Solid form of nucleoside reverse transcriptase translocation inhibitors

Abstract

This disclosure relates to crystalline and solvate forms of nucleoside reverse transcriptase translocation inhibitors (NRTTIs), and their pharmaceutical compositions, which are useful for the treatment and prevention of Retroviridae virus infections, including infections caused by the HIV virus. This disclosure particularly provides crystalline forms of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate, selected from crystalline form II, crystalline form III, crystalline form IV, and crystalline form V.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the benefit under § 119(e) of U.S. Patent Provisional Application No. 63 / 523,505, filed on 27 June 2023, which is incorporated in its entirety by reference herein.

[0002] This disclosure relates to crystalline and solvate forms of nucleoside reverse transcriptase translocation inhibitors (NRTTIs), as well as pharmaceutical compositions thereof, for use in the treatment or prevention of Retroviridae virus infections, including infections caused by the HIV virus. [Background technology]

[0003] Positive-sense single-stranded RNA viruses, including those belonging to the Retroviridae family, include viruses from the Orthoretrovirinae subfamily and the genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Spumavirus, and Lentivirus, which cause many diseases in humans and animals. Human infection with HIV-1, a type of Lentivirus, leads to helper T cell depletion and immunodeficiency, causing immunocompromise and making individuals more susceptible to opportunistic infections. One approach to treating HIV-1 infection is by administering NRTTIs. NRTTIs inhibit HIV-1 reverse transcriptase. Since reverse transcriptase function is essential for viral replication and viral protein production, NRTTIs may be effective against HIV-1 infection. Curr Opin HIV AIDS. 2018 July;13(4):294-299. However, historically, the treatment of HIV has led to the emergence of HIV strains resistant to current treatments. Expert Opin Emerg Drugs. 2018 June;23(2):149-157. Therefore, the discovery of new antiretroviral agents, the development of methods for their preparation and purification, and the preparation of improved pharmaceutical formulations remain necessary. The solid form of NRTTI disclosed herein helps to meet these and other needs. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Curr Opin HIV AIDS.2018 July;13(4):294-299 [Non-Patent Document 2] Expert Opin Emerg Drugs.2018 June;23(2):149-157 [Overview of the project] [Means for solving the problem]

[0005] This disclosure provides, in particular, crystalline forms of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate, selected from crystalline form II, crystalline form III, crystalline form IV, and crystalline form V.

[0006] This disclosure further provides a solvate form of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate.

[0007] This disclosure further provides pharmaceutical compositions comprising a crystalline or solvate form disclosed herein and at least one pharmaceutically acceptable excipient.

[0008] This disclosure further provides a method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the crystalline or solvate form disclosed herein to a subject in need of treatment or prevention of HIV infection.

[0009] This disclosure further provides the crystalline or solvate forms disclosed herein for use in therapeutic purposes.

[0010] This disclosure further provides crystalline or solvate forms disclosed herein for use in a method of treating or preventing human immunodeficiency virus (HIV) infection, which includes administering a therapeutically effective amount of the crystalline or solvate form to a subject in need of treatment or prevention of HIV infection. [Brief explanation of the drawing]

[0011] [Figure 1] The typical X-ray powder diffraction (XRPD) pattern of compound 1's acetone solvate 1 is shown. [Figure 2] This shows a typical XRPD pattern of crystalline form II of compound 1. [Figure 3] A representative differential scanning calorimetry (DSC) thermogram of crystalline form II of compound 1 is shown. [Figure 4]Figure showing a representative thermogravimetric analysis (TGA) thermogram of crystalline form II of compound 1. [Figure 5] Figure showing a representative dynamic vapor sorption (DVS) analysis of crystalline form II of compound 1. [Figure 6] Figure showing representative XRPD patterns of solvate forms of compound 1. From top to bottom: DCM solvate, acetone solvate 2, methyl ethyl ketone solvate, ethyl acetate solvate, methyl acetate solvate, n-butyl acetate solvate, tetrahydrofuran solvate, 1-butanol solvate, p-dioxane solvate and heptane solvate. [Figure 7] Figure showing the asymmetric unit of crystalline form III of compound 1. [Figure 8] Figure showing a representative XRPD pattern of crystalline form III of compound 1. [Figure 9] Figure showing a representative DSC thermogram of crystalline form III of compound 1. [Figure 10] Figure showing a representative TGA thermogram of crystalline form III of compound 1. [Figure 11] Figure showing a representative DVS analysis of crystalline form III of compound 1. [Figure 12] Figure showing a representative XRPD pattern of the toluene solvate of compound 1. [Figure 13] Figure showing a representative XRPD pattern of crystalline form IV of compound 1. [Figure 14] Figure showing a representative DSC thermogram of crystalline form IV of compound 1. [Figure 15] Figure showing a representative TGA thermogram of crystalline form IV of compound 1. [Figure 16] Figure showing a representative DVS analysis of crystalline form IV of compound 1. [Figure 17] Figure showing representative XRPD patterns of the xylene solvate (top) and DMAc solvate (bottom) of compound 1. <​ [Figure 19] A representative DSC thermogram of crystalline form V of compound 1 is shown. [Figure 20] A typical TGA thermogram of crystalline form V of compound 1 is shown. [Figure 21] A typical DVS analysis of crystalline form V of compound 1 is shown. [Modes for carrying out the invention]

[0012] The present invention relates to a novel solid form, either crystalline or solvate, of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate (i.e., Compound 1 whose structure is shown below; see, for example, U.S. Patent Application Publication No. 20220323476(A1) and No. 20220332751(A1), the entirety of each disclosure of which is incorporated herein by reference).

[0013] [ka]

[0014] Compound 1 is a prodrug of 4'-ethynyl-2-fluoro-2'-deoxyadenosine (i.e., islatravir or (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol), which is a nucleoside reverse transcriptase translocation inhibitor (NRTTI).

[0015] [ka]

[0016] Those skilled in the art will understand that compound structures can be named or identified using generally recognized nomenclature systems and symbols. For example, compounds can be named or identified by common names, systematic names, or non-systematic names. Examples of generally recognized nomenclature systems and symbols in the field of chemistry include, but are not limited to, the Chemical Abstract Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). Accordingly, the compound structure of Compound 1 provided herein can also be named or identified as (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl-2-phenylacetate.

[0017] The present invention provides crystalline forms of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate, selected from crystalline form II, crystalline form III, crystalline form IV, and crystalline form V.

[0018] As used herein, “crystalline form” is intended to refer to a particular lattice arrangement of a crystalline material. Different crystalline forms of the same material typically have different crystalline lattices (e.g., unit cells) resulting from different physical properties characteristic of each crystalline form. In some cases, different lattice arrangements have different water or solvent content. In some embodiments, the crystalline forms provided herein may be substantially anhydrous.

[0019] Crystalline form of compound 1 II In some embodiments, the crystalline form provided herein is crystalline form II.

[0020] In some embodiments, the crystal morphology II has at least five XRPD peaks selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4° in 2-theta ±0.2° notation.

[0021] In some embodiments, the crystal morphology II has at least four XRPD peaks selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4° in 2-theta ±0.2° notation.

[0022] In some embodiments, the crystal morphology II has at least three XRPD peaks selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4° in 2-theta ±0.2° notation.

[0023] In some embodiments, crystal morphology II has at least two XRPD peaks selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4° in 2-theta ±0.2° notation.

[0024] In some embodiments, crystal morphology II has at least one XRPD peak selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4° in 2-theta ±0.2° notation.

[0025] In some embodiments, crystalline morphology II has XRPD peaks selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4° in 2-theta ±0.2° notation.

[0026] In some embodiments, crystalline morphology II is characterized by an XRPD pattern substantially as shown in Figure 2.

[0027] In some embodiments, crystalline form II is characterized by a DSC thermogram having an endothermic transition at approximately 93°C.

[0028] In some embodiments, crystalline form II is characterized by a DSC thermogram having an endothermic transition at approximately 93°C, corresponding to the transition from crystalline form II of compound 1 to crystalline form V of compound 1.

[0029] In some embodiments, crystalline morphology II is characterized substantially by a DSC thermogram, as shown in Figure 3.

[0030] In some embodiments, crystalline morphology II is characterized substantially by a TGA thermogram as shown in Figure 4.

[0031] In some embodiments, crystalline morphology II is characterized by DVS analysis, substantially as shown in Figure 5.

[0032] Crystallographic form III of compound 1 In some embodiments, the crystalline form provided herein is crystalline form III.

[0033] In some embodiments, crystal morphology III has at least five XRPD peaks selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0° in 2-theta ±0.2° notation.

[0034] In some embodiments, crystal morphology III has at least four XRPD peaks selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0° in 2-theta ±0.2° notation.

[0035] In some embodiments, crystal morphology III has at least three XRPD peaks selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0° in 2-theta ±0.2° notation.

[0036] In some embodiments, crystal morphology III has at least two XRPD peaks selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0° in 2-theta ±0.2° notation.

[0037] In some embodiments, crystal morphology III has at least one XRPD peak selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0° in 2-theta ±0.2° notation.

[0038] In some embodiments, crystalline form III has XRPD peaks selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0° in 2-theta ±0.2° notation.

[0039] In some embodiments, crystalline morphology III is characterized by an XRPD pattern substantially as shown in Figure 8.

[0040] In some embodiments, crystalline form III is characterized by a DSC thermogram having an endothermic transition at approximately 125°C. In some embodiments, crystalline form III is characterized by a DSC thermogram having an endothermic transition at approximately 125°C, corresponding to the transition from crystalline form III of compound 1 to crystalline form V of compound 1.

[0041] In some embodiments, crystalline morphology III is characterized substantially by a DSC thermogram, as shown in Figure 9.

[0042] In some embodiments, crystalline morphology III is characterized substantially by a TGA thermogram as shown in Figure 10.

[0043] In some embodiments, crystalline morphology III is characterized by DVS analysis, substantially as shown in Figure 11.

[0044] Crystalline form IV of compound 1 In some embodiments, the crystalline form provided herein is crystalline form IV.

[0045] In some embodiments, crystal morphology IV has at least five XRPD peaks selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8° in 2-theta ±0.2° notation.

[0046] In some embodiments, crystal morphology IV has at least four XRPD peaks selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8° in 2-theta ±0.2° notation.

[0047] In some embodiments, crystal morphology IV has at least three XRPD peaks selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8° in 2-theta ±0.2° notation.

[0048] In some embodiments, crystal morphology IV has at least two XRPD peaks selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8° in 2-theta ±0.2° notation.

[0049] In some embodiments, crystal morphology IV has at least one XRPD peak selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8° in 2-theta ±0.2° notation.

[0050] In some embodiments, crystal morphology IV has XRPD peaks selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°, in 2-theta ±0.2° notation.

[0051] In some embodiments, crystalline morphology IV is characterized substantially by an XRPD pattern as shown in Figure 13.

[0052] In some embodiments, crystalline form IV is characterized by a DSC thermogram having an endothermic transition at approximately 114°C. In some embodiments, crystalline form IV is characterized by a DSC thermogram having an endothermic transition at approximately 114°C, corresponding to the transition from crystalline form IV of compound 1 to crystalline form I of compound 1.

[0053] In some embodiments, crystalline morphology IV is characterized substantially by a DSC thermogram, as shown in Figure 14.

[0054] In some embodiments, crystalline morphology IV is characterized substantially by a TGA thermogram, as shown in Figure 15.

[0055] In some embodiments, crystal morphology IV is characterized by DVS analysis, substantially as shown in Figure 16.

[0056] Crystalline form of compound 1 V In some embodiments, the crystalline form provided herein is crystalline form V.

[0057] In some embodiments, the crystal morphology V has at least five XRPD peaks selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3° in 2-theta ±0.2° notation.

[0058] In some embodiments, the crystal morphology V has at least four XRPD peaks selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3° in 2-theta ±0.2° notation.

[0059] In some embodiments, the crystal morphology V has at least three XRPD peaks selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3° in 2-theta ±0.2° notation.

[0060] In some embodiments, the crystal morphology V has at least two XRPD peaks selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3° in 2-theta ±0.2° notation.

[0061] In some embodiments, the crystal morphology V has at least one XRPD peak selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3° in 2-theta ±0.2° notation.

[0062] In some embodiments, the crystal morphology V has XRPD peaks selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3° in 2-theta ±0.2° notation.

[0063] In some embodiments, the crystal morphology V is characterized substantially by an XRPD pattern as shown in Figure 18.

[0064] In some embodiments, crystalline morphology V is characterized by a DSC thermogram with a melting initiation point of approximately 156°C.

[0065] In some embodiments, the crystal morphology V is characterized substantially by a DSC thermogram, as shown in Figure 19.

[0066] In some embodiments, the crystal morphology V is characterized substantially by a TGA thermogram, as shown in Figure 20.

[0067] In some embodiments, the crystal morphology V is characterized by DVS analysis, substantially as shown in Figure 21.

[0068] Solvate form of compound 1 A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the compounds provided herein are also provided. Accordingly, the present invention further provides the solvate form of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate.

[0069] In some embodiments, the solvate form of Compound 1 provided herein is selected from acetone solvate, methyl ethyl ketone solvate, dichloromethane solvate, tetrahydrofuran solvate, toluene solvate, n-butyl acetate solvate, methyl acetate solvate, xylene solvate, heptane solvate, 1-butanol solvate, p-dioxane solvate, ethyl acetate solvate, DMAc solvate, and dimethylacetamide solvate.

[0070] In some embodiments, the solvate form is acetone solvate form.

[0071] In some embodiments, the solvate form is form I of acetone solvate.

[0072] In some embodiments, form I of the acetone solvate is characterized by an XRPD pattern substantially as shown in Figure 1.

[0073] In some embodiments, the solvate form is form II of acetone solvate.

[0074] In some embodiments, form II of the acetone solvate is characterized by an XRPD pattern substantially as shown in Figure 6.

[0075] In some embodiments, the solvate form is the methyl ethyl ketone solvate form.

[0076] In some embodiments, the methyl ethyl ketone solvate form is characterized by an XRPD pattern substantially as shown in Figure 6.

[0077] In some embodiments, the solvate form is the dichloromethane solvate form.

[0078] In some embodiments, the dichloromethane solvate form is characterized substantially by an XRPD pattern as shown in Figure 6.

[0079] In some embodiments, the solvate form is the tetrahydrofuran solvate form.

[0080] In some embodiments, the tetrahydrofuran solvate form is characterized by an XRPD pattern substantially as shown in Figure 6.

[0081] In some embodiments, the solvate form is toluene solvate form.

[0082] In some embodiments, the toluene solvate form is characterized substantially by an XRPD pattern as shown in Figure 12.

[0083] In some embodiments, the solvate form is n-butyl acetate solvate.

[0084] In some embodiments, the n-butyl acetate solvate form is characterized substantially by an XRPD pattern as shown in Figure 6.

[0085] In some embodiments, the solvate form is methyl acetate solvate.

[0086] In some embodiments, the methyl acetate solvate form is characterized by an XRPD pattern substantially as shown in Figure 6.

[0087] In some embodiments, the solvate form is xylene solvate form.

[0088] In some embodiments, the xylene solvate form is characterized substantially by an XRPD pattern as shown in Figure 17.

[0089] In some embodiments, the solvate form is the heptane solvate form.

[0090] In some embodiments, the heptane solvate form is characterized substantially by an XRPD pattern as shown in Figure 6.

[0091] In some embodiments, the solvate form is the 1-butanol solvate form.

[0092] In some embodiments, the 1-butanol solvate form is characterized by an XRPD pattern substantially as shown in Figure 6.

[0093] In some embodiments, the solvate form is the p-dioxane solvate form.

[0094] In some embodiments, the p-dioxane solvate form is characterized by an XRPD pattern substantially as shown in Figure 6.

[0095] In some embodiments, the solvate form is ethyl acetate solvate.

[0096] In some embodiments, the ethyl acetate solvate form is characterized substantially by an XRPD pattern as shown in Figure 6.

[0097] In some embodiments, the solvate form is the dimethylacetamide solvate form.

[0098] In some embodiments, the dimethylacetamide solvate form is characterized substantially by an XRPD pattern as shown in Figure 17.

[0099] According to the present invention, the crystalline or solvate forms of Compound 1 provided herein may be useful for the synthesis and / or purification of Compound 1. For example, the crystalline forms of Compound 1 provided herein (e.g., crystalline form II, crystalline form III, crystalline form IV, and crystalline form V) may be intermediates in the synthesis of Compound 1. In addition, different crystalline and solvate forms of Compound 1 may have different properties with respect to bioavailability, stability, purity, and / or manufacturability for medical or pharmaceutical applications. Variations in the crystalline structure of a pharmaceutical raw material or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to enable consistent preparation of doses of known strength), and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical formulation or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage forms or delivery forms, such as liquid formulations or solid oral dosage forms including tablets and capsules. Compared to other forms such as amorphous or noncrystalline forms, crystalline forms can provide desired or preferred hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Accordingly, the crystalline and / or solvate forms of Compound 1 provided herein can provide advantages such as improved manufacturing processes of the compound, stability or storability of the compound in drug formulation form, stability or storability of the compound's active pharmaceutical ingredient, and / or bioavailability and / or stability of the compound as an activator.

[0100] It has been found that by using certain solvents and / or methods, different crystalline and / or solvate forms of compound 1 can be produced that exhibit one or more of the preferred characteristics described above. Methods for preparing the crystalline and solvate forms described herein, as well as characterizations of these crystalline and solvate forms, are described in detail below.

[0101] In some embodiments, the crystalline and solvate forms described herein are purified or substantially isolated. "Substantially isolated" means that the crystalline or solvate form is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, a composition in which the crystalline or solvate form of the present invention is concentrated. Substantially separated may include a composition 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 or solvate form of the present invention. In some embodiments, the crystalline or solvate form of the present invention can be prepared with a purity of about 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more.

[0102] Different crystalline and solvate forms can be identified by solid-state characterization methods such as X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC), further help in identifying the form and determining stability and solvent / water content.

[0103] XRPD patterns of reflections (peaks) are typically considered fingerprints of a particular crystal morphology. It is well known that the relative intensity of XRPD peaks can vary considerably depending, among other things, on sample preparation techniques, crystal size distribution, the various filters used, sample mounting procedures, and the specific instruments used. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or settings of the instrument. As used herein, the term “peak” refers to a reflection with a relative height / intensity of at least about 5% of the maximum peak height / intensity. Furthermore, instrument variations and other factors may affect the 2-theta values. Therefore, the attribution of peaks, such as those reported herein, may vary by plus or minus about 0.2° (2-theta), and the terms “substantially” and “about” as used herein in the context of XRPD mean that these variations are included.

[0104] Similarly, temperature readings associated with DSCs can vary by approximately ±3°C depending on the instrument, specific settings, sample preparation, etc. Therefore, the crystalline morphologies reported herein with DSC thermograms that are "substantially" as shown in any of the figures, or the term "approximately," should be understood to allow for such variations.

[0105] The following description is made with the understanding that this disclosure should be considered as an example of the claimed subject matter and that the attached claims are not intended to limit the specific embodiments described herein. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims. Embodiments described under any heading may be combined with embodiments described under any other heading.

[0106] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art.

[0107] Where trade names are used herein, they are intended to refer separately to the trade name product and the active pharmaceutical ingredient of the trade name product.

[0108] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless otherwise explicitly indicated in the context. For example, a reference to "the compound" includes multiple such compounds, and a reference to "the assay" includes one or more assays.

[0109] "Pharmacologically acceptable" means compounds, crystalline forms, solvates, compositions, dosage forms, and other substances that are useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0110] "Pharmacologically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, colorants, flavor enhancers, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are approved by the U.S. Food and Drug Administration for use in humans or domesticated animals.

[0111] "Subject" and "subjects" refer to humans, domesticated animals (e.g., dogs and cats), livestock (e.g., cattle, horses, sheep, goats and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs and monkeys), etc.

[0112] As used herein, “treatment” or “doing treatment” means an approach to obtain a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, symptom relief and / or reduction in the severity of symptoms and / or prevention of exacerbation of symptoms associated with a disease or condition. In some embodiments, “treatment” or “doing treatment” includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of a disease or condition); b) delaying or suppressing the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the exacerbation or progression of a disease or condition); and / or c) mitigating a disease or condition, e.g., causing a regression of clinical symptoms, improving a disease state, delaying disease progression, improving quality of life, and / or extending survival.

[0113] As used herein, “delaying” the onset of a disease or condition means postponing, preventing, delaying, blocking, stabilizing, and / or postponing the onset of the disease or condition. This delay can be of varying lengths depending on the disease being treated and / or the medical history of the subject. As will be apparent to those skilled in the art, a sufficient or significant delay may include prevention in fact, in that the subject does not develop the disease or condition. For example, a method of “delaying” the onset of AIDS is a method that reduces the probability of disease onset and / or the severity of the disease in a given time frame compared to not using the method. Such a comparison may be based on a clinical trial using a statistically significant number of subjects. For example, the onset of AIDS can be detected using known methods, such as confirming the subject's HIV+ status and assessing the subject's T cell count or other indicators of AIDS onset, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swelling of lymph nodes in the neck, axilla, or groin, or the presence of opportunistic conditions known to be associated with AIDS (e.g., conditions that are generally absent in subjects with a functioning immune system but occur in AIDS patients). Onset may also refer to disease progression, including onset, relapse, and development, which may initially be undetectable.

[0114] As used herein, “prevention” or “preventing” refers to a regimen that prevents the onset of a disease or disorder so that the clinical symptoms of the disease do not develop. Therefore, “prevention” relates to treating a subject (e.g., administering a therapeutic substance) before signs of the disease become detectable in the subject (e.g., administering a therapeutic substance to a subject while there is no detectable infectious pathogen (e.g., a virus) in the subject). A subject may be an individual at risk of developing the disease or disorder, e.g., an individual with one or more risk factors known to be associated with the onset or development of the disease or disorder. Therefore, the term “preventing HIV infection” refers to administering an anti-HIV therapeutic substance to a subject who does not have detectable HIV infection. It is understood that subjects of anti-HIV prophylactic therapy may be individuals at risk of contracting the HIV virus. Furthermore, it is understood that prevention may not result in complete protection against the onset of the disease or disorder. In some cases, prevention includes reducing the risk of developing the disease or disorder. A reduction in risk may not result in the complete elimination of the risk of developing the disease or disorder.

[0115] As used herein, an individual at risk means an individual at risk of developing the condition being treated. An individual at risk may or may not have a detectable disease or condition, and may or may not have a detectable disease prior to treatment by the method described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters known in the art that correlate with the development of a disease or condition. An individual having one or more of these risk factors is more likely to develop a disease or condition than an individual without these risk factors. For example, an individual at risk of AIDS is an individual with HIV.

[0116] As used herein, the terms “therapeutic effective dose” or “effective dose” refer to a dose that is effective in eliciting a desired biological or medical response, or in preventing the onset of a disease, containing an amount of the compound sufficient to achieve such treatment of the disease when administered to a subject for the treatment of the disease. The effective dose varies depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. The effective dose may include a range of amounts. As understood in the art, the effective dose may be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment outcome. A monotherapy agent may be considered administered in an effective dose if a desirable or beneficial outcome can or does occur.

[0117] An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scalemic" mixture.

[0118] A "diastereomer isomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other.

[0119] Absolute stereochemistry is specified according to the Kahn-Ingold-Prelogue RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Split compounds whose absolute configuration is unknown may be designated (+) or (-) depending on the direction of rotation of plane polarization at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds and salts described herein involve bound rotations around one or more chiral centers and / or bond axes, and thus may result in enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry. This disclosure is intended to include all such possible isomers, including racemic mixtures, scaremic mixtures, diastereomeric mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or they may be split using prior art.

[0120] Unless expressly defined otherwise, this disclosure includes all tautomers of the compounds detailed herein, even if only one tautomer is expressly represented (for example, if a pair of two tautomers may exist, both tautomer forms are intended and described by the presentation of one tautomer form). For example, when referring to a compound containing an amide (e.g., by its structural or chemical name), it is understood that the corresponding imido acid tautomer is included in this disclosure and described in the same way as when the amide is expressly represented alone or together with an imido acid. If more than two tautomers may exist, this disclosure includes all such tautomers, even if only a single tautomer form is indicated by its chemical name and / or structure.

[0121] This disclosure includes, but is not limited to, any salt disclosed herein, deuterium ( 2 It is understood by those skilled in the art that one or more isotopes, such as H or D, can enrich any or all atoms beyond the naturally occurring isotopic ratios.

[0122] One to n hydrogen atoms bonded to a carbon atom can be replaced with deuterium atoms or D (where n is the number of hydrogen atoms in the molecule), and the crystalline forms and solvate forms of Compound 1 are disclosed. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such salts can enhance resistance to metabolism and thus can be useful for increasing the half-life of a compound when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524 - 527(1984). Such salts are synthesized by well-known means in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced with deuterium.

[0123] Examples of isotopes that can be incorporated into the disclosed salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I are also included. 11 C, 18 F, 15 O, and 13Substitution with positron-emitting isotopes such as 16N may be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled salts can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below, using appropriate isotope-labeled reagents instead of conventionally used unlabeled reagents.

[0124] The compounds described herein may have chiral centers and / or geometric isomer centers (E and Z isomers), and it should be understood that all such optical isomers, enantioisomers, diastereoisomers, and geometric isomers are encompassed. Where compounds are represented in their chiral form, the embodiments should be understood to encompass, but not be limited to, specific diastereolytic or enantiomerically enriched forms. Where chirality is not specified but present, the embodiments should be understood to cover either specific diastereolytic or enantiomerically enriched forms, or racemic or scaremic mixtures of such compounds.

[0125] In some embodiments, the present disclosure relates to the use of the crystalline or solvate form of the present invention in the treatment of Retroviridae virus infections, including infections caused by the HIV virus, the use comprising administering a therapeutically effective amount of the crystalline or solvate form to a subject in need of treatment for the infection.

[0126] Low e-commerce 50 The desirable goal is to discover compounds possessing [this characteristic], or their crystalline or solvate forms. 50 The value refers to the concentration of the compound in the assay that achieves 50% of the maximum efficacy. EC 50 Compounds, crystalline forms, or solvates with lower EC levels are 50 Compared to higher concentrations of the compound, crystalline form, or solvate form, similar efficacy can be achieved at lower concentrations of the compound, crystalline form, or solvate form. Therefore, for drug development, lower EC 50This is generally preferable.

[0127] A desirable goal is to discover compounds, crystalline forms, or solvates with good physical and / or chemical stability. Increased overall stability of a compound, crystalline form, or solvate can lead to increased circulation time in the body. With less degradation, the stable compound, crystalline form, or solvate can be administered at lower doses while still maintaining efficacy. Furthermore, with less degradation, there are fewer concerns regarding by-products resulting from the degradation of the compound, crystalline form, or solvate.

[0128] A desirable goal is to discover compounds, their crystalline or solvate forms, and other forms with improved pharmacokinetic and / or pharmacodynamic profiles, as well as longer half-lives. A drug having moderate or low clearance and a long half-life is advantageous because this can lead to good bioavailability and higher systemic exposure. Reducing the clearance of a compound, its crystalline or solvate form, and increasing its half-life can reduce the daily dose required for efficacy, thus potentially leading to a better efficacy and safety profile. Therefore, improved pharmacokinetic and / or pharmacodynamic profiles, as well as longer half-lives, can provide better patient compliance.

[0129] How to use In some embodiments, the crystalline or solvate forms disclosed herein are used to prevent HIV infection in subjects. In some embodiments, the crystalline or solvate forms disclosed herein are used to prevent HIV infection in subjects at risk of infection. In some embodiments, the crystalline or solvate forms disclosed herein are used in pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 acquired through sexual activity.

[0130] In a particular embodiment, a method is disclosed for treating or preventing HIV infection in a subject (e.g., a human), which includes administering compound 1 in crystalline or solvate form to the subject.

[0131] In certain embodiments, a method is disclosed for inhibiting the replication of the HIV virus, treating AIDS, or delaying the onset of AIDS in a subject (e.g., a human), comprising administering compound 1 in crystalline or solvate form to the subject.

[0132] In some embodiments, methods are disclosed for inhibiting the replication of the HIV virus, treating AIDS, or delaying the onset of AIDS in a subject (e.g., a human), the methods comprising administering compound 1 in crystalline or solvate form to the subject.

[0133] In certain embodiments, a method is disclosed for preventing HIV infection in a subject (e.g., a human), comprising administering compound 1 in crystalline or solvate form to the subject. In certain embodiments, the subject is at risk of contracting the HIV virus, such as having one or more risk factors known to be associated with contracting the HIV virus.

[0134] In some embodiments, a method is disclosed for preventing HIV infection in a subject (e.g., a human), comprising administering a therapeutically effective amount of compound 1 in crystalline or solvate form to the subject. In certain embodiments, the subject is at risk of contracting the HIV virus, such as a subject having one or more risk factors known to be associated with contracting the HIV virus.

[0135] In some embodiments, a method is disclosed for treating HIV infection in a subject (e.g., a human), which includes administering a crystalline form of compound 1 to the subject.

[0136] In some embodiments, a method is disclosed for treating HIV infection in a subject (e.g., a human), which includes administering a solvate form of compound 1 to the subject.

[0137] In some embodiments, crystalline forms of compound 1 are disclosed for use in the medical treatment of HIV infection (e.g., HIV-1, or replication of the HIV virus (e.g., HIV-1), or AIDS, or delay of the onset of AIDS, in a subject (e.g., a human)).

[0138] In some embodiments, solvates of Compound 1 are disclosed for use in the medical treatment of HIV infection (e.g., HIV-1, or replication of the HIV virus (e.g., HIV-1), or AIDS, or delay of the onset of AIDS, in a subject (e.g., a human)).

[0139] In some embodiments, crystalline or solvate forms of compound 1 are disclosed for use in the manufacture of a pharmaceutical product for treating HIV infection or HIV virus replication or AIDS in a subject (e.g., a human) or for delaying the onset of AIDS. In some embodiments, crystalline or solvate forms of compound 1 are disclosed for use in the prophylactic or therapeutic treatment of HIV infection or AIDS, or for use in the therapeutic treatment of AIDS or for delaying the onset of AIDS.

[0140] In some embodiments, crystalline forms of compound 1 are disclosed for use in the manufacture of pharmaceuticals for treating HIV infection or HIV virus replication or AIDS in a subject (e.g., a human) or for delaying the onset of AIDS. In some embodiments, crystalline forms of compound 1 are disclosed for use in the prophylactic or therapeutic treatment of HIV infection or AIDS, or for use in the therapeutic treatment of AIDS or for delaying the onset of AIDS.

[0141] In some embodiments, a solvate form of compound 1 is disclosed for use in the manufacture of a pharmaceutical product for treating HIV infection or HIV virus replication or AIDS in a subject (e.g., a human) or for delaying the onset of AIDS. In some embodiments, a solvate form of compound 1 is disclosed for use in the prophylactic or therapeutic treatment of HIV infection or AIDS, or for use in the therapeutic treatment of AIDS or for delaying the onset of AIDS.

[0142] In certain embodiments, a crystalline or solvate form of compound 1 is disclosed for the manufacture of a pharmacopoeia for HIV infection in a subject (e.g., a human). In certain embodiments, a crystalline or solvate form of compound 1 is disclosed for use in prophylactic or therapeutic treatment of HIV infection.

[0143] In certain embodiments, a crystalline form of compound 1 is disclosed for the manufacture of a pharmaceutical product for HIV infection in a subject (e.g., a human). In certain embodiments, a crystalline form of compound 1 is disclosed for use in prophylactic or therapeutic treatment of HIV infection.

[0144] In certain embodiments, a solvate form of compound 1 is disclosed for the manufacture of a pharmacopoeia for HIV infection in a subject (e.g., a human). In certain embodiments, a solvate form of compound 1 is disclosed for use in prophylactic or therapeutic treatment of HIV infection.

[0145] In certain embodiments, the method of use involves administration to subjects requiring treatment (e.g., humans). In certain embodiments, the method of use involves administration to subjects at risk of developing AIDS (e.g., humans).

[0146] The crystalline or solvate forms of Compound 1 for therapeutic use are disclosed herein. In some embodiments, the crystalline form of Compound 1 is for use in methods to treat HIV infection or HIV virus replication or AIDS in a subject (e.g., human) or to delay the onset of AIDS. In some embodiments, the solvate form of Compound 1 is for use in methods to treat HIV infection or HIV virus replication or AIDS in a subject (e.g., human) or to delay the onset of AIDS.

[0147] Furthermore, crystalline or solvate forms of compound 1 are disclosed herein for use in methods of treating or preventing HIV infection in subjects requiring treatment or prevention of HIV infection. In certain embodiments, crystalline or solvate forms of compound 1 are provided for use in methods of treating HIV infection in subjects requiring treatment of HIV infection. In certain embodiments, subjects requiring treatment of HIV infection are human beings infected with HIV. In certain embodiments, subjects requiring treatment of HIV infection are human beings infected with HIV but who have not developed AIDS. In certain embodiments, subjects requiring treatment of HIV infection are subjects at risk of developing AIDS. In certain embodiments, subjects requiring treatment of HIV infection are human beings infected with HIV and who have developed AIDS.

[0148] In some embodiments, crystalline or solvate forms of compound 1 are disclosed herein for use in methods of treating or preventing HIV infection in subjects requiring treatment or prevention of HIV infection. In certain embodiments, crystalline or solvate forms of compound 1 are provided for use in methods of treating HIV infection in subjects requiring treatment of HIV infection. In certain embodiments, subjects requiring treatment of HIV infection are human beings infected with HIV. In certain embodiments, subjects requiring treatment of HIV infection are human beings infected with HIV but who have not developed AIDS. In certain embodiments, subjects requiring treatment of HIV infection are subjects at risk of developing AIDS. In certain embodiments, subjects requiring treatment of HIV infection are human beings infected with HIV and who have developed AIDS.

[0149] In some embodiments, a crystalline or solvate form of compound 1 is provided for use, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), to prevent HIV infection from occurring when an individual is exposed to the virus, and / or to prevent the establishment of persistent viral infection, and / or to prevent the appearance of disease symptoms, and / or to prevent the virus from reaching detectable levels in the blood. Thus, in certain embodiments, a method is provided for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2). For example, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes the administration of a crystalline or solvate form of compound 1. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes the administration of a pharmaceutical composition comprising a therapeutically effective amount of a crystalline or solvate form of compound 1 and one or more excipients.

[0150] In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administration of compound 1 in crystalline or solvate form, combined with safer sexual practices. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administration to individuals at risk of acquiring HIV. Examples of individuals at high risk of acquiring HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

[0151] In certain embodiments, the reduction in the risk of acquiring HIV is at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In certain embodiments, the reduction in the risk of acquiring HIV is at least about 75%. In certain embodiments, the reduction in the risk of acquiring HIV is at least about 80%, 85%, or 90%.

[0152] In some embodiments, the use of compound 1 in crystalline or solvate form is disclosed for the manufacture of a pharmaceutical for the treatment of HIV infection in a person who has or is at risk of having HIV infection.

[0153] In some embodiments, crystalline or solvate forms of compound 1 are disclosed herein for use in the therapeutic treatment of AIDS or in delaying the onset of AIDS.

[0154] In certain embodiments, the crystalline or solvate form of compound 1 can be used as a research tool.

[0155] Route of administration Compound 1 in crystalline or solvate form (also referred to herein as the active ingredient) can be administered by any route appropriate to the condition being treated. Preferred routes include oral, rectal, nasal, topical (including buccal and sublingual), percutaneous, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It is understood that the preferred route may vary, for example, depending on the recipient's condition. In certain embodiments, the compound may be administered parenterally. In certain embodiments, the disclosed compound may be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the crystalline or solvate form of Compound 1 has oral bioavailability and may be administered orally.

[0156] In some embodiments, compound 1 may be administered by injection using an injection device. In some embodiments, the injection device is or includes a syringe, and the syringe may be used manually or as part of a syringe-containing injection device, such as but not limited to a syringe-containing injection device equipped with a needle safety shield. A wide variety of injection devices may be used, such as, but not limited to, handheld or wearable auto-injectors, handheld or wearable manual syringes, on-body syringes, syllets, jet syringes, or pen-type syringes, each of which may be reusable or disposable.

[0157] In some embodiments, the crystalline or solvate form of compound 1 may be administered using an auto-injector equipped with a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the crystalline or solvate form of compound 1.

[0158] Administration regimen Compound 1 can be administered to a subject (e.g., a human) in an effective dose, either in crystalline or solvate form. In some embodiments, compound 1 can be administered to a subject (e.g., a human) in a therapeutically effective dose.

[0159] Compound 1 in crystalline or solvate form may be administered to a subject according to an effective dosing regimen over a desired period or duration, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 12 months or more. In some embodiments, Compound 1 in crystalline or solvate form is administered daily or intermittently. In certain embodiments, Compound 1 in crystalline or solvate form is administered once daily. In some embodiments, Compound 1 in crystalline or solvate form is administered monthly. In some embodiments, Compound 1 in crystalline or solvate form is administered every 2 months. In some embodiments, Compound 1 in crystalline or solvate form is administered every 3 months. In some embodiments, Compound 1 in crystalline or solvate form is administered every 4 months. In some embodiments, Compound 1 in crystalline or solvate form is administered every 5 months. In some embodiments, compound 1 is administered in crystalline or solvate form every six months.

[0160] The dosage or frequency of administration of compound 1 in crystalline or solvate form may be adjusted throughout the course of treatment at the discretion of the administering physician.

[0161] The crystalline or solvate forms of Compound 1 disclosed herein can be administered in effective doses. For example, the dose may be 1 mg to 1000 mg of the compound. In certain embodiments, the dose is about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105, 110, 120, 130, 140, or 150 mg of the compound. In certain embodiments, the dose is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

[0162] In some embodiments, compound 1 is administered in a once-daily dose, either in crystalline or solvate form.

[0163] Pharmaceutical composition The pharmaceutical compositions disclosed herein comprise the crystalline or solvate form of Compound 1 disclosed herein, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration.

[0164] In some embodiments, the pharmaceutical compositions disclosed herein comprise the crystalline or solvate form of Compound 1 disclosed herein, together with one or more pharmaceutically acceptable excipients. The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration.

[0165] Pharmaceutical compositions comprising Compound 1 disclosed herein in crystalline or solvate form may be prepared with conventional carriers (e.g., non-active ingredients or excipient materials) selected according to common practice. Tablets may contain excipients, including flow enhancers, fillers, and binders. Aqueous compositions may be prepared in sterile form and may generally be isotonic if intended for delivery by means other than oral administration. All compositions may optionally contain excipients, such as those described in Rowe et al, Handbook of Pharmaceutical Excipients, 5th edition, American Pharmacists Association, 1986. Examples of excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid.

[0166] While it is possible to administer the active ingredient alone, it may be preferable to present the active ingredient as a pharmaceutical composition. Compositions for both veterinary and human use include at least one crystalline or solvate form of Compound 1 disclosed herein, along with one or more acceptable carriers. The carrier is "acceptable" in the sense that it is compatible with the other components of the composition and is physiologically harmless to its recipient.

[0167] Examples of compositions include those suitable for various routes of administration. The compositions may be conveniently presented in unit dosage forms and may be prepared by any method well known in the field of pharmacy. Such methods include the step of associating an active ingredient with one or more non-active ingredients (e.g., carriers, pharmaceutical excipients, etc.). Compositions may be prepared by homogeneously and closely associating an active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. The techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21 st It can be found in Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0168] The compositions described herein, which are suitable for oral administration, may be presented as separate units (unit dosage forms), including but not limited to capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient.

[0169] For example, when used orally, tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Even if the tablets are not coated, they may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying agents such as glyceryl monostearate or glyceryl distearate, either alone or with wax, may be used.

[0170] In some embodiments, oral dosage forms (e.g., tablets) that can be prepared by hot-melt extrusion or spray-drying dispersion (SDD) techniques are disclosed herein.

[0171] In some embodiments, hard capsules are disclosed herein, which are filled with powders, beads, or granules containing an active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of hard or soft capsules. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulators and disintegrants such as corn starch, or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0172] In some embodiments, hard or soft capsules are disclosed herein, which are filled with a liquid or semi-solid mixture containing an active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of hard or soft capsules. These excipients may be, for example, solubilizing oils such as corn oil, sesame oil, or corn oil; medium-chain triglycerides and related esters such as derivatized palm kernel oil or coconut oil; self-emulsifying lipid systems (SEDDS or SMEDDS) such as caprylic triglyceride or propylene glycol monocaprylate; viscosity modifiers such as cetyl alcohol, steryl alcohol, or glycerol stearate; and solubilizers and surfactants such as polyethylene glycol, propylene glycol, glycerin, ethanol, polyethoxylated castor oil, poloxamer, or polysorbate.

[0173] The pharmaceutical compositions of this disclosure may be in the form of sterile injection preparations, such as sterile aqueous or oily suspensions for sterile injection. These suspensions may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents as described herein. The sterile injection preparations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol, or may be prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixatives may conventionally be used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, may be used. In addition, fatty acids, such as oleic acid, may also be used in the preparation of injections.

[0174] In some embodiments, the sterile injection preparations disclosed herein may also be sterile injection solutions or suspensions prepared from reconstituted lyophilized powders in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixatives may conventionally be used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, may be used. In addition, fatty acids such as oleic acid may also be used in the preparation of injections.

[0175] Suitable formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes to make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. In certain embodiments, the suspension is a microsuspension. In certain embodiments, the suspension is a nanosuspension.

[0176] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) include one or more excipients. The excipients must be compatible with the other components of the formulation and physiologically harmless to its recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in the Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[0177] Examples of solubilizing excipients in parenteral formulations include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338, 188, or 207).

[0178] In some embodiments, the parenteral formulations disclosed herein are aqueous suspensions. In some embodiments, the parenteral formulations disclosed herein are aqueous suspensions comprising the crystalline or solvate form of compound 1 disclosed herein and physiological saline. In some embodiments, the parenteral formulations disclosed herein are aqueous suspensions comprising the crystalline or solvate form of compound 1 disclosed herein, physiological saline, and poloxamer.

[0179] In certain embodiments, the composition is disclosed as a solid dosage form, including a solid injection dosage form such as a solid depot form.

[0180] The amount of active ingredient that can be combined with non-active ingredients to produce a dosage form may vary depending on the intended treatment target and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active ingredient formulated with an appropriate and convenient amount of carrier material (e.g., non-active ingredient or excipient material). In certain embodiments, the carrier material may vary from about 5 to about 95% (by weight) of the total composition.

[0181] In addition to the components described in detail above, the compositions of these embodiments may also contain other conventional agents in the art, depending on the type of composition. For example, compositions suitable for oral administration may contain flavoring agents.

[0182] In certain embodiments, a composition containing the active ingredient disclosed herein in one variant does not contain any agents that may affect the rate at which the active ingredient is metabolized. Therefore, it is understood that, in certain embodiments, a composition containing compound 1 in crystalline or solvate form does not contain any agents that may affect (e.g., slow, hinder, or inhibit) the metabolism of compound 1 in crystalline or solvate form. It is also understood that, in certain embodiments, none of the methods, kits, products, etc., detailed herein contain any agents that may affect (e.g., slow, hinder, or inhibit) the metabolism of compound 1 in crystalline or solvate form.

[0183] Kits and manufactured products This disclosure relates to a kit comprising compound 1 disclosed herein in crystalline or solvate form. The kit may further include instructions for use, e.g., instructions for use in inhibition of HIV reverse transcriptase, e.g., for use in the treatment of HIV infection or AIDS, or for use as a research tool. Instructions for use are generally written instructions, but electronic storage media containing the instructions (e.g., magnetic diskettes or optical disks) are also acceptable.

[0184] This disclosure also relates to a pharmaceutical kit comprising one or more storage containers containing Compound 1 disclosed herein in crystalline or solvate form. Such storage containers may optionally be accompanied by a notice in the form prescribed by a government agency regulating the manufacture, use, or sale of a medicinal product, such notice reflecting the agency's approval for manufacture, use, or sale for human administration. Each component (if there are two or more components) may be packaged in a separate storage container, or several components may be combined in a single storage container where cross-reactivity and shelf life permit. The kit may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or subunit doses. The kit may also include multiple unit doses of the compound and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., hospital pharmacies and dispensing pharmacies).

[0185] In some embodiments, the disclosure also relates to a pharmaceutical kit comprising one or more storage containers containing Compound 1 disclosed herein in crystalline or solvate form. Such storage containers may optionally be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of a pharmaceutical product, such notice reflecting the agency's approval for manufacture, use, or sale for human administration.

[0186] Also disclosed are articles containing a unit dose of compound 1 in crystalline or solvate form within packaging suitable for use in the method described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, and flexible packaging. The articles may be further sterilized and / or sealed.

[0187] This specification may use the following abbreviations:

[0188] [Table 7] [Examples]

[0189] General materials and methods The following materials and methods were used throughout the examples.

[0190] X-ray powder diffraction (XRPD) analysis was performed using a diffractometer (PANalytical XPERT-PRO, PANalytical BV, Almelo, Netherlands) with copper radiation (Cu Kα, λ=1.541874). The sample was spread uniformly on a zero-background sample plate. The generator was operated at a voltage of 45kV and an amperage of 40mA. The slits were a solar slit of 0.02rad, a scattering prevention slit of 1.0°, and a divergent slit. Scanning was performed with a step size of 0.0167 at 2–40°2θ. Data analysis was performed using X'Pert Viewer V1.9a (PANalytical BV, Almelo, Netherlands).

[0191] Differential scanning calorimetry (DSC) and modulated differential scanning calorimetry (MDSC) were performed using a Model Q2000 (TA Instruments, New Castle, DE). Approximately 1–5 mg of material was placed in a Tzero standard aluminum pan with a manually made pinhole in the lid. By default, the sample pan and reference pan were heated to 20–300°C under a nitrogen purge of 50 mL / min. DSC was performed at a heating rate of 10°C / min, and MDSC was performed at a heating rate of 5°C / min with a modulation of ±1.00°C every 60 seconds. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0192] Using thermogravimetric analysis (TGA), sample weight loss was evaluated as a function of temperature using either Model Q5000 or Q500 (TA Instruments, New Castle, DE). Approximately 1–5 mg of material was placed on a sample pan, and the sample was heated from ambient temperature to over 300°C at a rate of 10°C / min. The sample pan was purged with nitrogen at 40 mL / min. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0193] The hygroscopic properties were studied using dynamic vapor adsorption (DVS) with a Model Q5000 SA (TA Instruments, New Castle, DE). Samples (1-10 mg) were placed in aluminum pans and positioned on the sample side of a twin-pan balance. Water adsorption and desorption were studied as a function of relative humidity (RH) at 25°C, increasing from 0% RH to 90% RH in 10% RH increments, and then returning to 0%. Each relative humidity increment had an equilibrium time of 120 minutes unless the weight change was less than 0.002% in 20 minutes. Data analysis was performed using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE).

[0194] Example 1. Preparation of crystalline form II of compound 1 Approximately 100 mg of free base crystalline form I of compound 1 (see, for example, U.S. Patent Application Publications 20220323476(A1) and 20220332751(A1), the entirety of which is incorporated herein by reference) was stirred with approximately 0.5 mL of acetone at approximately 22°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirrer. After 3 days, XRPD analysis of the wet solid showed a new pattern, which was named acetone solvate 1 of compound 1 (see Figure 1). After drying under vacuum at 50°C, the XRPD pattern changed, and the resulting new form was named crystalline form II of compound 1.

[0195] A typical XRPD pattern of crystalline form II of compound 1 is shown in Figure 2. This pattern is characterized by sharp reflections, indicating crystallinity. Table 1 shows a list of XRPD peakings for crystalline form II of compound 1.

[0196] [Table 1]

[0197] The DSC thermogram, as shown in Figure 3, showed a small endothermic transition at approximately 93°C, resulting from a morphological change of compound 1 from crystalline form II to crystalline form V, which has a melting initiation point at approximately 156°C (confirmed by XRPD in another experiment). The TGA thermogram, as shown in Figure 4, showed no substantial weight loss (0.01% over 25°C to 150°C), indicating the absence of residual solvent. The DVS analysis is shown in Figure 5. This analysis showed a weight change of approximately 0.1% over 0% to 90% RH at 25°C, indicating that this form is non-hygroscopic.

[0198] Example 2. Preparation of crystalline form III of compound 1 Approximately 100 mg of free base crystalline form I of compound 1 was stirred with approximately 0.5 mL of dichloromethane (DCM) at approximately 22°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirring bar. After 3 days, XRPD analysis of the wet solid covered with Kapton film showed a new pattern, which was named the DCM solvate of compound 1 (see Figure 6). After drying in air, the XRPD pattern changed, and the resulting new form was named crystalline form III of compound 1.

[0199] Alternatively, crystalline form III of compound 1 can be obtained by drying other solvates of compound 1, such as acetone solvate 2, methyl ethyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, tetrahydrofuran, 1-butanol, or p-dioxane solvate, under vacuum at 50°C. Representative XRPD patterns of these solvates are shown in Figure 6.

[0200] Single crystals of the dichloromethane (DCM) solvate of compound 1 were prepared by dissolving approximately 105 mg of compound 1 in 0.5 mL of DCM solution at approximately 40°C, and then holding at approximately 22°C for several weeks. A slurry was formed, and the sample was subjected to SCXRD analysis at approximately 298°C. Since DCM was volatile, it detached from the crystal lattice, and the results were consistent with form III of compound 1, which has the following crystal parameters.

[0201] [Table 2]

[0202] The molecules observed in the asymmetric unit of the single-crystal structure matched the molecular structure of compound 1. The asymmetric unit shown in Figure 7 contains one molecule of one compound. One of the phenylacetate moieties was disordered (as indicated by the dots), and upon refinement, its occupancy in the dominant orientation was 73%. The orientation, which consists of vacancies in the phenylacetate, contained sufficient space for the solvent.

[0203] Figure 8 shows a typical XRPD pattern of crystalline form III of compound 1, obtained after drying the DCM solvate. This pattern is characterized by sharp reflections, indicating crystallinity. Table 3 shows a list of XRPD peakings for crystalline form III of compound 1.

[0204] [Table 3]

[0205] The DSC thermogram, as shown in Figure 9, showed a small endothermic transition at approximately 125°C, resulting from a morphological change from crystalline form III to crystalline form V of compound 1 (confirmed by XRPD in another experiment). In another experiment, further heating of the sample (to 150°C) yielded a mixture of crystalline form V and crystalline form I of compound 1, indicated by a double peak in the temperature range of 150–165°C. The TGA thermogram, as shown in Figure 10, showed virtually no weight loss (0.04% over 25°C to 150°C), indicating very little residual solvent. The DVS analysis is shown in Figure 11. This analysis showed a weight change of approximately 1.2% over 0% to 90% RH at 25°C, indicating that this morphology is slightly hygroscopic.

[0206] Example 3. Preparation of crystalline form IV of compound 1 Approximately 50 mg of free base crystalline form I of compound 1 was stirred with approximately 0.5 mL of toluene in a 4 mL vial equipped with a Teflon®-coated magnetic stirring bar at approximately 22°C. After 3 days, XRPD analysis of the wet solid showed a new pattern, which was named toluene solvate of compound 1 (see Figure 12). After drying under vacuum at 50°C, the XRPD pattern changed, and the new form was named crystalline form IV of compound 1.

[0207] A typical XRPD pattern for crystalline form IV of compound 1 is shown in Figure 13. This pattern is characterized by sharp reflections, indicating crystallinity. Table 4 shows a list of XRPD peakings for crystalline form IV of compound 1.

[0208] [Table 4]

[0209] The DSC thermogram, as shown in Figure 14, showed a small endothermic transition at approximately 114°C, attributed to a morphological change from crystalline form IV to crystalline form I of compound 1 (confirmed by XRPD in another experiment). The TGA thermogram, as shown in Figure 15, showed virtually no weight loss (0.004% over 25°C to 150°C), indicating very little residual solvent. The DVS analysis is shown in Figure 16. This analysis showed a weight change of approximately 0.16% over 0% to 90% RH at 25°C, indicating that this morphology is non-hygroscopic.

[0210] Example 4. Preparation of crystalline form V of compound 1 The crystalline form V of compound 1 can be prepared by any of the following procedures. 1. Heat the crystalline form II of compound 1 to approximately 100°C. 2. Heat crystalline form III of compound 1 to approximately 125°C. Since crystalline form III of compound 1 can be obtained by drying different solvates, the temperature required to convert crystalline form III of compound 1 to crystalline form V of compound 1 may vary. 3. Dry the xylene solvate or DMAc solvate of compound 1 (see Figure 17) at 75-110°C. Small amounts of crystalline form I of compound 1 may also be present.

[0211] A typical XRPD pattern for crystalline form V of compound 1 is shown in Figure 18. This pattern is characterized by sharp reflections, indicating crystallinity. A list of XRPD peakings for crystalline form V of compound 1 is shown in Table 5.

[0212] [Table 5]

[0213] The DSC thermogram showed a melting initiation point at approximately 156°C, as shown in Figure 19. The TGA thermogram showed virtually no weight loss (0.12% from 25°C to 150°C), as shown in Figure 20, indicating very little residual solvent. The DVS analysis is shown in Figure 21. This analysis showed a weight change of approximately 0.1% from 0% to 90% RH at 25°C, indicating that this form is non-hygroscopic.

[0214] Example 5. Overview of the solid form of Compound 1 Table 6 shows the melting initiation point and DVS properties of crystalline forms I to V of compound 1.

[0215] [Table 6]

[0216] The DVS values ​​for forms II, III, IV, and V demonstrate the unique hygroscopic properties of these novel forms. These properties may provide unexpected benefits, such as improving the manufacturing process of the compound, increasing the stability or storability of the compound's drug formulation form, increasing the stability or storability of the compound's active pharmaceutical ingredient, improving the bioavailability and / or stability of the compound as an activator, and increasing the physical and / or chemical stability of the dosage form or delivery form.

[0217] All references, including publications, patents, and patent documents, are incorporated herein by reference as if they were individually incorporated by reference. This disclosure provides references to various embodiments and techniques. However, it should be understood that many variations and modifications are possible, while remaining within the spirit and scope of this disclosure.

Claims

1. Crystal forms of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate, selected from crystal form II, crystal form III, crystal form IV, and crystal form V.

2. The crystal form according to claim 1, which is crystal form II.

3. The crystal morphology according to claim 2, wherein the crystal morphology II has at least three XRPD peaks selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4° in 2-theta ± 0.2° notation.

4. The crystal morphology II described above is characterized substantially by an XRPD pattern as shown in Figure 2, according to claim 2.

5. The crystal morphology II is characterized by a DSC thermogram having an endothermic transition at approximately 93°C, according to any one of claims 2 to 4.

6. The crystal morphology II described above is characterized substantially by a DSC thermogram as shown in Figure 3, according to any one of claims 2 to 4.

7. The crystal form according to claim 1, which is crystal form III.

8. The crystal morphology according to claim 7, wherein the crystal morphology III has at least three XRPD peaks selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0° in 2-theta ± 0.2° notation.

9. The crystal morphology III described above is characterized substantially by an XRPD pattern as shown in Figure 8, according to claim 7.

10. The crystal morphology III is characterized by a DSC thermogram having an endothermic transition at approximately 125°C, according to any one of claims 7 to 9.

11. The crystal morphology III described above is characterized substantially by a DSC thermogram as shown in Figure 9, according to any one of claims 7 to 9.

12. The crystal form according to claim 1, which is crystal form IV.

13. The crystal morphology according to claim 12, wherein the crystal morphology IV has at least three XRPD peaks selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8° in 2-theta ± 0.2° notation.

14. The crystal morphology IV is characterized substantially by an XRPD pattern as shown in Figure 13, according to claim 12.

15. The crystal morphology IV is characterized by a DSC thermogram having an endothermic transition at approximately 114°C, according to any one of claims 12 to 14.

16. The crystal morphology IV is characterized substantially by a DSC thermogram as shown in Figure 14, according to any one of claims 12 to 14.

17. The crystal form according to claim 1, which is crystal form V.

18. The crystal morphology according to claim 17, wherein the crystal morphology V has at least three XRPD peaks selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3° in 2-theta ± 0.2° notation.

19. The crystal morphology V is characterized substantially by an XRPD pattern as shown in Figure 18, according to claim 17.

20. The crystal morphology V is characterized by a DSC thermogram having a melting initiation point of approximately 156°C, according to any one of claims 17 to 19.

21. The crystal morphology V is characterized substantially by a DSC thermogram as shown in Figure 19, according to any one of claims 17 to 19.

22. (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate in solvate form.

23. The solvate form according to claim 22, selected from acetone solvate form, methyl ethyl ketone solvate form, dichloromethane solvate form, tetrahydrofuran solvate form, toluene solvate form, n-butyl acetate solvate form, methyl acetate solvate form, xylene solvate form, heptane solvate form, 1-butanol solvate form, p-dioxane solvate form, DMAc solvate form, ethyl acetate solvate form, and dimethylacetamide solvate form.

24. The solvate form according to claim 22 or 23, which is in the form of an acetonitrile solvate.

25. The solvate form according to claim 22 or 23, which is an acetone solvate form.

26. The solvate form according to claim 25, which is form I of the acetone solvate.

27. The solvate form according to claim 25, which is form II of the acetone solvate.

28. The solvate form according to claim 22 or 23, which is a methyl ethyl ketone solvate form.

29. The solvate form according to claim 22 or 23, which is a dichloromethane solvate form.

30. The solvate form according to claim 22 or 23, which is a tetrahydrofuran solvate form.

31. The solvate form according to claim 22 or 23, which is a toluene solvate form.

32. The solvate form according to claim 22 or 23, which is a DMAc solvate form.

33. The solvate form according to claim 22 or 23, which is in the form of n-butyl acetate solvate.

34. The solvate form according to claim 22 or 23, which is a methyl acetate solvate form.

35. The solvate form according to claim 22 or 23, which is a xylene solvate form.

36. The solvate form according to claim 22 or 23, which is in the form of a heptane solvate.

37. The solvate form according to claim 22 or 23, which is in the form of 1-butanol solvate.

38. The solvate form according to claim 22 or 23, which is a chloroform solvate form.

39. The solvate form according to claim 22 or 23, which is in the form of a p-dioxane solvate.

40. The solvate form according to claim 22 or 23, which is in the form of N-methyl-2-pyrrolidone solvate.

41. The solvate form according to claim 22 or 23, which is an ethyl acetate solvate form.

42. The solvate form according to claim 22 or 23, which is a dimethylacetamide solvate form.

43. A pharmaceutical composition comprising a crystalline form, cocrystalline form, or salt form according to any one of claims 1 to 21, or a solvate form according to any one of claims 22 to 42, and at least one pharmaceutically acceptable excipient.

44. A method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the crystalline, co-crystalline, or salt form described in any one of claims 1 to 21, or the solvate form described in any one of claims 22 to 42, to a subject in need of treatment or prevention of HIV infection.

45. A crystalline form, cocrystal form, or salt form according to any one of claims 1 to 21, or a solvate form according to any one of claims 22 to 42, for use in treatment.

46. A crystalline form, cocrystalline form, salt form, or solvate form according to any one of claims 1 to 21, or a solvate form according to any one of claims 22 to 42, for use in a method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the crystalline form, cocrystalline form, salt form, or solvate form to a subject requiring treatment or prevention of HIV infection.

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