WO2025207435A1 - 2'-fluoro-6'-methylene carbocyclic nucleos(t)ides as potent antiviral agents for the treatment of wild-type and mutant hepatitis b virus (hbv) infections - Google Patents

Abstract

2'-Fluoro-6'-methylene-carbocyclic adenosine (FMCA, 21) and its phosphoramidate prodrug (FMCAP, 31) have demonstrated potential anti-HBV activity against both adefovir- resistant as well as lamivudine-resistant double (rtL180M/rtM204V) mutant hepatitis B virus (HBV). In addition, in vitro, these molecules have reinstated a significant activity against lamivudine/entecavir triple mutants (L180M+S202G+M204V). This invention is directed to compounds, pharmaceuticals and methods of treating HBV infections, especially including infections caused by resistant and multiple resistant HBV. Pursuant to the present invention, a complete structure-activity relationship (SAR) of 2'-fluoro-6'-methylene-carbocyclic derived nucleos(t)ides has been evaluated and that analysis is presented herein. Pursuant to the present invention, the synthesis and antiviral evaluation of purine and pyrimidine-derived nucleosides have been reported against wild-type and various HBV mutants. Guanosine analog (FMCG, 25) demonstrated an EC₅₀ value of 0.217μM and cytosine analog (FMCC, 41) expressed a potent EC50 value of 0.0025 μM compared to entecavir (EC50 = 0.0029) against wild-type HBV. Additionally, FMCC (41) maintains its antiviral potency against various HBV mutants. Furthermore, chiral pure FMCAP Sp (34) isomer demonstrated an EC₅₀ value of 1.3 nM and was more potent against several HBV mutants than entecavir.

Description

2ʹ-Fluoro-6ʹ-Methylene carbocyclic Nucleos(t)ide as Potent Antiviral Agents for the Treatment of Wild-Type and Mutant Hepatitis B Virus (HBV) Infections [0001] Field of the Invention [0002] The present invention relates to nucleoside compounds, including prodrug forms/ nucleotides and pharmaceutical compositions, that evidence unexpected enhanced activity for the treatment of Hepatitis B Virus (HBV) infections, including chronic HBV infections and infections caused by drug-resistant and multiple drug-resistant strains of HBV. [0003] Related Applications [0004] This application claims the benefit of priority of United States provisional applications serial numbers US63/569,280, filed March 25, 2024 and US63/722,659, filed November 20, 2024, both of which applications are incorporated by reference in their entirety herein. [0005] Background of the Invention [0006] Chronic hepatitis B (CHB) is still a leading cause of hepatocellular carcinoma (HCC). Although vaccines are preventative, no available therapeutics are effectively curative for CHB patients. The chronic infection of hepatitis B virus (HBV) is highly progressive and variable in different continents of the globe. Annually, HBV chronically infects 296 million people worldwide and causes approximately 820 thousand deaths due to cirrhosis.¹ The co- infection of HBV in immunocompromised and human immunodeficiency virus (HIV) infected patients is worrisome, and it enhances the cause of death.2 To manage the HBV infection, the use of conventional pegylated interferon limits the growth of virus at meager rates along with severe side effects.3 Several nucleoside/nucleotide drugs, such as lamivudine (3TC), adefovir dipivoxil (ADV), tenofovir (TDF), and entecavir (ETV), have been approved for the treatment of CHB (See FIGURE 1).4 These drugs exclusively target the viral DNA polymerase and inhibit viral replication. [0007] Additionally, clinically approved nucleos(t)ide analogs (NAs) effectively reduce HBV viral load with minimum side effects.5 However, the long-term administration of antiviral drugs promotes HBV mutations, which causes potential drug resistance.6 HBV mutations lead to impending challenges for the cure of CHB.7 [0008] Mutation in HBV alters the DNA polymerase domain and inhibits the interaction of approved nucleoside drugs with DNA polymerase, which reduces the inhibitory effect of drugs on the synthesis of HBV DNA.8 The primary mutational reactivation of the virus facilitates a double and triple mutation to retain the mutated viral population in chronic patients.9 Due to the high cross-resistance risks, managing the pre-existing antiviral resistance is more challenging. Initially, over a period of lamivudine (LMV) therapy, lamivudine- resistant HBV (LVDr) was observed in a significant number of patients.10 Studies have shown that LMV expresses a very low resistance barrier; 23% of patients developed LMV- resistant mutation after 12 months, and 80% of patients developed LMV resistance after 5- year treatments.11 Adefovir dipivoxil (ADF) demonstrates good activity against LMV- resistant; however, after 5 years of therapy, a 30% resistance rate was observed for ADV.12, 13 Currently, entecavir and tenofovir are the most prescribed drugs for HBV treatment.14 ETV expressed superior activity against ADF and LMV drug resistance.1516 Additionally, tenofovir demonstrates an effective antiviral activity against CHB. However, recently, it has been reported that long-term uses of entecavir promote double and triple mutations in the polymerase, and HBV develops resistance to ETV.17, 18 Also, the clones harboring rtA194T mutation showed partial resistance to tenofovir.19 To overcome these problems, combination therapies are in practice, but HBV progressively altered mutations still remain as a threat.20 Therefore, optimally designed NAs are in urgent need to treat drug-resistant HBV. [0009] In search of a better anti-HBV nucleoside agent, earlier, the inventors reported 2′- fluoro-6′-methylene carbocyclic adenosine (FMCA, 21) and its phosphoramidate prodrugs (FMCAP, 31, FIGURE 2) against the drug-resistant HBV. FMCA expressed potential anti- HBV activities against adefovir, as well as lamivudine drug-resistant mutants double (rtL180M/rtM204V) in vitro.21 Furthermore, FMCA (21) demonstrated superior activity in vitro against lamivudine/entecavir triple-resistant mutant (L180M+S20G+M204V) in comparison to lamivudine and entecavir.22 [0010] To increase the cellular bioavailability and cellular uptake of FMCA (21) and to cross the first rate-limiting step of mono phosphorylation, a phosphoramidate prodrug approach was adopted. Phosphoramidate prodrug FMCAP (31) was synthesized via FMCA (21).23 Prodrug FMCAP (31) demonstrated an enhanced anti-HBV activity compared to parent molecule FMCA (21) without elevated cellular toxicity.22 Often, nucleoside analogs are associated with mitochondrial toxicity, which sometimes turns into a significant roadblock for the development of nucleoside analogs as drugs. FMCA (21) had also been examined for potential mitochondrial toxicity via measuring the release of lactic dehydrogenase in HepG2 cells and was found nontoxic up to 100µM.22, 24 Also, in vivo, preliminary studies show that in chimeric mice having the lamivudine/entecavir triple mutant, FMCA (21) reduces HBV viral load, whereas entecavir was found ineffective. In female NOD/SCID mouse models, these molecules showed a higher rate of liver HBV DNA levels reduction than entecavir.25 [0011] After these findings, it was our keen interest to evaluate the complete structure- activity relationship (SAR) of 2ʹ-fluoro-6ʹ-methylene carbocyclic driven nucleos(t)ide analogs. Herein, the inventors described the synthesis and antiviral evaluation of 2ʹ-fluoro-6ʹ- methylene carbocyclic purine and pyrimidine analogs. In purine derivatives, 6-N-methyl analog of FMCA (22), guanosine analog (FMCG, 25), and 6-N-methyl prodrug of guanosine analog (26) have been reported. To enhance the cellular uptake and overcome the mono phosphorylation rate-limiting step, the synthesis and antiviral evaluation of phosphoramidate prodrug of purine analogs have also been reported against wild-type as well as drug-resistant HBV. In the case of pyrimidine analogs, synthesis and antiviral evaluation of uracil (39) and cytosine (41) analogs have been described. [0012] Brief Description of the Invention [0013] In an embodiment, the present invention is directed to compounds according to the chemical structure: ; Wherein NB is a nucleoside base moiety according to the structure: or Y is CH or N; Each R_c is independently H, OH, CN, nitro, C₁-C₄ alkyl, which is optionally substituted with CN, nitro or from 1-3 OH or halo groups, preferably a CF₃ group, halo (F, Cl, Br or I), - (CH₂)_n-CH=CHR_a, -(CH₂)_n-C≡C-R_b, or -(CH₂)_n-phenyl which is optionally substituted anywhere on the phenyl ring with OH, CN, or C₁-C₄ alkyl, which is optionally substituted with from 1-3 OH or halo groups, preferably a CF₃ group; Each n is an integer from 0-3, preferably 0 or 1; R_a is H, OH, halo or C₁-C₄ alkyl, which is optionally substituted with from 1-3 OH or halo, preferably F groups; R_b is H, OH, halo, or C₁-C₄ alkyl, which is optionally substituted with from 1-3 OH or halo, preferably F groups; R₁ is NH₂, NHCH₃, OH, SH or O; R₂ is H when R₁ is NH₂ or NHCH_3; R₂ is NH₂ when R₁ is OH or O; R₃ is NH₂, NHCH₃, OH, SH or O; R_N is absent when R₁ or R₃ is NH_2, NHCH₃ or OH; or R_N is H when R₁ and R₃ are O (O forms a double bond with the carbon atom to which it is bonded and the bond between the carbon atom and nitrogen atom is a single bond); and R1 is H or is a phosphoramidate group moiety according to the structure: A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. [0014] In embodiments of compounds set forth above, Y is N and X is N. [0015] In embodiments of compounds set forth above, R₁ is NH₂ or O, R_N is H when R₁ is O and R_N is absent when R₁ is NH₂. [0016] In embodiments of compounds set forth above, R₂ is H when R₁ is NH₂ or NHCH₃; often NH₂. [0017] In embodiments of compounds set forth above, R₂ is NH₂ when R₁ is O. [0018] In embodiments of compounds set forth above, R_N is absent when R₃ is NH₂. [0019] In embodiments of compounds set forth above, R_N is H when R₃ is O. [0020] In embodiments of compounds set forth above, R¹ is H. [0021] In embodiments of compounds set forth above, . [0022] In embodiments of compounds set forth above, R¹ is . [0023] In embodiments of compounds set forth above, . [0024] In embodiments, the compound . [0025] In embodiments, the compound racemic). [0026] In embodiments, the compound FMCAP, chiral pure). [0027] In embodiments, the compound is (rp FMCAP, chiral pure). [0028] In embodiments, the compound . (FMCGP). [0030] In embodiments, the compound (rp FMCGP). [0031] In embodiments, the compound is (sp FMCGP). [0032] In embodiments, the compound . [0033] In embodiments, the compound is (FMCCP). [0034] In embodiments, the compound is (sp FMCCP). [0035] In embodiments, the compound is (rp FMCCP). [0036] In embodiments, the compound is (FMCU). [0037] In embodiments, the compound is (FMCUP). . [0038] In embodiments, the compound (sp FMCUP). [0039] In embodiments, the compound is (rp FMCUP). [0040] In embodiments, the compound (FMCRibavirin). [0041] In embodiments, the compound (FMCRP). [0042] In embodiments, the compound (spFMCRP). [0043] In embodiments, the compound is (rpFMCRP). [0044] In embodiments, the present invention is directed to a pharmaceutical composition comprising an effective amount of at least one compound as described and set forth above in combination with a pharmaceutically acceptable carrier, additive or excipient. These compositions find particular use in the treatment of HBV infections, including wild-type, drug resistant and multiple drug resistant infections (resistant to one or more of lamivudine, adefovir and entecavir, among others as presented herein). In addition, compounds and pharmaceutical compositions according to the present invention find use in the treatment of disease states and conditions which occur secondary to HBV infection, including cirrhosis and hepatocellular cancer. [0045] In embodiments, drug resistant and multiple drug resistant infections include HBV strains rtM204V, rtM204I, rtL180M, rtLM/rtMV (which is a double mutant of rt180M/rtM204V), rtN236T, L180M+S202G+M204V (an entecavir mutant), and especially double and triple drug resistant mutants rL180M/T184L/M204V, rtV173L/L180m/M204V, rtL180M/T184L/M204V/A200V and rtL180Q/M204V/N238H/L2691, among others. The compounds according to the present invention are particularly useful alone or in combination with traditional anti-HBV agents including lamivudine, entecavir, telbivudine, tenofovir disoproxil, tenofovir alafenamide, adefovir, interferon alpha, pegylated interferon or a mixture thereof. [0046] In embodiments, the present invention is also directed to the chemical synthesis of one or more compounds according to the present invention as otherwise described in the FIGURES which are presented herein. [0047] Brief Description of the Figures [0048] FIGURE 1 shows the chemical structure of current nucleos(t)ides analogs for the treatment of HBV infection. [0049] FIGURE 2 shows structures of FMCA (21) and its phosphoramidate prodrug FMCAP (31). [0050] FIGURE 3, Scheme 1 shows the synthesis of critical carbocyclic sugar synthon intermediate (6) via ^D-ribose. Reagents and Conditions: (a) i) (HCHO)₄, i-Pr₂NH.TFA, diisopropylamine, THF; ii) NaBH₄, CeCl₃.7H₂O, Methanol; (b) Al (Me)₃ (2.0 M in hexane), DCM; (c) TBDPSCl, imidazole, DCM; (d) DAST, DCM; (e) TBAF, THF. [0051] FIGURE 4, Scheme 2 shows the synthesis of Boc-protected purines (15-18). Reagents and Conditions: (a) Boc anhydride, DMPA, THF; (b) Aqueous saturated NaHCO₃ solution in Methanol. [0052] FIGURE 5, Scheme 3 shows the synthesis of purine (21-26) and ribavirin analogs (29) of 2ʹ-fluoro-6ʹ-methyl carbocyclic nucleoside analogs. Reagents and Conditions: (a) Appropriate Boc-Protected purine, DIAD, TPP, THF; (b) TFA, DCM; (c) Methy-1H-1,2,4- triazole-3-carboxylate, DIAD, TPP, THF; (d) 2 N solution of ammonia in methanol; (e) 2 M solution of TFA in DCM. [0053] FIGURE 6, Scheme 4 shows the synthesis of phosphoramidate prodrugs of compounds 21, 22, & 26. Reagents and Conditions: (a) Phosphorochloridate reagent 30, NMI, THF. [0054] FIGURE 7, Scheme 5 shows the chiral separation of FMCAP via chiral chromatography. [0055] FIGURE 8, Scheme 6 shows the synthesis of uracil (39) and cytosine (41) pyrimidine analogs via intermediate 6. Reagents and Conditions: (a) DIAD, TPP, THF; (b) 7 N ammonia solution in methanol,; (c) 2 M solution of TFA in DCM; (d) 2,4,6- trisisopropylbenzeneslfonyl chloride, DMAP, Et₃N, CH₃CN; (e) 2 M solution of TFA in DCM. [0056] FIGURE 9, Scheme 7 shows the synthesis of the phosphoramidate prodrug of FMCC (41). Reagents and Conditions: (a) TBDMSCl, imidazole, DMF; (b) 3,4-dihydro-2H- pyran, p-TSA, DCM; (c) 1 M solution of TBAF in THF, THF; (d) phosphoramidate reagent 30, NMI, THF; (e) 2 M solution of TFA in DCM. [0057] FIGURE 10 shows Table 1 which presents the results of an HBV screen of compounds according to the present invention at 10 μM in Huh7-C3 Cells with RLU reporter (plasmid # 79). Results for 3TC (lamivudine) and ETV (entecavir) are presented as positive controls. [0058] FIGURE 11 shows Table 2 which presents anti-HBV activity of selected analogs according to the present invention in Huh-7 cells. a 50% inhibitory concentration 120 hpi was determined by bioluminescence imaging, mean from at least 3 experiments. b 50% cytotoxic concentration at 72 h determined by measurement of absorption of wells by a microplate (ELISA) reader. c Selectivity index = CC₅₀/EC₅₀. [0059] FIGURES 12(a) and (b) shows (a) Preliminary result showing the extent of the decrease in cccDNA-dependent HBeAg by FMCAP (31, EC₅₀ = 232 pM) and (b) A comparison study of FMCAP (31), lamivudine (3-TC), tenofovir (TDF) & entecavir (ETV) to inhibit cccDNA-dependent HBeAg. Inhibition of cccDNA-dependent eAg by FMCAP (31) reveals that prodrug 31 blocks HBV DNA replication and prevents HBV cccDNA formation. [0060] FIGURE 13, Table 3 shows cccDNA % activity at various micromolar concentrations FMCAP Sp (34) and FMCC (41). [0061] FIGURE 14 shows FMCAP Sp (34), FMCC (41) and their combination effect on the % cccDNA activity in comparison to entecavir and ccc_R08. [0062] FIGURE 15 shows a combination study of R08, tR08, FMCAP Sp (34), FMCC (41), entecavir. Concentrations for compounds identified: Compound R08 (ccc_R08) 10 μM; Compound tR08 (trans ccc_R08) 10 μM; Compound FMCAP (FMCAP Sp (34)) 0.02 μM; Compound FMCC (41), 0.02 μM concentration; Compound ETV (entecavir) 0.01 μM. [0063] FIGURE 16, Table 4, shows FMCAP Sp (34) and FMCC (41) anti-HBV activity a against wild-type and HBV mutants in Huh-7 Cells. ETV: entecavir; effective concentration b required to inhibit 50% of HBV growth. The > sign indicates that the 50% inhibition was not c reached at the highest concentration tested; The drug concentration required to reduce the d cellular viability by 50% as assayed by an XTT assay. HBV RT: hepatitis B virus (HBV) polymerase reverse transcriptase domain mutation A194T associated with treatment failure with tenofovir disoproxil fumarate (TDF): (See, Goto, et al., Sci Rep-Uk 2022, 12 (1). ND : Not determined. [0064] FIGURE 17 shows the mitochondrial toxicity of FMCC (41) at a range of 0.0002-200 μM concentration compared to 3-TX and AZT via lactic dehydrogenase (LDH) assay. [0065] Detailed Description of the Invention [0066] The following definitions are used to describe the invention. If a term is not specifically defined herein, the meaning given to the term is that which one of ordinary skill would apply to the term within the context of the term’s use. [0067] The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein, generally refers to β-D carbocyclic nucleos(t)ide analogs, but may include, within context, tautomers, regioisomers, geometric isomers, anomers, and where applicable, optical isomers (enantiomers), racemates or diastereomers (two chiral centers) thereof of these compounds, as well as pharmaceutically acceptable salts thereof, solvates and/or polymorphs thereof. Within its use in context, the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures and/or diastereomers as described herein) as well as specific enantiomers, enantiomerically enriched or individual diastereomers or mixtures of disclosed compounds, including Sp and Rp isomers or diastereomers of prodrug phosphoramidate compounds according to the present invention as other described herein. It is noted that in the event that a carbon or other element range is provided in the description of a compound, that range signifies that each and every carbon/element individually is considered part of the range. [0068] The term “pharmaceutically acceptable salt” or “salt” is used throughout the specification to describe, where applicable, a salt form of one or more of the compounds described herein which are presented to increase the solubility of the compound, in certain embodiments where administration has been effected, in the gastric juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of the phosphates according to the present invention. [0069] The term “patient” or “subject” is used throughout the specification to describe an animal, preferably a domesticated animal especially including a mammal or a human, more preferably a human to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal. In general, in the present invention, the term patient refers to a human patient unless otherwise stated. In the present invention, in addition to humans, domesticated animals (e.g., horses, cows, pigs, sheep, goats, dogs, cats, etc.) also may be treated. [0070] The term “Hepatitis B virus” or “HBV” is used to describe a virus which infects the liver of hominoidae, including humans, and causes an inflammation commonly referred to as hepatitis. Originally known as "serum hepatitis", the disease has caused epidemics in parts of Asia and Africa and is prevalent in China. About a third of the current world’s population, more than 2 billion people, have been infected with HBV. This includes 350-400+ million chronic carriers of the virus. Transmission of HBV results from exposure to infectious blood or body fluids containing blood. The acute illness causes liver inflammation, vomiting, jaundice and occasionally death. Chronic hepatitis B (CHB) may eventually cause liver cirrhosis and liver cancer, a fatal disease with very poor response to current chemotherapy. [0071] Hepatitis B virus is an hepadnavirus (etymology from hepa of hepatotrophic and dna because it is a DNA virus, and it has a circular genome composed of partially double- stranded DNA. The viruses replicate through an RNA intermediate form by cellular polymerases and used by the viral reverse transcriptase to generate viral DNA; thus, HBV has mechanistic similarities to retroviruses. Although replication takes place in the liver, the virus spreads to the blood where virus-specific proteins and their corresponding antibodies are found in infected people. Blood tests for these proteins and antibodies are used to diagnose the infection. [0072] Cirrhosis of the liver and liver cancer sometimes develop from HBV infection. HBV primarily interferes with the functions of the liver by replicating in liver cells (hepatocytes). The primary method of transmission reflects the prevalence of chronic HBV infection in a given area. In low prevalence areas such as the United States and Europe, less than 2% of the population is chronically infected, often caused by drug abuse injection and unprotected sex, although other factors may be important. In moderate prevalence areas, which include Eastern Europe, Russia and Japan, where 2-7% of the population is chronically infected, the disease is predominantly spread among children. In high prevalence areas such as China and Southeast Asia, transmission during childbirth is most common, and in Africa, transmission during childhood is a significant factor. The prevalence of chronic HBV infection in certain areas may be at least 8%. [0073] Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood. Possible forms of transmission include (but are not limited to) blood transfusions, use of contaminated needles/syringes, transmission from mother to child during childbirth as well as unprotected sexual intercourse. [0074] Compounds which have been shown to be useful in the treatment and/or inhibition of HBV infections and which may be combined with 2ʹ-fluoronucleoside compounds according to the present invention for the treatment of HBV infections include, for example, Hepsera (adefovir dipivoxil), lamivudine, entecavir, telbivudine, tenofovir, alafenamide (TAF), tenofovir disoproxil fumarate (DF), emtricitabine, clevudine, valtoricitabine, amdoxovir, pradefovir, racivir, BAM 205, nitazoxanide, UT 231-B, Bay 41-4109, EHT899, zadaxin (thymosin alpha-1), and mixtures thereof. The term “drug resistant” or “drug resistant mutants” of HBV includes all strains of HBV which are resistant to one or more (including multiple drug resistant strains) of the above-referenced anti-HBV agents, especially including one or more of lamivudine, adefovir and entecavir. These strains include, for example, HBV strains rtM204V, rtM204I, rtL180M, rtLM/rtMV (which is a double mutant of rt180M/rtM204V), rtN236T, L180M+S02G+M204V (an entecavir resistant HBV mutant), and especially double and triple drug resistant mutants rL180M/T184L/M204V, rtV173L/L180m/M204V, rtL180M/T184L/M204V/A200V and rtL180Q/M204V/N238H/L2691, among others. The present compounds are therefore useful against all types of drug resistant HBV strains, including multiple drug resistant strains. _{[0075] The symbol “ when used in a compound to describe a bond within that} compound designates a bond between a carbon and nitrogen atom (e.g. C and N) which may be a double bond or a single bond depending on the substituents or absence of substituents on the C or N atom within the compound. This symbol also accommodates tautomeric forms of a compound. Thus, where the C atom is substituted with an exocyclic group through a double bond (e.g., a keto group =O) instead of a single bond and the substituent (e.g., H) on the adjacent nitrogen is linked with the nitrogen through a single bond, the the adjacent C and N will be a single bond rather than a double bond (e.g, as in guanine). Likewise, when the C is substituted with an exocyclic group through a single bond rather than a double bond and the adjacent N atom is unsubstituted, the bond between the adjacent C and N will be a double bond (e.g., as in adenine). [0076] The term “enantiomerically enriched” is used throughout the specification to describe a nucleoside/nucleotide which includes more than 75%, at least about 95%, preferably at least about 96%, more preferably at least about 97%, even more preferably, at least about 98%, and even more preferably at least about or more of a single enantiomer of that nucleoside. When the present compounds according to the present invention are referred to in this specification, it is presumed that the nucleosides have the D-nucleoside configuration and are enantiomerically enriched (preferably, approximately 100% of the D-nucleoside), unless otherwise stated. The term “diasteromerically enriched” or “diastereomerically pure” is used to describe a single diastereomer of a compound according to the present invention which contains at least 95%, 96%, 97%, 98%, 99%, 99.5% or 100% by weight of a single diastereomer to the inclusion of other possible diastereomers. Single diastereomer compounds according to the present isomers of phosphoramidate compounds of the present invention which have a particular set configuration (as opposed to a mixture of configurations which characterize a racemic mixture of these compounds) of the substituents on the phosphate group of the identified phosphoramidate nucleos(t)ide compound as otherwise identified herein. [0077] The terms “coadminister” and “coadministration” are used synonymously to describe the administration of at least one of the nucleoside compounds according to the present invention in combination with at least one other agent, preferably at least one additional anti- viral agent, including other nucleoside anti-viral agents which are specifically disclosed herein in amounts or at concentrations which would be considered to be effective amounts at or about the same time. While it is preferred that coadministered agents be administered to a patient or subject at exactly the same time, consecutively or at a time close in proximity (simultaneously), including by different routes of administration, agents may be administered at times such that effective concentrations of both (or more) agents appear in the patient at the same time for at least a brief period of time. Alternatively, in certain aspects of the present invention, it may be possible to have each coadministered agent exhibit its inhibitory or therapeutic effect at different times in the patient, with the ultimate result being the inhibition of the virus and the treatment of the aforementioned infections. Of course, when more than one viral or other infection or other condition is present, the present compounds may be combined with agents to treat that other infection or condition as required. In certain preferred compositions and methods, the present anti-HBV compounds compounds are coformulated and/or coadministered with at least one additional antiviral agent described here, or at least another anti-HBV agent such as lamivudine, entecavir, telbivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, adefovir, interferon alpha, pegylated interferon or a mixture thereof. In addition, other antiviral agents may be combined with compounds according to the present invention including acyclovir, famciclovir, ganciclovir, valaciclovir, vidaribine, foscarnet, zoster-immune globulin (ZIG) and mixtures thereof. Coadministration with 5-fluorouracil (5-FU) may also be contemplated by the present invention. [0078] The term “independently” is used herein to indicate that the variable, which is independently applied, varies independently from application to application. [0079] The term “phosphoramidate” is used to describe a group which is introduced at the 5’- O position of nucleoside compounds according to the chemical structure to instill prodrug properties to the compound. Phosphoramidate groups which are most often used in prodrugs compounds according to the present invention include chemical moieties according to the chemical structure: . As noted herein, the Sp and Rp isomers of the above-identified phosphoramidate groups are diastereomeric groups and when introduced onto the 5’ position of the carbocyclic sugar synthon in compounds according to the present invention provide distinguishable isomeric compounds exhibiting distinguishable inhibitory activity against HBV as presented in the experimental section, presented herein. [0080] The term “stereoselective” is used to describe a synthetic step or series of steps in which a single reactant produces a particular isomer (of at least two possible isomers) in greater quantities than one or more possible isomer(s) from that reactant. In some instances the stereoselectivity of a reaction may be close to 100%. [0081] The term “protecting group” or “blocking group” is used to describe a chemical group or moiety which is introduced into a molecule by chemical modification of a functional group to obtain chemo selectivity in a subsequent chemical reaction. The group plays an important role in providing precursors to chemical components which provide compounds according to the present invention. Blocking groups may be used to protect hydroxyl groups on the pseudosugar/carbocyclic synthon or the purine or pyrimidine base in order to form compounds according to the present invention. Typical blocking groups are used on alcohol groups and amine groups in the present invention. [0082] Exemplary alcohol/hydroxyl protecting groups include acetyl (removed by acid or base), benzoyl (removed by acid or base), benzyl (removed by hydrogenolysis, β- methoxyethoxymethyl ether (MEM, removed by acid), dimethoxytrityl [bis-(4- methoxyphenyl)phenylmethyl] (DMT, removed by weak acid), methoxymethyl ether (MOM, removed by acid), methoxytrityl [(4-methoxyphenyl)diphenylmethyl], (MMT, removed by acid and hydrogenolysis), p-methoxylbenzyl ether (PMB, removed by acid, hydrogenolysis, or oxidation), isopropylidene (removed by acid), methylthiomethyl ether (removed by acid), pivaloyl (Piv, removed by acid, base or reductant agents. More stable than other acyl protecting groups, tetrahydropyranyl (THP, removed by acid), tetrahydrofuran (THF, removed by acid), trityl (triphenyl methyl, (Tr, removed by acid), silyl ether (e.g. trimethylsilyl, TMS, tert-butyldimethylsilyl or TBDMS, tri-iso-propylsilyloxymethyl or TOM, triisopropylsilyl or TIPS, and t-buyldiphenylsilyl, all removed by acid or fluoride ion such as such as NaF, TBAF (tetra-n-butylammonium fluoride, HF-Py, or HF-NEt₃); alkyl ethers, including methyl or t-butyl ether (removed by strong acid, TMSI in DCM, MeCN or chloroform or by BBr₃ in DCM) or ethoxyethyl ethers (removed by strong acid). In aspects of the present invention, the use of a t-butyl ether group may be used. In other aspects, the hydroxyl protecting groups used in the sugar synthon are t-butyl ether, isopropylidene and t- butyldiphenylsilyl protecting groups as otherwise disclosed herein. [0083] Exemplary amine-protecting groups include carbobenzyloxy (Cbz group, removed by hydrogenolysis), p-Methoxylbenzyl carbon (Moz or MeOZ group, removed by hydrogenolysis), tert-butyloxycarbonyl (BOC group, removed by concentrated strong acid or by heating at elevated temperatures), 9-Fluorenylmethyloxycarbonyl (FMOC group, removed by weak base, such as piperidine or pyridine), acyl group (acetyl, benzoyl, pivaloyl, by treatment with base), benzyl (Bn groups, removed by hydrogenolysis), carbamate, removed by acid and mild heating, p-methoxybenzyl (PMB, removed by hydrogenolysis), 3,4- dimethoxybenzyl (DMPM, removed by hydrogenolysis), p-methoxyphenyl (PMP group, removed by ammonium cerium IV nitrate or CAN); tosyl (Ts group removed by concentrated acid and reducing agents, other sulfonamides, Mesyl, Nosyl & Nps groups, removed by samarium iodide, tributyl tin hydride. In aspects of the present invention, one or two BOC groups are used to protect the exocyclic purine (adenine or guanine) amine which is condensed with the sugar synthon to produce FMCA, N-methyl-FMCA FMCG, N-Methyl- FMCG pursuant to the present invention. In aspects of the invention, the hydroxyl protecting groups used in the sugar synthon are t-butyl ether, isopropylidene and t-butyldiphenylsilyl protecting groups as otherwise disclosed herein. [0084] The present invention also relates to pharmaceutical compositions comprising an effective amount of a compound as described above, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. In alternative embodiments, pharmaceutical compositions may also contain one or more additional bioactive agents, including antiviral agents as otherwise described herein in combination with an additive, carrier or excipient. [0085] Methods of treatment represent further embodiments according to the present invention. In this aspect, a method of treating or reducing the likelihood of a viral infection or a secondary disease state or condition thereof, in particular, a viral infection from HBV, including a drug-resistant or multiple drug-resistant HBV infection in a patient in need of therapy or at risk for infection or a secondary disease state or condition thereof comprises administering to said an effective amount of a compound or composition as otherwise described above. Alternative embodiments rely on co-administering compounds according to the present invention in combination with additional antiviral agents to said patient. In preferred aspects, a method of treating or reducing the likelihood of HBV infection, including a drug-resistant strain thereof or a secondary disease or condition which occurs as a consequence of HBV (e.g. cirrhosis or hepatocellular cancer) is directed to administering to a patient in need an effective amount of compound according to the present invention as described herein, or a pharmaceutically acceptable salt, solvate or polymorph thereof. [0086] Pharmaceutical compositions based upon the nucleoside compounds according to the present invention comprise one or more of the above‑described compounds in an effective amount for treating or reducing the likelihood of a viral infection, especially a HBV infection, including a drug-resistant or multiple drug-resistant HBV infection in a patient in need of therapy thereof, optionally in combination with a pharmaceutically acceptable additive, carrier or excipient. One of ordinary skill in the art will recognize that a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient or subject (animal or human) to be treated. [0087] In the pharmaceutical aspect according to the present invention, the compound according to the present invention is formulated preferably in admixture with a pharmaceutically acceptable carrier. In general, it is preferable to administer the pharmaceutical composition in orally‑administrable form, but certain formulations may be administered via a parenteral, e.g. intravenous, intramuscular, topical, transdermal, buccal, intranasal, subcutaneous, inhalation, suppository, or other routes. Intravenous and intramuscular formulations are often administered in sterile saline. In certain instances, topical or transdermal administration may be used. Of course, one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. In particular, the modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, etc.) which are well within the ordinary skill in the art. It is also well within the routineer's skill to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients. [0088] In certain pharmaceutical dosage forms prodrug (phosphoramidate esters) and various salt forms of the present compounds, may be favored. In embodiments, phosphoramidate esters are used. One of ordinary skill in the art will recognize how to readily modify the present compounds to enhance the prodrug compounds according to the present invention to facilitate delivery of active compounds to a targeted site within the host organism or patient. The routineer also will take advantage of favorable pharmacokinetic parameters of the pro‑drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound. [0089] The amount of compound included within active formulations according to the present invention is an effective amount for treating the infection or condition, especially a viral infection as otherwise described herein. In general, a therapeutically effective amount of the present compound in pharmaceutical dosage form usually ranges from about 0.05 mg/kg to about 100 mg/kg per day or more, more preferably, slightly less than about 1 mg/kg to about 25 mg/kg per day of the patient or considerably more, depending upon the compound used, the condition or infection treated and the route of administration. The active nucleoside compound according to the present invention is often administered in amounts ranging from about 0.5 mg/kg to about 25 mg/kg per day of the patient, depending upon the pharmacokinetics of the agent in the patient. This dosage range generally produces effective blood level concentrations of active compound which may range from about 0.05 to about 100 micrograms/cc of blood in the patient. For purposes of the present invention, a prophylactically or preventive effective amount (i.e. an amount which is effective to reduce the likelihood of a patient at risk from contracting a viral infection) of the compositions according to the present invention falls within the same concentration range as set forth above for therapeutically effective amount and is often/usually the same as a therapeutically effective amount. [0090] Administration of the active compound may range from continuous (intravenous drip) to up to several oral administrations per day (for example, once daily, or four times daily or Q.I.D.) or transdermal administration and may include oral, topical, parenteral, intramuscular, intravenous, sub‑cutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration. Enteric coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration. The most effective dosage form will depend upon the bioavailability/pharmacokinetics of the particular agent chosen as well as the severity of disease in the patient and the size and weight of the patient. Oral dosage forms are particularly preferred as are topical dosage forms, because of ease of administration and prospective favorable patient compliance. [0091] To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more of the compounds according to the present invention is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. If desired, the tablets or capsules may be enteric‑coated or sustained release by standard techniques to favorably influence the pharmacokinetics and/or bioavailability of administered drugs. The use of these dosage forms may significantly enhance the bioavailability of the compounds in the patient. [0092] For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients, including those which aid dispersion, also may be included. Of course, where sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. [0093] Liposomal suspensions (including liposomes targeted to viral antigens) may also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be appropriate for the delivery of free nucleosides, acyl/alkyl nucleosides or phosphate ester pro-drug forms of the nucleoside or other compounds used according to the present invention. [0094] In particularly preferred embodiments according to the present invention, the compounds and compositions are used to treat, prevent, reduce the likelihood of or delay the onset of a viral infection as otherwise disclosed herein (HBV). Preferably, to treat, prevent, reduce the likelihood of or delay the onset of these infections or disease states and/or conditions which occur secondary to these viral infections, the compositions will be administered in oral dosage form in amounts ranging from about 250 micrograms up to about 500 mg-1 gram or more at least once a day, up to four times a day. In embodiments, the compounds are formulated in sustained release form and administered less frequently. The present compounds are preferably administered orally, but often may be administered parenterally, topically or in suppository form. [0095] In the case of the co-administration of the present compounds in combination with an another compound used to treat a viral infection, in particular, a viral infection such as a HBV infection, the amount of the prodrug nucleoside compound according to the present to be administered ranges from about 1 mg/kg of the patient to about 500 mg/kg or more of the patient or considerably more, depending upon the second agent to be co-administered and its potency against each of the viral infections to be inhibited, the condition or infection treated and the route of administration. In the case of coadministration, the other antiviral agent may be preferably administered in amounts ranging from about 100 μg/kg (micrograms per kilogram) to about 500 mg/kg. In certain preferred embodiments, these compounds may be preferably administered in an amount ranging from about 1 mg/kg to about 50 mg/kg or more (usually up to about 100 mg/kg), generally depending upon the pharmacokinetics of the two agents in the patient. These dosage ranges generally produce effective blood level concentrations of active compound in the patient. [0096] The compounds according to the present invention, may advantageously be employed prophylactically to prevent or reduce the likelihood of a viral infection or to prevent or reduce the likelihood of the occurrence of clinical symptoms associated with the viral infection or to prevent or reduce the likelihood of the spread of a viral infection to another person. Thus, the present invention also encompasses methods for the prophylactic treatment of a HBV infection. According to the present invention, the present compositions may be used to prevent, reduce the likelihood of and/or delay the onset of a viral infection or a virus-related disease state or condition or the spread of infection to other people. This prophylactic method comprises administering to a patient in need of such treatment or who is at risk for the development of a HBV infection, including a virus related disease state or condition or an infected patient who wishes to prevent or reduce the likelihood of a viral infection from spreading to another person, an amount of a compound according to the present invention alone or in combination with another anti-viral effective for alleviating, preventing, reducing the likelihood of or delaying the onset of the viral infection. In the prophylactic treatment according to the present invention, it is preferred that the antiviral compound utilized should be as low in toxicity and preferably non‑toxic to the patient. It is particularly preferred in this aspect of the present invention that the compound which is used should be maximally effective against the virus and should exhibit a minimum of toxicity to the patient. In the case of compounds of the present invention for the prophylactic treatment of viral infections, these compounds may be administered within the same dosage range for therapeutic treatment (i.e., about 250 micrograms up to about 500 mg. or more from one to four times per day for an oral dosage form) as a prophylactic agent to prevent the proliferation of the viral infection or alternatively, to prolong the onset of or reduce the likelihood of a patient contracting a virus infection which manifests itself in clinical symptoms. [0097] In addition, compounds according to the present invention may be administered alone or in combination with other agents, including other compounds of the present invention. Certain compounds according to the present invention may be effective for enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or inactivation of other compounds and as such, are co‑administered for this intended effect. [0098] RATIONALE FOR THE INVENTION [0099] Entecavir is a 2ʹ-deoxy- 6ʹ-methylene carbocyclic nucleoside analog in which the oxygen of 2ʹ-deoxy ribose is replaced by the methylene group.²⁶ Whereas in the case of FMCA (21), 2ʹ-position of carbocyclic moiety is substituted by a fluorine atom, and the base is replaced by adenine in place of guanine (FIGURE 2). It has been shown that insertion of a fluorine atom at the 2ʹ-position of the nucleoside renders strength to the glycosidic bond towards the nucleoside hydrolase/phosphorylase enzyme and provides metabolic stability. In the inventor’s previous prior experiences, they designed 2ʹ-fluoro-5-methyl-β-L- arabinofuranosyluracil (L-FMAU or clevudine, FIGURE 1), 27 which was found to be active against HBV. Another fluorine-containing drug, clofarabine, 28 also demonstrated significant biological activity. Additionally, the insertion of 2ʹ-fluorine demonstrated additive hydrogen bonding with the HBV polymerase, which turns out to be beneficial for anti-HBV activity.22 That’s why it was concluded that due to the installation of 2ʹ-fluoro, FMCA has expressed its anti-HBV potency and retains its antiviral profile against the double and triple mutants of HBV. Therefore, 2ʹ-fluoro-6ʹ-methylene derivatives of nucleoside needed to be explored against the DNA and RNA viruses. However, the tedious and challenging synthesis of carbocyclic rings restricts researchers from much exploration of these analogs as an antiviral agent. [0100] After encouraging antiviral results of FMCA (21) and FMCAP (31), the inventors focused on exploring the complete SAR of this class of nucleosides. It was thought that the guanosine analog of FMCA resembles entecavir, where it was thought that the insertion of 2ʹ- fluoro may demonstrate enhanced activity against the wild-type and drug-resistant HBV. Considering these improvements, the inventors synthesized purine analogs FMCA (21), N- methyl FMCA (22), FMCG (25), and its N-6-methyl prodrug of FMCG (26). In a previous communication, antiviral activity of racemic FMCAP Sp/Rp (31) was reported.22 Therefore, the antiviral evaluation of chiral pure Sp and Rp isomers of FMCA was essential. Chiral separation of the racemic FMCAP was performed to obtain chiral pure FMCAP Sp (34) and Rp (35) isomers. The nucleos(t)ide analogs exhibit their antiviral effect either by the DNA/RNA polymerase inhibition or by the DNA chain termination or, in some cases, both.29 It is well known that in DNA, adenine binds with thymine, and cytosine binds with guanosine. It is also speculated that FMCAP may foster a rapid HBV mutation; in that case, cytosine or guanosine analogs of this class of nucleoside, either alone or in combinations, may play a vital role in curing HBV-mutation surrendered treatments. Additionally, a combination therapy either of FMCAP Sp (34), or FMCG (26), or cytosine analogs (FMCC 41) with currently approved drugs such as lamivudine, entecavir, telbivudine, tenofovir disoproxil, tenofovir alafenamide, adefovir, interferon alpha, pegylated interferon or a mixture thereof may combat drug-resistant HBV and delay or nullify mutations in the course of the therapy. In this regard, the SAR of this class of molecules has been elaborated. [0101] CHEMISTRY [0102] Previously, the inventors reported the process development for the large-scale synthesis of FMCAP (31) via Vince lactam and carbocyclic ketone (1).23, 30 To synthesize the purine and pyrimidine analogs, first, synthesis of ketone (1) was commenced from D-ribose in 9 steps.31 Furthermore, compound 1 was converted to key 2ʹ-fluoro-containing key intermediate 6 via our earlier reported procedure (FIGURE 3, Scheme 1).23 [0103] Compound 6 was coupled with the Boc-protected purine base under Mitsunobu conditions. Synthesis of appropriate Boc-protected purine bases (15-18) was prepared by the reported protocol of Dey, S. et al. and illustrated in FIGURE 4, Scheme 2.32 The appropriate purine bases (7-10) were treated with di-tert-butyl dicarbonate [(Boc)₂O] in the presence of 4-(dimethylamino)pyridine (DMAP) in THF, followed by the deprotection of 9-Boc of purine bases (11-14) with saturated aqueous sodium bicarbonate (NaHCO₃) solution in methanol yielded 80-92% of the desired Boc-protected purine analogs (15-18). [0104] Coupling of 2-fluoro-1-hydroxy carbocyclic ring (6) with an appropriate N-Boc- protected base renders coupled compounds in 50-70% yield. N-Boc-protected purines (15-18) of interest were stirred with key intermediate 6 in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (TPP) in THF under Mitsunobu condition to produce coupled product 19, 20, 23, and 24. The tert-butyl and Boc protecting groups of compounds 19, 20, 23, and 24 were removed by using 2 M TFA solution in DCM at room temperature (rt), affording final targeted target compounds FMCA (21), 6-N-methyl FMCA (22), FMCG (25), and 6-N-methyl FMCG (26) in 75-80% yield (FIGURE 5, Scheme 3). The inventors also synthesized the carbocyclic ribavirin analog by replacing the ribose sugar with a 2ʹ-fluoro-6ʹ-methylene cyclopentyl ring. Ribavirin demonstrates broad-spectrum antiviral activity33 and it is being used in combination for the treatment and management of the hepatitis C viral infection (HCV).34 To synthesize 2ʹ-fluoro-6ʹ-methylene derivatized ribavirin analog (29), intermediate 6 was condensed with the methy-1H-1,2,4-triazole-3-carboxylate in the presence of DIAD and TPP in THF to obtain coupled product 27 in 71% yield. Methyl ester of 27 was converted to amide by treating compound 27 with 2 N ammonia solution in methanol to give compound 28 in 88% yield. Tert-butyl deprotection of 28 was carried out by a 2 M solution of TFA in DCM. Compound 28 was dissolved in 2 M TFA solution in DCM and stirred for 28 hours at rt to afford ribavirin analog 29 in 76% yield. [0105] To enhance the antiviral profile and to reduce the polarity of molecules with improved cellular uptake, phosphoramidate prodrugs of final compounds 21, 22, and 26 were synthesized. These prodrugs also assist in bypassing the first-step rate limiting mono phosphorylation, which is often a significant roadblock for the carbocyclic nucleosides.35 The phosphoramidate prodrug of compounds 21, 22, and 26 were synthesized by condensing nucleosides with phosphorochloridate intermediate 30. The phosphorochloridate reagent 30 was furnished by reacting phenyl phosphoryl chloride with L-alanine isopropyl ester in DCM at -78 ºC in good yield. Furthermore, nucleosides 21, 22 & 26 were treated with 30 in the presence of N-methyl imidazole (NMI) in THF at room temperature to produce target prodrugs 31, 32, & 33 (FIGURE 6, Scheme 4).23 [0106] However, several attempts were carried out to construct the phosphoramidate prodrug of guanosine analog (FMCG, 25), but in each case, the starting material (25) was unreacted with reagent 30. Then, it was concluded that poor solubility of 25 was attributed to no reaction with the phosphorochloridate reagent. However, an altered synthetic approach has been adopted to synthesize phosphoramidate prodrug of 25 and will be published in future communications. Since the inventors were aware of the anti-HBV activity of racemic (Sp/Rp) FMCAP (31), 22 it was our great interest to separate chiral pure Sp & Rp isomer of FMCAP. The racemic Sp/Rp, FMCAP (31) via chiral chromatography was separated into chiral pure Sp and Rp isomer of FMCAP (34 & 35, FIGURE 7, Scheme 5). After chiral separation, the next challenge was the identification of chirally separated Sp (34) and Rp (35) isomer of FMCAP. Several attempts were made to develop an X-ray crystal of both isomers, but the results were unsatisfactory due to the low quantity of chiral isomers. Then, Sp and Rp isomers were determined by the published studies of sofosbuvir by Bruce Ross et al. via phosphorus NMR.36 The studies revealed that in 31P-NMR, phosphoramidate prodrug of Sp isomer demonstrated a high field ppm peak value of phosphorus compared to Rp isomers.37 Chirally separated FMCAP Sp (34) demonstrated a value of 3.42 ppm, and FMCAP Rp (35) expressed 2.89 ppm of phosphorus in 31P-NMR analysis. [0107] The inventors’ next aim was to synthesize pyrimidine analogs of the 2ʹ-fluoro-6ʹ- methylene carbocyclic nucleoside analogs. In this effort, 3-N-benzoyl-protected uracil base (36) was first condensed with critical intermediate 6 (FIGURE 8, Scheme 6). Compound 36 was treated with intermediate 6 under Mitsunobu coupling conditions with DIAD and TPP in THF to give coupled product 37 in 41% yield. Benzoyl deprotection of 37 was performed with 7 N methanolic ammonia. Compound 37 was treated with 7 N solution of ammonia in methanol at rt to render compound 38 in 83 % yield. The t-butyl protecting groups of 38 were removed by 2 M solution of TFA in DCM to yield the final uracil analog 39 (FMCU) in 83% yield. To synthesize the cytosine nucleoside (41, FMCC), intermediate 38 was converted into the cytosine moiety. Compound 38 was treated with 2,4,6-triisopropylbenzenesulfonyl chloride in the presence of 4-(dimethylamino)pyridine (DMAP) and triethylamine (Et₃N) in acetonitrile to obtain cytosine intermediate 40 in 72% yield. Finally, after deprotection of t- butyl protecting groups of 40 by 2 N solution of TFA in DCM furnish cytosine analog (41, FMCC) in 85% yield. [0108] The synthesis of the phosphoramidate prodrug of FMCC (41) was accomplished as illustrated in FIGURE 9, Scheme 7. Initially, nucleoside 41 was treated with phosphorochloridate intermediate 30, either in the presence of NMI or tBuMgCl (2 M solution in THF), but in each case, the reaction was unsuccessful. Then, it was concluded that the lower solubility of compound 41 plays a critical role in the phosphoramidate coupling reaction with reagent 30. Therefore, to increase the solubility of compound 41 for coupling with reagent 30, 3ʹ-hydroxy of 41 was protected with dihydropyran (DHP). First, the protection of 5ʹ-hydroxy of 41 was carried out with tert-butyl diphenyl silyl chloride (TBDPSCl). Compound 41 was treated with the TBDPSCl in the presence of imidazole in DMF to produce 5ʹ-hydroxy protected intermediate 42 in 69% yield. [0109] Furthermore, 3ʹ-hydroxy of 42 was protected with DHP; compound 42 was treated with 3,4-dihydro-2H-pyran in the presence of para toluene sulfonic acid (p-TSA) in DCM to give 3ʹ and 5ʹ-protected compound 43 in 76% yield. Selective deprotection of TBDPS of 43 was carried out with tetra-butylammonium fluoride (TBAF). Compound 43 was stirred with 1 M solution of TBAF in THF to afford 44 in 82% yield. Coupling of 44 with phosphoramidate reagent 30 was accomplished in the presence of 1 M solution tBuMgCl in THF to obtain product 45 in 54%. Finally, 3ʹ-deprotection of DHF of 44 was performed with a 2 M solution of TFA in DCM to produce phosphoramidate prodrug of FMCC (46) in 48% yield. [0110] ANTIVIRAL ACTIVITY [0111] To evaluate these new analogs, the inventors tested them in Huh-7 cells transfected with HBV replication reporter plasmid. Huh-7 cells were seeded at a density of 2 x104 cells per well in 96-well plates and allowed to incubate overnight. On the second day, the cells were transfected with the HBV replication reporter plasmid, either the wild-type or mutant HBV packaging plasmid, using X-tremeGENE™ HP DNA Transfection Reagent. Compounds were introduced 4 hours post-transfection and incubated for 5 days. Nano luciferase activity was measured using the Nano-Glo® Luciferase Assay System (Cat#N1150, Promega) and a GloMax Navigator Microplate Luminometer (Promega), following the manufacturer’s protocol. [0112] The cytotoxicity of compounds was evaluated in Huh-7 cells in CellTiter 96 Non- Radioactive Cell Proliferation assay system (Promega) using the 2,3-Bis-(2-Methoxy-4-nitro- 5-sulfophenyl)-2H-tetrazolium-5-carboxanilide, disodium salt (XTT) method. Dose-response curves (EC₅₀) and cell viability (CC₅₀) were determined using GraphPad software (San Diego, California, graphpad.com). [0113] Initial screening of synthesized compounds was performed at 10 µM concentration in the Huh7-C3 cells with RLU reporter (plasmid # 70). Lamivudine (3-TC) and entecavir (ETV) were used as positive control at the concentrations of 5 µM and 25 µM, respectively. The synthesized compounds, which have demonstrated HBV inhibition ≥ 99% at 10 µM, were selected for the dose-dependent anti-HBV activity and determined their EC₅₀ values. The percentage of HBV inhibition of compounds has been mentioned in FIGURE 10, Table 1. In the preliminary screening at 10 µM concentration, nucleoside analogs FMCA (21), FMCG (25), and FMCC (41) have demonstrated ≥ 99% inhibition of HBV. However, purine analog 6-N-methyl FMCA (22) and 6-N-methyl amino prodrug of guanosine (26) expressed 6.31 and 19.72% inhibition, respectively. Then, it was speculated that compounds 22 and 26 may not be a suitable substrate for mono phosphorylation, demonstrating low HBV inhibition. To overcome this hurdle, phosphoramidate prodrugs of purine analogs 21, 22, and 26 were synthesized and screened for HBV inhibition. Consequently, the phosphoramidate prodrug of 6-N-methyl FMCA (32) and 6-N-methyl double prodrug of guanosine (33) expressed 99.77% and 74% inhibition of HBV (FIGURE 10, Table 1). [0114] The inventors previously reported that FMCAP (31), a phosphoramidate prodrug of FMCA (21), had a potential anti-HBV activity against the wild-type as well as drug-resistant HBV.21, 2224 Therefore, it was their great interest to evaluate the antiviral potency of chiral pure Sp and Rp analog of racemic FMCAP. Both Sp (34) and Rp (35) chiral pure analog of FMCAP (31) exhibited 99.96% inhibition of HBV at 10 µM concentration. Furthermore, the screening of pyrimidine analogs was performed and cytosine analog (FMCC, 41) exhibited 99.95% inhibition of HBV. After the initial screening, the analogs that have demonstrated HBV inhibition ≥ 99% at 10 µM were selected for further dose-dependent screening. [0115] The nucleosides FMCA (21), FMCG (25), FMCC (41) and phosphoramidate prodrugs FMCAP (31), N-methyl prodrug of FMCAP (32), and chiral isomers of FMCAP Sp (34), & Rp (35) were selected for further dose-dependent anti-HBV evaluation. The antiviral activity, EC₅₀, and CC₅₀ values of the selected compounds have been mentioned in FIGURE 11, Table 2. [0116] Purine analogs FMCA (21) and FMCG (25) had good anti-HBV activity with EC₅₀ values of 0.255 µM (SI >391) and 0.2715 (SI> 368) µM, respectively without cytotoxicity up to > 100 µM. However, in SAR studies, it was found that 6-N- methyl-FMCA (22) and 6-N- methyl prodrug of guanosine (26) had no activity. It is noteworthy to mention that the cytosine analog, FMCC (41) had a better activity of EC₅₀ of 0.0025 (SI >40,000) in wild-type HBV, which is similar to the currently approved FDA drug entecavir EC₅₀ value of 0.00297 (SI>33,670). It was an encouraging finding because nucleoside analog FMCA (21) and FMCG (25) demonstrated low potency against wild-type HBV compared to ETV. However, the racemic phosphoramidate prodrug of FMCAP (31) had expressed a better antiviral profile with EC₅₀ of 0.0013µM (SI>76,923) than ETV, which also proves that phosphoramidate prodrug assists in bypassing mono phosphorylation of carbocyclic nucleoside and improves the antiviral potency of parental molecule. Next, Chirally separated pure Sp (34) and Rp (35) isomers of FMCA were examined for anti-HBV activity. FMCAP Sp (34) analogs exhibited good anti-HBV activity with an EC₅₀ value of 0.0013 µM (SI>76,923) compared to its Rp analog EC₅₀ value of 0.0030 µM (SI>33,333). The Sp isomer of FMCAP (31) was found to be 2.3 fold more active than its Rp isomer. Surprisingly, no significant improved anti-HBV activity was observed with phosphoramidate prodrugs of 6-N-methyl-FMCA (32). Prodrug 32 expressed EC₅₀ value of 0.321 µM with a SI of > 312. It was inventors’ keen interest to determine the antiviral profile of phosphoramidate prodrug of guanosine analog (25). However, the inventors encountered many challenges in the phosphoramidate prodrug synthesis of 25. [0117] Further, the inventors examined the inhibition of HBV relaxed circular DNA (rcDNA) by FMCAP (31) in the DESAe82 cell line using entecavir (ETV), lamivudine (3- TC) and tenofovir (TDF) as standard with parallel cell viability. FMCAP (31) effectively inhibits cccDNA-dependent HBeAg with an EC₅₀ value of 232 pm FIGURE 12(a) in comparison to entecavir EC₅₀ of 250 pm, tenofovir (TDF) EC₅₀ of 1.5 nM and lamivudine (3TC) EC₅₀ of 4 nM (FIGURE 12(b)). Inhibition of cccDNA-dependent HBeAg by FMCAP (31) occurs due to the block in HBV DNA replication. These results indicate that FMCAP (31) impedes rcDNA synthesis that precludes cccDNA formation, which results in inhibition of cccDNA-dependent HBeAg.38 Our in vitro results indicate that the FMCAP (31) inhibits the formation of HBV replication and expresses a better antiviral potency than TDF & 3-TC. [0118] The perseverance of covalently closed circular DNA (cccDNA) in infected hepatocytes is a significant hurdle in preventing viral eradication with current CHB therapies. Due to the multi-faced life cycle of HBV, developing therapeutic molecules or chemotherapies that are effective, such as polymerase, mRNA, nucleocapsid, HbsAg, and entry inhibitors, have not been proven as a practical approach for the entire elimination of the HBV virus in infected patients. cccDNA mini chromosome resides in the nuclei of the hepatocytes and serves as the DNA substrate for transcription for all viral pregenomic RNAs (pgRNA) and mRNAs. The formation of pgRNA and mRNAs eventually constructs the circulating DNA and viral antigen, which play a biphasic role in viral multiplication and immunity suppression. Therefore, effectively targeting cccDNA is a novel strategy for inhibiting HBV. HBV cccDNA has a long half-life, and the pool of cccDNA in infected cells can be reloaded by the new round of infection, intracellular amplification, and compromised immunity via HBV surface proteins. Despite the effectiveness of approved nucleoside therapies in achieving substantial viremia suppression, cccDNA persists even after prolonged treatment. IFNα treatments were also unsuccessful in eliminating cccDNA. Therefore, to cure CHB, clearance of long-lived cccDNA viral genomic reservoir is vital. Several antiviral strategies targeting cccDNA are being implemented. Notably, reported cccDNA inhibitors are effective in inhibiting the formation of new cccDNA but ineffective in impeding the established cccDNA pool. Annihilating the established cccDNA in hepatocytes is a more practical approach for achieving successful HBV treatment and complete viral eradication. An antiviral capable of inhibiting cccDNA formation and reducing its load, ultimately leading to cccDNA elimination, is urgently needed after witnessing the interesting data of FMCAP Sp (31) that effectively inhibits cccDNA-dependent HBeAg. The next goal was to examine the effects of the compounds of this series against cccDNA. It is exciting that both compounds FMCAP Sp (34) and FMCC (41) have shown strong potency as cccDNA inhibitors. In the HBV cccDNA reporter assay, at the 0.02 µM concentration and 0.1 µM concentration of FMCAP Sp (34) 6.5 (93.5% reduction of cccDNA) & 1.2 (98.8% reduction of cccDNA), % cccDNA formation was observed, respectively (FIGURE 13, Table 3). The potency of FMCC at 0.1 µM was 24.9 (75.1% reduction of cccDNA) % activity of cccDNA observed. It was surprising data because at least under these conditions entecavir at 0.1 µM was found less effective and showed 21.5 % cccDNA formation reduction. Recently, Roche Pharma has developed a compound known as ccc_R08, which expresses cccDNA reducer potency.⁴⁰ Consequently, in the same assay, a comparison study of FMCAP Sp (34) and FMCC (41) with the reference compound ccc_ R-08 was performed. Compound ccc_R08 at 10µM concentration revealed 11% reduction in the cccDNA activity. [0119] These data were encouraging. Next, a combination effect of FMCAP and FMCC has been examined for the % reduction activity of ccc DNA. First, a combination of FMCAP Sp (34, 0.02 µM) and FMCC (41, 0.1 µM) was evaluated, which expressed a 97.6 reduction in the cccDNA formation (2.4 % cccDNA formation was observed). Furthermore, in the same assay, a combination of FMCAP Sp (0.1 µM) & FMCC (0.1 µM) reduced the activity of cccDNA by 99.2% (FIGURE 14). It was important to evaluate a variety of combinational effects on the cccDNA reduction. In these efforts, a combination of ccc_R08 (10 µM), entecavir (0.1 µM), FMCAP Sp (34, 0.02 µM) and FMCC (41, 0.02 µM) were examined. The effective reduction of cccDNA was obtained at the combination of FMCAP Sp, FMCC, and entecavir; however, the combination of both entecavir and ccc_R08 was not much effective in comparison to either R08 or entecavir molecules (FIGURE 15). [0120] The results indicated that the combination of FMCAP Sp (34) and FMCC (41) is unique for further development against both wild-type and drug-resistant HBV. FMCAP Sp (34) is an adenosine analog, and FMCC is cytosine, which has a synergetic effect on the formation of cccDNA and a sequential impact on the viral DNA polymerase. Moreover, FMCC has almost similar activity against wild-type HBV compared to entecavir, whereas FMCAP Sp retained its antiviral potency against various HBV mutated strains (FIGURE 16, Table 4). The effect of these analogs on both cccDNA and viral DNA polymerase is an important finding that may pave the path for eliminating the HBV virus from chronic patients. We have already reported FMCA is not a substrate for the adenosine deaminase and does not show any mitochondrial toxicity.21, 22 Furthermore, FMCC was evaluated for mitochondrial toxicity via lactic dehydrogenase (LDH) assay and found not toxic up to 200 µM with standard 3-TC (lamivudine) and AZT (zidovudine, Figure 17). Therefore, to understand the full antiviral profile of these analogs, further PK/ PD evaluation of FMCAP and FMCC is essential. [0121] Furthermore, after examining the antiviral profile of chiral pure phosphoramidate prodrug FMCAP Sp (34) and FMCC (41) against wild-type (WT) HBV, these analogs were selected for antiviral evaluation against the various HBV mutants compared to standard drug entecavir (ETV). Both compounds were tested in Huh-7 cells transfected with HBV mutants. In the case of pHBV-Ep-s wild-type plasmid, FMCAP Sp (34) expressed 0.49 nM antiviral activity compared to ETV, which revealed EC₅₀ value of 2.9 nM (FIGURE 16, Table 4). Against the wild-type HVB FMCAP Sp was found 6-fold more active than ETV. However, FMCC (41) expressed almost similar antiviral activity, an EC₅₀ value of 2.5 nM in comparison to ETV. Both compounds (34 & 41) demonstrated less potency against triple mutant rtL180M/T184L/M204V with an EC₅₀ value of 0.5933 and 0.700 µM respectively, in comparison to ETV (0.279 µM). [0122] However, against triple mutant rtV173L/L180M/M204V, FMCAP Sp (34) was found 7.4 -fold more potent (EC₅₀ = 0.0053 nM) compared to ETV (EC₅₀ = 0.0039 μM). Additionally, cytosine analog FMCC (41), against rtV173L/L180M/M204V mutant, retained almost similar antiviral potency compared to ETV (EC_{50 =} 0.039 µM). Against the mutated strain rtL180M/T184L/M204V/A200V, FMCG (41) showed an EC₅₀ value of 0.131 µM, which is 4 times less than standard ETV (EC₅₀ = 0.032 µM). Though, against rtL180Q/M204V/N238H/L269I mutant, FMCAP Sp (34) and FMCC (41) expressed EC₅₀ values of 0.1738 and 0.246 µM respectively, which is very similar to ETV (EC₅₀ value of 0.207 µM) antiviral activity. Notably, in the case of tenofovir-resistant mutant HBV RT_194Td, FMCAP Sp (31) revealed EC₅₀ value of 0.33 nM, which is 10 times more potent than the ETV (EC₅₀ value of 3.0 nM). Also, FMCG (41) exhibited 1.5 times more potency (EC₅₀ value of 1.9 nM) than ETV. [0123] The anti-HBV results demonstrated that chiral pure phosphoramidate prodrug (34 FMCP Sp) and FMCC (41) are potential analogs against wild-type and HBV mutants. The inventors expect that the phosphoramidate prodrug of FMCC (41) will express an enhanced antiviral profile compared to the parent molecule. Furthermore, guanosine analog FMCG (25) demonstrated potential activity against the wild-type HBV. The above findings conclude that the 2ʹ-β-fluoro-methylene carbocyclic nucleoside analogs have the potential for preclinical development against wild-type and drug-resistant HBV. To improve the cellular uptake and bioavailability of described analogs, an exploration of phosphoramidate and phosphate ester prodrugs is needed. In vivo, the prodrugs of these analogs may express a better anti-HBV activity and lead to a potential candidate for drug development against HBV infection. [0124] OBSERVATIONS [0125] The inventors described an elaborated structure-activity relationship (SAR) of purine and pyrimidine derived 2ʹ-fluoro-6ʹ-methylene carbocyclic nucleos(t)ide analogs have reported. The synthesis of targeted nucleosides has been carried out via carbocyclic key intermediate 6. In vitro adenosine FMCA (21), and guanosine FMCG (25) analogs, exhibited significant anti-HBV activity. Furthermore, chiral pure phosphoramidate prodrug, FMCAP Sp (34), demonstrated potent antiviral activity against the wild-type and several HBV mutants. Notably, pyrimidine analog cytosine FMCC (41) expressed excellent activity against the WT and HBV mutants. Based on the data, the inventors concluded that a number of compounds including FMCG (25), chiral pure FMCAP Sp (34), and FMCC (41) have potent antiviral profiles and warrant continued developments as novel antiviral agents for the treatment of wild-type as well as drug-resistant HBV infections. The combination of both FMCAP Sp (34) and FMCC (41) efficiently inhibits the activity of cccDNA which offers a promising approach for the complete elimination of HBV virus. Additional studies are planned to evaluate these compounds in more clinically relevant systems, including NOD/SCID mouse models, as well as the pharmacokinetic profile of prodrugs to select them as potential clinical candidates. [0126] EXPERIMENTAL SECTION [0127] General Analytical Methods. [0128] Reagents and anhydrous solvents were purchased from commercial sources and used without further purification. Moisture-sensitive reactions were performed using oven-dried glassware under a nitrogen or argon atmosphere. Reactions were monitored by thin-layer chromatography plates (TLC silica gel GF 250 microns) that were visualized using a Spectroline UV lamp (254 nm) and developed with 15% solution of sulfuric acid in methanol. Column chromatography was performed on silica gel 60Å, 40-63µM (230 X 400 mesh, Sorbent Technologies). Preparative normal phase chromatography was performed on a CombiFlash Rf 150 (Teledyne Isco) with pre-packed RediSep Rf silica gel cartridges or on RediSep® gold C18 reverse phase columns. Melting points were recorded on a Mel-temp II laboratory device and are uncorrected. Nuclear magnetic spectra were recorded on Varian Inova 500 spectrometer at 500 MHz for 1H NMR, 202 MHz for 31P NMR, 125 MHz for 13C NMR and 470 MHz for 19F NMR with tetramethylsilane as an internal standard. CFCl₃ (trichloro-fluoro methane was used as the internal standard (reference) for 19F-NMR. Chemical shifts (δ) are quoted as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet) and dt (double triplet). Optical rotations were measured on a JASCO DIP-370 digital polarimeter. High-resolution mass spectroscopy (HRMS) spectra were measured on Bruker Ultra-high resolution QTOF MS Impact II spectrometer. Samples were infused at 3 μL/min, and spectra were obtained in the positive or negative ionization mode with a typical resolution of 20,000 or greater. Purity of all tested compounds is ≥95%, as determined by their elemental analysis (Table-S1) or by HPLC/UV. Elemental analysis was performed by the Atlantic Microlab Inc. Norcross, GA. HPLC/UV were determined with a Waters HPLC coupled to a photodiode array.5 μL of sample 0.5 mg/mL in methanol, or in acetonitrile or in mixture of DMSO/MeOH (0.5:10) were injected, using an XBrigde C18, 3.5 μm, (4.6 X 150) mm column at 25 °C with flow rate 0.8 mL/min or with UPLC BEH C18, 1.7 μm (100 X 2.1) mm at 50 °C with a flow rate 0.55 mL/min. The mobile phases were a mixture of A = 10 mM ammonium acetate in water and B = acetonitrile (ACN), and A = 0.05% formic acid (FA) in water and B = 0.05% in acetonitrile (ACN). Purity is given as % of absorbance at Max plot. Optical purity of chiral intermediates and final compound were determined by the chiral HPLC. Chiral HPLC/UV was determined with a Waters HPLC coupled to a photodiode array.10 μL of samples 0.5 mg/mL in methanol, were injected, using a CHIRALCEL OX-H, 5µmm (4.6 X 250mm) column at 30 °C with flow rate 3.0 mL/min. [0129] General procedure for the synthesis of compounds 11-14 [0130] To a stirred solution of adenine (7, 1.35 g, 10.0 mmol) in dry THF (50 mL), DMAP (0.13 g, 1.00 mmol) and di-tert-butyl dicarbonate [(Boc)₂O] (9.2mL, 40 mmol) were added. The reaction mixture was stirred at room temperature (rt) for 24 h. The excess solvent was removed under reduced pressure and crude was purified by silica gel flash column chromatography (30% EtOAc/hexane) to afford tri-boc protected compound 11 (3.87 g, 90% yield) as a white foam.1H NMR (500 MHz, CDCl₃) δ: 9.05 (s, 1H), 8.55 (s, 1H), 1.78 (s, 9H), 1.46 (s, 18H). [0131] Compounds 12 to 14 were synthesized according to the above-described procedure. [0132] tert-butyl 6-((tert-butoxycarbonyl)(methyl)amino)-9H-purine-9-carboxylate (12): 1H NMR (500 MHz, CDCl₃) δ: 8.93 (s, 1H), 8.46 (s, 1H), 3.54 (s, 1H), 1.74 (s, 9H), 1.51 (s, 9H). [0133] tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-6-chloro-9H-purine-9-carboxylate (13): 1H NMR (500 MHz, CDCl₃) δ: 8.62 (s, 1H), 1.73 (s, 9H), 1.50 (s, 18H). [0134] tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-6-((tert- butoxycarbonyl)(methyl)amino)-9H-purine-9-carboxylate (14): 1H NMR (500 MHz, CDCl₃) δ: 8.38 (s, 1H), 3.38 (s, 3H), 1.61 (s, 9H), 1.40 (s, 27H). [0135] General procedure for the synthesis of compounds 15-18 [0136] To a stirring solution of tris-Boc adenine (11, 2.5 gm) in MeOH (100 mL), saturated aq. solution of NaHCO₃ (25 mL) was added. The turbid reaction mixture was stirred at 50 °C for 1h. The excess solvent was removed under reduced pressure. The residue was diluted with water (100 ml) and the suspension was extracted with DCM (2 X 100 mL). The combined organic layer was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The crude was purified by silica gel chromatography to afford compound (15) as white solid (3.24 g, 97% yield). 1H NMR (500 MHz, CDCl₃) δ: 8.87 (s, 1H), 8.44 (s, 1H), 1.57 (s, 9H), 1.40 (s, 9H). [0137] tert-butyl methyl(9H-purin-6-yl)carbamate (16): ¹H NMR (500 MHz, CDCl₃) δ: 11.06 (s, 1H), 8.89 (s, 1H), 8.29 (s, 1H), 3.61 (s, 3H), 1.65 (s, 9H). [0138] tert-butyl (tert-butoxycarbonyl)(6-chloro-9H-purin-2-yl)carbamate (17): ¹H NMR (500 MHz, CDCl₃) δ: 8.38 (s, 1H), 1.56 (s, 18H). [0139] tert-butyl (2-(bis(tert-butoxycarbonyl)amino)-9H-purin-6-yl)(methyl)carbamate (18): 1H NMR (500 MHz, CDCl₃) δ: 11.15 (s, 1H), 8.30 (s, 1H), 3.54 (s, 3H), 1.64 (s, 9H), 1.45 (s, 18H). [0140] 9-((1R,3R,4R)-3-tert-butoxy-4-(tert-butoxymethyl)-2-fluoro-5- methylenecyclopentyl)-N,N-diboc-9H-purin-6-amine (19): To a stirred solution of triphenylphosphine (4.79 g, 18.24 mmol), in THF (50 mL) at −10 °C, DIAD was added (3.68 g, 18.24 mmol) drop wise, reaction mixture was stirred at this temperature for 30 minutes, and then a solution of N,N-diBoc-protected adenine (3.6 g, 10.9 mmol) in THF (20 mL) was added. This mixture was stirred for 30 min at 0 °C. Then reaction mixture was again cooled to -20 º and compound 6 (2 g, 7.29 mmol) in THF (10 mL) was added drop wise. The reaction temperature was raised to room temperature and stirred for 1.5 h. Reaction was quenched with methanol and solvent was removed under reduced pressure, crude residue was purified by silica gel column chromatography (5% EtOAc/ hexane) to give 19 as white foam. Yield (3.2 g, 74 %). [^]24 = -51.47 (c 1.0 1 D , CHCl₃); H-NMR (500 MHz, CDCl₃) δ 8.91 (s, 1H), 8.24 (s, 1H), 5.97 (d, J = 30.5 Hz, 1H), 5.32 (s, 1H), 4.90 (dd, J = 9.0, 52.5 Hz, 1H), 4.49-4.77 (m, 1H), 4.33 (d, J = 14 Hz, 1H), 3.62-3.60 (m, 1H), 3.54-3.50 (m, 1H), 2.85 (bs, 1H), 1.47 (s, 18H), 1.28 (s, 9H), 1.27 (s, 9H); 19F-NMR (470 MHz, CDCl₃ -191.1 (ddd, J = 17.5, 35.0 & 49 Mz, 1F); 13C{1H} NMR (125 MHz, CDCl₃) ^ 153.9, 152.0, 150.4, 150.2, 150.0, 146.4, 145.3, 128.1, 111.7, 109.9, 83.7, 75.7, 73.2, 62.6, 49.8, 28.2, 27.8, 27.5 ; HRMS (EI) Calcd for (C + 3₀H₄₇FN₅O₆+2H) 592.3589, found 592.3592. [0141] (+)-9-[(1′R, 2′R, 3′R, 4′R)-2′-Fluoro-3′-hydroxy-4′-(hydroxymethyl)-5′- methylene-cyclopentan-1′-yl]adenine (FMCA, 21). Compound 19 (3.3 g, 5.58 mmol) was dissolved in DCM (30 mL). Added trifluoroacetic acid (6 mL) to this solution and mixture was stirred at room temperature for 16 h. TFA with excess solvent was removed under reduced pressure and residue was co-evaporated three times with methanol to remove residual trifluoroacetic acid and neutralized with aqueous ammonia solution, concentrated under reduced pressure. The obtained crude was purified by column chromatography on silica gel (6%methanol/DCM) to give 21 as white solid. (Yield 1.2 g, 77%). Mp 215−218 °C; [^]24 D = +152.10° (c 0.5, MeOH); 1H-NMR (500 MHz, CD₃OD) δ 8.26 (s, 1H), 8.10 (d, 1H), 5.90 (d, J = 26.0 Hz, 1H), 5.46 (s, 1H), 4.96 (dt, J = 2.5, 52.5 Hz, 1H), 4.95 (s, 1H), 4.44 (dd, J = 13.5 Hz, 1H), 3.88−3.82 (m, 2H), 2.81 (bs, 1H); 19F NMR (500 MHz, CD₃OD) δ −192.93 (ddd, J = 14.0, 28.0 & 56.0 Hz, 1F); 13C{1 H} NMR [125 MHz, CD₃OD]: δ156.0, 152.5, 149.9, 146.0, 141.1 (d, J = 5.3 Hz), 117.9, 111.7, 95.9 (d, J = 184.0 Hz), 72.9 (d, J = 23.6 Hz ), 61.7, 57.5 (d, J =17.4 Hz), 51.0; HRMS (EI) Calcd for (C + 1₂H₁₅FN₅O₂+H) 280.1210, found 280.1216. [0142] tert-butyl(9-((1R,2R,4R)-3-(tert-butoxy)-4-(tert-butoxymethyl)-2-fluoro-5- methylenecyclo-pentyl)-9H-purin-6-yl)(methyl)carbamate (20). Compound 20 (500 mg) was synthesized in the quantitative yield by condensation of the carbocyclic ring 6 with N- Methyl Boc-protected adenine (16) by following the same procedure as described for the synthesis of compound 19. Mp 215−218 °C; [^]24 = -46 1 D (c 0.5, MeOH); H-NMR (500 MHz, CDCl₃) δ 8.80 (s, 1H), 8.18 (s, 1H), 5.97 (d, J = 31.0 Hz, 1H), 5.33 (s, 1H), 4.97 (dt, J = 6.0, 56.5 Hz, 1H), 4.97 (s, 1H), 4.32 (d, J = 14.0 Hz, 1H), 3.61−3.51 (m, 2H), 3.56 (s, 3H),2.85 (bs, 1H), 1.52 (s, 9H), 1.28, (s, 18H); 19F NMR (500 MHz, CDCl₃) δ −191.22 (ddd, J =32.0, 45.5 & 46.0 Hz, 1F); 13C{1 H} NMR [125 MHz, CDCl₃]: δ 154.0, 153.6, 153.1, 151.7, 146.5, 143.5, 126.1, 111.6, 81.9, 73.5, 73.2, 62.7, 49.8, 35.0, 28.2, 27.5, 21.9; HRMS (EI) Calcd for (C + 2₆H₄₀FN₅O₄+H) 506.3143, found 506.3138. [0143] (+)-9-[(1′R, 2′R, 3′R, 4′R)-2′-Fluoro-3′-hydroxy-4′-(hydroxymethyl)-5′- methylene-cyclopentan-1′-yl]-6-N-methyladenine (22). The deprotection of all the protecting groups of compound 20 was done by the following the same procedure as described for compound 21. Mp 215−218 °C; [^]24 1 D = +129.10° (c 0.5, MeOH); H-NMR (500 MHz, CD₃OD) δ 8.30 (s, 1H), 8.03 (s, 1H), 5.88 (d, J = 26.0 Hz, 1H), 5.44 (s, 1H), 4.94 (d, J = 52.5 Hz, 1H), 4.92 (s, 1H), 4.43 (d, J = 13.5 Hz, 1H), 3.90−3.82 (m, 2H), 3.15 (s, 3H),2.80 (bs, 1H); 19F NMR (500 MHz, CD₃OD) δ −195.84 (ddd, J = 17.5, 28.0 & 42.0 Hz, 1F); 13C{1 H} NMR [125 MHz, CD₃OD]: δ 155.4, 152.5, 146.1, 140.5, 118.4, 111.7, 95.9 (d, J = 197.0 Hz), 73.0, 72.8, 61.7, 57.6, 57.4, 51.1; HRMS (EI) Calcd for (C + 1₃H₁₆FN₅O₂+H) 294.1366, found 294.1366. [0144] di-tert-butylacetyl(9-((1R,2R,4R)-3-(tert-butoxy)-4-(tert-butoxymethyl)-2-fluoro- 5-methylenecyclopentyl)-6-chloro-9H-purin-2-yl)carbamate (23). Compound 23 (300 mg) was synthesized in the quantitative yield by condensation of the carbocyclic ring 6 with 6- chloro-2-amino-Boc-protected base (17) following the same procedure as described for the compound 19. The yielded compound 23 was contaminated with reduced DIAD impurity. 1H-NMR (500 MHz, CDCl₃) δ 8.25 (s, 1H), 7.19 (s, 1H), 5.77 (d, J = 28.0 Hz, 1H), 5.26 (s, 1H), 4.78 (s, 1H), 4.73 (d, J = 49.5 Hz, 1H), 4.47 (d, J = 13.5 Hz, 1H), 3.53−3.43 (m, 2H),2.73 (bs, 1H), 1.38 (s, 18H), 1.18 (s, 9H), 1.17 (s, 9H); 19F NMR (500 MHz, CDCl₃) δ −191.75 (ddd, J = 14.0, 28.0 & 42.0 Hz, 1F); 13C{1 H} NMR [125 MHz, CDCl₃]: δ 153.2, 152.0, 151.0, 150.6, 150.0, 145.7, 129.395.9 (d, J = 197.0 Hz), 83.6, 75.7, 73.328.2, 27.9, 27.5; HRMS (EI) Calcd for (C H Cl + 3_{0 45} N₅O₆+H) 626.3121, found 626.3118 [0145] (+)-9-[(1R, 2R, 3R, 4R)-2-Fluoro-3-hydroxy-4-(hydroxymethyl)-5- methylenecyclo-pentan-1-yl]-guanosine (25). Compound 25 (50 mg) was synthesized in qualitative yield from 23 ( 120 mg) by following the same procedure as described for compound 21. Mp : 215-218 °C (dec.) [α]25 D + 44.69° (c 0.64, H₂O) UV (H₂O) ^max 253.0 nm (^ 13300, pH 2), 251.0 nm (^ 13600, pH 7), 260.0 nm (^ 11400, pH 11); 1H NMR (500 MHz, DMSO-d₆) ^ 10.70 (s, 1H, NH), 7.46 (d, J = 2.5 Hz, 1H), 6.59 (s, 1H), 5.65 (d, J = 3.0 Hz, 1H), 5.50 (d, J = 28.5 Hz, 1H), 5.31 (s, 1H), 5.01 (s, 1H), 4.85 (d, 1H), 4.80 (s, 1H), 4.25 (d, J = 12.5 Hz, 1H), 3.66-3.64 (m, 1H), 3.54 (s, 1H), 2.61 (s, 1H); 19F NMR (470 MHz, DMSO-d6) δ -192.93 (m); 13C NMR (125 MHz, DMSO-d₆) ^ 157.2, 154.3, 152.1, 147.3, 136.9, 116.0, 111.5, 97.2, 96.5 (d, J = 183.1 Hz) 72.6 (d, J = 22.8 Hz), 62.3, 57.3 (d, J = 16.6 Hz); Anal. Calcd. For C₁₂H₁₄FN₅O₃.2.5H₂O C, 42.35; H, 5.63; N, 20.58; Found C, 42.25; H, 5.51; N, 20.59. [0146] tert-butyl (2-(bis(tert-butoxycarbonyl)amino)-9-((1R,2R,4R)-3-(tert-butoxy)-4- (tert-butoxymethyl)-2-fluoro-5-methylenecyclopentyl)-9H-purin-6-yl)(methyl)carbamate (24). Compound 24 (600 mg) was synthesized in the quantitative yield by condensation of the carbocyclic ring 6 with Boc-protected-2-amino-6-methyl adenine (18) following the same procedure as described for compound 19.1H-NMR (500 MHz, CDCl₃) δ 8.17 (s, 1H), 7.29 (s, 1H), 5.88 (d, J = 31.0 Hz, 1H), 5.28 (s, 1H), 4.82 (d, J = 51.5 Hz, 1H), 4.77 (s, 1H), 4.30 (d, J = 13.5 Hz, 1H), 3.60−3.53 (m, 2H), 3.50 (s, 3H), 2.83 (bs, 1H), 1.49 (s, 9H), 1.47 (s, 18H), 1.27 (s, 18H); 19F NMR (500 MHz, CDCl₃) δ −191.33 (ddd, J = 10.5, 31.5 & 45.5 Hz, 1F); 13C{1 H} NMR [125 MHz, CDCl₃]: δ 154.5, 154.1, 153.4, 151.8, 151.1, 146.4, 144.0124.3, 111.5, 97.3, 83.1, 81.9, 75.6, 73.4, 62.6, 58.3, 49.7, 34.8, 28.2, 27.9, 27.5, 21.9, 21.7; HRMS (EI) Calcd for (C H FN O + + 3_{6 57 6 8} H) 721.4300, found 721.4295. [0147] (+)-9-[(1′R, 2′R, 3′R, 4′R)-2′-Fluoro-3′-hydroxy-4′-(hydroxymethyl)-5′- methylene-cyclopentan-1′-yl]-2-amino-6-N-methyladenine (26). Compound 26 (100 mg) was synthesized in qualitative yield from 24 (400 mg) by following the same procedure as compound 21. Mp 206−208 °C; [^]24 1 D = +139.10° (c 0.5, MeOH); H-NMR (500 MHz, CD₃OD) δ 7.65 (s, 1H), 5.70 (d, J = 28.0 Hz, 1H), 5.40 (s, 1H), 4.92 (s, 1H), 4.88 (d, J = 39.5 Hz, 1H), 4.40 (d, J =13.5 Hz, 1H), 3.87−3.75 (m, 2H), 3.08 (s, 3H), 2.78 (bs, 1H); 19F NMR (500 MHz, CD OD) δ −195.74 (ddd 13 3 , J = 19.5, 28.0 & 42.0 Hz, 1F); C{1 H} NMR [125 MHz, CD₃OD]: δ 160.7, 155.8, 146.4, 137.4, 112.4, 111.1, 96.0 (d, J = 184.0 Hz), 73.0, 72.8, 62.0, 57.2, 57.1; HRMS (EI) Calcd for (C₁₃H₁₇FN₆O₂+H) + 309.1475, found 306.1475. [0148] methyl1-((1R,2R,4R)-3-(tert-butoxy)-4-(tert-butoxymethyl)-2-fluoro-5- methylenecyclopentyl)-1H-1,2,4-triazole-3-carboxylate (27). To a stirred solution of triphenylphosphine (0.48 g, 1.80 mmol), in THF (5 mL) at −10 °C, DIAD was added (0.37 g, 1.80 mmol) dropwise, reaction mixture was stirred at this temperature for 30 minutes, and then a solution of Methyl 1H-1,2,4-triazole-5-carboxylate (0.14 g, 1.10 mmol) in THF (3 mL) was added. This mixture was stirred for 30 min at 0 °C. Then the reaction mixture was again cooled to -20 º and compound 6 (0.2 g, 0.72 mmol) in THF (3 mL) was added dropwise. The resulting solution was allowed to stir at rt for 1.5 h. The progress of reaction was monitored by TLC. On complete consumption of reactants, the mixture was quenched with methanol and the solvent was removed under reduced pressure. Crude residue was purified by silica gel column chromatography (5% EtOAc/ hexane) to give 27 as a white solid. Yield (0.2 g, 71 %). [^]24 D = +57.26° (c 01.0, CHCl₃); 1H-NMR (500 MHz, CDCl₃) δ 8.06 (s, 1H), 6.51 (d, J = 20.0 Hz, 1H), 5.44 (s, 1H), 4.92 (dd, J = 2.5 & 52.0 Hz, 1H), 4.91 (s, 1H), 4.34 (d, J = 13.5 Hz, 1H), 4.04 (s, 3H), 3.62 (d, J = 7.5 Hz, 2H), 2.74 (bs, 1H), 1.62 (s, 9H), 1.23 (s, 9H); 19F NMR (470 MHz, CDCl ) δ −195.04 (dt, J = 17.5 & 56.0 H 13 3 z, 1F); C{1 H} NMR [125 MHz, CDCl₃]: δ 158.4, 151.0, 145.3, 144.4, 113.6, 96.3 (d, J = 193.6 Hz), 74.3, 73.1, 63.4, 53.2, 49.1, 28.5, 27.5; HRMS (EI) Calcd for (C H FN O + 1_{9 30 3 4}+H) 384.2299, found 384.2320. [0149] 1-((1R,2R,4R)-3-(tert-butoxy)-4-(tert-butoxymethyl)-2-fluoro-5- methylenecyclopentyl)-1H-1,2,4-triazole-3-carboxamide (28). To a solution of compound 27 (200 mg, 0.52 mmol) in 10 ml anhydrous methanol, 2 N ammonia solution in methanol (15 mL) was added. The resulting basic solution was continued to stir at rt for 12 h. The solvent and ammonia were evaporated under reduced pressure, and the crude residue was purified by column chromatography (30% ethyl acetate/hexane) to give 170 mg of compound28 as yellow gummy solid in 88% yield. [^]24 1 D = +47.97° (c 01.0, CHCl₃); H-NMR (500 MHz, CDCl₃) δ 7.97 (s, 1H), 7.38 (s, 1H), 6.80 (d, J = 21.0 Hz, 1H), 6.11 (s, 1H), 5.43 (s, 1H), 4.94 (d, J = 53.0 Hz, 1H), 4.93 (s, 1H), 4.35 (d, J = 14.0 Hz, 1H), 3.62 (d, J = 7.0 Hz,2H), 2.70 (bs, 1H), 1.26 (s, 9H), 1.24 (s, 9H); 19F NMR (500 MHz, CDCl₃) δ −195.5 (dt, J =17.5 & 52.5 Hz, 1F); 13C{1 H} NMR [125 MHz, CDCl₃]: δ 159.0, 150.0, 146.6, 144.7, 113.2, 96.5 (d, J = 192.6 Hz), 75.1, 74.4, 73.0, 63.2, 49.2, 28.4, 27.5; HRMS (EI) Calcd for (C₁₈H₂₉FN₄O₃+H) + 369.2320, found 369.2319. [0150] 1-((1R,2R,4R)-2-fluoro-3-hydroxy-4-(hydroxymethyl)-5-methylenecyclopentyl)- 1H-1,2,4-triazole-3-carboxamide (29). To a solution of compound 28 (170 mg, 0.46 mmol) at 0 °C in 10 mL DCM was added 2 M solution of TFA in DCM and stirred the solution 12 h at rt. The solvent and TFA were evaporated under reduced pressure and the residual TFA in crude was removed by repeatable co-evaporation with methanol. The residue was purified by column chromatography (5% Methanol/DCM) to give white solid compound 29. (Yield 90 mg, 76%). Mp 220−222 °C; [^]24 D = +54.34°, 1H-NMR (500 MHz, CD₃OD) δ 7.99 (s, 1H), 6.71 (s, 1H), 5.54 (s, 1H), 5.20 (s, 1H), 4.98 (dt, J = 6.5 & 45.5 Hz, 1H), 4.53-4.47 (m, 1H),4.01-392 (m, 2H), 2.63 (bs, 1H); 19F NMR (500 MHz, CDOD₃) δ −203.3 (dd, J = 14.0 & 52.5 Hz, 1F); 13C{1 H} NMR [125 MHz, CD₃OD]: δ 159.7, 149.5, 147.5, 144.0, 115.2, 95.7 (d, J = 195.0 Hz), 74.5, 62.5, 61.0, 48.9; HRMS (EI) Calcd for (C + 1₀H₁₃FN₄O₃+H) 257.1050, found 257.1060. [0151] {[(1R,3R,4R)-3-(6-amino-9H-purin-9-yl)-4-fluoro-5-hydroxy-2-methylenecyclo pentyl)methoxy](phenoxyphosphoryl amino} propionic Acid Isopropyl Ester (31) Phenyl dichlorophosphate (1.0 mol equiv) and the L-alanine isopropyl ester hydrochloride salt (1.0 mol) were taken in anhydrous dichloromethane and cooled to -78 ºC. Added triethylamine (2.0 mol.) dropwise at -78 °C and stirred for 1h. After 1 h the reaction mixture was slowly allowed to warm to rt and stirred for an additional 2 h. The solvent was removed under reduced pressure and the crude residue was re-suspended in anhydrous ether and filtered through a celite bed under nitrogen. Filtrate was concentrated to produce compound 30, which was used as such for the next step without further purification. [0152] N-Methylimidazole, NMI (0.9 mL, 10.7 mmol) was added to a stirring suspension of compound 21 (0.5 g, 1.79 mmol) in dry THF under argon atmosphere at 0 ºC. The phosphorochloridate 30 (2.2 g, 7.10 mmol) was added dropwise by dissolving in THF. The reaction mixture was warm to rt and continued stirring for 16 h. Then volatiles were evaporated under reduced pressure and the crude was purified by silica gel column chromatography (2% methanol/DCM) to give the compound 31 as an off white solid. (Yield0.55 g, 61%).1H-NMR (500 MHz, CDCl₃) δ d 8.36 (s, 1H), 7.84 (d, J = 24.5 Hz, 1H), 7.28- 7.10 (m, 5H), 5.88 (d, J = 30.0 Hz, 1H), 5.80 (bs, 2H), 5.18 (d, J = 9.0 Hz 1H), 4.96-4.76 (m, 3H), 4.39-4.34 (m, 2H), 4.17- 4.04 (m, 2H), 3.90-3.88 (m, 2H), 3.00 (bs, 1H), 1.31 (d, J = 6.5 Hz, 3H), 1.16 (dd, J = 6.0, & 14.0 Hz, 6H); 19F NMR (470 MHz, CDCl₃) δ −192.81 (ddd, J = 17.5, 31.5 & 53.0 Hz, 1F); 31P NMR (CDCl 13 3, 202 MHz): δ 2.84, 2.37; C{1 H} NMR [125 MHz, CDCl₃]: δ 187.7, 173.3, 155.4, 153.1, 150.5, 144.5, 142.4, 140.9, 129.8, 125.2, 120.3, 118.7, 112.3, 95.9, 73.7, 50.5, 49.6, 21.6, 20.8; HRMS (EI) Calcd for (C₂₄H₃₁FN₆O₆P+H) + 549.2027, found 549.2026. [0153] Isopropyl ((((1R,3R,4R)-3-fluoro-2-hydroxy-4-(6-(methylamino)-9H-purin-9-yl)- 5-methylenecyclopentyl)methoxy)(phenoxy)phosphoryl)-D-alaninate (32). Prodrug 32 (60 mg) was synthesized in qualitative yield from 22 ( 100 mg) by following the same procedure as described for compound 31.1H NMR (500 MHz, CDCl₃): δ 8.44 (s, 1H), 7.84 (d, J = 11 Hz, 1H), 7.39-7.32 (m, 2H), 7.25-7.23 (m, 2H), 7.22-7.19 (m, 1H), 6.01-5.95 (m, 2 H), 5.33 (s, 1H), 5.27 (d, J = 8.5 Hz, 1 H), 5.10-5.03 (m, 2H), 4.92 (s, 0.5 H), 4.85 (s, 1H), 4.55-4.43 (m, 3H), 4.23 (t, J = 10 Hz, 1H), 4.01-3.92 (m, 2H), 3.24 (s, 3H), 3.10 (s, 1H), 1.41 (d, J = 5.5 Hz, 3H), 1.30 (s, 7H); 19F NMR (470 MHz, CDCl ) δ: -19 31 3 2.60 to -192.99; P NMR (202 MHz, CDCl₃) δ: 2.75 & 2.46; 13C NMR (125 MHz, CDCl₃) δ: 173.3, 173.1, 155.5, 153.1, 150.6, 145.0, 144.9, 140.2, 129.8, 125.1, 120.1, 119.0, 112.3, 73.6, 69.5, 69.4, 67.0, 50.5, 49.7, 21.7, 20.9. [0154] Isopropyl((((1R,3R,4R)-3-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-5- hydroxy-2-methylenecyclopentyl)methoxy)(phenoxy)phosphoryl)-D-alaninate (33). Prodrug 33 (45 mg) was synthesized in qualitative yield from 26 (100 mg) by following the same procedure as described for compound 31.1HNMR (500 MHz, CDCl₃) δ: 7.43 (s, 1H), 7.25-7.10 (m, 5H), 6.23 (brs, 1H), 5.66 (d, J = 32.0 Hz, 1H), 5.23 (s, 0.5H), 5.08-4.94 (brs, 3H), 4.86 (s, 0.5 H), 4.75 (s, 1.5 H), 4.41 (t, J = 11.5 Hz, 1H), 4.27 (brs, 1H), 4.28-4.08 (m, 1.5H), 3.98-3.89 (m, 2H), 3.62 (s, 0.5H), 3.10 (d, J = 15.5 Hz), 1.30 (s, 3H), 1.18– 1.13 (m, 7H); 19F NMR (470 MHz, CDCl₃) δ: -193.3; 31P NMR (202 MHz, CDCl₃) δ: 2.75 & 2.34; 13C NMR (125MHz, CDCl₃) δ: 173.3, 173.2, 155.9, 150.7, 144.8, 128.8, 125.1, 120.2, 113.4, 112.2, 110.0, 95.0, 73.4, 73.3, 69.5, 67.3, 57.5, 53.5, 50.5, 49.8, 29.7, 21.6, 20.9. [0155] isopropyl((S)-(((1R,3R,4R)-3-(6-amino-9H-purin-9-yl)-4-fluoro-5-hydroxy-2- methylenecyclopentyl)methoxy)(phenoxy)phosphoryl)-D-alaninate (34).1H NMR (500 MHz, CDCl₃) δ 8.36 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.325 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 5.99-5.84 (m, 3H), 5.25 (s, 1H), 5.04-4.97 (m, 1.5H), 4.88 (m, 0.5 H), 4.82 (s, 1H), 4.50-4.38 (m, 2H), 4.23 (q, J = 10.4 Hz, 1H), 4.03 (dt, J = 10.7, 20.3 Hz, 2H), 3.09-3.03 (m, 1H), 1.38 (d, J = 6.6 Hz, 3H), 1.20 (t, J = 7.5 Hz, 6H); 13C NMR (125 MHz, CDCl₃) δ 173.3, 173.2, 155.6, 153.1, 150.7, 150.6, 144.8, 141.0, 129.8, 125.2, 120.4, 120.3, 112.3, 100.0, 96.4, 94.9, 74.0, 69.5, 57.8, 57.6, 50.6, 49.8, 49.7, 21.8, 21.7, 20.1, 20.0; 19F NMR (470 MHz, CD OD) δ -192.6 to -192.8 31 3 (m, 1F); P NMR (202 MHz, CD₃OD) δ 3.42; HRMS (EI) Calcd for (C₂₄H₃₁FN₆O₆P+H) + 549.2027, found 549.2021. [0156] isopropyl((R)-(((1R,3R,4R)-3-(6-amino-9H-purin-9-yl)-4-fluoro-5-hydroxy-2- methylenecyclopentyl)methoxy)(phenoxy)phosphoryl)-D-alaninate (35).1H NMR (500 MHz, CDCl₃) δ 8.37 (s, 1H), 7.87 (d, J = 3.0 Hz, 1H), 7.34 (t, J = 7.9 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 5.99-5.89 (m, 1H), 5.69 (brs, 2H), 5.24 (s, 1H), 5.04 (dt, J = 6.3, 12.6 Hz, 1.5H), 4.92 (d, J = 4.2 Hz, 0.5H), 4.83 (s, 1H), 4.53-4.41 (m, 2H), 4.20 (q, J = 10.7 Hz, 1H), 4.03-3.92 (m, 3H), 3.08 (brs, 1H), 1.39 (d, J = 6.6 Hz, 3H), 1.25 (d, J = 6.2 Hz, 6H); 13C NMR (125 MHz, CDCl₃) δ 173.4173.3, 155.5, 153.2, 150.8, 150.7, 150.6, 144.7, 141.1, 140.0, 129.9, 125.2, 120.2, 118.8, 112.3, 74.0, 73.7, 69.6, 57.9, 57.7, 50.6, 49.9, 21.8, 21.7, 20.1, 20.9; 19F NMR (470 MHz, CD OD) δ -192.6 to -193.0 (m 31 3 , 1F); P NMR (202 MHz, CD₃OD) δ 2.89; HRMS (EI) Calcd for (C₂₄H₃₁FN₆O₆P+H) + 549.2027, found 549.2024. [0157] Synthesis of Pyrimidine analogue [0158] 3-benzoyl-1-((1R,2R,3R,4R)-3-(tert-butoxy)-4-(tert-butoxymethyl)-2-fluoro-5- methylenecy-clopentyl)pyrimidine-2,4(1H,3H)-dione (37). To a stirred mixture of N3- benzoyluracil 36 (236 mg, 1.09 mmol) and Ph₃P (449 mg, 1.82 mmol) in anhydrous THF (15 mL) was added dropwise diisopropyl azodicarboxylate (DIAD, 0.36 mL, 1.82 mmol) at 0 °C under nitrogen atmosphere. After complete addition of DIAD, reaction mixture was cooled to -15 °C, added intermediate 6 (200 mg, 1.73 mmol) by dissolving in THF at this temperature. The mixture was stirred at -10 oC for 2.5 h and then quenched with methanol; the solvent was removed under vacuum. The residue was purified by flash silica gel column chromatography (17% EtOAc/hexane) to give 37. (121 mg, 41% yield) as a gummy solid.1HNMR (500 MHz, CDCl₃): δ 7.96 (d, J = 7.0 Hz, 1H, 2H), 7.66 (t, J = 7.4 Hz, 1H, 1H), 7.51 (t, J = 7.9 Hz, 1H, 2H), 7.45 (dd, J = 8.3, 2.0 Hz, 1H, 1H), 5.81-5.73 (m, 2H), 5.41 (t, J = 2.7 Hz, 1H), 5.09 (t, J = 2.7 Hz, 1H), 4.87 (d, J = 5.0 Hz, 0.5H), 4.76 (d, J = 3.2 Hz, 0.5H), 4.21 (dt, J = 14.5, 2.6 Hz, 1H), 3.53 (td, J = 5.8, 2.8 Hz, 1H), 3.44 (td, J = 8.9, 2.2 Hz, 1H), 2.73 (brs, 1H), 1.22 (s, 1H), 1.20 (s, 9H); 19F NMR (470 MHz, CDCl 13 3) δ: -193.69 to -193.90; C NMR (125 MHz, CDCl₃) δ: 162.2, 154.5, 153.6, 153.0, 135.4, 132.0, 130.6, 129.3, 128.9, 128.3, 110.2, 73.0, 70.8, 48.1, 28.4, 27.5, 22.0, 21.4; HRMS-ESI (m/z): [M + H]+ calculated for [C + 2₆H₃₃FN₂O₅] 495.2266; found 495.2251. [0159] 1-((1R,2R,3R,4R)-3-(tert-butoxy)-4-(tert-butoxymethyl)-2-fluoro-5- methylenecyclopentyl)pyrimidine-2,4(1H,3H)-dione (38). Compound 37 (120 mg, 0.25 mmol) was dissolved in 2 M ammonia solution in methanol (20 mL) and stirred for 24 h at rt. The solvent was evaporated under vacuum and the residue was purified by column chromatography (4% Methanol/DCM) to give 38 as a white solid (62 mg 52% yield). 1H- NMR (500 MHz, CDCl₃) δ 9.50 (bs, NH), 7.25 (d, J = 8.0 Hz, 1H), 5.73 (d, J = 30.0 Hz, 1H), 5.62 (d, J = 8.0 Hz, 1H), 5.27 (s, 1H), 4.91 (s, 1H), 4.71 (d, J = 53.5 Hz, 1H), 4.11 (d, J = 14.5 Hz, 1H), 3.43-3.31 (m, 2H), 2.65 (bs, 1H), 1.26 (s, 9H), 1.23 (s, 9H); 19F NMR (500 MHz, CDCl ) δ −193.6 (ddd, J = 14.0, 31.5 & 49.0 Hz, 1F) 13 3 ; C{1 H} NMR [125 MHz, CDCl₃]: δ 163.5, 151.5, 145.4, 144.0, 112.1, 101.6, 97.8, 72.9, 62.4, 59.1, 49.8, 28.2, 27.4; HRMS (EI) Calcd for (C₁₉H₂₉FN₂O₄+H) + 369.2190, found 369.2187. [0160] 1-((3aR,4R,6R,6aS)-6-(tert-butoxymethyl)-2,2-dimethyl-5-methylenetetrahydro- 3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (39). Compound 38 (120 mg, 0.33 mmol) was dissolved in DCM (20 mL). Added 3 ml of 2 M solution TFA in DCM and stirred for 24 h at rt. The solvent and TFA were evaporated under vacuum and the obtained residue was dissolved in methanol and neutralized with 27% aqueous ammonia solution. After that, volatiles were removed under reduced pressure and the crude was purified by column chromatography (4% Methanol/DCM) to give the 39 as a white solid. Yield (100 mg, 83%). Mp 152-154 oC; ; [^]24 D = +52.34° (c 1.0, MeOH); 1H NMR (500 MHz, CD₃OD) ^ 7.47 (d, J = 7.5 Hz, 1H), 5.84 (d, J = 28.5 Hz, 1H), 5.69 (d, J = 8.5 Hz, 1 H), 5.47 (s, 1H), 5.09 (s, 1H), 4.87 (d, J = 42.5 Hz, 1H), 4.30 (d, J = 13.5 Hz, 1H), 3.77-3.70 (m, 2H), 2.73 (bs, 1H); 19F NMR (470 MHz, CD OD) δ −197.4 (m, 1F 13 3 ); C NMR (125 MHz, CD₃OD) ^: 164.6, 151.8, 145.2, 144.5, 130.1, 111.7, 100.6, 96.3 (d, J = 185.0 Hz), 73.0, 60.3, 58.7, 51.4; ES HRMS calcd C₁₁H₁₃FN₂O₄ [M+H+] 257.0938 , found 257.0933. [0161] 4-amino-1-((1R,2R,3R,4R)-3-(tert-butoxy)-4-(tert-butoxymethyl)-2-fluoro-5- methylenecyclopentyl)pyrimidin-2(1H)-one (40). To a stirred solution of compound 38 (1.5 g, 4.08 mmol) in anhydrous acetonitrile (30 mL), 2,4,6-triisopropyl benzenesulfonyl chloride (2.46 g, 8.16 mmol), 4-(dimethylamino)pyridine(DMAP) (0.49 g, 4.08 mmol) and triethylamine (2.28 ml, 16.3 mmol) were added at 0 °C. The mixture was stirred at ambient temperature for 12 h. After that, 28% solution of ammonium hydroxide (15 mL) was added and stirred at room rt for 6h. The reaction mixture was concentrated under reduced pressure and the crude was purified by column chromatography (5% MeOH/DCM) to give the compound 40 as a white solid (Yield 1.1 g, 74%). Mp 189−192 °C; [^]24 D = +68.34° (c 1.0, CHCl₃); 1H-NMR (500 MHz, CDCl₃) δ 7.24 (d, J = 7.0 Hz, 1H), 5.91 (d, J = 33.0 Hz, 1H), 5.72 (d, J = 7.0 Hz, 1H), 5.20 (s, 1H), 4.83 (s, 1H), 4.70 (d, J = 53.0 Hz, 1H), 4.08 (d, J = 14.0 Hz, 1H), 3.40−3.28 (m, 2H), 2.65 (bs, 1H), 1.14 (s, 18H); 19F NMR (470 MHz, CDCl₃) δ −193.6 (ddd, J = 14.0, 35.0 & 52.5 Hz, 1F); 13C{1 H} NMR [125 MHz, CDCl₃]: δ 165.2, 156.7, 146.6, 145.4, 94.0, 75.4, 73.4, 62.9, 60.1, 50.2, 28.2, 28.1, 27.5, 27.4; HRMS (EI) Calcd for (C₁₉H₃₀FN₃O₃+H) + 368.2349, found 368.2348. [0162] 4-amino-1-((1R,2R,3R,4R)-2-fluoro-3-hydroxy-4-(hydroxymethyl)-5- methylenecyclopentyl)pyrimidin-2(1H)-one (41). Compound 40 (0.3 g, 0.82 mmol) was dissolved in DCM (20 mL). Added 2.5 ml of trifluoroacetic acid (TFA) and stirred for 24 h at rt. The solvent and TFA were evaporated under vacuum and the obtained residue was dissolved in methanol and neutralized with 28% aqueous ammonia solution. The mixture was concentrated under reduced pressure and purified by column chromatography (5% Methanol/DCM) to give the 41 as a white solid. Yield (170 mg, 81%). Mp 192-193 °C; ; [^]24 = +65.34° (c 1 1 D .0, MeOH); H-NMR (500 MHz, CD₃OD) δ 7.63 (d, J = 8.0 Hz, 1H), 6.00 (d, J = 7.5 Hz, 1H), 5.94 (d, J = 29.0 Hz, 1H), 5.49 (s, 1H), 5.09 (s, 1H), 4.88 (d, J = 38.5 Hz, 1H), 4.31 (d, J = 13.5 Hz, 1H), 3.80−3.68 (m, 2H), 2.75 (bs, 1H); 19F NMR (470 MHz, CD OD) δ − 13 3 197.4 (m, 1F); C{1 H} NMR [125 MHz, CDCl₃]: δ 167.2, 157.8, 150.5, 149.4, 115.8, 100.1 (d, J = 187.0 Hz), 97.8, 76.9, 65.9, 63.6, 55.5; HRMS (EI) Calcd for (C H FN O + 1_{1 14 3 3}+H) 256.1097, found 256.1095. [0163] 4-amino-1-((1R,3R,4R,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluoro-4- hydroxy-2-methylenecyclopentyl)pyrimidin-2(1H)-one (42). To a stirred solution of 4- amino-1-((1R,2R,3R,4R)-2-fluoro-3-hydroxy-4-(hydroxymethyl)-5- methylenecyclopentyl)pyrimidin-2(1H)-one (FMCC) (90 mg, 0.35 mmol) in dry DMF (1.5 mL), imidazole (72 mg, 1.05 mmol) and TBDPS-Cl (77 µL, 0.29 mmol) was added. The mixture was stirred at rt for 6 h. After that, the reaction mixture was quenched with 20 mL of water and extracted into EtOAc (3 X 10 mL). The combined organic layer was washed with brine (20 mL), finally with water (10 mL) and dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The obtained crude was purified byflash silica gel column chromatography (8% MeOH/DCM) to give compound 42 as a colorless thick liquid. Yield (120 mg, 69%).1H NMR (500 MHz, CDCl₃) δ 7.66 (t, J = 7.5 Hz, 4H), 7.45-7.35 (m, 6H), 7.25 (s, 1H), 7.19-7.09 (m, 1H), 6.02 (d, J = 31.2 Hz, 1H), 5.67 (d, J = 9.2 Hz, 1H), 5.14 (s, 1H), 5.01 (s, 0.5H), 4.90 (s, 0.5 H), 4.80 (s, 1H), 4.40 (d, J = 16.4 Hz, 1H), 3.75 (q, J = 8.3 Hz, 2H), 2.84 -2.79 (m, 1H), 1.06 (s, 9H); 13C NMR (125 MHz, CDCl₃) δ 168.5, 165.3, 157.4, 145.9, 145.4, 135.8, 133.4, 133.3, 129.9, 127.9, 111.8, 100.0, 94.7, 64.5, 53.9, 51.8,31.8, 29.4, 27.0, 19.4; 19F NMR (470 MHz, CDCl₃) δ -195.22 (d, J = -103.4 Hz, 1F); HRMS- ESI (m/z): [M + H]+ calculated for [C H + 2_{7 33}FN₃O₃Si] 494.2270; found 494.2257. [0164] 4-amino-1-((1R,3R,4R,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluoro-2- methylene-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)pyrimidin-2(1H)-one (43). To a stirred solution of compound 42 (90 mg, 0.18 mmol, 1.0 eq) in dry DCM (2 mL), 4- dihydro-2H-pyran (50 µL, 0.54 mmol) and catalytic amount of p-TSA was added. The reaction mixture was stirred at rt for 6 h. After that, volatiles were removed under reduced pressure and the obtained residue was purified by flash silica gel column chromatography (8% MeOH/DCM) to give 43 as a white fluffy solid. Yield (80 mg, 76%). Mp: 82-85 °C; 1H NMR (500 MHz, CDCl₃) ^ δ 7.73-7.65 (m, 4H), 7.47-7.36 (m, 6H), 7.19 (t, J = 7.4 Hz, 1H), 5.99 (dd, J = 7.0, 34.2 Hz), 5.77-5.71 (m, 1H), 5.25-5.10 (m, 1H), 4.98 (dd, J = 2.9, 23.7 Hz, 0.5H), 4.90-4.79 (m, 1.5H), 4.75-4.70 (m, 0.5H), 4.50 (d, J = 13.2 Hz, 0.5H), 4.39 (d, J = 14.5 Hz, 0.5H), 3.90-3.63 (m, 3H), 3.55-3.44 (m, 1H), 3.02-2.97 (m, 0.5H), 2.87-2.81 (m,0.5H), 1.85-1.45 (m, 7H), 1.09-1.05 (m, 9H); 13C NMR (125 MHz, CDCl₃) ^ 164.9, 164.8, 156.4, 156.2, 145.8, 145.6, 135.7, 135.4, 133.4, 133.2, 130.0, 129.9, 129.8, 127.9, 127.8, 112.1, 111.8, 100.0, 98.5, 97.5, 96.6, 95.1, 94.3, 64.5, 62.9, 62.2, 60.4, 60.3, 50.6, 50.5, 30.9,30.5, 29.8, 26.9, 25.3, 19.5, 19.3, 18.9; 19F NMR (470 MHz, CDCl₃) δ -195.9 to -196.5 (m, 1F); HRMS-ESI (m/z): [M + Na]+ calculated for [C + 3₂H₄₀FN₃O₄SiNa] 600.2670; found 600.2643. [0165] 4-amino-1-((1R,2R,3R,4R)-2-fluoro-4-(hydroxymethyl)-5-methylene-3- ((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)pyrimidin-2(1H)-one (44). To a stirred solution of compound 43 (100 mg, 0.17 mmol) in dry THF (1.5 mL) at 0 °C, 1 M solution of TBAF in THF was added (0.2 mL, 0.2 mmol) and the mixture was stirred at rt for 4 h. The mixture volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (9% MeOH/DCM) to give 44 as a white fluffy solid. Mp 96-98 °C; yield (48 mg, 82%); 1H NMR (500 MHz, CD₃OD) ^ 7.46 (ddd, J = 1.5, 7.5, 13.9 Hz, 1H), 6.04-5.87 (m, 2H), 5.48-5.40 (m, 1H), 5.18 & 5.09-5.05 (m, 0.5H), 5.01-4.96 (m , 1H), 4.90 (d, J = 3.7 Hz, 1H), 4.84 (d, J = 3.5 Hz, 1H), 4.44 (d, J = 13.7 Hz, 0.5H), 4.34 (d, J = 14.1 Hz, 0.5H), 3.98-3.90 (m, 1H), 3.85-3.76 (m, 1H), 3.75-3.69 (m, 0.5H), 3.60 (m, 1.5H), 3.30-3.24 (m, 1H), 2.95-2.82 (m, 1H), 1.91-1.52 (m, 7H), 1.50-1.41 (m, 1H), 1.05 (t, J = 7.4 Hz, 1H); 13C NMR (125 MHz, CD₃OD) ^ 166.2, 157.9, 146.1, 145.9, 145.2, 145.0, 110.8, 98.7, 97.5, 96.4, 95.0, 94.9, 94.4, 93.5, 78.7, 78.5, 76.9, 76.7, 62.5, 62.4, 62.2, 60.2, 60.0, 58.2, 53.5, 50.6, 50.3, 30.6, 30.3, 25.1, 23.5, 19.4, 19.2, 18.8, 12.7; 19F NMR (470 MHz, CDCl ) δ -197.3 to -198.1 (m, 1F); HRMS-ESI (m/z): [ + 3 M + H] calculated for [C₁₆H₂₃FN₃O₄]+ 340.1667; found 340.1653. [0166] isopropyl ((((1R,3R,4R,5R)-3-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-fluoro-2- methylene-5-((tetrahydro-2H-pyran-2- yl)oxy)cyclopentyl)methoxy)(phenoxy)phosphoryl)-L-alaninate (45). To a stirred solution of compound 44 (60 mg, 0.17 mmol) in dry THF (2 mL) at -78 °C, 1M tBuMgCl solution in THF (0.37 mL, 0.38 mmol) was added dropwise. After that, the mixture was warmed to 0 °C and stirred at the same temperature for 30 min. Again, the mixture was cooled to -78 °C and a solution of isopropyl (chloro(phenoxy)phosphoryl)-L-alaninate (115 mg, 0.38 mmol) was added by dissolving in dry THF (1.5 mL) and continued stirring at rt for 16 h. The reaction mixture was quenched with MeOH (2 mL), and volatiles were removed under reduced pressure. The obtained residue was diluted with DCM (20 mL), washed with water (2 X 15 mL), and finally with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (6% MeOH/DCM) to give compound 45 as a white fluffy solid. Mp 58-63 °C; Yield (58 mg,54%); 1H NMR (500 MHz, CDCl₃) δ 7.35-7.28 (m, 2H), 7.18 (dd, J = 5.6, 35.8 Hz, 4H), 6.05 (dd, J = 18.1, 33.5 Hz, 1H), 5.72 (q, J = 6.0, 6.8 Hz, 1H), 5.32 (d, J = 17.1 Hz, 1H), 5.13 (d, J = 3.3 Hz, 0.2H), 5.05-4.92 (m, 2H), 4.89-4.77 (m, 0.3H), 4.75-4.63 (m, 1H), 4.42-3.94 (m, 3H), 3.92-3.76 (m, 2H), 3.57-3.43 (m, 1H), 3.13-2.93 (m, 1H), 2.89-2.57 (m , 1H), 1.82-1.44 (m, 5H), 1.41-1.32 (m, 3H), 1.26-1.17 (m, 6H); 13C NMR (125 MHz, CDCl₃) δ 173.1, 173.0, 165.3, 156.8, 151.0, 150.8, 145.2, 144.5, 144.4, 129.8, 129.7, 125.0, 124.9, 120.4, 120.2, 112.6, 112.5, 98.5, 98.0, 94.4, 69.3, 69.2, 66.9, 62.9, 62.5, 53.5, 50.4, 30.6, 25.3, 21.8, 21.7; 19F NMR (470 MHz, CDCl ) δ -195.6 to -195.9 (m, 1F); 31 3 P NMR (202 MHz, CDCl₃) δ 3.21-2.82; HRMS-ESI (m/z): [M + Na]+ calculated for [C + 2₈H₃₈FN₄O₈PNa] 631.2309; found 631.2296. [0167] isopropyl ((((1R,3R,4R,5R)-3-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-fluoro-5- hydroxy-2-methylenecyclopentyl)methoxy)(phenoxy)phosphoryl)-L-alaninate (46). To a stirred solution of compound 45 (30 mg, 0.04 mmol) in DCM (1 mL) at 0 °C, 20% TFA in DCM (0.2 mL) was added and the mixture was stirred at the same temperature for 2 h. After that, the reaction mixture was concentrated under reduced pressure and the obtained residue was re-dissolved in DCM (20 mL), washed with 10% NaHCO₃ (5 mL), and finally with brine (10 mL), dried over Na₂SO₄ and filtered. The organic layer was concentrated under reduced pressure. The crude was purified by silica gel column chromatography (8% MeOH/DCM) to give 46 as an off-white solid. Yield (12 mg, 48%); 1H NMR (500 MHz, CD₃OD) δ 7.46-7.37 (m, 3H), 7.30-7.21 (m, 3H), 6.01 (d, J = 31.3 Hz, 1H), 5.88 (t, J = 6.3 Hz, 1H), 5.49 (s, 1H), 5.06-4.98 (m, 2H), 4.92 (d, J = 4.9 Hz, 0.5H), 4.82 (d, J = 4.1 Hz, 0.5H), 4.35-4.18 (m, 3H), 4.00-3.91 (m, 1H), 3.01-2.91 (m, 1H), 1.37 (dd, J = 7.2, 13.2 Hz, 4H), 1.33-1.1.31 (m, 1H), 1.27 (q, J = 5.9 Hz, 7H); 13C NMR (125 MHz, CDCl₃) δ 173.2, 166.1150.1, 145.1, 144.9, 129.5, 124.8, 120.2, 120.1, 120.0, 97.0, 95.5, 94.4, 73.0, 72.8, 66.3, 59.6, 50.3, 20.6, 19.2; 19F NMR (470 MHz, CD₃OD) δ -196.8 to -197.05 (m, 1F); 31P NMR (202 MHz, CD₃OD) δ 4.36 & 4.03; HRMS-ESI (m/z): [M + Na]+ calculated for [C + 2₃H₃₀FN₄O₇PNa] 547.1734; found 547.1714. [0168] Cells and Viruses: Human hepatoma-derived Huh-7 cells were used for all cell culture-based glutamine, and sodium pyruvate (DMEM, 1X, Corning, Manassas, VA) supplemented with 10% heat- inactivated fetal bovine serum (Benchmark FBS; Gemini Bio Products, West Sacramento, CA), penicillin–streptomycin (5,000 IU/mL), and amphotericin B (250 μg/mL). Cells were transfected with the HBV replication reporter plasmids, either the wild-type or mutant HBV packaging plasmid, using X-tremeGENETM HP DNA Transfection Reagent. [0169] Compounds and formulations: All compounds were prepared as 10 mM stocks in DMSO and stored at -80 °C. The control compounds, entecavir (ETV; BEI Resources, Manassas, VA) and lamivudine (3-TC; Millipore Sigma, Burlington, MA), are commercially available. Stock compounds were diluted in DMSO and/or complete tissue culture media prior to being added to cells. [0170] Antiviral Efficacy Assay: Huh-7 cells were seeded at a density of 2x10⁴ cells per well in 96-well plates and allowed to incubate overnight. On the second day, the cells were transfected with the HBV replication reporter plasmid using X-tremeGENE™ HP DNA Transfection Reagent. Compounds were introduced at 4 hours post-transfection and incubated for 5 days. Nano luciferase activity was measured using a GloMax Navigator Microplate Luminometer (Promega), and dose-response curves were generated using Prism software (Graphpad, San Diego, CA, USA). [0171] Evaluation of Cytotoxicity: The cytotoxic effects of test compounds for Huh-7 cells were determined by CellTiter 96 Non-Radioactive Cell Proliferation assay system (Promega) using the 2,3-Bis-(2-Methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide, disodium salt (XTT) method under the same conditions as the anti-HBV assay but in the absence of the HBV replication reporter plasmid. Huh-7 cells were seeded at a density of 2x104 cells per well in 96-well plates and allowed to incubate overnight. On the second day, different concentrations of test compounds were added to Huh-7 cells. Following 4 days of incubation at 37°C in a CO2 incubator, the XTT reagent was added, and the cells were incubated for 3 hours at 37°C. Subsequently, the absorbance of the samples was measured using a microplate reader (Biotek). The cytotoxic concentration (CC50) was determined based on the viability of mock-infected cells. [0172] Supporting Information: Copies of ¹H NMR, ¹³C NMR, ¹⁹F NMR and ³¹P NMR spectra of compounds 2 and 3-12. This material is available free of charge at the website pubs.acs.org. [0173] ASSOCIATED CONTENT [0174] Supporting Information [0175] The supporting information is free of charge at the website pubs.acs.org [0176] ¹H, ¹³C & ³¹P NMR spectra of all intermediates and final compounds, elemental analysis of compounds table S1. 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Claims

Claims: 1. A compound according to the chemical structure: Wherein NB is a nucleoside base moiety according to the structure: Wherein each X is independently N or C-R_c; Y is CH or N; Each R_c is independently H, OH, CN, nitro, C₁-C₄ alkyl, which is optionally substituted with CN, nitro or from 1-3 OH or halo groups, preferably a CF₃ group, halo (F, Cl, Br or I), -(CH₂)_n-CH=CHR_a, -(CH₂)_n-C≡C-R_b, or -(CH₂)_n-phenyl which is optionally substituted at any position on the phenyl ring with OH, CN, or C₁-C₄ alkyl, which is optionally substituted with from 1-3 OH or halo groups, preferably a CF₃ group; Each n is an integer from 0-3, preferably 0 or 1; R_a is H, OH, halo or C₁-C₄ alkyl, which is optionally substituted with from 1-3 OH or halo, preferably F groups; R_b is H, OH, halo, or C₁-C₄ alkyl, which is optionally substituted with from 1-3 OH or halo, preferably F groups; R₁ is NH₂, NHCH₃, OH, SH or O; R₂ is H when R₁ is NH₂ or NHCH_3; R₂ is NH₂ when R₁ is OH or O; R₃ is NH₂, NHCH₃, OH, SH or O; R_N is absent when R₁ or R₃ is NH_2, NHCH₃ or OH; R_N is H when R₁ and R₃ are O (O forms a double bond with the carbon atom to which it is bonded and the bond between the carbon atom and nitrogen atom is a single bond); and R1 is H or is a phosphoramidate group moiety according to the structure: A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. 2. The compound according to claim 1 wherein R₁ is NH₂ or O, R_N is H when R₁ is O and R_N is absent when R₁ is NH₂. 3. The compound according to claim 1 wherein R₂ is H when R₁ is NH₂ or NHCH₃; often NH₂. 4. The compound according to claim 1 wherein R₁ is NH₂. 5. The compound according to claim 1 wherein R₂ is NH₂ when R₁ is O and R_N is H. 6. The compound according to claim 1 wherein R_N is absent when R₃ is NH₂. 7. The compound according to claim 1 wherein R_N is H when R₃ is O. 8. The compound according to any one of claims 1-7 wherein R¹ is H. 9. The to any one of claims 1-7, wherein R¹ is . 10. The compound according to any one of claims 1-7 wherein R¹ is 11. The compound according to any one of claims 1-7 wherein R¹ is 12. A compound according to claim 1 which . 13. A compound according to claim 1 which (FMCAP racemic). 14. A compound according to claim 1 which is (sp FMCAP). 15. A compound according to claim 1 which FMCAP). 16. A compound according to claim 1 which . 17. A compound according to claim 1 which is . 18. A to claim 1 which is (rp FMCGP). 19. A compound according to claim 1 which is . 20. A compound according to claim 1 which . 21. A compound according to claim 1 which (FMCCP). 22. A compound according to claim 1 which is (sp FMCCP). 23. A compound according to claim 1 which (rp FMCCP). 24. A compound according to claim 1 which is (FMCU). 25. A compound according to claim 1 which is (FMCUP). . 26. A compound according to claim 1 which is (sp FMCUP). 27. A compound according to claim 1 which (rp FMCUP). 28. A compound according to claim 1 which (FMCRibavirin). 29. A compound according to claim 1 which (FMCRP). 30. A compound according to claim 1 which is (spFMCRP). 31. A compound according to claim 1 which (rpFMCRP). 32. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1-31 in combination with a pharmaceutically acceptable carrier, additive or excipient. 33. The composition according to claim 32 comprising an effective amount of an additional bioactive agent. 34. The composition according to claim 33 wherein said bioactive agent is an anti-HBV agent selected from the group consisting of lamivudine, entecavir, telbivudine, tenofovir disoproxil, tenofovir alafenamide, adefovir, interferon alpha, pegylated interferon or a mixture thereof 35. A method for treating an HBV infection comprising administering to a patient or subject in need an effective amount of at least one compound according to any one of claims 1-31 or a composition according to any one of claims 32-34. 36. The method according to claim 35 wherein said HBV infection is caused by wild type or drug resistant HBV. 37. The method according to claim 36 wherein said drug resistant HBV is HBV strain is rtM204V, rtM204I, rtL180M, rtLM/rtMV, rt180M/rtM204V, rtN236T, L180M/S02I/M202V, rL180M/T184L/M204V, rtV173L/L180m/M204V, rtL180M/T184L/M204V/A200V or rtL180Q/M204V/N238H/L2691. 38. The method according to claim 36 wherein said drug resistant HBV strain is L180M/S02I/M202V, rL180M/T184L/M204V, rtV173L/L180m/M204V, rtL180M/T184L/M204V/A200V or rtL180Q/M204V/N238H/L2691. 39. The method according to any one of claims 35-38 wherein said compound is a mixture of spFMCAP and FMCC. 40. A method of treating a disease state or condition which occurs secondary to HBV infection comprising administering to a patient or subject in need an effective amount of at least one compound according to any one of claims 1-31 or a composition according to any one of claims 32-34. 41. The method according to claim 40 wherein said disease state or condition is cirrhosis. 42. The method according to claim 40 wherein said disease state or condition is hepatocellular cancer.