Solid forms of nucleoside analogs and uses thereof

Abstract

The present disclosure provides solid forms of a compound of Formula (I) and uses thereof. Also provided are methods of making these solid forms and pharmaceutical formulations comprising these solid forms.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 614,078, filed December 22, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to a solid form of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-cyano-5-(((ethoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-dimethyldiacetate for the treatment of viral infections. This disclosure also relates to pharmaceutical compositions comprising the solid form disclosed herein, methods for treating or preventing viral infections, and methods for preparing the solid form disclosed herein. Background Technology

[0003] There is a continued need for treatment of viral infections, such as those in the Paramyxoviridae family ( paramyxoviridae ) infection, pulmonary virus department ( pneumoviridae ) infection, microribonucleoviridae ( picornaviridae ) infection, Flaviviridae ( flaviviridae ) infection, Filoviridae ( filoviridae ) infection, Arenaviridae ( arenaviridae ) infection, orthomyxovirus ( orthomyxovirus ) Department of Infectious Diseases and Coronaviruses ( coronaviridae Antiviral agents and methods for treating infections. There has been a ongoing need to develop methods for preparing and purifying antiviral agents, as well as improved pharmaceutical formulations for preparing these antiviral agents. The solid forms disclosed herein help to meet these and other needs. Summary of the Invention

[0004] This article provides the crystalline form of the compound of formula (I): Formula (I).

[0005] This article also provides solvates of compounds of formula (I).

[0006] This article also provides solid forms (e.g., salts or eutectics) of compounds of formula (I).

[0007] This article also provides a method for preparing the crystalline form disclosed herein.

[0008] This document also provides pharmaceutical compositions comprising the crystalline form, the solvate of the present disclosure, or the solid form of the present disclosure (e.g., salts or cocrystals of compounds of the present disclosure).

[0009] This document also provides kits containing crystalline forms, solvates, or solid forms of the present disclosure (e.g., salts or eutectics of compounds of the present disclosure).

[0010] This document also provides methods for treating or preventing viral infections in patients in need, wherein the method comprises administering to the patient a crystalline form of the present disclosure, a solvate of the present disclosure, a solid form of the present disclosure (e.g., a salt or cocrystal of a compound of the present disclosure), or a pharmaceutical composition of the present disclosure. Attached Figure Description

[0011] Figure 1 The XRPD pattern of maleate form I is shown.

[0012] Figure 2 The DSC thermogram of maleate form I is shown.

[0013] Figure 3 The TGA thermogram of maleate form I is shown.

[0014] Figure 4 The XRPD pattern of oxalate form I is shown.

[0015] Figure 5 The DSC thermogram of oxalate form I is shown.

[0016] Figure 6 The TGA thermogram of oxalate form I is shown.

[0017] Figure 7 The XRPD pattern of fumarate material A is shown.

[0018] Figure 8 The DSC thermal spectrum of fumarate material A is shown.

[0019] Figure 9 The XRPD pattern of fumarate material B is shown.

[0020] Figure 10 The DSC thermogram of fumarate material B is shown.

[0021] Figure 11 The TGA thermogram of fumarate material B is shown.

[0022] Figure 12 The XRPD pattern of fumarate material C is shown.

[0023] Figure 13 The DSC thermal spectrum of fumarate material C is shown.

[0024] Figure 14 The TGA thermogram of fumarate material C is shown.

[0025] Figure 15 The XRPD pattern of free base methanol solvate I is shown.

[0026] Figure 16 The XRPD pattern of free base form I is shown.

[0027] Figure 17 The DSC thermogram of free base form I is shown.

[0028] Figure 18 The TGA thermogram of free base form I is shown.

[0029] Figure 19 The XRPD pattern of free base form II is shown.

[0030] Figure 20 The DSC thermogram of free base form II is shown.

[0031] Figure 21 The TGA thermogram of free base form II is shown.

[0032] Figure 22 The XRPD pattern of free alkali ethanol and aqueous solvate I is shown.

[0033] Figure 23 The XRPD pattern of free base form III is shown.

[0034] Figure 24 The DSC thermogram of free base form III is shown.

[0035] Figure 25 The TGA thermogram of free base form III is shown.

[0036] Figure 26 The XRPD pattern of free base methanol solvate II is shown. Detailed Implementation

[0037] This disclosure relates to a novel solid form of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-cyano-5-(((ethoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-dimethyldiacetate (i.e., compound (I), see below). Those skilled in the art will understand that the structure of a compound can be named or identified using generally accepted nomenclature systems and symbols. For example, a compound can be named or identified using a common name, a systematic name, or a non-systematic name. Generally accepted nomenclature systems and symbols in the field of chemistry include, but are not limited to, the Chemical Abstracts Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC).

[0038] Compound of formula (I) As used herein, "solid form" generally refers to a solid chemical substance that can be amorphous or crystalline. Solid forms of this disclosure include salt forms (both amorphous and crystalline) and eutectic forms (both amorphous and crystalline) of compounds of formula (I). In some embodiments, the solid form of this disclosure is a salt of a compound of formula (I), which can be amorphous or crystalline. In another embodiment, the solid form can be a eutectic of a compound of formula (I), wherein the compound of formula (I) forms a crystalline solid together with a coformer molecule. In some embodiments, the solid form is a solvate (e.g., a hydrate). Both crystalline salts and eutectic forms of compounds of formula (I) can exist in different crystalline forms (i.e., forms with different polymorphisms or pseudopolymorphisms). The crystalline forms of the solid forms of this disclosure can include either salts of formula I or crystalline forms of eutectic forms.

[0039] As used herein, the term "cocrystal" refers to a compound (such as compound (I)) that crystallizes together with one or more co-formed molecules (e.g., molecules other than the compound itself). Depending on the chemical properties and proportions of the co-formed molecules present in the cocrystal, different physical properties, such as solubility and dissolution, can be observed compared to the solid form of the compound itself or its salts. In some cases, the co-formed molecules may be protic acids, and whether a protic acid forms a salt or a cocrystal generally depends on the relative pKa of the compound and the co-formed molecules. See, for example, Regulatory Classification of Pharmaceutical Co-Crystals: Guidance for Industry Revised in August 2016, published by the U.S. Department of Health and Human Services, the FDA, and the Center for Drug Evaluation and Research (CDER).

[0040] As used herein, "crystalline form" refers to a particular crystal lattice configuration of a crystalline substance (e.g., a salt or a eutectic). Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells), which are attributed to the different physical properties characteristic of each crystalline form. In some cases, different lattice configurations have different water or solvent contents.

[0041] According to this disclosure, the crystalline form, solvate, crystalline form of the solvate, or solid form of the compound of formula (I) can be used for the synthesis and / or purification of the compound of formula (I). For example, the crystalline form of the compound of formula (I) can be an intermediate in the synthesis of compound 1 of formula (I). Furthermore, different crystalline forms, solvates, crystalline forms of the solvate, or solid forms of the solvate may have different properties in terms of bioavailability, stability, purity, and / or manufacturability for medical or pharmaceutical use. Changes in the crystal structure of a pharmaceutical substance or active ingredient can affect the dissolution rate of the pharmaceutical product or active ingredient (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling, the ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.). Such changes can affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solutions or solid oral dosage forms, including tablets and capsules. Compared to other forms such as amorphous or non-crystalline forms, crystalline forms, solvates, crystalline forms of solvates, or solid forms can provide the desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Therefore, crystalline forms, solvates, crystalline forms of solvates, or solid forms of solvates can offer advantages such as improved methods of manufacturing the compound, stability or storability of the compound in pharmaceutical form, stability or storability of the compound as a pharmaceutical substance, and / or bioavailability and / or stability of the compound as an active agent.

[0042] It has been found that the use of certain solvents and / or methods produces different crystalline forms, solvates, crystalline forms of solvates, or solid forms of solvates, which may exhibit one or more of the advantageous characteristics described above. The preparation methods of the crystalline forms, solvates, crystalline forms of solvates, or solid forms of solvates described herein, as well as the characterization of these crystalline and eutectic forms, are described in detail below.

[0043] In some embodiments, the crystalline form, solvate, or solid form of the solvate described herein is purified or substantially isolated. "Substantially isolated" means that the crystalline form, solvate, or solid form of the solvate is at least partially or substantially isolated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions rich in the crystalline form, solvate, or solid form of the solvate disclosed herein. Substantially isolated may include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the crystalline form, solvate, or solid form of the solvate disclosed herein. In some embodiments, the crystalline form, solvate, or solid form of the solvate disclosed herein may be prepared with a purity of about 75% or higher, 80% or higher, 85% or higher, 90% or higher, 95% or higher, 98% or higher, or 99% or higher.

[0044] Different crystalline forms, solvates, and crystalline or solid forms of solvates can be identified using solid-state characterization methods, such as X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), further aid in identifying the form and in determining stability and solvent / water content.

[0045] The XRPD pattern of reflections (peaks) is generally considered a fingerprint of a specific crystal form. It is well known that the relative intensities of XRPD peaks can vary widely, particularly depending on sample preparation techniques, crystal size distribution, the various filters used, sample setup procedures, and the specific instrument employed. In some cases, depending on the type or setting of the instrument, new peaks may be observed, or existing peaks may disappear. As used herein, the term "peak" refers to a reflection with a relative height / intensity of at least about 1% of the maximum peak height / intensity. Furthermore, instrument variations and other factors can affect the 2θ values. Therefore, peak assignments (such as those reported herein) can vary by about 0.2° (2θ) positive or negative, and the terms "substantially" and "about" as used herein in the context of XRPD are intended to encompass such variations.

[0046] Similarly, temperature readings associated with DSC can vary by approximately ±3°C depending on the instrument, specific settings, sample preparation, etc. Therefore, the crystalline form, solvate, crystalline form of the solvate, or solid form, or the term "approximately" for DSC thermograms reported herein that are "substantially" as shown in any figure, should be understood to accommodate such variations.

[0047] This disclosure provides crystalline forms, solvates, crystalline forms of solvates, or solid forms of compounds of formula (I) (e.g., crystalline forms of maleate, oxalate, or fumarate of formula (I)). In some embodiments, the crystalline form may be substantially anhydrous. In some embodiments, the crystalline form may be hydrated or solvated.

[0048] This article provides the crystalline form of the compound of formula (I): Formula (I).

[0049] Free base crystal form Free base form I This article also provides a crystalline form of a compound of formula (I), wherein the crystalline form is a free base form I.

[0050] In some embodiments, free alkali form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 2θ) at 8.4°, 16.8°, and 25.1°. In some embodiments, free alkali form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 2θ) at 7.3°, 8.4°, 14.2°, 16.8°, 24.1°, and 25.1°. In some embodiments, free alkali form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 2θ) at 6.9°, 7.3°, 8.4°, 13.9°, 14.2°, 16.8°, 22.4°, 24.1°, and 25.1°.

[0051] In some embodiments, free alkali form I is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: degree 2θ reflections (±0.2 degrees 2θ) at 6.9°, 7.3°, 8.4°, 13.9°, 14.2°, 16.8°, 22.4°, 24.1°, and 25.1°. In some embodiments, free alkali form I is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: degree 2θ reflections (±0.2 degrees 2θ) at 8.4°, 16.8°, and 25.1°, and degree 2θ reflections (±0.2 degrees 2θ) at 6.9°, 7.3°, 13.9°, 14.2°, 22.4°, and 24.1°.

[0052] In some implementations, the free base form of the XRPD pattern is essentially as follows: Figure 16 As shown.

[0053] In some embodiments, the free base form I is characterized by including a differential scanning calorimetry pattern with two endothermic events initiating at approximately 68°C and approximately 104°C. In some embodiments, the free base form I is characterized by substantially as... Figure 17 The differential scanning calorimetry pattern shown is as follows.

[0054] In some embodiments, free base form I is non-solventized. In some embodiments, free base form I is characterized by being substantially as follows: Figure 18 The thermogravimetric analysis pattern shown.

[0055] Free base form II This article also provides a crystalline form of a compound of formula (I), wherein the crystalline form is a free base form II.

[0056] In some embodiments, the free alkali form II is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.5°, 14.1°, and 25.6°. In some embodiments, the free alkali form II is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.2°, 7.5°, 12.8°, 14.1°, 18.2°, and 25.6°. In some embodiments, the free alkali form II is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.2°, 7.5°, 10.3°, 12.8°, 14.1°, 16.0°, 18.2°, 24.2°, and 25.6°.

[0057] In some embodiments, the free alkali form II is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 7.5°, 10.3°, 12.8°, 14.1°, 16.0°, 18.2°, 24.2°, and 25.6°. In some embodiments, the free alkali form II is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: degree 2θ reflections (±0.2 degrees 2θ) at 7.5°, 14.1°, and 25.6°, and degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 10.3°, 12.8°, 16.0°, 18.2°, and 24.2°.

[0058] In some implementations, the free base form II XRPD pattern is essentially as follows: Figure 19 As shown.

[0059] In some embodiments, the free base form II is characterized by a differential scanning calorimetry (DSC) pattern comprising two overlapping peaks and an endothermic event initiating at approximately 55°C, and a second endothermic event initiating at approximately 101°C. In some embodiments, the free base form II is characterized by substantially as follows: Figure 20 The differential scanning calorimetry pattern shown is as follows.

[0060] In some embodiments, the free alkali form II is characterized by a thermogravimetric analysis pattern including approximately 1.6% weight loss at the same time as the first endothermic event. In some embodiments, the free alkali form II is characterized by a thermogravimetric analysis pattern including approximately 1.6% weight loss. In some embodiments, the free alkali form II is characterized by substantially as... Figure 21 The thermogravimetric analysis pattern shown.

[0061] Free base form III This article also provides a crystalline form of a compound of formula (I), wherein the crystalline form is a free base form III.

[0062] In some embodiments, the free alkali form III is characterized by XRPD patterns comprising 2θ reflections (±0.2 2θ) at 8.4°, 16.8°, and 25.1°. In some embodiments, the free alkali form III is characterized by XRPD patterns comprising 2θ reflections (±0.2 2θ) at 8.4°, 9.4°, 16.0°, 16.8°, 24.1°, and 25.1°. In some embodiments, the free alkali form III is characterized by XRPD patterns comprising 2θ reflections (±0.2 2θ) at 8.4°, 9.4°, 13.8°, 16.0°, 16.8°, 22.3°, 24.1°, 25.1°, and 26.9°.

[0063] In some embodiments, the free base form III is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: degree 2θ reflections (±0.2 degrees 2θ) at 8.4°, 9.4°, 13.8°, 16.0°, 16.8°, 22.3°, 24.1°, 25.1°, and 26.9°. In some embodiments, the free base form III is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: degree 2θ reflections (±0.2 degrees 2θ) at 8.4°, 16.8°, and 25.1°, and degree 2θ reflections (±0.2 degrees 2θ) at 9.4°, 13.8°, 16.0°, 22.3°, 24.1°, and 26.9°.

[0064] In some implementations, the free base form III XRPD pattern is essentially as follows: Figure 23 As shown.

[0065] In some embodiments, the free base form III is characterized by including a differential scanning calorimetry pattern having two consecutive endothermic events starting at approximately 54°C. In some embodiments, the free base form III is characterized by essentially as... Figure 24 The differential scanning calorimetry pattern shown is as follows.

[0066] In some embodiments, the free base form III is non-solventized. In some embodiments, the free base form III is characterized by essentially as follows: Figure 25 The thermogravimetric analysis pattern shown.

[0067] solvates This article also provides a solvate of the compound of formula (I).

[0068] This article also provides a crystalline form of a solvate of compound (I).

[0069] In some embodiments, the solvent includes methanol, ethanol, isopropanol, 1-butanol, 2-butanol (e.g., (S)-2-butanol or (R)-2-butanol), acetone, acetonitrile, ethyl acetate, butyl acetate, methyl tert-butyl ether (MTBE), tetrahydrofuran, toluene, 2-butanone (methyl ethyl ketone), 2-methyltetrahydrofuran, heptane (e.g., n-heptane), cyclohexane, cyclopentyl methyl ether, dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, ethylene glycol, hexane (e.g., n-hexane), propylene glycol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, tert-butanol, acetic acid, anisole, dimethyl sulfoxide, isobutyl acetate, methyl acetate, 2-methyl-1-propanol, diethyl ether, ethyl formate, formic acid, pentane (e.g., n-pentane), 1-pentanol, propyl acetate (e.g., isopropyl acetate), triethylamine, or mixtures thereof.

[0070] In some embodiments, the solvate of the compound of formula (I) is C 1-6 Alcohol solvates. In some embodiments, the solvate of the compound of formula (I) is C 1-5Alcohol solvates. In some embodiments, the solvate of compound (I) is a C3 alcohol solvate, a C4 alcohol solvate, a C5 alcohol solvate, or a C6 alcohol solvate. In some embodiments, the solvate of compound (I) is a methanol solvate, an ethanol solvate, an isopropanol solvate, a 1-butanol solvate, a 2-butanol solvate, a tert-butanol solvate, a 1-pentanol solvate, an aqueous solvate, or a combination thereof. In some embodiments, the solvate of compound (I) is a methanol solvate, an ethanol solvate, an aqueous solvate, or an ethanol and aqueous solvate. In some embodiments, the solvate of compound (I) is a methanol solvate. In some embodiments, the solvate of compound (I) is an ethanol and an aqueous solvate.

[0071] Free base methanol solvate I This article also provides a crystalline form of a solvate of compound (I), wherein the crystalline form is free base methanol solvate I.

[0072] In some embodiments, free base methanol solvate I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.1°, 14.3°, and 25.7°. In some embodiments, free base methanol solvate I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.1°, 14.1°, 14.3°, 21.5°, 24.4°, and 25.7°. In some embodiments, free base methanol solvate I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.1°, 11.5°, 14.1°, 14.3°, 15.8°, 21.5°, 24.4°, 25.7°, and 28.7°.

[0073] In some embodiments, the free base methanol solvate I is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: degree 2θ reflections (±0.2 degrees 2θ) at 7.1°, 11.5°, 14.1°, 14.3°, 15.8°, 21.5°, 24.4°, 25.7°, and 28.7°. In some embodiments, the free base methanol solvate I is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: degree 2θ reflections (±0.2 degrees 2θ) at 7.1°, 14.3°, and 25.7°, and degree 2θ reflections (±0.2 degrees 2θ) at 11.5°, 14.1°, 15.8°, 21.5°, 24.4°, and 28.7°.

[0074] In some implementations, the free base methanol solvate 1 XRPD pattern is essentially as follows: Figure 15 As shown.

[0075] Free base methanol solvate II This article also provides a crystalline form of a solvate of compound (I), wherein the crystalline form is a free base methanol solvate II.

[0076] In some embodiments, the free base methanol solvate II is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.2°, 14.4°, and 24.5°. In some embodiments, the free base methanol solvate II is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.2°, 11.6°, 14.0°, 14.4°, 24.5°, and 25.8°. In some embodiments, the free base methanol solvate II is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.2°, 10.1°, 11.6°, 14.0°, 14.4°, 21.8°, 24.5°, 25.8°, and 29.0°.

[0077] In some embodiments, the free base methanol solvate II is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 10.1°, 11.6°, 14.0°, 14.4°, 21.8°, 24.5°, 25.8°, and 29.0°. In some embodiments, the free base methanol solvate II is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 14.4°, and 24.5°, and degree 2θ reflections (±0.2 degrees 2θ) at 10.1°, 11.6°, 14.0°, 21.8°, 25.8°, and 29.0°.

[0078] In some implementations, the free base methanol solvate II XRPD pattern is essentially as follows: Figure 26 As shown.

[0079] Free base ethanol and aqueous solvates I This article also provides a crystalline form of a solvate of compound (I), wherein the crystalline form is a solvate I of free alkali ethanol and water.

[0080] In some embodiments, the free alkali ethanol and aqueous solvate I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.0°, 14.0°, and 25.8°. In some embodiments, the free alkali ethanol and aqueous solvate I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.0°, 7.2°, 14.0°, 15.7°, 24.5°, and 25.8°. In some embodiments, the free alkali ethanol and aqueous solvate I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.0°, 7.2°, 11.5°, 14.0°, 14.6°, 15.7°, 22.3°, 24.5°, and 25.8°.

[0081] In some embodiments, the free alkali ethanol and aqueous solvate I are characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: degree 2θ reflections (±0.2 degrees 2θ) at 7.0°, 7.2°, 11.5°, 14.0°, 14.6°, 15.7°, 22.3°, 24.5°, and 25.8°. In some embodiments, the free alkali ethanol and aqueous solvate I are characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: degree 2θ reflections (±0.2 degrees 2θ) at 7.0°, 14.0°, and 25.8°, and degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 11.5°, 14.6°, 15.7°, 22.3°, and 24.5°.

[0082] In some implementations, the free alkali ethanol and aqueous solvate I XRPD pattern is essentially as follows Figure 22 As shown.

[0083] solid form This article also provides a solid form of a compound of formula (I), wherein the solid form is a salt of formula (I) or a eutectic of formula (I).

[0084] In some embodiments, the solid form is formula (I) maleate, formula (I) oxalate, or formula (I) fumarate. In some embodiments, the solid form is formula (I) maleate, formula (I) oxalate, or formula (I) fumarate. In some embodiments, the solid form is formula (I) maleate. In some embodiments, the solid form is formula (I) oxalate. In some embodiments, the solid form is formula (I) fumarate.

[0085] In some embodiments, the solid form is crystalline. In some embodiments, the crystalline solid form is formula (I) maleate, formula (I) oxalate, or formula (I) fumarate. In some embodiments, the crystalline solid form is formula (I) maleate, formula (I) oxalate, or formula (I) fumarate. In some embodiments, the crystalline solid form is formula (I) maleate. In some embodiments, the crystalline solid form is formula (I) oxalate. In some embodiments, the crystalline solid form is formula (I) fumarate.

[0086] Maleate form I This article also provides a crystalline form of maleate of formula (I): Formula (I) maleate The crystalline form is maleate form I.

[0087] In some embodiments, maleate form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 3.9°, 9.8°, and 18.7°. In some embodiments, maleate form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 3.9°, 7.8°, 9.8°, 11.7°, 17.2°, and 18.7°. In some embodiments, maleate form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 3.9°, 7.8°, 9.8°, 11.7°, 13.6°, 17.2°, 18.7°, 19.6°, and 26.1°.

[0088] In some embodiments, maleate form I is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: 2θ reflections (±0.2 2θ) at 3.9°, 7.8°, 9.8°, 11.7°, 13.6°, 17.2°, 18.7°, 19.6°, and 26.1°. In some embodiments, maleate form I is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: 2θ reflections (±0.2 2θ) at 3.9°, 9.8°, and 18.7°, and 2θ reflections (±0.2 2θ) at 7.8°, 11.7°, 13.6°, 17.2°, 19.6°, and 26.1°.

[0089] In some implementations, the maleate form of the XRPD pattern is essentially as follows: Figure 1 As shown.

[0090] In some embodiments, maleate form I is characterized by including a differential scanning calorimetry pattern of an endothermic transition at about 166°C. In some embodiments, maleate form I is characterized by essentially as... Figure 2 The differential scanning calorimetry pattern shown is as follows.

[0091] In some embodiments, maleate form I is non-solventized. In some embodiments, maleate form I is characterized by being substantially as follows: Figure 3 The thermogravimetric analysis pattern shown.

[0092] Oxalate form I This article also provides a crystalline form of oxalate of formula (I): Formula (I) oxalate The solid form is oxalate form I.

[0093] In some embodiments, oxalate form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 3.9°, 17.5°, and 24.0°. In some embodiments, oxalate form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 3.9°, 5.9°, 10.0°, 17.5°, 20.8°, and 24.0°. In some embodiments, oxalate form I is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 3.9°, 5.9°, 6.3°, 9.0°, 10.0°, 17.5°, 20.8°, 23.3°, and 24.0°.

[0094] In some embodiments, oxalate form I is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: 2θ reflections (±0.2 2θ) at 3.9°, 5.9°, 6.3°, 9.0°, 10.0°, 17.5°, 20.8°, 23.3°, and 24.0°. In some embodiments, oxalate form I is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: 2θ reflections (±0.2 2θ) at 3.9°, 17.5°, and 24.0°, and 2θ reflections (±0.2 2θ) at 5.9°, 6.3°, 9.0°, 10.0°, 20.8°, and 23.3°.

[0095] In some implementations, the oxalate form of the XRPD pattern is essentially as follows: Figure 4 As shown.

[0096] In some embodiments, oxalate form I is characterized by a differential scanning calorimetry pattern comprising a first endothermic transition at about 103°C and a second endothermic transition having an initiation at about 182°C. In some embodiments, oxalate form I is characterized by substantially as Figure 5 The differential scanning calorimetry pattern shown is as follows.

[0097] In some embodiments, oxalate form I is characterized by including a thermogravimetric analysis pattern of approximately 0.9% weight loss prior to the first endothermic event. In some embodiments, oxalate form I is characterized by substantially as... Figure 6 The thermogravimetric analysis pattern shown.

[0098] Fumarate materials A This article also provides a crystalline form of fumarate of formula (I): Formula (I) fumarate The crystalline form is fumarate material A.

[0099] In some embodiments, fumarate material A is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.2°, 12.9°, and 25.7°. In some embodiments, fumarate material A is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 12.9°, 15.3°, 20.6°, and 25.7°. In some embodiments, fumarate material A is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 8.0°, 12.9°, 14.7°, 15.3°, 20.6°, 25.7°, and 28.3°.

[0100] In some embodiments, the fumarate material A is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 8.0°, 12.9°, 14.7°, 15.3°, 20.6°, 25.7°, and 28.3°. In some embodiments, the fumarate material A is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: 2θ reflections (±0.2 degrees 2θ) at 7.2°, 12.9°, and 25.7°, and 2θ reflections (±0.2 degrees 2θ) at 6.8°, 8.0°, 14.7°, 15.3°, 20.6°, and 28.3°.

[0101] In some implementations, the fumarate material A XRPD pattern is essentially as follows: Figure 7 As shown.

[0102] In some embodiments, the fumarate material A is characterized by including a differential scanning calorimetry pattern of an endothermic transition at approximately 146°C. In some embodiments, the fumarate material A is characterized by substantially as... Figure 8 The differential scanning calorimetry pattern shown is as follows.

[0103] Fumarate materials B This article also provides a crystalline form of fumarate of formula (I), wherein the crystalline form is fumarate material B.

[0104] In some embodiments, the fumarate material B is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.2°, 13.1°, and 25.8°. In some embodiments, the fumarate material B is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 13.1°, 14.7°, 23.9°, and 25.8°. In some embodiments, the fumarate material B is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 8.0°, 13.1°, 14.7°, 18.1°, 23.2°, 23.9°, and 25.8°.

[0105] In some embodiments, the fumarate material B is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 8.0°, 13.1°, 14.7°, 18.1°, 23.2°, 23.9°, and 25.8°. In some embodiments, the fumarate material B is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: 2θ reflections (±0.2 degrees 2θ) at 7.2°, 13.1°, and 25.8°, and 2θ reflections (±0.2 degrees 2θ) at 6.8°, 8.0°, 14.7°, 18.1°, 23.2°, and 23.9°.

[0106] In some implementations, the fumarate material B XRPD pattern is essentially as follows: Figure 9 As shown.

[0107] In some embodiments, the fumarate material B is characterized by including a differential scanning calorimetry pattern of an endothermic transition at about 150°C. In some embodiments, the fumarate material B is characterized by substantially as... Figure 10 The differential scanning calorimetry pattern shown is as follows.

[0108] In some embodiments, fumarate material B is unsolvated. In some embodiments, fumarate material B is characterized by substantially as follows: Figure 11 The thermogravimetric analysis pattern shown.

[0109] Fumarate materials C This article also provides a crystalline form of fumarate of formula (I), wherein the crystalline form is fumarate material C.

[0110] In some embodiments, the fumarate material C is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.1°, 13.0°, and 20.7°. In some embodiments, the fumarate material C is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 6.9°, 7.1°, 10.6°, 13.0°, 15.2°, and 20.7°. In some embodiments, the fumarate material C is characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 6.9°, 7.1°, 8.1°, 10.6°, 13.0°, 13.7°, 15.2°, 20.7°, and 23.1°.

[0111] In some embodiments, the fumarate material C is characterized by an XRPD pattern comprising one, two, three, four, five, six, seven, eight, or nine of the following: 2θ reflections (±0.2 degrees 2θ) at 6.9°, 7.1°, 8.1°, 10.6°, 13.0°, 13.7°, 15.2°, 20.7°, and 23.1°. In some embodiments, the fumarate material C is characterized by an XRPD pattern comprising one, two, three, four, five, or six of the following: 2θ reflections (±0.2 degrees 2θ) at 7.1°, 13.0°, and 20.7°, and 2θ reflections (±0.2 degrees 2θ) at 6.9°, 8.1°, 10.6°, 13.7°, 15.2°, and 23.1°.

[0112] In some implementations, the fumarate material C XRPD pattern is essentially as follows: Figure 12 As shown.

[0113] In some embodiments, the fumarate material C is characterized by a differential scanning calorimetry pattern including an endothermic transition at approximately 147°C. In some embodiments, the fumarate material C is characterized by substantially as... Figure 13 The differential scanning calorimetry pattern shown is as follows.

[0114] In some embodiments, the fumarate material C is unsolvated. In some embodiments, the fumarate material C is characterized by substantially as follows: Figure 14The thermogravimetric analysis pattern shown.

[0115] Preparation method This article also provides a method for preparing the crystalline form of the solvate of the compound of formula (I) disclosed herein.

[0116] In some implementations, the method for preparing the crystalline form of the solvate includes (i) The compound of formula (I) is slurried or dissolved in solvent A to form mixture A; and (ii) Separate the solid from mixture A to obtain the crystalline form of the solvate.

[0117] In some embodiments, the method for preparing the crystalline form of the solvate further includes adding a seed crystal to mixture A. In some embodiments, the seed crystal is a fumarate material B.

[0118] In some embodiments, the method for preparing the crystalline form of the solvate includes slurrying the compound of formula (I) in solvent A to form mixture A. In some embodiments, the method for preparing the crystalline form of the solvate includes dissolving the compound of formula (I) in solvent A to form mixture A.

[0119] In some embodiments, the method for preparing the crystalline form of the solvate includes slurrying or dissolving about 10 mg to 500 mg of compound (I) per mL of solvent A. In some embodiments, the method for preparing the crystalline form of the solvate includes slurrying or dissolving about 75 mg to 350 mg of compound (I) per mL of solvent A. In some embodiments, the method for preparing the crystalline form of the solvate includes slurrying or dissolving about 100 mg to 250 mg of compound (I) per mL of solvent A. In some embodiments, the method for preparing the crystalline form of the solvate includes slurrying or dissolving about 50 mg to 150 mg of compound (I) per mL of solvent A.

[0120] In some embodiments, solvent A comprises a polar solvent. In some embodiments, solvent A comprises a proton solvent. In some embodiments, solvent A comprises C 1-6 Alcohol. In some embodiments, solvent A includes C. 1-5 Alcohol. In some embodiments, solvent A includes a C3 alcohol, a C4 alcohol, a C5 alcohol, or a C6 alcohol. In some embodiments, solvent A includes water, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, acetonitrile, or mixtures thereof. In some embodiments, solvent A includes methanol. In some embodiments, the solvent includes ethanol and water. In some embodiments, solvent A includes ethanol and water in a ratio of about 50:50 (v / v).

[0121] In some embodiments, slurrying or dissolving the compound of formula (I) in solvent A to form mixture A further includes adding acid A to mixture A. In some embodiments, acid A comprises an organic acid. In some embodiments, acid A comprises a carboxylic acid. In some embodiments, acid A comprises fumaric acid, maleic acid, oxalic acid, or mixtures thereof.

[0122] In some embodiments, solvent A includes methanol, and acid A includes fumaric acid.

[0123] In some embodiments, the method for preparing the crystalline form of the solvate includes separating the solid by centrifugation.

[0124] This document also provides a method for preparing compounds of formula (I) in crystalline form or in solid form of formula (I) disclosed herein (e.g., crystalline form of maleate of formula (I), crystalline form of oxalate of formula (I) and crystalline form of fumarate of formula (I)).

[0125] In some embodiments, the method for preparing the crystalline or solid form (e.g., the crystalline form of formula (I) maleate, the crystalline form of formula (I) oxalate, or the crystalline form of formula (I) fumarate) includes... (i) The compound of formula (I) is slurried or dissolved in solvent B to form mixture B; (ii) Separate the solid from mixture B to obtain solid B; and (iii) Dry solid B to obtain a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate).

[0126] In some embodiments, the method of preparing a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) further includes adding a seed crystal to mixture B. In some embodiments, the seed crystal is fumarate material B.

[0127] In some embodiments, the method of preparing a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) comprises slurrying a compound of formula (I) in solvent B to form a mixture B. In some embodiments, the method of preparing a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) comprises dissolving a compound of formula (I) in solvent B to form a mixture B.

[0128] In some embodiments, the method of preparing a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) comprises slurrying or dissolving about 10 mg to 500 mg of the compound of formula (I) per mL of solvent B. In some embodiments, the method of preparing a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) comprises slurrying or dissolving about 75 mg to 350 mg of the compound of formula (I) per mL of solvent B. In some embodiments, the method of preparing a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) comprises slurrying or dissolving about 100 mg to 250 mg of the compound of formula (I) per mL of solvent B. In some embodiments, the method of preparing a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) comprises slurrying or dissolving about 50 mg to 150 mg of the formula (I) compound per mL of solvent B.

[0129] In some embodiments, solvent B comprises a polar solvent. In some embodiments, solvent B comprises a proton solvent. In some embodiments, solvent B comprises C. 1-6 Alcohol. In some embodiments, solvent B includes C. 1-5 Alcohol. In some embodiments, solvent B includes C3, C4, C5, or C6 alcohols. In some embodiments, solvent B includes water, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, acetonitrile, or mixtures thereof. In some embodiments, solvent B includes methanol. In some embodiments, solvent B includes acetonitrile. In some embodiments, solvent B includes ethanol and water. In some embodiments, solvent B includes ethanol and water in a ratio of about 50:50 (v / v).

[0130] In some embodiments, the method of preparing a crystalline or solid form (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) further includes adding acid B to mixture B. In some embodiments, acid B comprises an organic acid. In some embodiments, acid B comprises a carboxylic acid. In some embodiments, acid B comprises fumaric acid, maleic acid, oxalic acid, or mixtures thereof.

[0131] In some embodiments, solvent B comprises acetonitrile, and acid B comprises maleic acid. In some embodiments, solvent B comprises methanol, and acid B comprises fumaric acid. In some embodiments, solvent B comprises acetonitrile, and acid B comprises oxalic acid.

[0132] In some embodiments, the method for preparing crystalline or solid forms (e.g., crystalline forms of maleate of formula (I), crystalline forms of oxalate of formula (I), or crystalline forms of fumarate of formula (I)) includes separating solid B by centrifugation.

[0133] In some embodiments, drying is performed at a temperature of about 20°C to about 100°C. In some embodiments, drying is performed at a temperature of about 50°C. In some embodiments, drying is performed under a vacuum. In some embodiments, drying is performed at a temperature of about 50°C and under a vacuum.

[0134] Pharmaceutical Composition The crystalline forms, solvates, crystalline or solid forms of solvates disclosed herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and are generally isotonic when intended for delivery by non-oral administration. All formulations may optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Pharmaceutically acceptable excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In some embodiments, the formulation contains one or more pharmaceutically acceptable excipients. The pH range of the formulation is from about 3 to about 11, but is generally from about 7 to 10. In some embodiments, the pH range of the formulation is from about 2 to about 5, but is generally from about 3 to 4.

[0135] Although the crystalline, solvated, crystalline or solid forms of the solvated (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) (“active ingredients”) of this disclosure may be administered alone, they are preferably presented as pharmaceutical formulations. Both veterinary and human formulations of this disclosure comprise at least one active ingredient as defined above, together with one or more of its acceptable carriers and optional other therapeutic ingredients, particularly those additional therapeutic ingredients discussed herein. The carrier must be “acceptable,” meaning compatible with the other components of the formulation and physiologically harmless to the recipient.

[0136] These formulations include those suitable for the aforementioned routes of administration. Formulations are readily available in unit dosage forms and can be prepared by any suitable method known in the pharmaceutical field. Techniques and formulations are commonly found at Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve the step of associating the active ingredient with a carrier constituting one or more auxiliary ingredients. Generally, formulations are prepared by uniformly and tightly associating the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product.

[0137] In some implementations, the pharmaceutical preparation is used for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

[0138] In some embodiments, the crystalline forms, solvates, crystalline or solid forms of solvates described herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, the crystalline forms, solvates, crystalline or solid forms of solvates disclosed herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) have improved bioavailability and are therefore suitable for oral administration.

[0139] In some embodiments, formulations of this disclosure suitable for oral administration may be provided as discrete units such as capsules, pouches, or tablets each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be administered as pills, granules, or pastes.

[0140] In some embodiments, tablets are prepared by compression or molding, optionally with one or more excipients. Compressed tablets are prepared by compressing an active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets are prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored, and optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0141] For infections of the eyes or other external tissues (e.g., the mouth and skin), the formulation is applied as a topical ointment or cream containing active ingredients in amounts, for example, from 0.075% w / w to 20% w / w (including active ingredients in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably from 0.2% w / w to 15% w / w, and most preferably from 0.5% w / w to 10% w / w. When formulated as an ointment, the active ingredient may be used with a paraffin base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water emulsion base.

[0142] If desired, the aqueous phase of the cream matrix may contain, for example, at least 30% w / w polyols, i.e., alcohols having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may ideally include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0143] The oil phase of the emulsion disclosed herein can be composed of known components in a known manner. While this phase may consist only of emulsifiers (or simply emulsifiers), it ideally includes at least one emulsifier with fats or oils, or with a mixture of both fats and oils. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. It is also preferable to include both oils and fats. Emulsifiers, with or without stabilizers, together constitute a so-called emulsified wax, and the wax, together with the oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the ointment formulation.

[0144] Emulsifiers and emulsion stabilizers suitable for the formulations disclosed herein include Tween. ® 60. Span ® 80. Cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Other emulsifiers and emulsion stabilizers suitable for formulations disclosed herein include Tween. ® 80.

[0145] The appropriate oil or fat is selected for the formulation based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining, and washable product with a suitable consistency to prevent leakage from tubes or other containers. Straight-chain or branched monoalkyl or dialkyl esters can be used, such as diisohexyl adipate, isohexadecanoyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or mixtures of branched esters known as Crodamol CAP, the last three being preferred esters. These esters can be used alone or in combination, depending on the desired properties. Alternatively, high-melting-point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, can be used.

[0146] Pharmaceutical formulations according to this disclosure comprise the crystalline forms, solvates, crystalline or solid forms of solvates disclosed herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate), and one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, when intended for oral use, they may be prepared as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing the active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated using known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0147] Formulations intended for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium phosphate or kaolin) or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0148] The aqueous suspension of the present invention contains an active substance mixed with excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of olefinic oxygen and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), and condensation products of ethylene oxide and esters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin. Other non-limiting examples of suspending agents include cyclodextrin. In some examples, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol. ® .

[0149] Oily suspensions can be prepared by suspending the active ingredients in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those mentioned above) and flavoring agents may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

[0150] The dispersible powders and granules of this disclosure, suitable for preparing aqueous suspensions by adding water, provide an active ingredient that can be mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0151] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth; naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, or coloring agents.

[0152] The pharmaceutical compositions disclosed herein can be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. The sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as solutions in 1,3-butanediol), or prepared as lyophilized powders. Acceptable solvents and media are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectable formulations. Acceptable solvents and media are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0153] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 1000 mg of active material mixed with an appropriate and convenient amount of carrier material, which may vary between approximately 5% to approximately 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosages. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 mg to 500 mg of active ingredient per milliliter of solution to allow for the infusion of an appropriate volume at a rate of approximately 30 mL / hr.

[0154] Formulations suitable for topical application to the eyes also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly in an aqueous solution of the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w.

[0155] Preparations suitable for topical application in the oral cavity include lozenges containing flavoring active ingredients, typically sucrose and gum arabic or tragacanth; tablets containing inert active ingredients, such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing the active ingredients in a suitable liquid carrier.

[0156] Formulations for rectal administration may be provided as suppositories with a suitable matrix, including, for example, cocoa butter or salicylates.

[0157] In some embodiments, the crystalline forms, solvates, crystalline forms of solvates, or solid forms (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or intranasal administration have particle sizes, such as 0.5 micrometers, 1 micrometer, 30 micrometers, 35 micrometers, etc., in the range of 0.1 micrometers to 500 micrometers, and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents. In some embodiments, the crystalline forms, solvates, crystalline forms of solvates, or solid forms (crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) used herein are formulated into dry powders and administered. In some embodiments, the crystalline form, solvate, crystalline form of a solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) used herein is formulated as an aerosol formulation and administered. In some embodiments, the crystalline form, solvate, crystalline form of a solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) used herein is formulated for delivery via a face mask. In some embodiments, the crystalline form, solvate, crystalline form of a solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) used herein is formulated for delivery via a face mask inhaler.

[0158] Preparations suitable for vaginal application may be provided in the form of pessaries, tampons, creams, gels, pastes, foams or sprays, and contain, in addition to the active ingredient, a suitable carrier known in the art.

[0159] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents and solutes to make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners.

[0160] The formulation is present in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred single-dose formulations are those containing a daily dose or a sub-daily dose of the active ingredient as described above, or a suitable portion thereof.

[0161] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations disclosed herein may include other agents conventional in the art in relation to the type of formulation discussed, such as those suitable for oral administration, which may include flavoring agents.

[0162] This disclosure also provides veterinary drug compositions comprising at least one active ingredient as defined above and its veterinary drug carrier.

[0163] Veterinary drug carriers are materials that can be used to administer compositions and can be solid, liquid, or gaseous materials. They are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary drug compositions can be administered orally, parenterally, or via any other desired route.

[0164] The crystalline form, solvate, crystalline form of the solvate, or solid form of the present disclosure (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) are used to provide a controlled-release pharmaceutical formulation (“controlled-release formulation”) containing one or more of the crystalline form, solvate, crystalline form of the solvate, or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) as the active ingredient, wherein the release of the active ingredient is controlled and modulated to allow for lower frequency of administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0165] Reagent test kit This document also provides kits that comprise the crystalline, solvated, crystalline, or solid forms of the solvated forms disclosed herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate). In some embodiments, the kits described herein may include a label and / or instructions for use to treat a disease or condition in a subject (e.g., a human) in the crystalline, solvated, crystalline, or solid form of the solvated form (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate). In some embodiments, the disease or condition is a viral infection.

[0166] In some embodiments, the kit may also include one or more additional therapeutic agents and / or use the additional therapeutic agents in combination with the crystalline form, solvate, crystalline or solid form of the solvate disclosed herein (crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate or crystalline form of formula (I) fumarate) to treat the disease or condition of the subject (e.g., a person) in need.

[0167] In some embodiments, the kits provided herein comprise individual dose units in crystalline, solvated, crystalline, or solid forms as described herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate). Examples of individual dose units may include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each containing a therapeutically effective amount of the discussed crystalline, solvated, crystalline, or solid form (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate). In some embodiments, the kit may contain a single dose unit, and in other embodiments, multiple dose units are present, e.g., the number of dose units required for a specified regimen or cycle.

[0168] Articles of manufacture are also provided, including crystalline forms, solvates, crystalline or solid forms of solvates (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) and containers. In some embodiments, the containers for the articles of manufacture are vials, cans, ampoules, pre-filled syringes, blister packs, cans, tins, bottles, boxes, intravenous bags, inhalers, or nebulizers.

[0169] application One or more crystalline forms, solvates, crystalline forms of solvates, or solid forms of the present disclosure (crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) are administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, local (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). In some embodiments, the crystalline forms, solvates, crystalline forms of solvates, or solid forms of the present disclosure (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) are administered by inhalation or intravenous administration. In some embodiments, the crystalline forms, solvates, crystalline forms of solvates, or solid forms of the present disclosure (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) are administered orally. It should be understood that the preferred approach may change depending on, for example, the conditions of the recipient.

[0170] In the methods for treating viral infections disclosed herein, the crystalline forms, solvates, crystalline or solid forms of solvates disclosed herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) may be administered at any time to persons who may have been exposed to a virus or who have already contracted a viral infection. In some embodiments, the crystalline forms, solvates, crystalline or solid forms of solvates disclosed herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) may be administered prophylactically to persons who have been exposed to or are at risk of exposure to persons who have been exposed to a viral infection (e.g., healthcare providers). In some embodiments, the application of the crystalline forms, solvates, crystalline or solid forms of solvates disclosed herein (e.g., crystalline forms of formula (I) maleate, formula (I) oxalate, or formula (I) fumarate) may be used to persons who test positive for a viral infection but have not yet shown symptoms of a viral infection. In some embodiments, the application of the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein may be used on a person at the onset of symptoms of viral infection.

[0171] In some implementations, the methods disclosed herein include event-driven administration to a subject of the crystalline form, solvate, crystalline form of the solvate, or solid form of the crystalline form of the solvate disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate).

[0172] As used herein, the terms “event-driven” or “event-driven administration” mean that the crystalline form, solvate, crystalline or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) (1) is administered before an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event); and / or (2) is administered during an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (or more than one repeated event); and / or (3) is administered after an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (or after the final event in a series of repeated events). In some embodiments, event-driven administration is performed before the subject is exposed to the virus. In some embodiments, event-driven administration is performed after the subject is exposed to the virus. In some implementations, event-driven administration is performed both before and after the subject is exposed to the virus.

[0173] In some embodiments, the methods disclosed herein involve administration, for example as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP), before and / or after an event that will expose an individual to a virus or otherwise increase the individual's risk of acquiring a viral infection. In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0174] In some implementations, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein is administered to the subject prior to exposure to the virus.

[0175] In some implementations, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein are administered to the subject before and after exposure to the virus.

[0176] In some implementations, the crystalline form, solvate, crystalline or solid form of the solvate disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate or crystalline form of formula (I) fumarate) is administered after the subject has been exposed to the virus.

[0177] Examples of event-driven dosing regimens include administering the crystalline form, solvate, crystalline form of the solvate, or solid form of the product disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) every 24 hours to 2 hours prior to exposure, followed by administration of the crystalline form, solvate, crystalline form of the solvate, or solid form of the product disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) every 24 hours during the exposure period. The crystalline form of the salt), followed by further application of the crystalline form, solvate, crystalline form of the solvate or solid form disclosed herein (e.g., the crystalline form of formula (I) maleate, the crystalline form of formula (I) oxalate or the crystalline form of formula (I) fumarate) after the last exposure, and a final application of the crystalline form, solvate, crystalline form of the solvate or solid form disclosed herein (e.g., the crystalline form of formula (I) maleate, the crystalline form of formula (I) oxalate or the crystalline form of formula (I) fumarate) 24 hours later.

[0178] Another example of an event-driven dosing regimen involves administering the crystalline, solvated, crystalline or solid form of the solvated form disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate or crystalline form of formula (I) fumarate) within 24 hours prior to viral exposure, followed by daily administration during the exposure period, and then a final administration approximately 24 hours after the last exposure (which may be an increased dose, such as a double dose).

[0179] The specific dose level for any particular subject in the crystalline form, solvate, crystalline form of the solvate, or solid form disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) will depend on a number of factors, including the activity of the specific crystalline form, solvate, crystalline form of the solvate, or solid form used (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate), age, weight, general health condition, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, and the severity of a particular disease in the subject receiving the therapy. For example, the dose may be expressed as milligrams per kilogram of subject weight (mg / kg) in the crystalline form, solvate, crystalline form of the solvate, or solid form disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate). Doses between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, doses between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting doses among subjects with large size differences (such as when using the drug in children and adults, or when converting an effective dose for non-human subjects such as dogs to a dose suitable for human subjects).

[0180] The daily dose may also be described as the total amount of the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein administered per dose or per day. The daily dose of the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein may be between about 1 mg and 4,000 mg, between about 2,000 mg / day and 4,000 mg / day, between about 1 mg / day and 2,000 mg / day, between about 1 mg / day and 1,000 mg / day, between about 10 mg / day and 500 mg / day, between about 20 mg / day and 500 mg / day, between about 50 mg / day and 300 mg / day, between about 75 mg / day and 200 mg / day, or between about 15 mg / day and 150 mg / day.

[0181] The dosage or frequency of administration of the crystalline form, solvate, crystalline form or solid form of the solvate disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate or crystalline form of formula (I) fumarate) may be adjusted during treatment based on the judgment of the administering physician.

[0182] A therapeutically effective amount may be administered to an individual (e.g., a human) in the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate). In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) is administered once daily.

[0183] In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) is applied twice daily. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) is applied three times daily. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) is applied four times daily. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) is applied five times daily.

[0184] The crystalline form, solvate, crystalline or solid form of the solvate disclosed herein (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate or crystalline form of formula (I) fumarate) may be administered by any useful route and device, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., the crystalline form of formula (I) maleate, the crystalline form of formula (I) oxalate, or the crystalline form of formula (I) fumarate) may include about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, the therapeutically effective amounts of the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) provided herein include about 0.3 mg / day to about 30 mg / day, or about 30 mg / day to about 300 mg / day, or about 0.3 mg / day to about 30 mg / day, or about 30 mg / day to about 300 mg / day.

[0185] The crystalline form, solvate, crystalline or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate or crystalline form of formula (I) fumarate) of this disclosure may be combined with one or more additional therapeutic agents at any dose (e.g., 1 mg to 1000 mg of the crystalline form, solvate, crystalline or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate or crystalline form of formula (I) fumarate)). Therapeutic effective doses may include from about 0.1 mg / dose to about 1000 mg / dose, such as from about 50 mg / dose to about 500 mg / dose, or such as from about 100 mg / dose to about 400 mg / dose, or such as from about 150 mg / dose to about 350 mg / dose, or such as from about 200 mg / dose to about 300 mg / dose, or such as from about 0.01 mg / dose to about 1000 mg / dose, or such as from about 0.01 mg / dose to about 100 mg / dose, or such as from about 0.1 mg / dose to about 100 mg / dose, or such as from about 1 mg / dose to about 100 mg / dose, or such as from about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective doses of the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose.Other therapeutically effective doses of the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein are about 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose. mg / dose, 450mg / dose, 475mg / dose, 500mg / dose, 525mg / dose, 550mg / dose, 575mg / dose, 600mg / dose, 625mg / dose, 650mg / dose, 675mg / dose, 700mg / dose, 725mg / dose, 750mg / dose, 775mg / dose, 800mg / dose, 825mg / dose, 850mg / dose, 875mg / dose, 900mg / dose, 925mg / dose, 950mg / dose, 975mg / dose or approximately 1000mg / dose.

[0186] In some embodiments, the method described herein comprises administering to a subject an initial daily dose of about 1 mg to 500 mg in the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) provided herein, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0187] When administered orally, the total daily dose for human subjects may range from about 1 mg / day to 4,000 mg / day, from about 1 mg / day to 3,000 mg / day, from 1 mg / day to 2,000 mg / day, from about 1 mg / day to 1,000 mg / day, from about 10 mg / day to 500 mg / day, from about 50 mg / day to 300 mg / day, from about 75 mg / day to 200 mg / day, or from about 100 mg / day to 150 mg / day. In some implementations, the total daily dose for human subjects may be approximately 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, 1400 mg / day, or 1500 mg / day. The daily doses for human subjects may be approximately 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, or 800 mg / day, administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, or 600 mg / day, administered as a single dose. In some implementations, the total daily dose for human subjects may be approximately 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, 1400 mg / day, 1500 mg / day, 1600 mg / day, 1700 mg / day, 1800 mg / day, 1900 mg / day, 200 mg / day, etc. 0 mg / day, 2100 mg / day, 2200 mg / day, 2300 mg / day, 2400 mg / day, 2500 mg / day, 2600 mg / day, 2700 mg / day, 2800 mg / day, 2900 mg / day, 3000 mg / day, 3100 mg / day, 3200 mg / day, 3300 mg / day, 3400 mg / day, 3500 mg / day, 3600 mg / day, 3700 mg / day, 3800 mg / day, 3900 mg / day, or 4000 mg / day.In some implementations, the total daily dose for human subjects may be approximately 100 mg / day - 200 mg / day, 100 mg / day - 300 mg / day, 100 mg / day - 400 mg / day, 100 mg / day - 500 mg / day, 100 mg / day - 600 mg / day, 100 mg / day - 700 mg / day, 100 mg / day - 800 mg / day, 100 mg / day - 900 mg / day, 100 mg / day - 1000 mg / day, or 500 mg / day. -1100mg / day, 500mg / day-1200mg / day, 500mg / day-1300mg / day, 500mg / day-1400mg / day, 500mg / day-1500mg / day, 500mg / day-1600mg / day, 500mg / day-1700mg / day, 500mg / day-1800mg / day, 500mg / day-1900mg / day, 500mg / day-2000mg / day, 1500mg / day-21 00mg / day, 1500mg / day-2200mg / day, 1500mg / day-2300mg / day, 1500mg / day-2400mg / day, 1500mg / day-2500mg / day, 2000mg / day-2600mg / day, 2000mg / day-2700mg / day, 2000mg / day-2800mg / day, 2000mg / day-2900mg / day, 2000mg / day-3000mg / day, 2500mg / day The daily doses are 3100 mg / day, 2500 mg / day, 3200 mg / day, 3300 mg / day, 3400 mg / day, 3500 mg / day, 3600 mg / day, 3700 mg / day, 3800 mg / day, 3900 mg / day, or 4000 mg / day. In some embodiments, the total daily dose for human subjects is approximately 500 mg / day to 1000 mg / day, administered once or twice daily.

[0188] In some embodiments, the total daily dose of the human subject may be about 100 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 150 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 200 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 250 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 300 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 350 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 400 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 450 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 500 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 550 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 600 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 650 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 700 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 750 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 800 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 850 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 900 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 950 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 1000 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 1500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 2000 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 2500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 3000 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 4000 mg / day, administered as a single dose.

[0189] In some embodiments, the total daily dose for a human subject may be about 100 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be about 150 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be about 200 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be about 250 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be about 300 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be about 350 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be about 400 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be about 450 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be about 500 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 550 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 600 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 650 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 700 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 750 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 800 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 850 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 900 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 950 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 1000 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 1500 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 2000 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 2500 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 3000 mg / day, administered at two doses per day. In some embodiments, the total daily dose for a human subject may be approximately 4000 mg / day, administered at two doses per day.

[0190] A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose may be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose may also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose may also be administered every 1 week, 2 weeks, 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein is administered once daily in the methods disclosed herein. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein is applied twice daily. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein is applied three times daily.

[0191] In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein is administered once daily at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein is administered twice daily at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein is administered three times daily at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein is administered once daily at a total daily dose of 300 mg / day to 900 mg / day.

[0192] The dosage frequency of the crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) disclosed herein will be determined by the individual patient's needs and may be, for example, once daily or twice daily or more. The crystalline form, solvate, crystalline form of the solvate, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) will be continuously administered to a person infected with a virus for a period of 20 to 180 days, or for example, for a period of 20 to 90 days, or for example, for a period of 30 to 60 days.

[0193] Administration may be intermittent, with periods of several days or more during which the patient receives a daily dose of the crystalline form, solvate, crystalline form of the solvate, or solid form of the present disclosure (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate), followed by periods of several days or more during which the patient does not receive a daily dose of the crystalline form, solvate, crystalline form of the solvate, or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate). For example, the patient may receive one dose of the crystalline form, solvate, crystalline form of the solvate, or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) every other day or three times a week. To reiterate, a patient may receive one dose daily in crystalline, solvated, crystalline, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive one dose daily in crystalline, solvated, crystalline, or solid form (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate), followed by a subsequent period (e.g., 1 to 14 days) during which the patient again receives the daily dose of crystalline, solvated, crystalline, or solid form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate, followed by a subsequent period (e.g., 1 to 14 days) during which the patient again receives the daily dose of crystalline, solvated, crystalline, or solid form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate. The solvate, the crystalline form or solid form of the solvate (e.g., the crystalline form of formula (I) maleate, the crystalline form of formula (I) oxalate, or the crystalline form of formula (I) fumarate) may be repeatedly applied to the patient as needed clinically, followed by alternating periods of non-application of the crystalline form, solvate, the crystalline form or solid form of the solvate (e.g., the crystalline form of formula (I) maleate, the crystalline form of formula (I) oxalate, or the crystalline form of formula (I) fumarate).

[0194] The crystalline form, solvate, crystalline or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) or pharmaceutical compositions thereof disclosed herein may be administered once, twice, three or four times daily in any suitable manner described above. Furthermore, administration or treatment with the crystalline form, solvate, crystalline or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) may continue for several days; for example, for a treatment cycle, treatment typically lasts for at least 3 days, at least 5 days, at least 7 days, 14 days, or 28 days.

[0195] How to use This disclosure also provides a method for treating or preventing viral infection in a subject (e.g., a person) in need of such treatment, the method comprising administering to the subject the crystalline form, solvate, crystalline form of the solvate, or solid form thereof (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate).

[0196] In some embodiments, this disclosure provides a method of treating a viral infection in a subject (e.g., a human) in need of treatment, the method comprising administering to the subject in need of treatment the crystalline form, solvate, crystalline form of the solvate, or solid form thereof (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate).

[0197] In some embodiments, the crystalline form, solvate, crystalline or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate or crystalline form of formula (I) fumarate) described herein is administered to humans via oral, intramuscular, intravenous, subcutaneous or inhalation administration.

[0198] In some embodiments, this disclosure provides a method for treating or preventing viral infection in a subject (e.g., a person) in need of such treatment, the method comprising administering to the subject a crystalline form, a solvate, a crystalline or solid form of a solvate (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) and at least one additional active therapeutic or preventative agent.

[0199] In some embodiments, this disclosure provides a method of treating a viral infection in a subject (e.g., a person) in need of such treatment, the method comprising administering to the subject a crystalline form, a solvate, a crystalline or solid form of a solvate (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) and at least one additional active therapeutic or preventative agent.

[0200] In one embodiment, this disclosure provides a method for inhibiting viral polymerase in cells, the method comprising contacting virus-infected cells with crystalline forms, solvates, crystalline or solid forms of solvates disclosed herein (e.g., crystalline forms of maleate, oxalate, or fumarate of formula (I)) thereby inhibiting the viral polymerase.

[0201] In one embodiment, this disclosure provides a method for inhibiting viral polymerase in cells, the method comprising contacting a virus-infected cell with a crystalline form, a solvate, a crystalline or solid form of a solvate (e.g., a crystalline form of formula (I) maleate, a crystalline form of formula (I) oxalate, or a crystalline form of formula (I) fumarate) and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0202] This document also provides for the use of the crystalline forms, solvates, crystalline or solid forms of the solvates disclosed herein (e.g., crystalline forms of formula (I) maleate, crystalline forms of formula (I) oxalate, or crystalline forms of formula (I) fumarate) for the treatment or prevention of viral infections in subjects in need. For example, this document provides for the use of the crystalline forms, solvates, crystalline or solid forms of the solvates disclosed herein (e.g., crystalline forms of formula (I) maleate, crystalline forms of formula (I) oxalate, or crystalline forms of formula (I) fumarate) for the treatment of viral infections in subjects in need.

[0203] In some embodiments, the viral infection is a paramyxoviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a paramyxoviridae infection in a subject (e.g., a human) in need, the method comprising administering the compounds described herein to the subject. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles, mumps, and parainfluenza viruses.

[0204] In some implementations, the viral infection is human parainfluenza virus infection, Nipah virus infection, Hendra virus infection, measles infection, or mumps infection.

[0205] In some embodiments, the viral infection is a pulmonaviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a pulmonaviridae virus infection, the method comprising administering to the person the compounds described herein. Pulmonaviridae viruses include, but are not limited to, respiratory syncytial virus (RSV) and human metapneumovirus (HMV). In some embodiments, the pulmonaviridae virus infection is a respiratory syncytial virus (RSV) infection. In some embodiments, the pulmonaviridae virus infection is a human metapneumovirus (HMV) infection.

[0206] In some embodiments, this disclosure provides the compounds described herein for treating pulmonary viral infections in persons of need. In some embodiments, the pulmonary viral infection is respiratory syncytial virus infection. In some embodiments, the pulmonary viral infection is human metapneumovirus infection.

[0207] In some embodiments, this disclosure provides a method for treating RSV infection in a person of need, the method comprising administering the compound described herein to the person. In some embodiments, the person has a chronic respiratory syncytial virus infection. In some embodiments, the person is acutely infected with RSV.

[0208] In some implementations, a method for inhibiting RSV replication is provided, wherein the method includes administering the compound described herein to a person in need, wherein the administration is by inhalation.

[0209] In some embodiments, this disclosure provides a method for reducing viral load associated with RSV infection, wherein the method includes administering the compounds described herein to a person infected with RSV.

[0210] In some embodiments, the viral infection is a picoriviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a picoriviridae virus infection, the method comprising administering the compound described herein to that person. Picoriviridae viruses are heterogeneous enteroviruses that cause infections including herpetic pharyngitis, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), nonparalytic poliomyelitis-like syndrome, epidemic pleuropneumonia (an acute, febrile, infectious disease that typically occurs during epidemics), hand-foot-mouth disease, pancreatitis in children and adults, and severe myocarditis. In some embodiments, the picoriviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the picoriviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0211] In some implementations, the viral infection is selected from: Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

[0212] In some embodiments, this disclosure provides compounds for treating microribonucleoviridae virus infections in people of need. In some embodiments, the microribonucleoviridae virus infection is a human rhinovirus infection.

[0213] In some embodiments, the viral infection is a flaviviridae virus infection. Therefore, in some embodiments, this disclosure provides a method of treating a person in need of a flaviviridae virus infection, the method comprising administering the compound described herein to that person. Representative flaviviridae viruses include, but are not limited to, dengue fever, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the flaviviridae virus infection is dengue virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile virus infection. In some embodiments, the flaviviridae virus infection is Zika virus infection. In some embodiments, the flaviviridae virus infection is Japanese encephalitis virus infection. In some embodiments, the flaviviridae virus infection is hepatitis C virus infection.

[0214] In some implementation schemes, Flaviviridae virus infection includes dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunzin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

[0215] In some embodiments, this disclosure provides the use of the compounds described herein for treating flaviviridae virus infections in persons of need. In some embodiments, the flaviviridae virus infection is dengue virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile virus infection. In some embodiments, the flaviviridae virus infection is Zika virus infection. In some embodiments, the flaviviridae virus infection is hepatitis C virus infection.

[0216] In some embodiments, the viral infection is a filoviridae virus infection. Therefore, in some embodiments, this document provides a method for treating a person in need of a filoviridae virus infection, the method comprising administering the compound described herein to that person. Representative filoviridae viruses include, but are not limited to, Ebola virus (variants Zaire, Bundibugio, Sudan, Tai Forest, or Reston) 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.

[0217] In some embodiments, this disclosure provides compounds for treating filoviridae virus infections in people of need. In some embodiments, the filoviridae virus infection is Ebola virus infection. In some embodiments, the filoviridae virus infection is Marburg virus infection.

[0218] In some embodiments, the viral infection is a coronavirus infection. Therefore, in some embodiments, this document provides a method for treating a person in need of a coronavirus infection, wherein the method comprises administering the compound described herein to that person. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS-CoV) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus infection (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9). In some embodiments, the viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is 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 with a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 80% sequence homology with a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 90% sequence homology with a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 95% sequence homology with a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0219] In some embodiments, viral infection is caused by a variant of SARS-CoV-2, such as variant B.1.1.7 (UK variant), variant B.1.351 (South African variant), variant P.1 (Brazilian variant), variants B.1.1.7 and E484K, variant B.1.1.207, variant B.1.1.317, variant B.1.1.318, variant B.1.429, variant B.1.525, or variant P.3. In some embodiments, viral infection is caused by variant B.1.1.7 of SARS-CoV-2. In some embodiments, viral infection is caused by variant B.1.351 of SARS-CoV-2. In some embodiments, viral infection is caused by variant P.1 of SARS-CoV-2.

[0220] In some embodiments, this disclosure provides compounds for treating coronavirus infections in people in need. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1), and zoonotic coronaviruses (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9). In some embodiments, the viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection (COVID-19).

[0221] In some implementations, the viral infection is a coronavirus infection. In some implementations, the coronavirus is an alpha coronavirus, beta coronavirus, gamma coronavirus, delta coronavirus, ε coronavirus, η coronavirus, ι coronavirus, κ coronavirus, ο coronavirus, ζ coronavirus, or μ coronavirus.

[0222] In some implementations, coronavirus infection is alpha coronavirus infection. In some implementations, alpha coronavirus is feline coronavirus (FcoV), FcoV-II, transmissible gastroenteritis virus (TGEV), swine respiratory coronavirus (PRCV), canine coronavirus (CcoV), CcoV-II, CRCoV, human coronavirus 229E (HcoV-229E), human coronavirus NL63 (HcoV-NL63), porcine epidemic diarrhea virus (PEDV), porcine acute diarrhea syndrome coronavirus (SADS-CoV), bat coronavirus (bat CoV), or FRCoV.

[0223] In some implementations, the coronavirus infection is a beta coronavirus infection. In some implementations, the beta coronavirus is human coronavirus OC43 (HcoV-OC43), human coronavirus HKU-1 (HcoV-HKU1), human enteric coronavirus-4408 (HECoV-4408), bovine coronavirus (BcoV), BcoV-like CoV, BcoV-like CoV, canine respiratory coronavirus (CRCoV), equine coronavirus (EcoV), porcine hemagglutinating encephalomyocarditis virus (PHEV), mouse hepatitis virus (MHV), Middle East respiratory syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), bat coronavirus (bat CoV), rabbit coronavirus (RbCoV), or buffalo coronavirus (BuCoV).

[0224] In some implementations, the β-coronavirus is sarbecovirus. In some implementations, sarbecovirus is Longquan 140, pangolin-CoV, RmYN02, RaTG13, CoVZC45, CoVZXC21, GX-P4L, RshSTT182, RshSTT200, RacCS203, Rc-o319, RpYN06, or PrC31.

[0225] In some implementations, coronavirus infection is gamma coronavirus infection. In some implementations, gamma coronavirus is infectious bronchitis virus (IBV), turkey coronavirus (TcoV), bottlenose whale coronavirus (BdCoV), beluga whale coronavirus (BWCoV), or PhCoV.

[0226] In some implementations, the coronavirus infection is a delta coronavirus infection. In some implementations, the delta coronavirus is a porcine delta coronavirus (PDCoV).

[0227] In some implementations, coronavirus infection is o-coronavirus infection. In some implementations, o-coronavirus is WA1 (lineage A), BF.7, BQ.1, XBB.1.5, CH.1.1, XBF, XBB.1.16, or XBB.1.9.1.

[0228] In some embodiments, the viral infection is an infection of a arenaviridae virus. Therefore, in some embodiments, this disclosure provides a method for treating an arenaviridae virus infection in a person of need, the method comprising administering the compound described herein to the person. In some embodiments, the arenaviridae virus infection is a lassa virus infection or a juniper virus infection.

[0229] In some embodiments, this disclosure provides compounds for treating arenaviridae virus infections in persons in need. In some embodiments, the arenaviridae virus infection is lassa virus infection or Junin virus infection.

[0230] In some implementations, the viral infection is an orthomyxovirus infection, such as an influenza virus infection. In some implementations, the viral infection is an influenza A virus infection, an influenza B virus infection, or an influenza C virus infection.

[0231] In some implementations, the viral infection is a poxvirus infection. In some implementations, the poxvirus infection is an orthopoxvirus infection. In some implementations, the poxvirus infection is a camelpoxvirus infection, cowpoxvirus infection, mousepoxvirus infection, horsepoxvirus infection, monkeypoxvirus infection, raccoonpoxvirus infection, skunkpoxvirus infection, gerbilpoxvirus infection, uasin gishu virus infection, vaccinia virus infection, smallpox virus infection, or volepoxvirus infection.

[0232] In some implementations, poxvirus infection is vaccinia virus infection.

[0233] In some embodiments, the poxvirus infection is a monkeypoxvirus infection. The methods described herein can be used to treat or prevent infections caused by any strain of monkeypoxvirus. In some embodiments, the poxvirus infection is caused by a West African strain of monkeypoxvirus. In some embodiments, the poxvirus infection is caused by a Congo Basin strain of monkeypoxvirus.

[0234] In some implementations, poxvirus infection is a parapoxvirus infection. In some implementations, poxvirus infection is bovine papulopoxvirus infection, aphthous stomatitis virus infection, pseudovaccinia virus infection, red deer parapoxvirus infection, or squirrel parapoxvirus infection. In some implementations, poxvirus infection is camel infectious pustular virus infection, antelope infectious pustular virus infection, reindeer parapoxvirus infection, or seal poxvirus infection.

[0235] In some implementations, poxvirus infection is an infection of the molluscum poxvirus genus. In some implementations, poxvirus infection is an infection of molluscum contagiosum.

[0236] In some implementations, poxvirus infection is a Tapoxvirus infection. In other implementations, poxvirus infection is Turner pox, Yaba-like disease virus infection, or Yaba monkey tumor virus infection.

[0237] In some implementations, poxvirus infection is a goatpoxvirus infection. In some implementations, poxvirus infection is sheep poxvirus infection, goatpoxvirus infection, or bovine nodular herpesvirus infection.

[0238] In some implementations, poxvirus infection is a swinepoxvirus infection.

[0239] In some implementations, poxvirus infection is a tularemic virus infection. In other implementations, poxvirus infection is myxomavirus infection, Shop fibromavirus (rabbit fibroma) infection, squirrel fibromavirus infection, or tularemic fibromavirus infection.

[0240] In some implementations, poxvirus infection is an infection of the fowlpoxvirus genus. In some implementations, poxvirus infection is canarypoxvirus infection, fowlpoxvirus infection, fowlpoxvirus infection, myna poxvirus infection, pigeon poxvirus infection, parrot poxvirus infection, quail poxvirus infection, sparrow poxvirus infection, swallow myna poxvirus infection, or turkey poxvirus infection. In some implementations, poxvirus infection is crowpoxvirus infection, peacock poxvirus infection, or penguin poxvirus infection.

[0241] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a virus, together with one or more adjunctive therapeutic agents. The adjunctive therapeutic agents can be administered to the infected individual simultaneously with, before, or after the administration of the compounds of this disclosure.

[0242] Combination therapy The crystalline form, solvate, crystalline or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) described herein may also be used in combination with one or more additional therapeutic agents. Therefore, this document also provides methods for treating viral infections in subjects in need, wherein these methods include administering to the subject in need the crystalline form, solvate, crystalline or solid form of the solvate (e.g., crystalline form of formula (I) maleate, crystalline form of formula (I) oxalate, or crystalline form of formula (I) fumarate) and a therapeutically effective amount of one or more additional therapeutic agents.

[0243] In some implementations, the additional treatment is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein.

[0244] In some implementations, the adjunctive therapeutic agents are 2,5-oligoadenylate synthase stimulators, 5-HT 2a receptor antagonists, 5-lipoxygenase inhibitors, ABL family tyrosine kinase inhibitors, Abl tyrosine kinase inhibitors, aldehyde dehydrogenase inhibitors, acetyl-CoA carboxylase inhibitors, actin antagonists, actin modulators, activity-dependent neuroprotective modulators, adenosine A3 receptor agonists, adrenergic receptor antagonists, adrenal medullary ligands, adrenal medullary ligand inhibitors, late glycosylation product receptor antagonists, late glycosylation product receptor modulators, AKT protein kinase inhibitors, alanine-proline-rich secretory protein stimulators, aldose reductase inhibitors, alkaline phosphatase stimulators, α2-adrenergic receptor antagonists, α2B-adrenergic receptor agonists, AMP-activated protein kinase stimulators, AMPA receptor modulators, amyloid deposition inhibitors, androgen receptor antagonists, angiotensin II AT-1 receptor antagonists, and 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, antihyperxia drugs, antithrombotic agents, AP1 transcription factor modulators, apralin 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 modulators, Axl tyrosine kinase receptor inhibitors, bactericidal permeability-increasing protein inhibitors, basigin inhibitors, basigin modulators, BCL2 gene inhibitors, BCL2L11 gene stimulators, Bcr protein inhibitors, β1-adrenergic receptor modulators, β2-adrenergic receptor agonists β-adrenergic receptor agonists, β-inhibitor protein stimulants, 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, bromine-domain-containing protein 2 inhibitors, bromine-domain-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, calpain-I inhibitors, calpain-II inhibitors, calpain-IX inhibitors, cannabinoid CB2 receptor agonists, cannabinoid receptor modulators, casein kinase II inhibitors, CASP8-FADD-like regulatory factor inhibitors, caspase inhibitors, catalase stimulants, CCL26 gene inhibitors, CCR2 chemokine antagonists.CCR5 chemokine antagonists, CD11a agonists, CD122 agonists, CD3 antagonists, CD4 agonists, CD40 ligands, CD40 ligand modulators, CD40 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 transporter inhibitors, collagen modulators, complement. C1s subfraction inhibitors, complement C3 inhibitors, complement C5 factor inhibitors, complement C5a factor inhibitors, complement factor H stimulants, 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, COVID-19 envelope small membrane protein modulators, COVID-19 nonstructural protein 8 modulators, COVID-19 nucleoprotein modulators, COVID-19 protein 3a inhibitors, COVID-19 9. Replicaase polyprotein 1a inhibitors, COVID-19 replicaase polyprotein 1a modulators, COVID-19 replicaase polyprotein 1ab inhibitors, COVID-19 replicaase polyprotein 1ab modulators, COVID-19 spike glycoprotein inhibitors, COVID-19 spike glycoprotein modulators, COVID-19 structural glycoprotein modulators, CRF-2 receptor agonists, CSF-1 agonists, CSF-1 antagonists, CX3CR1 chemokine antagonists, CXC10 chemokine ligand inhibitors, CXC5 chemokine ligand inhibitors, CXCL1 gene modulators, CXCL2 Gene regulators, CXCL3 gene regulators, 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, cyclic protein 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 δ4 dehydrogenase 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 1α2 regulators, endoplasmic reticulum regulators, endonuclease DICER regulators, endothelin ET-A receptor antagonists, epidermal growth factor receptor antagonists, E-selectin antagonists, estrogen receptor β agonists, estrogen receptor regulators, eukaryotic initiation factor 4A-I inhibitors, exo-α-sialic acid oxidase regulators, export protein 1 inhibitors, factor Ia regulators, factor Iia regulators, factor VII antagonists, factor Xa antagonists, factor Xia antagonists, FGF receptor antagonists, FGF-1 ligands, FGF-1 ligand inhibitors, FGF-2 ligand inhibitors, FGF1 receptor antagonists, FGF2 receptor antagonists, FGF3 receptor antagonists, Flt3 tyrosine kinase inhibitors, Fractalkine ligand inhibitors, free fatty acid receptor 2 agonists, free fatty acid receptor 3 agonists, furin protease inhibitors, Fyn tyrosine kinase inhibitors, FYVE (phosphatidylinositol kinase inhibitors), G protein-coupled bile acid receptor 1 agonists, GABA Alpha receptor modulators, galactoglobulin-3 inhibitors, gamma-secretase inhibitors, GDF agonists, colloid stimulants, glial cell neurotrophic factor ligands, glucocorticoid receptor agonists, glutathione peroxidase stimulants, GM-CSF ligand inhibitors, GM-CSF receptor agonists, GM-CSF receptor modulators, Griffithsin modulators, growth regulator protein α-ligand inhibitors, Grp78 calcium-binding protein inhibitors, heat shock protein HSP90α inhibitors, heat shock protein HSP90β inhibitors Inhibitors, heat shock protein inhibitors, heat shock protein stimulants, hemagglutinin modulators, hemoglobin modulators, hemolysin α 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 box B1 inhibitors, histamine H1 receptor antagonists, histamine H2 receptor antagonists, histone deacetylase-6 inhibitors, histone inhibitors, HIV protease inhibitors, HIV-1 gp120 protein inhibitor, HIV-1 protease inhibitor, HIV-1 reverse transcriptase inhibitor, HLA class I antigen modulator, HLA class II antigen modulator, host cytokine modulator, Hsp90 inhibitor, human papillomavirus E6 protein modulator, human papillomavirus E7 protein modulator, hypoxia-inducible factor inhibitor gene inhibitor, hypoxia-inducible factor-2α modulator, I-κB kinase inhibitor, I-κB kinase modulator, ICAM-1 stimulator, IgG receptor FcRn large subunit p51 modulator, IL-12 receptor antagonist.IL-15 receptor agonists, IL-15 receptor modulators, IL-17 antagonists, IL-18 receptor cofactor antagonists, IL-2 receptor agonists, IL-22 agonists, IL-23 antagonists, IL-6 receptor agonists, IL-6 receptor antagonists, IL-6 receptor modulators, IL-7 receptor agonists, IL-8 receptor antagonists, IL-12 gene stimulators, IL-8 gene modulators, immunoglobulin G modulators, immunoglobulin G1 agonists, immunoglobulin G1 modulators, immunoglobulin agonists, immunoglobulin γFc receptor I modulators, immunoglobulin κ modulators, inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, integrin agonists, integrin α-4 / β-7 antagonists, integrin α-V / β-1 antagonists, integrin α-V / β-6 antagonists, interferon agonists, interferon α14 ligands Interferon α2 ligand, interferon α2 ligand modulator, interferon α ligand, interferon α ligand inhibitor, interferon α ligand modulator, interferon β ligand, interferon γ ligand inhibitor, interferon γ receptor agonist, interferon γ receptor antagonist, interferon receptor modulator, interferon type I receptor agonist, interleukin 17A ligand inhibitor, interleukin 17F ligand inhibitor, interleukin 18 ligand inhibitor, interleukin 22 ligand, interleukin-1β ligand inhibitor, interleukin-1β 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, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak2 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, 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 stimulants, 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, listeriin stimulants, liver X receptor antagonists, low molecular weight heparin, lung surfactant-associated protein B stimulants, lung surfactant-associated protein D modulators, Lyn tyrosine kinase inhibitors, Lyn tyrosine kinase stimulants, lysine-specific histone demethylase 1 inhibitors, macrophage migration 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 Potassium K channel inhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitorsMelanocortin MC1 receptor agonists, melanocortin MC3 receptor agonists, metalloproteinase-12 inhibitors, METTL3 gene inhibitors, membrane spike protein inhibitors, membrane spike protein modulators, monocyte chemotactic protein 1 ligand inhibitors, monocyte differentiation antigen CD14 inhibitors, mRNA guanine N7 methyltransferase modulators, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, mTOR inhibitors, mucoprotein modulators, muscarinic receptor antagonists, myeloperoxidase inhibitors, NACHT LRR PYD domain protein 3 inhibitors, NAD synthase regulators, NADPH oxidase inhibitors, neurocilia protein 2 regulators, neuroplastic protein inhibitors, NFE2L2 gene stimulators, NK cell receptor agonists, NK1 receptor antagonists, NMDA receptor antagonists, NMDA receptor ε2 subunit inhibitors, non-receptor tyrosine kinase TYK2 antagonists, non-nucleoside reverse transcriptase inhibitors, nsp12 polymerase inhibitors, nucleoerythroid 2-related factor 2 stimulators, nuclear factor κB inhibitors, nuclear factor κB regulators, nuclease stimulators, nucleolarine inhibitors, nucleoprotein inhibitors, nucleoprotein regulators, nucleoside reverse transcriptase inhibitors, opioid receptor agonists, opioid receptor antagonists, opioid receptor µ regulators, opioid receptor σ antagonists, ORF1ab polyprotein inhibitors, ornithine decarboxylase inhibitors, outer membrane protein inhibitors, OX40 ligands, p38 MAP kinase α 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 α antagonists, PDGF receptor antagonists, PDGF receptor β antagonists, peptidyl-prolyl cis-trans isomerase A inhibitors, peroxidase 6 modulators, PGD2 antagonists, PGI2 agonists, P-glycoprotein inhibitors, phosphoinositol 3-kinase inhibitors, phosphoinositol-3-kinase δ inhibitors, phosphoinositol-3-kinase γ inhibitors, phospholipase A2 inhibitors, PIKfyve inhibitors, plasma kallikrein inhibitors, plasminogen activator inhibitor 1 inhibitors, platelet inhibitors, platelet glycoprotein VI inhibitors, Po Io-like kinase 1 inhibitors, poly-ADP-ribose polymerase 1 inhibitors, poly-ADP-ribose polymerase 2 inhibitors, polymerase cofactor VP35 inhibitors, PPARα 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 β inhibitors, protein tyrosine phosphatase-2C inhibitors, proto-oncogene Mas agonists, purine receptor antagonists.Raf protein kinase inhibitors, RANTES ligands, Ras gene inhibitors, retinoic acid 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-like protease inhibitors, serine protease inhibitors, serine threonine protein kinase ATR inhibitors, serine threonine protein kinase TBK1 inhibitors, serum amyloid A modulators, signal transduction protein CD24 stimulators, silencing regulator inhibitors, 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-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, 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 immune receptor 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 regulators, anchored polymerase-1 inhibitors, anchored polymerase-2 inhibitors, Tek tyrosine kinase receptor stimulators, telomerase regulators, tetanus toxin regulators, TGFβ receptor antagonists, TGFB2 gene inhibitors, thymosin β4 ligands, thyroid hormone receptor β agonists, tissue factor inhibitors, tissue plasminogen activator regulators, tissue plasminogen activator stimulators, TLR agonists, TLR regulators, TLR-2 agonists, TLR-2 antagonists, TLR-3 agonists, TLR-4 agonists, TL... TLR-4 antagonists, TLR-6 agonists, TLR-7 agonists, TLR-7 antagonists, TLR-8 antagonists, TLR-9 agonists, TMPRSS2 gene inhibitors, TNFα ligand inhibitors, TNFα ligand modulators, TNF binding agents, TNF gene inhibitors, topoisomerase inhibitors, transcription factor EB stimulators, transferrin modulators, transketolase inhibitors, translocation-related protein inhibitors, transmembrane serine protease 2 inhibitors, thyroxine transporter 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 α inhibitors, tubulin β inhibitors, tumor necrosis factor 14 ligand inhibitors, TYK2 gene inhibitors, type I IL-1 receptor antagonists, tyrosine protein kinase ABL1 inhibitors, ubiquitin cytochrome C reductase 14 kDa inhibitors, ubiquitin ligase modulators, unspecified GPCR agonists, unspecified cytokine receptor modulators, unspecified enzyme stimulants, unspecified gene inhibitors, unspecified receptor modulators, urokinase plasminogen activator inhibitors, vascular cell adhesion protein 1 agonists, vasodilators, VEGF ligand inhibitors, VEGF receptor antagonists, VEGF-1 receptor antagonists, VEGF-1 receptor modulators, VEGF-2 receptor antagonists, VEGF-3 receptor antagonists, vimentin inhibitors, vimentin modulators, VIP receptor agonists, viral envelope protein inhibitors, viral protease inhibitors, viral protease modulators, viral protein target modulators, viral ribonuclease inhibitors, viral structural protein modulators, vitamin D3 receptor agonists, X-linked inhibitors of apoptosis protein inhibitors, xanthine oxidase inhibitors, or ligand inhibitors. ,

[0245] In some embodiments, the compounds and compositions of this disclosure may be administered in combination with Sars-Cov-2 treatments such as parenteral fluids (including glucose saline and Ringer's lactate), nutrients, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin / clavulanic acid, trimethoprim / sulfamethoxazole, R-327 and cephalosporin antibiotics such as ceftriaxone and cefuroxime), antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, 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 drugs (e.g., interferon), vaccines and analgesics.

[0246] In some implementations, the adjunctive treatment is an Abl tyrosine kinase inhibitor, such as ladotinib or imatinib.

[0247] In some implementations, the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor, such as ADX-629.

[0248] In some implementations, the additional therapeutic agent is an adenosine A3 receptor agonist, such as piclidenoson.

[0249] In some implementations, the additional therapeutic agent is an adrenomedullin ligand, such as adrenomedullin.

[0250] In some implementations, the additional therapeutic agent is a p38 MAPK + PPAR γ agonist / insulin sensitizer, such as KIN-001.

[0251] In some implementations, the additional therapeutic agent is a PPARα agonist, such as DWTC-5101 (fenofibratecholine).

[0252] In some implementations, the adjunctive treatment is a cyclin inhibitor, such as rencofilstat.

[0253] In some implementations, the additional therapeutic agent is a p38 MAP kinase inhibitor, such as PRX-201 or Gen-1124.

[0254] In some implementations, the additional therapeutic agent is an aldose reductase inhibitor, such as cabifrestat.

[0255] In some implementations, the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin.

[0256] In some implementations, the additional therapeutic agent is an annexin A5 stimulant, such as AP-01 or SY-005.

[0257] In some implementations, the additional therapeutic agent is an apalynide receptor agonist, such as CB-5064MM.

[0258] In some implementations, the adjunctive therapeutic agent is an anticoagulant, such as heparin (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparin.

[0259] In some implementations, the adjunctive therapeutic agent is an androgen receptor antagonist, such as bicalutamide, denlutamide, enzalutamide, or proxalutamide.

[0260] In some implementations, the additional treatment is an anti-hypoxia drug, such as disodium crocin.

[0261] In some implementations, the adjunctive therapeutic agent is an antithrombotic agent, such as defibrinoside, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tenecteplase.

[0262] In some implementations, the additional treatment is an antihistamine, such as clopidogrel or clomaste.

[0263] In some implementations, the additional therapeutic agent is an apolipoprotein A1 agonist, such as CER-001.

[0264] In some implementations, the additional therapeutic agent is a phospholipase A2 inhibitor, such as icosapentaenoic acid ethyl.

[0265] In some implementations, the additional therapeutic agent is an axl tyrosine kinase receptor inhibitor, such as besentinib.

[0266] In some implementations, the adjunctive treatment is a corticosteroid / β2-adrenergic receptor agonist, such as budesonide plus formoterol fumarate.

[0267] In some implementations, the additional therapeutic agent is a BET bromide domain inhibitor / APOA1 gene stimulator, such as apabetalone.

[0268] In some implementations, the adjunctive therapeutic agent is a blood coagulation modifier, such as lanaruzumab.

[0269] In some implementations, the additional therapeutic agent is a bradykinin B2 receptor antagonist, such as ateband.

[0270] In some implementations, the adjunctive therapeutic agent is an EGFR gene inhibitor / Btk tyrosine kinase inhibitor, such as abivertinib.

[0271] In some implementations, the adjunctive treatment is a Btk tyrosine kinase inhibitor, such as ibrutinib or zanubrutinib.

[0272] In some implementations, the additional therapeutic agent is a calpain-I / II / IX inhibitor, such as BLD-2660.

[0273] In some implementations, the adjunctive therapeutic agent is a cannabinoid CB2 receptor agonist, such as onternabez or PPP-003.

[0274] In some implementations, the additional therapeutic agent is a Ca2+ release-activating Ca2+ channel 1 inhibitor, such as zegocractin (CM-4620).

[0275] In some implementations, the additional treatment is an ATR inhibitor, such as bezosertib.

[0276] In some implementations, the additional therapeutic agent is a cadherin-5 modulator, such as FX-06.

[0277] In some implementations, the additional therapeutic agent is a casein kinase II inhibitor, such as silicataserb.

[0278] In some implementations, the additional therapeutic agent is a caspase inhibitor, such as emricasan.

[0279] In some implementations, the additional therapeutic agent is a catalase stimulator / superoxide dismutase stimulator, such as MP-1032.

[0280] In some implementations, the additional therapeutic agent is a CCR2 chemokine antagonist / CCR5 chemokine antagonist, such as cineviro.

[0281] In some implementations, the adjunctive treatment is a CCR5 chemokine antagonist, such as maraviro or lelimumab.

[0282] In some implementations, the additional therapeutic agent is a CD122 agonist / IL-2 receptor agonist, such as beempegaldesleukin.

[0283] In some implementations, the additional therapeutic agent is a CD73 agonist / interferon beta ligand, such as FP-1201.

[0284] In some implementations, the additional therapeutic agent is a cholesterol ester transporter inhibitor, such as dacetropeptide.

[0285] In some implementations, the additional therapeutic agent is a mannan-binding lectin serine protease / complement C1s subcomponent inhibitor / myeloperoxidase inhibitor, such as RLS-0071.

[0286] In some implementations, the additional therapeutic agent is a complement C5 factor inhibitor / leukotriene BLT receptor antagonist, such as nomacopan.

[0287] In some implementations, the adjunctive treatment is a complement factor C5 inhibitor, such as eculizumab, STSA-1002, or zilucoplan.

[0288] In some implementations, the additional therapeutic agent is a CXCR4 chemokine antagonist, such as praxafol or motixafortide.

[0289] In some implementations, the adjunctive therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidyl prolyl cis-trans isomerase A inhibitor, such as arapovir.

[0290] In some implementations, the additional therapeutic agent is a cysteine ​​protease inhibitor, such as SLV-213.

[0291] In some implementations, the additional treatment agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, buquina, RP-7214, farudostat, or emvododstat.

[0292] In some implementations, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as Metablok.

[0293] In some implementations, the additional treatment is a dihydroorotate dehydrogenase inhibitor / IL-17 antagonist, such as vidofluradim.

[0294] In some implementations, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.

[0295] In some implementations, the additional therapeutic agent is a deoxyribonuclease I stimulator, such as GNR-039 or dornase alfa.

[0296] In some implementations, the additional treatment agent is a NET inhibitor, such as NTR-441.

[0297] In some implementations, the additional therapeutic agent is a dihydroceramide δ4 desaturase inhibitor / sphingosine kinase 2 inhibitor, such as opaganib.

[0298] In some implementations, the additional therapeutic agent is a DNA methyltransferase inhibitor, such as azoxymidine.

[0299] In some implementations, the additional treatment agent is an LXR antagonist, such as larsucosterol.

[0300] In some implementations, the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brensocatib.

[0301] In some implementations, the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044.

[0302] In some implementations, the additional therapeutic agent is an extension factor 1 α2 regulator, such as privitin.

[0303] In some implementations, the adjunctive therapeutic agent is a eukaryotic initiation factor 4A-I inhibitor, such as zotatifin.

[0304] In some implementations, the additional therapeutic agent is an exocrine α-sialidase modulator, such as DAS-181.

[0305] In some implementations, the additional therapeutic agent is an export protein 1 inhibitor, such as selinexor.

[0306] In some implementations, the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567.

[0307] In some implementations, the additional therapeutic agent is an FYVE finger phosphoinositol kinase inhibitor / IL-12 receptor antagonist / IL-23 antagonist, such as apimod dimethylsulfonate.

[0308] In some implementations, the additional therapeutic agent is a GABA A receptor modulator, such as brinolone.

[0309] In some implementations, the adjunctive therapeutic agent is a glucocorticoid receptor agonist, such as ccyclosone, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005.

[0310] In some implementations, the additional therapeutic agent is a GM-CSF receptor agonist, such as saxaglastine.

[0311] In some implementations, the additional therapeutic agent is a GPCR agonist, such as esuberaprostsodium.

[0312] In some implementations, the additional therapeutic agent is a Griffithsin modulator, such as Q-Griffithsin.

[0313] In some implementations, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast.

[0314] In some implementations, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, or levocetirizine hydrochloride.

[0315] In some implementations, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine.

[0316] In some implementations, the additional therapeutic agent is a heat shock protein stimulator / insulin sensitizer / PARP inhibitor, such as BGP-15.

[0317] In some implementations, the additional therapeutic agent is a histone inhibitor, such as STC-3141.

[0318] In some implementations, the additional therapeutic agent is a histone deacetylase-6 inhibitor, such as CKD-506.

[0319] In some implementations, the additional treatment agent is a HIF prolyl hydroxylase-2 inhibitor, such as dedustat.

[0320] In some implementations, the additional treatment agent is a HIF prolyl hydroxylase inhibitor, such as valdustat.

[0321] In some implementations, the additional treatment agent is an IL-8 receptor antagonist, such as reparixin.

[0322] In some implementations, the additional therapeutic agent is an IL-7 receptor agonist, such as CYT-107.

[0323] In some implementations, the additional therapeutic agent is an IL-7 receptor agonist / interleukin-7 ligand, such as efineptakin alfa.

[0324] In some implementations, the additional therapeutic agent is an IL-22 agonist, such as efmarodocokin alfa.

[0325] In some implementations, the additional therapeutic agent is an IL-22 agonist / interleukin-22 ligand, such as F-652.

[0326] In some implementations, additional therapeutic agents target IL-33, such as toretzimab.

[0327] In some implementations, the additional treatment is an IL-15 agonist, such as nogapendekinalfa.

[0328] In some implementations, the additional therapeutic agent is an integrin α-V / β-1 antagonist / integrin α-V / β-6 antagonist, such as bexotegrast.

[0329] In some implementations, the additional therapeutic agent is an interferon alpha2 ligand, such as interferon alpha-2b or Virafin.

[0330] In some implementations, the additional therapeutic agent is an interferon β ligand, such as a follow-up biologic to interferon β-1a, interferon β-1b, or SNG-001.

[0331] In some implementations, the additional therapeutic agent is an interferon receptor modulator, such as peginterferon lambda-1a.

[0332] In some implementations, the additional therapeutic agent is an interleukin-2 ligand, such as adeleukin.

[0333] In some implementations, the additional treatment is an IRAK-4 protein kinase inhibitor, such as zimlovisertib.

[0334] In some implementations, the adjunctive therapy is a JAK inhibitor, such as baricitinib, filgortinib, jaktinib, tofacitinib, or nezulcitinib (TD-0903).

[0335] In some implementations, the additional therapeutic agent is a neutral leukocyte elastase inhibitor, such as avelestat.

[0336] In some implementations, the additional therapeutic agent is a lung surfactant-associated protein D modulator, such as AT-100.

[0337] In some implementations, the additional therapeutic agent is a plasma kallikrein inhibitor, such as donidalorsen.

[0338] In some implementations, the adjunctive therapeutic agent is a lysine-specific histone demethylase 1 / MAO B inhibitor, such as varifidestat.

[0339] In some implementations, the additional therapeutic agent is a mannan-binding lectin serine protease inhibitor, such as conestat alfa.

[0340] In some implementations, the additional therapeutic agent is a maxi K potassium channel inhibitor, such as ENA-001.

[0341] In some implementations, the adjunctive therapeutic agent is a MEK protein kinase inhibitor, such as zapnometinib.

[0342] In some implementations, the adjunctive therapeutic agent is a MEK-1 protein kinase inhibitor / Ras gene inhibitor, such as androidquinolol.

[0343] In some implementations, the adjunctive therapeutic agent is a melanocortin MC1 receptor agonist, such as PL-8177. In some implementations, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, such as resomelega acetate.

[0344] In some implementations, the additional therapeutic agent is a matrix metalloproteinase-12 inhibitor, such as FP-025.

[0345] In some implementations, the additional therapeutic agent is a NACHT LRR PYD domain protein 3 inhibitor, such as dapansutrile, DFV-890, or ZYIL-1.

[0346] In some implementations, the additional therapeutic agent is an NADPH oxidase inhibitor, such as isuzinaxib.

[0347] In some implementations, the adjunctive therapeutic agent is a neuropilin 2 modulator, such as efzofitimod.

[0348] In some implementations, the additional therapeutic agent is an NK1 receptor antagonist, such as aprepitant or tripipitant.

[0349] In some implementations, the additional therapeutic agent is an NMDA receptor antagonist, such as crocin or fenfenidil.

[0350] In some implementations, the adjunctive therapeutic agent is a nuclear factor κB inhibitor / p38 MAP kinase inhibitor, such as zenuzolac.

[0351] In some implementations, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as efornithine.

[0352] In some implementations, the additional therapeutic agent is an opioid receptor σ antagonist, such as MR-309.

[0353] In some implementations, the additional therapeutic agent is a PGD2 antagonist, such as asapiprant.

[0354] In some implementations, the additional therapeutic agent is a PDGF receptor antagonist / TGFβ receptor antagonist / p38 MAP kinase inhibitor, such as deupirfenidone.

[0355] In some implementations, the additional therapeutic agent is a phospholipase A2 inhibitor, such as methylvarenaradil.

[0356] In some implementations, the adjunctive therapeutic agent is a phosphoinositol 3-kinase inhibitor / mTOR complex inhibitor, such as dactolisib.

[0357] In some implementations, the additional treatment is an mTOR inhibitor, such as sirolimus.

[0358] In some implementations, the additional therapeutic agent is a phosphoinositol-3 kinase δ / γ inhibitor, such as duveliximab.

[0359] In some implementations, the additional treatment agent is a PIKfyve inhibitor, such as VRG-101.

[0360] In some implementations, the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor, such as TM-5614.

[0361] In some implementations, the additional therapeutic agent is a protein tyrosine phosphatase β inhibitor, such as ralotafine.

[0362] In some implementations, the adjunctive therapeutic agent is a RIP-1 kinase inhibitor, such as eclitasertib (DNL-758) or SIR-0365.

[0363] In some implementations, the additional therapeutic agent is a Rev protein modulator, such as obefazimod.

[0364] In some implementations, the adjunctive therapeutic agent is an S-phase kinase-associated protein 2 inhibitor, such as niclosamide, CP-COV3, SCAI-502, or DWRX-2003.

[0365] In some implementations, the additional therapeutic agent is a CD24 signal transduction protein stimulator, such as EXO-CD24.

[0366] In some implementations, the additional therapeutic agent is a sodium glucose transporter-2 inhibitor, such as dapagliflozin propylene glycol.

[0367] In some implementations, the additional therapeutic agent is a sodium channel inhibitor, such as solnatide.

[0368] In some implementations, the additional therapeutic agent is a sphingosine-1-phosphate-1 agonist / sphingosine-1-phosphate-5 agonist, such as ozamod.

[0369] In some implementations, the adjunctive therapeutic agent is a nonsteroidal anti-inflammatory drug, such as Ampion.

[0370] In some implementations, the additional therapeutic agent is a superoxide dismutase agonist, such as avasopasem manganese.

[0371] In some implementations, the additional therapeutic agent is a Syk tyrosine kinase inhibitor, such as futtatinib disodium salt.

[0372] In some implementations, the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist, such as AV-001.

[0373] In some implementations, the adjunctive therapeutic agent is a TGFB2 gene inhibitor, such as trabedsen.

[0374] In some implementations, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.

[0375] In some implementations, the additional treatment is a TLR-3 agonist, such as lentamod.

[0376] In some implementations, the additional treatment agent is a TLR-4 antagonist, such as ApTLR-4FT, EB-05, or iritolen.

[0377] In some implementations, the additional treatment is a TLR-7 / 8 antagonist, such as enpatoran.

[0378] In some implementations, the additional therapeutic agent is a TLR-2 / 6 agonist, such as INNA-051.

[0379] In some implementations, the additional therapeutic agent is a TLR-7 agonist, such as PRTX-007 or APR-002.

[0380] In some implementations, the additional therapeutic agent is a TLR agonist, such as PUL-042.

[0381] In some implementations, the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.

[0382] In some implementations, the additional therapeutic agent is a TLR-2 / 4 antagonist, such as VB-201.

[0383] In some implementations, the additional therapeutic agent is a TNF α ligand inhibitor, such as pegipanermin.

[0384] In some implementations, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anaspirin.

[0385] In some implementations, the additional therapeutic agent is a TREM receptor 1 antagonist, such as nangibotide.

[0386] In some implementations, the additional therapeutic agent is a trypsin inhibitor, such as ulinastatin.

[0387] In some implementations, the adjunctive therapeutic agent is a microtubule inhibitor, such as sabizabulin, CCI-001, PCNT-13, CR-42-24, albendazole, entabulin, SAR-132885, or ON-24160.

[0388] In some implementations, the additional therapeutic agent is a VIP receptor agonist, such as aviptadil.

[0389] In some implementations, the additional therapeutic agent is a xanthine oxidase inhibitor, such as hydroxypurine.

[0390] In some implementations, the adjunctive therapeutic agent is a vasodilator, such as iloprost, evoraprost (VentaProst), vazegepant, TXA-127, USB-002, ambesentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamole.

[0391] In some implementations, the additional therapeutic agent is a vitamin D3 receptor agonist, such as cholecalciferol.

[0392] In some implementations, the additional therapeutic agent is a zonulin inhibitor, such as larazotideacetate.

[0393] In some implementations, the additional therapeutic agent is a synthetic retinoic acid derivative, such as fenivel-Amin.

[0394] In some implementations, the additional therapeutic agent is a glucose metabolism inhibitor, such as WP-1122 or WP-1096.

[0395] In some implementations, the adjunctive treatment agents are adalimumab, AT-H201, 2-deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer, AZD-1656, belapectin, spiramycin, buxicamin, budesonide, CNM-AgZn-17, codivir, CT-38, and danicopane. anicopan), bis(dodecylaminomethopterin), DW-2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, genistein, GLS-1200, hzVSF-v13, imidazolylacetamide glutaric acid, IMM-101, MAS-825, MRG-001, Nasitrol, Nilexar (N ylexa), olverembatinib, OP-101, OPN-019, Orynotide, rhesus monkey theta defense-1, phenazine + artesunate, dapsone, RPH-104, sodium pyruvate, Sulforadex, tafenoxanone, TB-006, telacebec, Tempol, TL-895, timosola (thimesoral), trimodulin, XC-221, XC-7, zunsemetinib, glycine metformin, lucinactant, EOM-613, mosedipimod, ivermectin, leflunomide, isobutylasteride, RBT-9, raloxifene, prothione, zicarbene, or azithromycin.

[0396] In some implementations, the additional treatment agent is a CD73 antagonist, such as AK-119.

[0397] In some implementations, the additional therapeutic agent is a CD95 protein fusion, such as asunercept.

[0398] In some implementations, the additional therapeutic agent is a complement factor C2 modulator, such as ARGX-117.

[0399] In some implementations, the additional treatment agent is a complement C3 inhibitor, such as AMY-101 or NGM-621.

[0400] In some implementations, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor, such as EB-06.

[0401] In some implementations, the adjunctive therapeutic agent is a cytotoxic T-lymphocyte protein-4 fusion protein, such as abatacept. In some implementations, the adjunctive therapeutic agent is an anti-Staphylococcus aureus antibody, such as tosatoxumab.

[0402] In some implementations, the additional therapeutic agent is an anti-LPS antibody, such as IMM-124-E.

[0403] In some implementations, the adjunctive therapeutic agent is an adrenaline ligand inhibitor, such as embarreximab.

[0404] In some implementations, the additional treatment is a basigin inhibitor, such as meperizumab.

[0405] In some implementations, the adjunctive treatment is a CD3 antagonist, such as francirumab.

[0406] In some implementations, the adjunctive therapeutic agent is a connective tissue growth factor ligand inhibitor, such as PRS-220 or perrirumab.

[0407] In some implementations, the adjunctive therapeutic agent is a complement C5a factor inhibitor, such as BDB-1 or virolimab.

[0408] In some implementations, the adjunctive therapeutic agent is a complement factor C5 inhibitor, such as eculizumab.

[0409] In some implementations, the adjunctive therapeutic agent is a mannan-binding lectin serine protease-2 inhibitor, such as nasoribimab.

[0410] In some implementations, the adjunctive treatment is a GM-CSF modulator, such as STSA-1005, netlimumab, namexilumab, punelimumab, otelilimumab, or lenzrulimab.

[0411] In some implementations, the adjunctive therapeutic agent is a heat shock protein inhibitor / IL-6 receptor antagonist, such as sutuximab.

[0412] In some implementations, the adjunctive therapeutic agent is an IL-6 receptor antagonist, such as clazazumab, levilimab, olokizumab, tocilizumab, or sirukumab.

[0413] In some implementations, the additional therapeutic agent is an IL-8 receptor antagonist, such as BMS-986253.

[0414] In some implementations, the additional therapeutic agent is an interleukin-1β ligand inhibitor, such as canakinumab.

[0415] In some implementations, the additional therapeutic agent is an interferon-gamma ligand inhibitor, such as epavamab.

[0416] In some implementations, the additional therapeutic agent is an anti-ILT7 antibody, such as daxdilimab.

[0417] In some implementations, the adjunctive therapeutic agent is a CD14 inhibitor, such as atibuclimab.

[0418] In some implementations, the additional therapeutic agent is a plasma kallikrein inhibitor, such as lanarumab.

[0419] In some implementations, the adjunctive treatment is a platelet glycoprotein VI inhibitor, such as glenzocimab.

[0420] In some implementations, the adjunctive therapeutic agent is a T-cell differentiation antigen CD6 inhibitor, such as itolizumab.

[0421] In some implementations, the adjunctive therapeutic agent is a TNF α ligand inhibitor / TNF binder, such as infliximab.

[0422] In some implementations, the additional therapeutic agent is an anti-LIGHT antibody, such as AVTX-002.

[0423] In some implementations, the adjunctive treatment is IMC-2 (valacyclovir + celecoxib) or AXA-1125.

[0424] In some implementations, the additional treatment is COVID-HIG.

[0425] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are co-administered with one or more agents that can be used to treat and / or prevent COVID-19.

[0426] 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 thalidomab; Janus kinase (JAK) inhibitors such as baricitinib, ruxolitinib, or tofacitinib; and antiviral agents such as monopivir, sotromab, or remdesivir.

[0427] In another embodiment, the compounds of this disclosure or pharmaceutically acceptable salts thereof are co-administered with two or more agents that can be used to treat COVID-19. Agents that can be used to treat and / or prevent COVID-19 include, but are not limited to, the compounds of this disclosure and two additional therapeutic agents, such as nematvir and ritonavir, camrelizumab and edevimab, or ruxolitinib and tofacitinib.

[0428] In some embodiments, the adjunctive therapeutic agent is 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 adjunctive therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0429] In some implementations, the antiviral agent is selected from angiotensin-converting enzyme 2 inhibitors, angiotensin-converting enzyme 2 modulators, angiotensin-converting enzyme 2 stimulators, angiotensin II AT-2 receptor agonists, angiotensin II AT-2 receptor antagonists, angiotensin II receptor modulators, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, SARS-CoV-2 envelope small membrane protein inhibitors, SARS-CoV-2 envelope small membrane protein modulators, and 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-like protease inhibitors, SARS-CoV-2 Nsp14 methyltransferase inhibitors, 3Clpro / Mpro inhibitors, serine protease inhibitors, transmembrane serine protease 2 inhibitors, transmembrane serine protease 2 modulators, viral envelope protein inhibitors, viral protease inhibitors, viral protease modulators, viral protein target modulators, viral ribonuclease inhibitors, and viral structural protein modulators.

[0430] In some implementations, the adjunctive therapeutic agent is an entry inhibitor. For example, in some implementations, the adjunctive therapeutic agent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor.

[0431] In some implementations, the additional therapeutic agent is an angiotensin-converting enzyme 2 inhibitor, such as SBK-001.

[0432] In some implementations, the additional therapeutic agent is an angiotensin-converting enzyme 2 modulator, such as neumifil or JN-2019.

[0433] In some implementations, the additional therapeutic agent is an entry inhibitor, such as MU-UNMC-1 or SAI-4.

[0434] In some implementations, the additional therapeutic agent is an angiotensin-converting enzyme 2 stimulator, such as alunase alfa.

[0435] In some implementations, the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, such as VP-01.

[0436] In some implementations, the additional therapeutic agent is an ACE II receptor antagonist, such as DX-600.

[0437] In some implementations, the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127.

[0438] In some implementations, the additional therapeutic agent is a transmembrane serine protease 2 modulator, such as BC-201 or N-0385.

[0439] In some implementations, the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004.

[0440] In some implementations, the additional therapeutic agent is an RNAi agent, such as ARO-COV or SNS-812.

[0441] In some implementations, the adjunctive therapeutic agent is a vaccine. For example, in some implementations, the adjunctive 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 cell vaccine, or a dendritic cell vaccine.

[0442] In some implementations, the adjunctive therapeutic agent is a vaccine, such as tozinameran, NVX-CoV2373, elasomeran, KD-414, Ad26.COV2-S, Vaxzevria, SCB-2019, AKS-452, VLA-2001, HDT-301, S-268019, MVC-COV1901, mRNA-1273.214, mRNA-1273.213, mRNA-1273.222, NVX-CoV2515, and Covaxin. BBIBP-CorV, GBP-510, mRNA-1273.351+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 protein subunit recombinant vaccine, Sputnik M, ZyCoV-D, COVID-19 XWG-03, mRNA-1273.529, mRNA-1010, CoronaVac, AZD-2816, Sputnik V, inactivated SARS-CoV-2 vaccine (Vero cells, COVID-19), DS-5670, PHH-1V, INO-4800, UB-612, coronavirus vaccine (whole virus particles, inactivated / purified), ReCOV, MT-2766, ARCT-154, SP-0253, CORBEVAX, mRNA-1273.211, ZF-2001, SputnikLight, Recombinant Protein Vaccine (COVID-19 / SARS-CoV-2 Infection), VSV Vector-Based 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 CovPars, 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 strain, 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.

[0443] In some embodiments, the adjunctive therapeutic agent is a protease inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is a 3C-like cysteine ​​protease inhibitor (3Clpro, also known as the main protease, Mpro), a papain-like protease inhibitor (Plpro), a serine protease inhibitor, or a transmembrane serine protease 2 inhibitor (TMPRSS2).

[0444] In some implementations, the adjunctive treatment is a 3Clpro / Mpro inhibitor, such as ABBV-903, AB-343, CDI-873, GC-373, GC-376, pomotrelvir (PBI-0451), UCI-1, bofutrelvir (FB-2001, DC-402234), DC-402267, GDI-4405, HS-10517, RAY-1216, MPI-8, SH-879, SH-580, EDP-235, VV-993, CDI-988, MI-30, and nirmatrelvir. Ensitrelvir, ASC-11, ASC-11 + ritonavir, EDDC-2214, SIM-0417, PF-07817883, simnotrelvir, simnotrelvir + ritonavir, SYH-2055, ISM-3312, CDI-45205, LHP-803 (COR-803), ALG-097111, TJC-642, CVD-0013943, olgotrelvir (STI-1558), eracycline, cynarine, WPV-01, or prexasertib.

[0445] In some implementations, the additional therapeutic agent is a papain-like protease inhibitor (Plpro), such as SBFM-PL4 or GRL-0617.

[0446] In some implementations, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp13 inhibitor, such as EIS-4363.

[0447] In some implementations, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp14 inhibitor, such as TO-507.

[0448] In some implementations, the additional therapeutic agents are the SARS-CoV-2 spike protein (S) and protease modulators, such as ENU-200.

[0449] In some implementations, the additional therapeutic agent is a protease inhibitor, such as ALG-097558 or MRX-18.

[0450] In some implementations, the adjunctive therapeutic agent is a serine protease inhibitor, such as upparstat, naphthostat, carmostat mesylate, naphthostat mesylate, or carmostat.

[0451] In some implementations, the additional therapeutic agent is a 3Clpro / transmembrane serine protease 2 inhibitor, such as SNB-01 (pentarlandir) or SNB-02.

[0452] In some implementations, the additional therapeutic agent is a viral protease inhibitor such as Pan-Corona, Cov-X, or benprodil.

[0453] In some embodiments, the adjunctive therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is an RNA polymerase inhibitor, or an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0454] In some implementations, the adjunctive therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor, such as remdesivir, NV-CoV-2, NV-CoV-2-R, NV-CoV-1-encapsulated remdesivir, CMX-8521, GS-621763, GS-5245, GS-441524, DEP remdesivir, ATV-006, deuterated remdesivir (VV-116), LGN-20, CMX-521, SHEN-26, MB-905, and compounds disclosed in WO2022142477, WO2021213288, and WO2022047065.

[0455] In some implementations, the adjunctive treatment is an RNA polymerase inhibitor, such as monoupivir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galidivir.

[0456] In some implementations, the additional treatment is a viral entry inhibitor, such as brilacidin.

[0457] In some implementations, the additional therapeutic agent is an antibody that binds to the coronavirus, such as an antibody that binds to SARS or MERS.

[0458] In some implementations, the adjunctive therapeutic agent is an antibody, such as a monoclonal antibody. For example, adjunctive therapeutic agents are antibodies against SARS-CoV-2, neutralizing nanobodies, antibodies targeting the SARS-CoV-2 spike protein, fusion proteins, multispecific antibodies, and antibodies capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies).

[0459] In some implementations, the adjunctive therapeutic agent is an antibody that targets a specific site on ACE2. In some implementations, the adjunctive therapeutic agent is a peptide that targets the SARS-CoV-2 spike protein (S-protein).

[0460] In some implementations, the additional treatment is a SARS-CoV-2 virus antibody.

[0461] In some implementations, the antibodies are ABBV-47D11, COVI-GUARD (STI-1499), C144-LS+C135-LS, DIOS-202, DIOS-203, DIOS-301, DXP-604, JMB-2002, LY-CovMab, bamlanivimab (LY-CoV555), GIGA-2050, and IBI-314. S309, SAB-185, etesevimab (CB6), COR-101, JS016, VNAR, VIR-7832 and / or sotramab (VIR-7831), camrelizumab + edevimab (REGN-COV2 or REGN10933+REGN10987), BAT2020, BAT2019, 47D11, YBSW-015 or PA-001.

[0462] In some implementations, the additional treatment agent is STI-9199 (COVI-SHIELD), STI-9167, or AR-701 (AR-703 and AR-720).

[0463] In some implementations, the adjunctive treatment agents are BRII-196, BRII-198, ADG-10, adintrevimab (ADG-20), ABP-300, BA-7208, BI-767551, BHV-1200, CT-P63, JS-026, sotraza (GSK-4182136), tixagevimab + cilgavimab (AZD-7442), regdanvimab, SAB-301, AOD-01, plutavimab (COVI-AMG), 9MW-3311 (MW-33), DXP-593, BSVEQAb, and anti-SARS-CoV-2. IgY, COVID-EIG, CSL-760, F-61, REGN-3048-3051, SARS-CoV-2 monoclonal antibody (COVID-19, ADM-03820), enuzovimab (HFB-30132A), INM-005, SCTA01, TY-027, XAV-19, ambavimab + romlusevimab, SCTA-01, bebtelovimab, beludavimab, IBI-O123, 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, AZD-3152, VYD-222, XVR-012 or ACV-200-17.

[0464] In some implementations, the adjunctive therapeutic agent is an engineered ACE-2-IgG1-Fc fusion protein that targets the SARS-CoV-2 RBD, such as EU-129 or a bivalent ACE2-IgG Fc zero fusion protein (SI-F019).

[0465] In some implementations, the additional therapeutic agent is an ACE2-Fc receptor fusion protein, such as HLX-71.

[0466] In some implementations, the additional treatment is ensovibep.

[0467] In some implementations, the additional therapeutic agent is SYZJ-001.

[0468] In some implementations, the adjunctive treatment is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 + ritonavir) or lopinavir + ritonavir.

[0469] In some implementations, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor, such as favirine.

[0470] In some implementations, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as azvudine.

[0471] In some implementations, the adjunctive therapeutic agents are AbbV-990, ABBV-903, 2b-11, 5-aminolevulinic acid phosphate, AGP-600, AGM-380, AIP-502, ALG-150150, BAT-2022, NED-260, burfiralimab, ALG-097431, bardoxolone, BW-PS-119, and clofibrate. Cephelin, CR-405, delcetravir, D4-102-01, D4-102-02, ESFAM-289, ENOB-CV-01, ENOB-CV-11, E IS-10700, EV-300, β-521, GEA-001, SIM-0417, Monupivir, Pan-Corona, Tollovir, Nematvir + Ritonavir (Paxlovid ®JTBC-00201, Favipiravir, Favipiravir + cathepsin inhibitor (TNX-3900), GC-376, Upatalstat, LeSoleil-01, LeSoleil-02+, Benfovir, VV-116, VV-993, SNB-01, EDP-235, Cov-X, Enstevir, MPI-8, Macitinib, ALG-097558, ASC-11, PBI-0451, Naphamostat, Naphamostat Mesylate, CDI-45205, LHP-803 (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, GS-5245, GLS-5310, Benifosbuvir, QLS-1128, ASC-10, SBFM-PL4, Carmostat Mesylate, UCI-1, FB-2001 (DC-402234), Ebuselenium, SH-580, LeSoleil-01, LeSoleil-02+, MRX-18, MXB-9, MI-09, MI-30, SNB-02, SJP-002C, TJC-642, ENU-200, CVD-0013943, GS-441524, Bempidil, MXB-004, Iracycline, GRL-0617, GST-HG171, GST-HG171+ritonavir, Carmostat, GC-373, KD-1, Nizoralide, Cinnarizine, Precreser, PL-M, RAY-1216, SACT-COVID-19, MP-18, EIDD-1931, EDDC-2214, Nitric Oxide, Apabelon, AnQlar, SBK-001, LQ-050, CG-SpikeDown, Barnivir, JTBC-00101 HLX-71, HT-002, HY-209, HY-3000, HSC-1553, FYB-207, Ensovip, SYZJ-001, EU-129, Nymifine, JN-2019 (KG-2019), LCB-99, AR-701, Vostesyl, PLM-402, PJS-539, CTB-ACE2, TB181-36, TB202-3, ABP-300, XVR-011, MSP-008-22, MU-UNMC-1, MU-UNMC-2, MIC-1930, MLT-103, Mpro inhibitor (Anixa)Biosciences), PBF-4554, alunase α, VP-01, TRV-027, DX-600, TXA-127, NVX-CoV2515, raphamin, RCYM-002, RCYM-003, riamilovir, SARS-CoV-2 PL pro inhibitor (Enanta), SBP-502, SM-4, STB-R040, THY-01, toznamil, elassomil, Ad5-nCoV, BBIBP-CorV, CoronaVac, MVC-COV1901, NVX-CoV2373, sotrometaclopramide, Sputnik V, TEE-001, Tyme-19, Vaxzevria, XW-001, ZF-2001 or ZyCoV-D.

[0472] Any compound of the present invention 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. Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0473] Co-administration of the compound of the present invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of the compound of the present invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the present invention and one or more other active therapeutic agents are present in the patient.

[0474] Co-administration includes administering a unit dose of the compound of the present invention before or after administering a unit dose of one or more other active therapeutic agents, for example, administering the compound of the present invention within seconds, minutes, or hours of administering one or more other active therapeutic agents. For example, a unit dose of the compound of the present invention may be administered first, followed by a unit dose of one or more other active therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents may be administered first, followed by a unit dose of the compound of the present invention within seconds or minutes. In some cases, it may be necessary to administer a unit dose of the compound of the present invention first, followed by a unit dose of one or more other active therapeutic agents several hours (e.g., 1-12 hours). In other cases, it may be necessary to administer a unit dose of one or more other active therapeutic agents first, followed by a unit dose of the compound of the present invention several hours (e.g., 1-12 hours).

[0475] Combination therapy can provide “synergistic” or “synergistic” effects, meaning that the combined effect of active ingredients is greater than the sum of the effects of using the compounds alone. Synergistic effects are achieved when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered alternately or in parallel as individual formulations; or (3) through some other protocol. Synergistic effects are achieved when delivered in alternating therapy, such as in separate tablets, pills, or capsules, or by different injection sequences in separate syringes. Generally, in alternating therapy, each active ingredient is administered in an effective dose sequentially (i.e., consecutively), while in combination therapy, two or more active ingredients are administered together in effective doses. A synergistic antiviral effect indicates that the antiviral effect is greater than the predicted additive effect of the individual compounds in the combination.

[0476] This disclosure will be described in more detail by way of specific embodiments. The following embodiments are provided for illustrative purposes and are not intended to limit this disclosure in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially the same results.

[0477] Example Equipment and materials XRPD patterns were collected using a PANalytical Empyrean diffractometer with an incident beam of Cu Kα radiation generated using a long, narrow focusing source and a nickel filter. A symmetrical Bragg-Brentano geometry was used to construct the diffractometer. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST-certified position. The sample was prepared as a circular thin layer centered on a silicon zero-background substrate. An anti-scattering slit (SS) was used to minimize background from air. A Soller slit was used for both the incident and diffracted beams to minimize broadening from axial divergence. The diffraction pattern was collected using a scanline detector PIXcel1D-Medipix3 PASS (programmable anti-scattering slit) located 240 mm from the sample and data collector software v. 7.2b.

[0478] Differential scanning calorimetry (DSC) data were collected using a TA Instruments Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium. The sample was placed in a Tzero aluminum DSC pan and covered with a cap pierced with a needle. The weight was then accurately recorded. The weighed aluminum pan, configured as the sample pan, was placed on the reference side of the cell. The sample was heated from 20°C to 300°C at a rate of 10°C / min.

[0479] Thermogravimetric analysis (TGA) data were collected using a TA Instruments Q5000 thermogravimetric analyzer. Nickel and Alumel were used. ™ Perform temperature calibration. Place each sample in an aluminum tray and insert it into the TG furnace. Heat the furnace under nitrogen purging. Heat the samples from ambient temperature to 300°C at a rate of 10°C / min.

[0480] Example 1. Maleate form I preparation Maleate form I was first prepared by dissolving approximately 45 mg of amorphous (I) free base in approximately 0.3 mL of acetonitrile. Approximately one molar equivalent of maleic acid was added to the solution, and the resulting slurry was stirred at ambient temperature for approximately one day. The solid was separated by centrifugation and dried in a vacuum oven at 50°C for approximately one day.

[0481] Characterization Maleate form I is the unsolvated phase. Its XRPD pattern is... Figure 1 As shown, and characterized by layer 1 reflections at 3.9°, 9.8°, and 18.7° 2θ, and layer 2 at 7.8°, 11.7°, and 17.2° 2θ, and layer 3 at 13.6°, 19.6°, and 26.1° 2θ.

[0482] DSC thermograms in Figure 2 The TGA thermogram shows that it exhibits an endothermic transition at approximately 166 °C. Figure 3 It is shown in the figure, and indicates that the phase is unsolvated.

[0483] Table 1A. List of XRPD peak values ​​by hierarchical maleate form I Table 1B. Complete list of XRPD peak values ​​for maleate form I Example 2. Oxalate Form I preparation First, oxalate form I was prepared by dissolving approximately 50 mg of the amorphous form (I) free base in approximately 0.3 mL of acetonitrile. Approximately one molar equivalent of oxalic acid was added, and the resulting clear solution was stirred at ambient temperature. A slurry was observed after stirring the mixture at ambient temperature for approximately one day. The solid was separated by centrifugation and dried in a vacuum oven at 50°C for approximately one day.

[0484] Characterization XRPD pattern of oxalate form I in Figure 4 As shown, and characterized by layer 1 reflections at 3.9°, 17.5°, and 24.0° 2θ, and layer 2 at 5.9°, 10.0°, and 20.8° 2θ and layer 3 at 6.3°, 9.0°, and 23.3° 2θ.

[0485] DSC thermograms in Figure 5 As shown in the figure, a first endothermic transition is observed at approximately 103 °C. A second endothermic transition initiating at approximately 182 °C is also observed. The TGA thermogram is shown in... Figure 6 As shown in the figure, it exhibits a 0.9% weight loss before the first endothermic event.

[0486] Table 2A. List of XRPD peak values ​​by stratified oxalate form I Table 2B. Complete list of XRPD peak values ​​for oxalate form I Example 3. Fumarate material A preparation Fumarate material A was first prepared by slurrying approximately 40 mg of amorphous (I) free base and about one molar equivalent of fumaric acid in approximately 0.3 mL of methanol. The suspension was stirred at ambient temperature for approximately two days. Samples of the stabilized slurry were taken for XRPD analysis. The wet solid was then dried in a vacuum oven at 50 °C for approximately one day to obtain fumarate material A.

[0487] Characterization XRPD pattern of fumarate material A in Figure 7 The image shows, and is characterized by, layer 1 reflections at 7.2°, 12.9°, and 25.7° 2θ, and layer 2 reflections at 6.8°, 15.3°, and 20.6° 2θ, and layer 3 reflections at 8.0°, 14.7°, and 28.3° 2θ. The DSC thermogram of fumarate material A is shown in... Figure 8 As shown in the figure, it exhibits an endothermic transition at approximately 146°C.

[0488] Table 3A. List of XRPD peak values ​​for tiered fumarate material A Table 3B. Complete XRPD Peak List for Fumarate Material A Example 4. Fumarate material B preparation Fumarate material B was first prepared by dissolving approximately 150 mg of amorphous (I) free base in approximately 1.2 mL of methanol. Approximately one molar equivalent of fumaric acid was added to the solution. The resulting suspension was stirred under ambient conditions for approximately one day, producing a slurry. The slurry was filtered under vacuum and washed with approximately 0.5 mL of methanol. The solid was dried in a vacuum oven at 50 °C for approximately three days to obtain fumarate material B.

[0489] Characterization XRPD pattern of fumarate material B in Figure 9 The image shows, and is characterized by, layer 1 reflections at 7.2°, 13.1°, and 25.8° 2θ, and layer 2 reflections at 6.8°, 14.7°, and 23.9° 2θ, and layer 3 reflections at 8.0°, 18.1°, and 23.2° 2θ. The DSC thermogram of fumarate material B is shown in... Figure 10 The TGA thermogram shows that it exhibits an endothermic transition at approximately 150°C. Figure 11 It is shown in the figure, and indicates that the phase is unsolvated.

[0490] Table 4A. List of XRPD peak values ​​for tiered fumarate material B Table 4B. Complete XRPD peak list for fumarate material B Example 5. Fumarate material C preparation Fumarate material C was first prepared by slurrying approximately 200 mg of amorphous (I) free base in approximately 1.5 mL of methanol. Approximately two molar equivalents of fumaric acid were added, and the slurry was stirred under ambient conditions for approximately one day. The slurry was then sonicated, and approximately 0.2 mL of methanol was added to allow it to flow. After stirring again under ambient conditions for approximately one day, the slurry was sonicated to improve flowability and filtered under vacuum. The wet filter cake was washed with approximately 0.3 mL of methanol. The solid was dried in a vacuum oven at 50 °C for approximately one day to obtain fumarate material C.

[0491] Characterization XRPD pattern of fumarate material C in Figure 12 The image shows, and is characterized by, layer 1 reflections at 7.1°, 13.0°, and 20.7° 2θ, and layer 2 reflections at 6.9°, 10.6°, and 15.2° 2θ, and layer 3 reflections at 8.1°, 13.7°, and 23.1° 2θ. The DSC thermogram of fumarate material C is shown in... Figure 13The TGA thermogram shows that it exhibits an endothermic transition at approximately 147°C. Figure 14 It is shown in the figure, and indicates that the phase is unsolvated.

[0492] Table 5A. List of XRPD peak values ​​for tiered fumarate material C Table 5B. Complete XRPD peak list for fumarate material C Example 6. Free base methanol solvate I, free base form I and free base form II preparation Free base form I was first prepared by dissolving approximately 2 g of amorphous (I) free base in approximately 15 mL of methanol. Approximately one molar equivalent of fumaric acid was added to the solution, resulting in a suspension. The suspension became a fixed slurry. The slurry was sonicated for approximately 15 minutes and inoculated with a small amount of fumarate material B. The slurry was then mixed with a spatula and stirred under ambient conditions for approximately one day. An additional 1 mL of methanol was added to allow the slurry to flow. A sample of the slurry was taken for XRPD analysis. An unstable solvate, free base methanol solvate I, was obtained as a wet solid. The wet solid was then dried in a vacuum oven at 50 °C for approximately one day to obtain free base form I.

[0493] The remaining slurry was stirred for another day, chilled for about 15 minutes, and filtered under vacuum. The solids were washed with the mother liquor and dried in a vacuum oven at 50°C for about three days to obtain free alkali form II.

[0494] Free base form II was also prepared by slurrying 100 mg of amorphous (I) free base in about 0.75 mL of methanol. About 0.75 molar equivalents of fumaric acid were added to the slurry. The slurry was flowed by sonication and stirred under ambient conditions for about two days. The slurry was filtered under vacuum. The solid was washed with about 0.3 mL of methanol and dried in a vacuum oven at 50 °C for about one day to obtain free base form II.

[0495] Characterization XRPD pattern of free base methanol solvate I in Figure 15 As shown, and characterized by layer 1 reflections at 7.1°, 14.3°, and 25.7° 2θ, and layer 2 at 14.1°, 21.5°, and 24.4° 2θ, and layer 3 at 11.5°, 15.8°, and 28.7° 2θ.

[0496] XRPD pattern of free base form I in Figure 16The DSC thermogram of free base form I is shown, and is characterized by layer 1 reflections at 8.4°, 16.8°, and 25.1° 2θ, and layer 2 reflections at 7.3°, 14.2°, and 24.1° 2θ, and layer 3 reflections at 6.9°, 13.9°, and 22.4° 2θ. Figure 17 The data is shown in [the figure], and exhibits two endothermic events initiating at approximately 68 °C and 104 °C. The TGA thermogram is shown in [the figure]. Figure 18 It is shown in the figure, and indicates that the phase is unsolvated.

[0497] XRPD pattern of free base form II in Figure 19 The DSC thermograms of free base form II are shown, and characterized by layer 1 reflections at 7.5°, 14.1°, and 25.6° 2θ, and layer 2 reflections at 7.2°, 12.8°, and 18.2° 2θ, and layer 3 reflections at 10.3°, 16.0°, and 24.2° 2θ. Figure 20 The image shows a second endothermic event with two overlapping peaks and an onset at approximately 55 °C. The second endothermic event has an onset at approximately 101 °C. (TGA thermogram) Figure 21 The results showed a weight loss of approximately 1.6% at the same time as the first endothermic event.

[0498] Table 6A. List of XRPD peak values ​​for free base methanol solvate I according to tiers Table 6B. Complete XRPD peak list for free alkaline methanol solvate I Table 6C. List of XRPD peak values ​​according to hierarchical free alkali form I Table 6D. Complete list of XRPD peak values ​​for free alkaline form I Table 6E. List of XRPD peak values ​​by free base form II. Table 6F. Complete list of XRPD peak values ​​for free alkaline form II Example 7. Free base in ethanol and water solvate I, free base form III, and free base in methanol solvate II preparation Free base form III was prepared by slurrying approximately 150 mg of amorphous (I) free base in approximately 1 mL of methanol. The slurry was flowed by sonication and stirred under ambient conditions for approximately 14 days. Samples of the slurry were taken for XRPD analysis. An unstable solvate, free base methanol solvate II, was obtained as a wet solid. The wet solid was then dried in a vacuum oven at 50 °C for approximately one day to obtain free base form III.

[0499] Free base form III was also prepared by slurrying approximately 50 mg of the amorphous form (I) of the free base in approximately 0.3 mL of an ethanol / water mixture (50% v / v). The slurry was stirred under ambient conditions for approximately one day and sampled for XRPD analysis. An unstable solvate, free base in ethanol and water, was obtained as a wet solid: solvate I. The wet solid was then dried in a vacuum oven at 50 °C for approximately one day to obtain free base form III.

[0500] Free base form III was also obtained by slurrying the amorphous form (I) free base in methanol in the presence of about 0.5 to 0.75 molar equivalents of fumaric acid. In each case, after stirring under ambient conditions for about one day, an unstable solvate, either free base methanol solvate I or free base methanol solvate II, was obtained as a wet solid. The wet solid was then dried in a vacuum oven at 50°C for one to three days to obtain free base form III.

[0501] Characterization XRPD pattern of free alkali ethanol and aqueous solvate I in Figure 22 As shown, and characterized by layer 1 reflections at 7.0°, 14.0°, and 25.8° 2θ, and layer 2 at 7.2°, 15.7°, and 24.5° 2θ, and layer 3 at 11.5°, 14.6°, and 22.3° 2θ.

[0502] XRPD pattern of free base form III in Figure 23 The DSC thermogram of free base form III is shown, and is characterized by layer 1 reflections at 8.4°, 16.8°, and 25.1° 2θ, and layer 2 reflections at 9.4°, 16.0°, and 24.1° 2θ, and layer 3 reflections at 13.8°, 22.3°, and 26.9° 2θ. Figure 24 As shown in the figure, it exhibits two consecutive endothermic events starting at approximately 54 °C. The TGA thermogram is shown in... Figure 25 It is shown in the figure, and indicates that the phase is unsolvated.

[0503] The XRPD pattern of free base methanol solvate II in Figure 26As shown, and characterized by layer 1 reflections at 7.2°, 14.4°, and 24.5° 2θ, and layer 2 at 11.6°, 14.0°, and 25.8° 2θ, and layer 3 at 10.1°, 21.8°, and 29.0° 2θ.

[0504] Table 7A. List of XRPD peak values ​​for free alkaline ethanol and aqueous solvate I Table 7B. Complete XRPD peak list for free alkaline ethanol and aqueous solvate I Table 7C. List of XRPD peak values ​​by free base form III. Table 7D. Complete list of XRPD peak values ​​for free alkaline form III Table 7E. List of XRPD peak values ​​for free base methanol solvate II Table 7F. Complete XRPD peak list for free alkaline methanol solvate II All references, including publications, patents, and patent documents, are incorporated herein by reference as if separately cited. This disclosure provides reference to various embodiments and techniques. However, it should be understood that many changes and modifications can be made while maintaining the spirit and scope of this disclosure. In making this description, it should be understood that it is intended to be illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments described.

Claims

1. The crystalline form of a compound of formula (I): Formula (I).

2. The crystalline form of a compound of formula (I): Formula (I) The crystalline form described therein is a free alkali form I characterized by XRPD patterns comprising degree 2θ reflections (±0.2 degrees 2θ) at 8.4°, 16.8°, and 25.1°.

3. The crystalline form according to claim 2, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 7.3°, 8.4°, 14.2°, 16.8°, 24.1° and 25.1°.

4. The crystalline form according to claim 2 or 3, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 6.9°, 7.3°, 8.4°, 13.9°, 14.2°, 16.8°, 22.4°, 24.1° and 25.1°.

5. The crystalline form according to any one of claims 2 to 4, wherein the XRPD pattern is substantially as shown in FIG16.

6. The crystalline form according to any one of claims 2 to 5, wherein the free alkali form I is characterized by comprising a differential scanning calorimetry pattern having two endothermic events starting at about 68°C and about 104°C.

7. The crystalline form according to any one of claims 2 to 6, wherein the free alkali form I is characterized by a differential scanning calorimetry pattern substantially as shown in FIG17.

8. The crystalline form according to any one of claims 2 to 7, wherein the free alkali form I is unsolvated.

9. The crystalline form according to any one of claims 2 to 8, wherein the free alkali form I is characterized by a thermogravimetric analysis pattern substantially as shown in FIG18.

10. The crystalline form of a compound of formula (I): Formula (I) The crystalline form described therein is a free alkali form II characterized by XRPD patterns comprising degree 2θ reflections (±0.2 degrees 2θ) at 7.5°, 14.1°, and 25.6°.

11. The crystalline form according to claim 10, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 7.5°, 12.8°, 14.1°, 18.2° and 25.6°.

12. The crystalline form according to claim 10 or 11, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 7.5°, 10.3°, 12.8°, 14.1°, 16.0°, 18.2°, 24.2° and 25.6°.

13. The crystalline form according to any one of claims 10 to 12, wherein the XRPD pattern is substantially as shown in FIG19.

14. The crystalline form according to any one of claims 10 to 13, wherein the free alkali form II is characterized by a differential scanning calorimetry pattern comprising two overlapping peaks and an endothermic event starting at about 55°C, and a second endothermic event starting at about 101°C.

15. The crystalline form according to any one of claims 10 to 14, wherein the free alkali form II is characterized by a differential scanning calorimetry pattern substantially as shown in FIG20.

16. The crystalline form according to any one of claims 10 to 15, wherein the free alkali form II is characterized by a thermogravimetric analysis pattern comprising about 1.6% weight loss.

17. The crystalline form according to any one of claims 10 to 16, wherein the free alkali form II is characterized by a thermogravimetric analysis pattern substantially as shown in FIG21.

18. The crystalline form of a compound of formula (I): Formula (I) The crystalline form described therein is free alkali form III, characterized in that... Reflection at 2θ degrees at 8.4° and 16.8° (±0.2 degrees 2θ).

19. The crystalline form according to claim 18, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 8.4°, 9.4°, 16.0°, 16.8°, 24.1°, and 25.1°.

20. The crystalline form according to claim 18, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 8.4°, 9.4°, 13.8°, 16.0°, 16.8°, 22.3°, 24.1°, 25.1° and 26.9°.

21. The crystalline form according to any one of claims 18 to 20, wherein the XRPD pattern is substantially as shown in FIG23.

22. The crystalline form according to any one of claims 18 to 21, wherein the free alkali form III is characterized by comprising a differential scanning calorimetry pattern having two consecutive endothermic events starting at about 54°C.

23. The crystalline form according to any one of claims 18 to 22, wherein the free alkali form III is characterized by a differential scanning calorimetry pattern substantially as shown in FIG24.

24. The crystalline form according to any one of claims 18 to 23, wherein the free alkali form III is unsolvated.

25. The crystalline form according to any one of claims 18 to 24, wherein the free alkali form III is characterized by a thermogravimetric analysis pattern substantially as shown in FIG25.

26. A solvate of a compound of formula (I): Formula (I).

27. The solvate form according to claim 26, wherein the solvate is a methanol solvate, an ethanol solvate, an isopropanol solvate, a 1-butanol solvate, a 2-butanol solvate, a tert-butanol solvate, a 1-pentanol solvate, an aqueous solvate, or a combination thereof.

28. The solvate form according to claim 26, wherein the solvate is a methanol solvate, an ethanol solvate, an aqueous solvate, or an ethanol and aqueous solvate.

29. The solvate form according to claim 26, wherein the solvate is a methanol solvate.

30. The solvate form according to claim 26, wherein the solvate is an ethanol and water solvate.

31. Crystalline form of a solvate of a compound of formula (I) Formula (I).

32. The crystalline form according to claim 31, wherein the solvate of the compound of formula (I) is a methanol solvate, an ethanol solvate, an isopropanol solvate, a 1-butanol solvate, a 2-butanol solvate, a tert-butanol solvate, a 1-pentanol solvate, an aqueous solvate, or a combination thereof.

33. The crystalline form according to claim 31, wherein the solvate of the compound of formula (I) is a methanol solvate, an ethanol solvate, an aqueous solvate, or an ethanol and aqueous solvate.

34. The crystalline form according to claim 31, wherein the solvate of the compound of formula (I) is a methanol solvate.

35. The crystalline form according to claim 31, wherein the solvate of the compound of formula (I) is an ethanol and water solvate.

36. Crystalline form of a solvate of a compound of formula (I) Formula (I) The crystalline form described therein is a free base methanol solvate I characterized by XRPD patterns comprising degree 2θ reflections (±0.2 degrees 2θ) at 7.1°, 14.3° and 25.7°.

37. The crystalline form according to 36, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 7.1°, 14.1°, 14.3°, 21.5°, 24.4° and 25.7°.

38. The crystalline form according to claim 36 or 37, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 7.1°, 11.5°, 14.1°, 14.3°, 15.8°, 21.5°, 24.4°, 25.7° and 28.7°.

39. The crystalline form according to any one of claims 36 to 38, wherein the XRPD pattern is substantially as shown in FIG15.

40. Crystalline form of a solvate of a compound of formula (I) Formula (I), The crystalline form described therein is a free base methanol solvate II characterized by XRPD patterns comprising degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 14.4° and 24.5°.

41. The crystalline form according to claim 40, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 11.6°, 14.0°, 14.4°, 24.5° and 25.8°.

42. The crystalline form according to claim 40 or 41, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 7.2°, 10.1°, 11.6°, 14.0°, 14.4°, 21.8°, 24.5°, 25.8° and 29.0°.

43. The crystalline form according to any one of claims 40 to 42, wherein the XRPD pattern is substantially as shown in FIG26.

44. Crystalline form of a solvate of a compound of formula (I) Formula (I), The crystalline form described therein is a free alkali ethanol and water solvate I characterized by XRPD patterns comprising degree 2θ reflections (±0.2 degrees 2θ) at 7.0°, 14.0° and 25.8°.

45. The crystalline form according to claim 44, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 7.0°, 7.2°, 14.0°, 15.7°, 24.5° and 25.8°.

46. ​​The crystalline form according to claims 44 and 45, wherein the XRPD pattern includes degree 2θ reflection (±0.2 degrees 2θ) at 7.0°, 7.2°, 11.5°, 14.0°, 14.6°, 15.7°, 22.3°, 24.5° and 25.8°.

47. The crystalline form according to any one of claims 44 to 46, wherein the XRPD pattern is substantially as shown in FIG22.

48. A solid form of a compound of formula (I): Formula (I), The solid form therein is a salt of formula (I) or a eutectic of formula (I).

49. The solid form according to claim 48, wherein the solid form is formula (I) maleate, formula (I) oxalate or formula (I) fumarate.

50. The solid form according to claim 48, wherein the solid form is formula (I) maleate, formula (I) oxalate or formula (I) fumarate.

51. The solid form according to claim 48, wherein the solid form is a maleate of formula (I).

52. The solid form according to claim 48, wherein the solid form is an oxalate of formula (I).

53. The solid form according to claim 48, wherein the solid form is a fumarate of formula (I).

54. The solid form according to any one of claims 48 to 53, wherein the solid form is crystalline.

55. A crystalline form of maleate of formula (I): Formula (I) maleate The crystalline form described therein is maleate form I characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 3.9°, 9.8° and 18.7°.

56. The crystalline form according to claim 55, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 3.9°, 7.8°, 9.8°, 11.7°, 17.2° and 18.7°.

57. The crystalline form according to claim 55 or 56, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 3.9°, 7.8°, 9.8°, 11.7°, 13.6°, 17.2°, 18.7°, 19.6° and 26.1°.

58. The crystalline form according to any one of claims 55 to 57, wherein the XRPD pattern is substantially as shown in FIG1.

59. The crystalline form according to any one of claims 55 to 58, Its features Differential scanning calorimetry transformation at approximately 166 °C.

60. The crystalline form according to any one of claims 55 to 59, wherein the maleate form I is characterized by a differential scanning calorimetry pattern substantially as shown in FIG2.

61. The crystalline form according to any one of claims 55 to 60, wherein the maleate form I is unsolvated.

62. The crystalline form according to any one of claims 55 to 61, wherein the maleate form I is characterized by a thermogravimetric analysis pattern substantially as shown in FIG3.

63. A crystalline form of oxalate of formula (I): Formula (I) oxalate The crystalline form described therein is oxalate form I characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 3.9°, 17.5° and 24.0°.

64. The crystalline form according to claim 63, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 3.9°, 5.9°, 10.0°, 17.5°, 20.8° and 24.0°.

65. The crystalline form according to claim 63 or 64, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 3.9°, 5.9°, 6.3°, 9.0°, 10.0°, 17.5°, 20.8°, 23.3° and 24.0°.

66. The crystalline form according to any one of claims 63 to 65, wherein the XRPD pattern is substantially as shown in FIG4.

67. The crystalline form according to any one of claims 63 to 66, wherein the oxalate form I is characterized by a differential scanning calorimetry pattern comprising a first endothermic transition at about 103°C and a second endothermic transition having an initiation at about 182°C.

68. The crystalline form according to any one of claims 63 to 67, wherein the oxalate form I is characterized by a differential scanning calorimetry pattern substantially as shown in FIG5.

69. The crystalline form according to any one of claims 63 to 68, wherein the oxalate form I is characterized by including a thermogravimetric analysis pattern of about 0.9% weight loss prior to the first endothermic event.

70. The crystalline form according to any one of claims 63 to 69, Its features Thermogravimetric analysis pattern.

71. A crystalline form of fumarate of formula (I): Formula (I) fumarate The crystalline form described therein is a fumarate material A characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.2°, 12.9° and 25.7°.

72. The crystalline form according to claim 71, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 12.9°, 15.3°, 20.6° and 25.7°.

73. The crystalline form according to claim 71 or 72, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 8.0°, 12.9°, 14.7°, 15.3°, 20.6°, 25.7° and 28.3°.

74. The crystalline form according to any one of claims 71 to 73, wherein the XRPD pattern is substantially as shown in FIG7.

75. The crystalline form according to any one of claims 71 to 74, wherein the fumarate material A form is characterized by including a differential scanning calorimetry pattern of an endothermic transition at about 146°C.

76. The crystalline form according to any one of claims 71 to 75, wherein the fumarate material A is characterized by a differential scanning calorimetry pattern substantially as shown in FIG8.

77. A crystalline form of fumarate of formula (I): Formula (I) fumarate The crystalline form mentioned above is fumarate material B. Includes 2θ reflection at 7.2° (±0.2 degrees 2θ).

78. The crystalline form according to claim 77, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 13.1°, 14.7°, 23.9° and 25.8°.

79. The crystalline form according to claim 77 or 78, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 6.8°, 7.2°, 8.0°, 13.1°, 14.7°, 18.1°, 23.2°, 23.9° and 25.8°.

80. The crystalline form according to any one of claims 77 to 79, wherein the XRPD pattern is substantially as shown in FIG9.

81. The crystalline form according to any one of claims 77 to 80, wherein the fumarate material B form is characterized by a differential scanning calorimetry pattern comprising an endothermic transition at about 150°C.

82. The crystalline form according to any one of claims 77 to 81, wherein the fumarate material B is characterized by a differential scanning calorimetry pattern substantially as shown in FIG10.

83. The crystalline form according to any one of claims 77 to 82, wherein the fumarate material B is unsolvated.

84. The crystalline form according to any one of claims 77 to 83, wherein the fumarate material B is characterized by a thermogravimetric analysis pattern substantially as shown in FIG11.

85. A crystalline form of a fumarate of formula (I): Formula (I) fumarate The crystalline form described therein is a fumarate material C characterized by XRPD patterns comprising 2θ reflections (±0.2 degrees 2θ) at 7.1°, 13.0° and 20.7°.

86. The crystalline form according to claim 85, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 6.9°, 7.1°, 10.6°, 13.0°, 15.2° and 20.7°.

87. The crystalline form according to claim 85 or 86, wherein the XRPD pattern includes degree 2θ reflections (±0.2 degrees 2θ) at 6.9°, 7.1°, 8.1°, 10.6°, 13.0°, 13.7°, 15.2°, 20.7° and 23.1°.

88. The crystalline form according to any one of claims 85 to 87, wherein the XRPD pattern is substantially as shown in FIG12.

89. The crystalline form according to any one of claims 85 to 88, Its features Differential scanning calorimetry transformation at approximately 147°C.

90. The crystalline form according to any one of claims 85 to 89, wherein the fumarate material C is characterized by a differential scanning calorimetry pattern substantially as shown in FIG13.

91. The crystalline form according to any one of claims 85 to 90, wherein the fumarate material C is unsolvated.

92. The crystalline form according to any one of claims 85 to 91, wherein the fumarate material C is characterized by a thermogravimetric analysis pattern substantially as shown in FIG14.

93. A method for preparing the crystalline form of the solvate according to any one of claims 31 to 47, wherein the method comprises (i) Slurrying or dissolving the compound of formula (I) in solvent A to form mixture A; and (ii) Separate the solid from mixture A to obtain the crystalline form of the solvate.

94. The method of claim 93, wherein the method further comprises adding seed crystals to mixture A.

95. The method according to claim 94, wherein the seed crystal is fumarate material B.

96. The method according to any one of claims 93 to 95, wherein the method comprises slurrying the compound of formula (I) in solvent A to form mixture A.

97. The method according to any one of claims 93 to 95, wherein the method comprises dissolving the compound of formula (I) in solvent A to form mixture A.

98. The method according to any one of claims 93 to 97, wherein about 10 mg to 500 mg of the compound of formula (I) is slurried or dissolved per mL of solvent A.

99. The method according to any one of claims 93 to 97, wherein about 75 mg to 350 mg of the compound of formula (I) is slurried or dissolved per mL of solvent A.

100. The method according to any one of claims 93 to 97, wherein about 100 mg to 250 mg of the compound of formula (I) is slurried or dissolved per mL of solvent A.

101. The method according to any one of claims 93 to 97, wherein about 50 mg to 150 mg of the compound of formula (I) is slurried or dissolved per mL of solvent A.

102. The method according to any one of claims 93 to 101, wherein solvent A comprises water, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, acetonitrile, or mixtures thereof.

103. The method according to any one of claims 93 to 101, wherein solvent A comprises methanol.

104. The method according to any one of claims 93 to 101, wherein solvent A comprises ethanol and water.

105. The method according to any one of claims 93 to 101, wherein The ratio is approximately 50:50 (v / v).

106. The method according to any one of claims 93 to 105, wherein slurrying or dissolving the compound of formula (I) in solvent A to form mixture A further comprises adding acid A to mixture A.

107. The method of claim 106, wherein acid A comprises fumaric acid, maleic acid, oxalic acid, or a mixture thereof.

108. The method according to claim 106 or 107, wherein solvent A comprises methanol and acid A comprises fumaric acid.

109. The method according to any one of claims 93 to 108, wherein separating the solid comprises centrifugation.

110. A method for preparing the crystalline form according to any one of claims 1 to 25, the solid form according to claim 54, or the crystalline form according to any one of claims 55 to 92, wherein the method comprises (i) The compound of formula (I) is slurried or dissolved in solvent B to form mixture B; (ii) Separate the solid from mixture B to obtain solid B; as well as (iii) Dry solid B to obtain the crystalline form, the solid form, the crystalline form of formula (I) maleate, the crystalline form of formula (I) oxalate, or the crystalline form of formula (I) fumarate.

111. The method of claim 110, wherein the method further comprises adding seed crystals to mixture B.

112. The method according to claim 111, wherein the seed crystal is fumarate material B.

113. The method according to any one of claims 110 to 112, wherein the method comprises slurrying the compound of formula (I) in solvent B to form mixture B.

114. The method according to any one of claims 110 to 112, wherein the method comprises dissolving the compound of formula (I) in solvent B to form mixture B.

115. The method according to any one of claims 110 to 114, wherein about 10 mg to 500 mg of the compound of formula (I) is slurried or dissolved per mL of solvent B.

116. The method according to any one of claims 110 to 114, wherein about 75 mg to 350 mg of the compound of formula (I) is slurried or dissolved per mL of solvent B.

117. The method according to any one of claims 110 to 114, wherein about 100 mg to 250 mg of the compound of formula (I) is slurried or dissolved per mL of solvent B.

118. The method according to any one of claims 110 to 114, wherein about 50 mg to 150 mg of the compound of formula (I) is slurried or dissolved per mL of solvent B.

119. The method according to any one of claims 110 to 118, wherein Methanol, ethanol, isopropanol, 1-butanol, 2-butanol A mixture of them.

120. The method according to any one of claims 110 to 118, wherein solvent B comprises methanol.

121. The method according to any one of claims 110 to 118, wherein solvent B comprises acetonitrile.

122. The method according to any one of claims 110 to 118, wherein solvent B comprises ethanol and water.

123. The method according to any one of claims 110 to 118, wherein solvent B comprises ethanol and water in a ratio of about 50:50 (v / v).

124. The method according to any one of claims 110 to 123, wherein slurrying or dissolving the compound of formula (I) in solvent B to form mixture B further comprises adding acid B to mixture B.

125. The method of claim 124, wherein acid B comprises fumaric acid, maleic acid, oxalic acid, or a mixture thereof.

126. The method according to claim 124 or 125, wherein solvent B comprises acetonitrile, and acid B comprises maleic acid.

127. The method of claim 124 or 125, wherein solvent B comprises methanol and acid B comprises fumaric acid.

128. The method according to claim 124 or 125, wherein solvent B comprises acetonitrile, and acid B comprises oxalic acid.

129. The method according to any one of claims 110 to 128, wherein separating solid B comprises centrifugation.

130. The method according to any one of claims 110 to 129, wherein the drying is performed at a temperature of about 20°C to 100°C.

131. The method according to any one of claims 110 to 129, wherein the drying is performed at a temperature of about 50°C.

132. The method according to any one of claims 110 to 131, wherein the drying is performed under vacuum.

133. The method according to any one of claims 110 to 129, wherein the drying is performed at a temperature of about 50°C and under vacuum.

134. A pharmaceutical composition comprising: (i) the crystalline form according to any one of claims 1 to 25, the solvate according to any one of claims 26 to 30, the crystalline form of the solvate according to any one of claims 31 to 47, the solid form according to any one of claims 48 to 54, or the crystalline form according to any one of claims 55 to 92; and (ii) Pharmaceutically acceptable excipients.

135. The pharmaceutical composition according to claim 134, Four additional treatments.

136. A reagent kit, the reagent kit comprising: (i) the crystalline form according to any one of claims 1 to 25, the solvate according to any one of claims 26 to 30, the crystalline form of the solvate according to any one of claims 31 to 47, the solid form according to any one of claims 48 to 54, or the crystalline form according to any one of claims 55 to 92; and (ii) Instructions for use.

137. The kit according to claim 136, wherein the kit further comprises one, two, three or four additional therapeutic agents.

138. A method of treating or preventing a viral infection in a patient in need, wherein the method comprises administering to the patient a crystalline form according to any one of claims 1 to 25, a solvate according to any one of claims 26 to 30, a crystalline form of a solvate according to any one of claims 31 to 47, a solid form according to any one of claims 48 to 54, or a crystalline form according to any one of claims 55 to 92, or a pharmaceutical composition according to claims 139 or 140.

139. The method of claim 138, wherein the viral infection is a coronavirus infection.

140. The method of claim 139, wherein the coronavirus infection is a zoonotic coronavirus infection.

141. The method of claim 139, wherein the coronavirus infection is selected from the group consisting of 229E virus infection, NL63 virus infection, OC43 virus infection and HKU1 virus infection.

142. The method according to any one of claims 139, wherein the coronavirus infection is SARS-CoV-2 infection.

143. The method according to any one of claims 139, wherein the coronavirus infection is SARS-CoV virus infection or MERS-CoV virus infection.

144. The method of claim 138, wherein the viral infection is a pulmonary virus infection.

145. The method of claim 144, wherein the pulmonary virus infection is respiratory syncytial virus infection or patient metapneumovirus infection.

146. The method of claim 138, wherein the viral infection is a piconerivirus infection.

147. The method of claim 146, wherein the piconeriviridae virus is an enterovirus infection.

148. The method of claim 146, wherein the piconeriviridae virus is selected from the group consisting of: Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

149. The method of claim 146, wherein the piconeriviridae virus... The infection is caused by human rhinovirus (HRV).

150. The method of claim 146, wherein the microribonucleovir infection is HRV-A, HRV-B, or HRV-C infection.

151. The method of claim 138, wherein the viral infection is a flaviviridae virus infection.

152. The method according to claim 151, wherein the flaviviridae virus infection is dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunzin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

153. The method of claim 138, wherein the viral infection is a filoviridae virus infection.

154. The method of claim 153, wherein the filoviridae virus infection is an Ebola virus infection or a Marburg virus infection.

155. The method of claim 138, wherein the viral infection is an orthomyxovirus infection.

156. The method of claim 155, wherein the orthomyxovirus is an influenza virus infection.

157. The method of claim 155, wherein the orthomyxovirus is an influenza A virus infection or an influenza B virus infection.

158. The method of claim 138, wherein the viral infection is a paramyxoviridae virus infection.

159. The method of claim 158, wherein the paramyxoviridae family is a patient with parainfluenza virus infection, Nipah virus infection, Hendra virus infection, measles infection, or mumps infection.

160. The method according to any one of claims 138 to 159, wherein the method comprises administering at least one additional therapeutic or preventative agent to the patient.

161. The method of claim 160, wherein the additional therapeutic agent or the prophylactic agent is cobistat, monorapvir, nematvir, ritonavir, or a combination thereof.

162. The method of claim 160, wherein the additional therapeutic agent or the prophylactic agent is monorapvir.

163. The method of claim 160, wherein the additional therapeutic agent or the prophylactic agent is nematvir, ritonavir, or a combination thereof.

164. The method of claim 160, wherein the additional therapeutic agent or the preventive agent is S-217622.

165. A method for manufacturing a medicament for treating or preventing viral infections in patients in need, characterized in that... The crystalline form according to any one of claims 1 to 25, the solvate according to any one of claims 26 to 30, the crystalline form of the solvate according to any one of claims 31 to 47, the solid form according to any one of claims 48 to 54, or the crystalline form according to any one of claims 55 to 92 Or the pharmaceutical composition according to claim 134 or 135.

166. The use of the crystalline form according to any one of claims 1 to 25, the solvate according to any one of claims 26 to 30, the crystalline form of the solvate according to any one of claims 31 to 47, the solid form according to any one of claims 48 to 54, the crystalline form according to any one of claims 55 to 92, or the pharmaceutical composition according to claim 134 or 135 for the manufacture of a medicament for the treatment or prevention of viral infections in persons in need.

167. The use according to claim 166, wherein the drug is used in conjunction with at least one additional therapeutic or preventative agent.

168. The use according to claim 167, wherein the additional therapeutic agent or the preventive agent is S-217622.

169. The use according to claim 167, wherein the additional therapeutic agent or the prophylactic agent is cobistat, monorapvir, nematvir, ritonavir, or a combination thereof.

170. The use according to claim 167, wherein the additional therapeutic agent or the preventive agent is monorapvir.

171. The use according to claim 167, wherein the additional therapeutic agent or the prophylactic agent is nematvir, ritonavir, or a combination thereof.

172. The crystalline form according to any one of claims 1 to 25, the solvate according to any one of claims 26 to 30, the crystalline form of the solvate according to any one of claims 31 to 47, the solid form according to any one of claims 48 to 54, the crystalline form according to any one of claims 55 to 92, or the pharmaceutical composition according to claim 134 or 135, for the treatment or prevention of viral infections in persons in need.

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