Antiviral prodrugs and pharmaceutical compositions thereof.

Description

1 / 27 “ANTIVIRAL PRODRUGS AND PHARMACEUTICAL COMPOSITIONS THEREOF” DESCRIPTIVE REPORT Separated from BR112022004417-8, filed on September 11, 2020. REFERENCE TO RELATED REQUESTS

[001] This Application claims the benefit of U.S. Provisional Application Serial No. 62 / 898,679, filed September 11, 2019, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[002] This invention relates to antiviral compounds and compositions useful for the treatment of acquired immunodeficiency syndrome (AIDS). BACKGROUND OF THE INVENTION

[003] 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) (MK-8591) represented by formula I: (I) is an effective nucleoside analog as a nucleoside reverse transcriptase inhibitor (Current Opinion in HIV and AIDS 2018, 13, 294-299) and useful as an antiretroviral in the treatment and pre-exposure prophylaxis of HIV-1 infection. EFdA is metabolized in cells into an active triphosphate anabolite (EFdA-TP), which inhibits HIV reverse transcriptase.

[004] EFdA, however, has a relatively high water solubility and a relatively short plasma concentration-to-resistance time course. As a result, EFdA may provide only a limited duration of viral suppression when administered to a patient for treatment of Petition 870260074759, dated 07 / 27 / 2026, page 9 / 107 2 / 27 infection with the human immunodeficiency virus (HIV) or for pre-exposure prophylaxis. Consequently, there is a need for formulations that can prolong the duration of viral suppression after administration. The pharmaceutical compounds and preparations of the present invention satisfy this need. SUMMARY OF THE INVENTION

[005] The antiviral compounds of the present invention are EFdA diesters and have limited solubility in water. While EFdA has an aqueous solubility of 0.877 mg / mL at physiological pH, the present EFdA diesters have an aqueous solubility of less than 0.03 mg / mL at physiological pH, preferably less than 0.002 mg / mL. These EFdA diesters are crystalline, are useful for providing a prolonged duration of HIV suppression, and can be administered parenterally as a suspension in a pharmaceutically acceptable carrier. A preferred prophylactic dose for a human subject is in the range of about 80 mg to about 800 mg of the EFdA diester administered parenterally at intervals of about six months in a dose volume of about 0.5 to about 4 milliliters per dose.A preferred treatment dose for a human patient is in the range of about 80 mg to about 800 mg of EFdA diester administered parenterally at intervals of about three months in a dose volume of about 0.5 to about 4 milliliters per dose.

[006] Parenteral formulations containing an antiviral compound of the present invention may be dry formulations comprising the antiviral compound together with pharmaceutically acceptable excipients or stable suspensions of the antiviral compound in an aqueous or oil-based medium. BRIEF DESCRIPTION OF THE DRAWINGS

[007] In the drawings,

[008] FIG. 1 shows an X-ray Powder Diffractogram (XPRD) of EFdA. Petition 870260074759, dated 07 / 27 / 2026, page 10 / 107 3 / 27

[009] FIG. 2 shows data provided by Differential Scanning Calorimetry (DSC) and Thermo-Gravimetric Analysis (TGA) of EFdA.

[010] FIG. 3 shows DSC and TGA data for Compound 2. [Oil] FIG. 4 shows XPRD data for Compound 3.

[012] FIG. 5 shows DSC data for Compound 3.

[013] FIG. 6 shows TGA data for Compound 3.

[014] FIG. 7 shows XPRD data for Compound 5.

[015] FIG. 8 shows DSC data for Compound 5.

[016] FIG. 9 shows TGA data for Compound 5.

[017] FIG. 10 shows graphically the data provided in Table 2.

[018] FIG. 11 shows graphically the data provided in Table 3.

[019] FIG. 12 shows graphically the data provided in Table 4.

[020] FIG. 13 shows in graphical form the data provided in Example 10.

[021] FIG. 14 shows XPRD data for Compound 2. FIG. 15 shows XPRD data for Compound 6. DESCRIPTION OF PREFERRED MODALITIES

[022] Extended viral suppression in vivo is achieved by diesters represented by Formula (II): (li) where R1 and R2 are independently -C(=O)R2 and R2 is a member of the group consisting of isopropyl, 3-pentyl, cyclopentyl, and phenylmethyl. The preceding diesters are prepared by reacting EFdA with the desired acid or acid anhydride and recovering the diester as a crystalline compound. The examples below illustrate the preparation of the preferred diesters. Petition 870260074759, dated 07 / 27 / 2026, p. 11 / 107 4 / 27 Petition 870260074759, dated 07 / 27 / 2026, p. 12 / 107 5 / 27 Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2ethynyl-2-((isobutyryloxy)methyl) tetrahydrofuran-3-yl isobutyrate (6 equivalents) DMAP (0.4 equiv) DCC (4 equiv) EFdA DMF, rt. 5h NH, Compound 2

[023] A mixture of EFdA (Compound 1) (3 g, 6.8 mmol, 1 equiv.), 4-dimethylaminopyridine (DMAP) (499 mg, 2.73 mmol, 0.4 equiv.) in anhydrous dimethylformamide (DMF) (100 mL) isobutyric acid (8.4 g, 27.3 mmol, 6 equiv.) was added dropwise at room temperature. The reaction was stirred for 5 h at room temperature. The reaction was monitored by LC-MS due to occasional alkylation of the NH2 group observed over prolonged reaction time. The reaction mixture was then filtered to remove the byproduct urea. Acetonitrile was used to rinse the reaction mixture. The reaction mixture was then washed twice with water and once with brine, and then the solvent was dried, filtered, and evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 60-70% ethyl acetate (EtOAc) in hexanes to obtain Compound 2 as a glassy solid.The resulting glassy solid was dispersed in a minimal amount of isopropanol followed by rotary evaporation to obtain pure Compound 2 as a white solid (2.5 g, 85% yield). LC-MS (ESI+): m / z 434.49 [M+H]+.

[024] Approximately 250 mg / g of Compound 2 was suspended in 0.25% aqueous CMCNa / 0.5% TWEEN-80 (26-gauge syringe) and stabilized for 2 weeks at 40°C / 75% relative humidity. Figure 14 provides XPRD data for Compound 6 of the incubated suspension, before incubation (lower graph), after one week (middle graph), and after Petition 870260074759, dated 07 / 27 / 2026, page 13 / 107 6 / 27 two weeks (top graph), showing that the compound retains good crystallinity in suspension. Preparation of 2-ethylbutanoate (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-(((2ethylbutanoyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl EFdA DMAP (0.2 equiv) TEA (8 equiv) Compound 3 MeCN, r.t., 5h

[025] To a mixture of EFdA (1 g, 3.4 mmol, 1 equiv.), 2-ethylbutanoic anhydride (4.4 g, 20.4 mmol, 6 equiv.), triethanolamine (TEA) (3.8 mL, 27.2 mmol, 8 equiv.) in anhydrous acetonitrile (MeCN) (43 mL) and cooled to 0°C, 4-dimethylaminopyridine (DMAP) (83 mg, 0.68 mmol, 0.2 equiv.) was added at 0°C. The resulting mixture was stirred for 0.5 h at 0°C and then for 5 h at room temperature. The reaction was monitored by LC-MS due to occasional alkylation of the NH2 group observed over prolonged reaction time. The reaction mixture was quenched with methanol and the solvent was evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 60-70% ethyl acetate (EtOAc) in hexanes to obtain Compound 3 as a glassy solid. The glassy solid obtained was dispersed in a minimum amount of isopropanol followed by rotary evaporation to obtain pure Compound 3 as a white solid (1.33 g, 80% yield). Petition 870260074759, dated 07 / 27 / 2026, page 14 / 107 7 / 27 LC-MS (ESI+): m / z 490.56 [M+H]+. Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-9Hpurin-9-yl)-2-(((cyclopentanecarbonyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl cyclopentanecarboxylate Compound 4 Compound 4 was prepared using the procedure followed for Compound 4. 2, but using cyclopentanoic acid instead of isotyric acid. LC-MS (ESI+): m / z 486.44 [M+H]+. Preparation of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2ethynyl-2-((2-phenylacetoxy)methyl) tetrahydrofuran-3-yl 2-phenylacetate oo (6 equivalents) DMAP (0.2 equiv) TEA (8 equiv) MeCN, rt, 3h Compound 5 EFdA

[026] A mixture of EFdA (499 mg, 1.7 mmol, 1 equiv.), 2-phenylacetic anhydride (2.6 g, 10.2 mmol, 6 equiv.), triethanolamine (TEA) (1.9 mL, 13.6 mmol, 8 equiv.) in anhydrous acetonitrile (MeCN) (22 mL) and cooled to 0°C was added to 4-dimethylaminopyridine (DMAP) (42 mg, 0.34 mmol, 0.2 equiv.) at 0°C. The reaction was stirred for 0.5 h at 0°C and then for up to 3 h at room temperature. Petition 870260074759, dated 07 / 27 / 2026, p. 15 / 107 8 / 27 The reaction was monitored by LC-MS due to occasional alkylation of the NH2 group observed over prolonged reaction time. The reaction mixture was quenched with methanol and the solvent was evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 60–70% ethyl acetate (EtOAc) in hexanes to obtain Compound 5 as a glassy solid. The glassy solid obtained was dispersed in minimal isopropanol followed by rotary evaporation to obtain pure Compound 5 as a white solid (694 mg, 77% yield). LC-MS (ESI+): m / z 530.52 [M+H]

[027] Table 1 presents the characterization data of the compound obtained by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS). (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-((benzoyloxy)methyl)-2-ethynyl tetrahydrofuran-3-yl benzoate, Compound 6

[028] Compound 6 was prepared using a procedure similar to that used for Compound 2 using 4.5 equiv of the corresponding acid. LC-MS (ESI+): m / z 502.41 [M+H]+. Approximately 275 mg / g of Compound 6 was suspended in 0.25% aqueous CMC-Na / 0.5% TWEEN-80 (26-gauge syringe) and stabilized for 2 weeks at 40°C / 75% relative humidity. Figure 15 provides XPRD data for Compound 6 from the incubated suspension, before incubation (lower graph), after one week (middle graph), and after two weeks (upper graph), showing that the compound retains good crystallinity in suspension. Table 1: Preferred Compounds Cpd # Structure Characterization Data (NMR and LCMS) !h NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 6.35 (t, Petition 870260074759, dated 07 / 27 / 2026, page 16 / 107 9 / 27 2 Π . Η / ) \ wz\^z o xo 6,6 Hz, 1H), 5,68 (t, J = 5,6 Hz, 1H), 4,40 (dd, J = 11,9, 1,5 Hz, 1H), 4,21 (d, J = 10,4 Hz, 1H), 3,81 (s, 1H), 3,18 (dt, J = 13,6, 6,8 Hz, 1H), 2,69 - 2,57 (m, 2H), 1,2 - 1,1 (m, 6H), 1,08-0,98 (m, 6H), MS-ESI: m / z 434,49 observado (M+H)+ Calc. Anal, para C20H24FN5O5: C, 55,42; H, 5,58; N, 16,16, Constatado: C, 55,48; H, 5,73; N, 15,94 Solubilidade aquosa (pH 7,4): 0,028 mg / mL 3 Π ~~7 Hv □v V / í Z^Z xo !h NMR (400 MHz, DMSO-c / 6) δ 8,35 (s, 1H), 7,91 (d, J = 39,8 Hz, 2H), 6,35 (t, J = 6,8 Hz, 1H), 5,73 (t, J = 6,5 Hz, 1H), 4,38 (dd, J = 11,8, 2,5 Hz, 1H), 4,24 (dd, J = 11,7, 2,5 Hz, 1H), 3,81 (s, 1H), 3,20 (dt, J = 13,5, 6,8 Hz, 1H), 2,61 (dt, J = 13,2, 6,6 Hz, 1H), 2,29 (ddd, J = 8,3, 5,6, 2,6 Hz, 1H), 2,13 (tt, J = 8,9, 5,9 Hz, 1H), 1,72 - 1,31 (m, 8H), 0,88 (td, J = 7,5, 2,3 Hz, 6H), 0,80 -0,66 (m, 6H), MS-ESI: m / z 490,56 observado (M+H)+ Petição 870260074759, de 27 / 07 / 2026, pág. 17 / 107 10 / 27 Cpd # Structure Characterization Data (NMR and LCMS) Aqueous solubility (pH 7.4): <0.002 mg / mL 4 nh2 ooh' < ó · XH NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.92 (d, J = 36.1 Hz, 2H), 6.34 (t, J = 6.8 Hz, 1H), 5.68 (t, J = 6.2 Hz, 1H), 4.39 (dt, J = 11.6, 1.8 Hz, 1H), 4.21 (dd, J = 11.6, 2.4 Hz, 1H), 3.81 (s, 1H), 3.18 (dt, J = 13.9, 6.9 Hz, 1H), 2.90 - 2.78 (m, 1H), 2.74 - 2.57 (m, 2H), 1.93 - 1.44 (m, 16H), MS-ESI: m / z 486.44 observed (M+H) + Aqueous solubility (pH 7.4): <0.001 mg / mL 5 Π ° Vz ,1Z^ZO xo U ZT !h NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.93 (d, J = 37.3 Hz, 2H), 7.39 7.12 (m, 10H), 6.35 (t, J = 6.7 Hz, 1H), 5.71 (t, J = 6.0 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 4.25 (d, J = 11.3 Hz, 1H), 3.88 - 3.71 (m, 3H), 3.63 (q, J = 15.8 Hz, 2H), 3.11 (dt, J = 14.0, 7.0 Hz, 1H), 2.63 (dt, J = 12.5, 6.4 Hz, 1H), MS-ESI: m / z 530.52 observed (M+H)+ Aqueous solubility (pH 7.4): <0.002 mg / mL Petition 870260074759, dated 07 / 27 / 2026, p. 18 / 107 11 / 27 Cpd # Structure Characterization Data (NMR and LCMS) 6 nh2 X- Ph <X / °^ 0 / A Ph !h NMR (400 MHz, DMSO-c / 6) δ 8,38 (S, 1H), 8,09 (dt, J = 8,6, 1,4 Hz, 2H), 8,02 - 7,83 (m, 4H), 7,76 - 7,68 (m, 1H), 7,66 (td, J = 7,4, 1,5 Hz, 1H), 7,59 (td, J = 7,6, 7,1, 1,7 Hz, 2H), 7,53 - 7,44 (m, 2H), 6,54 (t, = 6,8 Hz, 1H), 6,16 - 6,08 (m, 1H), 4,72 (d, J = 11,6 Hz, 1H), 4,59 (d, J = 11,5 Hz, 1H), 3,84 (s, 1H), 3,41 - 3,32 (m, 1H), 2,85 (dt, J = 13,4, 6,3 Hz, 1H), Petition 870260074759, dated 07 / 27 / 2026, page 19 / 107 12 / 27 MS-ESI: m / z 502.41 observed (M+H) Aqueous solubility (pH 7.4): <0.002 mg / mL

[029] The preceding discussion and examples are illustrative and should not be taken as limiting. Still other variations within the landscape of minds of this invention are possible and will readily present themselves to those skilled in the art. Synthesis of Stable Crystalline Forms EXAMPLE 1

[030] Compound 2 (-200 mg) was completely dissolved in a minimal amount of acetone with stirring. This was followed by slow evaporation of the solvents at room temperature. This resulted in a recrystallized sample as a white powder. Other solvents including ethyl acetate, methanol and tetrahydrofuran can also be used. General Examples for the Formulation of Compounds of the Invention

[031] All formulation protocols generated a stable aqueous suspension with 26-gauge syringe capacity. EFdA formulation.

[032] The EFdA was ground and sieved through a No. 80 sieve. A preformed solution of 0.25% sodium carboxymethylcellulose (sodium CMC) and 0.1% polyoxyethylene (20) sorbitan monooleate (TWEEN-80) was added to approximately 300 mg of EFdA (Compound 1) to provide a suspension of approximately 1 gram (300 mg of 1 ± 700 mg of polymer solution) of the final formulation (approximately 300 mg / g). The suspension was then sonicated for 10 minutes in an ice bath. The density of the formulation was 1.064 g / mL and provided a concentration of 319.2 mg / mL of EFdA. EXAMPLE 2

[033] The recrystallized Compound 2 was ground and sieved through a No. 80 Series US standard sieve for wire mesh screens (nominal sieve opening of 0.180 mm). 250 mg of Compound 2 Petition 870260074759, dated 07 / 27 / 2026, page 20 / 107 13 / 27 were withdrawn into a suitable container and a solution of pre-formed Sodium Carboxymethylcellulose (CMC) at 0.25% and TWEEN-80 at 0.1% was added to obtain 1 gram (250 mg of Compound 2 + -750 mg of polymer solution) of the final formulation (-250 mg / g). The suspension was then sonicated by probe for 5 min in an ice bath (Sonication time: 5 min; Pulse amplitude: 20; Pulse on time: 30 sec.; Pulse off time: 20 sec.). EXAMPLE 3

[034] Compound 3 was ground and sieved through No. 80 Series US standard wire mesh screen sieves (nominal sieve opening of 0.180 mm). 250 mg of Compound 3 were taken in a suitable container and a pre-formed solution of 0.25% Sodium CMC and 0.5% TWEEN-80 was added to obtain 1 gram (250 mg of Compound 3 + -750 mg of polymer solution) of the final suspension (-250 mg / g). The suspension was then sonicated by probe for 5 min in an ice bath (Sonication time: 5 min; Pulse amplitude: 20; Pulse on time: 30 sec.; Pulse off time: 20 sec.). The density of the suspension was 1.004 g / mL. The suspension above contained 250.88 mg / mL of Compound 3 (-150 mg / mL of EFdA). EXAMPLE 4

[035] Compound 5 was ground and sieved through a No. 80 US Standard Sieve Series for wire mesh screens (nominal sieve opening of 0.180 mm). 200 mg of Compound 5 were placed in a suitable container and a pre-formed solution of 0.25% Sodium CMC and 0.5% TWEEN-80 was added to obtain 1 gram (200 mg of Compound 5 + -800 mg of polymer solution) of the final suspension (-200 mg / g). The suspension was then sonicated by probe for 5 min in an ice bath (Sonication time: 5 min; Pulse amplitude: 20; Pulse on time: 30 sec; Pulse off time: 20 sec). The density of the suspension was 1.047 g / mL. The suspension above contained 209.4 mg / mL of Compound 5 (-115.97 mg / mL of EFdA). Pharmacokinetic (PK) Studies

[036] Animals: The animals (male rats SD - 200-250 g and monkeys Petition 870260074759, dated 07 / 27 / 2026, page 21 / 107 14 / 27 male rhesus fish (2-3 kg) were obtained from an approved supplier (SLAC Laboratory Animal Co. Ltd., Shanghai, China and / or Topgene Biotechnology, Wuhan City, Hubei Province, China).

[037] Acclimation / Quarantine: Upon arrival, the animals were assessed for their general health by a member of the veterinary staff or other authorized personnel. The animals were acclimated for at least 3 days before being placed in the study.

[038] Livestock: The animals were housed in groups during acclimation and housed individually during the study. The environment of the animals' room will be controlled (target conditions: temperature of 18 to 26°C, relative humidity of 30 to 70%, 12 hours of artificial light and 12 hours of darkness). Temperature and relative humidity were monitored daily.

[039] Animal Cannulation: None.

[040] The animals fasted for at least 12 hours before administration. All animals had access to Certified Rodent and Non-Rodent Diet (Catalog # M01-F, SLAC Laboratory Animal Cl. Ltd., Shanghai, China) i libitum 4 hours after dosing.

[041] The water was autoclaved before being provided to the animals ad libitum. Periodic water analyses were performed and the results archived. There are no known contaminants in the diet or water that, at detection levels, could interfere with the objective, conduct, or outcome of the study. 1. Dose Formulation

[042] SC Formulation: Suspensions were prepared on the day of dosing according to the procedure described in Examples 2-5 above and Tables 2-4. Animals were dosed within four hours of suspension preparation. Two 20 pL aliquots of each prepared suspension were transferred to 1.5 mL polypropylene microcentrifuge tubes and dose validation was performed by LC / UV or LC-MS / MS. 2. Dose Administration

[043] The suspensions were administered by subcutaneous (SC) injection. Petition 870260074759, dated 07 / 27 / 2026, page 22 / 107 15 / 27 following the facility's standard operating procedures (SOPs). 3. Sample Collection

[044] Approximately 200 pL of blood were collected from the saphenous vein at each time point for rats and 0.5 mL for rhesus monkeys. All blood samples were transferred to microcentrifuge tubes containing 4 pL of K2EDTA (0.5 M) as an anticoagulant and placed on moist ice until processed to plasma. 4. Blood / Plasma Processing

[045] Blood: Blood samples were processed to plasma by centrifugation at approximately 4°C, 3000 g 15 min within half an hour of collection. Plasma samples were stored in polypropylene tubes, flash-frozen on dry ice, and kept at -70±10°C until LC / MS / MS analysis. 5. Sample Analysis Dose concentration verification Samples of the prepared suspension were collected from the central position of each duplicate suspension. The concentration of the active ingredient in each aliquot was determined by the LC / UV or LC / MS / MS method. Bioanalytical method and sample analysis LC-MS / MS methods for the quantitative determination of the active ingredient (test compound) in the corresponding biological matrix were developed under GLP non-compliance. A calibration curve with 8 non-zero calibration standards was applied to the method including the lower limit of quantification (LLOQ). A set of quality control (QC) samples consisting of low, medium, and high concentrations was applied to the method. The analysis of the study sample will be performed simultaneously with a set of calibration standards and two sets of QC samples using the LC-MS / MS method (if the sample numbers are...). Petition 870260074759, dated 07 / 27 / 2026, page 23 / 107 16 / 27 greater than 48, so two calibration curves with 2 sets of QC samples were applied). Acceptance Criteria: Linearity: a minimum of 6 calibration standards were recalculated to within ± 20% of their nominal values ​​in plasma. Accuracy: A minimum of 4 out of 6 QC samples were recalculated to within ± 20% of their nominal values ​​in plasma. Specificity: The average concentration calculated in the single blank matrix should be 0.5 times the LLOQ. Sensitivity: LLOQ will target 1~3 ng / mL. Transport: The calculated average transport concentration in the single blank matrix immediately after injection of the highest standard should be LLOQ. If the transfer does not meet the criteria, the percentage of transfer should be estimated following the internal bioanalytical SOP. 6. Data analysis

[046] Plasma concentration versus time data were analyzed by non-compartmental approaches using the Phoenix WinNonlin 6.3 software program. Cmax, Tmax, T%, AUC(Ot), AUC(O-inf), MRT(Ot), MRT(O-inf), %F and plasma concentration versus time profile graphs were generated. EXAMPLE 5:

[047] Several prodrugs, including EFdA (1) as a control, were subjected to single-dose pharmacokinetic studies in rats via subcutaneous administration. All animals were injected with equivalent doses of 10 mg / kg and a concentration of 4 mg / mL of EFdA as an aqueous suspension in 0.5% CMC-Na and 0.5% TWEEN-80. Although similar exposure was observed, all compounds 2, 3 and 5 exhibited plasma levels of EFdA above the lower limit of quantification (LLOQ) for more than one week with a much lower Cmax than for EFdA.

[048] Table 2 shows rat PK data for Compounds 1, 2, 3 and 5 after subcutaneous (SC) administration at a 10 mg / kg equivalent dose. Petition 870260074759, dated 07 / 27 / 2026, page 24 / 107 17 / 27 of EFdA. The data in graph form are shown in Figure 10. Table 2: SC Rat PK: EFdA Levels for EFdA, Compounds 1, 2, 3 and 5 Comp SC 1 (EFdA) Comp SC 2 Comp SC 3 Comp SC 5 EFdA Dose (mg / kg) 10 10 10 10 EFdA Concentration 4 4 4 4 (mg / kg) Excipients 0.5% CMC-Na / 0.5% TWEEN-80 Tl / 2 (h) 1.3 ± 0.2 17 ± 4 NA 12 ± 4 MRTO-last (h) 1.6 ± 0.1 12 ± 1.2 20 ± 4 13 ± 3 Tmax (h) 0.5 2 ± 1.1 4 ± 2.3 7 ± 0 Cmax (nM) 11.548 ± 3.173 1.795 ± 337 287 ± 177 968 ​​± 374 AUCO-last (nM*h) 22.528 ± 1.680 19.771 ± 1.219 6.475 ± 2.909 18.516 + 4.409 AUCO-inf (nM*h) 23.235 ± 2.000 22.745 ± 748 NA 19,993 + 3,525 EXAMPLE 6:

[049] After optimization, rat SC PK studies were performed again with a high equivalent dose of 100 mg / kg at concentration Petition 870260074759, dated 07 / 27 / 2026, page 25 / 107 The 18 / 27 equivalent of 120 mg / mL for Compound 3, 116 mg / mL for Compound 5, and 319 mg / mL for EFdA, respectively, was observed. Compound 3 provided a delayed Cmax and was 100 times lower than EFdA. Increased half-life and mean residence time were also observed, making Compound 3 and Compound 5 suitable for prophylaxis.

[050] Table 3A and Table 3B show rat PK data for Compounds 1, 3, and 5 after SC administration. Data for Compound 3 are shown graphically in Figure 11. Table 3A: SC Rat PK: EFdA Levels for EFdA and Compound 3 Comp SC 3 Comp SC 3 Comp SC 1 (EFdA) Comp SC (EFdA) Dose of EFdA (mg / kg) 10 100 100 10 Excipients 0.5% CMC- Na / 0.5% TWEEN-80 0.25% CMC- Na / 0.1% TWEEN-80 0.25% CMC- Na / 0.1% TWEEN-80 0.5% CMC- Na / 0.5% TWEEN-80 Cone. of EFdA (mg / mL) 4 120 319 4 Tl / 2 (h) NA 474 ± ​​168 99 ± 13 1.3 ±0.2 MRTO-last (h) 20 ± 4 456 ± 17 67 ± 24 1.6 ±0.1 Tmax (h) 4 ± 2.3 312 ± 0 1 ± 0 0.5 Cmax (nM) 287 ±177 66 ± 21 7.429 ± 1.584 11.548 3.173 AUCO-last (nM*h) 6.475 ± 38.306 ± 158.500 ± 22.528 Petition 870260074759, dated 07 / 27 / 2026, page 26 / 107 19 / 27 2909 101 17 1.680 AUCO-inf (nM*h) NA 52.531 ± 39 159.373 ± 16 23.235 2.000 Table 3B: SC Rat PK: EFdA Levels for EFdA and Compound 5 Comp SC 5 Comp SC 1 (EFdA) Dose of EFdA 100 100 (mg / kg) Excipients 0.25% CMC-Na / 0.1% TWEEN-80 Cone. of EFdA (mg / mL) 116 319 Tl / 2 (h) 363 ± 411 99 ± 13 MRTO-last (h) 225 ± 64 67 ± 24 Cmax (nM) 244 ± 54 7,429 ± 1,584 AUCO-last (nM*h) 68,848 ± 16,728 158,500 ± 17 AUCO-inf (nM*h) 129,209 ± 117,423 159,373 ± 16 EXAMPLE 7:

[051] After the rat PK analysis, the focus shifted to non-rodents, namely rhesus monkeys. Compound 5 and EFdA were subjected to single-dose subcutaneous rhesus monkey PK studies with equivalent doses of 50 mg / kg of EFdA. The aqueous suspensions contained 0.25% CMC-Na and 0.1% / 0.5% TWEEN-80 with equivalent concentrations of 116 mg / mL and 319 mg / mL of EFdA for Compound 5 and EFdA, respectively. With Compound 5, plasma levels of Petition 870260074759, dated 07 / 27 / 2026, p. 27 / 107 20 / 27 EFdA above LLOQ for more than a month with Cmax 24 times lower than EFdA itself.

[052] Table 4 shows Rhesus PK data for Compounds 1 and 5 after SC administration at 50 mg / kg EFdA equivalent dose. The data are shown graphically in Figure 12. Table 4: SC Rhesus PK: Plasma EFdA levels after EFdA or Compound 5 measurement in plasma. SC EFdA EFdA (Plasma) SC Compound 5 EFdA (Plasma) Dose of EFdA (mg / kg) 50 50 Excipients 0.25% CMC-Na 0.1%TWEEN-80 0.25% CMC-Na 0.5%TWEEN-80 Cone, of EFdA (mg / mL) 319 116 Tl / 2 (h) 165 ± 56 1.063 ± 608 MRTO-last (h) 79 ± 37 1.449 ± 517 Tmax (h) 4 ± 3.6 264 ±125 Cmax (nM) 3.060 ± 1.058 128 ± 52 C42days (nM) 0.6 ± 0.3 60 ± 16 AUCO-last (nM*h) 135.691 ± 22.574 143.330 ± 33.727 AUCO-inf (nM*h) 135.748 ± 22.594 145.643 ± 32.180

[053] The suspension medium for the present compounds may be an aqueous vehicle such as water for injection (WFI) or a vegetable oil vehicle such as sesame oil, olive oil and the like. The suspension medium may also contain pharmaceutically acceptable excipients such as nonionic surfactants, suspending or flocculating agents, preservatives, Petition 870260074759, dated 07 / 27 / 2026, page 28 / 107 21 / 27 buffers, toxicity adjusters, chelating agents, antioxidants and the like.

[054] For prophylaxis, a preferred prophylactic dose for a human subject is in the range of about 80 mg to about 800 mg of the antiviral compound administered parenterally at intervals of about six months (semi-annually) in a dose volume of about 0.5 to about 4 milliliters (mL) per dose.

[055] For the treatment of a human patient, the effective amount of the antiviral compound of this invention preferably ranges from about 80 mg to about 800 mg in a dose volume of about 0.5 to about 4 mL per dose, more preferably an effective amount in the range of about 200 to about 400 mg, for a three-month dosing regimen. The dosing regimen may vary, however, depending on the time interval between doses administered in a particular dosing regimen.

[056] The term “effective amount”, as used in this document and in the claims, means an amount of the antiviral compound sufficient to inhibit HIV reverse transcriptase, inhibit HIV replication, exert a prophylactic effect and / or exert a therapeutic effect after administration.

[057] The term “administration” and its variants, for example, “administering a compound”, with reference to the claimed treatment method, means providing the antiviral compound to the patient and includes self-administration as well as administration to the patient by another person.

[058] Preferably, the parenteral suspensions suitable for injection contain the present antiviral compound in an amount in the range of about 3 to 45 percent by weight, based on the weight of the suspension. The preferred particle size is not more than about 50 micrometers (µm), more preferably an average particle size in the range of about 6 µm to about 15 µm.

[059] Preferred flocculating or suspending agents are linear polymers, particularly substituted celluloses, such as methylcellulose, carboxymethylcellulose (CMC), hydroxypropylcellulose, hydroxypropylmethylcellulose and the like. Petition 870260074759, dated 07 / 27 / 2026, page 29 / 107 22 / 27

[060] The preferred surfactants are nonionic surfactants. The particularly preferred surfactant is polyoxyethylene (20) sorbitan monooleate (TWEEN-80).

[061] In addition to parenteral dosage forms, the present compounds can also be administered in oral dosage forms and as implants.

[062] Dosage forms containing the present compounds may also include additional anti-HIV and / or anti-HBV agents, such as cabotegravir, dolutegravir, doravirine, evilegravir, lesiverine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, lamivudine and the like.

[063] The invention further provides, in various embodiments, a method of viremia prophylaxis or treatment of a viral infection in a patient where reverse transcriptase inhibition is clinically indicated, comprising administering to the patient an effective amount or concentration of a compound of Formula (II). More specifically, the compound of Formula (II) can be administered in a formulation that provides slow or controlled or sustained release of EFdA from these prodrugs. More specifically, the compound of Formula (II) can be formulated as an aqueous suspension, solutions, and can be encapsulated in particles for slow release, including PLGA and other materials known in the art. More specifically, the viral infection can be caused by HIV or HBV. Routes of administration for these prodrugs may include, but are not limited to, oral, parenteral, and implant release (drug delivery composition and device).In the method for treating or preventing viral infection, the method may further comprise an additional anti-HIV and / or anti-HBV agent including, but not limited to, cabotegravir, dolutegravir, doravirine, elvitegravir, lersiverin, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, lamivudine and the like. EXAMPLE 8

[064] The surfactant concentration was optimized with 0.3% and 0.5% methylcellulose in a formulation containing 400 mg / g of Compound 5 Petition 870260074759, dated 07 / 27 / 2026, p. 30 / 107 23 / 27 micronized. The formulations were prepared with different concentrations of TWEEN-80 (0.1, 0.2 and 0.3%). No significant effect of surfactant concentration on viscosity, flowability and redispersion time was observed in the formulations after 10 days of storage. The observations are reported in Table 5. Table 5: Optimization of Surfactant Concentration with 400 mg / g of Compound 5 Composition: Cone, Surfactant TWEEN-80 Syringability (26G) Viscosity Flow Time to resuspend 0.3% Methylcellulose 0.1% z ++++ ++++ 2.2 min. 0.2% z ++++ ++++ 2.5 min. 0.3% z ++++ ++++ 2.3 min. 0.5% Methylcellulose 0.1% z ++++ ++++ 2.5 min. 0.2% z ++++ ++++ 2.5 min. 0.3% z ++++ ++++ 3.0 min. Viscosity: ++++ Slightly viscous, +++ Viscous, ++ Very viscous, + Semi-solid Flow: + No Flow, ++ Less Flow, +++ Good Flow, ++++ Very Good Flow / : Servingable EXAMPLE 9

[065] A bulk batch (40 g) of the Compound 5 suspension was prepared with 0.3% methylcellulose and a 0.2% concentration of TWEEN- 80. Although polymer and surfactant concentrations were optimized with a 40% by weight drug concentration, a bulk batch was also prepared with a 35% by weight drug concentration during accelerated and long-term stability studies. The composition of the formulation loaded into the stability chamber is provided in Table 8. 6. A detailed manufacturing procedure for the preparation and composition of the formulation is provided below. Petition 870260074759, dated 07 / 27 / 2026, page 31 / 107 24 / 27 Table 6: Formulation Composition Ingredient Quantity (mg / g) Quantity, g / 40 g Compound 5 350 14 Methylcellulose 3 0.120 TWEEN-80 2 0.08 Water for injection (WFI) 645 25.8

[066] Methylcellulose was slowly added to the required amount of water for injection (WFI) in a glass bottle with continuous stirring. The resulting mixture was stirred until the solution was clear and free of any lumps using a magnetic stirrer. TWEEN-80 (0.08 g) was added to the resulting solution and stirred well.

[067] The micronized Compound 5 (14 g; average particle size 11 µm) was slowly added to the prepared polymer surfactant solution under vigorous stirring at 1400 rpm using a magnetic stirrer. After complete addition of Compound 5, the resulting suspension was stirred (600 rpm) for 20 minutes to uniformly disperse the particles.

[068] The prepared formulation was characterized by several physicochemical properties, such as assay, pH, % purity, redispersibility, injectability, polymorphic form and particle size. The results are presented in Table 7. Table 7: Physicochemical characterization of the formulation in preparation Test Parameter Appearance White dispersion pH 5.78 Matrix by HPLC (% of label claim) 108.8% Purity 99.34% Redispersibility Yes Petition 870260074759, dated 07 / 27 / 2026, page 32 / 107 25 / 27 Injectability: Yes. Polymorphic form: Same as API. Average particle size: 14 µm.

[069] The formulation shown in Table 6 was considered acceptable based on the characteristics shown in Table 7. EXAMPLE 10

[070] Aqueous suspensions of EFdA and Compounds 3 and 5 were administered subcutaneously to Rhesus Monkeys, peripheral blood mononuclear cells (PBMCs) were periodically retrieved, and pharmacokinetic data were evaluated. The observed results are presented in Tables 8, 9, and 10 for both compounds, and in Figure 13 for Compound 5. Table 8: SC Rhesus PK: EFdA-TP PBMC levels after Compound 5 or EFdA dosage Compound SC 5: EFdATP (PBMC) EFdA SC: EFdA-TP (PBMC) Nominal Dose of EFdA (mg / kg) 50 50 Formulation 0.25% CMC-Na / 0.5% TWEEN-80 0.25% CMC-Na / 0.1% TWEEN-80 Cone. of EFdA (mg / mL) 116 319 Dose volume (mL / kg) 0.43 (total vol. 1.39 mL) 0.16 (total vol. 0.47 mL) Tl / 2 (d) 31 ± 17 12 ± 5 MRT 0-last (d) 72 ± 19 6 ± 1 MRT O-inf (d) 73 ± 21 6 ± 1 Tmax (d) 21 ± 13 2 ± 0 Petition 870260074759, dated 07 / 27 / 2026, page 33 / 107 26 / 27 Cmax (pM) 192 ± 96 789 ± 154 Clast (μΜ) 0.71 0.03 AUCO-last (pM*h) 233.2743 ± 37.553 127.176 ± 29, 205 AUCO-inf (pM*h) 234.062 ± 37.077 127.201 ± 29.225 Table 9: SC Rhesus PK: Plasma EFdA and PBMC EFdA-TP levels after Compound 3 dosage. SC Compound 3: EFdA (Plasma) SC Compound 3: EFdATP (PBMC) Nominal Dose of EFdA (mg / kg) 50 Formulation 0.25% CMC-Na / 0.5% TWEEN80 Cone. of EFdA (mg / mL) 150 Dose volume (mL / kg) 0.335 (total vol. 1.57 mL) Tl / 2 (h) 566 ± 344 1.022 ± 463 MRT0-last (h) 1.071 ± 488 394 ± 36 Tmax (h) 440 ± 270 784 ± 485 cmax (nM) 40 ± 28 627 ± 60 AUC0-last (nM*h) 35,385 ± 18,522 807,473 ± 519,381 AUC0.jnf (nM*h) 45,293 ± 14,840 1,447,998 ± 576.163 Table 10: SC Rhesus PK: EFdA Levels for Compounds 3 and 5 in Plasma SC EFdA EFdA Compound SC 5: Compound SC 3: (Plasma) EFdA EFdA Petition 870260074759, dated 07 / 27 / 2026, page 34 / 107 27 / 27 (Plasma) (Plasma) Nominal Dose of EFdA (mg / kg) 50 50 50 Formulation 0.25% CMC-Na / 0.1% Tween 80 0.25% CMC-Na / 0.5% Tween 80 0.25% CMC-Na / 0.5% Tween 80 Cone. From EfdA (mg / mL) 319 116 150 Ti / 2 (h) 165 ± 56 1.063 ± 608 566 ± 344 MRTg_|ast (h) 79 ± 37 1.449 ± 517 1.071 ± 488 Tmax (h) 4 ± 3.6 264 ±125 440 ± 270 cmax (nM) 3060 ±1058 128 ± 52 40 ± 28 AUC0-last (nM*h) 135,691 ± 22,574 143,330 ± 33,727 35,385 ± 18,522 AUCO-inf (nM*h) 135.748 ± 22.594 145.643 ± 32.180 45.293 ± 14.840 Petition 870260074759, dated 07 / 27 / 2026, p. 35 / 107

Claims

1 / 5 CLAIMS 1. Compound, characterized in that it has Formula (II): wherein Rx and R2 are independently -C(=O)R3 and R3 is selected from the group consisting of isopropyl, 3-pentyl, cyclopentyl, phenyl and phenylmethyl.

2. Compound according to Claim 1, characterized in that it is in a crystalline form.

3. Compound, in accordance with Indication 2, characterized by its crystalline form comprising: crystalline isobutyrate of (2R,3S,5R)-5-(6-amino-2-fluor-9Hpurin-9-yl)-2-ethinyl-2-(isobutyryloxy)methyl) tetrahidrofuran-3-yl; Crystalline 2-ethylbutanoate de (2R,3S,5R)-5-(6-amino-2-fluor-9Hpurin-9-yl)-2-((2-ethylbutanoyl)oxi)methyl-2-ethynyltetrahydrofuran-3-yl; crystalline cyclopentanocarboxylate of (2R,3S,5R)-5-(6-amino-2-fluor-9H-purin-9-yl)-2-(((cyclopentanocarbonyl)oxi)metil)-2-ethynyltetrahidrofurano-3-yl; or crystalline 2-phenylacetate of (2R,3S,5R)-5-(6-amino-2-fluor-9H-purin-9-yl)-2-ethynyl-2-((2phenlacetoxi)metil)tetrahidrofurano-3-yl.

4. Aqueous Parenteral Suspension, comprising a compound of Formula (II): nh2 Petition 870260074759, dated 27 / 07 / 2026, p. 36 / 107 2 / 5 characterized in that R1 and R2 are independently C(=O)R3 and R3 is selected from the group consisting of isopropyl, 3-pentyl (letoxypropyl, cyclopentyl and phenylmethyl); a nonionic surfactant; a suspending agent; and water.

5. Aqueous Parenteral Suspension, according to Claim 4, characterized in that said compound is present in an amount in the range of 3 to 4.5 percent by weight of the suspension, said nonionic surfactant is present in an amount in the range of 0.1 to 0.5 percent by weight of the suspension and said suspending agent is present in an amount in the range of 0.1 to 0.5 percent by weight of the suspension.

6. Aqueous Parenteral Suspension, according to Claim 4, characterized in that the nonionic surfactant is polyoxyethylene (20) sorbitan monooleate.

7. Aqueous Parenteral Suspension, according to Claim 4, characterized in that the suspending agent is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose.

8. Aqueous Parenteral Suspension, according to Claim 4, characterized in that the compound is in a crystalline form.

9. Method for in vivo suppression of Human Immunodeficiency Virus (HIV) in a patient, characterized in that it comprises administering to the patient the compound as defined in Claim 1.

10. Method for Prophylaxis of HIV or HBV Infection in a Human Subject Not Infected with HIV or HBV, characterized in that it comprises administering to the human subject the compound, as defined in Claim 1.

11. Method according to Claim 9 or 10, characterized in that the compound is formulated as an aqueous suspension, a solution, or encapsulated in particles for slow release.

12. Method, according to Claim 9 or 10, characterized in that Petition 870260074759, dated 07 / 27 / 2026, p. 37 / 107 3 / 5 also includes the administration of an additional anti-HIV and / or anti-HBV agent.

13. Use of a Compound, as defined in any one of Claims 1 to 3, or of an Aqueous Parenteral Suspension, as defined in any one of Claims 4 to 8, characterized in that it is in the manufacture of medicaments to treat or prevent a viral infection of HIV or HBV in a human subject.

14. Use of an Aqueous Parenteral Compound or Suspension, according to Claim 13, characterized in that the compound is formulated as an aqueous suspension, solution, or encapsulated in particles for slow release.

15. Use of an aqueous parenteral compound or suspension, according to Claim 13, characterized in that the viral infection is caused by HIV.

16. Use of an aqueous parenteral compound or suspension, according to Claim 13, characterized in that the viral infection is caused by HBV.

17. Compound according to Claim 1, characterized in that the compound is a crystalline form of the compound: nh2 Compound according to Claim 17, characterized in that the crystalline form consists of an XRPD pattern as shown in Figure 4.

18. Compound according to Claim 17, characterized in that the crystalline form consists of a DSC thermogram having an endothermic transition at 134.3°C. Compound according to Claim 17, characterized in that the crystalline form consists of a DSC thermogram as shown in Figure 5.

19. Compound, according to Claim 1, characterized in that the compound is a crystalline form of the compound: Petition 870260074759, dated 07 / 27 / 2026, page 38 / 107 4 / 5 20. Compound according to Claim 1, characterized in that the compound is a crystalline form of the compound:

21. Compound according to Claim 22, characterized in that the crystalline form consists of an XRPD pattern as shown in Figure 7.

22. Compound according to Claim 22, characterized in that the crystalline form consists of a DSC thermogram having an endothermic transition at 158.9°C.

23. Compound according to Claim 22, characterized in that the crystalline form consists of a DSC thermogram as shown in Figure 8.

24. Compound, according to Claim 1, characterized in that the compound is:

25. Compound, according to Claim 1, characterized by the fact that Petition 870260074759, dated 07 / 27 / 2026, page 39 / 107 5 / 5, the compound is:

26. Compound, according to Claim 1, characterized in that the 27. Method for Inhibiting Viral Reverse Transcriptase Bioactivity, characterized in that it comprises contacting a virus expressing a bioactive reverse transcriptase enzyme with a compound, as defined in Claim 1. Petition 870260074759, dated July 27, 2026, p. 40 / 107

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