Solid forms of nucleoside reverse transcriptase translocation inhibitors

Abstract

The present disclosure relates to crystalline and solvate forms of nucleoside reverse transcriptase translocation inhibitor (NRTTI) and pharmaceutical compositions thereof for use in the treatment and prevention of retroviridae viral infections, including infections caused by HIV virus.

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 523,505, filed June 27, 2023, pursuant to 35 USC § 119(e), the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to crystalline and solvated forms of nucleoside reverse transcriptase translocation inhibitors (NRTTIs) and pharmaceutical compositions thereof for the treatment or prevention of retroviral infections, including infections caused by HIV. Background Technology

[0003] Positive single-stranded RNA viruses, including those in the family Retroviridae, include the subfamily Orthoviridiae, which causes many diseases in humans and animals. Orthoretrovirinae ) and alpha retrovirus ( Alpharetrovirus ), β retrovirus ( Betaretrovirus ), γ retrovirus ( Gammaretrovirus ), δ retrovirus ( Deltaretrovirus ε retrovirus ( Epsilon retrovirus ), foam virus ( Spumavirus ) and lentiviruses ( Lentivirus Those belonging to the genus lentivirus. In lentiviruses, HIV-1 infection in humans leads to the depletion of T helper cells and immune dysfunction, resulting in immunodeficiency and susceptibility to opportunistic infections.

[0004] One approach to treating HIV-1 infection is through the administration of NRTTIs. NRTTIs inhibit HIV-1 reverse transcriptase, and since reverse transcriptase function is essential for viral replication and the production of viral proteins, NRTTIs are effective against HIV-1 infection. Curr Opin HIV AIDS. 2018 July; 13(4): 294–299. However, HIV treatment has historically led to the emergence of HIV strains resistant to current therapies. Expert Opin Emerg Drugs. 2018 June; 23(2):149–157. Therefore, there is an ongoing need to discover new antiretroviral agents and develop methods for their preparation and purification, as well as improved pharmaceutical formulations for preparing these antiretroviral agents. The solid form of NRTTIs disclosed herein helps to meet these and other needs. Summary of the Invention

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

[0006] This disclosure also provides a (2) R ,3 S 5 R The solvated form of 5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl-2-phenylacetic acid ester.

[0007] This disclosure also provides a pharmaceutical composition comprising the crystalline or solvated form disclosed herein, and at least one pharmaceutically acceptable excipient.

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

[0009] This disclosure also provides the crystalline or solvated forms disclosed herein for use in therapeutics.

[0010] This disclosure also provides the crystalline or solvated forms disclosed herein for use in the treatment or prevention of human immunodeficiency virus (HIV) infection, the method comprising administering a therapeutically effective amount of the crystalline or solvated form to a subject in need. Attached Figure Description

[0011] Figure 1 A representative X-ray powder diffraction (XRPD) pattern of compound 1, acetone solvate 1, is shown.

[0012] Figure 2 A representative XRPD pattern of crystalline form II of compound 1 is shown.

[0013] Figure 3 A representative differential scanning calorimetry (DSC) thermogram of crystalline form II of compound 1 is shown.

[0014] Figure 4 A representative thermogravimetric analysis (TGA) chromatogram of crystalline form II of compound 1 is shown.

[0015] Figure 5 A representative dynamic vapor adsorption (DVS) analysis of crystalline form II of compound 1 is shown.

[0016] Figure 6Representative XRPD patterns of the solvate form of compound 1 are shown. 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.

[0017] Figure 7 The asymmetric unit of crystalline form III of compound 1 is shown.

[0018] Figure 8 A representative XRPD pattern of crystalline form III of compound 1 is shown.

[0019] Figure 9 A representative DSC thermogram of crystalline form III of compound 1 is shown.

[0020] Figure 10 A representative TGA thermogram of crystalline form III of compound 1 is shown.

[0021] Figure 11 A representative DVS analysis of crystalline form III of compound 1 is shown.

[0022] Figure 12 A representative XRPD pattern of the toluene solvate of compound 1 is shown.

[0023] Figure 13 A representative XRPD pattern of crystalline form IV of compound 1 is shown.

[0024] Figure 14 A representative DSC thermogram of the crystalline form IV of compound 1 is shown.

[0025] Figure 15 A representative TGA thermogram of the crystalline form IV of compound 1 is shown.

[0026] Figure 16 Representative DVS analysis of crystalline form IV of compound 1 is shown.

[0027] Figure 17 Representative XRPD patterns of compound 1 xylene solvate (top) and DMAc solvate (bottom) are shown.

[0028] Figure 18 A representative XRPD pattern of crystalline form V of compound 1 is shown.

[0029] Figure 19 A representative DSC thermogram of crystalline form V of compound 1 is shown.

[0030] Figure 20A representative TGA thermogram of crystalline form V of compound 1 is shown.

[0031] Figure 21 A representative DVS analysis of crystalline form V of compound 1 is shown. Detailed Implementation

[0032] This invention relates to a new solid form, which is (2) R ,3 S 5 R )-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate (i.e., compound 1, the structure of which is shown below; see, for example, U.S. Publications 20220323476A1 and 20220332751A1, the entire contents of which are incorporated herein by reference) in crystalline or solvated form.

[0033] Compound 1 Compound 1 is 4'-ethynyl-2-fluoro-2'-deoxyadenosine (i.e., islatravir or (2) R ,3 S 5 R )-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (a nucleoside reverse transcriptase translocation inhibitor (NRTTI)).

[0034] Islatrovir Those skilled in the art will understand that compound structures can be named or identified using generally accepted nomenclature systems and symbols. For example, compounds can be named or identified using common names, systematic names, or non-systematic names. 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). Therefore, the compound structure of compound 1 provided herein can also be named or identified as (2 R ,3 S 5 R )-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl-2-phenylacetate.

[0035] This invention provides a (2) R ,3 S 5 RThe crystalline form of 5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate is selected from crystalline form II, crystalline form III, crystalline form IV and crystalline form V.

[0036] As used herein, "crystalline form" refers to a particular crystal lattice configuration of a crystalline substance. 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. In some embodiments, the crystalline forms provided herein may be substantially anhydrous.

[0037] compound 1 Crystalline form II In some implementations, the crystalline form provided herein is crystalline form II.

[0038] In some embodiments, crystalline form II has at least five XRPD peaks, denoted as 2θ ± 0.2°, selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4°.

[0039] In some embodiments, crystalline form II has at least four XRPD peaks, denoted as 2θ ± 0.2°, selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4°.

[0040] In some embodiments, crystalline form II has at least three XRPD peaks, denoted as 2θ ± 0.2°, selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4°.

[0041] In some embodiments, crystalline form II has at least two XRPD peaks, denoted as 2θ ± 0.2°, selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4°.

[0042] In some embodiments, crystalline form II has at least one XRPD peak, denoted as 2θ ± 0.2°, selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4°.

[0043] In some embodiments, crystalline form II has an XRPD peak, denoted as 2θ ± 0.2°, selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4°.

[0044] In some implementations, crystal form II is characterized by an XRPD pattern that is substantially as follows: Figure 2 As shown.

[0045] In some implementations, crystalline form II is characterized by an endothermic transition in the DSC thermogram at approximately 93°C.

[0046] In some embodiments, crystalline form II is characterized by an endothermic transition in the DSC thermogram at approximately 93°C, which corresponds to the transition from crystalline form II of compound 1 to crystalline form V of compound 1.

[0047] In some implementations, crystalline form II is characterized by a DSC thermogram that is essentially as follows: Figure 3 As shown.

[0048] In some implementations, crystalline form II is characterized by a TGA thermogram that is essentially as follows: Figure 4 As shown.

[0049] In some implementations, crystalline form II is characterized by DVS analysis being essentially as follows: Figure 5 As shown.

[0050] compound 1 Crystalline form III In some implementations, the crystalline form provided herein is crystalline form III.

[0051] In some embodiments, crystalline form III has at least five XRPD peaks, denoted as 2θ ± 0.2°, selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0°.

[0052] In some embodiments, crystalline form III has at least four XRPD peaks, denoted as 2θ ± 0.2°, selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0°.

[0053] In some embodiments, crystalline form III has at least three XRPD peaks, denoted as 2θ ± 0.2°, selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0°.

[0054] In some embodiments, crystalline form III has at least two XRPD peaks, denoted as 2θ ± 0.2°, selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0°.

[0055] In some embodiments, crystalline form III has at least one XRPD peak, denoted as 2θ ± 0.2°, selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0°.

[0056] In some embodiments, crystalline form III has an XRPD peak, denoted as 2θ ± 0.2°, selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0°.

[0057] In some implementations, crystal form III is characterized by an XRPD pattern that is substantially as follows: Figure 8 As shown.

[0058] In some embodiments, crystalline form III is characterized by an endothermic transition in its DSC thermogram at approximately 125°C. In some embodiments, crystalline form III is characterized by an endothermic transition in its DSC thermogram at approximately 125°C, which corresponds to a transition from crystalline form III of compound 1 to crystalline form V of compound 1.

[0059] In some implementations, crystalline form III is characterized by a DSC thermogram that is essentially as follows: Figure 9 As shown.

[0060] In some implementations, crystalline form III is characterized by a TGA thermogram that is essentially as follows: Figure 10 As shown.

[0061] In some implementations, crystalline form III is characterized by DVS analysis being essentially as follows: Figure 11 As shown.

[0062] compound 1 Crystalline form IV In some implementations, the crystalline form provided herein is crystalline form IV.

[0063] In some embodiments, crystalline form IV has at least five XRPD peaks, denoted as 2θ ± 0.2°, selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°.

[0064] In some embodiments, crystalline form IV has at least four XRPD peaks, denoted as 2θ ± 0.2°, selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°.

[0065] In some embodiments, crystalline form IV has at least three XRPD peaks, denoted as 2θ ± 0.2°, selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°.

[0066] In some embodiments, crystalline form IV has at least two XRPD peaks, denoted as 2θ ± 0.2°, selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°.

[0067] In some embodiments, crystalline form IV has at least one XRPD peak, denoted as 2θ ± 0.2°, selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°.

[0068] In some embodiments, crystalline form IV has an XRPD peak, denoted as 2θ ± 0.2°, selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°.

[0069] In some implementations, crystalline form IV is characterized by an XRPD pattern that is substantially as follows: Figure 13 As shown.

[0070] In some embodiments, crystalline form IV is characterized by an endothermic transition in its DSC thermogram at approximately 114°C. In some embodiments, crystalline form IV is characterized by an endothermic transition in its DSC thermogram at approximately 114°C, which corresponds to a transition from crystalline form IV of compound 1 to crystalline form I of compound 1.

[0071] In some implementations, crystalline form IV is characterized by a DSC thermogram that is essentially as follows: Figure 14 As shown.

[0072] In some implementations, crystalline form IV is characterized by a TGA thermogram that is essentially as follows: Figure 15 As shown.

[0073] In some implementation schemes, the crystalline form IV is characterized by DVS analysis being essentially as follows: Figure 16 As shown.

[0074] compound 1 Crystalline form V In some implementations, the crystalline form provided herein is crystalline form V.

[0075] In some embodiments, the crystalline form V has at least five XRPD peaks, denoted as 2θ ± 0.2°, selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3°.

[0076] In some embodiments, the crystalline form V has at least four XRPD peaks, denoted as 2θ ± 0.2°, selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3°.

[0077] In some embodiments, the crystalline form V has at least three XRPD peaks, denoted as 2θ ± 0.2°, selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3°.

[0078] In some embodiments, the crystalline form V has at least two XRPD peaks, denoted as 2θ ± 0.2°, selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3°.

[0079] In some embodiments, the crystalline form V has at least one XRPD peak, denoted as 2θ ± 0.2°, selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3°.

[0080] In some embodiments, the crystalline form V has an XRPD peak, denoted as 2θ ± 0.2°, selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3°.

[0081] In some implementations, the crystalline form V is characterized by an XRPD pattern that is substantially as follows: Figure 18 As shown.

[0082] In some implementations, the crystalline form V is characterized by a DSC thermogram showing a melt initiation at approximately 156°C.

[0083] In some implementations, crystalline form V is characterized by a DSC thermogram that is essentially as follows: Figure 19 As shown.

[0084] In some implementations, crystalline form V is characterized by a TGA thermogram that is essentially as follows: Figure 20 As shown.

[0085] In some implementations, crystalline form V is characterized by DVS analysis being essentially as follows: Figure 21 As shown.

[0086] compound 1 solvate form "Solvates" are formed through the interaction of a solvent and a compound. Solvates of the compounds provided herein are also provided. Therefore, the present invention also provides (2) R ,3 S 5 R The solvated form of 5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl-2-phenylacetic acid ester.

[0087] In some embodiments, the solvate form of Compound 1 provided herein is selected from the solvate forms of acetone, methyl ethyl ketone, dichloromethane, tetrahydrofuran, toluene, n-butyl acetate, methyl acetate, xylene, heptane, 1-butanol, p-dioxane, ethyl acetate, DMAc, and dimethylacetamide.

[0088] In some implementations, the solvate is in the form of acetone solvate.

[0089] In some implementations, the solvate is in the form of acetone solvate I.

[0090] In some embodiments, acetone solvate form I is characterized by an XRPD pattern that is substantially as follows: Figure 1 As shown.

[0091] In some implementations, the solvate is in the form of acetone solvate II.

[0092] In some embodiments, the acetone solvate form II is characterized by an XRPD pattern that is substantially as follows: Figure 6 As shown.

[0093] In some implementations, the solvate is in the form of a methyl ethyl ketone solvate.

[0094] In some embodiments, the methyl ethyl ketone solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0095] In some implementations, the solvate is in the form of a dichloromethane solvate.

[0096] In some implementations, the dichloromethane solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0097] In some implementations, the solvate is in the form of a tetrahydrofuran solvate.

[0098] In some implementations, the tetrahydrofuran solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0099] In some implementations, the solvate is in the form of toluene solvate.

[0100] In some embodiments, the toluene solvate form is characterized by the XRPD pattern being substantially as follows: Figure 12 As shown.

[0101] In some implementations, the solvate is in the form of n-butyl acetate solvate.

[0102] In some embodiments, the n-butyl acetate solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0103] In some implementations, the solvate is in the form of methyl acetate solvate.

[0104] In some embodiments, the methyl acetate solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0105] In some implementations, the solvate is in the form of xylene solvate.

[0106] In some implementations, the xylene solvate form is characterized by the XRPD pattern being substantially as follows: Figure 17 As shown.

[0107] In some implementations, the solvate is in the form of a heptane solvate.

[0108] In some implementations, the heptane solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0109] In some implementations, the solvate is in the form of a 1-butanol solvate.

[0110] In some embodiments, the 1-butanol solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0111] In some implementations, the solvate form is the dioxane solvate form.

[0112] In some embodiments, the dioxane solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0113] In some implementations, the solvate is in the form of an ethyl acetate solvate.

[0114] In some embodiments, the ethyl acetate solvate form is characterized by the XRPD pattern being substantially as follows: Figure 6 As shown.

[0115] In some implementations, the solvate is in the form of dimethylacetamide solvate.

[0116] In some embodiments, the dimethylacetamide solvate form is characterized by the XRPD pattern being substantially as follows: Figure 17 As shown.

[0117] According to the present invention, the crystalline or solvated forms of Compound 1 provided herein can be used in 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) can be intermediates in the synthesis of Compound 1. Furthermore, different crystalline and solvated forms of Compound 1 may have different properties in terms of bioavailability, stability, purity, and / or manufacturability for medical or pharmaceutical use. Variations 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, ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.). Such variations 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 offer the desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Therefore, the crystalline and / or solvate forms of Compound 1 provided herein offer advantages such as improved methods of manufacturing the compound, stability or storability of the compound in pharmaceutical product form, stability or storability of the compound as a pharmaceutical substance, and / or bioavailability and / or stability of the compound as an active agent.

[0118] It has been found that the use of certain solvents and / or methods produces different crystalline and / or solvated forms of Compound 1, which may exhibit one or more of the advantageous features described above. The methods for preparing the crystalline and solvated forms described herein, as well as the characterization of these crystalline and solvated forms, are described in detail below.

[0119] In some embodiments, the crystalline and solvate forms described herein are purified or substantially separated. "Substantially separated" means that the crystalline or solvate form is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation may include, for example, compositions rich in the crystalline or solvate forms of the invention. Substantially separated 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 or solvate forms of the invention. In some embodiments, the crystalline or solvate forms of the invention may be prepared at 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.

[0120] Different crystalline and solvate forms can be identified using solid-state characterization methods, such as X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC), further aid in identifying the forms, as well as in determining stability and solvent / water content.

[0121] 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 5% of the maximum peak height / intensity. Furthermore, instrument variations and other factors can affect the 2θ value. 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.

[0122] 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 or the term "approximately" used in this report, which describes DSC thermograms as "substantially" as shown in any figure, should be understood to accommodate such variations.

[0123] It should be understood in the following description that this disclosure is considered illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments exemplified under any heading may be combined with embodiments exemplified under any other heading.

[0124] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0125] When a trade name is used in this article, it is intended to refer independently to the product under that trade name and the active pharmaceutical ingredient of that product.

[0126] As used herein and in the appended claims, the singular forms “an,” “a,” and “the” include multiple referents unless the context clearly specifies otherwise. Thus, for example, reference to “compound” includes multiple such compounds, and reference to “determination” includes reference to one or more determinations, etc.

[0127] "Pharmaceutical acceptable" means compounds, crystalline forms, solvates, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0128] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for acceptable use in humans or livestock.

[0129] "Subjects" refers to humans, livestock (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), etc.

[0130] As used herein, “treatment” is a method for achieving a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, the reduction of symptoms and / or the lessening of the severity of symptoms and / or the prevention of the worsening of symptoms associated with a disease or condition. In some embodiments, “treatment” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or lessening the severity of a disease or condition); b) slowing or halting the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, such as causing the disappearance of clinical symptoms, improving the disease state, delaying the progression of the disease, improving quality of life, and / or prolonging survival.

[0131] As used herein, “delaying” the development of a disease or condition means slowing, hindering, mitigating, blocking, stabilizing, and / or postponing the development of a disease or condition. This delay can vary in length depending on the history of the disease and / or the subject to be treated. It will be apparent to those skilled in the art that a sufficient or significant delay can effectively encompass prevention, as the subject does not develop the disease or condition. For example, a method of “delaying” the development of AIDS is a method of reducing the likelihood of disease development and / or reducing the severity of the disease within a given timeframe (compared to not using this method). Such comparisons can be based on clinical studies using statistically significant numbers of subjects. For example, the development 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 indications for AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits, and groin, or the presence of opportunistic conditions known to be associated with AIDS (e.g., conditions that are not normally present in subjects with a functioning immune system but do occur in patients with AIDS). Development can also refer to disease progression that may initially be undetectable, including onset, relapse, and exacerbation.

[0132] As used herein, “prevention” refers to a protocol that prevents the onset of a disease or disorder, thus preventing the development of clinical symptoms of the disease. Therefore, “prevention” involves administering a therapy (e.g., administering a therapeutic substance) to a subject before signs of disease are detectable in the subject (e.g., administering a therapeutic substance to a subject in the absence of a detectable infectious agent (e.g., virus) in the subject). Subjects may be individuals at risk of developing a disease or disorder, such as individuals with one or more known risk factors associated with the development or onset of a disease or disorder. Therefore, the term “prevention of HIV infection” refers to administering an anti-HIV therapeutic substance to a subject who does not have a detectable HIV infection. It should be understood that subjects receiving anti-HIV prophylactic therapy may be individuals at risk of HIV infection. Furthermore, it should be understood that prevention may not completely prevent the onset of a disease or disorder. In some cases, prevention includes reducing the risk of developing a disease or disorder. Reducing the risk may not completely eliminate the risk of developing a disease or disorder.

[0133] As used herein, an "at-risk" individual is an individual who is at risk of developing a condition to be treated. An "at-risk" individual may or may not have a detectable disease or condition, and may or may not show a detectable disease prior to the treatment described herein. "At-risk" means that an individual has one or more so-called risk factors that are associated with the development of a disease or condition and are measurable parameters known in the art. An individual with 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 for AIDS is an individual who has HIV.

[0134] As used herein, the term "therapeutic effective amount" or "effective amount" refers to an amount that effectively elicits the desired biological or medical response, including an amount of compound sufficient to achieve such treatment of a disease when administered to a subject, or an amount effective in preventing infection or onset of a disease. Effective amounts will vary depending on the compound being treated, the disease and its severity, and factors such as age and weight. Effective amounts may include a range of amounts. As understood in the art, an effective amount may be one or more doses; that is, a single dose or multiple doses may be required to achieve the desired therapeutic outcome. If the desired or beneficial outcome can be achieved or realized, a single agent may be considered to have been administered at an effective amount.

[0135] An enantiomer is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. A mixture of enantiomers in a different 1:1 ratio is a non-racemic mixture.

[0136] A "diastereomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0137] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configurations can be specified as (+) or (-) based on the direction (right-handed or left-handed) of their rotational plane-polarized light at the wavelength of the sodium D line. Some compounds and salts described herein contain one or more asymmetric centers and / or hindered rotations around bond axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- according to absolute stereochemistry. This disclosure is intended to include all such possible isomers, including racemic mixtures, non-racemic mixtures, diastereomers, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0138] Unless otherwise expressly defined, this disclosure includes all tautomers of the compounds detailed herein, even if only one tautomer is explicitly stated (e.g., both tautomer forms are anticipated and described by presenting a tautomer form that may have a pair of two tautomers). For example, if a compound containing an amide is referred to (e.g., by its structure or chemical name), it should be understood that the corresponding imine tautomer is included in this disclosure and described as if the amide were described alone or together with the imine. In cases where more than two tautomers may exist, this disclosure includes all such tautomers, even if the chemical name and / or structure describes only a single tautomer form.

[0139] Those skilled in the art will understand that this disclosure also includes any salts disclosed herein, and that one or more isotopes, such as but not limited to deuterium, may be enriched at any or all atoms at ratios higher than those naturally occurring. 2 H or D).

[0140] The crystalline and solvated forms of compound 1 are also disclosed, wherein one to n hydrogen atoms bonded to carbon atoms can be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium is a non-radioactive isotope of hydrogen. Such salts can increase resistance to metabolism and are therefore used to increase the half-life of compounds when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527, 1984. Such salts are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0141] Examples of isotopes that can bind to the disclosed salts also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 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. Using positron-emitting isotopes such as 11 C 18 F, 15 O and 13 Substitution of N can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotope-labeled salts can typically be prepared using conventional techniques known to those skilled in the art, or by methods similar to those described in the examples listed below, using a suitable isotope-labeled reagent instead of the previously used unlabeled reagent.

[0142] 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, enantiomeric, diastereomeric, and geometric isomers are included. When a compound is represented in its chiral form, it should be understood that the embodiments cover, but are not limited to, specific diastereomeric or enantiomerically enriched forms. When chirality is not specified but is present, it should be understood that the embodiments relate to specific diastereomeric or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds.

[0143] In some embodiments, this disclosure relates to the use of the crystalline or solvated form of the invention in the treatment of retroviral viral infections, including infections caused by HIV, the use of which includes administering a therapeutically effective amount of the crystalline or solvated form to a subject in need.

[0144] The desired goal is to discover those with low EC 50 The compound or its crystalline or solvated form. EC 50 The value refers to the concentration of a compound that achieves 50% of its maximum efficacy during testing. This is relative to a higher EC value. 50 The compound, in crystalline or solvated form, has a low EC 50 The compound, crystalline form, or solvate form achieves similar efficacy at lower concentrations of the compound, crystalline form, or solvate form. Therefore, lower EC 50 It is usually preferred for drug development.

[0145] The desired goal is to discover compounds, crystalline forms, or solvates with good physical and / or chemical stability. Increased overall stability of the compound, crystalline form, or solvate form can provide an increase in in vivo circulation time. Due to less degradation, stable compounds, crystalline forms, or solvates can be administered at lower doses while still maintaining efficacy. Similarly, due to less degradation, there are fewer problems with byproducts arising from the degradation of the compound, crystalline form, or solvate form.

[0146] The desired objective is to discover compounds, crystalline or solvated forms, that possess improved pharmacokinetic and / or pharmacodynamic properties and a long half-life. Advantageously, drugs with moderate or low clearance and a long half-life are desirable, as this may result in good bioavailability and high systemic exposure. Reducing the clearance of a compound and increasing the half-life of the compound, crystalline or solvated form, can reduce the daily dose required for efficacy, and thus produce better efficacy and safety characteristics. Therefore, improved pharmacokinetic and / or pharmacodynamic properties and a long half-life can provide better patient compliance.

[0147] How to use In some embodiments, the crystalline or solvated forms disclosed herein are used to prevent HIV infection in subjects. In some embodiments, the crystalline or solvated forms disclosed herein are used to prevent HIV infection in subjects at risk of infection. In some embodiments, the crystalline or solvated forms disclosed herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually transmitted HIV-1 infection.

[0148] In some embodiments, a method for treating or preventing HIV infection in a subject (e.g., a human) is disclosed, the method comprising administering compound 1 in crystalline or solvated form to the subject.

[0149] In some embodiments, a method for inhibiting HIV viral replication in a subject (e.g., a human), treating AIDS, or delaying the onset of AIDS is disclosed, the method comprising administering compound 1 in crystalline or solvated form to the subject.

[0150] In some embodiments, a method for inhibiting HIV viral replication in a subject (e.g., a human), treating AIDS, or delaying the onset of AIDS is disclosed, the method comprising administering compound 1 in crystalline or solvated form to the subject.

[0151] In some embodiments, a method for preventing HIV infection in a subject (e.g., a human) is disclosed, the method comprising administering compound 1 in crystalline or solvated form to the subject. In some embodiments, the subject is at risk of HIV infection, such as having one or more known risk factors associated with HIV infection.

[0152] In some embodiments, a method for preventing HIV infection in a subject (e.g., a human) is disclosed, the method comprising administering to the subject a therapeutically effective amount of compound 1 in crystalline or solvated form. In some embodiments, the subject is at risk of HIV infection, such as having one or more known risk factors associated with HIV infection.

[0153] In some embodiments, a method for treating HIV infection in a subject (e.g., a human) is disclosed, the method comprising administering a crystalline form of compound 1 to the subject.

[0154] In some embodiments, a method for treating HIV infection in a subject (e.g., a human) is disclosed, the method comprising administering to the subject a solvate form of compound 1.

[0155] In some embodiments, a crystalline form of compound 1 is disclosed for use in the medical treatment of HIV infection (e.g., the replication of HIV-1 or HIV virus (e.g., HIV-1) in a subject (e.g., a human) or the onset of AIDS or delayed AIDS).

[0156] In some embodiments, a solvate form of compound 1 is disclosed for use in the medical treatment of HIV infection (e.g., the replication of HIV-1 or HIV virus (e.g., HIV-1) in a subject (e.g., a person) or the onset of AIDS or delayed AIDS).

[0157] In some embodiments, a crystalline or solvated form of compound 1 is disclosed for use in the manufacture of a medicament for treating a subject (e.g., a human) with HIV infection or HIV viral replication or AIDS or for delaying the onset of AIDS. In some embodiments, a crystalline or solvated form of compound 1 is disclosed for preventative or therapeutic treatment of HIV infection or AIDS or for therapeutic treatment or delaying the onset of AIDS.

[0158] In some embodiments, a crystalline form of compound 1 is disclosed for use in the manufacture of a medicament for treating a subject (e.g., a human) with HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS. In some embodiments, a crystalline form of compound 1 is disclosed for preventative or therapeutic treatment of HIV infection or AIDS or for therapeutic treatment or delaying the onset of AIDS.

[0159] In some embodiments, a solvated form of compound 1 is disclosed for use in the manufacture of a medicament for treating a subject (e.g., a human) with HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS. In some embodiments, a solvated form of compound 1 is disclosed for preventative or therapeutic treatment of HIV infection or AIDS or for therapeutic treatment or delaying the onset of AIDS.

[0160] In some embodiments, a crystalline or solvated form of compound 1 is disclosed for use in the manufacture of a medicament for HIV infection in a subject (e.g., a human). In some embodiments, a crystalline or solvated form of compound 1 is disclosed for use in the preventive or therapeutic treatment of HIV infection.

[0161] In some embodiments, a crystalline form of compound 1 is disclosed for use in the manufacture of a medicament for HIV infection in a subject (e.g., a human). In some embodiments, a crystalline form of compound 1 is disclosed for use in the preventive or therapeutic treatment of HIV infection.

[0162] In some embodiments, a solvated form of compound 1 is disclosed for use in the manufacture of a medicament for HIV infection in a subject (e.g., a human). In some embodiments, a solvated form of compound 1 is disclosed for use in the preventive or therapeutic treatment of HIV infection.

[0163] In some embodiments, the administration is directed to a subject requiring treatment (e.g., a person). In some embodiments, the administration is directed to a subject at risk of developing AIDS (e.g., a person).

[0164] This document discloses a crystalline or solvated form of compound 1 for use in therapy. In some embodiments, the crystalline form of compound 1 is used in methods for treating a subject (e.g., a human) with HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS. In some embodiments, the solvated form of compound 1 is used in methods for treating a subject (e.g., a human) with HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS.

[0165] This document also discloses a crystalline or solvated form of compound 1 used in a method for treating or preventing HIV infection in a subject of need. In some embodiments, a crystalline or solvated form of compound 1 is provided in a method for treating HIV infection in a subject of need. In some embodiments, the subject of need is a person infected with HIV. In some embodiments, the subject of need is a person infected with HIV but who has not yet developed AIDS. In some embodiments, the subject of need is a subject at risk of developing AIDS. In some embodiments, the subject of need is a person infected with HIV and who has developed AIDS.

[0166] In some embodiments, this document also discloses a crystalline or solvated form of compound 1 used in methods for treating or preventing HIV infection in a subject of need. In some embodiments, a crystalline or solvated form of compound 1 is provided in methods for treating HIV infection in a subject of need. In some embodiments, the subject of need is a person already infected with HIV. In some embodiments, the subject of need is a person already infected with HIV but who has not yet developed AIDS. In some embodiments, the subject of need is a subject at risk of developing AIDS. In some embodiments, the subject of need is a person already infected with HIV and who has developed AIDS.

[0167] In some embodiments, a crystalline or solvated form of compound 1 is provided for preventing HIV infection and / or preventing the establishment of permanent infection and / or preventing the onset of disease symptoms and / or preventing the virus from reaching detectable levels in the blood, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Therefore, in some embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) are provided. For example, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering a crystalline or solvated form of compound 1. In some embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering a pharmaceutical composition comprising a therapeutically effective amount of a crystalline or solvated form of compound 1 and one or more excipients.

[0168] In some embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering compound 1 in its crystalline or solvated form in combination with safer sexual practices. In some embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering it to an individual at risk of HIV infection. Examples of individuals at high risk of HIV infection include, but are not limited to, individuals at risk of sexually transmitted HIV.

[0169] In some embodiments, the risk of HIV infection is reduced by at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the risk of HIV infection is reduced by at least about 75%. In some embodiments, the risk of HIV infection is reduced by about 80%, 85%, or 90%.

[0170] In some embodiments, the use of compound 1 in crystalline or solvated form for manufacturing a medicament for treating the infection in persons who are infected with HIV or at risk of HIV infection is disclosed.

[0171] In some embodiments, this document also discloses a crystalline or solvated form of compound 1 for use in therapeutic treatment or to delay the onset of AIDS.

[0172] In some embodiments, the crystalline or solvated form of compound 1 can be used as a research tool.

[0173] Application route The crystalline or solvated form of Compound 1 (also referred to herein as the active ingredient) may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. In some embodiments, the compound may be administered parenterally. In some embodiments, the disclosed compound may be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the crystalline or solvated form of Compound 1 is orally bioavailable and may be administered orally.

[0174] In some embodiments, the crystalline or solvated form of compound 1 can be administered by injection using an injection device. In some embodiments, the injection device is or includes a syringe that can be used manually, or is part of an injection device that includes a syringe (such as, but not limited to, a device equipped with a needle safety guard). A variety of injection devices can be used, such as, for example, but not limited to, handheld or wearable autoinjectors, handheld or wearable manual injectors, body-worn injectors, syringes, jet injectors, or pen injectors, each of which can be reusable or disposable.

[0175] In some embodiments, the crystalline or solvated form of compound 1 can be administered using an auto-injector comprising 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 solvated form of compound 1.

[0176] Dosing regimen The crystalline or solvated form of compound 1 may be administered to a subject (e.g., a human) in an effective amount. In some embodiments, the crystalline or solvated form of compound 1 may be administered to a subject (e.g., a human) in a therapeutically effective amount.

[0177] The crystalline or solvated form of Compound 1 may be administered to the subject for the desired duration of time or duration, according to an effective dosing regimen, such as at least about one day, at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about six months, or at least about twelve months or longer. In some embodiments, the crystalline or solvated form of Compound 1 is administered once daily or intermittently. In some embodiments, the crystalline or solvated form of Compound 1 is administered once daily. In some embodiments, the crystalline or solvated form of Compound 1 is administered once monthly. In some embodiments, the crystalline or solvated form of Compound 1 is administered every two months. In some embodiments, the crystalline or solvated form of Compound 1 is administered every three months. In some embodiments, the crystalline or solvated form of Compound 1 is administered every four months. In some embodiments, the crystalline or solvated form of Compound 1 is administered every five months. In some embodiments, the crystalline or solvated form of Compound 1 is administered every six months.

[0178] The dosage or frequency of administration of compound 1 in its crystalline or solvated form may be adjusted during treatment based on the judgment of the administering physician.

[0179] The crystalline or solvated form of Compound 1 disclosed herein can be administered in effective doses. For example, the dose can be from 1 mg to 1000 mg of the compound. In some embodiments, the dose is about 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of the compound. In some embodiments, the dose is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

[0180] In some implementations, compound 1 is administered in crystalline or solvated form at a once-daily dose.

[0181] Pharmaceutical Composition The pharmaceutical compositions disclosed herein comprise either the crystalline or solvated form of compound 1 disclosed herein, and one or more pharmaceutically acceptable excipients. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration.

[0182] In some embodiments, the pharmaceutical compositions disclosed herein comprise a crystalline or solvated form of compound 1 disclosed herein, and 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.

[0183] Pharmaceutical compositions containing Compound 1 disclosed herein, in crystalline or solvated form, may be prepared using conventional carriers (e.g., inactive ingredients or excipient materials) selected according to routine practice. Tablets may contain excipients, including flow aids, fillers, binders, etc. Aqueous compositions may be prepared aseptically and are typically isotonic when 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. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc.

[0184] While the active ingredient may be administered alone, it may be preferred to provide the active ingredient as a pharmaceutical composition. Compositions intended for both veterinary and human use comprise at least a crystalline or solvated form of compound 1 disclosed herein, and one or more acceptable carriers. The carrier is “acceptable” meaning it is compatible with the other components of the composition and physiologically harmless to the recipient.

[0185] The compositions include those suitable for various routes of administration. The compositions may conventionally be present in unit dosage forms and can be prepared by any of the methods well known in the pharmaceutical field. Such methods involve the step of associating the active ingredient with one or more inactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.). The compositions can be prepared by uniformly and tightly associating the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then, if desired, shaping the product. Techniques and formulations are generally available in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0186] The compositions described herein suitable for oral administration may exist as discrete units (unit dosage forms), including but not limited to capsules, sachets or tablets each containing a predetermined amount of active ingredient.

[0187] For example, when intended for oral use, tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can 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 an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, polyvinylpyrrolidone, calcium phosphate, or sodium phosphate; granulating 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. Tablets may be uncoated or 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.

[0188] In some embodiments, oral dosage forms (e.g., tablets) are disclosed herein, which can be prepared by hot melt extrusion or spray dry dispersion (SDD) technology.

[0189] In some embodiments, this document discloses hard capsules filled with powders, beads, or granules containing an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing hard or soft capsules. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, polyvinylpyrrolidone, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0190] In some embodiments, this document discloses hard or soft capsules filled with liquid or semi-solid mixtures containing an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing hard or soft capsules. These excipients may be, for example, solubilizing oils such as corn oil, sesame oil, or soybean oil; medium-chain triglycerides and related esters such as derived palm kernel oil or coconut oil; self-emulsifying lipid systems (SEDDS or SMEDDS) such as caprylic / capric triglyceride or propylene glycol monocaprylate; viscosity modifiers such as cetyl alcohol, stearoyl alcohol, or glyceryl stearate; and solubilizers and surfactants such as polyethylene glycol, propylene glycol, glycerin, ethanol, polyethoxylated castor oil, poloxamer, or polysorbate.

[0191] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents already mentioned herein, according to known techniques. Sterile injectable formulations may 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 that may be used 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 may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectable formulations.

[0192] In some embodiments, the sterile injectable formulations disclosed herein can also be sterile injectable solutions or suspensions (such as solutions in 1,3-butanediol) prepared from reconstituted lyophilized powders in non-toxic, parenteral-acceptable diluents or solvents. Acceptable solvents and media that can be used 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.

[0193] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes to make the formulation isotonic with the intended recipient's blood; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. In some embodiments, the suspension is a microsuspension. In some embodiments, the suspension is a nanosuspension.

[0194] In some implementations, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will contain one or more excipients. The excipients should be compatible with the other components of the formulation and physiologically harmless to the 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 (edited by Rowe, Sheskey, and Quinn), 6th edition, 2009.

[0195] Examples of solubilizing excipients in parenteral preparations include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamer (such as poloxamer 338, 188 or 207).

[0196] In some embodiments, the parenteral formulation disclosed herein is an aqueous suspension. In some embodiments, the parenteral formulation disclosed herein is an aqueous suspension comprising the crystalline or solvated form of compound 1 disclosed herein and saline. In some embodiments, the parenteral formulation disclosed herein is an aqueous suspension comprising the crystalline or solvated form of compound 1 disclosed herein, saline, and poloxamer.

[0197] In some embodiments, the composition is disclosed in a solid dosage form (including solid injectable dosage forms, such as solid reservoirs).

[0198] The amount of active ingredient that can be combined with an inactive ingredient to produce a dosage form can vary depending on the intended treatment subjects and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 mg to 1000 mg of the active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In some embodiments, the carrier material varies between about 5% to about 95% (weight:weight) of the total composition.

[0199] It should be understood that, in addition to the ingredients specifically mentioned above, the compositions of these embodiments may include other conventional agents in the art that take into account the types of compositions discussed, such as flavoring agents, those suitable for oral administration.

[0200] In some embodiments, a composition comprising the active ingredient disclosed herein in a variant does not contain any agent that affects the metabolic rate of the active ingredient. Therefore, it should be understood that in some embodiments, a composition comprising the crystalline or solvated form of compound 1 does not contain any agent that would affect (e.g., slow down, inhibit, or delay) the metabolism of the crystalline or solvated form of compound 1. It should also be understood that in some embodiments, any methods, kits, articles, etc., detailed herein do not contain any agent that would affect (e.g., slow down, inhibit, or delay) the metabolism of the crystalline or solvated form of compound 1.

[0201] reagent kits and products This disclosure relates to a kit comprising the crystalline or solvated form of Compound 1 disclosed herein. The kit may also include instructions for use, for example, for inhibiting HIV reverse transcriptase, such as for treating HIV infection or AIDS, or as a research tool. Instructions for use are typically written, but electronic storage media (e.g., disks or optical discs) containing instructions are also acceptable.

[0202] This disclosure also relates to pharmaceutical kits comprising one or more containers containing the crystalline or solvated form of Compound 1 disclosed herein. Optionally associated with such containers may be a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of the drug, reflecting the agency's approval for its manufacture, use, or sale for human administration. Each component (if more than one component is present) may be packaged in a separate container, or several components may be combined in a single container permissible by cross-reactivity and shelf life. The kit may be a unit dosage form, a bulk package (e.g., a multi-dose package), or a subunit dose. 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., a hospital pharmacy and a dispensing pharmacy).

[0203] In some embodiments, this disclosure also relates to pharmaceutical kits comprising one or more containers containing the crystalline or solvated form of compound 1 disclosed herein. Optionally associated with such containers may be a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of the drug, reflecting the agency's approval for its manufacture, use, or sale for human administration.

[0204] Articles are also disclosed comprising a unit dose, in suitable packaging, of the crystalline or solvated form of compound 1 disclosed herein for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, wide-mouth bottles, flexible packaging, etc. The articles may be further sterilized and / or sealed.

[0205] The following abbreviations may be used in this article:

[0206] Example General Materials and Methods The following materials and methods are used throughout the embodiments: X-ray powder diffraction (XRPD) analysis was performed using copper radiation (Cu Kα, λ = 1.541874) on a diffractometer (PANalytical XPERT-PRO, PANalytical BV, Almelo, Netherlands). The sample was uniformly spread on a zero-background sample plate. The generator was operated at a voltage of 45 kV and a current of 40 mA. The slits were a Soler slit at 0.02 rad, an anti-scattering slit at 1.0°, and a diverging slit. Scans were performed from 2° to 40° 2θ with a step size of 0.0167. Data analysis was performed using an X'Pert Viewer V1.9a (PANalytical BV, Almelo, Netherlands).

[0207] Differential scanning calorimetry (DSC) and modulated differential scanning calorimetry (MDSC) were run on a Q2000 (TA Instruments, New Castle, DE). Approximately 1 to 5 mg of material was loaded into Tzero standard aluminum disks, the caps of which had a manually pierced pinhole. By default, the sample and reference disks were heated from 20 °C to 300 °C under nitrogen purging at 50 mL / min. DSC was run at a heating rate of 10 °C / min; while MDSC was run at a heating rate of 5 °C / min, adjusted by ±1.00 °C every 60 s. Data analysis was performed using Universal Analysis 2000 version 4.5A (TA Instruments, New Castle, DE).

[0208] Thermogravimetric analysis (TGA) was used on a Q5000 or Q500 (TA Instruments, New Castle, DE) to evaluate sample weight loss based on temperature. Approximately 1 to 5 mg of material was loaded onto the sample tray, and the sample was heated from ambient temperature to 300°C or higher at a rate of 10°C / min. The sample tray was purged with nitrogen at 40 mL / min. Data analysis was performed using Universal Analysis 2000 version 4.5A (TA Instruments, New Castle, DE).

[0209] Hygroscopicity was studied using dynamic gas phase adsorption (DVS) on a model Q5000 SA (TA Instruments, New Castle, DE). Samples (1 mg to 10 mg) were placed in aluminum pans and loaded onto the sample side of a dual-pan balance. Water adsorption and desorption were studied by increasing relative humidity (RH) in 10% increments from 0% RH to 90% RH and then back to 0% RH at 25°C. Each RH increment had an equilibration time of 120 minutes unless the weight change was less than 0.002% within 20 minutes. Data analysis was performed using Universal Analysis 2000 version 4.7A (TA Instruments, New Castle, DE).

[0210] Example 1. Preparation of crystalline form II of compound 1 At approximately 22°C, approximately 100 mg of the free base crystalline form I of compound 1 (see, for example, U.S. Publications 20220323476A1 and 20220332751A1, the entire contents of each of which are incorporated herein by reference) was stirred with approximately 0.5 mL of acetone in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. Three days later, XRPD analysis of the wet solid revealed a new pattern, named compound 1 acetone solvate 1 (see...). Figure 1 After drying under vacuum at 50°C, the XRPD pattern changed, and the resulting new form was named Compound 1 Crystal Form II.

[0211] Representative XRPD pattern of crystalline form II of compound 1 in Figure 2 The peaks are shown in the table and are characterized by sharp reflections, indicating crystallinity. A list of XRPD peaks for crystalline form II of compound 1 is provided in Table 1.

[0212] Table 1 .

[0213] The DSC thermogram indicates that at approximately 93 o The small endothermic transition at point C, attributed to the form change from crystalline form II of compound 1 to crystalline form V of compound 1 (confirmed in another experiment by XRPD), exhibits a melting initiation at approximately 156 °C, as... Figure 3 As shown in the figure. The TGA thermogram does not show a significant weight loss (0.01%, from 25°C to 150°C), indicating that there is no residual solvent, as... Figure 4 As shown. DVS analysis in Figure 5 The diagram shows that the form is non-hygroscopic, and indicates that it has a weight change of about 0.1% at 25°C between 0%RH and 90%RH.

[0214] Example 2. Preparation of crystalline form III of compound 1 At approximately 22°C, approximately 100 mg of the free base crystalline form of compound 1 was stirred together with approximately 0.5 mL of dichloromethane (DCM) in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. Three days later, XRPD analysis of the wet solid coated with a Kapton membrane revealed a new pattern, named compound 1 DCM solvate (see [link to article]). Figure 6 After drying in air, the XRPD pattern changed, and the resulting new form was named Compound 1 Crystal Form III.

[0215] 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 diagrams of these solvates are shown in... Figure 6 middle.

[0216] Single crystals of a 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, followed by holding at approximately 22 °C for several weeks. A slurry was formed, and the sample was analyzed by SCXRD at approximately 298 °C. Since DCM is volatile, it escapes from the crystal lattice, and the results are consistent with those of form III of compound 1, which has the following crystal parameters.

[0217] Table 2 .

[0218] The molecules observed in the asymmetric units of the single-crystal structure are consistent with the molecular structure of compound 1. Figure 7 The asymmetric unit shown contains one molecule of compound. A portion of the phenyl acetate moiety is disordered (as indicated by dots), refined to a 73% occupancy in the main orientation. Sufficient interstitial spaces exist in the vacant orientation of the phenyl acetate moiety for solvent application.

[0219] Representative XRPD patterns of compound 1 crystalline form III obtained after drying the DCM solvate are shown in... Figure 8 The peaks are shown in the table and are characterized by sharp reflections, indicating crystallinity. A list of XRPD peaks for crystalline form III of compound 1 is provided in Table 3.

[0220] Table 3 .

[0221] The DSC thermogram shows a small endothermic transition at approximately 125 °C, which is attributed to the form change from crystalline form III of compound 1 to crystalline form V of compound 1, as shown in the figure. Figure 9 As shown (confirmed by XRPD in another experiment). Further heating of the sample in another experiment (at 150 °C) yielded a mixture of crystalline form V and crystalline form I of compound 1, indicated by a bimodal distribution over the temperature range of 150 °C to 165 °C. The TGA thermogram did not show a significant weight loss (0.04%, from 25 °C to 150 °C), indicating very low residual solvent, such as... Figure 10 As shown. DVS analysis in Figure 11 The figure shows that the form is slightly hygroscopic, and indicates that it has a weight change of about 1.2% at 25°C from 0%RH to 90%RH.

[0222] Example 3. Preparation of crystalline form IV of compound 1 At approximately 22°C, approximately 50 mg of the free base crystalline form I of compound 1 was stirred together with approximately 0.5 mL of toluene in a 4 mL vial equipped with a Teflon-coated magnetic stir bar. Three days later, XRPD analysis of the wet solid revealed a new pattern, named compound 1 toluene solvate (see [link to product description]). Figure 12 After drying under vacuum at 50°C, the XRPD pattern changed, and the new form was named Compound 1 Crystal Form IV.

[0223] Representative XRPD pattern of crystalline form IV of compound 1 in Figure 13 The peaks are shown in the figure and are characterized by sharp reflections, thus indicating crystallinity. A list of XRPD peaks for crystalline form IV of compound 1 is provided in Table 4.

[0224] Table 4 .

[0225] The DSC thermogram shows a small endothermic transition at approximately 114 °C, which is attributed to the form change from crystalline form IV of compound 1 to crystalline form I of compound 1. Figure 14 As shown (confirmed by XRPD in another experiment). The TGA thermogram does not show a significant weight loss (0.004%, from 25). o (C to 150℃), indicating very low residual solvent, such as Figure 15 As shown. DVS analysis in Figure 16 The diagram shows that the form is non-hygroscopic, and indicates that it has a weight change of approximately 0.16% at 25°C between 0%RH and 90%RH.

[0226] Example 4. Preparation of crystalline form V of compound 1 Compound 1 in crystalline form V can be prepared by any of the following procedures: 1. Heating compound 1 in crystalline form II to approximately 100°C.

[0227] 2. Heating compound 1 crystalline form III to approximately 125°C. Since compound 1 crystalline form III can be obtained by drying different solvates, the temperature required to convert compound 1 crystalline form III to compound 1 crystalline form V can vary.

[0228] 3. Dry compound 1, xylene solvate or DMAc solvate, at 75℃-110℃ (see [link to product description]). Figure 17 It is also possible that a small amount of compound 1 exists in crystalline form I.

[0229] A representative XRPD pattern of crystalline form V of compound 1 in Figure 18 The peaks are shown in the figure and are characterized by sharp reflections, thus indicating crystallinity. A list of XRPD peaks for crystalline form V of compound 1 is provided in Table 5.

[0230] Table 5 .

[0231] The DSC thermogram indicates melting initiation at approximately 156 °C, such as Figure 19 As shown. The TGA thermogram does not show a significant weight loss (0.12%, from 25°C to 150°C), indicating that the residual solvent is very low, such as Figure 20 As shown. DVS analysis in Figure 21 The diagram shows that the form is non-hygroscopic, and indicates that it has a weight change of about 0.1% at 25°C between 0%RH and 90%RH.

[0232] Example 5. Overview of Compound 1 in Solid Form The melt initiation and DVS properties of crystalline form IV of compound 1 are shown in Table 6.

[0233] Table 6 .

[0234] The DVS values ​​of forms II, III, IV, and V demonstrate the unique hygroscopicity of these novel forms. These properties can provide unexpected benefits, such as improved methods of compound manufacture, increased stability or storability of the compound in pharmaceutical product form, increased stability or storability of the compound as a pharmaceutical substance, improved bioavailability and / or stability of the compound as an active agent, and increased physical and / or chemical stability in dosage or delivery forms.

[0235] All references, including publications, patents, and patent documents, are incorporated herein by reference as if they were separately incorporated by reference. This disclosure provides reference to various embodiments and techniques. However, it should be understood that many changes and modifications may be made while maintaining the spirit and scope of this disclosure.

Claims

1. A crystalline form of (2 R ,3 S ,5 R )-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((2-phenylacetyloxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate, said crystalline form selected from the group consisting of crystalline Form II, crystalline Form III, crystalline Form IV, and crystalline Form V.

2. The crystalline form of claim 1, which is crystalline Form II.

3. The crystalline form of claim 2, wherein the crystalline Form II has at least three XRPD peaks, in terms of 2Θ ± 0.2°, selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4°.

4. The crystalline form of claim 2, wherein the crystalline Form II is characterized by an XRPD pattern substantially as set forth in FIG.

2.

5. The crystalline form of any one of claims 2 to 4, wherein the crystalline Form II is characterized by a DSC thermogram having an endothermic transition at about 93 °C.

6. The crystalline form of any one of claims 2 to 4, wherein the crystalline Form II is characterized by a DSC thermogram substantially as set forth in FIG.

3.

7. The crystalline form of claim 1, which is crystalline Form III.

8. The crystalline form of claim 7, wherein the crystalline Form III has at least three XRPD peaks, in terms of 2Θ ± 0.2°, selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°, 25.8°, 26.1°, and 28.0°.

9. The crystalline form of claim 7, wherein the crystalline Form III is characterized by an XRPD pattern substantially as set forth in FIG.

8.

10. The crystalline form of any one of claims 7 to 9, wherein the crystalline Form III is characterized by a DSC thermogram having an endothermic transition at about 125 °C.

11. The crystalline form of any one of claims 7 to 9, wherein the crystalline Form III is characterized by a DSC thermogram substantially as set forth in FIG.

9.

12. The crystalline form of claim 1, which is crystalline Form IV.

13. The crystalline form of claim 12, wherein the crystalline Form IV has at least three XRPD peaks, in terms of 2Θ ± 0.2°, selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°.

14. The crystalline form of claim 12, wherein the crystalline Form IV is characterized by an XRPD pattern substantially as set forth in FIG.

13.

15. The crystalline form of any one of claims 12 to 14, wherein the crystalline Form IV is characterized by a DSC thermogram having an endothermic transition at about 114 °C.

16. The crystalline form of any one of claims 12 to 14, wherein the crystalline Form IV is characterized by a DSC thermogram substantially as set forth in FIG.

14.

17. The crystalline form of claim 1, which is crystalline Form V.

18. The crystalline form of claim 17, wherein the crystalline Form V has at least three XRPD peaks, in terms of 2Θ ± 0.2°, selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3°.

19. The crystalline form of claim 17, wherein the crystalline Form V is characterized by an XRPD pattern substantially as set forth in FIG.

18.

20. The crystalline form of any one of claims 17 to 19, wherein the crystalline Form V is characterized by a DSC thermogram having a melting onset at about 156 °C.

21. The crystalline form of any one of claims 17 to 19, wherein the crystalline Form V is characterized by a DSC thermogram substantially as set forth in FIG.

19.

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

23. The solvate form of claim 22, selected from the group consisting of an acetone solvate form, a methyl ethyl ketone solvate form, a dichloromethane solvate form, a tetrahydrofuran solvate form, a toluene solvate form, a n-butyl acetate solvate form, a methyl acetate solvate form, a xylene solvate form, a heptane solvate form, a 1-butanol solvate form, a p-dioxane solvate form, a DMAc solvate form, an ethyl acetate solvate form, and a dimethylacetamide solvate form.

24. The solvate form of claim 22 or 23, which is an acetonitrile solvate form.

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

26. The solvate form of claim 25, which is an acetone solvate, Form I.

27. The solvate form of claim 25, which is an acetone solvate, Form II.

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

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

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

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

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

33. The solvate form of claim 22 or 23, which is a n-butyl acetate solvate form.

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

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

36. The solvate form of claim 22 or 23, which is a heptane solvate form.

37. The solvate form of claim 22 or 23, which is a 1-butanol solvate form.

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

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

40. The solvate form of claim 22 or 23, which is N - methyl-2-pyrrolidinone solvate form.

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

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

43. A pharmaceutical composition comprising a crystalline, co-crystalline 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 of treating or preventing a human immunodeficiency virus (HIV) infection, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline, co-crystalline 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.

45. A crystalline, co-crystalline 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 therapy.

46. A crystalline, co-crystalline 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 a method of treating or preventing a human immunodeficiency virus (HIV) infection, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline, co-crystalline, salt or solvate form.

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