound of formula I.

78. 78. A method of treating a viral infection in a human in need thereof, comprising administering to said human a pharmaceutical formulation according to any one of claims 1 to 23, or a tablet according to any one of claims 24 to 77.

79. 79. The method of claim 78, comprising administering to the human at least one additional therapeutic or prophylactic agent.

80. 80. The method of claim 78 or 79, wherein the viral infection is a coronavirus infection.

81. 81. The method of any one of claims 78 to 80, wherein the viral infection is a zoonotic coronavirus infection.

82. 82. The method of any one of claims 78-81, wherein the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

83. 83. The method of any one of claims 78-82, wherein the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

84. 84. The method of any one of claims 78-83, wherein the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

85. 85. The method of any one of claims 78-84, wherein the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

86. 82. The method of any one of claims 78 to 81, wherein the viral infection is selected from the group consisting of a 229E viral infection, an NL63 viral infection, an OC43 viral infection, and an HKU1 viral infection.

87. 82. The method of any one of claims 78 to 81, wherein the viral infection is SARS-CoV-2 infection (COVID-19).

88. 82. The method of any one of claims 78 to 81, wherein the viral infection is a SARS-CoV viral infection.

89. 82. The method of any one of claims 78 to 81, wherein the viral infection is a MERS-CoV viral infection.

90. 80. The method of claim 78 or 79, wherein the viral infection is a pneumoviridae viral infection.

91. 90. The method of claim 89, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

92. 90. The method of claim 89, wherein the Pneumoviridae virus infection is a human metapneumovirus infection.

93. 80. The method of claim 78 or 79, wherein the viral infection is a Picornaviridae viral infection.

94. 94. The method of claim 93, wherein the viral infection is an enterovirus infection.

95. 95. The method of any one of claims 78, 79, 93, and 94, wherein the viral infection is selected from the group consisting of a Coxsackie A virus infection, a Coxsackie A virus infection, an Enterovirus D68 infection, an Enterovirus B69 infection, an Enterovirus D70 infection, an Enterovirus A71 infection, and a Poliovirus infection.

96. 94. The method of claim 93, wherein the Picornaviridae virus infection is a human rhinovirus infection (HRV).

97. The method of claim 93 or 96, wherein the Picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

98. 80. The method of claim 78 or 79, wherein the viral infection is a flaviviridae viral infection.

99. 99. The method of claim 98, wherein the Flaviviridae virus infection is dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

100. 80. The method of claim 78 or 79, wherein the viral infection is a Filoviridae virus infection.

101. 101. The method of claim 100, wherein the Filoviridae virus infection is an Ebola virus infection or a Marburg virus infection.

102. 80. The method of claim 78 or 79, wherein the viral infection is an orthomyxovirus infection.

103. 103. The method of claim 102, wherein the viral infection is an influenza virus infection.

104. 104. The method of claim 102 or 103, wherein the viral infection is an influenza A virus infection or an influenza B virus infection.

105. 80. The method of claim 78 or 79, wherein the viral infection is a paramyxoviridae viral infection.

106. 106. The method of claim 105, wherein the viral infection is a human parainfluenza virus infection, a Nipah virus infection, a Hendra virus infection, a measles virus infection, or a mumps virus infection.

107. 24. A method for producing a medicament for the treatment or prevention of a viral infection in a human being in need thereof, wherein a pharmaceutical formulation according to any one of claims 1 to 23 is used.

108. Use of a pharmaceutical formulation according to any one of claims 1 to 23 for the manufacture of a medicament for the treatment or prevention of a viral infection in a human being in need thereof.

109. 109. The use of claim 108, wherein the medicament is used in conjunction with at least one additional therapeutic or prophylactic agent.

110. A pharmaceutical formulation according to any one of claims 1 to 23 or a tablet according to any one of claims 24 to 77 for use in the treatment or prevention of a viral infection in a human in need thereof.

111. 111. The pharmaceutical formulation or tablet of claim 110, for use with at least one additional therapeutic agent.

112. 1. A method for preparing a pharmaceutical composition or tablet comprising a compound of formula I or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 11】 The method, wherein said compound of formula I is present in an amount of about 40 wt% to about 70 wt%, comprises dry granulation.

113. The composition comprises: fillers; disintegrants; and lubricant 113. The method of claim 112, further comprising:

114. 114. The method of claim 113, wherein the dry granulation process is performed on a blend of the compound of formula I, the filler, the disintegrant, and the lubricant.

115. 115. The method of claim 113 or 114, wherein the filler is microcrystalline cellulose.

116. 116. The method of any one of claims 113 to 115, wherein the disintegrant is crospovidone.

117. 117. The method of any one of claims 113 to 116, wherein the lubricant is magnesium stearate.

118. 118. The method of any one of claims 113 to 117, wherein the filler is microcrystalline cellulose and the disintegrant is crospovidone.

119. 119. The method of any one of claims 113 to 118, wherein the filler is microcrystalline cellulose and the lubricant is magnesium stearate.

120. 120. The method of any one of claims 113 to 119, wherein the disintegrant is crospovidone and the lubricant is magnesium stearate.

121. 121. The method of any one of claims 113 to 120, wherein the filler is microcrystalline cellulose, the disintegrant is crospovidone, and the lubricant is magnesium stearate.

122. 122. The method of claims 112-121, wherein the composition comprises microcrystalline cellulose in an amount of about 20 wt% to about 60 wt%.

123. 123. The method of any of claims 112-122, wherein the dry granulation is carried out by roller compaction.

124. The method according to claims 112 to 123, wherein the pharmaceutical composition or tablet has the characteristics of any of claims 1 to 77.

125. 78. A dry granulated pharmaceutical composition or tablet according to any one of claims 1 to 77.

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