Antiviral prodrugs and formulations thereof

Abstract

Provided herein are compounds, compositions and methods of using thereof for treatment and / or prevention infections of viruses such as HIV and HBV by administering a certain esters and other derivatives of 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) or a pharmaceutically acceptable salt thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS Iliis application claims the benefit of U.S. Provisional Application Serial No. 62 / 898,679, filed on September 11,2019, which is incorporated herein by reference in its entirety. FIELD OF INVENTION Tills invention relates to antiviral compounds and compositions useful for the treatment of acquired immunodeficiency syndrome (AIDS). BACKGROUND The compound EFdA (MK-8591) is a nucleoside analog known to be effective as an inhibitor of the enzyme reverse transcriptase (Current Opinion in HIV and AIDS 2018,13, 294-299) NH2 fl’ F^hL N ft” H° w MK-8591 (Islatravir, EFdA). Certain EFdA analogs are described in a U.S. application published as US2019 / 185508, including phosphates, esters, carbonates, carbamates where at least one of the substitutions in the glycosyl donor ring contain a "D" atom (D:::: deuterium:::: 2H). Reverse transcriptase inhibitors can be effective in the treatment of viral infections caused by viruses where reverse transcriptase function is essential for viral replication and production of viral proteins, such as HIV (Human Immunodeficiency Virus) and HBV (Hepatitis B Virus). In the case of HIV, the virus is an RNA virus that uses reverse transcriptase to synthesize DNA reverse transcripts of the vital genome which are translated by the host to provide the viral proteins. In the case of HBV, a DNA virus, the DNA viral polymerase also has a reverse transcriptase function, generating viral DNA from a viral RNA SUBSTITUTE SHEET (RULE 26) -2 - intermediate during replication. An antiviral example of a compound that hits both HIV and HBV is lamivudine. SUMMARY Tire invention provides, in various embodiments, (1) novel compositions of chemical matter comprising bioactive prodrugs of MK-8591 or pharmaceutically acceptable salt of these prodrugs, and (2) novel formulations of these prodrugs providing therapeutic and prophylactic treatment of patients against viral infections of viruses such as HIV and HBV, wherein inhibition of a reverse transcriptase enzyme (RNA-directed DNA polymerase) slows or blocks the viral infection. The route of administration for these treatments can include, but not limited to, oral, parenteral and implants (composition and device). The formulations of this invention provide for slow or controlled or sustained release of EFdA from these prodrugs when injected as an aqueous suspension formulation. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows an X-ray Powder Diffractogram (XPRD) of EFdA. Figure 2 shows data provided by Differential Scanning Calorimetry’ (DSC) and Thermo-Gravimetric Analysis (TGA) of EFdA. Figure 3 shows DSC and TGA data for compound 2. Figure 4 shows XPRD data for compound 3. Figure 5 shows DSC data for compound 3. Figure 6 shows TGA data for compound 3. Figure 7 shows XPRD data for compound 5. Figure 8 shows DSC data for compound 5. Figure 9 shows TGA data for compound 5. Figure 10 shows in graphic form the data provided in Table 2. Figure 11 shows in graphic form the data provided in Table 3. Figure 12 shows in graphic form the data provided in Table 4. DETAILED DESCRIPTION Ilie invention provides, in various embodiments, a compound of Formula (I) -3 - wherein R1 is H or is X-Lm, wherein m = 1 or 2, and wherein X-Lm is -C(=O)L, -C(=O)OL, -( ;O)XH(L), -C{ ())X(Lb. -CH(R)OC(=0)1.. -C( 0)(   R)-\H{L) -C{ O)CH(R)-X(Lb. -P(=O)(NHL)2, -P(=O)(NHL)(NL2), or -P(=O)(NL2)2, and each independently selected L is (Ci-22)alkyl, (C3-22)alkenyl wherein the alkenyl can comprise 1-6 unsaturations, (C3-7)cycloalkyl, (CHR)n-phenyl wherein n:=0 or 1, or -CHR-N(R)2, or R1 is -OCH(R)OP(=O)(OH)2 or R1 is a phosphate residue or its derivative residue comprising a monophosphate, a diphosphate, a triphosphate, a phosphonate, a phosphate polyester, a phosphate amidate (mono and di), a phosphorothioate, a phosphoroselenoate, or a phophoroboranoate R is H, (Ci.22)alkyl, or (C3.22)alkenyl wherein the alkenyl can comprise 1-6 unsaturations, or is (C3-7)cycloalkyl; R2 is H or is X-Lm, or R2 is - OCH(R)OP(:=O)(OH)2 or R2 is a phosphate residue or its derivative residue comprising a monophosphate, a diphosphate, a triphosphate, a phosphonate, a phosphate polyester, a phosphate amidate (mono and di), a phosphorothioate, a phosphoroselenoate, or a phophoroboranoate; excluding following combinations:! a) R1 := R2 := acetyl, (b) R1 = R2 ::: H, and (c) R2 := H when R1 is a phosphate residue or its derivative residue comprising a monophosphate, a diphosphate, a triphosphate, a phosphonate, a phosphate polyester, a phosphate amidate (mono and di), a phosphorothioate, a phosphoroselenoate, or a phophoroboranoate; or a pharmaceutically acceptable salt thereof. In various embodiments, a compound of Formula (I) can be any of the specific compounds 2-51, shown in Table 1. The in vention further provides, in various embodiments, a method of inhibiting viral reverse transcriptase bioactivity, comprising contacting a virus expressing an enzyme with -4- reverse transcriptase bioactivity with an effective amount or concentration of a compound of Formula (I). The invention further provides, in various embodiments, a method of prophylaxis of viremia or treatment of a viral infection in a patient wherein inhibition of a reverse transcriptase is medically indicated, comprising administering to the patient an effective amount or concentration of a compound of Formula (I). More specifically, the compound of Formula (I) can be administered in a formulation that provides for slow or controlled or sustained release of EFdA from these prodrugs. More specifically, the compound of Formula (I) can be formulated as aqueous suspension, solutions, and can be encapsulated in particles for slow-release including PLGA and those known in the art. More specifically, the viral infection can be caused by HIV or HBV. The routes of administration for these prodrugs can include, but not limited to, oral, parenteral and implants (drug delivery composition and device). In the method for the treatment or prevention of the 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, lersiverine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate or lamivudine. Table 1: Compounds of the Invention Cpd # Structure Characterization Data (NMR and LCMS) 2 nh2 f^n^n \ yv ° !H NMR (400 MHz, DMSO-76) 5 8.34 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 6.35 (t, J= 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 (tn, 6H). MS-ESI: m / z 434.49 observed (M+H)+ Anal calcd for C20H24FN5O5: C, 55.42; H, 5.58; N, 16.16. Found: C, 55.48; H, 5.73; N, 15.94 Aqueous solubility (pH 7.4): 0.028 mg / mL 3 nh2 k 1 >     / a.w 0 fH NMR (400 MHz, DMSO-d6) 5 8.35 (s, 1H), 7.91 (d. 7 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,. / 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,7=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 observed iM+H) Aqueous solubility (pH 7.4): <0.002 mg / mL 4 nh2 FW 0 o 'H NMR (400 MHz, DMSO-tZ6) 6 8.34 (s, 1H), 7.92 (d, 7=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, 7= 11.6, 2.4 Hz, 1H), 3.81 (s, 1H), 3.18 (dt, 7 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)+ Cpd # Structure Characterization Data (NMR and LCMS) 5 nh2 X y° \\ Ph-^ NMR (400 MHz, DMS(W6) 8 8.31 (s, 1H), 7.93 (d, J= 37.3 Hz, 2H), 7.39 - 7.12 (m, 10H), 6.35 (t, ■ / 6 7 Hz, 1H), 5.71 (t, J 6.0 Hz, IH), 4.41 (d, J = 11.7 Hz, 1H), 4.25 (d, J = 11.3 Hz, IH), 3.88 - 3.71 (m, 3H), 3.63 (q, J == 15.8 Hz, 2H), 3.11 (dt, J = 14.0, 7.0 Hz, IH), 2.63 (dt, J = 12.5, 6.4 Hz, IH). MS-ESI: m / z 530.52 observed (M+H)T Aqueous solubility (pH 7.4): <0.002 mg / mL 6 nh2 T p n         t Ao     / ph / i 0- / A - Ph-A^ jH NMR (400 MHz, DMSO-O 8 8.26 (s, IH), 7.93 (d, J= 34.8 Hz, 2H), 7.38 - 7.13 (m, 10H), 6.35 - 6.25 (m, IH), 5.59 (t, J= 6.3 Hz, IH), 4.38 (d, J MS Hz, IH), 4.09 (d, J = 11.4 Hz, IH), 3.88 (q,, / 7.0 Hz, IH), 3.70 (q, J 7 1 Hz, IH), 3.48 (s, IH), 3.04 (dt, J = 14.3, 7.0 Hz, IH), 2.61 -2 53 (m, IH), 1.47 (d, J == 7.4 Hz, 3H), 1.28 (d,. / 7.3 Hz, 3H). MS-ESI: m / z 558.65 observed (M+H / 7 nh2 x £> F^hT N y° % Ph !H NMR (400 MHz, DMSOx£) 6 8.38 (s, IH), 8.09 (dt, J = 8.6, 1.4 Hz, 2H), 8.02 - 7.83 (m, 4H), 7.76 - 7.68 (m, IH), 7.66 (td, . / 7 4. 1.5 Hz, IH), 7.59 (td, J= 7.6, 7.1, 1.7 Hz, 2H), 7.53 - 7.44 (m, 2H), 6.54 (t, . / 6.8 Hz, IH), 6.16 - 6.08 (m, IH), 4.72 id. J 11.6 Hz, IH), 4.59 (d. J == 11.5 Hz, IH), 3.84 (s, IH), 3.41 - 3.32 (m, IH), 2.85 (dt, J == 13.4, 6.3 Hz, IH). MS-ESI: m / z 502.41 observed (M+H)’ -7 - Cpd # Structure Characterization Data (NMR and LCMS) 8 Me nh2 IIO J) Me ( fA          C\ °-7 0 NMR (400 MHz, Chloroform-^ / ) 5 8.02 (s, 1H), 6.39 (t, J = 6.4 Hz, 1H), 5.64 (t, J = 6.2 Hz, 1H), 5.49 - 5.25 (m, 24H), 4.50 (d, .7= 12.0 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 3.00 (dt, J= 13.6, 6.7 Hz, 1H), 2.90 - 2.66 (m, 21H), 2.53 - 2.30 (m, 10H), 2.07 (p, J= 7.3 Hz, 5H), 0.97 (t, J = 7.5 Hz, 6H). MS-ESI: m / z 457.23 observed (M / 2+HV 9 nh2 n<=O-N 1Y> F^N^N / —n     £16^33 ■Jv ° y° C16H33 jH NMR (400 MHz, Chloroform-d) 5 7.92 (s, 1H), 6.40 (t, J= 6.4 Hz, 1H), 5.76 (brs, 2H), 5.65 (dd, J ------7.1, 5.3 Hz, 1H), 4.49 (d,. / 12.0 Hz, 1H), 4.38 (d, J 12.1 Hz, 1H), 2.99 (dt, J= 13.5, 6.7 Hz, 1H), 2.75 - 2,64 (m, 2H), 2.41 (t,. / 7.5 Hz, 2H), 2.34 (q, J= 3.8 Hz, 1H), 1.71 - 1.57 (m, 9H), 1.41 - 1.17 (m, 48H), 0.88 (t, J - 6.8 Hz, 6H). MS-ESI: m / z no signal observed (M+H)1 10 nh2 7 T> F N N / -o     £15^31 vA 0 C15H31 SH NMR (400 MHz, DMSO-O 5 8.34 (s, 1H), 7.91 (d. J = 30.8 Hz, 2H), 6 34 (t, J= 6.9 Hz, 1H), 5.70 (t, J =6.4 Hz, 1H), 4.39 (d,J= 11.6 Hz, 1H), 4.22 (d, J= 11.9 Hz, 1H), 3.81 - 3.73 (m, 1H), 3.14 (dt, J = 14.1, 6.9 Hz, 1H), 2.60 (dt, J= 12.9, 6.0 Hz, 1H), 2.39 (td, J= 7.3, 2.4 Hz, 2H), 2.32 -2.17 (m, 2H), 1.64 - 1.52 (m, 2H), 1.51 - 1.39 (m, 2H), 1.38 - 1.11 (m, 48H), 0.92 - 0.78 (m, 6H). MS-ESI: m / z no signal observed (M+H)+ Cpd # Structure Characterization Data (NMR and LCMS) 11 nh2 11> F N N / -Q      / C6H13 C6Hi3 NMR (400 MHz, DMSO--7,,) 8 8.33 (s, 1H), 7.91 (d, 7= 31.7 Hz, 2H), 6.34 (t, J = 6.7 Hz, 1H), 5.70 (t, 7 6 3 Hz, 1H), 4.40 (d,. / 11.6 Hz, 1H), 4.21 (d, J= 11.6 Hz, 1H), 3.82-3.78 (m, 1H), 3.14 (dt, J = 13.8, 6.9 Hz, 1H), 2.61 (dt, 7 = 13.2, 6.2 Hz, 1H), 2.39 (td, J = 7.4, 2.9 Hz, 2H), 2.32 -2.15 (m, 2H), 1.63 - 1.51 (m, 2H), 1.50 - 1.37 (m, 2H), 1.35 - 1.13 (m, 12H), 0.91 - 0.76 (m, 6H). MS-ESI: m / z 518.25 observed (M+H)+ 12 nh2 11 •»     / f^n^n    \ O °~< NH2 Ml ° HaN-'k, MS-ESI: m / z 492.64 observed (M+H)+ 13 CM X z Xck^O ox z^z^x / ^O \ X "X ZX      £ u_ MS-ESI: m / z 492.55 observed (M+H)+ 14 CM X z z^z"’\ / ^*O X- °A z \         X u. MS-ESI: m / z 408.3 observed (M+H)+ Aqueous solubility7 (pH 7.4): >106 mg / rnL (HC1 salt) Cpd # Structure Characterization Data (NMR and LCMS) 15 nh2 1 v> fanA    t A? 0 >nh2 0 H2N-A MS-ESI: m / z 436.5 observed (M+H)+ 16 nh2 xA F^nA A? °h AL, / fH NMR (400 MHz, DMSO-d6) 5 8.35 (s, IH), 7.93 id. J 35.7 Hz, 2H), 6.32 (i,. / 7.2 Hz, 1H), 5.64 - 5.50 (m, 2H), 3.73 - 3.66 (m, 2H), 3.66 -3.55 (tn, 1H), 3.01 (dt, .7= 14.4, 7.3 Hz, 1H), 2.67 - 2.57 (m, 1H), 2.55 - 2.51 (m, 1H), 1.16 (ddd, J = 11.3, 7:. 1.7 Hz, 6H). MS-ESI: m / z 364.53 observed (MH) 17 X ox 2^ 2"‘A**O MS-ESI: m / z 392.47 observed (M+H)+ 18 nh2 w<An : Y) fanA A° OH A fH NMR (400 MHz, Methanol-^) 5 8.30 (s, 1H), 6.45 (t, J= 7.1 Hz, 1H), 5.70 (dd, J= 6.8, 3.3 Hz, 1H), 3.94 - 3.80 (m, 2H), 3.21 - 3.17 (m, 1H), 3.03 (dt, J= 14.1, 7.3 Hz, IH), 2.90 (p, J= 8.3 Hz, 1H), 2.63 (ddt, J = 12.4, 5.8, 2.7 Hz, IH), 2.04 -1.87 (m, 4H), 1.79- 1.60 (m, 4H). MS-ESI: m / z no signal observed (M+H)+ Cpd # Structure Characterization Data (NMR and LCMS) 19 nh2 IO F^N^N / ^9 OH mA Ph"'' NMR (400 MHz, DMSO-X) 8 8.35 (s, 1H), 7.93 (d, J= 35.1 Hz, 2H), 7.40 - 7.20 (m, 5H), 6.33 (t, ■ / 7.0 Hz, 1H), 5.59 (t,, / 6.3 Hz, 2H), 3.85 - 3.71 (m, 2H), 3.69 (dd, J= 11.8, 5.6 Hz, IH), 3.65 - 3.63 (m, 1H), 3.59 (dd. J 11.9, 7.0 Hz, IH), 3.01 (dt, J= 14.4, 7.3 Hz, IH), 2.58 -2 52 (m, IH). MS-ESI: m / z 412.43 observed (MH) 20 nh2 w F^N^N / ^9 OH mA Ph--\ jH NMR (400 MHz, DMSOx / 6) 0 8.34 (s, IH), 7.92 (s, 2H), 7.41 - 7.23 (m, 5H), 6.30 (t, J= 7.0 Hz, IH), 5.59 - 5.49 (m, 2H), 3.87 (q, J= 7.1 Hz, IH), 3.64 (dd, J = 11.9, 5.4 Hz, IH), 3.57 - 3.47 (m, IH), 3.01 (dt, ■ / 14.2, 7.2 Hz, IH), 2.58 -2.54 (m, IH), 1.49 (d, J= 7.2 Hz, 3H). MS-ESI: m / z 426.56 observed (MH) 21 nh2 x V> F^N^N / ^9 / OH yA\ Ph 41 NMR (400 MHz, DMSO-X) 8 8.39 (s, IH), 8.11 - 8.04 (m, 2H), 7.94 (d, J= 35.1 Hz, 2H), 7.71 (dddd, J= 8.2, 7.3, 2.7, 1.3 Hz, IH), 7.62 -7.51 (m, 2H), 6.45 (t, J= 7.2 Hz, IH), 5.87 - 5.75 (m, IH), 5.71 - 5.61 (m, IH), 3.82 - 3.63 (m, 3H), 3.13 (dt, J = 14.2, 7.1 Hz, IH), 2.77 - 2.65 (m, IH). MS-ESI: m / z 398.47 observed (MH) 22 nh2 w F^N^N / ^9 OH y°A C16H33 H NMR (400 MHz, Mclhanok-M 8 8.29 (s, 1H), 6.49 - 6.41 (m, IH), 5.73 (dd, 6.9, 3.4 Hz, IH), 3 90 (d. J = 12.1 Hz, IH), 3 84 (d, J= 12.1 Hz, IH), 3.17 (s, IH), 3.03 (dt, J= 14.4, 7.3 Hz, IH), 2.63 (ddd, J= 13.8, 6.2, 3.4 Hz, IH), 2.46 (t, J = 7.5 Hz, 2H), 1.75 - 1.57 (m, 3H), 1.33 - 1.28 (m, 25H), 0.92 (t, J = 6.7 Hz, 3H). Cpd # Structure Characterization Data (NMR and LCMS) MS-ESI: m / z no signal observed (M+H)+ 23 nh2 1 v> F^N^N / OH yA C15H31 M NMR (400 MHz, DMSO-7.) 6 8.35 (s, 1H), 7.93 (d, J =38.4 Hz, 2H), 6.31 (t, J =7.2 Hz. 1H), 5.63 - 5.54 (m, 2H), 3.75 - 3.64 (m, 2H), 3.60 (dd, 7= 11.9, 7.1 Hz, 1H), 3.00 (dt,7 = 14.4, 7.3 Hz, 1H), 2.55 - 2.51 (m, 1H), 2.46 - 2.31 (m, 2H), 1.64 - 1.50 (m, 2H), 1.36 - 1.16 (m, 24H), 0.89 -0.81 (m, 3H). MS-ESI: m / z 532.74 observed (MH) 24 nh2 03 F^N^N / ^9 / OH CgHi3 lH NMR (400 MHz, DMSO-76) 8 8.35 (s, 1H), 7.93 (d, J =37.5 Hz, 2H), 6.31 (t, J =7.2 Hz, 1H), 5.64 - 5.54 (m, 2H), 3.74-3.65 (m, 2H), 3.60 (dd, J= 11.9, 7.0 Hz, 1H), 3.00 (dt, J= 14.2, 7.2 Hz, 1H), 2.56 - 2.51 (m, 1H), 2.46 - 2.31 (m, 2H), 1.64 - 1.50 (m, 2H), 1.37 - 1.21 (m, 6H), 0.92 -0.80 (m, 3H). MS-ESI: m / z 406.55 observed (M H) 25 nh2 io F N N 09 / OH Ml H2N-^\. !H NMR (400 MHz, DMSO-76) 5 8.35 (s, 1H), 7.93 (d, 7= 31.1 Hz, 2H), 6.33 (t, 7= 7.0 Hz, 1H), 5.59 (dd, 7= 6.6, 3.8 Hz, 2H), 3.74 - 3.65 (m, 2H), 3.61 (dd, 7=11.9, 6.8 Hz, 1H), 3.20 (d, 7= 5.3 Hz, 1H), 3.09 - 2.99 (m, 4H), 2.00 - 1.92 (m, 1H), 0.93 (d,. / 6.7 Hz, 3H), 0.88 (d, 7= 6.7 Hz, 3H). MS-ESI: m / z 393.52 observed (M+H)+ Cpd # Structure Characterization Data (NMR and LCMS) 26 nh2 7 £> F^hT N / OH mA h2nA MS-ESI: m / z 393.48 observed (MH; 27 nh2 1T> F^hT N rA o HO hl NMR (400 MHz, DMS(W6) 5 8.28 (s, 1H), 7.86 (s, 2H), 6.24 (dd, J= 8.0, 4.0 Hz, 1H), 5.80 (d, J--- 5.4 Hz, 1H), 4.70 (q, J 7.4 Hz, 1H), 4.39 (d, J 11.7 Hz, 1H), 4.09 (d, J = 11.7 Hz, 1H), 3.65 (d.. / 1.0 Hz, 1H), 2.77 (ddd,J- 12.1, 7.2, 4.0 Hz, 1H), 2.47 - 2.43 (m, 1H), 1.94 (s, 3H). MS-ESI: m / z 336.42 observed (M+H)+ 28 nh2 1¾ f^n^n O / °M yA" o HO MS-ESI: m / z 350.49 observed (M+H)+ 29 Ox LL MS-ESI: m / z 364.57 observed (M+H)+ Cpd # Structure Characterization Data (NMR and LCMS) 30 nh2 03 F^bT N           / YA" o HO MS-ESI: m / z 364.49 observed (MH) 31 nh2 m Z F^N^N     \ / c? A yA"7 o h° MS-ESI: m / z 392.48 observed (M H) 32 nh2 A’ o F^hT N_        \ / an H0 MS-ESI: m / z 390.3 observed (M+H)+ 33 nh2 1 T> f^n^n     \ / CW YA"7 o h° MS-ESI: m / z 350.18 observed (M+H)+ 34 nh2 03 F^N^N r? o^rPh yA"17 o h° MS-ESI: m / z 412.43 observed (M+H)+ Cpd # Structure Characterization Data (NMR and LCMS) 35 nh2 F^N^N     t Ao     / ph VA"  0 HO MS-ESI: m / z 426.54 observed (MH; 36 nh2 ) < liv C F^hT N, \ .   \ nA Vv7 o h° % 4-1 NMR (499 MHz, DMS(W6) 8 8.26 (s, 1H), 7.84 (s, 2H), 6.24 (dd, J = 8.0, 4.0 Hz, 1H), 5.78 (d, J= 5.5 Hz, 1H), 5.35 - 5.26 (m, 2H), 4.74 -4.66 (m, 1H), 4.41 (d, J= 11.7 Hz, 1H), 4.09 (d, J = 11.8 Hz, 1H), 3.62 (s, 1H), 2.78 (ddd, J= 13.4, 7.3, 4.0 Hz, 1H), 2.18 (ddt, J =30.6, 15.6, 7.8 Hz, 2H), 1.96 (p, J= 6.2 Hz, 5H), 1.45 - 1.35 (m, 2H), 1.31 - 1.14 (m, 19H), 0.87 - 0.82 (m, 3H). MS-ESI: m / z no signal observed (M+H)+ 37 nh2 w An      j,Ci6H33 Cm HO MS-ESI: m / z 546.67 observed (M+H)+ 38 nh2 m F^hT N 7^o     P15H31 HO SH NMR (400 MHz, DMSO-O 8 8.27 (s, 1H), 7.84 (s, 2H), 6.23 (dd, J= 8.0, 3.9 Hz, 1H), 5.79 (d, J= 4.9 Hz, 1H), 4.70 (q, J= 7.3 Hz, 1H), 4.41 (d, J= 11.7 Hz, 1H), 4.08 (d, J= 11.7 Hz, 1H), 3.63 (s, 1H), 2.78 (ddd, J= 13.3, 7.3, 4.0 Hz, 1H), 2.44 (d, J= 8.0 Hz, 1H), 2.28 - 2.06 (m, 2H), 1.45 - 1.34 (m, 2H), 1.29-1.11 (m, 25H), 0.85 (1,. / = 6.6 Hz, 3H). MS-ESI: m / z no signal observed. (M+H)+ Cpd # Structure Characterization Data (NMR and LCMS) 39 nh2 m F^hC N 7^o     £1^23 HO NMR (500 MHz, DMSO-D) 8 8.26 (s, 1H), 7.82 (s, 2H), 6.24 (dd, J= 8.0, 4.0 Hz, 1H), 5.77 (d, J == 5.4 Hz, IH), 4.70 (id. J 7.7, 5.4 Hz, IH), 4.41 (d, J = 11.8Hz, 1H), 4.09 (d, J= 11.8Hz, IH), 3.61 (s, IH), 2.78 (ddd, .7=== 13.5, 7.3, 4.0 Hz, 1H), 2.48 - 2.43 (m, IH), 2.18 (ddt, J= 30.5, 15.6, 7.8 Hz, 2H), 1.46 - 1.35 (m, 2H), 1.29-1.13 (m, 16H), 0.85 (t, J= 6.9 Hz, 3H). MS-ESI: m / z 476.66 observed (M+H)+ 40 nh2 ID F^hT N 7^0     zC6H13 (X. / h rA 0 h° X NMR (400 MHz, DMSO-X) 6 8.27 (s, IH), 7.84 (s, 2H), 6.24 (dd, J == 8.0, 4.0 Hz, IH), 5.78 (d, J = 5.4 Hz, IH), 4.71 (td, J = 7.8, 5.5 Hz, IH), 4.42 (d, .7=== 11.7 Hz, IH), 4.09 (d. .7=== 11.8 Hz, IH), 3.63 (s, IH), 2.79 (ddd, J= 13.4, 7.3, 4.0 Hz, IH), 2.49 - 2.42 (m, IH), 2,26 - 2,09 (m, 2H), 1.44 - 1.33 (m, 2H), 1.25 - 1.09 (m, 6H), 0.82 (t, J = 7.0 Hz, 3H). MS-ESI: m / z 406.57 observed (M+H)+ 41 nh2 m / F^tc n     "~a r? oa NH2 yA"7 0 h° MS-ESI: m / z. 415.47 observed (M+Na)+ 42 nh2 Ay F^rr N_ Ao 0 A™, YA"7 0 h° % MS-ESI: m / z. 393.32 observed (MH) Cpd # Structure Characterization Data (NMR and LCMS) 43 nh2 H0 MS-ESI: m / z 797.4 observed (M-H)’ 44 "71 \   / I \    f NJ Oy'X, ° xo 0^0 MS-ESI: m / z 562.8 observed (M+H) + 45 z O \_ / I / ) c M >0-0 MS-ESI: m / z 488.6 observed (M+H)+ 46 nh2                  / ~~~\ .w cS N—Z a,°i h° MS-ESI: m / z 488.7 observed (M+H)+ 47 o ^16^33^ J] °A F                 • -7-¾ I Xl ___<\ Y ClsH33 H2N MS-ESI: m / z= 828.4 observed (M-H)' Cpd # Structure Characterization Data (NMR and LCMS) 48 F X     ph / W X / ~\ == \ V. h2nz^\             J N= /             II               ) o'            r MS-ESI: m / z 604.8 observed (M+H) + 49 n \__ / I I           /  \ (Q MS-ESI: m / z 398.5 observed (M+H) + 50 T| /    "D          Y V m xo X MS-1 .SI: m / z 428.3 observed (M+H)’ EXAMPLES Abbreviations The following abbreviations are used: tetrahydro furan (THF), dichloromethane (DCM), Acetonitrile (MeCN), AuV-dimethylformamide (DMF), dimethylsulfoxide (DMSO), trifluoroacetic acid (TFA), triethylamine (TEA), diisopropylethylamine (DIPEA), methanol (MeOH), Ethyl acetate (EtOAc), 4-Dimethylaminopyridine (DMAP), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC®HC1), N,N'-Dicyclohexylcarbodiimide (DCC). General Examples for the Preparation of Compounds of the Invention The starting materials and intermediates for the compounds of this invention may be prepared by the application or adaptation of the methods described below, their obvious chemical equivalents, or, for example, as described in literature such as The Science of Synthesis, Volumes 1-8. Editors E. M. Carreira et al. Thieme publishers (2001-2008). Details of reagent and reaction options are also available by structure and reaction searches using commercial computer search engines such as Scifinder (www.cas.org) or Reaxys (w w w. reaxys. com). Part I: Preparation of Intermediates and EFdA (MK-8591) Example 1 Synthesis of intermediate-A, -B and Compound 1 (EFdA): Intermediate -A (2R3S,5R)-5-(6-amino-2-nuoro-9H-pnrin-9-yI)-2-(((tert-butyMiphenyIsHyI)oxy)methyI)- 2-ethynyltetrahydrofuran-3-yl acetate, A: Intermediate A is prepared according to the reported procedure in the literature (Org. Lett. 2011,13, 5264-5266.). LC-MS (ES1+): m / z 574.19 iM • Hi . NH3 in MeOH (excess) MeOH 25 °C, 12 h Intermediate -B (2R,3S,5R)-5-(6-amino-2-nuoro-9H-pnrin-9-yI)-2-(((tert-butyIdiphenyisiiyI)oxy)methyI)-2-ethynyltetrahydrofuran-3-oI, B: To a solution of intermediate A (500 mg, 0.87 mmol) in MeOH (10mL) was added methanolic ammonia (10mL) at rt and stirred for 12h. The reaction mixture was concentrated under reduced pressure to obtained crude material and the resulting crude material was purified by silica-gel column chromatography using 2% MeOH in DCM to obtain the intermediate B (400 mg, 86.33%). LC-MS (ESI+): m / z 532.4 [M+H] \ 1 (EFdA) (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yI)-2-ethynyI-2-(hydroxymethyI) tetrahydrofuran-3-oI, 1: Compund 1 (EFdA) is prepared according to the reported procedure in the literature (Org. Lett. 2011,13, 5264-5266.). 'HNMR (400 MHz, DMSO-d6) 8 8.30 (s, 1H), 7.86 (d, J = 27.7 Hz, 2H), 6.24 (dd, J = 7.4, 5.0 Hz, 1H), 5.63 - 5.54 (m, 1H), 5.35 - 5.25 (m, 1H), 4.56 (q, J= 6.4 Hz, 1H), 3.67 - 3.60 (m, 1H), 3.60 - 3.49 (m, 2H), 2,74 - 2.63 (m, 1H), 2.46 - 2.36 (m, 1H). LC-MS (ESI+): m / z 294.2 | M H | Part II: Preparation of Example Compounds (2R,3S,5R)-5-(6-ammo-2-fluoro-9H-purin-9-yl)-2-ethynyI-2-((isobutyryloxy)methyl) tetrahydrofuran-3-yI isobutyrate, 2: To a mixture of EFdA (3 g, 6.8 mmol, 1 equiv.), DMAP (499 mg, 2.73 mmol, 0.4 equiv.) in anhydrous DMF (100 mb) was added isobutyric acid (8.4 g, 27.3 mmol, 6 equiv.) dr op wise at ambient temperature. The reaction stirred for 5 h at rt. The reaction is monitored by LCMS due to the occasional alkylation of NH2 group observed for elongated reaction time. The reaction mixture was then filtered to remove byproduct urea. Acetonitrile was used to rinse the reaction mixture. Thereafter, the reaction was 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%% EtOAc in Hexanes to obtain the compound 2 as a glassy solid. The obtained solid was dispersed in minimum amount of isopropanol followed by its rotatory evaporation to obtain pure compound as a white solid (2.5 g, 85% yield). LC-MS (INI ): m / 434.49 | M l H Example 3 DMAP (0.2 equiv) TEA (8 equiv) MeCN, r.t., 5h (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yI)-2-(((2-ethyIbutanoyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl 2-ethyIbutanoate, 3: To a mixture of EFdA (1 g, 3.4 mmol, 1 equiv.), 2-ethylbutanoic anhydride (4.4 g, 20.4 mmol, 6 equiv.), TEA (3.8 ml, 27.2 mmol, 8 equiv.) in anhydrous MeCN (43 mL) and cooled to 0 °C was added DMAP (83 mg, 0.68 mmol, 0.2 equiv.) at 0 °C. The reaction stirred for 0.5 h at 0 °C and then to 5 h at rt. The reaction is monitored by LCMS due to the occasional alkylation of NH2 group observed for elongated reaction time. The reaction was further quenched with methanol and solvent was evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using 60-70%% EtOAc in Hexanes to obtain the compound 3 as a glassy solid. The obtained solid was dispersed in minimum amount of isopropanol followed by its rotatory evaporation to obtain pure compound as a white solid (1.33 g, 80% yield). LCMS (ESI+): m / 490.56 | M • H i Example 4 NH2 (2R,3S,5R)-5-(6-aminQ-2-fIuoro-9H-purm-9-yI)-2-(((cydopentmiecarbmiyI)oxy)methyI)-2-ethynyltetrahydrofuran-3-yI cydopentanecarboxylate, 4: Compound 4 was prepared by using the procedure followed for the compound 2. LC-MS (ESI+): m / z 486.44 [M+H]+. Example 5 EFdA (6 equiv) DMAP (0.2 equiv) TEA (8 equiv) MeCN, r.t., 3h (2R,3S,5R)-5-(6-ammo-2-fluoro-9H-purm-9-yI)-2-ethynyI-2-((2-phenyIaeetoxy)methyI) tetrahydrofuran-3-yl 2-phenylacetate, 5: To a mixture of EFdA(499 mg, 1.7 mmol, 1 equiv.), 2-phenylacetic anhydride (2.6 g, 10.2 mmol, 6 equiv.), TEA (1.9 ml, 13.6 mmol, 8 equiv.) in anhydrous MeCN (22 mL) and cooled to 0 °C was added DMAP (42 mg, 0.34 mmol, 0.2 equiv.) at 0 °C. The reaction stirred for 0.5 h at 0 °C and then to 3 h at ri. The reaction is monitored by LCMS due to the occasional alkylation of NH2 group observed for elongated reaction time. The reaction was further quenched with methanol and solvent was evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using 60-70%% EtOAc in Hexanes to obtain the compound 5 as a glassy solid. The obtained solid was dispersed in minimum amount of isopropanol followed by its rotatory evaporation io obtain pure compound as a white solid (694 mg, 77% yield). LC-MS (ESI+): m / z 530.52 [M+H]+. Example 6 6 (2R,3S,5R)-5-(6-amino-2-fluoro-9H-pimn-9-yi)-2-ethynyI-2-((((S)-2-phenylpropanoyl)oxy) methyI)tetrahydrofuran-3-yI (S)-2-phenyIpropanoate, 6: Compound 6 was prepared by using the procedure followed for the compound 2 with following differences: a) 4 equiv of corresponding acid used instead of 6; b) After remove urea via filtration, the solvent was evaporated under reduced pressure and resulting white solid was then suspended in minimum amount of isopropanol and stirred for an hour. The suspension was then filtered to obtain pure compound as a white solid in 75 % yield. LC-MS (ESI+): m / z 558.65 [M+H]+. Example 7 Ph (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purhi-9-yI)-2-((benzoyIoxy)methyI)-2-ethynyI tetrahydrofuran-3-yl benzoate, 7: Compound 7 was prepared by using the procedure followed for the compound 2 using 4.5 equiv of corresponding acid, LC-MS (EST+): m / z 502.41 [M+H]+. Example 8 EDC HCI (4 equiv.) DIPEA (4 equiv.) DMAP (10mol%) EFdA DMF 0 °C to 25 °C 8 h 8 (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-((((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13916,19-hexaenoyi)oxy)methyI)-2-ethyiiyItetrahydrofiiran-3-yI (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate, 8: To a mixture of EFdA (117 mg, 0.4 mmol, 1 equiv.), Docosahexaenoic Acid (0.39 g, 1.2 mmol, 3 equiv.), DMAP (4.9 mg, 0.04 mmol, 0.1 equiv.), EDOHC1 (307 rag, 1.6 mmol, 4 equiv.) in anhydrous DMF (4 mL) and cooled to 0 °C was added DIPEA (0.3 mL, 1.6 mmol, 4 equiv.) at 0 °C. The reaction stirred for 8 h at ri. The reaction is monitored by LCMS due to the occasional alkylation of NH2 group observed for elongated reaction time. Thereafter, the reaction was diluted with EtOAc and washed thrice with 2.5% NaCl, thrice with buffer pH~7 solution 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 5% DCM in MeOH to obtain the compound 8 as gel-like semi solid (183 mg, 50% yield). LC-MS (ESI+): m / z 457.23 i M 2 H P . Example 9 C16H33 9 (2R,3S,5R)-5-(6-ammo-2-fluoro-9H-purin-9-yI)-2-ethynyI-2-((heptadecanoyIoxy)methyi) tetrahydrofuran-3-yi heptadecanoate, 9: Compound 9 was prepared by using the procedure followed for the compound 2 using 8 equiv of corresponding acid and 6 equiv of DCC. !H NMR (400 MHz, Chloroform-^ / ) 5 7.92 (s, 1H), 6.40 (t, J = 6.4 Hz, 1H), 5.76 (brs, 2H), 5.65 (dd.. / 7.1,5.3 Hz, 1H), 4.49 (d,. / 12.0Hz, 1H), 4.38 (d., / 12.1 Hz, 1H), 2.99 (dt,. / 13.5, 6.7 Hz, 1H), 2.75 - 2.64 (m, 2H), 2.41 (t, J= 7.5 Hz, 2H), 2.34 (q, J= 3.8 Hz, 1H), 1.71 - 1.57 (m, 9H), 1.41-1.17 (m, 48H), 0.88 (t, J = 6.8 Hz, 6H). LC-MS (ESI+): m / z no signal observed. Example 10 EFdA 10 (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purhi-9-yI)-2-ethynyI-2-((paImitoyIoxy)methyI) tetrahydrofuran-3-yl palmitate, 10: To a flask containing EFdA (202 mg, 0.7 mmol, 1 equiv.) was added anhydrous pyridine (7 mL). The mixture was stirred for 1-2 min and cooled to 0 °C. To this mixture was added palmitoyl chloride (1.3 mL, 4.2 mmol, 6 equiv.) dropwise ai 0 °C. The reaction stirred for overnight at rt. The reaction is monitored by LCMS due to the occasional alkylation of NH2 group observed for elongated reaction time. Thereafter, the reaction was diluted with EtOAc and washed thrice with water, once with NaHCO? 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%% EtOAc in Hexanes to obtain the compound 10 as a glassy solid. The obtained solid was dispersed in minimum amount of isopropanol followed by its rotatory evaporation to obtain pure compound as a white solid (372 mg, 70% yield). NMR (400 MHz, DMSO-O 8 8.34 (s, 1H), 7.91 (d, J= 30.8 Hz, 2H), 6.34 (t, J= 6.9 Hz, 1H), 5.70 (t, J=6.4Hz, 1H), 4.39 (d, J= 11.6Hz, 1H), 4.22 (d, J= 11.9 Hz, 1H), 3.81-3.73 (m, 1H), 3.14 (dt, J= 14.1, 6.9 Hz, 1H), 2.60 (dt, J= 12.9, 6.0 Hz, 1H), 2.39 (td, J= 7.3, 2.4 Hz, 2H), 2.32 - 2.17 (m, 2H), 1.64 - 1.52 (m, 2H), 1.51 - 1.39 (m, 2H), 1.38 - 1.11 (m, 48H), 0.92 -0.78 (m, 6H). LC-MS (ESI+): wzno signal observed. Example 11 (2R3S,5R)-5-(6-ammo-2-fkwro-9H-purin-9-yI)-2-ethynyl-2-((heptanoyIoxy)methyI) tetrahydrofuran-3-yl heptanoate, 11: Compound 11 was prepared by using the procedure followed for the compound 2 using 8 equiv of corresponding acid and 6 equiv of DCC. LCMS (ESI+): m / z 518.25 |M ■ H| . Example 12 ((2R,3S,5R)-3-((D-vaIyI)oxy)-5-(6-amino-2-fIuoro-9H-purin-9-yI)-2-ethynyitetrahydrofiiran-2-yl)methyl D-vaiinate, 12: Compound 12 was prepared by using the procedure followed for the compound 2 using 7 equiv of corresponding boc protected amino acid and 7 equiv of DCC followed by typical deprotection of Boc group using HC1 in dioxane. LC-MS (ESI+): m / z 492.64 | M H | . Examples 13-15 Compounds 13-15 were prepared by using the procedure followed for the compound 12. Examples 16-23 Compounds 16-23 were prepared by using the procedure followed for the compound 24 described below in Example 24. Example 24 O 0 (2 equiv) DIPEA (5 equiv) DMAP (0.2 equiv) intermediate B MeCN 0 °C - rt, 12 h intermediate C 24 (2R,3S,5R)-5-(6-amino-2-fIuoro-9H-purin-9-yI)-2-ethynyI-2-(hydroxymethyI)tetra hydrofuran-3-yi heptanoate, 24: Step-1: To a solution of intermediate B (400 mg, 0.75 mmol, 1 equiv.) in anhydrous MeCN (12 mL) was added DIPEA (0.6 mL, 3.77 mmol, 5 equiv.) and DMAP (18.4 mg, 0.15 mmol, 0.2 equiv.). To this stirrd solution at 0 °C was added dropwise heptanoic anhydride (365 mg, 1.5 mmol, 2 equiv.) in MeCN (5 mL). The resulting mixture was then stirred at rt for 1 h. The reaction is monitored by LCMS. After completion of reaction, reaction mixture was quenched in ice cold water (20ml) and was extracted with ethyl acetate (3 X 20 mL). The combined organic layer was dried, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using 1.5% DCM in MeOH to obtain the intermediate C (430 mg, 88.8% yield). LC-MS (ESI+): m / z 645.00 [M+H]+. Step-2: To a solution of intermediate C (430 mg, 0.67 mmol, 1 equiv.) in anhydrous MeOH (5 mL) was added NH4F (495 mL, 13.35 mmol, 20 equiv.). The resulting mixture was then stirred at rt for 12 h. The reaction is monitored by LCMS. After completion of reaction, reaction mixture was quenched in ice coid water (20ml) and was extracted with ethyl acetate (3 X 20 mL). The combined organic layer was dried, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using 2.5% DCM in MeOH to obtain the compound 24 as an off-white solid (187 mg, 69.1% yield). LC-MS (ESI+): m / z 406.55 [M+HJ+. Note: If reaction not completed after 12h stirring at rt then stirred for additional 2 h at 60 °C for other compounds including compound 24. Examples 25-26 Compounds 25-26 were prepared by using the procedure followed for the compound 24 described above in Example 24. Examples 27-38 Compounds 27-38 were prepared by using the procedure followed for the compound 39 described below in Example 39. Example 39 EFdA                                            39 ((2R,3S,5R)-5-(6-ammo-2-Huoro-9H-purin-9-yI)-2-ethynyI-3-hydroxytetrahydrofuran-2-yl)methyl dodecanoate, 39: To a flask containing EFdA (997 mg, 3.4 mmol, 1 equiv.) was added anhydrous pyridine (34 mL). The mixture was stirred for 1-2 min and cooled to 0 °C. To this mixture w?as added lauroyl chloride (2.0 mL, 8.5 mmol, 2.5 equiv.) dropwise at 0 °C. The reaction stirred for overnight at rt. The reaction is monitored by LCMS due to the occasi onal alky lation of NH2 group observed for elongated reaction time. Thereafter, the reaction was diluted with EtOAc and washed thrice with waler, once with NaHCO- and once with brine and then the solvent wzas dried, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using using 1.5% DCM in MeOH to obtain the compound 39 as an off-white solid (1.0 g, 65% yield). LC-MS (ESI+): m / z 476.66 [M+H]+. Examples 40-42 Compounds 40-42 were prepared by using the procedure followed for the compound 39 described above in Example 39. Examples 43-50 Compound 43 can be prepared by using the procedure followed for the compound 39 using the acid chloride of known acid dihexadecylglycine. Compound 44 can be prepared by the reaction between EFdA and the corresponding chloroformate in the pyridine as the solvent. Compounds 45-50 can be prepared following procedures similar to those of the other examples described herein. Synthesis of Stable Crystalline Forms Example 51 Compound 2 (~200 mg) was completely dissolved in minimum quantity of acetone with stirring. This was followed by slow evaporation of the solvents at ambient temperature. This resulted in a recrystallized sample as a white powder. Other solvents including EtOAc, MeOH and THF can also be used. General Examples for the formulation of Compounds of the Invention All formulation protocols generated a stable aqueous suspension with 26-gauge syringeability. Example 52 Compound 1 (EFdA) was grinded and sieved through #80. 300 mg of 1 was taken in suitable container and a solution of preformed 0.25% sodium carboxymethyl cellulose (Sodium CMC) and 0.1% poly oxy ethlene (20) sorbitan monooleate (TWEEN-80) was added to obtain 1 gram (300 mg of 1 + -700 mg of polymer solution) of the final formulation (300 mg / g). The suspension was then bath sonicated for 10 min in an Ice bath. The density of formulation of is 1,064 g / mL. Henceforth, the above formulation suspension will be 319.2 mg / mL concentration of compound 1 (EFdA). Example 53 Recrystallized Compound 2 was grinded and sieved through #80. 250 mg of 1 was taken in suitable container and a solution of preformed 0.25% Sodium CMC and 0.1% TWEEN-80 was added to obtain 1 gram (250 mg of 1 + -750 mg of polymer solution) of the final formulation (~ 250 mg / g). The suspension was then probe sonicated 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 54 Compound 3 was grinded and sieved through #80. 250 mg of 3 was taken in suitable container and a solution of preformed 0.25% Sodium CMC and 0.5% TWEEN-80 was added to obtain 1 gram (250 rng of 3 + -750 mg of polymer solution) of the final formulation (250 mg / g). The suspension was then probe sonicated 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 formulation of is 1.004 g / mL. Henceforth, the above formulation suspension will be 250.88 mg / mL. concentration of compound 3 (~ 150 mg / mL of EFdA). Example 55 Compound 5 was grinded and sieved through #80. 200 mg of 5 was taken in suitable container and a solution of preformed 0.25% Sodium CMC and 0.5% TWEEN-80 was added to obtain 1 gram (200 mg of 5 + -800 mg of polymer solution) of the final formulation (~ 200 mg / g). The suspension was then probe sonicated for 5 mm in an ice bath (Sonication time: 5 min; Pulse Amplitude: 20; Pulse on Time: 30 sec; Pulse off time: 20 sec). The density of formulation of is 1.047 g / mL. Henceforth, the above formulation suspension will be 209.4 mg / mL concentration of compound 5(- 115.97 mg / mL of EFdA). Pharmacokinetic Studies 1. Animals Animals (Male SD rats ~ 200-250 g and Male rhesus macaques ~2-3 kg) were obtained from an approved vendor (SLAC Laboratory Animal Co. Ltd., Shanghai, China and / or Topgene Biotechnology, Wuhan city, Hubei Province, China), Acclimation / Quarantine: Following arrival, animals were assessed as to their general health by a member of the veterinary staff or other authorized personnel. Animals were acclimated for at least 3 days before being placed on study. Animal Husbandry: Animals were group housed during acclimation and individually housed during the study. The animal room environment will be controlled (target conditions: temperature 18 to 26°C, relative humidity 30 to 70%, 12 hours artificial light and 12 hours dark). Temperature and relative humidity were monitored daily. Animal Cannulation: No. Animals were fasted at least 12 hours prior to the administration. All animals had access to Certified Rodent and non-Rodent Diet (Catalog # M01-F, SLAC Laboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours post dosing. Water was autoclaved before provided to the animals ad libitum. Periodic analyses of the water was performed and the results archived. There are no known contaminants in the diet or water that, at the levels of detection, is expected to interfere with the purpose, conduct or outcome of the study. 2. Dose Formulation SC Formulation: The formulations were prepared according to the procedure given in Examples 52-55 and Table 2-4. The formulations were prepared on the day of dosing. Animals were dosed within four hours after the formulation is prepared. Two 20 pL aliquots of each formulation were removed from each of the formulation solutions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and run dose validation by LC / UV or LC-MS / MS. 3. Dose Administration For SC dosing, the dose formulation was administered via subcutaneous injection following facility SOPs. 4. Sample Collection Approximately 200 pL blood was collected from saphenous vein at each time point for rats and 0.5 mL for rhesus macaques. All blood samples were transferred into microcentrifuge tubes containing 4pL of K2EDTA (0.5M) as anti-coagulant and placed on wet ice until processed for plasma. 5. Blood / PIasma processing Blood: Blood samples were processed for plasma by centrifugation at approximately 4 °C, 3000 g 15 min within half an hour of collection. Plasma samples was stored in polypropylene tubes, quick frozen over dry ice and kept at -70±10 °C until LC / MS / MS analysis. 6. Sample Analysis Dose formulation concentration verification 8 Aliquots of the formulations were collected in the middle position of each dose formulation in duplicate 8 The concen trations of the test compound in dose formulation samples were determined by the LC / UV or LC / MS / MS method Bioanalytlcal method and sample analysis B LC-MS / MS methods for the quantitative determination of test compound in corresponded biological matrix was developed under non-GLP compliance. s A calibration curve with 8 non-zero calibration standards was applied for the method including LLOQ. 5 A set of QC samples consisting of low, middle, and high concentration was applied for the method. a The study sample analysis will be performed concurrently with a set of calibration standards and two sets of QC samples using the LC-MS / MS method (If sample numbers were more than 48, then two calibration curves with 2 sets of QC samples were applied). = Acceptance criteria: Linearity; a minimum of 6 calibration standards was back calculated to within ±20% of their nominal values in plasma Accuracy: A minimum of 4 out of 6 QC samples was back calculated to within ±20% of their nominal values in plasma. Specificity: The mean calculated concentration in the single blank matrix should be 0.5 times the LLOQ. Sensitivity: the LLOQ will be tried to target 1~3 ng / mL. Carry over: the mean calculated carry -over concentration in the single blank matrix immediately after the highest standard injection should be £ LLOQ. If the carry'over couldn’t meet the criteria, then the percent of carry'over should be estimated following in-house bioanalytical SOP. 7. Data Analysis Plasma concentration versus time data was analyzed by non-compartmental approaches using the Phoenix WINNONLIN 6.3 software program. Cmax, Tmax, Ty2, AUC(o-t), AUC(o-mf), MRT(0. ¢,, MRT(o-inf), %F and graphs of plasma concentration versus time profile were reported. Example 56 Several prodrugs including EFdA (1) as a control were subjected to a single dose rat PK studies via subcutaneous route of administration. All were injected with equivalent doses of 10 mg / kg and concentration of 4 mg / mL of EFdA as an aqueous suspension formulation derived from 0.5% CMC-Na and 0.5% TWEEN-80. While similar exposure was observed, all prodrugs 2, 3 and 5 exhibited plasma levels of EFdA above LLOQ for more than a week with Cmax much lower than EFdA itself. Table 2 shows the rat PK data for compounds 1, 2, 3 and 5 following SC administration at 10 mg / kg equivalent dose of EFdA. The data are shown in graphic form is shown in Figure 10. Table 2 SC Comp 1 (EFdA) SC Comp 2 SC Comp 3 SC Comp 5 Dose of EFdA (mg / kg) 10 10 10 10 Concentration of EFdA (mg / kg) 4 4 4 4 Formulation 0.5% CMC- Na / 0,5%TWEEN- 80 0.5% CMC- Na / 0.5%TWEEN-80 0.5% CMC- Na' 0.5%TWEEN- 80 0.5% CMC- Na' 0.5%TWEEN- 80 Tv2 (h) 1.3 :02 17 ± 4 NA 12 ±4 MRTo-iast (h) 1.6 ± 0.1 12± 1.2 20 ±4 13 ± 3 Tmax (h) 0.5 2± 1.1 4 ±2.3 7± 0 Cmai (nM) 11548± 3173 1795 ±337 287±177 968 ± 374 AUCo-jaSi (nM“h) 22528 ± 1680 19771±1219 6475 ± 2909 18516 ±4409 AUC0.inf(nM*h) 23235 ± 2000 22745 ± 748 NA 19993 ± 3525 Example 57 After a series of formulation optimization, SC rat PK studies were performed again with high equivalent dose of 100 mg / kg at high equivalent concentration of 120 mg / mL and 319 mg / mL of EFdA for prodrug 3 and EFdA respectively. Prodrug 3 provides a delayed and 100-fold lower Cmax than EFdA. Enhanced half life and mean residence life were also observed in case of prodrug 3 making it suitabl e for prophylaxis. Table 3 shows the rat PK data for compounds 1 and 3 following SC administration at 10 mg / kg and 100 mg / kg equivalent dose of EFdA at high concentration formulation. The data are shown in graphic form in Figure 11. Table 3 SC Comp 3 SC Comp 3 SC Comp 1 (EFdA) SC Comp 1 (EFdA) Dose of EFdA (mg / kg) 10 100 100 10 Formulation 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 Ti / 2 (h) NA 474+ 168 53 + 8 1.3 + 0.2 MRTo-iast (h) 20 + 4 456+ 17 59 + 20 1.6 + 0.1 Tmax (h) 4 + 2.3 312 + 0 1 ± 0 0.5 Cmax (nM) 287 ±177 66 + 21 7429+ 1584 11548 + 3173 AUCo-ia* (nM*h) 6,475 ± 2909 38306+ 101 156462+ 19 22528 ± 1680 AUC0.inf(nM*h) NA 52531 + 39 156462+ 19 23235 ± 2000 Example 58 After rat PK analysis, the focus was shifted to non-rodents i.e. rhesus macaque. Prodrug 5 and EFdA were subjected to a single dose rhesus macaque PK studies via subcutaneous route of administration with equivalent doses of 50 mg / kg of EFdA. The aqueous suspension formulations were derived from 0.25% CMC-Na and 0.1% / 0.5% TWEEN-80 with equivalent concentration of 116 mg / mL and 319 mg / mL of EFdA for prodrug 5 and EFdA respectively. Prodrugs 5 exhibited plasma levels of EFdA above LLOQ for more than a month with 24-fold lower Cmax than EFdA itself. Table 4 shows the Rhesus PK data for compounds 1 and 5 following SC administration at 50 mg / kg equivalent dose of EFdA at high concentration formulation. The data are shown in graphic form in Figure 12. 2020346908   08 Jun 2026 Table 4 SC Comp 1 (EFdA) SC Comp 5 Dose of EFdA (mg / kg) 50 50 Formulation 0.25% CMC-Na / 0.1%TWEEN-80 0.25% CMC-Na / 0.5%TWEEN-80 Conc of EFdA (mg / mL) 319 116 T1 / 2 (h) 69 ± 14 ND MRT0-last (h) 76 ± 36 350 ± 25 Tmax (h) 4 ± 3.6 264 ±125 Cmax (nM) 3060±1058 128 ± 52 C28days (nM) 1.4 ± 0.3 73 ± 29 AUC0-last (nM*h) 135294±22629 61934±27834 AUC0-inf (nM*h) 135429±22675 ND Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. A compound, which is:, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is3.     A compound, which is:, or a pharmaceutically acceptable salt thereof.2020346908   08 Jun 20264     The compound of claim 3, wherein the compound is5.     A compound, which is:, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein the compound is7.     A pharmaceutical composition comprising the compound of any one of claims 1to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.2020346908   08 Jun 20268.     A method for treating or preventing human immunodeficiency virus (HIV) in apatient, comprising administering to the patient an effective amount of the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the method comprises treating HIV infection.

10. The method of claim 8, wherein the method comprises preventing HIV infection.

11. Use of a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing human immunodeficiency virus (HIV) in a patient.

12. The use of claim 11, wherein the medicament is for treating HIV infection.

13. The use of claim 11, wherein the medicament is for preventing HIV infection.

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