Beta-d-2'-deoxy-2'alpha-fluoro-2'-beta-c-substituted-2-modified-n6-substituted purine nucleotides for HCV treatment

Abstract

A compound of the structure: or a pharmaceutically acceptable salt or composition thereof for the treatment of a host infected with or exposed to an HCV virus or other disorders more fully described herein.

Description

(19) *EP004667053A2* (11) EP 4 667 053 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 24.12.2025 Bulletin 2025 / 52 (21) Application number: 25196377.3 (22) Date of filing: 07.03.2016 (51) International Patent Classification (IPC): A61P 31 / 14 (2006.01) (52) Cooperative Patent Classification (CPC): C07H 19 / 207; A61K 31 / 7076; A61P 31 / 14; C07H 19 / 16; C07H 19 / 20 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR Designated Validation States: MD (30) Priority: 06.03.2015 US 201562129319 P 11.11.2015 US 201562253958 P 08.01.2016 US 201662276597 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 16762325.5 / 3 265 102 (71) Applicant: ATEA Pharmaceuticals, Inc. Boston, MA 02110 (US) (72) Inventors: • SOMMADOSSI, Jean-Pierre Boston, MA 02111 (US) • MOUSSA, Adel Burlington, MA 01803 (US) (74) Representative: Boult Wade Tennant LLP Salisbury Square House 8 Salisbury Square London EC4Y 8AP (GB) Remarks: •This application was filed on 18.08.2025 as a divisional application to the application mentioned under INID code 62. •Claims filed after the date of receipt of the divisional application (Rule 68(4) EPC). (54) BETA‑D‑2’‑DEOXY‑2’ALPHA‑FLUORO‑2’‑BETA‑C‑SUBSTITUTED‑2‑MODIFIED‑N6‑SUBSTI- TUTED PURINE NUCLEOTIDES FOR HCV TREATMENT (57) A compound of the structure: or a pharmaceutically acceptable salt or composition thereof for the treatment of a host infected with or ex- posed to an HCV virus or other disorders more fully described herein. EP 4 66 7 05 3 A 2 Processed by Luminess, 75001 PARIS (FR) (Cont. next page) 2 EP 4 667 053 A2 Description PRIORITY

[0001] This application claims priority to U.S.S.N. 62 / 129,319 filed on March 6, 2015, U.S.S.N. 62 / 253,958 filed on November 11, 2015, and U.S.S.N 62 / 276,597 filed on January 8, 2016, each of which is incorporated herewith in their entirety. FIELD OF THE INVENTION

[0002] The present invention is directed to nucleotide compounds and compositions and uses thereof to treat the Hepatitis C virus ("HCV"). BACKGROUND OF THE INVENTION

[0003] HepatitisC (HCV) is anRNAsingle stranded virusandmember of theHepacivirus genus. It is estimated that 75% of all cases of liver disease are caused byHCV. HCV infection can lead to cirrhosis and liver cancer, and if left to progress, liver failure which may require a liver transplant. Approximately 170‑200 million people worldwide are infected, with an estimated 3‑4 million infections in the United States.

[0004] RNA polymerase is a key component in the targeting of RNA single stranded viruses. The HCV non-structural protein NS5B RNA-dependent RNA polymerase is a key enzyme responsible for initiating and catalyzing viral RNA synthesis. As a result, HCV NS5B is an attractive target for the current drug discovery and development of anti-HCV agents. There are two major subclasses of NS5B inhibitors: nucleoside analogs, which are anabolized to their active triphosphates -whichact asalternative substrates for thepolymerase -andnon-nucleoside inhibitors (NNIs),whichbind to allosteric regions on the protein. Nucleoside or nucleotide inhibitors mimic natural polymerase substrate and act as chain terminators. They inhibit the initiation of RNA transcription and elongation of a nascent RNA chain.

[0005] In addition to targetingRNApolymerase, otherRNAviral proteinsmayalsobe targeted in combination therapies. For example, HCV proteins that are additional targets for therapeutic approaches are NS3 / 4A (a serine protease) and NS5A (a non-structural protein that is an essential component of HCV replicase and exerts a range of effects on cellular pathways).

[0006] In December 2013, the first nucleoside NS5B polymerase inhibitor sofosbuvir (Sovaldi®, Gilead Sciences) was approved. Sovaldi® is a uridine phosphoramidate prodrug that is taken up by hepatocytes and undergoes intracellular activation to afford the active metabolite; 2’-deoxy‑2’-α-fluoro-β-C-methyluridine‑5’-triphosphate; see structures below: 3 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0007] Sovaldi® is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infectionwithout the need for co-administration of interferon. Sovaldi® is the third drug with breakthrough therapy designation to receive FDA approval.

[0008] In 2014, theU.S. FDAapprovedHarvoni® (ledispasvir, aNS5A inhibitor, and sofosbuvir) to treat chronic hepatitis C virus genotype 1 infection. Harvoni® is the first combination pill approved to treat chronic HCV genotype 1 infection. It is also the first approved regimen that does not require administration with interferon or ribavirin. In addition, the FDA approved simeprevir (Olysio™) in combination with sofosbuvir (Sovaldi®) as a once-daily, all oral, interferon and ribavirin- free treatment for adults with genotype 1 HCV infection.

[0009] The U.S. FDA also approved AbbVie’s VIEKIRA Pak™ in 2014, a multipill pack containing dasabuvir (a non- nucleosideNS5B polymerase inhibitor), ombitasvir (a NS5A inhibitor), paritaprevir (a NS3 / 4A inhibitor), and ritonavir. The VIEKIRA Pak™ can be used with or without the ribavirin to treat genotype 1 HCV infected patients including patients with compensated cirrhosis. VIEKIRA Pak™ does not require interferon co-therapy.

[0010] In July 2015, the U.S. FDA approved Technivie™ and Daklinza™ for the treatment of HCV genotype 4 and HCV genotype 3 respectively. Technivie™ (Ombitasvir / paritaprevir / ritonavir) was approved for use in combinationwith ribavirin for the treatment of HCV genotype 4 in patients without scarring and cirrhosis and is the first option for HCV‑4 infected patients who do not require co-administration with interferon. Daklinza™was approved for use with Sovaldi® to treat HCV genotype 3 infections. Daklinza™ is the first drug that has demonstrated safety and efficacy in treating HCV genotype 3 without the need for co-administration of interferon or ribavirin.

[0011] In October 2015, the U.S. FDA warned that HCV treatments Viekira Pak and Technivie can cause serious liver injury primarily in patientswith underlying advanced liver disease, and required that additional information about safety be added to the label.

[0012] Other current approved therapies for HCV include interferon alpha‑2b or pegylated interferon alpha‑2b (Pegin- tron®), which can be administeredwith ribavirin (Rebetol®), NS3 / 4A telaprevir (Incivek®, Vertex and Johnson& Johnson), boceprevir (Victrelis™, Merck), simeprevir (Olysio™, Johnson & Johnson), paritaprevir (AbbVie), Ombitasvir (AbbVie), (NNI)Dasabuvir (ABT‑333) andMerck’sZepatier™ (asingle-tablet combinationof the twodrugsgrazoprevir andelbasvir).

[0013] Additional NS5B polymerase inhibitors are currently under development. Merck is developing the uridine nucleotide prodrug MK‑3682 (formerly Idenix IDX21437). The drug is currently in Phase II combination trials.

[0014] UnitedStates patents andWOapplicationswhich describe nucleoside polymerase inhibitors for the treatment of Flaviviridae, including HCV, include those filed by Idenix Pharmaceuticals (6,812,219; 6,914,054; 7,105,493; 7,138,376; 7,148,206; 7,157,441; 7,163,929; 7,169,766; 7,192,936; 7,365,057; 7,384,924; 7,456,155; 7,547,704; 7,582,618; 7,608,597; 7,608,600; 7,625,875; 7,635,689; 7,662,798; 7,824,851; 7,902,202; 7,932,240; 7,951,789; 8,193,372; 8,299,038; 8,343,937; 8,362,068; 8,507,460; 8,637,475; 8,674,085; 8,680,071; 8,691,788, 8,742,101, 8,951,985; 9,109,001; 9,243,025; US2016 / 0002281; US2013 / 0064794; WO / 2015 / 095305; WO / 2015 / 081133; WO / 2015 / 061683; WO / 2013 / 177219; WO / 2013 / 039920; WO / 2014 / 137930; WO / 2014 / 052638; WO / 2012 / 154321); Merck (6,777,395; 7,105,499; 7,125,855; 7,202,224; 7,323,449; 7,339,054; 7,534,767; 7,632,821; 7,879,815; 8,071,568; 8,148,349; 8,470,834; 8,481,712; 8,541,434; 8,697,694; 8,715,638, 9,061,041; 9,156,872 andWO / 2013 / 009737); EmoryUniversity (6,348,587; 6,911,424; 7,307,065; 7,495,006; 7,662,938; 7,772,208; 8,114,994; 8,168,583; 8,609,627; US 2014 / 0212382; and WO2014 / 1244430); Gilead Sciences / Pharmasset Inc. (7,842,672; 7,973,013; 8,008,264; 8,012,941; 8,012,942; 8,318,682; 8,324,179; 8,415,308; 8,455,451; 8,563,530; 8,841,275; 8,853,171; 8,871,785; 8,877,733; 8,889,159; 8,906,880; 8,912,321; 8,957,045; 8,957,046; 9,045,520; 9,085,573; 9,090,642; and 9,139,604) and (6,908,924; 6,949,522; 7,094,770; 7,211,570; 7,429,572; 7,601,820; 7,638,502; 7,718,790; 7,772,208; RE42,015; 7,919,247; 7,964,580; 8,093,380; 8,114,997; 8,173,621; 8,334,270; 8,415,322; 8,481,713; 8,492,539; 8,551,973; 8,580,765; 8,618,076; 8,629,263; 8,633,309; 8,642,756; 8,716,262; 8,716,263; 8,735,345; 8,735,372; 8,735,569; 8,759,510 and 8,765,710); Hoffman La-Roche (6,660,721), Roche (6,784,166; 7,608,599, 7,608,601 and 8,071,567); AliosBioPharma Inc. (8,895,723; 8,877,731; 8,871,737, 8,846,896, 8,772,474; 8,980,865; 9,012,427;US2015 / 0105341; US 2015 / 0011497; US 2010 / 0249068; US2012 / 0070411; WO 2015 / 054465; WO 2014 / 209979; WO 2014 / 100505; WO 4 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 2014 / 100498; WO 2013 / 142159; WO 2013 / 142157; WO 2013 / 096680; WO 2013 / 088155; WO 2010 / 108135), Enanta Pharmaceuticals (US 8,575,119; 8,846,638; 9,085,599; WO 2013 / 044030; WO 2012 / 125900), Biota (7,268,119; 7,285,658; 7,713,941; 8,119,607; 8,415,309; 8,501,699 and 8,802,840), Biocryst Pharmaceuticals (7,388,002; 7,429,571; 7,514,410; 7,560,434; 7,994,139; 8,133,870; 8,163,703; 8,242,085 and 8,440,813), Alla Chem, LLC (8,889,701 and WO 2015 / 053662), Inhibitex (8,759,318 and WO / 2012 / 092484), Janssen Products (8,399,429; 8,431,588, 8,481,510, 8,552,021, 8,933,052; 9,006,29 and 9,012,428) the University of Georgia Foundation (6,348,587; 7,307,065; 7,662,938; 8,168,583; 8,673,926, 8,816,074; 8,921,384 and 8,946,244), RFS Pharma, LLC (8,895,531; 8,859,595; 8,815,829; 8,609,627; 7,560,550; US 2014 / 0066395; US 2014 / 0235566; US 2010 / 0279969; WO / 2010 / 091386 and WO 2012 / 158811) University College Cardiff Consultants Limited (WO / 2014 / 076490, WO 2010 / 081082; WO / 2008 / 062206), Achillion Pharmaceuticals, Inc. (WO / 2014 / 169278 and WO 2014 / 169280), Cocrystal Pharma, Inc. (US 9,173,893), Katholieke Universiteit Leuven (WO 2015 / 158913), Catabasis (WO 2013 / 090420) and the Regents of the University of Minnesota (WO 2006 / 004637).

[0015] Nonetheless, there remains a strong medical need to develop anti-HCV therapies that are safe, effective and well-tolerated. The need is accentuated by the expectation that drug resistance.More potent direct-acting antivirals could significantly shorten treatment duration and improve compliance and SVR rates for patients infected with all HCV genotypes.

[0016] It is therefore an object of the present invention to provide compounds, pharmaceutical compositions, and methods and uses to treat and / or prevent infections of HCV. SUMMARY OF THE INVENTION

[0017] It has been discovered that the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, FormulaVII and includingβ-D‑2’-deoxy‑2’-α-fluoro‑2’-β-C-substituted-N6‑(mono‑or di-methyl) purinenucleotides, are highly active against the HCV virus when administered in an effective amount to a host in need thereof. The host can be a human or any animal that carries the viral infection.

[0018] Disclosed nucleotides include those with nanomolar activity against HCV in vitro and therapeutic indices that range to 25,000 or more.

[0019] Surprisingly, the parent N6‑(methyl) purine nucleosides of disclosed compounds had not been developed or specifically disclosed as drug candidates prior to this invention. For example, it was reported in 2010 that 3’-azido-N6- dimethyl‑2,6-diaminopurine is not substantially deaminated by adenosine deaminase over a long period (120 minutes), and for that reason it had been considered an inappropriate compound to derivatize as a drug (see for example, WO 2010 / 091386, page 86 and corresponding US Patent 8,609,627).

[0020] However, it has now been discovered that compounds of the present invention are anabolized to a 5-monopho- sphate of the N6-substituted-purine without substantial N6-deamination and then subsequently anabolized at the 6- position to generate active guanine triphosphate compounds, in a manner that provides exceptional activity and therapeutic index.

[0021] In particular, it has been discovered that a 5’-stabilized phosphate prodrug or derivative of β-D‑2’-deoxy‑2’-α- fluoro‑2’-β-methyl-N6-methyl‑2,6-diaminopurine nucleotide, as well as β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-di- methyl‑2,6-diaminopurine nucleotide, and other β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted pur- ine nucleotides as described below, are highly active against HCV. This is surprising because the activity of the parent nucleoside β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diaminopurine in a replicon assay (EC50 = 15.7 micro- molar) indicates that it is not suitable for use as a human drug due to insufficient activity (in combination with the reference WO2010 / 091386, page86andcorrespondingUSPatent 8,609,627 that suggests thatN6-methyl‑2,6-diaminopurinesare not deaminated in vivo) however, the stabilized racemic phosphate prodrug (phosphoramidate) exhibits an EC50 = 26 nanomolar (nM), in a replicon assay, which is at least an 600 fold increase in activity. The corresponding (S)‑phosphor- amidate exhibits an EC50 = 4 nM, which is at least a 3,900 fold increase in activity; see the structure below and compound 5‑2 in Table 7. With a TC50 greater than one hundred micromolar, the compound thus has a therapeutic index of greater than 25,000. For comparison, Sofosbuvir has an EC50 = 53 nM, a TC50 greater than one hundred micromolar and a therapeutic index greater than 1,920. 5 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0022] Likewise, the activity of the parent nucleoside β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-dimethyl‑2,6-diamino- purine ina repliconassay (EC50=10.7micromolar, "µM") indicates that it is alsonot suitable for useasahumandrugdue to insufficient activity, however, the stabilized racemic phosphate prodrug (phosphoramidate) exhibits an EC50 = 12 nM, in a replicon assay, which ismore than a890 fold increase in activity. The corresponding (S)‑phosphoramidate (compound25, Table 7) also exhibits anEC50 = 4 nM,which is at least a 2,600 fold increase in activity; see the structure below. In addition, compound 25 also has a therapeutic index of greater than 25,000.

[0023] In another example, the compound isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-N-cyclopropyl- amino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate ex- hibited an EC50 = 7 nM and the corresponding (S)‑phosphoramidate exhibited an EC50 = 5 nM in a replicon assay; see compound 27 in Table 7 and the structure below.

[0024] As stated above, the metabolism of the β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diaminopurine nucleoside as a phosphoramidate involves the production of a 5’-monophosphate and the subsequent anabolism of 6 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 the N6-methyl‑2,6-diaminopurine base to generate the β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-guanine nucleoside as the 5’-monophosphate. Themonophosphate is then further anabolized to the active species; the 5’-triphosphate. The β-D‑2’- deoxy‑2’-α-fluoro‑2’-β-methyl-guanine triphosphate has an IC50 = 0.15 µM against the HCV genotype 1b NS5B poly- merase.

[0025] Thus, in one embodiment, the invention is: wherein: Y is NR1R2; R1 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CH2F, CHF2, CF3, CH2CF3, CF2CH3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, ‑C(O)R3C (including ‑C(O)CH3, ‑C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, - C(O) OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R2 is hydrogen, C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑C(O) R3C (including ‑C(O)CH3, ‑C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and ‑C(O)OC5H11), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(heteroaryl); and wherein at least one of R1 and R2 is methyl, CH2F, CHF2 or CF3; R3 is hydrogen, diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or ‑C(O)R3C; R3A can be selected from O-, OH, an ‑O-optionally substituted aryl, an ‑O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl; R3B can be selected from O-, OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester; R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), or ‑O‑(C0‑C2)(het- eroaryl), each of which can be optionally substituted; R4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or anyothermoiety that ismetabolized to amonophosphate, diphosphate or triphosphate in vivo in the host human or animal; or R3andR4 togetherwith theoxygens that theyarebonded to can forma3’,5’-cyclic prodrug, includingbut not limited to, a 3’,5’-cyclic phosphate prodrug; R12 is CH3, CH2F, CHF2, CF3, or ethynyl.

[0026] In one embodiment, the invention is: 7 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein: Y is NR1R2; R1 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CH2F, CHF2, CF3, CH2CF3, CF2CH3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, ‑C(O)R3C (including ‑C(O)CH3, ‑C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, - C(O) OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R2 is hydrogen, optionally substituted C1‑C5alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, tert-butyl andpentyl),C1‑C5haloalkyl (includingCHF2,CHF2,CF3,CH2CF3andCF2CF3), optionally substituted ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), optionally substituted ‑(C0‑C2alkyl)(heterocycle), optionally substituted ‑(C0‑C2alkyl) (aryl), optionally substituted ‑(C0‑C2alkyl)(heteroaryl), ‑C(O)R3C (including ‑C(O)CH3, - C(O)CH2CH3‑C(O) CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28; and wherein at least one of R1 and R2 is methyl, CH2F, CHF2 or CF3; R3 is hydrogen, , diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or ‑C(O)R3C; R3A can be selected from O-, OH, an ‑O-optionally substituted aryl, an ‑O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl; R3B can be selected from O-, OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester; R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), ‑O‑(C0‑C2)(hetero- aryl), ‑S-alkyl, ‑S-alkenyl, ‑S-alkynyl, ‑S‑(C0‑C2)(cycloalkyl), ‑S‑(C0‑C2)(heterocyclo), ‑S‑(C0‑C2)(aryl), or ‑S‑(C0‑C2) (heteroaryl) each of which can be optionally substituted; R3D is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), or ‑O‑(C0‑C2)(het- eroaryl), each of which can be optionally substituted; R4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or anyothermoiety that ismetabolized to amonophosphate, diphosphate or triphosphate in vivo in the host human or animal; or R3andR4 togetherwith theoxygens that theyarebonded to can forma3’,5’-cyclic prodrug, includingbut not limited to, a 3’,5’-cyclic phosphate prodrug; R5 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl) (C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, ‑C(O)R3C (in- cluding ‑C(O)CH3, - C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and 8 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R6 is hydrogen, optionally substituted C1‑C5alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, tert-butyl andpentyl),C1‑C5haloalkyl (includingCHF2,CHF2,CF3,CH2CF3andCF2CF3), optionally substituted ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), optionally substituted ‑(C0‑C2alkyl)(heterocycle), optionally substituted ‑(C0‑C2alkyl) (aryl), optionally substituted ‑(C0‑C2alkyl)(heteroaryl), ‑C(O)R3C (including ‑C(O)CH3, - C(O)CH2CH3‑C(O) CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and - C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28; or R5 and R6 together with the nitrogen that they are bonded to can form a heterocyclic ring; R12 is CH3, CH2F, CHF2, CF3, or ethynyl; R22 is Cl, Br, F, CN, N3, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C1‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl) (C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl); ‑ONHC(=O)OR23, ‑NHOR24, ‑OR25, ‑SR25, ‑NH(CH2)1‑4N(R26)2, ‑NHNHR26, ‑N-NR27, ‑NHC(O)NHNHR27, ‑NHC(S)NHNHR27, ‑C(O)NHNHR27, ‑NR27SO2R28, ‑SO2NR27R29, ‑C(O)NR27R29, ‑CO2R29, ‑SO2R29, , ‑P(O)H(OR29), ‑P(O)(OR29)(OR3 ), ‑P(O)(OR29)(NR29R30) or ‑NR5R6; for example includingbut not limited to the followingembodiments, chloro, bromo, fluoro, cyano, azido, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl andn-pentyl, 1,1-dimethylpropyl, 2,2-dimtheylpropyl, 3-methylbutyl, 1-methylbutyl, 1-ethylpropyl, vinyl, allyl, 1-butynyl, 2-butynyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl, ‑(CH2)‑cyclopropyl, ‑(CH2)‑cyclobutyl, ‑(CH2)‑cyclopentyl, ‑(CH2)‑cyclohexyl, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, piperidine, oxane, thiane, ‑(CH2)‑a- ziridine, ‑(CH2)‑oxirane, ‑(CH2)‑thiirane, - (CH2)‑azetidine, ‑(CH2)‑oxetane, ‑(CH2)‑thietane, ‑(CH2)‑pyrrolidine, ‑(CH2)‑ tetrahydrofuran, - (CH2)‑thiolane, ‑(CH2)‑pyrazolidine, ‑(CH2)‑piperidine, ‑(CH2)‑oxane, ‑(CH2)‑thiane, phe- nyl, pyridyl, ‑ONHC(=O)OCH3, ‑ONHC(=O)OCH2CH3, ‑NHOH, NHOCH3, ‑OCH3, OC2H5, ‑OPh, OCH2Ph, ‑SCH3, ‑SC2H5, ‑SPh, SCH2Ph, ‑NH(CH2)2NH2, ‑NH(CH2)2N(CH3)2, ‑NHNH2, ‑NHNHCH3, ‑N=NH, ‑N=NCH3, ‑N=NCH2CH3, ‑NHC(O)NHNH2, ‑NHC(S)NHNH2, ‑C(O)NHNH2, ‑NHSO2CH3, ‑NHSO2CH2CH3, ‑SO2NHCH3, ‑SO2N(CH3)2, ‑C(O)NH2, ‑C(O)NHCH3, ‑C(O)N(CH3)2, ‑CO2CH3, ‑CO2CH2CH3, ‑CO2Ph, ‑CO2CH2Ph, ‑SO2CH3, ‑SO2CH2CH3, ‑SO2Ph, ‑SO2CH2Ph, , ‑P(O)H(OH), - P(O)H(OCH3), ‑P(O)(OH)(OH), ‑P(O)(OH)(OCH3), ‑P(O)(OCH3)(OCH3), ‑P(O)(OH)(NH2), ‑P(O) (OH)(NHCH3), ‑P(O)(OH)N(CH3)2, ‑NHC(O)CH3, ‑NHC(O)CH2CH3, ‑NHC(O)CH(CH3)2, ‑NHC(O)OCH3, ‑NHC(O) OCH2CH3, ‑NHC(O)OCH(CH3)2, ‑NHC(O)OCH2CH2CH3, ‑NHC(O)OCH2CH2CH2CH3 and ‑NHC(O) OCH2CH2CH2CH2CH3; R23 is C1‑C5alkyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle)‑(C0‑2alkyl)(aryl) or ‑(C0‑C2alkyl)(het- eroaryl) each of which can be optionally substituted; R24 is hydrogen, C1‑C6 alkyl, ‑(C1‑C2alkyl)(C3‑C6cycloalkyl), ‑(C1‑C2alkyl)(C3‑C6heterocycle) ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R25 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6he- terocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R26 is independently selected fromhydrogen,C1‑C6alkyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R27 hydrogen or optionally substituted C1‑C6 alkyl; R28 is C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) each of which can be optionally substituted; R29 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6he- 9 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 terocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; or R27 and R29 together with the nitrogen that they are bonded to can form a heterocyclic ring; R30 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; or R29 and R30 can be bonded together to form a heterocyclic ring; x is 1, 2 or 3.

[0027] Themetabolismof theβ-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-dimethyl‑2,6-diaminopurine nucleotide involves both the formationof theβ-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-dimethyl‑2,6-diaminopurinenucleoside triphosphateas well as the generation of the corresponding guanine nucleoside triphosphate. See Scheme 2 and 3.

[0028] 2’-Deoxy‑2’-α-fluoro‑2’-β-C-substituted-N6-substituted‑2,6-diaminopurine nucleotides can be further substi- tuted at the N2-position by alkylation or acylated which can modify the lipophilicity, pharmacokinetics and / or targeting of the nucleotide to the liver. It has been discovered that 2’-deoxy‑2’-α-fluoro‑2’-β-C-substituted-N6-substituted‑2,6- diaminopurine nucleotides modified at the 2-position of the diaminopurine can be dealkylated or deacylated by hepatic enzymes to further increase the specificity of thenucleotide derivatives both in vitro and in vivo, unless theN2-aminogroup is completely replaced by a different moiety, as described herein, such as fluoro. For example, the nucleoside phosphor- amidate 2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N2-methyl-N6-methyl‑2,6-diaminopurine nucleoside phosphoramidate is deal- kylated to 2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diaminopurine nucleoside phosphoramidate when incubated with a human liver S9 fraction in vitro, up to 60minutes, these conditionsmimics in vivo conditions. In one embodiment, N2 modifications will increase cell permeability and hepatitic targeting.

[0029] Despite thevolumeof antiviral nucleoside literatureandpatent filings, the5’-stabilizedphosphatederivativeof 2’- deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diaminopurine nucleoside, 2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-di- methyl‑2,6-diaminopurine nucleoside, and other β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted pur- inenucleosidederivativesasdescribedhereinhavenot beenspecificallydisclosed, norhave their advantageousactivities been described.

[0030] Unless otherwise specified, the compounds described herein are provided in the β-D-configuration. Likewise, when in phosphoramide or thiophosphoramidate form, the amino acid portion can be in the L‑ or D-configuration. In an alternative embodiment, the compounds can be provided in a β-L-configuration. Likewise, any substituent group that exhibits chirality can be provided in racemic, enantiomeric, diastereomeric form or any mixture thereof. Where a phosphoramidate, thiophosphoramidateor other stabilizedphosphorusprodrug inwhich thephosphorus exhibits chirality is used as the R4 stabilized phosphate prodrug, it can be provided as an R or S chiral phosphorus derivative or a mixture thereof, including a racemic mixture. All of the combinations of these stereoconfigurations are included in the invention described herein.

[0031] Accordingly, the present invention includes a compound of Formula I-VII, or a pharmaceutically acceptable composition, salt, or prodrug thereof, as described herein:

[0032] In one specific embodiment, the parent nucleoside, i.e., the nucleoside wherein R4 is hydrogen and the 5’- position thus has a hydroxyl group, is not substantially deaminated by adenosine deaminase under conditions that mimic the in vivo environment (e.g., ambient temperature and aqueous physiological pH), for a period of 7 minutes, 10minutes, 30 minutes, 60 minutes or 120 minutes. Unless otherwise stated, the time period is 30 minutes. In this embodiment, the term "not substantially deaminated" means that the parent compound is not converted to the corresponding guanine 10 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 derivative, or 6-oxo derivative, in an amount sufficient to provide a therapeutic effect in vivo.

[0033] Compounds, methods, and compositions are provided for the treatment of a host infected with a HCV virus via administration of an effective amount of the compound or its pharmaceutically acceptable salt.

[0034] The compounds and compositions can also be used to treat related conditions such as anti-HCV antibody positive and antigen positive conditions, viral-based chronic liver inflammation, liver cancer resulting from advanced hepatitisC, cirrhosis, chronic or acute hepatitisC, fulminant hepatitisC, chronic persistent hepatitisCandanti-HCV-based fatigue. The compound or formulations that include the compounds can also be used prophylactically to prevent or restrict theprogression of clinical illness in individualswhoareanti-HCVantibodyor antigenpositive orwhohavebeenexposed to hepatitis C.

[0035] In another embodiment, compounds of Formula Ia are disclosed: wherein: Y, R3 and R4 are as defined above.

[0036] In one embodiment of Formula Ia, R3 is hydrogen.

[0037] In one embodiment of Formula Ia, when Y is NR1R2, R1 is methyl and R2 is hydrogen.

[0038] In one embodiment of Formula Ia, when Y is NR1R2, both R1 and R2 are methyl.

[0039] In one embodiment of Formula Ia, when Y is NR1R2, R1 is methyl and R2 is cyclopropyl.

[0040] In another embodiment, compounds of Formula Ib are disclosed: wherein: Y, R3 and R4 are as defined above.

[0041] In one embodiment of Formula Ib, R3 is hydrogen.

[0042] In one embodiment of Formula Ib, when Y is NR1R2, R1 is methyl and R2 is hydrogen.

[0043] In one embodiment of Formula Ib, when Y is NR1R2, both R1 and R2 are methyl.

[0044] In one embodiment, compounds of Formula II are disclosed: 11 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein: Y, R3, R4, R12 and R22 are as defined above.

[0045] In another embodiment, compounds of Formula IIa are disclosed: wherein: Y, R3, R4 and R22 are as defined above.

[0046] In another embodiment, compounds of Formula IIb are disclosed: wherein: Y, R3, R4, and R22 are as defined above.

[0047] In one embodiment, compounds of Formula III are disclosed: 12 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein the variables Y, R3, R7, R8, R9a, R9b, R10, R12 and R22 are described herein.

[0048] In one embodiment, compounds of Formula IV are disclosed: wherein the variables Y, R3, R7, R8, R9a, R9b, R10 and R22 are described herein.

[0049] In one embodiment, compounds of Formula V are disclosed: wherein the variables Y, R3, R7, R8, R9a, R9b, R10 and R22 are described herein.

[0050] In one embodiment, compounds of Formula VI are disclosed: 13 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein: R41 is halogen (in particular F or Cl), OR3, N3, NH2 or CN; and the variables Y, R3, R4, and R12 are described herein.

[0051] In one embodiment, compounds of Formula VII are disclosed: Wherein the variables Y, R3, R4, R12 and R41 are described herein.

[0052] Thephosphorus in any of the Formulas abovemaybe chiral and thus canbe provided as anRorSenantiomer or mixture thereof, including a racemic mixture.

[0053] Compound 5 was separated into the enantiomer compounds 5‑1 and 5‑2. Compound 5‑2 was also prepared by chiral synthesis and assigned compound 24.

[0054] In one embodiment, compounds, methods, and compositions are provided for the treatment of a host infected with or exposed to hepatitis C described herein. The compounds of the invention can be administered in an effective amountaloneor in combinationwithanother anti-HCVdrug, to treat the infectedhost. In certainembodiments, it is useful to administer a combination of drugs that modulates the same or a different pathway or inhibits a different target in the virus. As the disclosed β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted purine nucleotides are NS5B poly- merase inhibitors, itmaybeuseful toadminister thecompound toahost in combinationwithaprotease inhibitor, suchasan NS3 / 4A protease inhibitor (for example, telaprevir (Incivek®) boceprevir (Victrelis™) simeprevir (Olysio™), or paritaprevir, or an NS5A inhibitor (for example, Ombitasvir). The compounds of the invention can also be administered in combination with a structurally different NS5B polymerase inhibitor such as another compound described herein or below, including Gilead’sSovaldi®. The compounds of the invention can also be administered in combinationwith interferon alfa‑2a, which may be pegylated or otherwise modified, and / or ribavirin.

[0055] The β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted purine nucleotides of the invention are typically administered orally, for example in pill or tablet form, but may be administered via an other route which the attending physician considers appropriate, including via intravenous, transdermal, subcutaneous, topical, parenteral, or other suitable route. 14 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 BRIEF DESCRIPTION OF THE FIGURES

[0056] Figure 1 is a sample chromatogramof a semi-prep run illustrating the separation of the stereoisomers of Compound 5 usingaPhenominexLunacolumnasdisclosed inExample9. Theyaxis is shown inmAUand thexaxis ismeasured in minutes. Figure 2 is agraphof theHCVreplication inhibition curves forCompound5‑2 (Table 7) andSofosbuvir. Compound5‑2 has an EC50 = 4 nM, a TC50 greater than one hundred micromolar and a therapeutic index of greater than 25,000. Sofosbuvir has an EC50 = 53 nM, a TC50 greater than one hundred micromolar and a therapeutic index greater than 1,920. The y-axis is the percent of virus control and the x-axis is the concentration of drug in µM. Figure 3 is a graph of theHCVreplication inhibition curves forCompound 25 (Table 7) andSofosbuvir. As described in Example27,Compound25hasanEC50=4nM,aTC50of greater than100µM,anda therapeutic indexofgreater than 25,000.Sofosbuvir hasanEC50=53nM,aTC50greater thanonehundredmicromolar anda therapeutic indexgreater than 1,920. The y-axis is the percent of virus control and the x-axis is the concentration of drug in µM. Figure4 isan intra-assaycomparisonof theanti-HCVactivity forCompounds5‑2,25, 27 (Table7)andSofosbuvir. The y-axis is the percent of virus control and the x-axis is the concentration of drug in µM. See, Example 27. Figure 5 is a graph that shows the stability of compounds 5‑2; the N2-acetate of compound 5‑2, the N2-butyrate of compound 5‑2; the N2-methyl derivative of compound 5‑2; and theN2-n-pentylcarbamate of compound 5‑2 in human blood.Thexaxis is incubation timemeasured inminutesand theyaxis is themeasurement of thepercent of theparent compound remaining. Figure 6 is a graph showing the in vitro time course dealkylation of 2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N2-methyl-N6- methyl‑2,6-diaminopurine nucleoside phosphoramidate to 2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diamino- purine nucleoside phosphoramidate in the presence of a human liver S9 fraction. The x axis is measured in minutes and the y axis is the measurement of the concentration of the compound remaining in nM. Figure 7 is a graph showing the stability of compounds 5‑2; the N2-acetate of compound 5‑2, the N2-butyrate of compound 5‑2; the N2-methyl derivative of compound 5‑2; and the N2-n-pentylcarbamate of compound 5‑2 in the presence of a human liver S9 fraction. The x axis ismeasured inminutes and the y axis is themeasurement of percent compound remaining. Figure 8 shows thepredominantCompound25metabolites generated in humanhepatocytes. The xaxis is incubation time in hours. The y axis is intracellular concentration in pmol / 106 cells. See Example 33. Figure 9 shows thepredominantCompound27metabolites generated in humanhepatocytes. The xaxis is incubation time in hours. The y axis is intracellular concentration in pmol / 106 cells. See Example 33. Figure 10 shows the predominant Compound 5‑2 metabolites generated in human hepatocytes. The x axis is incubation time in hours. The y axis is intracellular concentration in pmol / 106 cells. See Example 33. Figure 11 is a graph showing the activation pathways forCompounds 25, 27 and5‑2. As canbe seen,Compounds 25, 27 and 5‑2 are converted to their corresponding monophosphate analogs which are subsequently metabolized to a common MP analog; β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-guanine monophosphate. The monophosphate is then stepwise phosphorylated to the active triphosphate: β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-guanine triphosphate. See Example 33. DETAILED DESCRIPTION OF THE INVENTION

[0057] The invention disclosed herein is a compound, method, and composition for the treatment of infections in or exposure to humans and other host animals of the HCV virus that includes the administration of an effective amount of a compound of Formula I-VII as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral activity, or aremetabolized to a compound that exhibits such activity.

[0058] Thecompoundsandcompositions canalsobeused to treat conditions related to or occurring asa result of aHCV viral exposure. For example, the active compound can be used to treat HCVantibody positive and HCVantigen positive conditions, viral-based chronic liver inflammation, liver cancer resulting from advanced hepatitis C, cirrhosis, acute hepatitis C, fulminant hepatitis C, chronic persistent hepatitis C, and anti-HCV-based fatigue. In one embodiment, the compounds or formulations that include the compounds can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are HCVantibody or HCVantigen positive or who have been exposed to hepatitis C.

[0059] In particular, it has been discovered that a 5’-stabilized phosphate prodrug or derivative of β-D‑2’-deoxy‑2’-α- fluoro‑2’-β-methyl-N6-methyl‑2,6-diamino purine nucleotide, as well as β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-di- methyl‑2,6-diamino purine nucleotide, and other β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted pur- 15 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 ine nucleotides as described below, are highly active against HCV. This is surprising because the activity of the parent nucleoside β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diamino purine in a replicon assay (EC50 = 15.7 micro- molar) indicates that it is not suitable for use as ahumandrug due to insufficient activity, however, the stabilized phosphate prodrug (phosphoramidate) exhibits an EC50 = 26 nanomolar, in a replicon assay, which is at least an 870 fold increase in activity. Likewise, the activity of the parent nucleoside β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-dimethyl‑2,6-diamino- purine ina repliconassay (EC50=10.7micromolar, "µM") indicates that it is alsonot suitable for useasahumandrugdue to insufficient activity, however, the stabilized phosphate prodrug (phosphoramidate) exhibits an EC50 = 12 nanomolar, ("nM"), in a replicon assay, which is more than a 1,300 fold increase in activity.

[0060] Despite thevolumeof antiviral nucleoside literatureandpatent filings, the5’-stabilizedphosphatederivativeof 2’- deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diamino purine nucleotide, 2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-di- methyl‑2,6-diamino purine nucleotide, and other β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted pur- ine nucleotides have not been specifically disclosed.

[0061] Unless otherwise specified, the compounds described herein are provided in the β-D-configuration. In an alternative embodiment, the compounds can be provided in a β-L-configuration. Likewise, any substituent group that exhibits chirality can be provided in racemic, enantiomeric, diastereomeric form or any mixture thereof. Where a phosphoramidate, thiophosphoramidateor other stabilizedphosphorusprodrug inwhich thephosphorus exhibits chirality is used as the R4 stabilized phosphate prodrug, it can be provided as an R or S chiral phosphorus derivative or a mixture thereof, includinga racemicmixture.Theaminoacidof thephosphoramidateor thiophosphoramidate canbe in theD‑or L- configuration, or amixture thereof, including a racemic mixture. All of the combinations of these stereo configurations are included in the invention described herein.

[0062] The present invention includes the following features: (a) a compound of Formula I-VII as described herein, and pharmaceutically acceptable salts and prodrugs thereof; (b) Formulas I-VII as described herein, and pharmaceutically acceptable salts and prodrugs thereof for use in the treatment or prophylaxis of a hepatitis C virus infection; (c) use of Formulas I-VII, and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for treatment of a hepatitis C virus infection; (d) amethod formanufacturing amedicament intended for the therapeutic use for treating ahepatitisC virus infection, characterized in that a Formulas I-VII as described herein is used in the manufacture; (e) a pharmaceutical formulation comprising an effective host-treating amount of the Formulas I-VII or a pharma- ceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent; (f) Formulas I-VII as described herein substantially in the absence of stereoisomers of the described compound, or substantially isolated from other chemical entities; and, (g) processes for the preparation of therapeutic products that contain an effective amount of a Formulas I-VII, as described herein. I. 2’-Deoxy‑2’-α-Fluoro‑2’-β-C-Substituted‑2-Modified-N6-Substituted Purine Nucleotides of the Invention

[0063] The active compounds of the invention are those depicted, for example, in Formula I, which can be provided in a pharmaceutically acceptable composition, salt or prodrug thereof: wherein: 16 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Y is NR1R2; R1 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CH2F, CH2F, CF3, CH2CF3, CF2CH3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, ‑C(O)R3C (including ‑C(O)CH3, ‑C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, - C(O) OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R2 is hydrogen, optionally substituted C1‑C5alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, tert-butyl andpentyl), C1‑C5haloalkyl (includingCHF2,CH2F,CF3,CH2CF3andCF2CF3), optionally substituted ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), optionally substituted ‑(C0‑C2alkyl)(heterocycle), optionally substituted ‑(C0‑C2alkyl) (aryl), optionally substituted ‑(C0‑C2alkyl)(heteroaryl), ‑C(O)R3C (including ‑C(O)CH3, - C(O)CH2CH3‑C(O) CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28; and wherein at least one of R1 and R2 is methyl, CH2F, CHF2 or CF3; R3 is hydrogen, , diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or ‑C(O)R3C; R3A can be selected from O-, OH, an ‑O-optionally substituted aryl, an ‑O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl; R3B can be selected from O-, OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester; R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), or ‑O‑(C0‑C2)(het- eroaryl), each of which can be optionally substituted; R4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or anyothermoiety that ismetabolized to amonophosphate, diphosphate or triphosphate in vivo in the host human or animal; or R3andR4 togetherwith theoxygens that theyarebonded to can forma3’,5’-cyclic prodrug, includingbut not limited to, a 3’,5’-cyclic phosphate prodrug; R12 is CH3, CH2F, CHF2, CF3, or ethynyl.

[0064] A stabilized phosphate prodrug is any moiety that can deliver a mono, di, or triphosphate.

[0065] In another embodiment, compounds of Formula Ia are disclosed: wherein: Y, R3 and R4 are as defined above.

[0066] In another embodiment, compounds of Formula Ib are disclosed: 17 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein: Y, R3 and R4 are as defined above.

[0067] In another embodiment, the compound is according to Formula Ic: wherein: R7 is hydrogen, C1‑6alkyl; C3‑7cycloalkyl; heteroaryl, heterocyclic, or aryl, which includes, but is not limited to, phenyl or naphthyl, wherephenyl or naphthyl areoptionally substitutedwithC1‑6alkyl,C2‑6alkenyl,C2‑6 alkynyl,C1‑6alkoxy, F, Cl, Br, I, nitro, cyano, C1‑6haloalkyl, ‑N(R7)2, C1‑6acylamino, NHSO2C1‑6alkyl, ‑SO2N(R7’)2, COR7", and ‑SO2C1‑6alk- yl; (R7’ is independently hydrogen or C1‑6alkyl; R7" is ‑OR11 or-N(R7)2); R3 is hydrogen,C1‑6alkyl, orR9aorR9bandR8 together are (CH2)n soas to formacyclic ring that includes theadjoining N and C atoms; where n is 2 to 4; R9a and R9b are (i) independently selected from hydrogen, C1‑6alkyl, cycloalkyl, ‑(CH2)c(NR9)2 , C1‑6hydroxyalkyl, --CH2SH, ‑(CH2)2S(O)(Me, ‑(CH2)3NHC(=NH)NH2, (1H-indol‑3-yl)methyl, (lH-imidazol‑4-yl)methyl, ‑(CH2)cCOR9", aryl and aryl(C1‑3alkyl)‑, the aryl groups can be optionally substituted with a group selected from hydroxyl, C1‑6alkyl, C1‑6alkoxy, halogen, nitro and cyano; (ii) R9a and R9b both are C1‑6alkyl; (iii) R9a and R9b together are (CH2)r so as to form a spiro ring; (iv) R9a is hydrogen and R9b and R8 together are (CH2)n so as to form a cyclic ring that includes the adjoiningNandCatoms (v)R9b is hydrogenandR9aandR8 together are (CH2)n soas to formacyclic ring that includes theadjoiningNandCatoms,wherec is1 to6,n is2 to4, r is2 to5andwhereR9’ is independently hydrogenorC1‑6 alkyl and R9" is ‑OR11 or ‑N(R11’)2); (vi) R9a is hydrogen and R9b is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol‑3-yl, ‑CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH,CH2CH2C(O) NH2, CH2CH2CH2CH2NH2, ‑CH2CH2CH2NHC(NH)NH2, CH2-imidazol‑4-yl, CH2OH, CH(OH)CH3, CH2((4’- OH)‑Ph), CH2SH, or lower cycloalkyl; or (vii) R9a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol‑3-yl, -CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, ‑CH2CH2CH2NHC(NH)NH2, CH2-imidazol‑4-yl, CH2OH, CH(OH)CH3, CH2((4’-OH)‑Ph), CH2SH, or lower cycloalkyl and R9b is hydrogen; R10 is hydrogen, C1‑6alkyl optionally substituted with an alkoxy, di(lower alkyl)‑amino, or halogen, C1‑6haloalkyl, C3‑7cycloalkyl, heterocycloalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or 18 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 substituted heteroaryl; R11 is an optionally substitutedC1‑6alkyl, an optionally substituted cycloalkyl; an optionally substitutedC2‑6alkynyl, an optionally substituted C2‑6alkenyl, or optionally substituted acyl, which includes but is not limited to C(O)(C1‑6 alkyl); and Y, R3 and R12 are as defined herein.

[0068] In one embodiment, compounds of Formula II are disclosed: wherein: Y is NR1R2; R1 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CH2F, CHF2, CF3, CH2CF3, CF2CH3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, ‑C(O)R3C (including ‑C(O)CH3, ‑C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, - C(O) OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R2 is hydrogen, optionally substituted C1‑C5alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, tert-butyl andpentyl),C1‑C5haloalkyl (includingCHF2,CHF2,CF3,CH2CF3andCF2CF3), optionally substituted ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), optionally substituted ‑(C0‑C2alkyl)(heterocycle), optionally substituted ‑(C0‑C2alkyl) (aryl), optionally substituted ‑(C0‑C2alkyl)(heteroaryl), ‑C(O)R3C (including ‑C(O)CH3, - C(O)CH2CH3‑C(O) CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28; and wherein at least one of R1 and R2 is methyl, CH2F, CHF2 or CF3; R3 is hydrogen, , diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or ‑C(O)R3C; R3A can be selected from O-, OH, an ‑O-optionally substituted aryl, an ‑O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl; R3B can be selected from O-, OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester; R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), ‑O‑(C0‑C2)(hetero- aryl), ‑S-alkyl, ‑S-alkenyl, ‑S-alkynyl, ‑S‑(C0‑C2)(cycloalkyl), ‑S‑(C0‑C2)(heterocyclo), ‑S‑(C0‑C2)(aryl), or ‑S‑(C0‑C2) (heteroaryl) each of which can be optionally substituted; R3D is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), or ‑O‑(C0‑C2)(het- eroaryl), each of which can be optionally substituted; R4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a 19 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 phosphoramidate, a thiophosphoramidate, or anyothermoiety that ismetabolized to amonophosphate, diphosphate or triphosphate in vivo in the host human or animal; or R3andR4 togetherwith theoxygens that theyarebonded to can forma3’,5’-cyclic prodrug, includingbut not limited to, a 3’,5’-cyclic phosphate prodrug; R5 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl) (C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, ‑C(O)R3C (in- cluding ‑C(O)CH3, - C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R6 is hydrogen, optionally substituted C1‑C5alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, tert-butyl andpentyl), C1‑C5haloalkyl (includingCHF2,CH2F,CF3,CH2CF3andCF2CF3), optionally substituted ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), optionally substituted ‑(C0‑C2alkyl)(heterocycle), optionally substituted ‑(C0‑C2alkyl) (aryl), optionally substituted ‑(C0‑C2alkyl)(heteroaryl), ‑C(O)R3C (including ‑C(O)CH3, - C(O)CH2CH3‑C(O) CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and - C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28; or Rand R6 together with the nitrogen that they are bonded to can form a heterocyclic ring; R12 is CH3, CH2F, CHF2, CF3, or ethynyl; R22 is Cl, Br, F, CN, N3, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C1‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0-C2alkyl) (C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl); ‑ONHC(=O)OR23, ‑NHOR24, ‑OR25, ‑SR25, ‑NH(CH2)1‑4N(R26)2, ‑NHNHR26, ‑N=NR27, ‑NHC(O)NHNHR27, ‑NHC(S)NHNHR27, ‑C(O)NHNHR27, ‑NR27SO2R28, ‑SO2NR27R29, ‑C(O)NR27R29, ‑CO2R29, ‑SO2R29, -P(O)H(OR29), ‑P(O)(OR29)(OR30), ‑P(O)(OR29)(NR29R30) or ‑NR5R6; for example includingbut not limited to the followingembodiments, chloro, bromo, fluoro, cyano, azido, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl andn-pentyl, 1,1-dimethylpropyl, 2,2-dimtheylpropyl, 3-methylbutyl, 1-methylbutyl, 1-ethylpropyl, vinyl, allyl, 1-butynyl, 2-butynyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl, ‑(CH2)‑cyclopropyl, ‑(CH2)‑cyclobutyl, ‑(CH2)‑cyclopentyl, ‑(CH2)‑cyclohexyl, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, piperidine, oxane, thiane, ‑(CH2)‑a- ziridine, ‑(CH2)‑oxirane, ‑(CH2)‑thiirane, - (CH2)‑azetidine, ‑(CH2)‑oxetane, ‑(CH2)‑thietane, ‑(CH2)‑pyrrolidine, ‑(CH2)‑ tetrahydrofuran, ‑ (CH2)‑thiolane, ‑(CH2)‑pyrazolidine, ‑(CH2)‑piperidine, ‑(CH2)‑oxane, ‑(CH2)‑thiane, phe- nyl, pyridyl, ‑ONHC(=O)OCH3, ‑ONHC(=O)OCH2CH3, ‑NHOH, NHOCH3, ‑OCH3, OC2H5, ‑OPh, OCH2Ph, ‑SCH3, ‑SC2H5, ‑SPh, SCH2Ph, ‑NH(CH2)2NH2, ‑NH(CH2)2N(CH3)2, ‑NHNH2, ‑NHNHCH3, ‑N=NH, ‑N=NCH3, ‑N=NCH2CH3, ‑NHC(O)NHNH2, ‑NHC(S)NHNH2, ‑C(O)NHNH2, ‑NHSO2CH3, ‑NHSO2CH2CH3, ‑SO2NHCH3, ‑SO2N(CH3)2, ‑C(O)NH2, ‑C(O)NHCH3, ‑C(O)N(CH3)2, ‑CO2CH3, ‑CO2CH2CH3, ‑CO2Ph, ‑CO2CH2Ph, ‑SO2CH3, ‑SO2CH2CH3, ‑SO2Ph, ‑SO2CH2Ph, -P(O)H(OH), -P(O)H(OCH3), ‑P(O)(OH)(OH), ‑P(O)(OH)(OCH3), ‑P(O)(OCH3)(OCH3), ‑P(O)(OH)(NH2), ‑P(O)(OH) (NHCH3), ‑P(O)(OH)N(CH3)2, ‑NHC(O)CH3, ‑NHC(O)CH2CH3, ‑NHC(O)CH(CH3)2, ‑NHC(O)OCH3, ‑NHC(O) OCH2CH3, ‑NHC(O)OCH(CH3)2, ‑NHC(O)OCH2CH2CH3, ‑NHC(O)OCH2CH2CH2CH3 and ‑NHC(O) OCH2CH2CH2CH2CH3; R23 is C1‑C5alkyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle)‑(C0‑2alkyl)(aryl) or ‑(C0‑C2alkyl)(het- eroaryl) each of which can be optionally substituted; R24 is hydrogen, C1‑C6 alkyl, ‑(C1‑C2alkyl)(C3‑C6cycloalkyl), ‑(C1‑C2alkyl)(C3‑C6heterocycle) ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R25 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6he- terocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be 20 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 optionally substituted; R26 is independently selected fromhydrogen,C1‑C6alkyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R27 hydrogen or optionally substituted C1‑C6 alkyl; R28 is C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) each of which can be optionally substituted; R29 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6he- terocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; or R27 and R29 together with the nitrogen that they are bonded to can form a heterocyclic ring; R30 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3C6cycloalkyl), ‑(C0-C2alkyl)(C3‑C6he- terocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; or R29 and R30 can be bonded together to form a heterocyclic ring; x is 1, 2 or 3.

[0069] In another embodiment, compounds of Formula IIa are disclosed: wherein: Y, R3, R4 and R22 are as defined above.

[0070] In another embodiment, compounds of Formula IIb are disclosed: wherein: Y, R3, R4 and R22 are as defined above.

[0071] Ina typical embodiment, thecompound isaβ-D isomerwith reference to thecorrespondingnucleoside (i.e., in the naturally occurring configuration). In an alternative configuration, the compound is provided as a β-L isomer. The compound is typically at least 90% free of the opposite enantiomer, and can be at least 98%, 99% or even 100% free 21 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 of the opposite enantiomer. Unless described otherwise, the compound is at least 90% free of the opposite enantiomer.

[0072] In another embodiment, the compound is according to Formula III: wherein: R7 is hydrogen, C1‑6alkyl; C3‑7cycloalkyl; heteroaryl, heterocyclic, or aryl, which includes, but is not limited to, phenyl or naphthyl, wherephenyl or naphthyl areoptionally substitutedwithC1‑6alkyl,C2‑6alkenyl,C2‑6 alkynyl,C1‑6alkoxy, F, Cl, Br, I, nitro, cyano,C1‑6haloalkyl, ‑N(R7’)2,C1‑6acylamino,NHSO2C1‑6alkyl, ‑SO2N(R7’)2,COR7", and ‑SO2C1‑6alk- yl; (R7’ is independently hydrogen or C1‑6alkyl; R7" is ‑OR11 or-N(R7)2); R8 is hydrogen,C1‑6alkyl, orR9aorR9bandR8 together are (CH2)n soas to formacyclic ring that includes theadjoining N and C atoms; where n is 2 to 4; R9a and R9b are (i) independently selected from hydrogen, C1‑6alkyl, cycloalkyl, ‑(CH2)c(NR9’)2 , C1‑6hydroxyalkyl, --CH2SH, ‑(CH2)2S(O)(Me, ‑(CH2)3NHC(=NH)NH2, (1H-indol‑3-yl)methyl, (lH-imidazol‑4-yl)methyl, ‑(CH2)cCOR9", aryl and aryl(C1‑3alkyl)‑, the aryl groups can be optionally substituted with a group selected from hydroxyl, C1‑6alkyl, C1‑6alkoxy, halogen, nitro and cyano; (ii) R9a and R9b both are C1‑6alkyl; (iii) R9a and R9b together are (CH2)r so as to form a spiro ring; (iv) R9a is hydrogen and R9b and R8 together are (CH2)n so as to form a cyclic ring that includes the adjoiningNandCatoms (v)R9b is hydrogenandR9aandR8 together are (CH2)n soas to formacyclic ring that includes theadjoiningNandCatoms,wherec is1 to6,n is2 to4, r is2 to5andwhereR9’ is independently hydrogenorC1‑6 alkyl and R9" is ‑OR11 or ‑N(R11’)2 ); (vi) R9a is hydrogen and R9b is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol‑3-yl, ‑CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH,CH2CH2C(O) NH2, CH2CH2CH2CH2NH2, ‑CH2CH2CH2NHC(NH)NH2, CH2-imidazol‑4-yl, CH2OH, CH(OH)CH3, CH2((4’- OH)‑Ph), CH2SH, or lower cycloalkyl; or (vii) R9a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol‑3-yl, ‑CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, ‑CH2CH2CH2NHC(NH)NH2, CH2-imidazol‑4-yl, CH2OH, CH(OH)CH3, CH2((4’-OH)‑Ph), CH2SH, or lower cycloalkyl and R9b is hydrogen; R10 is hydrogen, C1‑6alkyl optionally substituted with an alkoxy, di(lower alkyl)‑amino, or halogen, C1‑6haloalkyl, C3‑7cycloalkyl, heterocycloalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; R11 is an optionally substitutedC1‑6alkyl, an optionally substituted cycloalkyl; an optionally substitutedC2‑6alkynyl, an optionally substituted C2‑6alkenyl, or optionally substituted acyl, which includes but is not limited to C(O)(C1‑6 alkyl); and Y, R3 R12 and R22 are as defined above.

[0073] In one embodiment, compounds of Formula IV are disclosed: 22 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein the variables Y, R3, R7, R8, R9a, R9b, R10 and R22 are described herein.

[0074] In one embodiment, compounds of Formula V are disclosed: wherein the variables Y, R3, R7, R8, R9a, R9b, R10 and R22 are described herein.

[0075] In an alternative embodiment, compounds, methods, and compositions are provided for the treatment of a host infected with or exposed to hepatitis C.

[0076] In one embodiment, compounds of Formula VI are disclosed: wherein: R41 is halogen (in particular F or Cl), OR3 (including OH), N3, NH2 or CN; and the variables Y, R3, R4, and R12 are described herein. 23 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0077] In one embodiment, compounds of Formula VII are disclosed: Wherein the variables Y, R3, R4, R12 and R41 are described herein. Metabolism of β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-C-substituted-N6-substituted‑2,6-diaminopurine nucleotides

[0078] The metabolism of the β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diaminopurine nucleoside phos- phoramidate involves the production of a 5’-monophosphate and the subsequent anabolism of the N6-methyl‑2,6- diaminopurine base to generate the β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-guanine nucleoside as the 5’-monophosphate. Themonophosphate is then further anabolized to theactive species; the 5’-triphosphate. Theβ-D‑2’-deoxy‑2’-α-fluoro‑2’- β-methyl-guanine triphosphate has an IC50 = 0.15 µM against the HCV genotype 1b NS5B polymerase. The metabolic pathway for the β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6-diaminopurine nucleoside phosphoramidate is illu- strated in Scheme 1 below. 24 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0079] Themetabolismof theβ-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-dimethyl‑2,6-diaminopurine nucleotide involves both the formationof theβ-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-dimethyl‑2,6-diaminopurinenucleoside triphosphateas well as the generation of the corresponding guanine nucleoside triphosphate. Thesemetabolic pathways are illustrated in Schemes 2 and 3 below. 25 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 26 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Stabilized Phosphate Prodrugs

[0080] Stabilized phosphate prodrugs are moieties that can deliver a mono, di, or triphosphate in vivo. For example, McGuigan has disclosed phosphoramidates in US Patent Nos.: 8,933,053; 8,759,318; 8,658,616; 8,263,575; 8,119,779; 7,951,787 and 7,115,590. Alios has disclosed thiophosphoramidates in US 8,895,723 and 8,871,737 incorporated by referenceherein.Alios hasalsodisclosedcyclic nucleotides inUSPatentNo. 8,772,474 incorporatedby referenceherein. Idenix has disclosed cyclic phosphoramidates and phosphoramidate / SATEderivatives inWO2013 / 177219 incorporated by reference herein. Idenix has also disclosed substituted carbonyloxymethylphosphoramidate compounds in WO 2013 / 039920 incorporated by reference herein. Hostetler has disclosed lipid phosphate prodrugs, see, for example, US 7,517,858. Hostetler has also disclosed lipid conjugates of phosphonate prodrugs, see, for example, US 8,889,658; 8,846,643; 8,710,030; 8,309,565; 8,008,308; and 7,790,703. Emory University has disclosed nucleotide sphingoid and lipid derivatives in WO 2014 / 124430. RFS Pharma has disclosed purine nucleoside monophosphate prodrugs in WO 2010 / 091386. Cocrystal Pharma Inc. has also disclosed purine nucleoside monophosphate prodrugs in US Patent No.: 9,173,893 incorporated by reference herein. HepDirect™ technology is disclosed in the article "Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver," (J. Am. Chem. Soc. 126, 5154‑5163 (2004). Additional phosphate prodrugs include, but are not limited to phosphate esters, 3’,5’-cyclic phosphates including CycloSAL, SATE derivatives (S- acyl‑2thioesters) and DTE (dithiodiethyl) prodrugs. For literature reviews that disclose non-limiting examples see: A. Ray and K. Hostetler, "Application of kinase bypass strategies to nucleoside antivirals," Antiviral Research (2011) 277‑291;M. Sofia, "Nucleotide prodrugs forHCV therapy," Antiviral Chemistry andChemotherapy 2011; 22‑23‑49; andS. Peyrottes et al., "SATE Pronucleotide Approaches: An Overview," Mini Reviews in Medicinal Chemistry 2004, 4, 395. In one embodiment, a 5’-prodrug described in any of these patent filings or literature can be used in the R4 position of the presented compounds.

[0081] In one alternative embodiment, the stabilized phosphate prodrugs, include, but are not limited to those described in U.S. Patent No. 9,173,893 andU.S. Patent No. 8,609,627, incorporated by reference herein, including for processes of preparation. For example, 5’-prodrugs of Formula I-V can be represented by the group: 27 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0082] In an alternate embodiment, 3’,5’-prodrugs of Formula I-V can be represented by the group: wherein: when chirality exists at the phosphorous center it may be wholly or partially Rp or Sp or any mixture thereof. Z is O or S; R33 is selected from OR34, and fatty alcohol derived (for example but not limited to: linoleyl-O , oleyl-O ) wherein R34, R35, and R36 are as defined below; R31 and R32, when administered in vivo, are capable of providing the nucleoside monophosphate or thiomo- nophosphate, which may or may not be partially or fully resistant to 6-NH2 deamination in a biological system. Representative R31 and R32 are independently selected from: (a) OR34 where R34 is selected from H, Li, Na, K, phenyl and pyridinyl; phenyl and pyridinyl are substituted with one to three substituents independently selected from the group consisting of (CH2)0‑6CO2R37 and (CH2)0‑6CON(R37)2; R37 is independently H, C1‑20 alkyl, the carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, and etc) or C1‑20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)‑amino, fluoro, C3‑10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1‑5 alkyl, or C1‑5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)‑amino, fluoro, C3‑10 cycloalkyl, or cycloalkyl; (b) (c) the ester of a D-amino acid or L-amino acid 28 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 where R36 is restricted to those sidechains occurring in natural L-amino acids, and R35 is H, C1‑20 alkyl, the carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, and etc) or C1‑20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)‑a- mino, fluoro, C3‑10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1‑5 alkyl, or C1‑5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)‑amino, fluoro, C3‑10 cycloalkyl, or cycloalkyl; (d) R31 and R32 can come together to form a ring whereR38 is H,C1‑20 alkyl, C1‑20 alkenyl, the carbon chain derived froma fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc) or C1‑20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)‑amino, fluoro,C3‑10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such asphenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1‑5 alkyl, or C1‑5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)‑amino, fluoro, C3‑10 cycloalkyl, or cycloalkyl; (e) R31 and R32 can come together to form a ring selected from and where R39 is O or NH and R40 is selected fromH,C1‑20alkyl,C1‑20 alkenyl, thecarbonchainderived froma fatty acid (suchasoleic acid, linoleic acid, and the like), and C1‑20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)‑amino, fluoro, C3‑10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1‑5 alkyl, or C1‑5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)‑amino, fluoro, C3‑10 cycloalkyl, or cycloalkyl.

[0083] The compounds can be prepared, for example, by preparing the 5’-OH analogs, then converting these to the 29 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 monophosphate analogs. Embodiments

[0084] In particular embodiments: (i) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, R4 is a stabilized phosphate prodrug; (ii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a stabilized thiophosphate prodrug; (iii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a phosphoramidate; (iv) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a thiophosphoramidate: (v) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a monophosphate; (vi) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a diphosphate; (vii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a triphosphate; (viii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, R4 is a stabilized phosphate prodrug; (ix) in Formula Ia, Y isNR1R2, R1 ismethyl, R2 ismethyl, R3 is hydrogen, andR4 is a stabilized thiophosphate prodrug; (x) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a phosphoramidate; (xi) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a thiophosphoramidate: (xii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a monophosphate; (xiii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a diphosphate; (xiv) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a triphosphate; (xv) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, R4 is a stabilized phosphate prodrug; (xvi) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a stabilized thiophosphate prodrug; (xvii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a phosphoramidate; (xviii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a thiophosphoramidate: (xix) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a monophosphate; (xx) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is methyl, and R4 is a diphosphate; (xxi) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a triphosphate; (xxii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is propyl, R3 is hydrogen, R4 is a stabilized phosphate prodrug; (xxiii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is propyl, R3 is hydrogen, and R4 is a stabilized thiophosphate prodrug; (xxiv) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is propyl, R3 is hydrogen, and R4 is a phosphoramidate; (xxv) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is propyl, R3 is hydrogen, and R4 is a thiophosphoramidate: (xxvi) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is propyl, R3 is hydrogen, and R4 is a monophosphate; (xxvii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is propyl, R3 is hydrogen, and R4 is a diphosphate; (xxviii)in Formula Ia, Y is NR1R2, Y is NR1R2, R1 is methyl, R2 is propyl, R3 is hydrogen, and R4 is a triphosphate; (xxix) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is ethyl, R3 is hydrogen, R4 is a stabilized phosphate prodrug; (xxx) in Formula Ia, Y isNR1R2, R1 ismethyl, R2 is ethyl, R3 is hydrogen, andR4 is a stabilized thiophosphate prodrug; (xxxi) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is ethyl, R3 is hydrogen, and R4 is a phosphoramidate; (xxxii) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is ethyl, R3 is hydrogen, and R4 is a thiophosphoramidate: (xxxiii)in Formula Ia, Y is NR1R2, R1 is methyl, R2 is ethyl, R3 is hydrogen, and R4 is a monophosphate; (xxxiv)in Formula Ia, Y is NR1R2, R1 is methyl, R2 is ethyl, R3 is hydrogen, and R4 is a diphosphate; (xxxv) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is ethyl, R3 is hydrogen, and R4 is a triphosphate; (xxxvi)in Formula Ib, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, R4 is a stabilized phosphate prodrug; (xxxvii) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a stabilized thiophosphate prodrug; (xxxviii) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a phosphoramidate; (xxxix)in Formula Ib, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a thiophosphoramidate: (xl) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a monophosphate; (xli) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a diphosphate; (xlii) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is methyl, R3 is hydrogen, and R4 is a triphosphate; (xliii) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, R4 is a stabilized phosphate prodrug; (xliv) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a stabilized thiophosphate prodrug; (xlv) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a phosphoramidate; (xlvi) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a thiophosphoramidate: (xlvii) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a monophosphate; 30 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (xlviii) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a diphosphate; (xlix) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, and R4 is a triphosphate; (l) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, R4 is a stabilized phosphate prodrug; (li) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a stabilized thiophosphate prodrug; (lii) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a phosphoramidate; (liii) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a thiophosphoramidate: (liv) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a monophosphate; (lv) in Formula Ib, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is methyl, and R4 is a diphosphate; (lvi) in Formula Ia, Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, and R4 is a triphosphate.

[0085] In alternative embodiments of any of the above, the compound has an R22 substituent. In some of these specific embodiments, theR22 is F, amideor carbamate. In other specific aspects of the embodiments above,R22 is chloro, bromo, cyano, azido, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and n-pentyl, 1,1-dimethylpropyl, 2,2- dimtheylpropyl, 3-methylbutyl, 1-methylbutyl, 1-ethylpropyl, vinyl, allyl, 1-butynyl, 2-butynyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ‑(CH2)‑cyclopropyl, ‑(CH2)‑cyclobutyl, - (CH2)‑cyclopentyl, ‑(CH2)‑cyclohexyl, azir- idine, oxirane, thiirane,azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, piperidine,oxane, thiane, ‑(CH2)‑aziridine, - (CH2)‑oxirane, ‑(CH2)‑thiirane, ‑(CH2)‑azetidine, ‑(CH2)‑oxetane, ‑(CH2)‑thietane, ‑(CH2)‑pyr- rolidine, ‑(CH2)‑ tetrahydrofuran, ‑(CH2)‑thiolane, ‑(CH2)‑pyrazolidine, ‑(CH2)‑piperidine, - (CH2)‑oxane, ‑(CH2)‑thiane, phenyl, pyridyl, ‑ONHC(=O)OCH3, ‑ONHC(=O)OCH2CH3, - NHOH, NHOCH3, ‑OCH3, OC2H5, ‑OPh, OCH2Ph, ‑SCH3, ‑SC2H5, ‑SPh, SCH2Ph, - NH(CH2)2NH2, ‑NH(CH2)2N(CH3)2, ‑NHNH2, ‑NHNHCH3, ‑N=NH, ‑N=NCH3, ‑N=NCH2CH3, - NHC(O)NHNH2, ‑NHC(S)NHNH2, ‑C(O)NHNH2, ‑NHSO2CH3, ‑NHSO2CH2CH3, ‑SO2NHCH3, ‑SO2N(CH3)2, ‑C(O)NH2, ‑C(O)NHCH3, ‑C(O)N(CH3)2, ‑CO2CH3, ‑CO2CH2CH3, ‑CO2Ph, CO2CH2Ph, ‑SO2CH3, ‑SO2CH2CH3, ‑SO2Ph, ‑SO2CH2Ph, ,‑P(O)H(OH), ‑P(O)H(OCH3), ‑P(O)(OH)(OH), ‑P(O)(OH)(OCH3), ‑P(O)(OCH3)(OCH3), - P(O)(OH)(NH2), ‑P(O)(OH) (NHCH3), ‑P(O)(OH)N(CH3)2, ‑NHC(O)CH3, ‑NHC(O)CH2CH3, - NHC(O)CH(CH3)2, ‑NHC(O)OCH3, ‑NHC(O) OCH2CH3, ‑NHC(O)OCH(CH3)2, - NHC(O)OCH2CH2CH3, ‑NHC(O)OCH2CH2CH2CH3 and ‑NHC(O) OCH2CH2CH2CH2CH3;

[0086] In alternative embodiments of compounds (i) through (lvi), an L-nucleoside is used in Formula I-VII.

[0087] In an alternate embodiment, the Formula I R12 variable is CH2F.

[0088] In an alternate embodiment, the Formula I R12 variable is CHF2.

[0089] In an alternate embodiment, the Formula I R12 variable is CF3.

[0090] In one embodiment, a compound of Formula Ia is provided. Non-limiting examples of compounds of Formula Ia include: 31 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 32 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 33 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and 34 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0091] In one embodiment, a thiophosphoramidate of Formula Ia is provided. Non-limiting examples of thiopho- sphoramidates of Formula Ia include, but are not limited to: 35 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 36 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 37 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0092] Inoneembodiment, a stabilizedphosphateprodrugofFormula Ia isprovided.Non-limitingexamplesof stabilized phosphate prodrugs of Formula Ia are illustrated below: and

[0093] In another embodiment, a compound of Formula Ia is provided.Non-limiting examples of compounds of Formula 38 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Ia include: 39 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 40 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 41 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and

[0094] In one embodiment, a thiophosphoramidate of Formula Ia is provided. Non-limiting examples of thiopho- sphoramidates of Formula Ia include, but are not limited to: 42 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 43 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 44 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0095] Inoneembodiment, a stabilizedphosphateprodrugofFormula Ia isprovided.Non-limitingexamplesof stabilized phosphate prodrugs of Formula Ia are illustrated below: 45 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and

[0096] In one embodiment, a compound of Formula II is provided. Non-limiting examples of compounds of Formula II include: 46 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 47 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 48 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 49 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 50 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 51 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0097] In one embodiment, a compound of Formula I is provided. Non-limiting examples of compounds of Formula I include: 52 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 53 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0098] In one embodiment, a compound of Formula II is provided. Non-limiting examples of compounds of Formula II include: 54 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and

[0099] In one embodiment, and R4 is

[0100] In one embodiment, a compound of Formula II is provided. Non-limiting examples of compounds of Formula II include: 55 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 56 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 57 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 58 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 59 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and

[0101] In some embodiments, R3 is H and R4 is

[0102] In some embodiments, R3 is H and R4 is

[0103] In some embodiments, R3 is H and R4 is 60 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0104] In one embodiment, a compound of Formula II is provided. Non-limiting examples of compounds of Formula II include: 61 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 62 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 63 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 64 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 65 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 66 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 67 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 68 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 69 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0105] In some embodiments, R3 is H and R4 is

[0106] In some embodiments, R3 is H and R4 is

[0107] In some embodiments, R3 is H and R4 is 70 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0108] In some embodiments, R1 is CH3, R2 is H, R3 is H and R4 is

[0109] In some embodiments, R1 is CH3, R2 is H, R3 is H and R4 is

[0110] In some embodiments, R1 is CH3, R2 is H, R3 is H and R4 is

[0111] In some embodiments, R1 is CH3, R2 is CH3, R3 is H and R4 is

[0112] In some embodiments, R1 is CH3, R2 is CH3, R3 is H and R4 is 71 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0113] In some embodiments, R1 is CH3, R2 is CH3, R3 is H and R4 is

[0114] In some embodiments, R1 is cyclopropyl, R2 is CH3, R3 is H and R4 is

[0115] In some embodiments, R1 is cyclopropyl, R2 is CH3, R3 is H and R4 is

[0116] In some embodiments, R1 is cyclopropyl, R2 is CH3, R3 is H and R4 is 72 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 II. Definitions

[0117] The following terms are used to describe the present invention. In instances where a term is not specifically definedherein, that term isgivenanart-recognizedmeaningby thoseofordinary skill applying that term incontext to its use in describing the present invention.

[0118] The term "alkyl" shall mean within its context, a linear, or branch-chained fully saturated hydrocarbon radical or alkyl group which can be optionally substituted (for example, with halogen, including F). For example, an alkyl group can have 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., C1 ‑C8 alkyl), 1, 2, 3, 4, 5 or 6 carbon atoms (i.e., C1‑C6 alkyl) or 1 to 4 carbon atoms (i.e.,C1‑C4alkyl).Examplesof suitablealkyl groups include, butarenot limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2- dimethylbutyl and 2,3-dimethylbutyl.

[0119] The term "alkenyl" refers to a non-aromatic hydrocarbon groupwhich contains at least one double bond between adjacent carbon atoms and a similar structure to an alkyl group as otherwise described herein. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2‑C8 alkenyl), or 2 to 4 carbon atoms (i.e., C2‑C4 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-butenyl (-C=CH- CH2CH3) and 2-butenyl (-CH2CH=CHCH2). The alkenyl group can be optionally substituted as described herein.

[0120] The term "alkynyl" refers to a non-aromatic hydrocarbon group containing at least one triple bond between adjacent carbon atoms and a similar structure to an alkyl group as otherwise described herein. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C2‑C8 alkyne,), or 2 to 4 carbon atoms (i.e., C2‑C4 alkynyl). Examples of alkynyl groups include, but are not limited to, acetylenic or ethynyl and propargyl. The alkynyl group can be optionally substituted as described herein.

[0121] The term "acyl" refers to themoiety ‑C(O)R inwhich the carbonyl moiety is bonded toR, for example, ‑C(O)alkyl. R can be selected from alkoxy, alkyl, cycloalkyl, lower alkyl (i.e., C1‑C4); alkoxyalkyl, including methoxymethyl; aralkyl‑ including benzyl, aryloxyalkyl‑ such as phenoxymethyl; aryl including phenyl optionally substituted with halogen, C1 to C4 alkyl or C1 to C4 alkoxy. In one embodiment, the term "acyl" refers to a mono, di or triphosphate.

[0122] The term "lower acyl" refers to an acyl group in which the carbonyl moiety is lower alkyl (i.e., C1‑C4).

[0123] The term "alkoxy" refers to the group ‑OR’where ‑OR’ is ‑O-alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), or ‑O‑(C0‑C2)(heteroaryl), each of which can be optionally substituted.

[0124] The term "amino" refers to the group ‑NH2.

[0125] The term "amino acid" or "amino acid residue" refers to a D‑ or L‑ natural or non-naturally occurring amino acid. Representative amino acids include, but are not limited to, alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine, among others.

[0126] The term "azido" refers to the group ‑N3.

[0127] The term "aryl" or "aromatic", in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., phenyl or benzyl) or condensed rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and canbe bound to the compoundaccording to thepresent invention at any available stable position on the ring(s) or asotherwise indicated in the chemical structurepresented. Thearyl group canbeoptionally substitutedas described herein.

[0128] "Cycloalkyl", "carbocycle", or "carbocyclyl" refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a monocycle. Monocyclic carbocycles have 3 to 7 ringatoms, stillmore typically 5or 6 ringatoms.Non-limitingexamplesof cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent‑1-enyl, 1-cyclopent‑2-enyl, 1-cyclopent‑3-enyl, cyclohexyl, 1-cyclohex‑1-enyl, 1-cyclohex‑2- enyl, and l-cyclo-hex‑3-enyl.

[0129] The term "cyano" refers to the group ‑CN.

[0130] The term "halogen" or "halo" refers to chloro, bromo, fluoro or iodo.

[0131] A heteroaryl ring system is a saturated or unsaturated ring with one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic) including but not limited to imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, purine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, etc., among others, which may be optionally substituted as described above. Heteroaryl groups include nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, purine, indazole, quinoline, isoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carba- zole, carbazoline, perimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-contain- ing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic hetero- cyclescomprising twoormoreheteroatomsselected fromamongnitrogen, sulfur andoxygen, suchas thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazolox- 73 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 azole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxa- zole, among others, all of which may be optionally substituted.

[0132] The term "heterocycle" or "heterocyclo" refers to a cyclic groupwhich contains at least oneheteroatom, i.e.,O,N, or S, and may be aromatic (heteroaryl) or non-aromatic. Exemplary non-aromatic heterocyclic groups for use in the present invention include, for example, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, imidazolinyl, pyrazoli- dinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2-pyrrolidone, ethyle- neurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide, and succinimide, among others, all of which may be optionally substituted.

[0133] The term "hydroxyl" refers to the group ‑OH.

[0134] The term "nitro" refers to the group ‑NO2.

[0135] The term "pharmaceutically acceptable salt" or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphoramidate, thiophosphoramidate, phosphate ester, salt of an ester, or a related group) of a β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted purine nucleotide which, upon administration to a patient, provides the desired active compound. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycer- ophosphate. Suitable inorganic salts may also be formed, including sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an aminewith a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium, or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

[0136] "Pharmaceutically acceptable prodrug" refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that havebiologically labile protectinggroupsona functionalmoiety of theactivecompound.Prodrugs includecompounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, thiophoshoramidated, dethiophoshoramidated, phoshoramidated or dephosphoramidated to produce the active compound. The compounds of this invention possess antiviral activity against HCV, or are metabolized to a compound that exhibits such activity. The β-D‑2’-D‑2’-α-fluoro‑2’-β- C-substituted‑2-modified-N6-substituted purine nucleoside can also be administered as a 5’-phosphoether lipid, a bisphosphoramidate, a 3’,5’-cyclic phosphoramidate, a 3’,5’-cyclic thiophosphoramidate, a DTE conjugate, a mixed phosphoramidate-SATE derivative or a "SATE" derivative.

[0137] The term "phosphonic acid" refers to the group ‑P(O)(OH)2.

[0138] In one embodiment, the term purine or pyrimidine base includes, but is not limited to, adenine, N6-alkylpurines, N6-acylpurines (wherein acyl is ‑C(O)alkyl, ‑C(O)(aryl)C0‑C4alkyl, or ‑C(O)(C0‑C4alkyl)aryl), N6-benzylpurine, N6-halo- purine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkylpurines, N2-alkyl‑6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2‑ and / or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C5-alkylpyrimidines, C5-benzylpyrimidines, C5-halopyrimidines, C5 -vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-ami- dopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, N2-alkylpurines, N2-alkyl‑6-thiopurines, 5- azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolo-pyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include benzyl, trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphe- nylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl; methanesulfonyl, and p-toluenesulfonyl. Alternatively, the purine or pyrimidine base can optionally be substituted such that it forms a viable prodrug, which can be cleaved in vivo. Examples of appropriate substituents include an acyl moiety.

[0139] The term "substituted" or "optionally substituted" indicates that the moiety can have at least one additional substituent including, but not limited to, halogen (F, Cl, Br, I), OH, phenyl, benzyl, N3, CN, acyl, alkyl, including methyl; alkenyl, alkynyl, alkoxy, haloalkyl; including CHF2, CH2F and CF3; etc. In one embodiment, the term "substituted" or "optionally substituted" indicates that the moiety can have at least one additional substituent including, but not limited to, azido, cyano, halogen (fluoro, chloro, bromo, or iodo), alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, haloalkyl, hydroxyl, alkoxy, amino, ‑NH(C1‑C6 unsubstituted alkyl), ‑NH(C1‑C6 substituted alkyl), ‑NH‑(C0‑C2alkyl) (C3‑C8cycloalkyl), ‑NH‑(C0‑C2alkyl)(C3‑C8heterocycle),‑NH‑(C0‑C2alkyl)(aryl), ‑N(C1‑C6 unsubstituted alkyl)2, ‑N(C1‑C6 unsubstituted alkyl)(C1‑C6 substituted alkyl), ‑N(C1‑C6 substituted alkyl)2,‑NH‑(C0‑C2alkyl)(C3‑C8cycloalkyl), -NH‑(C0‑C2alkyl)(C3‑C8heterocycle),‑NH‑(C0‑C2alkyl)(aryl), acyl, nitro, sulfonic acid, sulfate, phosphonic acid, phos- phate, phosphonate, or thiol.

[0140] The term "sulfonate esters", represented by the formula, R14S(O)2OR15, comprise R14 wherein R14 is alkyl, haloalkyl, aralkyl or aryl. R15 is alkyl, aryl or aralkyl. 74 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0141] The term "sulfonic acid" refers to the group ‑SO2OH.

[0142] The term "thiol" refers to the group ‑SH.

[0143] The term "nitrogen-protecting group" as used herein refers to amoiety that is covalently attached to nitrogen and which can be removed, and typically replacedwith hydrogen, when appropriate. For example, a nitrogen-protecting group may be a group that is removed in vivo after administration to a host, in vitro by a cell, or it may be removed during a manufacturing process. Suitable nitrogen-protecting groups useful in the present invention are described by Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.

[0144] The term "oxygen-protecting group" as used herein refers to a moiety that is covalently attached to oxygen and which canbe removed, and typically replacedwith hydrogen,whenappropriate. For example, anoxygen-protecting group may be a group that is removed in vivo after administration to a host, in vitro by a cell, or it may be removed during a manufacturing process. Suitable oxygen-protecting groups useful in the present invention are described by Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.

[0145] "Phosphate" refers to the group ‑OP(O)(OH)2.

[0146] "Phosphate ester" refers to mono, di, and tri phosphates unless otherwise indicated.

[0147] The term "phosphoamidate", "phosphoramidate", or "phosphoroamidate" is a moiety that has a phosphorus bound to three oxygen groups and an amine (which may optionally be substituted). Suitable phosphoramidates useful in the present invention are described by Madela, Karolina and McGuigan in 2012, "Progress in the development of anti- hepatitis C virus nucleoside and nucleotide prodrugs", Future Medicinal Chemistry 4(5), pages 625‑650 10:1021 / jm300074y and Dominique, McGuigan and Balzarini in 2004, "Aryloxy Phosphoramidate Triesters as Pro- Tides", Mini Reviews in Medicinal Chemistry 4(4), pages 371‑381. Additional phosphoramidates useful in the present invention are described in U.S. Patent Nos. 5,233,031, 7,115,590, 7,547,704, 7,879,815, 7,888,330, 7,902,202, 7,951,789, 7,964,580, 8,071,568; 8,148,349, 8,263,575, 8,324,179, 8,334,270, 8,552,021, 8,563,530, 8,580,765, 8,735,372, 8,759,318; EP 2120565; EP 1143995; 6,455,513; and 8,334,270. Other phosphoramidates are described in the nucleoside patents described in the Background of the Invention.

[0148] Phosphoramidate groups for use in the present invention include those of the structures: 75 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0149] Other phosphoramidates for use in the present invention include those of the structure: wherein: RP1 is an optionally substituted linear, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl or heterocyclic group or a linked combination thereof; and RP2 is a ‑NRN1RN2 group or a B’ group; wherein: RN1 and RN2 are each independently H, C1‑8alkyl, (C3‑C7cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocy- clo)C0‑C4alkyl‑, or (heteroaryl)C0‑C4alky‑; which may be optionally substituted; or RN1 andRN2 alongwith the nitrogen atom to which that are attached, join to form a 3 to 7membered heterocyclic ring; B’ is a group; wherein: R16 is hydrogen, (C1‑C8)alkyl, (C2‑C8)alkenyl, (C2‑C8)alkynyl, (C3‑C8cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocyclo)C0‑C4alkyl‑, (heteroaryl)C0‑C4alky‑, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine (often R16 is hydrogen, methyl, isopropyl, or isobutyl); R17 is hydrogen, (C1‑C8)alkyl, (C2‑C8)alkenyl, (C2‑C8)alkynyl, (C3‑C8cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocyclo)C0‑C4alkyl‑, (heteroaryl)C0‑C4alky‑, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine (often R17 is hydrogen, methyl, isopropyl, or isobutyl); R18 is hydrogen or C1‑C3alkyl; or R16 and R17 can form a (C3‑C7)cycloalkyl or (C3‑C7)heterocyclic group; or R18 and R16 or R17 can form (C3‑C6)heterocyclic group; and R19 is hydrogen, (C1‑C6)alkyl, (C3‑C6)alkenyl, (C3‑C6)alkynyl, (C3‑C8cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocyclo)C0‑C4alkyl‑, (heteroaryl)C0‑C4alky‑; or 76 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 B’ is a group; wherein: R20 is hydrogen, (C1‑C3)alkyl, (C3‑C8cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocyclo)C0‑C4alkyl‑, or (heteroaryl)C0‑C4alky‑; R21 is hydrogen, (C1‑C3)alkyl, (C3‑C8cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocyclo)C0‑C4alkyl‑, or (heteroaryl)C0‑C4alky‑; and R18 and R19 are as defined above.

[0150] Preferred RP1 groups include optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) which enhance bioavailability of the compounds in the cells of the patient and which exhibit reduced toxicity, enhanced therapeutic index and enhanced pharmacokinetics (the compounds are metabolized and excreted more slowly).

[0151] The term phosphoramidate is used throughout the specification to describe a group that is found at the 5’ or 3’ position of the furanose ring of the nucleoside compound and forms a prodrug form of the nucleoside compound. In one embodiment, phosphoramidates can be found at both the 5’ and 3’ position of the furanose ring of the nucleoside compound and form a prodrug form of the nucleoside compound. In another embodiment, the phosphoramidate found at the 5’ position of the furanose ring of the nucleoside can form a cyclic phosphoramidate compound by forming a bondwith the3’-hydroxyl substituent at the3’ positionof the furanose ringof thenucleosidecompoundand formaprodrug formof the nucleoside compound.

[0152] The term "thiophosphoamidate", "thiophosphoramidate", or "thiophosphoroamidate" is a moiety that has a phosphorus bound to sulfur, two oxygen groups and an amine (which may optionally be substituted). Thiophosphor- amidates useful in the present invention are described in US Patent No. 8,772,474 and WO 2012 / 040124.

[0153] Thiophosphoramidate groups for use in the present invention include those of the structures: 77 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0154] Other thiophosphoramidates include those of the structure: wherein: RP1 is an optionally substituted linear, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl or heterocyclic group or a linked combination thereof; and RP2 is a ‑NRN1RN2 group or a B’ group; wherein: RN1 and RN2 are each independently H, C1‑C8 alkyl, (C3‑C7cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heter- ocyclo)C0‑C4alkyl‑, or (heteroaryl)C0‑C4alky‑; or RN1 andRN2 alongwith the nitrogen atom to which that are attached, join to form a 3 to 7membered heterocyclic ring; B’ is a group; wherein: R16 is hydrogen, (C1‑C8)alkyl, (C2‑C8)alkenyl, (C2‑C8)alkynyl, (C3‑C8cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocyclo)C0‑C4alkyl‑, (heteroaryl)C0‑C4alky‑, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine (often R16 is 78 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 hydrogen, methyl, isopropyl, or isobutyl); R17 is hydrogen, (C1‑C8)alkyl, (C2‑C8)alkenyl, (C2‑C8)alkynyl, (C3‑C8cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocyclo)C0‑C4alkyl‑, (heteroaryl)C0‑C4alky‑, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine (often R17 is hydrogen, methyl, isopropyl, or isobutyl); R18 is hydrogen or C1‑C3alkyl; or R16 and R17 can form a (C3‑C7)cycloalkyl or (C3‑C7)heterocyclic group; or R18 and R16 or R17 can form (C3‑C6) heterocyclic group; and R19 is hydrogen, (C1‑C6)alkyl, (C3‑C6)alkenyl, (C3‑C6)alkynyl, (C3‑C8cycloalkyl)C0‑C4alkyl‑, (aryl)C0‑C4alkyl‑, (C3‑C6heterocyclo)C0‑C4alkyl‑, (heteroaryl)C0‑C4alky‑; or B’ is a group; and R18, R19, R20 and R21 are as defined above.

[0155] Preferred RP1 groups include optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) which enhance bioavailability of the compounds into the cells of the patient and which exhibit reduced toxicity, enhanced therapeutic index and enhanced pharmacokinetics (the compounds are metabolized and excreted more slowly).

[0156] The thiophosphoramidate can beat the 5’ or 3’ position of the furanose ring of the nucleoside compound to forma prodrug form of the nucleoside compound. In one embodiment, thiophosphoramidates can be found at both the 5’ and 3’ position of the furanose ring of the nucleoside compound and formaprodrug formof the nucleoside compound. In another embodiment, the thiophosphoramidate found at the 5’ position of the furanose ring of the nucleoside can form a cyclic thiophosphoramidate compoundby forming abondwith the3’-hydroxyl substituent at the 3’ position of the furanose ring of the nucleoside compound and form a prodrug form of the nucleoside compound.

[0157] The term "D-configuration" as used in the context of the present invention refers to the principle configuration which mimics the natural configuration of sugar moieties as opposed to the unnatural occurring nucleosides or "L" configuration. The term "β" or "β anomer" is used with reference to nucleoside analogs in which the nucleoside base is configured (disposed) above the plane of the furanose moiety in the nucleoside analog.

[0158] The terms "coadminister" and "coadministration" or combination therapy are used to describe the administration of at least oneof the 2’-deoxy‑2’-α-fluoro‑2’-β-C-nucleoside compoundsaccording to thepresent invention in combination with at least one other active agent, for example where appropriate at least one additional anti-HCVagent, including other 2’-deoxy‑2’-α-fluoro‑2’-β-C-nucleoside agents which are disclosed herein. The timing of the coadministration is best determined by the medical specialist treating the patient. It is sometimes preferred that the agents be administered at the same time. Alternatively, the drugs selected for combination therapymay be administered at different times to the patient. Of course, when more than one viral or other infection or other condition is present, the present compounds may be combined with other agents to treat that other infection or condition as required.

[0159] The term "host", as used herein, refers to a unicellular or multicellular organism in which a HCV virus can replicate, including cell lines and animals, and typically a human. The term host specifically refers to infected cells, cells transfectedwith all or part of aHCVgenome, and animals, in particular, primates (including chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees). The host can be for example, bovine, equine, avian, canine, feline, etc. 79 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Isotopic Substitution

[0160] The present invention includes compounds and the use of compounds with desired isotopic substitutions of atoms, at amounts above the natural abundance of the isotope, i.e., enriched. Isotopes are atomshaving the sameatomic numberbut differentmassnumbers, i.e., the samenumberof protonsbut adifferent numberof neutrons.Bywayof general example andwithout limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H)may be used anywhere indescribedstructures.Alternatively or inaddition, isotopesof carbon, e.g., 13Cand14C,maybeused.Apreferred isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug. The deuterium can be bound in a location of bond breakage during metabolism (an α-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a β-deuterium kinetic isotope effect). Achillion Pharmaceuticals, Inc. (WO / 2014 / 169278 and WO / 2014 / 169280) describes deuteration of nucleotides to improve their pharmacokinetics or pharmacodynamics, including at the 5-position of the molecule.

[0161] Substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Substitution of deuterium forhydrogenat a site ofmetabolic breakdowncan reduce the rate of or eliminate themetabolismat that bond.At any position of the compound that a hydrogen atommay be present, the hydrogen atom can be any isotope of hydrogen, including protium (1H), deuterium (2H) and tritium (3H). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0162] The term"isotopically-labeled"analog refers toananalog that isa "deuteratedanalog", a "13C-labeledanalog," or a "deuterated / 13C-labeled analog." The term "deuterated analog" means a compound described herein, whereby a H- isotope, i.e., hydrogen / protium (1H), is substituted by a H-isotope, i.e., deuterium (2H). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium. Incertainembodiments, the isotope is90,95or99%ormoreenriched inan isotopeatany locationof interest. In someembodiments it is deuterium that is 90, 95or 99%enrichedat a desired location.Unless indicated to the contrary, the deuteration is at least 80% at the selected location. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired results. III. Methods of Treatment or Prophylaxis

[0163] Treatment, asusedherein, refers to theadministration of anactive compound toahost that is infectedwithaHCV virus.

[0164] The term "prophylactic" or preventative,whenused, refers to theadministrationof anactivecompound toprevent or reduce the likelihood of an occurrence of the viral disorder. The present invention includes both treatment and prophylactic or preventative therapies. In one embodiment, the active compound is administered to a host who has been exposed to and thus at risk of infection by a hepatitis C virus infection. The invention is directed to a method of treatment or prophylaxis of a hepatitis C virus, including drug resistant and multidrug resistant forms of HCVand related disease states, conditions, or complications of an HCV infection, including cirrhosisand relatedhepatotoxicities, aswell asother conditions that aresecondary toaHCVinfection, suchasweakness, loss of appetite, weight loss, breast enlargement (especially in men), rash (especially on the palms), difficulty with clotting of blood, spider-like blood vessels on the skin, confusion, coma (encephalopathy), buildup of fluid in the abdominal cavity (ascites), esophageal varices, portal hypertension, kidney failure, enlarged spleen, decrease in blood cells, anemia, thrombocytopenia, jaundice, and hepatocellular cancer, among others. Themethod comprises administering to a host in need thereof an effective amount of at least one β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted purine nucleotide as described herein, optionally in combination with at least one additional bioactive agent, for example, an additional anti-HCV agent, further in combination with a pharmaceutically acceptable carrier additive and / or excipient.

[0165] In yet another aspect, the present invention is a method for prevention or prophylaxis of a an HCV infection or a disease state or related or follow-on disease state, condition or complication of an HCV infection, including cirrhosis and related hepatotoxicities, weakness, loss of appetite, weight loss, breast enlargement (especially inmen), rash (especially on the palms), difficulty with clotting of blood, spider-like blood vessels on the skin, confusion, coma (encephalopathy), buildup of fluid in the abdominal cavity (ascites), esophageal varices, portal hypertension, kidney failure, enlarged spleen, decrease in blood cells, anemia, thrombocytopenia, jaundice, and hepatocellular (liver) cancer, among others, said method comprising administering to a patient at risk with an effective amount of at least one compound according to the present invention as described above in combination with a pharmaceutically acceptable carrier, additive, or excipient, optionally in combinationwith another anti-HCVagent. In another embodiment, the active compounds of the invention can be administered to a patient after a hepatitis-related liver transplantation to protect the new organ.

[0166] The 5’-stabilized β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted purine nucleotide can be administered if desired as any salt or prodrug that upon administration to the recipient is capable of providing directly or indirectly the parent compound, or that exhibits activity itself. Nonlimiting examples are the pharmaceutically acceptable 80 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 salts and a compound, which has been modified at a function group, such as a hydroxyl or amine function, to modify the biological activity, pharmacokinetics, half-life, controlleddelivery, lipophilicity, absorption kinetics, easeofphosphorylation to the active 5’-triphosphate or efficiency of delivery using a desired route of administration of the compound. Methods to modify the properties of an active compound to achieve target properties are known to those of skill in the art or can easily beassessedby standardmethods, for example, acylation, phosphorylation, thiophosphoramidation, phosphoramidation, phosphonation, alkylation, or pegylation. IV. Pharmaceutical Compositions

[0167] In an aspect of the invention, pharmaceutical compositions according to the present invention comprise an anti- HCV virus effective amount of at least one of the 5’-stabilized β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6- substituted purine nucleotide compounds described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, further optionally in combination or alternation with at least one other active compound.

[0168] In an aspect of the invention, pharmaceutical compositions according to the present invention comprise an anti- HCV effective amount of at least one of the active β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted purine nucleotide compounds described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, further optionally in combination with at least one other antiviral, such as an anti-HCV agent.

[0169] The invention includes pharmaceutical compositions that include an effective amount to treat a hepatitis C virus infection, of oneof theβ-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substitutedpurinenucleotidecompoundsof the present invention or its salt or prodrug, in a pharmaceutically acceptable carrier or excipient. In an alternative embodiment, the invention includes pharmaceutical compositions that includeaneffective amount to prevent a hepatitisC virus infection, of one of the β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted purine nucleotide com- pounds of the present invention or its salt or prodrug, in a pharmaceutically acceptable carrier or excipient.

[0170] 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 beemployed, the pharmacokinetics of the agent used, aswell as thepatient or subject (animal or human) to be treated, and such therapeutic amount can bedeterminedby theattending physician or specialist.

[0171] The 5’-stabilized β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2‑ modified ‑N6-substituted purine nucleotide com- poundsaccording to thepresent inventioncanbe formulated inanadmixturewithapharmaceutically acceptable carrier. In general, it is preferable to administer thepharmaceutical composition inorally-administrable form,but certain formulations may be administered via a parenteral, intravenous, intramuscular, topical, transdermal, buccal, subcutaneous, suppo- sitory, or other route, including intranasal spray. Intravenous and intramuscular formulations are often administered in sterile saline. One of ordinary skill in the art may modify the formulations to render them more soluble in water or other vehicle, for example, this can be easily accomplished by minor modifications (salt formulation, esterification, etc.) which are well within the ordinary skill in the art. It is also well within the routineers’ 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.

[0172] In certain pharmaceutical dosage forms, the prodrug form of the compounds, especially including acylated (acetylated or other), and ether (alkyl and related) derivatives, phosphate esters, thiophosphoramidates, phosphorami- dates, and various salt forms of the present compounds, are preferred. One of ordinary skill in the art will recognize how to readily modify the present compounds to prodrug forms 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 prodrug forms,whereapplicable, in delivering thepresent compounds toa targeted sitewithin thehost organismor patient to maximize the intended effect of the compound.

[0173] Theamountof compound includedwithin therapeutically active formulationsaccording to thepresent invention is an effective amount for treating the HCV infection, reducing the likelihood of a HCV infection or the inhibition, reduction, and / or abolition of HCV or its secondary effects, including disease states, conditions, and / or complications which occur secondary toHCV. In general, a therapeutically effective amount of the present compound in pharmaceutical dosage form usually ranges fromabout 0.001mg / kg to about 100mg / kg per day ormore,more often, slightly less than about 0.1mg / kg to more than 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 0.1 mg / kg to about 15 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 0.001 to about 100, about 0.05 to about 100 micrograms / cc of blood in the patient.

[0174] Often, to treat, prevent or delay the onset of these infections and / or to reduce the likelihood of an HCV virus infection, or a secondary disease state, condition or complication of HCV, the compositions will be administered in oral dosage form in amounts ranging fromabout 250micrograms up to about 500mg ormore at least once a day, for example, 81 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 at least 25, 50, 100, 150, 250 or 500 milligrams, up to four times a day. The present compounds are often administered orally, butmay be administered parenterally, topically, or in suppository form, aswell as intranasally, as a nasal spray or as otherwise described herein.

[0175] In the case of the co-administration of the present compounds in combination with another anti-HCV compound as otherwise described herein, the amount of the compound according to the present invention to be administered ranges fromabout 0.01mg / kg of the patient to about 500mg / kg. ormore of the patient or considerablymore, depending upon the second agent to be co-administered and its potency against the virus, the condition of the patient and severity of the disease or infection to be treated and the route of administration. The other anti-HCV agent may for example be administered in amounts ranging from about 0.01 mg / kg to about 500 mg / kg. In certain preferred embodiments, these compoundsmay be often administered in an amount ranging from about 0.5mg / kg to about 50mg / kg ormore (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.

[0176] For purposes of the present invention, a prophylactically or preventive effective amount of the compositions according to the present invention falls within the same concentration range as set forth above for therapeutically effective amount and is usually the same as a therapeutically effective amount.

[0177] Administration of the active compoundmay range fromcontinuous (intravenousdrip) to several oral or intranasal administrations per day (for example, 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 for 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. Oral dosage forms are particularly preferred, because of ease of administration and prospective favorable patient compliance.

[0178] 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 often intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take awide 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 mediamay be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives includingwater, glycols, oils, alcohols, flavoringagents, preservatives, coloringagents, and the likemaybeused. 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, manifold, lactose, and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents, and the likemay be used. If desired, the tablets or capsules may be enteric-coated or sustained release by standard techniques. The use of these dosage forms may significantly enhance the bioavailability of the compounds in the patient.

[0179] For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, thoughother ingredients, including thosewhichaiddispersion,alsomaybe included.Ofcourse,wheresterilewater is tobe used andmaintained as sterile, the compositions and carriersmust also be sterilized. Injectable suspensionsmay also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be employed.

[0180] 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 prodrug forms of the nucleoside compounds according to the present invention.

[0181] In typical embodiments according to the present invention, the compounds and compositions are used to treat, prevent or delay a HCV infection or a secondary disease state, condition or complication of HCV. V. Combination and Alternation Therapy

[0182] It is well recognized that drug-resistant variants of viruses can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication. Theefficacyof a drugagainst anHCV infection, canbeprolonged, augmented, or restoredbyadministering the compound in combination or alternationwith another, andperhapseven twoor threeother, antiviral compounds that induceadifferent mutation or act through a different pathway, from that of the principle drug. Alternatively, the pharmacokinetics, bio distribution, half-life, or other parameter of the drug can be altered by such combination therapy (which may include alternation therapy if considered concerted). Since the disclosed β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2‑modified-N6- substituted purine nucleotides are NS5B polymerase inhibitors, it may be useful to administer the compound to a host in combination with, for example a: (1) Protease inhibitor, such as an NS3 / 4A protease inhibitor; 82 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (2) NS5A inhibitor; (3) Another NS5B polymerase inhibitor; (4) NS5B non-substrate inhibitor; (5) Interferon alfa‑2a, which may be pegylated or otherwise modified, and / or ribavirin; (6) Non-substrate-based inhibitor; (7) Helicase inhibitor; (8) Antisense oligodeoxynucleotide (S-ODN); (9) Aptamer; (10) Nuclease-resistant ribozyme; (11) iRNA, including microRNA and SiRNA; (12) Antibody, partial antibody or domain antibody to the virus, or (13) Viral antigen or partial antigen that induces a host antibody response. Non limiting examples of anti-HCVagents that can be administered in combination with the β-D‑2’-D‑2’-α-fluoro‑2’-β-C- substituted‑2- modified-N6-substituted purine nucleotides of the invention are: (i) protease inhibitors such as telaprevir (Incivek®), boceprevir (Victrelis™), simeprevir (Olysio™), paritaprevir (ABT‑450), ACH‑2684; AZD‑7295; BMS‑791325; danoprevir; Filibuvir; GS‑9256; GS‑9451; MK‑5172; Setrobuvir; Sovaprevir; Tegobuvir; VX‑135; VX‑222 and ALS‑220; (ii) NS5A inhibitor such as ACH‑2928, ACH‑3102, IDX‑719, daclatasvir, ledispasvir and Ombitasvir (ABT‑267); (iii) NS5B inhibitors such asACH‑3422; AZD‑7295; Clemizole; ITX‑5061; PPI‑461; PPI‑688, Sovaldi®,MK‑3682, and mericitabine; (iv) NS5B inhibitors such as ABT‑333, MBX‑700; and, (v) Antibody such as GS‑6624.

[0183] If the β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2‑ modified-N6-substituted purine nucleotide is administered to treatadvancedhepatitisCvirus leading to liver canceror cirrhosis, inoneembodiment, thecompoundcanbeadministered in combination or alternationwith another drug that is typically used to treat hepatocellular carcinoma (HCC), for example, as described by Andrew Zhu in "New Agents on the Horizon in Hepatocellular Carcinoma" Therapeutic Advances in MedicalOncology, V 5(1), January 2013, 41‑50. Examples of suitable compounds for combination therapywhere the host hasor isat riskofHCC includeanti-angiogenicagents, sunitinib, brivanib, linifanib, ramucirumab,bevacizumab, cediranib, pazopanib, TSU‑68, lenvatinib, antibodies against EGFR, mTor inhibitors, MEK inhibitors, and histone decetylace inhibitors.

[0184] Drugs that are currently approved for influenza are Amantadine, Rimantadine and Oseltamivir. Any of these drugs can be used in combination or alternation with an active compound provided herein to treat a viral infection susceptible to such. Ribavirin is used to treat measles, Influenza A, influenza B, parainfluenza, severe RSV bronchiolitis andSARSaswell asother viral infections,and therefore isparticularly useful in combinationwith thepresent compound for treatment of the host infectedwith a single strandedRNAvirus. Palivizumab is approved for use in infantswith high risk for RSV infection.

[0185] Currently, there are no approved drugs for West Nile virus. Physicians are recommended to provide intensive support therapy, whichmay involve hospitalization, intravenous fluids, use of a ventilator to assist breathing, medications tocontrol seizures, brain swelling, nauseaandvomiting, and theuseof antibiotics topreventbacterial infections formaking the disease even worse. This highlights the importance of the present compounds for viral medical therapy. VI. Process of Preparation of β-D‑2’-D‑2’-α-fluoro‑2’-β-C-substituted‑2-modified-N6-Substituted Purine Nu- cleotides of the Invention

[0186] General methods for providing the compounds of the present invention are known in the art or described herein. The synthesis of 2’-chloro nucleotides is described in US 20150366888, WO 2014058801; WO 2015 / 066370 and WO 2015200219.

[0187] The following abbreviations are used in the synthetic schemes. CBr4: Carbon tetrabromide DBU: 1,8-Diazabicyclo[5.4.0]undec‑7-ene DCM: Dichloromethane THF: Tetrahydrofuran (THF), anhydrous EtOAc: Ethyl acetate EtOH: Ethanol 83 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Li(OtBu)3AlH: Lithium tri-tert-butoxyaluminum hydride Na2SO4: Sodium sulphate (anhydrous) MeCN: Acetonitrile MeNH2:Methylamine MeOH: Methanol Na2SO4: Sodium sulfate NaHCO3: Sodium bicarbonate NH4Cl: Ammonium chloride NH4OH: Ammonium hydroxide PE: Petroleum ether Ph3P: Triphenylphosphine Silica gel (230 to 400 mesh, Sorbent) t-BuMgCl: t-Butyl magnesium chloride t-BuOK: Sodium tert-butoxide t-BuOH: Tert-butanol EXAMPLES General Methods

[0188] 1H, 19F and 31P NMR spectra were recorded on a 300 MHz Fourier transform Brücker spectrometer. Spectra were obtained from samples prepared in 5 mm diameter tubes in CDCl3, CD3OD or DMSO-d6. The spin multiplicities are indicatedby the symbols s (singlet), d (doublet), t (triplet),m (multiplet) and, br (broad).Coupling constants (J) are reported in Hz. MS spectra were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 quadrupole MS apparatus. The reactions were generally carried out under a dry nitrogen atmosphere using Sigma-Aldrich anhydrous solvents. All common chemicals were purchased from commercial sources. i) Li(OtBu)3AlH, THF, ‑30 °C-->‑15 °C; ii) PPh3, CBr4, DCM, ‑20°C-->0 °C; iii) 2-amino‑6-chloropurine, tBuOK, tBuOH / - MeCN 9:1, 65 °C; iv) MeNH2 (33%), MeOH, 85 °C; v) Isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L- alaninate, tBuMgCl, THF, 0 °C --> r.t. Example 1. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate Step 1. Preparation of ((2R,3R,4R,5R)‑3‑(benzoyloxy)‑5-bromo‑4-fluoro‑4-methyltetrahydrofuran‑2-yl)methyl benzo- ate (2).

[0189] To a solution of (2R)‑3,5-di-O-benzoyl‑2-fluoro‑2-C-methyl-D-ribono-y-lactone (24.8 g, 66.6 mmol) in dry THF (333mL), under a nitrogen atmosphere and cooled to ‑30 °C, was added lithium tri-tert-butoxyaluminum hydride (1.0M in THF, 22.6mL, 22.6mmol) dropwise. After completion of the addition the reactionmixture was slowly warmed up to ‑15 °C 84 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 over 90min thenEtOAcwasadded (300mL) and themixturewas quenchedwith a saturated aq.NH4Cl solution (200mL). The resulting solutionwas filtered onCelite® and the filtratewas extracted twicewith EtOAc. The combined organicswere dried (Na2SO4), filtered and concentrated. The residue was taken up in dry DCM (225mL) under a nitrogen atmosphere, cooled to ‑20 °C, thenPPh3 (19.1 g, 72.8mmol) was added. After 10min of stirring at ‑20 °C, CBr4 (26.0 g, 78.4mmol) was added and the reaction mixture was allowed to slowly warm up to 0 °C over 2 h. The resulting mixture was poured onto a silica gel column and eluted with PE / EtOAc (gradient 100:0 to 80:20). The fractions containing the α-bromofuranoside were collected and concentrated to afford the product 2 (18.1 g, 41.3 mmol, 62% over two steps) as a thick colorless oil. 1HNMR(300MHz,CDCl3)δ8.15‑8.11 (m,2H),8.04‑8.01 (m,2H),7.64‑7.55 (m,2H),7.51‑7.41 (m,4H),6.34 (d,J=1.6Hz, 1H), 5.29 (dd, J=5.5, 3.1Hz, 1H), 4.89‑4.85 (m, 1H), 4.78 (dd, J=12.5, 3.2Hz, 1H), 4.63 (dd, J=12.5, 4.5Hz, 1H), 1.72 (d, J = 21.6 Hz, 3H). 19F NMR (282 MHz, CDCl3) δ ‑150.0. Step 2. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6-chloro‑9H-purin‑9-yl)‑2‑(benzoyloxymethyl)‑4-fluoro‑4-methylte- trahydrofuran‑3-yl benzoate (3).

[0190] 2-Amino‑6-chloropurine (2.63 g, 15.5 mmol) was suspended in t‑BuOH (54 mL) under a nitrogen atmosphere. The reaction mixture was heated to 30 °C then potassium tert-butoxide (1.69 g, 15.1 mmol) was added. After 45 min a solution of bromofuranoside 2 (2.24 g, 5.12 mmol) dissolved in anhydrous MeCN (6mL) was added, the reaction mixture washeated to65 °C for16h thencooleddown to roomtemperature.Asaturatedaq.NH4Cl solution (70mL)wasaddedand the resulting solution was extracted with EtOAc (3 x 60mL). The combined organics were dried (Na2SO4), filtered and concentrated. The residuewaspurified twiceby columnchromatography (gradientPE / EtOAc80:20 to0:100 then60:40 to 20:80) to afford the product 3 (1.56 g, 2.96 mmol, 57%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.05‑8.02 (m, 2H), 7.95‑7.92 (m, 2H), 7.88 (s, 1H), 7.63‑7.57 (m, 1H), 7.53‑7.41 (m, 3H), 7.35‑7.30 (m, 2H), 6.43 (dd, J = 22.6, 9.1 Hz, 1H), 6.12 (d, J = 18.3 Hz, 1H), 5.34 (br s, 2H), 5.00 (dd, J = 11.9, 4.5 Hz, 1H), 4.79‑4.73 (m, 1H), 4.60 (dd, J= 11.9, 5.3Hz, 1H), 1.34 (d, J= 22.6Hz, 3H). 19FNMR (282MHz,CDCl3) δ ‑157.0.MS (ESI) m / z calcd. for C25H22FN5O5 [M+H]+ 526.9; found 527.0. Step 3. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylamino)‑9H-purin‑9-yl)‑4-fluoro‑2‑(hydroxymethyl)‑4- methyltetrahydrofuran‑3-ol (4).

[0191] To a solution of compound 3 (575 mg, 1.09 mmol) in MeOH (9 mL) was added methylamine (33% in absolute EtOH, 1.7 mL, 1.81 mmol). The reaction mixture was heated to 85 °C in a sealed tube for 16 h, cooled down to room temperature and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 85:15) then reverse phase column chromatography (gradient H2O / MeOH100:0 to 0:100) to afford the product 4 (286mg, 0.91 mmol, 84%) as a white solid. 1HNMR (300MHz,CD3OD)δ8.06 (s, 1H), 6.11 (d, J=18.1Hz, 1H), 4.41 (dd, J=24.4, 9.1Hz, 1H), 4.07‑4.01 (m, 2H), 3.86 (dd, J = 12.9, 3.3 Hz, 1H), 3.04 (br s, 3H), 1.16 (d, J = 22.3 Hz, 3H). 19F NMR (282 MHz, CD3OD) δ ‑163.7. MS (ESI) m / z calcd. for C12H19FN6O3 [M+H]+ 313.1; found 313.2. Step 4. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydro- xy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (5).

[0192] To a solution of compound 4 (114mg, 365µmol) in dry THF (4mL), under a nitrogen atmosphere and cooled to 0 °C was added t-butyl magnesium chloride (1.0 M in THF, 0.66mL, 660 µmol) dropwise over 10 min. The reaction mixture was stirred 15min at 0 °C then another 15min at room temperature. The reactionmixture was cooled down to 0 °C then a solution of isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, Ross, B.S., Reddy, P.G., Zhang, H.R., Rachakonda, S., andSofia,M.J., J. Org, Chem., (2011), (253mg, 558µmol) dissolved in dry THF (1mL) was added dropwise over 10 min. The reaction mixture was stirred at 0 °C for 30 min followed by 18 h at room temperature then quenched with a saturated aq. NH4Cl solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried, filtered (Na2SO4) and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 90:10) then reverse phase column chromatography (gradient H2O / MeOH 100:0 to 0:100) to afford product 5 (a mixture of diastereomers, 101 mg, 174 µmol, 48%) as a white solid. 1HNMR (300MHz,CD3OD) δ 7.83 (s, 0.55H), 7.82 (s, 0.45H), 7.38‑7.16 (m, 5H), 6.15 (d, J = 18.5Hz, 0.45H), (d, J= 18.8 Hz, 0.55 H), 4.99‑4.88 (overlapped with H2O, m, 1H), 4.65‑4.36 (m, 3H), 4.25‑4.17 (m, 1H), 3.97‑3.85 (m, 1H), 3.05 (br s, 3H), 1.32‑1.28 (m, 3H), 1.25‑1.15 (m, 9H). 19F NMR (282 MHz, CD3OD) δ ‑162.8 (s), ‑163.3 (s). 31P NMR (121 MHz, CD3OD) δ 4.10 (s), 3.99 (s). MS (ESI) m / z calcd. for C24H34FN7O7P [M+H]+ 582.2; found 582.2. 85 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 i) Me2NH·HCl, DBU, MeOH, 85 °C; v) Isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Example 2. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-Amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (7). Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4-fluoro‑2‑(hydroxymethyl)‑4- methyltetrahydrofuran‑3-ol (6).

[0193] To a solution of compound 3, from Example 1, (500 mg, 0.95 mmol) in MeOH (6 mL) was added dimethylamine hydrochloride (783mg, 9.6mmol) and1,8-diazabicyclo[5.4.0]undec‑7-ene (1.43mL, 9.6mmol). The reactionmixturewas heated at 85 °C in a sealed tube for 6 h, cooled down to room temperature and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 85:15) then by reverse phase column chromatography (gradient H2O / MeOH 100:0 to 0:100) to afford product 6 (200 mg, 0.61 mmol, 64%) as a white solid. 1HNMR(300MHz,CD3OD)δ8.07 (s, 1H), 6.14 (d, J=18.1Hz, 1H), 4.41 (dd, J=24.4, 9.2Hz, 1H), 4.08‑4.02 (m,2H), 3.87 (dd, J= 12.8, 2.9 Hz, 1H), 3.42 (br s, 6H), 1.16 (d, J = 22.0 Hz, 3H). 19F NMR (282 MHz, CD3OD) δ ‑163.8. MS (ESI) m / z calcd. for C13H20FN6O3 [M+H]+ 327.2; found 327.2. Step 2. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hy- droxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (7).

[0194] Toasolutionof compound6 (80mg,245µmol) indryTHF(4mL), underanitrogenatmosphereandcooled to0 °C was added tert-butyl magnesium chloride (1.0M in THF, 0.64mL, 640µmol) drop-wise over 10min. The reactionmixture was stirred 15min at 0 °C then another 15min at room temperature. The reactionmixture was cooled down to 0 °C then a solution of isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (167mg, 367µmol) dissolved in dry THF (4 mL) was added drop-wise over 10 min. The reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature. The reaction was quenchedwith a saturated aq. NH4Cl solution (4mL) and extractedwith EtOAc (3 x 5mL). The combined organics were dried, filtered (Na2SO4) and concentrated. The residue was purified by column chromato- graphy (gradient DCM / MeOH 100:0 to 90:10) and then by reverse phase column chromatography (gradient H2O / MeOH 100:0 to 0:100) to afford the product 7 (mixture of diastereomers, 35 mg, 58 µmol, 24%) as a white solid. 1HNMR(300MHz,CD3OD)δ7.83 (s, 0.5H), 7.82 (s, 0.5H), 7.34‑7.16 (m,5H), 6.15 (d, J=18.7Hz, 0. 5H), 6.13 (d,J=18.8 Hz, 0.5 H), 4.99‑4.85 (overlapped with H2O, m, 1H), 4.65‑4.26 (m, 3H), 4.27‑4.12(m, 1H), 3.99‑3.81 (m, 1H), 3.42, 3.41 (2br s, 6H), 1.36‑1.25 (m, 3H), 1.24‑1.11 (m, 9H). 19FNMR(282MHz,CD3OD)δ ‑162.7 (s), ‑163.2 (s). 31PNMR(121MHz, CD3OD) δ 4.08 (s), 4.00 (s). MS (ESI) m / z calcd. for C25H36FN7O7P [M+H]+ 596.5; found 596.2. 86 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 i) a) N‑Methylcyclopropylamine hydrochloride, Et3N, MeOH, 100 °C; b) NH4OH, MeOH, 100 °C; ii) Isopropyl ((R, S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Example 3. Preparation of Isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-cyclopropylamino)‑9H-pur- in‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (9). Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2-Amino‑6‑(N-methyl-cyclopropylamino)‑9H-purin‑9-yl)‑4-fluoro‑2‑(hydroxy- methyl)‑4-methyltetrahydrofuran‑3-ol (8).

[0195] To a solution of compound 3 (600 mg, 1.14 mmol) in MeOH (10 mL) was added N-methylcyclopropylamine hydrochloride (366mg, 3.40mmol) and triethylamine (470µL, 3.40mmol). The reactionmixturewas heated at 100°C in a sealed tube for15handcooleddown to roomtemperature.Anaqueoussolutioncontaining30%NH4OH(4mL)wasadded and the reaction mixture was heated at 100° C in a sealed tube for 2 h, cooled down and concentrated. The residue was purifiedbycolumnchromatography (gradientDCM / MeOH100:0 to90:10) toaffordproduct8 (351mg,0.99mmol, 87%)as a white solid. lH NMR (300 MHz, CD3OD) δ 8.13 (s, 1H), 6.15 (d, J = 18.0 Hz, 1H), 4.40 (dd, J = 24.3, 9.0 Hz, 1H), 4.06‑4.02 (m, 2H), 3.89‑3.83 (m,1H), 3.32 (m,3H), 3.18‑3.11 (m,1H), 1.16 (d,J =22.2Hz, 3H), 0.96‑0.89 (m,2H), 0.74‑0.69 (m,2H). 19FNMR (282 MHz, CD3OD) δ ‑163.8. MS (ESI) m / z calcd. for C15H22FN6O3 [M+H]+ 353.2; found 353.2. Step 2. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-cyclopropylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (9).

[0196] To a solution of compound 8 (200 mg, 0.57 mmol) in dry THF (15 mL) at 0° C was added tert-butyl magnesium chloride (1.0 M in THF, 680 µL, 0.68 mmol) dropwise over 10 min. The reaction mixture was stirred 15 min at 0° C then another 15 min at room temperature. The reaction mixture was cooled down to 0° C and a solution of isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (283 mg, 0.62 mmol) dissolved in dry THF (4 mL) was addeddropwiseover10min.The reactionmixturewasstirredat 0 °C for30minand18hat room temperature.The reaction was quenched with a saturated aq. NH4Cl solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 90:10) and thenby reverse phasecolumnchromatography (gradientH2O / MeOH100:0 to 0:100) to afford product 9 (mixture of 2 diastereoisomers, 160 mg, 0.26 mmol, 45%) as a white solid. 1HNMR(300MHz,CD3OD)δ7.85 (m, 1H), 7.38‑7.16 (m,5H), 6.18 (d,J =18.6Hz) and6.16 (d, J=18.9Hz, 1H), 4.95‑4.90 (overlappedwithH2O,m,1H), 4.58‑4.47 (m,3H), 4.22‑4.19 (m,1H), 3.95‑3.87 (m,1H), 3.36‑3.34 (overlappedwithMeOH, m, 3H), 3.19‑3.12 (m, 1H), 1.32‑1.22 (m, 12H), 0.96‑0.89 (m, 2H), 0.74‑0.69 (m,2H). 31P NMR (121MHz, CD3OD) δ 4.11 (s), 4.02 (s). MS (ESI) m / z calcd. for C27H38FN7O7P [M+H]+ 622.2; found 622.2. 87 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 i) 2,6-dichloropurine, tBuOK, tBuOH / MeCN, 65 °C; ii) MeNH2, MeOH, 130°C; iii) Isopropyl ((R,S)‑(pentafluorophenox- y)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C to RT Example 4. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2,6-bis-methylamino‑9H-purin‑9-yl)‑4-fluoro‑3- hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (12). Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2,6-dichloro‑9H-purin‑9-yl)‑2‑(benzoyloxymethyl)‑4-fluoro‑4-methyltetrahy- drofuran‑3-yl benzoate (10).

[0197] The compound 2,6-dichloropurine (1.30 g, 6.86 mmol) was suspended in t-BuOH (25 mL) under a nitrogen atmosphere.Potassium tert-butoxide (778mg,6.92mmol)wasaddedportion-wise then the reactionmixturewasstirredat room temperature.After 1h,a solutionofbromofuranoside2 (1.0g, 2.29mmol) dissolved inanhydrousMeCN(20mL)was added and the reactionmixturewasheated at 65 °Covernight and then cooled down to room temperature. A saturated aq. NH4Cl solution was added and the resulting solution was extracted with EtOAc (3 times). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (gradient PE / EtOAc 100:0 to 0:100) to afford product 10 (148 mg, 0.27 mmol, 12%) as a sticky solid. 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 8.12‑8.09 (m, 2H), 8.02‑7.99 (m, 2H), 7.64‑7.39 (m, 6H), 6.38 (d, J = 17.2 Hz, 1H), 6.02 (dd, J = 21.2, 8.9 Hz, 1H), 4.90‑4.68 (m, 3H), 1.33 (d, J = 22.4 Hz, 3H). 19FNMR (282MHz, CDCl3) δ ‑158.0. MS (ESI) m / z calcd. for C25H20Cl2FN4O5 [M+H]+ 546.4; found 546.3. Step 2. Preparation of (2R,3R,4R,5R)‑5‑(2,6-bis-methylamino‑9H-purin‑9-yl)‑4-fluoro‑2‑(hydroxymethyl)‑4-methylte- trahydrofuran‑3-ol (11).

[0198] A solution of compound 10 (148mg, 0.27mmol) inmethylamine (33% in EtOH, 30mL)was heated at 130 °C in a sealed tube for 4 days, cooled down to room temperature and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 50:50) followed by reverse phase column chromatography (gradient H2O / MeOH 100:0 to 0:100) to afford product 11 (33 mg, 0.10mmol, 37%) as a white solid. 1H NMR (300MHz, CD3OD) δ 8.00 (s, 1H), 6.12 (d, J=18.5Hz, 1H), 4.51 (dd, J=24.4, 9.5Hz, 1H), 4.06‑3.85 (m, 3H), 3.04 (s, 3H), 2.93 (s, 3H), 1.20 (d, J = 22.4 Hz, 3H). 19F NMR (282MHz, CD3OD) δ - 163.2. MS (ESI) m / z calcd. for C13H20FN6O3 [M+H]+ 327.2; found 327.2. Step 3. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2,6-bis-methylamino‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4- methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (12).

[0199] To a solution of compound 11 (55 mg, 0.17 mmol) in dry THF (2 mL) at 0 °C was added tert-butyl magnesium chloride (1M inTHF,304□L, 0.30mmol) dropwiseover10min. The reactionmixturewasstirred15minat 0 °Cand then15 min at room temperature. The solution was cooled down to 0 °C and a solution of isopropyl ((R,S)‑(pentafluorophenox- y)‑phenoxy-phosphoryl)‑L-alaninate (115 mg, 0.25 mmol) dissolved in dry THF (1 mL) was dropwise added over 10 min. Themixture was warmed slowly to room temperature and stirred for 4 days. The reaction was quenched with a saturated aq.NH4Cl solutionandextractedwithEtOAc (3 times).ThecombinedorganicsweredriedoverNa2SO4andconcentrated. The residuewas purified by column chromatography (gradient DCM / MeOH100:0 to 50:50) to yield product 12 (mixture of diastereomers, 13 mg, 0.02 mmol, 13%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.78 (s, 1H), 7.35‑7.12 (m, 5H), 6.13 (d, J = 19.1 Hz, 0.53H), 6.10 (d, J = 19.2 Hz, 0.47H), 4.99‑4.78 (overlapped with H2O, m, 1H), 4.72‑4.46 (m, 3H), 4.24‑4.15 (m, 1H), 3.79‑3.92 (m, 1H), 3.02 (br s, 3H), 2.92 (s+s, 3H), 1.29‑1.11 (m, 12H). 19F NMR (282 MHz, CD3OD) δ 88 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 ‑162.0 (s), - 162.3 (s). 31P NMR (121 MHz, CD3OD) δ 3.97 (s), 3.89 (s). MS (ESI) m / z calcd. for C25H36FN7O7P [M+H]+ 596.6; found 596.2. i) TIPDSCl2, imidazole, DMF; ii) isobutyryl chloride, pyridine; iii) TBAF, THF; iv) Isopropyl ((R,S)‑(pentafluorophenox- y)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Example 5. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-isobutyramido‑6-methylamino‑9H-purin‑9- yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (16). Step 1. Preparation of compound 13.

[0200] To a solution of compound 4 (286 mg, 0.92mmol) and imidazole (370 mg, 5.43mmol) in dry DMF (6 mL) at 0 °C was added 1,3-dichloro‑1,1,3,3-tetraisopropyldisiloxane (300 µL, 0.94 mmol). The reaction mixture was stirred for 2 h at RT, dilutedwithEtOAc (50mL) and the suspensionwaswashedwith saturatedaq.NH4Cl solution andbrine (40mLeach). The organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (gradient PE / EtOAc 7:3 to 3:7) to afford product 13 (283 mg, 0.51 mmol, 56%) as a white solid. MS (ESI) m / z calcd. for C24H44FN6O4Si2 [M+H]+ 555.8; found 555.2. Step 2. Preparation of compound 14.

[0201] Toasolutionof compound13 (200mg, 0.36mmol) in dry pyridine (3mL) at 0 °Cwasadded isobutyryl chloride (38 µL,0.36mmol).The reactionmixturewasstirred for2hatRT.The reactionwasquenchedby theadditionofwater (500µL). The mixture was concentrated and co-evaporated with toluene (3 x 10 mL). The residue was purified by column chromatography (gradient PE / EtOAc 1:0 to 1:1) to afford product 14 (99 mg, 0.16 mmol, 44%) as a white solid. MS (ESI) m / z calcd. for C28H50FN6O5Si2 [M+H]+ 625.9; found 625.3. Step 3. Preparation of (2R,3R,4R,5R)‑5‑(2-isobutyramido‑6-methylamino‑9H-purin‑9-yl)‑4-fluoro‑2‑(hydroxymethyl)‑4- methyltetrahydrofuran‑3-ol (15).

[0202] Toasolution of compound14 (90mg, 0.14mmol) in dryTHF (2mL)wasadded tetrabutylammoniumfluoride (1M in THF, 38 µL, 0.38 mmol). The mixture was stirred for 2 h at RTand concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 10:0 to 9:1) followed by reverse phase column chromatography (gradient H2O / MeOH 100:0 to 0:100) to give product 15 (42 mg, 0.11 mmol, 77%) as a white solid. 1H NMR (300 MHz, CD3OD) δ8.31 (s, 1H), 6.29 (d, J=17.9Hz, 1H), 4.70‑4.60 (m,1H), 4.07‑3.98 (m,2H), 3.89 (dd,J=12.5, 3.4Hz, 1H), 3.10 (br s, 3H), 89 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 2.87 (br s, 1H), 1.23‑1.16 (m, 9H). 19F NMR (282 MHz, CD3OD) δ ‑163.8. MS (ESI) m / z calcd. for C16H24FN6O4 [M+H]+ 383.4; found 383.2. Step 4. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-isobutyramido‑6-methylamino‑9H-purin‑9-yl)‑4-fluoro‑3- hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (16).

[0203] Toasolutionof compound15 (27mg,0.07mmol) in dryTHF (1mL)at 0 °Cwasadded t-butylmagnesiumchloride (1.0 M in THF, 130 µL, 0.13 mmol) dropwise over 10 min. The reaction mixture was stirred 15min at 0 °C then another 15 min at room temperature. The reaction mixture was cooled down to 0 °C and a solution of isopropyl ((R,S)‑(pentafluor- ophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (50 mg, 0.11 mmol) dissolved in dry THF (1 mL) was added dropwise over 10 min. The reaction mixture was stirred at 0 °C for 30 min followed by 18 h at room temperature then quenched with a saturated aq.NH4Cl solution (2mL) andextractedwith EtOAc (3 x 5mL). The combined organicswere dried overNa2SO4 and concentrated. The residuewaspurifiedby columnchromatography (gradientDCM / MeOH100:0 to 95:5) then reverse phase column chromatography (gradient H2O / MeOH100:0 to 0:100) to afford product 16 (mixture of 2 diastereoisomers, 25 mg, 0.04 mmol, 54%) as a white solid. 1HNMR (300MHz,CD3OD)δ 8.05 (s, 1H), 7.33‑7.13 (m, 5H), 6.27 (d, J=18.6Hz) and 6.21 (d, J=19.1Hz, 1H), 5.10‑4.95 (m, 1H), 4.93‑4.78 (overlappedwith H2O,m, 1H), 4.60‑4.42 (m, 2H), 4.26‑4.18 (m, 1H), 3.90‑3.80 (m, 1H), 3.09 (br s, 3H), 2.84‑2.80 (m, 1H), 1.33‑1.15 (m, 18H). 31P NMR (121 MHz, CD3OD) δ 3.69 (s). 31P NMR (121 MHz, CD3OD) δ 4.11 (s), 3.99 (s). MS (ESI) m / z calcd. for C28H40FN7O8P [M+H]+ 652.6; found 652.3. i) N‑Methylethylamine, MeOH, 100 °C; ii) Isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Example 6. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-ethylamino)‑9H-purin‑9- yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (18). Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-ethylamino)‑9H-purin‑9-yl)‑4-fluoro‑2‑(hydroxy- methyl)‑4-methyltetrahydrofuran‑3-ol (17).

[0204] To a solution of compound 3 (150mg, 0.29mmol) inMeOH (4mL)was addedN-methylethylamine (245µL, 2.90 mmol). The reaction mixture was heated at 100 °C in a sealed tube for 15 h, cooled down to room temperature and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 90:10) to afford product 31 (89 mg, 0.26 mmol, 89%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (s, 1H), 6.13 (d, J = 18.0 Hz, 1H), 4.40 (dd, J = 24.9, 8.7 Hz, 1H), 4.11‑4.01 (m, 4H), 3.98‑3.83 (m, 1H), 3.34 (br. s, 3H), 1.24‑1.11 (m, 6H). 19F NMR (282 MHz, CD3OD) δ ‑163.7. MS (ESI) m / z calcd. for C14H22FN6O3 [M+H]+ 341.2; found 341.2. Step 2. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-ethylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (18).

[0205] To a solution of compound 17 (30 mg, 0.09 mmol) in dry THF (2 mL) at 0 °C was added tert-butyl magnesium 90 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 chloride (1.0 M in THF, 110 µL, 0.11 mmol) dropwise over 10 min. The reaction mixture was stirred 15 min at 0 °C then another 15 min at room temperature. The reaction mixture was cooled down to 0 °C and a solution of isopropyl ((R, S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (48 mg, 0.11 mmol) dissolved in dry THF (1 mL) was added dropwise over 10min. The reactionmixture was stirred at 0 °C for 30min and 18 h at room temperature. The reaction was quenched with a saturated aq. NH4Cl solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were driedoverNa2SO4andconcentrated.The residuewaspurifiedbycolumnchromatography (gradientDCM / MeOH100:0 to 90:10) to afford the product 18 (mixture of 2 diastereoisomers, 22 mg, 0.04 mmol, 40%) as a white solid. 1HNMR(300MHz,CD3OD)δ7.69 (m, 1H), 7.26‑7.04 (m,5H), 6.05 (d,J =18.6Hz) and6.03 (d, J=18.9Hz, 1H), 4.86‑4.79 (overlappedwithH2O,m,1H), 4.50‑4.32 (m,3H), 4.12‑4.06 (m,1H),3.96‑3.79 (m,3H),3.25 (br. s, 3H), 1.24‑1.02 (m,15H). 31P NMR (121 MHz, CD3OD) δ 4.07 (s), 4.00 (s). MS (ESI) m / z calcd. for C26H38FN7O7P [M+H]+ 609.3; found 609.2. i) N-Methylpropylamine, MeOH, 100 °C; ii) Isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Example 7. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-propylamino)‑9H-purin‑9- yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (20). Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-propylamino)‑9H-purin‑9-yl)‑4-fluoro‑2‑(hydroxy- methyl)‑4-methyltetrahydrofuran‑3-ol (19).

[0206] Toasolutionof compound3 (150mg,0.29mmol) inMeOH(4mL)wasaddedN-methylpropylamine (295µL,2.90 mmol). The reaction mixture was heated at 100 °C in a sealed tube for 15 h, cooled down to room temperature and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 90:10) then reverse phase column chromatography (gradient H2O / MeOH 100:0 to 0:100) to afford product 19 (80 mg, 0.23 mmol, 78%) as a white solid. 1HNMR(300MHz,CD3OD)δ8.04 (s, 1H), 6.13 (d, J=18.3, 1H), 4.40 (dd, J=24.2, 9.2Hz, 1H),m, 4.06‑3.84 (m, 5H), 1.68 (sept, J=7.5Hz, 2H), 1.15 (d, J=22.2Hz, 3H), 0.93 (t, J=7.5Hz, 3H). 19FNMR(282MHz,CD3OD)δ ‑163.8.MS (ESI)m / z calcd. for C15H24FN6O3 [M+H]+ 355.2; found 355.2. Step 2. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-propylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (20).

[0207] To a solution of compound 19 (30 mg, 0.09 mmol) in dry THF (2 mL) at 0 °C was added tert-butyl magnesium chloride (1.0 M in THF, 110 µL, 0.11 mmol) dropwise over 10 min. The reaction mixture was stirred 15 min at 0 °C then another 15 min at room temperature. The reaction mixture was cooled down to 0 °C and a solution of isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (46 mg, 0.11 mmol) dissolved in dry THF (1 mL) was addeddropwiseover10min.The reactionmixturewasstirredat 0 °C for30minand18hat room temperature.The reaction was quenched with a saturated aq. NH4Cl solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 91 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 100:0 to 90:10) to afford product 20 (mixture of 2 diastereoisomers, 22 mg, 0.03 mmol, 33%) as a white solid. 1H NMR (300MHz, CD3OD) δ 7.78, 7.77 (s+s, 1H), 7.37‑7.13 (m, 5H), 6.15 (d, J = 18.6 Hz) and 6.13 (d, J = 18.9 Hz, 1H), 4.97‑4.89 (overlapped with H2O, m, 1H), 4.63‑4.30 (m, 3H), 4.22‑4.14 (m, 1H), 4.02‑3.84 (m, 2H), 1.74‑1.63 (3H, m), 1.32‑1.27 (m,3H),1.23‑1.13 (m,9H), 0.94 (t,J=7.4Hz)and0.93 (t,J=7.4Hz,3H). 31PNMR(121MHz,CD3OD)δ4.05 (s), 4.00 (s). MS (ESI) m / z calcd. for C27H40FN7O7P [M+H]+ 623.3; found 623.2. i) a) N‑Methylcyclobutylamine hydrochloride, Et3N, MeOH, 100 °C; b) NH4OH, MeOH, 100° C; ii) Isopropyl ((R, S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Example 8. Preparation of Isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-cyclobutylamino)‑9H-pur- in‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (22). Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-cyclobutylamino)‑9H-purin‑9-yl)‑4-fluoro‑2‑(hydroxy- methyl)‑4-methyltetrahydrofuran‑3-ol (21).

[0208] To a solution of compound 3 (150 mg, 0.29 mmol) in MeOH (4 mL) was added N-methylcyclobutylamine hydrochloride (105mg, 0.90mmol) and triethylamine (190µL, 1.00mmol). The reactionmixturewas heated at 100 °C in a sealed tube for15handcooleddown to roomtemperature.Anaqueoussolutioncontaining30%NH4OH(1mL)wasadded and the reaction mixture was heated at 100 °C in a sealed tube for 2 h, cooled down and concentrated. The residue was purifiedbycolumnchromatography (gradientDCM / MeOH100:0 to90:10) toaffordproduct21 (90mg,0.25mmol, 86%)as a pale yellow solid. 1H NMR (300MHz, CD3OD) δ 8.09 (s, 1H), 6.14 (d, J = 18.0 Hz, 1H), 5.80‑5.70 (m, 1H), 4.44‑4.33 (m, 1H), 4.06‑4.02 (m, 2H), 3.88‑3.84 (m, 1H), 3.34 (s, 3H), 2.38‑2.19 (m, 4H), 1.79‑1.71 (m, 2H), 1.17 (d, J = 22.2 Hz, 3H). 19F NMR (282 MHz, CD3OD) δ ‑163.8. MS (ESI) m / z calcd. for C16H24FN6O3 [M+H]+ 367.2; found 367.2. Step 2. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methyl-cyclobutylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (22).

[0209] To a solution of compound 21 (50 mg, 0.14 mmol) in dry THF (2 mL) at 0 °C was added tert-butyl magnesium chloride (1.0 M in THF, 210 µL, 0.21 mmol) dropwise over 10 min. The reaction mixture was stirred 15 min at 0 °C then another 15 min at room temperature. The reaction mixture was cooled down to 0 °C and a solution of isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (74 mg, 0.16 mmol) dissolved in dry THF (2 mL) was addeddropwiseover10min.The reactionmixturewasstirredat 0 °C for30minand18hat room temperature.The reaction was quenched with a saturated aq. NH4Cl solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 90:10) and thenby reverse phasecolumnchromatography (gradientH2O / MeOH100:0 to 0:100) to afford product 22 (mixture of 2 diastereoisomers, 24 mg, 0.04 mmol, 28%) as a white solid. 1HNMR(300MHz,CD3OD)δ7.79 (s, 0.2H),7.77 (s,0.8H), 7.38‑7.12 (m,5H),6.18 (d,J=17.6Hz)and6.16 (d,J=17.5Hz, 1H), 4.95‑4.81 (m, 2H), 4.62‑4.43 (m, 3H), 4.25‑4.18 (m, 1H), 3.96‑3.83 (m, 1H), 3.38 (s) and 3.36 (s, 3H), 2.38‑2.21 (m, 92 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 4H), 1.75‑1.63 (m, 2H), 1.32‑1.16 (m, 12H). 31P NMR (121 MHz, CD3OD) δ 4.04 (s), 3.97 (s). MS (ESI) m / z calcd. for C28H40FN7O7P [M+H]+ 636.3; found 636.2. Modification of the 2-amino moiety in the active compounds

[0210] Oneof ordinary skill in the art can add a substituent to the 2-amino purinemoiety bymethodswell known to those skilled in the art. One non-limiting process is provided here, and others can be easily adapted. ((2R,3R,4R,5R)‑3‑(ben- zoyloxy)‑5-bromo‑4-fluoro‑4-methyltetrahydrofuran‑2-yl)methyl benzoate, is treated with commercially available 2,6- dichloropurine, a base and a mixture of organic solvents at an elevated temperature to generate (2R,3R,4R,5R)‑5‑(2,6- dichloro‑9H-purin‑9-yl)‑2‑(benzoyloxymethyl)‑4-fluoro‑4-methyltetrahydrofuran‑3-yl benzoate. In one embodiment, the base is potassium tert-butoxide. In one embodiment, the mixture of organic solvents comprises tert-butanol and acetonitrile. The compound, (2R,3R,4R,5R)‑5‑(2,6-dichloro‑9H-purin‑9-yl)‑2‑(benzoyloxymethyl)‑4-fluoro‑4-methylte- trahydrofuran‑3-yl benzoate is treated with an amine, a base and an organic solvent at ambient temperature to generate 2-chloro-N6-substituted purines. In one embodiment, the amine is methylamine. In one embodiment, the base is triethylamine. In one embodiment, the organic solvent is ethanol. One skilled in the art will also recognize that upon treatmentwith an amineand base, the benzoate groups on the nucleosidewill simultaneously be removed to generate the deprotected furanosemoiety. 2-Chloro-N6-substituted purines can then be treated with an amine, and an organic solvent in a sealed tube at an elevated temperature of about 100 °C to generate N2,N6-disubstituted purine nucleosides of the present invention. In one embodiment, the amine is methylamine. In one embodiment, the organic solvent is ethanol. N2,N6‑Disubstituted purine nucleosides of the present invention can be treated with a base, isopropyl ((R,S)‑(penta- fluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate and an organic solvent at a reduced temperature to generate com- pounds of Formula I-V. In one embodiment, the base is tert-butyl magnesium chloride. In one embodiment, the organic solvent is tetrahydrofuran. Preparation of Stereospecific Phosphorus Enantiomers

[0211] Certain of theactive compoundsdescribedhereinhaveachiral phosphorusmoiety.Anyof theactive compounds described herein can be provided as an isolated phosphorus enantiomeric form, for example, at least 80, 90, 95 or 98%of theRorSenantiomer, usingmethodsknown to thoseof skill in the art. For example, thereareanumber of publications that describe how to obtain such compounds, including but not limited to column chromatography, for example as described in Example 17 below and U.S. Patent No. 8,859,756; 8,642,756 and 8,333,309 to Ross, et al. Example 9. Separation of the stereoisomers of compound 5.

[0212] The stereoisomers of Compound 5 were separated on a Phenominex Luna column using the following conditions: Column: Phenominex Luna 5 micron C18 (2) 250 x 10 mm part# OOG‑4252-BO Sample concentration: Approximately 50 mg / ml in acetonitrile Injection volume: 50 µl Mobile phase A: HPLC grade water Mobile phase B: HPLC grade acetonitrile. Flow: 5 ml / min UV: 283 nm Gradient: Time %B 0 2 40 50 41 50 41.1 2 45 2 Run time: 45 minutes Column Temperature: 40 °C A sample chromatogram of a semi-prep run is illustrated in Figure 1. 93 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0213] The combined fractions were evaluated using an analytical column with the following conditions: Column: Phenominex Luna 5 micron C18 (2) 250 x 2mm part# OOG‑4252-BO Injection volume: 10 µl Mobile phase A: HPLC grade water Mobile phase B: HPLC grade acetonitrile. Flow: 0.2 ml / min UV: 283 nm Gradient: Time %B 0 2 30 50 40 50 40.1 2 45 2 Run time: 45 minutes Column Temperature: 40 °C

[0214] The combined fractions for each stereoisomer were evaporated to dryness using a rotovap with a bath temperature of 30 °C. The resulting solids were dissolved in 1 ml of acetonitrile, transferred into 1.7 ml microcentrifuge tubes and the solvent evaporated on the vacuum centrifuge at a temperature of 30 °C.

[0215] The data on the final samples are as follows: 1. First eluding peak: Compound 5 #1 (5‑1) (21.7 mgs - 97.8% ee). 2. Second eluding Peak: Compound 5 #2 (5‑2) (13.2 mgs - 95.9% ee).

[0216] The final weights of the 1st and 2nd peak correspondwell to their percentages in the original mixture. (62.2% and 37.8% respectively). Stereospecific Syntheses of Compounds of Formula I-VII

[0217] Example 10. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6-chloro‑9H-purin‑9-yl)‑2‑(hydroxymethyl)‑4-fluoro‑4- methyltetrahydrofuran‑3-ol (23). Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6-chloro‑9H-purin‑9-yl)‑2‑(hydroxymethyl)‑4-fluoro‑4-methyltetrahy- drofuran‑3-ol (23).

[0218] The compound (2R,3R,4R,5R)‑5‑(2-amino‑6-chloro‑9H-purin‑9-yl)‑2‑(benzoyloxymethyl)‑4-fluoro‑4-methylte- trahydrofuran‑3-yl benzoate, 3, (80 g, 140mmol) was added to a solution of trimethylamine inmethanol (7M, 800mL) and stirred atRTovernight. Themixturewas concentrated and then purifiedby column chromatography (DCM:MeOH=100:1) to afford (2R,3R,4R,5R)‑5‑(2-amino‑6-chloro‑9H-purin‑9-yl)‑2‑(hydroxymethyl)‑4-fluoro‑4-methyl-tetrahydrofuran‑3-ol (23) (40 g, 90%). 94 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Example 11. Preparation of ((((S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydro- xy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0219] Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahy- drofuran‑3-ol (4).

[0220] To a solution of (2R,3R,4R,5R)‑5‑(2-amino‑6-chloro‑9H-purin‑9-yl)‑2‑(hydroxymethyl)‑4-fluoro‑4-methyl-tetra- hydrofuran‑3-ol (2.0 g, 1.0 eq) in dioxane (15mL) was addedMeNH2 aqueous solution (5.0 eq). After stirring overnight at RT, TLC showed that the starting material was consumed. The mixture was concentrated and purified by column chromatography (DCM:MeOH = 40:1‑ 30:1) to afford (2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑3-ol as a white powder (1.6 g, 81.6%). [M+H]+ = 313.5 Step 2. Preparation of ((((S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyl- tetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0221] The compound (2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetra- hydrofuran‑3-ol (1.47 g, 1.0 eq) and PPAL-S (2.35 g, 1.1 eq) were dissolved in anhydrous THF (29 mL). After cooling 95 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 the mixture to ‑10 °C, t-BuMgCl (5.8 mL, 1.7 M, 2.1 eq) was slowly added under a blanket of N2. After stirring at RT for 45 min, the mixture was quenched with aq. saturated NH4Cl, and extracted with EtOAc (20 mL× 3). The combined organic layers were washed with water, brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 50:1‑ 20:1) to afford ((((S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(methyla- mino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyl-tetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate as a white powder (1.1 g, 40.3%). 1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.33‑7.16 (m, 5H), 6.10 (d, J= 18.4 Hz, 1H), 4.90‑4.84(m, 5H), 4.55‑4.46 (m, 3H), 4.20‑4.16 (m, 1H), 3.91‑3.87 (m, 1H), 3.30 (m, 1H), 3.03 (s, 3H), 1.30‑1.20(m, 12H). [M+H]+ = 582.8. Example 12. Preparation of isopropyl ((((S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (25).

[0222] Step 1. Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetra- hydrofuran‑3-ol.

[0223] To a solution of (2R,3R,4R,5R)‑5‑(2-amino‑6-chloro‑9H-purin‑9-yl)‑2‑(hydroxymethyl)‑4-fluoro‑4-methyl-tetra- hydrofuran‑3-ol (2.8 g, 8mmol) in dioxane (20mL) was added dimethylamine aqueous solution (5mL). After stirring at RT for 3 h, TLC showed that the starting material was consumed. The mixture was concentrated and purified by column chromatography (DCM:MeOH = 60:1) to afford (2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4-fluoro‑3- hydroxy‑4-methyltetrahydrofuran‑3-ol (2.2 g). 1HNMR (400MHz,CD3OD) δ 8.08 (s, 1H), 6.13 (d, J =18.0Hz, 1H), 4.43 (dd, J =9.2, 9.2Hz, 1H), 4.06 (d, J=10.8Hz, 2H), 3.90 (m, 1H), 3.37 (s, 3H), 3.06 (s, 3H), 1.18(d, J = 22 Hz, 3H). 96 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 2. Preparation of isopropyl ((((S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydro- xy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (25).

[0224] The compound (2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methylte- trahydrofuran‑3-ol (8 g, 1.0 eq) and PPAL-S (11.1 g, 1 eq) were dissolved in anhydrous THF (100 mL). The mixture was cooled to ‑5‑0 °Cand t-BuMgCl (30.5mL, 1.7M, 2.1 eq) was slowly added under aN2 atmosphere. After stirring at RT for 2 h, themixturewas quenchedwith aq. saturatedNH4Cl solution and extractedwith EtOAc (70mL× 3). The combined organic layerswerewashedwithwater, brine (30mL), driedover anhydrousNa2SO4andconcentrated. Thecrudeproduct was purified by column chromatography (DCM:MeOH = 50:1) to afford isopropyl ((((S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(di- methylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alani- nate as a white powder (9.5 g, 65%). 1H NMR (400 MHz, CD3OD) δ 7.81(s, 1H), 7.35‑7.19 (m, 5H), 6.15 (d, J = 18.8 Hz, 1H), 4.90 (m, 1H), 4.54‑4.49 (m, 3H), 4.22‑4.19 (m, 1H), 3.90 (m, 1H), 3.43 (s, 3H), 1.32(d, J = 7.2 Hz , 3H), 1.24‑1.17(m, 9H). 31P NMR (160 MHz, CD3OD) δ 3.89. Example 13. Preparation of isopropyl ((((R)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate (26).

[0225] The compound (2R,3R,4R,5R)‑5‑(2-amino‑6‑(dimethylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methylte- trahydrofuran‑3-ol (3 g, 1.0 eq) and PPAL-R (4.17 g, 1 eq) were dissolved in anhydrous THF (60 mL). The mixture was cooled to ‑5‑0 °C and t-BuMgCl (11.4mL, 1.7M, 2.1 eq) was slowly added under aN2 atmosphere. After stirring at RT for16h, themixturewasquenchedwithaq. saturatedNH4Cl solutionandextractedwithEtOAc (50mL×3).Thecombined organic layerswerewashedwithwater, brine (30mL), driedover anhydrousNa2SO4andconcentrated. Thecrudeproduct was purified by column chromatography (DCM:MeOH = 50:1) to afford isopropyl ((((R)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(di- methylamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alani- nate as a white powder (2.2 g, 41%). 1HNMR (400MHz,CD3OD) δ7.8(s, 1H), 7.35‑7.29 (m, 5H), 6.18 (d, J=18.8Hz, 1H), 4.92 (m,1H), 4.60 (m, 1H), 4.51‑4.23 (m, 3H), 3.90 (m, 1H), 3.44 (s, 6H), 1.29(d, J = 6 Hz ,3H), 1.22‑1.16(m, 10H). 31P NMR (160 MHz, CD3OD) δ 3.98. 97 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Example 14. Preparation of isopropyl ((((S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylcyclopropanamino)‑9H-pur- in‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0226] Step 1: Preparation of (2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylcyclopropanamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4- methyltetrahydrofuran‑3-ol (8).

[0227] K2CO3 (53 g, 500mmol) was added to N-methylcyclopropanamine hydrochloride in aqueous solution (100mL). After stirring at RT for 10 min, a solution of (2R,3R,4R,5R)‑5‑(2-amino‑6-chloro‑9H-purin‑9-yl)‑2‑(hydroxymethyl)‑4- fluoro‑4-methyl-tetrahydrofuran‑3-ol (35g, 109mmol) in dioxane (300mL)wasadded.ThemixturewasstirredatRT for 16 h and HPLC indicated that the reaction was complete. The mixture was concentrated and purified by column chromato- graphy (DCM:MeOH = 60:1) to afford (2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylcyclopropanamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑3-ol (30 g, 82%). 1H NMR (400MHz, CD3OD) δ 8.16 (s, 1H), 6.17 (d, J = 18.0 Hz, 1H), 4.41 (dd, J = 9.2, 9.2 Hz, 1H), 4.06 (m, 2H), 3.90 (m, 1H), 3.37 (s, 3H), 3.16 (m, 1H),1.18 (d, J = 22.4 Hz, 3H), 0.94 (m, 2H), 0.74 (m, 2H). [M+H]+ = 353.2. 98 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 2: Preparation of isopropyl ((((S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylcyclopropanamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0228] The compound (2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylcyclopropanamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4- methyltetrahydrofuran‑3-ol (8 g, 1.0 eq) and PPAL-S (10.3 g, 1 eq) were dissolved in anhydrous THF (100 mL). After cooling themixture to ‑5‑0 °C, t-BuMgCl (28mL, 1.7M, 2.1 eq)was slowly addedunder aN2 atmosphere. Themixturewas stirred at RT for 1h, quenched with aq. saturated NH4Cl solution, and extracted with EtOAc (70 mL × 3). The combined organic layerswerewashedwithwater, brine (30mL), driedover anhydrousNa2SO4andconcentrated. Thecrudeproduct was purified by column chromatography (DCM:MeOH = 100:1 to 50:1) to afford isopropyl ((((S)‑(2R,3R,4R,5R)‑5‑(2- amino‑6‑(methylcyclopropanamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phe- noxy-phosphoryl)‑L-alaninate as a white powder (9.5 g, 65%). 1HNMR(400MHz,CD3OD) δ7.86 (s, 1H), 7.35‑7.19 (m, 5H), 6.17 (d, J =19.2Hz, 1H), 4.91 (m,1H), 4.52 (m, 3H), 4.21 (m, 1H), 3.93 (m, 1H), 3.35 (s, 3H), 3.16 (m, 1H), 2.0 (s, 1H), 1.26‑1.16 (m, 12H), 0.93 (m, 2H), 0.73 (m, 2H). 31P NMR (160 MHz, CD3OD) δ 3.90 Example 15. Preparation of isopropyl ((((R)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylcyclopropanamino)‑9H-pur- in‑9-yl)‑4-fluoro‑3-hydroxy‑4-methyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0229] The compound (2R,3R,4R,5R)‑5‑(2-amino‑6‑(methylcyclopropanamino)‑9H-purin‑9-yl)‑4-fluoro‑3-hydroxy‑4- methyltetrahydrofuran‑3-ol (3 g, 1.0 eq) andPPAL-R (2.8 g, 1 eq) were dissolved in anhydrous THF (60mL). After cooling themixture to ‑5‑0 °C, t‑BuMgCl (7.6mL, 1.7M,2.1eq)wasslowlyaddedunderN2.Then themixturewasstirredatRT for 1 h and quenched with aq. saturated NH4Cl solution, and extracted with EtOAc (50 mL× 3). The combined organic layers were washed with water, brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 100:1 to 50:1) to afford the product as a white powder (3 g, 55%). 1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.30‑7.25 (m, 5H), 6.16 (d, J = 24.8 Hz, 1H), 4.84 (m, 1H), 4.84‑4.50 (m, 3H), 4.22‑4.19 (m, 1H), 3.88 (m, 1H), 3.33 (s, 3H), 3.14 (m, 1H), 2.0 (s, 1H), 1.28‑1.13 (m, 12H), 0.92 (m, 2H), 0.90 (m, 2H). 31P NMR (160 MHz, CD3OD) δ 3.99. Example 16. Preparation of compound 32.

[0230] 99 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 1. Preparation of compound 29.

[0231] Toasolutionof6 (3.0g, 1.0eq) inpyridine (30mL)wasaddedTIPDSCl2 (4.35g, 1.5eq)at 0 °C.After stirringatRT for 4 h, TLC showed that starting material was consumed. The mixture was diluted with EtOAc, washed with 1M aq. HCl solution, saturated NaHCO3 aqueous solution, brine, dried over anhydrous Na2SO4 and concentrated to afford 29 as a yellow oil (6.3 g, 100%). Step 2. Preparation of compound 30.

[0232] To amixture of Compound 29 (800mg, 1.0 eq), DMAP (16mg, 0.1 eq), pyridine (1.6 mL) and DCM (10mL) was added isobutyryl chloride (209 mg, 1.5 eq) at 0 °C. After stirring at RT for 2 h, TLC showed that the starting material was consumed.Themixturewasquenchedwithwater,washedwithaq. 1MHCl solution, saturatedNaHCO3aqueoussolution, brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography to afford the product, 30, as a white oil (563 mg, 62.3%). 1HNMR(400MHz,CDCl3) δ7.98 (s, 1H), 787 (s, 1H), 6.20 (d, J=16.0Hz, 1H), 4.32‑4.07 (m, 4H), 3.50 (s, 6H), 2.3 (m, 1H), 1.29‑1.05 (m, 45H). Step 3. Preparation of compound 31.

[0233] Toamixture of 30 (560mg, 1.0 eq) in THF (10mL)was addedEt3N·3HF (706mg, 5 eq) andEt3N (890mg, 10 eq) at RT. After stirring at RT for 1.5 h, TLC showed that the starting material was consumed. The mixture was concentrated and purified by column chromatography to afford 31 as a white powder (288 mg, 83%). 1HNMR (400MHz,CDCl3) δ7.72 (s, 1H), 5.96 (d, J=44.0Hz, 1H), 5.22 (m, 1H), 4.13‑3.99 (m, 4H), 3.42 (s, 6H), 2.83‑2.63 (m, 2H), 1.29‑1.17 (m, 9H). 100 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 4. Preparation of compound 32.

[0234] Compound 31 (280 mg, 1.0 eq) and PPAL-S (320 mg, 1 eq) were dissolved in anhydrous THF (10 mL). After cooling themixture to ‑5 °C, t-BuMgCl (0.87mL, 1.7M, 2.1 eq)was slowly added under aN2 atmosphere. Themixturewas stirred at RT for 2 h, quenched with aq. saturated NH4Cl solution, and extracted with EtOAc (10 mL × 3). The combined organic layerswerewashedwithwater, brine (20mL), driedover anhydrousNa2SO4andconcentrated. Thecrudeproduct was purified by column chromatography to afford the product as a white powder (260 mg, 50%). 1HNMR (400MHz,CD3OD) δ 7.98 (s, 1H), 7.25 (m, 5H), 6.23 (d, J =18.8Hz, 1H), 4.52 (m, 3H), 4.38 (m, 1H), 3.81 (m, 1H), 3.75 (m, 1H), 3.48 (s, 6H), 2.81(m, 1H), 1.32 (m, 18H). [M+H]+ = 666.9. Example 17. Preparation of compound 35.

[0235] Step 1. Preparation of compound 33.

[0236] Toamixtureof29 (2.0g, 1.0eq),DMAP(0.04g, 0.1eq), pyridine (4mL)andDCM(20mL)wasaddedAcCl (0.414 g, 1.5 eq) at 0 °C. After stirring at RT for 2 h, TLC showed that the starting material was consumed. The mixture was quenched with water, washed with aq. 1M HCl solution, saturated NaHCO3 aqueous solution then brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography to afford the product, 33, as a white oil (1.73 g, 80.8%). 101 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.74 (s, 1H), 6.20 (d, J = 20.0 Hz, 1H), 4.33‑4.11 (m, 4H), 3.50 (s, 6H), 2.63 (s, 3H), 2.3 (m, 1H), 1.26‑1.05 (m, 29H). [M+H]+ = 611.9. Step 2. Preparation of compound 34.

[0237] To amixture of 33 (1.58 g, 1.0 eq) in THF (20mL)was addedEt3N·3HF (2.1 g, 5 eq) andEt3N (2.6 g, 10 eq) at RT. After stirring at RT for 1.5 h, TLC showed that the starting material was consumed. The mixture was concentrated and purified by column chromatography to afford 34 as a white powder (782 mg, 82%). [M+H]+ = 369.6. Step 3. Preparation of compound 35.

[0238] Compound 34 (136 mg, 1.0 eq) and PPAL-S (184 mg, 1.1 eq) were dissolved in anhydrous THF (3 mL). After cooling themixture to ‑5 °C, t‑BuMgCl (0.5mL, 1.7M, 2.1 eq) was slowly added under a N2 atmosphere. Themixture was stirred atRT for 30min, quenchedwith aq. saturatedNH4Cl solution and extractedwith EtOAc (10mL× 3). The combined organic layers were washed with water, brine (20 mL), dried over anhydrous and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 50:1‑ 20:1) to afford the phosphoramidate 35 as a white powder (150 mg, 63.8%). 1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.35‑7.16 (m, 5H), 6.10 (d, J = 18.4 Hz, 1H), 4.87 (m, 1H), 4.52‑4.46 (m, 3H), 4.21 (m,1H), 3.91‑3.87 (m, 1H), 3.03 (s, 3H), 1.30‑1.13 (m, 12H). 31PNMR(160MHz,CD3OD) δ3.84. 19FNMR(376MHz, CD3OD) δ ‑162.79. Synthesis of β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-ethynyl-N6-substituted‑2,6-diaminopurine nucleotides

[0239] 102 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Example 18. General route to β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-ethynyl-N6-substituted‑2,6-diaminopurine nucleo- tides

[0240] Step 1. Preparation of compound 36.

[0241] Toasolutionof6-chloroguanosine (100g,332mmol) inpyridine (400mL)wasaddedTPDSCl2 (110mL,1.05eq.) dropwiseat ‑5~5 °Cunder aN2atmosphere.After stirringat that temperature for 2 h, TLCshowed thestartingmaterialwas consumed. DCM (600mL) was added, and then TMSCl (85mL, 2 eq.) was added dropwise at 0‑5 °C. After stirring at that temperature for 2 h, TLC showed the intermediate was consumed.

[0242] Isobutyryl chloride was added dropwise at 0‑5 °C. After stirring at that temperature for 2 h, TLC showed the intermediate was consumed. Water was added, and the content was extracted with DCM. The organic phase was then washed with 0.5 N HCl to remove pyridine. After the pH of the content was washed to 5‑6, pTSA·H2O (9.2 g, 484.5 mmol) was added at 0‑5 °C. After stirring at that temperature for 1 h, TLC showed the intermediate was consumed. Water was then added, and the organic phase was washed with water, saturated aqueous NaHCO3 and brine. After being dried over Na2SO4, the solvent was removed in vacuo. The residue was then purified with column chromatography (PE / EA = 100‑10 / 1) to afford the product as a light yellow solid (82 g, 40%). 1HNMR (400MHz,DMSO‑d6) δ 10.88 (s, 1H), 8.55 (s, 1H), 5.91 (d, J= 1.6Hz, 1H), 5.53 (d, J= 4.6Hz, 1H), 4.72 - 4.58 (m, 2H), 4.16 (dd, J = 12.4, 4.8 Hz, 1H), 4.00 (ddd, J = 7.7, 4.8, 2.6 Hz, 1H), 3.93 (dd, J = 12.4, 2.7 Hz, 1H), 2.78 (h, J = 6.9 Hz, 1H), 1.26 - 1.12 (m, 3H), 1.10 (d, J = 6.7 Hz, 6H), 1.09 - 0.88 (m, 24H). 103 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 2. Preparation of compound 37.

[0243] Toasolutionof36 (10.0g, 16.3mmol) inDCM(100mL)wasaddedDess-Martin periodinaneat rt and the reaction was stirred for 12 h. TLC showed the starting material was consumed. The reaction mixture was then diluted with DCM (200 mL) and washed with saturated aqueous Na2S2O3 and brine. The organic phase was then dried over Na2SO4 and concentrated to afford crude 37 as a light yellow solid (12 g). The crude 53 can be used directly in the next step without purification. Step 3. Preparation of compound 38.

[0244] To a solution of ethynyltrimethylsilane (18.6mL, 142.7 mmol) in THF (240mL) was added n‑BuLi (46mL, 2.5 M, 115.0mmol) dropwiseat ‑15~‑20°CunderaN2atmosphere.After stirring for30min, the reactionwascooled to ‑70 °C,and 37 (crude, 16.3mmol) in THF (60mL) was added at that temperature. The content was thenwarmed to 0 °C. TLC showed the starting material was consumed. Saturated aqueous NH4Cl was added, and the reaction was extracted with EA (100 mL) three times.Theorganicphasewascombinedand thenwashedwithbrine, then furtherdriedoverNa2SO4.After being concentrated in vacuo, the residue was purified by column chromatography (PE / EA = 100->10 / 1) to afford a light yellow solid (6.0 g, 52%). Step 4. Preparation of compound 39.

[0245] To a solution of 38 (6.0 g, 8.4 mmol) in DCM (240 mL) was added pyridine (4.2 mL, 52.9 mmol) under a N2 atmosphere. The reactionwas cooled to ‑70 °C, andDAST (12mL, 90.4mmol) was added. The content was thenwarmed to ‑30 °C. TLC showed that the starting material was consumed. The reaction was poured into saturated aqueous NaHCO3, and then extractedwithDCM (200mL). The organic phasewaswashedwith brine and dried overNa2SO4. After being concentrated in vacuo, the residue was purified with column chromatography (PE / EA = 100->10 / 1) to afford a light yellow solid (3.8 g, 63%). 104 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 5. Preparation of compound 40.

[0246] To a solution of 39 (3.8 g, 5.3 mmol) in THF (120 mL) was added AcOH (1.3 g, 22 mmol) and TBAF (4.2 g, 15.9 mmol) at rt. The reaction was stirred at rt for 30 min. TLC showed the starting material was consumed. After being concentrated invacuo, the residuewaspurifiedwith columnchromatography (EA) toafford theproductasawhitesolid (2.0 g, 95%). General Procedure for Amino Displacement and Deprotection:

[0247] To a solution of 40 (350 mg, 0.88 mmol) in dioxane (20 mL) was added the methanol or water solution of the corresponding amine (free base or salt as hydrochloride plus DIEA) at rt. The content was stirred at rt for 1‑12 h. TLC showed the starting material was consumed. After being concentrated in vacuo, the residue was used directly in the next stepwithout purification. Theabovementioned residuewasdissolved inmethanol (10mL).AqueousNaOH (2.5N, 10mL) was added. After stirring overnight at rt, TLC showed that starting material was consumed. The pH of the content was adjusted to7‑8with1NHCl. Thesolutionwasconcentratedandpurifiedwith columnchromatography (DCM / MeOH=100- >20 / 1) to afford the product as an off-white solid (yield: 40‑80% over two steps). Table 1 illustrates the structures of compounds 57‑63 and the corresponding mass spectral and 1H NMR for the respective compounds. Table 1. Compound No. Structure 1H NMR / MS 41 1H NMR (400 MHz, Methanol‑d4) δ 8.05 (s, 1H), 6.27 (d, J = 16.9 Hz, 1H), 4.75 (dd, J = 21.7, 9.1 Hz, 1H), 4.06 (dd, J = 11.0, 2.4 Hz, 2H), 3.87 (dd, J = 13.1, 3.2 Hz, 1H), 3.42 (s, 6H), 3.37 (s, 2H), 3.18 (d, J = 5.4 Hz, 1H). [M+H]+ = 336.9 42 1H NMR (400 MHz, DMSO‑d6) δ 7.94 (s, 1H), 7.30 (s, 1H), 6.20 - 6.09 (m, 2H), 5.98 (s, 2H), 5.33 (t, J = 5.3 Hz, 1H), 4.57 (dt, J = 22.1, 8.0 Hz, 1H), 4.12 (q, J = 5.3 Hz, 1H), 3.91 (d, J = 9.3 Hz, 1H), 3.70 (t, J = 8.6 Hz, 1H), 3.36 (s, 1H), 3.18 (d, J = 5.2 Hz, 2H), 2.89 (d, J = 7.0 Hz, 3H). [M+H]+ = 323.0 105 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound No. Structure 1H NMR / MS 43 1H NMR (400 MHz, Methanol‑d4) δ 8.11 (s, 1H), 6.29 (d, J = 16.9 Hz, 1H), 4.76 (dd, J = 21.7, 9.0 Hz, 1H), 4.10 - 4.01 (m, 2H), 3.87 (dd, J = 13.1, 3.1 Hz, 1H), 3.37 (s, 1H), 3.24 - 3.11 (m, 2H), 1.00 - 0.87 (m, 2H), 0.74 (td, J = 4.6, 2.8 Hz, 2H). [M+H]+ = 363.0 44 1H NMR (400 MHz, Methanol‑d4) δ 8.07 (s, 1H), 6.26 (d, J = 16.9 Hz, 1H), 4.76 (dd, J = 21.8, 9.3 Hz, 1H), 4.11 - 4.01 (m, 2H), 3.89 (d, J = 3.0 Hz, 1H), 3.89 - 3.75 (m, 1H), 3.37 (s, 2H), 3.21 (d, J = 5.4 Hz, 1H), 2.97 - 2.86 (m, 1H), 1.00 - 0.77 (m, 2H), 0.67 - 0.46 (m, 2H). [M+H]+ = 348.8 Example 19. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,SR)‑5‑(2-amino‑6-dimethylamino‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-ethynyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate

[0248] i) Isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Step 1. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6-dimethylamino‑9H-purin‑9-yl)‑4-fluoro‑3-hydro- xy‑4-ethynyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0249] To a solution of compound 41 (30 mg, 0.09 mmol) in dry THF (2 mL) at 0 °C was added tert-butyl magnesium chloride (1.0 M in THF, 125 µL, 0.13 mmol) dropwise over 10 min. The reaction mixture was stirred 15 min at 0 °C then another 15 min at room temperature. The reaction mixture was cooled down to 0 °C and a solution of isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (49 mg, 0.11 mmol) dissolved in dry THF (2 mL) was addeddropwiseover10min.The reactionmixturewasstirredat 0 °C for30minand18hat room temperature.The reaction was quenched with a saturated aq. NH4Cl solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 90:10) to afford the product (mixture of 2 diastereoisomers, 12 mg, 0.02 mmol, 24%) as a white solid. 1HNMR (300MHz,CD3OD) δ7.79 (s, 0.45H), 7.77 (s, 0.55H), 7.36‑7.14 (m, 5H), 6.28 (d, J=17.4Hz) and 6.26 (d, J=17.5 Hz, 1H), 5.00‑4.44 (m, 5H), 4.23‑4.16 (m, 1H), 3.69‑3.81 (m, 1H), 3.42 (bs, 3H), 3.40 (bs, 3H), 1.32‑1.26 (m, 3H), 1.20‑1.15 (m, 6H). 31P NMR (121 MHz, CD3OD) δ 4.04 (s), 3.98 (s). MS (ESI) m / z calcd. for C26H34FN7O7P [M+H]+ 606.2; found 606.2. Example 20. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6-methylamino‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-ethynyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0250] 106 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 i) Isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Step 1. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6-methylamino‑9H-purin‑9-yl)‑4-fluoro‑3-hydro- xy‑4-ethynyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0251] To a solution of compound 42 (30 mg, 0.09 mmol) in dry THF (2 mL) at 0 °C was added tert-butyl magnesium chloride (1.0 M in THF, 125 µL, 0.13 mmol) dropwise over 10 min. The reaction mixture was stirred 15 min at 0 °C then another 15 min at room temperature. The reaction mixture was cooled down to 0 °C and a solution of isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (49 mg, 0.11 mmol) dissolved in dry THF (2 mL) was addeddropwiseover10min.The reactionmixturewasstirredat 0 °C for30minand18hat room temperature.The reaction was quenched with a saturated aq. NH4Cl solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 90:10) to afford the product (mixture of 2 diastereoisomers, 9 mg, 0.02 mmol, 18%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.81, 7.79 (0.9s+0.1s, 1H), 7.36‑7.14 (m, 5H), 6.26 (d, J = 17.4 Hz, 0.1H) and 6.24 (d, J = 17.4 Hz, 0.9H), 4.93‑4.89 (overlapped with H2O, m, 1H), 4.80‑4.78 (m, 1H), 4.53‑4.49 (m, 2H), 4.21‑4.18 (m, 1H), 3.95‑3.84 (m, 1H), 3.23‑3.20 (m, 1H), 3.04 (bs, 1H), 1.31‑1.14 (m, 9H). 31P NMR (121 MHz, CD3OD) δ 4.06 (s), 3.97 (s). MS (ESI) m / z calcd. for C25H32FN7O7P [M+H]+ 592.2; found 592.2. Example 21. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methylcyclopropylamino)‑9H- purin‑9-yl)‑4-fluoro‑3-hydroxy‑4-ethynyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate

[0252] i) Isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate, tBuMgCl, THF, 0 °C. Step 1. Preparation of isopropyl ((((R,S)‑(2R,3R,4R,5R)‑5‑(2-amino‑6‑(N-methylcyclopropylamino)‑9H-purin‑9-yl)‑4- fluoro‑3-hydroxy‑4-ethynyltetrahydrofuran‑2-yl)methoxy)‑phenoxy-phosphoryl)‑L-alaninate.

[0253] To a solution of compound 43 (40 mg, 0.11 mmol) in dry THF (2 mL) at 0 °C was added tert-butyl magnesium chloride (1.0 M in THF, 160 µL, 0.16 mmol) dropwise over 10 min. The reaction mixture was stirred 15 min at 0 °C then another 15 min at room temperature. The reaction mixture was cooled down to 0 °C and a solution of isopropyl ((R,S)‑(pentafluorophenoxy)‑phenoxy-phosphoryl)‑L-alaninate (55 mg, 0.12 mmol) dissolved in dry THF (2 mL) was addeddropwiseover10min.The reactionmixturewasstirredat 0 °C for30minand18hat room temperature.The reaction was quenched with a saturated aq. NH4Cl solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (gradient DCM / MeOH 100:0 to 90:10) to afford the product (mixture of 2 diastereoisomers, 18 mg, 0.03 mmol, 26%) as a white solid. 1H NMR (300MHz, CD3OD) δ 7.84, 7.82 (s+s, 1H), 7.35‑7.14 (m, 5H), 6.30 (d, J = 17.4 Hz) and 6.26 (d, J = 17.6 Hz, 1H), 4.99‑4.89 (overlappedwith H2O,m, 1H), 4.82‑4.69 (m, 1H), 4.59‑4.46 (m, 2H), 4.21 (m, 1H), 3.96‑3.82 (m, 1H), 3.24‑3.22 (m,1H), 3.17‑3.11 (m,1H)1.31‑1.26 (m, 3H), 1.20‑1.15 (m,6H), 0.93‑0.89 (m,2H), 0.75‑0.68 (m,2H). 31PNMR(121MHz, CD3OD) δ 4.06 (s), 3.98 (s). MS (ESI) m / z calcd. for C28H36FN7O7P [M+H]+ 632.2; found 632.2. 107 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Example 22. Preparation of PPAL-S

[0254] Step 1. Preparation of racemic PPAL

[0255] Toastirredsolutionofphenyl dichlorophosphate (250g) inEtOAc (800mL)wasadded isopropyl L-alaninate (200 g) in triethylamine (120 g) at ‑10 °C. The reaction was stirred at ‑10 °C for 1 h. The compound 2,3,4,5,6-pentafluorophenol (220 g) in triethylamine (120 g) and EtOAc (400 mL) was added at ‑5 °C and stirred at that temperature for 0.5 h. The reactionmixturewasallowed towarm to25 °Candstirredat that temperature for 2 h. Thesolutionwasfiltratedandwashed with EtOAc (2× 200mL), and the combined organic phases were evaporated under vacuum to afford the solidPPAL-RS (racemate). Step 2. Preparation of PPAL-RS

[0256] To a stirred solution of PPAL-RS in EtOAc (200 mL) and n-heptane (1.4 L) was added 2,3,4,5,6-pentafluor- ophenol (10.1 g) in triethylamine (6 g), and stirring was continued for about 4‑8 h. After the R-isomer of the solid was less than 0.5%, the solidwas filtered. The solidwasdissolved inEtOAc (4 L), washedwithwater (2× 100mL), brine (1 L), dried over anhydrous Na2SO4, and filtered. The solvent was removed under vacuum to afford the PPAL-S (350 g). 1H NMR (400MHz, DMSO‑ d6) δ = 7.42 - 7.40 (m, 2H), 7.24 - 7.22 (m, 3H), 6.87 (dd, J = 14.1, 9.9 Hz, 1H), 4.90 - 4.84 (m, 1H), 3.94 - 3.88 (m,1H), 1.27 (dd,J=7.1, 1.1Hz, 3H), 1.15 (dd,J=6.2, 1.2Hz, 6H)ppm. . 13PNMR(160MHz,DMSO‑d6) δ = 0.37 ppm. Example 23. Preparation of PPAL-R

[0257]

[0258] To a three-necked round bottom flask fittedwith amechanic stirrer were added phenyl dichlorophosphate (189.6 g, 0.90mol) andanhydrousEtOAc (750mL). The solutionwascooled to ‑10 °Cunder a nitrogenatmosphere. Iso-propyl L- alaninate (118g, 0.90mmol)and triethylamine (100g,1.1eq)wereadded to theabovesolution.Apre-cooled (below10°C) mixture of 2,3,4,5,6-pentafluorophenol (165 g, 1 eq) and triethylamine (90.5 g, 1 eq) in EtOAc (300 mL) was added to the mixture via an addition funnel at ‑5 °C and the resulting mixture was stirred between 20‑25 °C for 1 hour. The white precipitate (TEA·HCl)was filteredoffand rinsedwithEtOAc.Thefiltratewas concentratedunder reducedpressure to yield PPAL-RS about 280 g (S / R=1 / 1) as a white solid. PPAL-RS (280 g) was triturated in 300 mL of heptane / EtOAc (20:1) at room temperature for 5 min. The white suspension was filtered and the solid was rinsed with a mixture of heptane / EtOAc (20:1). The filtratewas cooled to 8 °Cand the solidwas collected by filtration.CrudePPAL-R (10 g)was obtainedwith 95% chiral purity. The crude product was purified following above step. PPAL-R (5 g) was obtained in NLT 98% chiral purity. 1H NMR (400MHz, DMSO‑ d6) δ = 7.43 - 7.39 (m, 2H), 7.27 - 7.22 (m, 3H), 6.87 (dd, J = 14.1, 9.9 Hz, 1H), 4.89 - 4.85 (m, 1H), 3.95 - 3.90 (m, 1H), 1.27 (dd, J = 7.1, 1.1 Hz, 3H), 1.14 (dd, J = 6.2, 1.2 Hz, 6H). 13P NMR (160 MHz, DMSO‑ d6) δ = 0.35. Example 24: Preparation of compound 52.

[0259] 108 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 1. Preparation of compound 49.

[0260] To a solution of 48 (1.81 g, 3.23 mmol) in dioxane (18 mL) was added 40% aqueous CH3NH2 solution (16.2 mmol). The reaction was stirred at 40 °C for 2 h. Themixture was concentrated, diluted with EtOAc (50 mL), washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford a white solid 49 (1.66 g, 92%). Step 2. Preparation of compound 50.

[0261] To a solution of 49 (1.34 g, 2.42 mmol) and 1-methylimidazole (794 mg, 9.68 mmol) in DCM (14 mL) was slowly added pentyl chloroformate (547 mg, 3.63 mmol) at 0 °C. The reaction was stirred at r.t overnight. The mixture was concentrated, and purified by column chromatography (PE: EtOAc = 5:1 - 2:1) to afford 50 (1.01 g, 62%) as a white solid. 1HNMR(400MHz,DMSO) δ7.96 (s, 1H), 6.73 (s, 1H), 6.06‑6.10 (d, J= 16.0Hz, 1H), 4.09‑4.30 (m, 2H), 3.97‑4.09 (m, 4H), 3.28 (s, 3H), 1.39‑1.46 (m, 2H), 1.0‑1.2 (m, 35H), 0.73‑0.76 (t, J= 8.0 Hz, 3H). 109 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 3. Preparation of compound 51.

[0262] Toasolutionof50 (1.00g, 1.5mmol) inTHF (11mL)wasaddedEt3N (2.0mL,15mmol) andEt3N.3HF (1.21g,7.5 mmol) at 0 °C. The reaction was stirred at r.t for 1.5 h. The mixture was concentrated, and purified by column chromatography (MeOH: CH2Cl2 = 50:1) to afford 75 (460 mg, 72.2%) as a white powder. Step 4. Preparation of compound 52.

[0263] To a solution of 51 (460 mg, 1.08 mmol) and PPAL-S (538 mg, 1.19 mmol) in anhydrous THF (9 mL) was slowly added t-BuMgCl (2.27mmol) at 5‑10 °CunderN2. The reactionwasstirredat r.t for 40min. Themixturewasquenchedwith aq. saturated NH4Cl solution, extracted with EtOAc, washedwith aq. 5%K2CO3 solution and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (CH2Cl2:MeOH=15:1) to afford 52 (280 mg, 37.3%) as a white solid. 1HNMR (400MHz,DMSO) δ8.12 (s, 1H), 7.34‑7.38 (m, 2H), 7.18‑7.23 (m, 3H), 6.74 (s, 2H), 6.11‑6.16 (d, J=16.0Hz, 1H), 5.99‑6.05 (m, 1H), 5.84 (m, 1H), 4.77‑4.81 (m, 1H), 4.30‑4.41 (m, 3H), 4.03‑4.11 (m, 3H), 3.78‑3.80 (m, 1H), 3.3 (s, 3H), 1.44‑1.51 (m, 2H), 1.00‑1.21 (m, 16H), 0.76‑0.80(t, J= 8.0 Hz, 3H). [M+H]+= 696.6. Example 25: Preparation of compound 56.

[0264] 110 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 1. Preparation of compound 48.

[0265] To a solution of 23 (600mg, 1 eq) in pyridine (30mL) was added TIPDSCl2 (1.5eq) at 0 °C. The resulting solution wasallowed to standat room temperature for 2 h. Themixturewasquenchedwith icewater andextractedwithEtOAc. The organic layer was washed with 1M aq. HCl solution, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to yield the crude residue. The residue was purified by chromatography (MeOH: CH2Cl2 = 1:50) to afford 48 (998 mg, 94.4%) as a white solid foam. Step 2. Preparation of compound 53.

[0266] A mixture of 48 (800 mg, 1 eq), pyridine (3.2 mL), DMAP (34.9 mg, 0.2 eq) in DCM (20 mL) was stirred at room temperature.N-amyl chloroformate (3.2mL)wasaddeddropwise at 0 °C, and themixturewasstirredat room temperature for 1 day. The organic layer was washed with 1M aqueous HCl solution, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on silica gel (MeOH: CH2Cl2 = 1:50) to afford 53 (255 mg, 26%) as a white solid foam. 111 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 3. Preparation of compound 54.

[0267] To the solution of 53 (270mg, 1 eq) in 1,4-dioxane (10mL), was dropwise added 40%aqueousCH3NH2 solution (225.7 mg, 5 eq). The mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel (methanol: dichloromethane= 1:40) to afford 54 (220 mg, 81.7%) as a white solid foam. Step 4. Preparation of compound 55.

[0268] Triethylamine (1011.9 mg, 10 eq) and Et3N·3HF (806.05 mg, 5 eq) were added to an ice-cooled solution of 54 (668 mg, 1 eq) in THF (10 mL), the mixture was stirred for 2 h at room temperature. The mixture was concentrated and chromatographed on silica gel (MeOH: CH2Cl2 = 1:30) to afford 55 (492 mg, 84%) as a white solid foam. Step 5. Preparation of compound 56.

[0269] To themixtureof55 (113mg,1eq)andPPAL-S (120mg,1eq) inTHF (4mL)wasdropwiseadded1.7M t-BuMgCl in THF (0.327mL, 2.1 eq) at ‑10 °C.Themixturewasstirredat room temperature for 1 h, and thenquenchedwith saturated aq.NH4Cl solution.TheaqueousphasewasextractedwithEtOAcand theorganicphasewaswashedwithbrine, driedand concentrated to obtain crude residue. The residuewas subjected to flash chromatography to afford 56 (126mg, 68.5%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.10‑7.45 (m, 5H), 6.15‑6.20 (d, J= 20.0 Hz, 1H), 5.00‑5.25 (s, 1H), 4.80‑4.86 (m, 1H), 4.45‑4.70 (m, 2H), 4.12‑4.19 (m, 3H), 3.80‑3.85 (m, 1H), 3.04 (s, 3H), 1.60‑1.75 (m, 2H), 1.10‑1.40 (m, 16H), 0.76‑0.80(t, J= 8.0 Hz, 3H). 31P NMR (160 MHz, DMSO) δ 3.57. [M+H]+= 696.5. Example 26: Preparation of compound 60.

[0270] 112 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 1. Preparation of compound 57.

[0271] To a solution of 6 (20 g, 1 eq) in CH3CN (100 mL) was added imidazole (16.6 g), TIPDSCl2 (28.9 g, 1.5 eq) in sequence at 5±5 °C. The resulting solution was allowed to stand at room temperature for 4 h. Themixture was quenched with icewaterandextractedwithEtOAc.Theorganic layerwaswashedwithwater, saturatedaqueoussodiumbicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to afford the crude residue (32 g). Step 2. Preparation of compound 58.

[0272] To the solution of 57 (9.8 g, 1 eq) in THF (4mL)was dropwise added 1.7M t-BuMgCl in THF (50mL, 4.8 eq) at 0‑5 °C.Themixturewasstirredat room temperature for 0.5h, andn-amyl chloroformate (2.7g, 1.05eq)wasslowlyadded.The mixture was stirred at 0‑5 °C for 3‑4 h. Themixture was quenched with saturated aq. NH4Cl solution. The aqueous phase was extracted with EtOAc (200 mL) and the organic phase was washed with brine, dried and concentrated to obtain 58 (10.7 g) as oil. 113 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Step 3. Preparation of compound 59.

[0273] Triethylamine (10.119g)andEt3N·3HF (8.6g,5eq)wereadded toan ice-cooledsolutionof58 (7.3g, 1eq) inTHF (100mL) and themixturewas stirred for 1 h at room temperature. Themixturewas concentrated and chromatographedon silica gel (MeOH: CH2Cl2 = 1:30) to afford 59 (4.3 g, 91%) as a white solid. Step 4. Preparation of compound 60.

[0274] To themixture of 59 (2 g, 1 eq) andPPAL-S (2.3 g, 1.1 eq) in THF (40mL)was dropwise added 1.7M t-BuMgCl in THF (5.6 mL, 2.1 eq) at ‑5 °C. The mixture was stirred at ‑20±5 °C for 1 h, and then quenched with saturated aq. NH4Cl solution. The aqueous phase was extracted with EtOAc and the organic phase was washed with brine, dried and concentrated to obtain crude residue. The residue was subjected to flash chromatography to afford 60 (1.5 g, 47%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.9 (s, 1H), 7.1~7.2 (m,5H), 6.2 (d, J = 20 Hz, 1H), 5.1 (br,1H), 4.84 (m, 1H), 4.49 (m,, 2H), 4.16 (m, 1H), 4.13 (m, 2H), 3.86 (m, 1H), 3.45 (br, 6H), 1.70 (m, 2H), 1.26 (m, 4H), 1.20 (m, 6H), 1.14 (m, 6H), 0.93 (m, 3H). [M+H]+ =710.5. Biological Data Example 27. Assay Methodology and Additional Biological Data

[0275] Huh‑7 luc / neo ETcells bearing a discistronic HCV genotype 1b luciferase reporter replicon were plated at 7.5 x 103 cells / ml in duplicate 96-well plates for theparallel determinationof antiviral efficacy (EC50) and cytotoxicity (TC50). The plateswere cultured for 24hours prior to the addition of compounds.Six serial onehalf log dilutionsof the test articles (high test concentration of 100.0 µM or high test concentration of 1.0 µM) and human interferon-alpha2b (high test 10.0 U / ml) were prepared in cell culturemediumand added to the cultured cells in triplicatewells for each dilution. Sixwells in the test plates receivedmedium alone as an untreated control. Following 72 hours of culture in the presence of compound, one of the plates was used for the determination of cytotoxicity by staining with XTT and the other for antiviral efficacy by determination of luciferase reporter activity. Cytotoxicity and efficacy data were collected and imported into a customized Excelworkbook for determinationof theTC50andEC50 values.Data for compoundsofFormula I-VII are illustrated inTable 7 below. In addition, Figure 2 illustrates theHCV replication inhibition curves for Compound 5‑2 andSofosbuvir. As can be seen in Figure 2, Compound 5‑2 has an EC50 = 4 nM, while Sofosbuvir has an EC50 = 53 nM. The y-axis is the percent of virus control and the x-axis is the concentration of drug inµM. Figure 3 illustrates the HCV replication inhibition curves for Compound 25 and Sofosbuvir. Compound 25 has an EC50 = 4 nM and Sofosbuvir has an EC50 = 53 nM. The y-axis is the percent of virus control and the x-axis is the concentration of drug inµM. Figure 4 illustrates an intra-assay comparison of the anti-HCVactivity for Compounds 5‑2, 25, 27 and Sofosbuvir. The y-axis is the percent of virus control and the x-axis is 114 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 the concentration of drug in µM.

[0276] Various patient-derived HCV genotypes containing wild-type and resistance-associated variants were used to determine their relative replication sensitivity to test compounds. Replicon resistance test vectors (RTVs) containing the NS5B genomic regions were prepared using viral RNA isolated from plasma of HCV patients. Each NS5B region was amplified by reverse-transcription polymerase chain reaction and cloned into an HCV replicon RTV which was then transferred by electroporation into Huh‑7 cells. After incubation in the absence and presence of serially diluted test compounds for 72‑96 hr, viral replication was measured by luciferase activity and 50% inhibitory concentrations (IC50 values) were determined.

[0277] Table 2 reports the IC50 and IC95 values for compound25, 27, 5‑2andSofosbuvir against various clinical isolates containing wild-type and resistance-associated variants.

[0278] All compounds were significantly more effective against HCV replication than sofosbuvir and neither 25, 27 nor 5‑2 compound showed any evidence of cross-resistance to L159F, L159F and S282T, and C316N mutants. Table 2: Antiviral Activity of Test Compounds in Patient-derived HCV Genotypes HCV NS5B Test IC50 Value IC95 Value Fold Change in IC50 Fold Change in IC95 Genotype Mutation Compound (nM) (nM) from Sofosbuvir from Sofosbuvir 1a none sofosbuvir 62.7 507.7 25 4.4 31.3 14.2 16.2 27 4.2 26.4 15.0 19.3 5‑2 10.5 60.8 6.0 8.4 1b none sofosbuvir 86.0 642.2 1.0 25 5.9 32.0 1.0 20.0 27 5.0 28.9 0.9 22.2 5‑2 10.6 72.4 0.8 8.9 2a none sofosbuvir 22.5 195.1 25 2.7 22.2 8.4 8.8 27 2.9 16.2 7.9 12.0 5‑2 6.2 45.4 3.6 4.3 2b none sofosbuvir 44.8 295.3 25 3.0 14.9 15.2 19.9 27 3.1 14.7 14.4 20.1 5‑2 6.3 32.5 7.1 9.1 3a‑1 none sofosbuvir 125.9 689.8 25 5.1 27.8 24.5 24.8 27 4.4 25.4 28.4 27.2 5‑2 11.8 59.3 10.7 11.6 3a‑2 none sofosbuvir 123.5 808.1 25 4.7 24.2 26.3 33.4 27 4.5 23.3 27.5 34.6 5‑2 10.4 56.5 11.9 14.3 4a none sofosbuvir 74.9 681.4 25 4.6 33.0 16.2 20.7 27 3.6 38.1 20.7 17.9 5‑2 9.9 74.4 7.5 9.2 115 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) HCV NS5B Test IC50 Value IC95 Value Fold Change in IC50 Fold Change in IC95 4d none sofosbuvir 93.7 1019.7 25 5.9 44.2 16.0 23.1 27 5.6 38.4 16.7 26.6 5‑2 14.0 79.9 6.7 12.8 1a L159F sofosbuvir 114.7 1067.5 25 5.2 40.4 22.0 26.4 27 5.1 36.2 22.3 29.5 5‑2 13.0 95.3 8.8 11.2 1a L159F and S282T sofosbuvir 1619.9 16950.9 25 17.2 158.5 94.0 107.0 27 14.9 141.6 108.4 119.7 5‑2 38.7 313.5 41.9 54.1 1b C316N sofosbuvir 73.9 472.8 25 3.2 18.1 23.1 26.2 27 3.1 16.5 23.5 28.7 5‑2 7.7 42.7 9.6 11.1

[0279] A transient transfectionassaywasperformed todetermine the sensitivity of thewild typeS282Tmutant ofHCV to test compounds. Huh‑7 cells were electroporated in the presence of RNA transcribed from wild type or S282T HCV replicon plasmids from the T7 promoter. The transfected cells were seeded in to 96-well plates at 7.5 x 103 cells per well in Dulbecco’s Modified Eagle’s medium. After 24 hr of incubation, medium was removed and replaced with fresh medium containing no or various concentrations of test compounds. Following an additional 96-hr incubation, the anti-HCVactivity was measured by luciferase endpoint with Britelite™ Plus luminescence reporter gene kit (Perkin Elmer, Shelton, CT). Duplicate plates were treated and incubated in parallel for assessment of cellular toxicity by staining with the tetrazolium dye XTT.

[0280] Table 3 reports the IC50 and IC95 values for compounds 25, 27, 5‑2 and Sofosbuvir against HCV wild type and S282T replicons.

[0281] All compounds were significantly more effective against HCV replication than sofosbuvir and neither 25, 27, nor 5‑2 compounds showed any evidence of cross-resistance to S282T variant. Table 3: Antiviral Activity of Test Compounds in a HCV Transient Infection Assay Compound NS5B Mutation IC50 Value (nM) IC95 value (nM) Fold change in IC50 from Sofosbuvir Fold change in IC95 from Sofosbuvir 5‑2 None 1.4 9.98 26 22.2 S282T 2.8 20.6 99.3 > 48.5 25 None < 1 2.7 > 36.4 80.7 S282T < 1 9.4 > 278 > 106.4 27 None < 1 4.1 > 36.4 53.2 S282T < 1 11.8 > 278 > 84.7 Sofosbuvir None 36.4 218 S282T 278 >1000

[0282] Thestability of selectedcompounds in freshhumanwholebloodand inhuman liverS9 fractionwasdetermined in incubations containing 10µMtest compound. After incubations of 0, 30, 60min, and up to 120min, aliquotswere removed and immediately extracted with 3 volumes of ice-cold methanol / acetonitrile (1:1, v / v). Extracts were centrifuged and 116 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 supernatants were analyzed by LC-MS / MS for concentrations of unchanged test compound and potential metabolites.

[0283] Figure 5 illustrates the excellent stability of compound 5‑2 and all 2-amino derivatives in human blood.

[0284] Interestingly, Figure 6 illustrates the in vitro time course dealkylation of the 2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N2- methyl-N6-methyl‑2,6-diaminopurine nucleoside phosphoramidate to 2’-deoxy‑2’-α-fluoro‑2’-β-methyl-N6-methyl‑2,6- diaminopurine nucleoside phosphoramidate with a human liver S9 fraction. Furthermore, unexpected, faster, and a more extensive rate of cleavage of the carbamate moiety by human liver S9 fraction was observed as compared to compound 5‑2 and its other 2-amino derivatives (Figure 7). Example 28. HCV (gt1b) NS5B Polymerase Assay

[0285] Inhibition of HCV (gtlb) NS5B polymerase was determined in triplicate by measuring de novo polymerization in reaction mixtures containing serial dilutions of TA, in vitro transcribed viral RNA complementary to the HCV (‑) strand 3’UTR region, polymerase, radiolabeled ribonucleotide, 250 µM non-competing rNTPs, and 1 µM competing rNTP. TA concentrations that produced 50% inhibition (IC50) were determined from resulting inhibition curves. Example 29. Human Bone Marrow Progenitor Cell Assay

[0286] Fresh human bonemarrow progenitor cells (Invitrogen) suspended in either BFU-E or GM-CSF-specific culture medium were added, at 105 cells / well, to triplicate serial dilutions of TA in 6-well plates. After 14-day incubations, colony counts were used to determine CC50 values. BFU-E colonies were confirmed using the benzidene technique.

[0287] Compounds 25, 27 and 5‑2 show no cytotoxicity against bone marrow stem cells in vitro. Example 30. iPS Cardiomyocyte Assay

[0288] iPS Cardiomyocytes (Cellular Dynamics) were seeded in microliter plates at 1.5 x 104 cells per well. After 48-hr incubation, cells were washed and maintenance medium containing serially diluted TA was added in triplicate. After incubating for an additional 3 days, cell viability was measured by staining with XTT and CC50 values were calculated.

[0289] Compounds 25, 27 and 5‑2 show no cytotoxicity against iPS cardiomyocytes in vitro. Example 31. Human DNA Polymerase Assays

[0290] Inhibition of human DNA polymerases α, β and γ (CHIMERx) was determined in triplicate in reaction mixtures of serially dilutedTA, 0.05mMdCTP, dTTP, and dATP, 10µCi [32P]-α-dGTP (800Ci / mmol), 20µgactivated calf thymusDNA and additional reagents specific for each polymerase. After 30-min incubations, incorporation of [α‑32P]‑GTP was measured and resulting incubation curves were used to calculate IC50 values.

[0291] The triphosphate, β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-guanine triphosphate, as well as the triphosphate analogs of compounds 25, 27 and 5‑2 do not inhibit human DNA polymerases α, β or γ. Example 32. Human Hepatocyte Co-Cultures

[0292] Cytotoxicity and hepatocyte health were assessed in triplicate by measuring ALT leakage, urea production, albumin secretion and cellular ATP contents in micro-patterned human hepatocyte co-cultures (HepatoPac®, Hepregen Corporation) preparedby seeding cryopreserved female humanhepatocytes (single donor) and3T3 J2mouse fibroblasts in microtiter plates according to procedures established by Hepregen. Culture media was replaced with fresh media containing TA, test article, (0, 1, 10 or 30µM) every 2 or 3 days through day 16. Spent culture media was assayed for ALT and urea content on days 2, 5, 7, 9, 12, 16 and 21 and for albumin content on days 2, 5, 7 and 9. Cellular ATP levels were measured on days 9 and 21. ATP signals in stromal-only control cultures (murine 3T3 fibroblasts) were subtracted from those of human HepatoPac co-cultures to obtain hepatocyte-specific effects. See, Table 4, 5 and 6 below.

[0293] Compound 5‑2 at concentrations up to 30 µM, showed no signs of cytotoxicity as measured by ALT leakage, albumin secretion, urea production and cellular ATP content when incubated for up to 12 days with micro-patterned co- cultured human hepatocytes. The minor indications of cytotoxicity detected with extended exposure (up to 21 days of culture) were significantly less than those observed with sofosbuvir. See, Table 4, 5 and 6 below.

[0294] INX‑189was highly cytotoxic to human co-cultured hepatocytes, showing decreased albumin secretion as early as day 2 and cytotoxicity by all measures. Sofosbuvir showed more cytotoxicity than AT‑511 under the same conditions. 117 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Table 4. Effect of Test Article on Cellular ATP Concentrations Test Article 50% Inhibitory Concentration (IC50) - µM Day 9 Day 21 Cmpd 5‑2 >30 12.8 Sofosbuvir 8.6 2.3 INX‑189 8.1 0.1 Table 5. Effect of Test Articles on Albumin Secretion Test Article 50% Inhibitory Concentration (IC50) - µM Day 2 Day 5 Day 7 Day 9 Cmpd 5‑2 >30 >30 >30 >30 Sofosbuvir >30 19.5 10.9 9.3 INX‑189 13.6 3.1 3.2 2.4 Table 6. Effect of Test Articles on Albumin Secretion Test Article 50% Inhibitory Concentration (IC50) - µM Day 2 Day 5 Day 7 Day 9 Day 12 Day 16 Day 21 Cmpd 5‑2 >30 >30 >30 >30 >30 24.2 14.5 Sofosbuvir >30 >30 >30 12.1 6.8 2.7 2.3 INX‑189 >30 4.2 1.8 1.8 1.3 <<1 <<1 Example 33. Metabolic Studies

[0295] The metabolism of compounds 25, 27 and 5‑2, at a concentration of 10 µM, were investigated in fresh primary cultures of human, dogandmousehepatocytes. Plated hepatocytes fromhumans (XenoTech,mixedgender, pooled from 10donors),maleBeagledog (BioreclamationIVT), andmale ICR / CD‑1mice (BioreclamationIVT,8donors) in6-well plates with matrigel overlay were incubated in singlet with 10 µM TA. After 2, 4, 6, 8 or 24 hr, intracellular levels of nucleotide prodrugs and their potential metabolites (prodrugs, monophosphates, triphosphates and nucleosides) were quantitated byLC-MS / MS.Concentrations below the lower limit of quantitation (1.5 pmol / 106 cells for prodrugs,monophosphates and nucleosides and 12 pmol / 106 cells for triphosphates) were extrapolated from the standard curves.

[0296] The compound β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-guanine triphosphate is the predominant metabolite of compounds 25, 27 and 5‑2 observed in cultured human hepatocytes and is a potent inhibitor of the HCV (gtlb) NS5B polymerase, with an IC50 of 0.15 µM.

[0297] Figure 8 shows the predominant Compound 25 metabolites in human hepatocytes.

[0298] Figure 9 shows the predominant Compound 27 metabolites in human hepatocytes.

[0299] Figure 10 shows the predominant Compound 5‑2 metabolites in human hepatocytes.

[0300] Figure 11 illustrates the activation pathways for Compounds 25, 27 and 5‑2. As can be seen, Compounds 25, 27 and 5‑2 are converted to their correspondingmonophosphate analogswhich are subsequentlymetabolized to a common MP analog; β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-guaninemonophosphate (Compound 61). Themonophosphate is then stepwise phosphorylated to the active triphosphate: β-D‑2’-deoxy‑2’-α-fluoro‑2’-β-methyl-guanine triphosphate (Com- pound 62). Example 34. Controls

[0301] INX‑189 (INX‑08189 / BMS‑986094) and sofosbuvir were used as controls in the Examples above.

[0302] The twomost potent nucleotide prodrugs, Compounds 25 and 27, demonstrated excellent selectivity, with CC50 values greater than 100 µM in Huh‑7 cells, human bone marrow stem cells and human cardiomyocytes. No inhibition of human DNA polymerase α, β or γ, no activity against other RNA or DNA viruses, and no toxicity in all host cell lines was observed at concentrations up to 100 µM.

[0303] Table 7 is a table illustrating the compounds tested in aHCVReplicon Assay alongwith the EC50 / EC95 (µM) and 118 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 CC50 (µM) results. 119 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Ta bl e 7. R ep lic on As sa y R es ul ts fo rC om po un ds Te st ed . C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 6. 7 >1 00 2. 1 / 9. 04 >1 00 3 4 15 .7 >1 00 120 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 5 0. 02 6 / 0. 12 4 >1 00 > 60 0 5‑ 1 0. 05 51 / 0 .2 82 >1 00 >2 80 121 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 5‑ 2 0. 00 4 / 0. 02 8 >1 00 >3 ,9 00 6 10 .7 >1 00 7 0. 01 21 / 0 .0 71 >1 00 >8 90 122 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 8 5. 56 >1 00 9 0. 00 91 / 0 .0 54 >1 00 >6 00 15 >1 00 >1 00 123 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 16 0. 57 6 / 3. 69 >1 00 17 11 .5 / 6 5. 4 >1 00 18 0. 04 8 / 0. 21 9 90 .0 124 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 19 7. 47 >1 00 20 0. 07 3 / 0. 31 5 >1 00 25 0. 00 4 / 0. 01 9 >1 00 >2 ,6 00 125 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 26 0. 03 51 / 0 .0 57 >1 00 27 0. 00 5 / 0. 02 5 >1 00 >1 ,1 00 126 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 28 0. 01 4 / 0. 07 6 >1 00 41 0. 50 8 / 25 .1 21 .8 42 4. 18 / 2 0. 4 >1 00 127 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 43 6. 43 / 2 4. 7 21 .6 45 0. 16 / 0 .8 76 0. 68 46 0. 22 4 / 0. 96 1 >1 00 128 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 47 0. 33 8 / 1. 72 1. 68 61 62 129 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 (c on tin ue d) C m pd N o. St ru ct ur e H C V R ep lic on EC 50 / E C 95 (µ M ) H C V R ep lic on C C 50 (µ M ) Fo ld in cr ea se in ac tiv ity co m pa re d to pa re nt nu cl eo si de 0. 05 2 / 0. 31 0 >1 00 0. 04 5 / 0. 25 9 >1 00 130 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55

[0304] The β-D‑2’-D‑2’-a-fluoro‑2’-β-C-substituted‑2-modified-N6-substituted purine nucleotides described herein ex- hibit significant activity against the HCV virus. Compounds according to the present invention are assayed for desired relative activity using well-known and conventional assays found in the literature.

[0305] For example, anti-HCV activity and cytotoxicity of the compounds may be measured in the HCV subgenomic RNA replicon assay system in Huh7 ET cells. (See, Korba, et al., Antiviral Research 2008, 77, 56). The results can be summarized in comparison to a positive control, 2’-C-Me-cytosine {2’-C-Me-C}(Pierra, et al., Journal of Medicinal Chemistry 2006, 49, 6614.

[0306] Another in-vitroassay for anti-hepatitisCvirusactivity is described inU.S.PatentNo.7,718,790byStuyver, et al., and assigned to Pharmasset, Inc.

[0307] This specificationhasbeendescribedwith reference toembodimentsof the invention.Given the teachingherein, one of ordinary skill in the art will be able to modify the invention for a desired purpose and such variations are considered within the scope of the invention.

[0308] The present invention is also exemplified by the following numbered clauses: 1. A compound of Formula I: wherein: Y is NR1R2; R1 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CH2F, CHF2, CF3, CH2CF3, CF2CH3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), - (C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, - C(O)R3C (including ‑C(O)CH3, ‑C(O)CH2CH3, ‑C(O)CH(CH3)2, ‑C(O)OCH3, -C(O)OC2H5, ‑C(O)OC3H7, ‑C(O) OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R2 is hydrogen, optionally substituted C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), optionally substituted ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), optionally substituted ‑(C0‑C2alkyl)(heterocycle), optionally substi- tuted ‑(C0‑C2alkyl)(aryl), optionally substituted ‑(C0‑C2alkyl)(heteroaryl), - C(O)R3C (including ‑C(O)CH3, ‑C(O) CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, - C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28; and wherein at least one of R1 and R2 is methyl, CH2F, CHF2 or CF3; R3 is hydrogen, diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or ‑C(O)R3C; R3A can be selected fromO-, OH, an ‑O-optionally substituted aryl, an ‑O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl; R3B can be selected from O-, OH, an optionally substituted N-linked amino acid or an optionally substituted N- 131 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 linked amino acid ester; R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), or ‑O‑(C0‑C2) (heteroaryl), each of which can be optionally substituted; R4 is amonophosphate, diphosphate, triphosphate, or a stabilizedphosphateprodrug, includingbut not limited to a phosphoramidate, a thiophosphoramidate, or any other moiety that is metabolized to a monophosphate, diphosphate or triphosphate in vivo in the host human or animal; or R3 and R4 together with the oxygens that they are bonded to can form a 3’,5’-cyclic prodrug; R12 is CH3, CH2F, CHF2, CF3, or ethynyl; R25 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl) (C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R28 is C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6hetero- cycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) each of which can be optionally substituted; or a pharmaceutically acceptable salt thereof. 2. The compound of clause 1, wherein: R4 is a stabilized phosphate prodrug and R12 is CH3, CH2F, CF2H or CF3. 3. The compound of clause 2, wherein: R4 is a phosphoramidate and R12 is CH3, CH2F, CF2H or CF3. 4. The compound of clause 2, wherein: Y is NR1R2; and R1 is methyl, R2 is hydrogen and R12 is CH3, CH2F, CF2H or CF3. 5. The compound of clause 2, wherein: Y is NR1R2; and R1 is methyl, R2 is methyl and R12 is CH3, CH2F, CF2H or CF3. 6. The compound of clause 2, wherein: Y is NR1R2; and R1 is methyl, R2 is cyclopropyl and R12 is CH3, CH2F, CF2H or CF3. 7. The compound of clause 1, wherein R12 is CH3. 8. The compound of clause 1, wherein R12 is ethynyl. 9. A compound of the formula: wherein: 132 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 R7 is hydrogen,C1‑6alkyl; C3‑7cycloalkyl; heteroaryl, heterocyclic, or aryl, where phenyl or naphthyl are optionally substituted with C1‑6alkyl, C2‑6alkenyl, C2‑6 alkynyl, C1‑6alkoxy, F, Cl, Br, I, nitro, cyano, C1‑6haloalkyl, ‑(CH2)1‑6COOH, ‑(CH2)1‑6COOC1‑6alkyl, ‑N(R 7’)2, C1‑6acylamino, NHSO2C1‑6alkyl, ‑SO2N(R7’)2, COR7", and ‑SO2C1‑6alkyl; (R7’ is independently hydrogen or C1‑6alkyl; R7" is ‑OR11 or-N(R7)2); R8 is hydrogen, C1‑6alkyl, or R9a or R9b and R8 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms; where n is 2 to 4; R9a and R9b are (i) independently selected from hydrogen, C1‑6alkyl, cycloalkyl, ‑(CH2)c(NR9’)2, C1‑6hydro- xyalkyl, ‑CH2SH, ‑(CH2)2S(O)(Me, ‑(CH2)3NHC(=NH)NH2, (lH-indol‑3-yl)methyl, (lH-imidazol‑4-yl)methyl, ‑(CH2)cCOR9", aryl and aryl(C1‑3alkyl)‑, the aryl groups can be optionally substituted with a group selected fromhydroxyl, C1‑6alkyl, C1‑6alkoxy, halogen, nitro and cyano; (ii) R9a andR9b both areC1‑6alkyl; (iii) R9a andR9b together are (CH2), soas to formaspiro ring; (iv)R9a is hydrogenandR9bandR8 together are (CH2)n soas to form a cyclic ring that includes the adjoining N andC atoms (v) R9b is hydrogen andR9a andR8 together are (CH2)n so as to form a cyclic ring that includes the adjoining N andC atoms, where c is 1 to 6, n is 2 to 4, r is 2 to 5 andwhere R9’ is independently hydrogen or C1‑6 alkyl and R9" is ‑OR11 or ‑N(R11’)2 ); (vi) R9a is hydrogen and R9b is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol‑3-yl, ‑CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, ‑CH2CH2CH2NHC(NH) NH2, CH2-imidazol‑4-yl, CH2OH, CH(OH)CH3, CH2((4’-OH)‑Ph), CH2SH, or lower cycloalkyl; or (vii) R9a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol‑3-yl, ‑CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, ‑CH2CH2CH2NHC(NH) NH2, CH2-imidazol‑4-yl, CH2OH, CH(OH)CH3, CH2((4’-OH)‑Ph), CH2SH, or lower cycloalkyl and R9b is hydro- gen; R10 is hydrogen, C1‑6alkyl optionally substituted with an alkoxy, di(lower alkyl)‑amino, or halogen, C1‑6haloalkyl, C3‑7cycloalkyl, heterocycloalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; R11 is an optionally substituted C1‑6alkyl, an optionally substituted cycloalkyl; an optionally substituted C2‑6alky- nyl, an optionally substituted C2‑6alkenyl, or optionally substituted acyl, which includes but is not limited to C(O) (C1‑6 alkyl); and Y, R3 and R12 are as defined in clause 1; or a pharmaceutically acceptable salt thereof. 10. The compound of clause 9, wherein: Y is NR1R2, R1 is methyl, R2 is hydrogen or methyl, and R12 is CH3. 11. The compound of clause 9, wherein: Y is NR1R2, R1 ismethyl, R2 ismethyl or hydrogen, R3 is hydrogen, R7 is phenyl, R8 is hydrogen, R9a is hydrogen, R9b is methyl, R10 is isopropyl and R12 is CH3. 12. The compound of clause 9, wherein: Y is NR1R2, R1 is methyl, R2 is cyclopropyl and R12 is CH3. 13. The compound of clause 9, wherein: Y is NR1R2, R1 is CH3, R2 is C(O)OR3, R3 is hydrogen and R12 is CH3. 14. A compound of Formula II: 133 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein: Y is NR1R2; R1 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CH2F, CHF2, CF3, CH2CF3, CF2CH3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), - (C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, - C(O)R3C (including ‑C(O)CH3, ‑C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, - C(O)OC2H5, ‑C(O)OC3H7, ‑C(O) OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R2 is hydrogen, optionally substituted C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), optionally substituted ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), optionally substituted ‑(C0‑C2alkyl)(heterocycle), optionally substi- tuted ‑(C0‑C2alkyl)(aryl), optionally substituted ‑(C0‑C2alkyl)(heteroaryl), ‑C(O)R3C (including ‑C(O)CH3, - C(O)CH2CH3‑C(O) CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28; and wherein at least one of R1 and R2 is methyl, CH2F, CHF2 or CF3; R3 is hydrogen, diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or ‑C(O)R3C; R3A can be selected fromO-, OH, an ‑O-optionally substituted aryl, an ‑O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl; R3B can be selected from O-, OH, an optionally substituted N-linked amino acid or an optionally substituted N- linked amino acid ester; R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), ‑O‑(C0‑C2)(het- eroaryl), ‑S-alkyl, ‑S-alkenyl, - S-alkynyl, ‑S‑(C0‑C2)(cycloalkyl), ‑S‑(C0‑C2)(heterocyclo), ‑S‑(C0‑C2)(aryl), or ‑S‑(C0‑C2)(heteroaryl) each of which can be optionally substituted; R3D is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O- alkyl, ‑O-alkenyl, ‑O-alkynyl, ‑O‑(C0‑C2)(cycloalkyl), ‑O‑(C0‑C2)(heterocyclo), ‑O‑(C0‑C2)(aryl), or ‑O‑(C0‑C2) (heteroaryl), each of which can be optionally substituted; R4 is amonophosphate, diphosphate, triphosphate, or a stabilizedphosphateprodrug, includingbut not limited to a phosphoramidate, a thiophosphoramidate, or any other moiety that is metabolized to a monophosphate, diphosphate or triphosphate in vivo in the host human or animal; or R3 and R4 together with the oxygens that they are bonded to can form a 3’,5’-cyclic prodrug, including but not limited to, a 3’,5’-cyclic phosphate prodrug; 134 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 R5 is C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl) (C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl), ‑OR25, ‑C(O)R3C (including ‑C(O)CH3, ‑C(O)CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, ‑C(O)OC2H5, - C(O)OC3H7, ‑C(O)OC4H9, and -C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28 each of which can be optionally substituted; R6 is hydrogen, optionally substituted C1‑C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1‑C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), optionally substituted ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), optionally substituted ‑(C0‑C2alkyl)(heterocycle), optionally substi- tuted ‑(C0‑C2alkyl)(aryl), optionally substituted ‑(C0‑C2alkyl)(heteroaryl), - C(O)R3C (including ‑C(O)CH3, ‑C(O) CH2CH3‑C(O)CH(CH3)2, ‑C(O)OCH3, - C(O)OC2H5, ‑C(O)OC3H7, ‑C(O)OC4H9, and ‑C(O)OC5H11), ‑C(S)R3D, or ‑SO2R28; or R5 and R6 together with the nitrogen that they are bonded to can form a heterocyclic ring; R12 is CH3, CH2F, CHF2, CF3, or ethynyl; R22 is F, Cl, Br, CN, N3, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C1‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl) (C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl); ‑ONHC(=O)OR23, ‑NHOR24, ‑OR25, ‑SR25, ‑NH(CH2)1‑4N(R26)2, - NHNHR26, ‑N=NR27, ‑NHC(O)NHNHR27, ‑NHC(S)NHNHR27, ‑C(O)NHNHR27, - NR27SO2R28, ‑SO2NR27R29, ‑C(O)NR27R29, ‑CO2R29, ‑SO2R29, , - P(O)H(OR29), ‑P(O)(OR29)(OR30), ‑P(O)(OR29)(NR29R30) or ‑NR5R6; R23 is C1‑C5alkyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(heterocycle)‑(C0‑2alkyl)(aryl) or ‑(C0‑C2alkyl) (heteroaryl) each of which can be optionally substituted; R24 is hydrogen,C1‑C6alkyl, ‑(C1‑C2alkyl)(C3‑C6cycloalkyl), ‑(C1‑C2alkyl)(C3‑C6heterocycle) ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R25 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl) (C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R26 is independently selected from hydrogen, C1‑C6alkyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(hetero- cycle), ‑(C0‑C2alkyl)(aryl), or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; R27 hydrogen or optionally substituted C1‑C6 alkyl; R28 is C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6hetero- cycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) each of which can be optionally substituted; R29 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl) (C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; or R27 and R29 together with the nitrogen that they are bonded to can form a heterocyclic ring; R30 is hydrogen, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C0‑C2alkyl)(C3C6cycloalkyl), ‑(C0‑C2alkyl) (C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl) or ‑(C0‑C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; or R29 and R30 can be bonded together to form a heterocyclic ring; x is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. 15. The compound of clause 14, wherein: R4 is a stabilized phosphate prodrug and R12 is CH3, CH2F, CF2H or CF3. 16. The compound of clause 15, wherein: R4 is a phosphoramidate and R12 is CH3, CH2F, CF2H or CF3. 17. The compound of clause 15, wherein: 135 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 Y is NR1R2 and R1 is methyl and R2 is hydrogen or methyl. 18. The compound of clause 15, wherein R22 is F. 19. The compound of clause 15, wherein: R22 is OR25 20. The compound of clause 15, wherein: R22 is NR5R6 and R6 is hydrogen. 21. The compound of clause 15, wherein: R22 is NR5R6 . 22. The compound of clause 15, wherein: R22 is selected from Cl, Br, CN, N3, C1‑C6 alkyl, C2‑C6 alkenyl, C2‑C6 alkynyl, ‑(C1‑C2alkyl)(C3‑C6cycloalkyl), ‑(C0‑C2alkyl)(C3‑C6heterocycle), ‑(C0‑C2alkyl)(aryl), ‑(C0‑C2alkyl)(heteroaryl); ‑ONHC(=O)OR23, ‑NHOR24, ‑OR25, and ‑SR25 23. The compound of clause 15, wherein: R22 is NR5R6; and R5 and R6 is hydrogen. 24. A compound of Formula III: wherein: R7 is hydrogen,C1‑6alkyl; C3‑7cycloalkyl; heteroaryl, heterocyclic, or aryl, where phenyl or naphthyl are optionally substituted with C1‑6alkyl, C2‑6alkenyl, C2‑6 alkynyl, C1‑6alkoxy, F, Cl, Br, I, nitro, cyano, C1‑6haloalkyl, ‑(CH2)1‑6COOH, ‑(CH2)1‑6COOC1‑6alkyl, ‑N(R7’)2, C1‑6acylamino, NHSO2C1‑6alkyl, ‑SO2N(R7’)2, COR7", and ‑SO2C1‑6alkyl; (R7’ is independently hydrogen or C1‑6alkyl; R7" is ‑OR11 or-N(R7)2); R8 is hydrogen, C1‑6alkyl, or R9a or R9b and R8 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms; where n is 2 to 4; R9a and R9b are (i) independently selected from hydrogen, C1‑6alkyl, cycloalkyl, ‑(CH2)c(NR9’)2 , C1‑6hydro- xyalkyl, --CH2SH, ‑(CH2)2S(O)(Me, ‑(CH2)3NHC(=NH)NH2, (lH-indol‑3-yl)methyl, (lH-imidazol‑4-yl)methyl, ‑(CH2)cCOR9", aryl and aryl(C1‑3alkyl)‑, the aryl groups can be optionally substituted with a group selected from hydroxyl, C1‑6alkyl, C1‑6alkoxy, halogen, nitro and cyano; (ii) R9a and R9b both are C1‑6alkyl; (iii) R9a and R9b together are (CH2)r soas to formaspiro ring; (iv)R9a is hydrogenandR9bandR8 together are (CH2)n soas to form a cyclic ring that includes the adjoining N andC atoms (v) R9b is hydrogen andR9a andR8 together are (CH2)n so as to form a cyclic ring that includes the adjoining N andC atoms, where c is 1 to 6, n is 2 to 4, r is 2 to 5 andwhere R9’ is independently hydrogen or C1‑6 alkyl and R9" is ‑OR11 or ‑N(R11’)2 ); (vi) R9a is hydrogen and R9b is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol‑3-yl, ‑CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, ‑CH2CH2CH2NHC(NH) NH2, CH2-imidazol‑4-yl, CH2OH, CH(OH)CH3, CH2((4’-OH)‑Ph), CH2SH, or lower cycloalkyl; or (vii) R9a is 136 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol‑3-yl, - CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, ‑CH2CH2CH2NHC(NH) NH2, CH2-imidazol‑4-yl, CH2OH, CH(OH)CH3, CH2((4’-OH)‑Ph), CH2SH, or lower cycloalkyl and R9b is hydro- gen; R10 is hydrogen, C1‑6alkyl optionally substituted with an alkoxy, di(lower alkyl)‑amino, or halogen, C1‑6haloalkyl, C3‑7cycloalkyl, heterocycloalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; R11 is an optionally substituted C1‑6alkyl, an optionally substituted cycloalkyl; an optionally substituted C2‑6alky- nyl, an optionally substituted C2‑6alkenyl, or optionally substituted acyl, which includes but is not limited to C(O) (C1‑6 alkyl); wherein Y, R3, R12 and R22 are defined in clause 14; or a pharmaceutically acceptable salt thereof. 25. The compound of clause 24, wherein: Y is NR1R2, R1 is methyl, R2 is hydrogen and R12 is CH3. 26. The compound of clause 24, wherein: Y is NR1R2, R1 is methyl, R2 is methyl and R12 is CH3. 27. The compound of clause 24, wherein: Y is NR1R2, R1 is methyl, R2 is cyclopropyl, R3 is hydrogen, R7 is phenyl, R8 is hydrogen, R9a is hydrogen, R9b is methyl, R10 is isopropyl and R12 is CH3. 28. The compound of clause 24, wherein: Y is NR1R2, R1 is CH3, R12 is CH3 and R22 is F. 29. A compound of Formula IV: wherein the variables Y, R3, R7, R8, R9a, R9b, R10 and R22 are defined in clause 24; or a pharmaceutically acceptable salt thereof. 30. A compound of Formula V: 137 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein the variables Y, R3, R7, R8, R9a, R9b, R10 and R22 are defined in clause 24; or a pharmaceutically acceptable salt thereof. 31. A compound of Formula VI: wherein: Y, R3, R4 and R12 are defined in clause 24; R41 is F, Cl, OR3, N3, NH2 or CN; or a pharmaceutically acceptable salt thereof. 32. A compound of Formula VII: 138 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein: Y, R3, R4, R12, R22 and R41 are defined in clauses 1, 24 and 31; or a pharmaceutically acceptable salt thereof. 33.Apharmaceutical compositioncomprisinganeffectiveamountof thecompoundof clause1 to treatHCV inahost in a pharmaceutically acceptable carrier. 34.Apharmaceutical compositioncomprisinganeffectiveamountof thecompoundof clause9 to treatHCV inahost in a pharmaceutically acceptable carrier. 35. Apharmaceutical composition comprising aneffective amount of the compoundof clause14 to treatHCV inahost in a pharmaceutically acceptable carrier. 36. A pharmaceutical composition comprising an effective amount of the compound of any of clauses 24 or 29‑32 to treat HCV in a host in a pharmaceutically acceptable carrier. 37. The pharmaceutical composition of clause 33, wherein the composition is suitable for oral delivery. 38. The pharmaceutical composition of clause 34, wherein the composition is suitable for oral delivery. 39. The pharmaceutical composition of clause 35, wherein the composition is suitable for oral delivery. 40. The pharmaceutical composition of clause 36, wherein the composition is suitable for oral delivery. 41. Amethod for the treatment of a hepatitis C infection or a condition resulting froma hepatitis C infection, in a host in need thereof, comprising administering an effective amount of a compound of clause 1, optionally in a pharmaceu- tically acceptable carrier. 42. Amethod for the treatment of a hepatitis C infection or a condition resulting froma hepatitis C infection, in a host in need thereof, comprising administering an effective amount of a compound of clause 9, optionally in a pharmaceu- tically acceptable carrier 43. Amethod for the treatment of a hepatitis C infection or a condition resulting froma hepatitis C infection, in a host in need thereof, comprising administering an effective amount of a compound of clause 14, optionally in a pharma- ceutically acceptable carrier. 44. Amethod for the treatment of a hepatitis C infection or a condition resulting froma hepatitis C infection, in a host in need thereof, comprisingadministeringaneffectiveamountof acompoundofanyof clauses24or29‑32optionally ina pharmaceutically acceptable carrier. 45. The method of clause 41, wherein the compound is administered transdermally. 46. The method of clause 41, wherein the compound is administered via controlled release. 47. The method of clause 41, wherein the compound is administered intravenously. 48. The method of clause 41, wherein the condition resulting from a hepatitis C infection is an antibody positive and antigen positive condition, viral-based chronic liver inflammation, liver cancer resulting from advanced hepatitis C, cirrhosis, or fatigue. 49. The method of clause 41, further comprising administering the compound in combination with another anti-HCV agent. 50.Themethodof clause49,wherein theadditional anti-HCVagent is selected from thegroupconsistingofaprotease inhibitor; an NS5A inhibitor; another NS5B polymerase inhibitor; a non-substrate (allosteric) inhibitor; interferon alfa‑2a, which may be pegylated; ribavirin; a helicase inhibitor; an antisense oligodeoxynucleotide (S-ODN); an aptamer; a nuclease-resistant ribozyme; iRNA; an antibody toHCV; a partial antibody toHCV; and a domain antibody 139 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 to HCV. 51. The method of clause 50, wherein the protease inhibitor is selected from the group consisting of telaprevir, boceprevir, simeprevir and paritaprevir. 52. The method of clauses 41‑51, wherein the host is a human. 53. A compound of the formula: wherein R4 is a stabilized phosphate prodrug or a pharmaceutically acceptable salt thereof. 54. A pharmaceutical composition comprising the compound: wherein R4 is a stabilized phosphate prodrug; or a pharmaceutically acceptable salt thereof. 55. A compound of the formula: wherein R4 is a stabilized phosphate prodrug or a pharmaceutically acceptable salt thereof. 56. A pharmaceutical composition comprising the compound: 140 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R4 is a stabilized phosphate prodrug or a pharmaceutically acceptable salt thereof. 57. A compound of the structure: wherein R4 is a stabilized phosphate prodrug or a pharmaceutically acceptable salt thereof. 58. A pharmaceutical composition comprising the compound: wherein R4 is a stabilized phosphate prodrug or a pharmaceutically acceptable salt thereof. 59. A compound of the structure selected from the group consisting of: 141 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; wherein R1, R2, R5 and R6 are as defined in clause 14; or a pharmaceutically acceptable salt thereof. 60. A pharmaceutical composition comprising the compound: 142 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R1 and R2 are as defined in clause 1; or a pharmaceutically acceptable salt thereof. 61. A compound of the structure selected from the group consisting of: and wherein R1, R2, R5 and R6 are as defined in clause 14; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 143 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 62. A pharmaceutical composition comprising the compound: wherein R1, R2, R5,R6, R7 andR10 are as defined in clauses 9 and 14; or a pharmaceutically acceptable salt thereof. 63. A compound of the structure selected from the group consisting of: and wherein R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 144 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 64. A pharmaceutical composition comprising the structure: wherein R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 65. A compound of the structure selected from the group consisting of: and wherein R3C, R7 and R10 are defined in clauses 1 and 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 145 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 66. A pharmaceutical composition comprising the structure: wherein R3C, R7 and R10 are defined in clauses 1 and 9; or a pharmaceutically acceptable salt thereof. 67. A compound of the structure selected from the group consisting of: and wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; 146 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 68. A pharmaceutical composition comprising the compound: wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 69. A compound of the structure selected from the group consisting of: and 147 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R7 and R10 are defined in clauses 1 and 9 and wherein R3C is selected from alkyl, alkenyl, alkynyl, ‑(C0‑C2) (cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 70. A pharmaceutical composition comprising the compound: wherein R3C, R7 and R10 are defined in clauses 1 and 9; or a pharmaceutically acceptable salt thereof. 71. A compound of the structure selected from the group consisting of: and 148 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 72. A pharmaceutical composition comprising the compound: wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 73. A compound of the structure selected from the group consisting of: 149 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R3C, R7 and R10 are defined in clauses 1 and 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 74. A pharmaceutical composition comprising the compound: wherein R3C, R7 and R10 are defined in clauses 1 and 9; or a pharmaceutically acceptable salt thereof. 75. A compound of the structure selected from the group consisting of: 150 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 76. A pharmaceutical composition comprising the structure: wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 77. A compound of the structure selected from the group consisting of: 151 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R7 and R10 are defined in clauses 1 and 9 and R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), ‑O-alkyl, alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl), and ‑O-alkyl, in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 78. A pharmaceutical composition comprising the structure: wherein R7 and R10 are defined in clauses 1 and 9; and R3C is alkyl, alkenyl, alkynyl, - (C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl or a pharmaceutically acceptable salt thereof. 79. A compound of the structure selected from the group consisting of: 152 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 80. A pharmaceutical composition comprising the compound: wherein R22 is selected from F and OR25; 153 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 81. A compound of the structure selected from the group consisting of: and wherein R7 and R10 are defined in clauses 1 and 9; and R3C is alkyl, alkenyl, alkynyl, - (C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl or a pharmaceutically acceptable salt thereof. 82. A pharmaceutical composition comprising the compound: 154 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 whereinR7 andR10 are defined in clauses 1and 9andR3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl or a pharmaceutically acceptable salt thereof. 83. A compound of the structure selected from the group consisting of: and wherein 155 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 R22 is selected from F and OR25; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 84. A pharmaceutical composition comprising the compound: wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 85. A compound of the structure selected from the group consisting of: and 156 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R3C, R7 and R10 are defined in clauses 1 and 9; in the form of an isolated phosphorus S enantiomer. 86. A pharmaceutical composition comprising the compound: wherein R3C, R7 and R10 are defined in clauses 1 and 9; or a pharmaceutically acceptable salt thereof. 87. A compound of the structure selected from the group consisting of: 157 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus S enantiomer or a pharmaceutically acceptable salt thereof. 88. A pharmaceutical composition comprising the structure: wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 89. A compound of the structure selected from the group consisting of: 158 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and whereinR7andR10aredefined in clauses1and9andR3C is selected fromalkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2)(heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl in the form of an isolated phosphorus R or S enantiomerwithat least 90%of thedesignatedenantiomer, or amixture thereof; or apharmaceutically acceptable salt thereof. 90. A pharmaceutical composition comprising the structure: wherein R7 and R10 are defined in clauses 1 and 9 and R3C is or a pharmaceutically acceptable salt thereof. 91. A compound of the structure selected from the group consisting of: 159 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 92. A pharmaceutical composition comprising the structure: wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 93. A compound of the structure selected from the group consisting of: 160 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R7 and R10 are defined in clauses 1 and 9 and R3C in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 94. A pharmaceutical composition comprising the compound: wherein R7 and R10 are defined in clauses 1 and 9 and R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl or a pharmaceutically acceptable salt thereof. 95. A compound of the structure selected from the group consisting of: 161 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 96. A pharmaceutical composition comprising the compound: wherein R22 is selected from F and OR25; 162 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 97. A compound of the structure selected from the group consisting of: and wherein R7 and R10 are defined in clauses 1 and 9 and R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 98. A pharmaceutical composition comprising the structure: 163 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R7 and R10 are defined in clauses 1 and 9; R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl or a pharmaceutically acceptable salt thereof. 99. A compound of the structure selected from the group consisting of: and wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 100. A pharmaceutical composition comprising the structure: 164 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 101. A compound of the structure selected from the group consisting of: and wherein R7 and R10 are defined in clauses 1 and 9; and R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 165 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 102. A pharmaceutical composition comprising the structure: wherein R3C, R7 and R10 are defined in clauses 1 and 9; or a pharmaceutically acceptable salt thereof. 103. A compound of the structure selected from the group consisting of: and wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; 166 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 104. A pharmaceutical composition comprising the structure: wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 105. A compound of the structure selected from the group consisting of: and 167 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R3C, R7 and R10 are defined in clauses 1 and 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 106. A pharmaceutical composition comprising the structure: wherein R7 and R10 are defined in clauses 1 and 9; R3C is alkyl, alkenyl, alkynyl, ‑(C0‑C2)(cycloalkyl), ‑(C0‑C2) (heterocyclo), ‑(C0‑C2)(aryl), ‑(C0‑C2)(heteroaryl) and ‑O-alkyl or a pharmaceutically acceptable salt thereof. 107. A compound of the structure selected from the group consisting of: 168 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 108. A pharmaceutical composition comprising the structure: wherein R22 is selected from F and OR25; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 109. A compound of the structure selected from the group consisting of: 169 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 and wherein R3C, R7 and R10 are defined in clauses 1 and 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 110. A pharmaceutical composition comprising the structure: wherein R3C, R7 and R10 are defined in clauses 1 and 9; 170 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof. 111. A compound of the structure selected from the group consisting of: and wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; in the form of an isolated phosphorus R or S enantiomer with at least 90% of the designated enantiomer, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 112. A pharmaceutical composition comprising the structure: 171 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R22 is selected from F, OR25, N3 or CN; R7 and R10 are defined in clause 9; or a pharmaceutically acceptable salt thereof. 113. A compound of any of clauses 1, 9, 14, 24, or 29‑32 wherein R3 is H. 114. A compound of any of clauses 1, 9, 14, 24, or 29‑32 wherein R4 is H. 115. A compound of any of clauses 1, 9, 14, 24, or 29‑32 wherein R4 is a mono, di or triphosphate. 116. A compound of any of clauses 1, 9, 14, 24, or 29‑32 wherein the phosphorus is of the S-configuration. 117. A compound of any of clauses 1, 9, 14, 24, or 29‑32 wherein the phosphorus is of the R-configuration. 118. A compound of any of clauses 1, 9, 14, 24, or 29‑32 wherein the aminoacid has a D-configuration. 119. A compound of any of clauses 1, 9, 14, 24, or 29‑32 wherein the aminoacid has a L-configuration. 120. A compound of any of clauses 14, 24, 29, 30 or 32 wherein R22 is selected from chloro, bromo, fluoro, cyano, azido, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and n-pentyl, 1,1-dimethylpropyl, 2,2- dimtheylpropyl, 3-methylbutyl, 1-methylbutyl, 1-ethylpropyl, vinyl, allyl, 1-butynyl, 2-butynyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ‑(CH2)‑cyclopropyl, ‑(CH2)‑cyclobutyl, ‑(CH2)‑cyclopentyl, ‑(CH2)‑cyclohexyl, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, piper- idine, oxane, thiane, ‑(CH2)‑aziridine, ‑(CH2)‑oxirane, ‑(CH2)‑thiirane, - (CH2)‑azetidine, ‑(CH2)‑oxetane, ‑(CH2)‑thietane, ‑(CH2)‑pyrrolidine, ‑(CH2)‑ tetrahydrofuran, - (CH2)‑thiolane, ‑(CH2)‑pyrazolidine, ‑(CH2)‑piperidine, ‑(CH2)‑oxane, ‑(CH2)‑thiane, phenyl, pyridyl, ‑ONHC(=O)OCH3, ‑ONHC(=O)OCH2CH3, ‑NHOH, NHOCH3, ‑OCH3, OC2H5, ‑OPh,OCH2Ph, ‑SCH3, ‑SC2H5, ‑SPh, SCH2Ph, ‑NH(CH2)2NH2, ‑NH(CH2)2N(CH3)2, ‑NHNH2, ‑NHNHCH3, ‑N=NH, ‑N=NCH3, ‑N=NCH2CH3, ‑NHC(O)NHNH2, ‑NHC(S)NHNH2, ‑C(O)NHNH2, ‑NHSO2CH3, ‑NHSO2CH2CH3, ‑SO2NHCH3, ‑SO2N(CH3)2, ‑C(O)NH2, ‑C(O)NHCH3, ‑C(O)N(CH3)2, ‑CO2CH3, ‑CO2CH2CH3, ‑CO2Ph, ‑CO2CH2Ph, ‑SO2CH3, ‑SO2CH2CH3, ‑SO2Ph, ‑SO2CH2Ph, -P(O)H(OH), - P(O)H(OCH3), ‑P(O)(OH)(OH), ‑P(O)(OH)(OCH3), ‑P(O)(OCH3)(OCH3), ‑P(O)(OH)(NH2), - P(O) (OH)(NHCH3), ‑P(O)(OH)N(CH3)2, ‑NHC(O)CH3, ‑NHC(O)CH2CH3, ‑NHC(O)CH(CH3)2, ‑NHC(O)OCH3, ‑NHC(O) OCH2CH3, ‑NHC(O)OCH(CH3)2, ‑NHC(O)OCH2CH2CH3, - NHC(O)OCH2CH2CH2CH3 or ‑NHC(O) OCH2CH2CH2CH2CH3. 121. A compound of clause 31, wherein R41 is fluoro. 172 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 122. A compound of clause 31, wherein R41 is chloro. 123. A compound of clause 31, wherein R41 is hydroxyl. 124. A compound of clause 32, wherein R41 is fluoro. 125. A compound of clause 32, wherein R41 is chloro. 126. A compound of clause 32, wherein R41 is hydroxyl. 127. The compound of any of clauses 1, 9, 14, 24 or 29‑32 and pharmaceutically acceptable salts and prodrugs thereof for use in the treatment or prophylaxis of a hepatitis C virus infection. 128. The use of a compound of any of clauses 1, 9, 14, 24 or 29‑32 and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for treatment of a hepatitis C virus infection. 129. A method for manufacturing a medicament intended for the therapeutic use for treating a hepatitis C virus infection, characterized in that a compound of any of clauses 1, 9, 14, 24 or 29‑32 is used in the manufacture. 130. A pharmaceutical formulation comprising an effective host-treating amount of the compound of any of clauses 1, 9, 14, 24 or 29‑32 or a pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent. 131. A compound selected from the group consisting of 173 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 174 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 175 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 176 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 wherein R7, R10, R22 and R41 are as defined in clauses 9, 14 and 31. 132. A compound of the formula: wherein R4 is a stabilized phosphate prodrug; and R 1, R2, R22 and R41 are as defined in clauses 1, 9, 14 and 31; or a pharmaceutically acceptable salt thereof. 133. A compound selected from: wherein R4 is a stabilized phosphate prodrug; and RI, R2, R22 and R41 are as defined in clauses 1, 9, 14 and 31; or a pharmaceutically acceptable salt thereof. Claims 1. A compound of the formula: 177 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-viral compound selected from a NS3 / 4A protease inhibitor and an NS5B polymerase inhibitor, optionally in a pharmaceutically acceptable carrier, for use to treat hepatitis C virus in a human in need thereof. 2. The compound for use of claim 1, wherein the compound is of the formula 3. The compound for use of claim 1, wherein the compound of the formula: 4. A compound of the formula: 178 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-viral compound selected from a NS3 / 4A protease inhibitor and an NS5B polymerase inhibitor, optionally in a pharmaceutically acceptable carrier, for use to treat hepatitis C virus in a human in need thereof. 5. The compound for use of claim 4, wherein the compound is of the formula 6. The compound for use of claim 4, wherein the compound is of the formula 7. The compound for use of any one of claims 1‑6, wherein the compound is administered orally. 8. The compound for use of any one of claims 1‑7, wherein the compound is administered once a day. 9. The compound for use of any one of claims 1‑7, wherein the compound is administered twice or three times a day. 10. The compound for use of any one of claims 1‑9, wherein the hepatitis C virus is Genotype 1a or 1b. 11. The compound for use of any one of claims 1‑9, wherein the hepatitis C virus is Genotype 2a or 2b. 179 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 12. The compound for use of any one of claims 1‑9, wherein the hepatitis C virus is Genotype 3a. 13. The compound for use of any one of claims 1‑9, wherein the hepatitis C virus is Genotype 4a or 4d. 14. The compound for use of any one of claims 1‑13, wherein the additional anti-viral compound is an NS3 / 4A protease inhibitor. 15. The compound for use of any one of claims 1‑13, wherein the additional anti-viral compound is anNS5B polymerase. 180 EP 4 667 053 A2 5 10 15 20 25 30 35 40 45 50 55 181 EP 4 667 053 A2 182 EP 4 667 053 A2 183 EP 4 667 053 A2 184 EP 4 667 053 A2 185 EP 4 667 053 A2 186 EP 4 667 053 A2 187 EP 4 667 053 A2 188 EP 4 667 053 A2 189 EP 4 667 053 A2 190 EP 4 667 053 A2 191 EP 4 667 053 A2 192 EP 4 667 053 A2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • US 62129319

[0001] • US 62253958

[0001] • US 62276597

[0001] • WO 6812219 A

[0014] • WO 6914054 A

[0014] • WO 7105493 A

[0014] • WO 7138376 A

[0014] • WO 7148206 A

[0014] • WO 7157441 A

[0014] • WO 7163929 A

[0014] • WO 7169766 A

[0014] • WO 7192936 A

[0014] • WO 7365057 A

[0014] • WO 7384924 A

[0014] • WO 7456155 A

[0014] • WO 7547704 A

[0014] • WO 7582618 A

[0014] • WO 7608597 A

[0014] • WO 7608600 A

[0014] • WO 7625875 A

[0014] • WO 7635689 A

[0014] • WO 7662798 A

[0014] • WO 7824851 A

[0014] • WO 7902202 A

[0014] • WO 7932240 A

[0014] • WO 7951789 A

[0014] • WO 8193372 A

[0014] • WO 8299038 A

[0014] • WO 8343937 A

[0014] • WO 8362068 A

[0014] • WO 8507460 A

[0014] • WO 8637475 A

[0014] • WO 8674085 A

[0014] • WO 8680071 A

[0014] • WO 8691788 A

[0014] • WO 8742101 A

[0014] • WO 8951985 A

[0014] • WO 9109001 A

[0014] • WO 9243025 A

[0014] • US 20160002281 A

[0014] • US 20130064794 A

[0014] • WO 2015095305 A

[0014] • WO 2015081133 A

[0014] • WO 2015061683 A

[0014] • WO 2013177219 A

[0014]

[0080] • WO 2013039920 A

[0014]

[0080] • WO 2014137930 A

[0014] • WO 2014052638 A

[0014] • WO 2012154321 A

[0014] • WO 6777395 A, Merck

[0014] • WO 7105499 A

[0014] • WO 7125855 A

[0014] • WO 7202224 A

[0014] • WO 7323449 A

[0014] • WO 7339054 A

[0014] • WO 7534767 A

[0014] • WO 7632821 A

[0014] • WO 7879815 A

[0014] • WO 8071568 A

[0014] • WO 8148349 A

[0014] • WO 8470834 A

[0014] • WO 8481712 A

[0014] • WO 8541434 A

[0014] • WO 8697694 A

[0014] • WO 8715638 A

[0014] • WO 9061041 A

[0014] • WO 9156872 A

[0014] • WO 2013009737 A

[0014] • WO 6348587 A, Emory University

[0014] • WO 6911424 A

[0014] • WO 7307065 A

[0014] • WO 7495006 A

[0014] • WO 7662938 A

[0014] • WO 7772208 A

[0014] • WO 8114994 A

[0014] • WO 8168583 A

[0014] • WO 8609627 A

[0014] • US 20140212382 A

[0014] • WO 20141244430 A

[0014] • WO 7842672 A, Gilead Sciences / Pharmasset Inc.

[0014] • WO 7973013 A

[0014] • WO 8008264 A

[0014] • WO 8012941 A

[0014] • WO 8012942 A

[0014] • WO 8318682 A

[0014] • WO 8324179 A

[0014] • WO 8415308 A

[0014] • WO 8455451 A

[0014] • WO 8563530 A

[0014] • WO 8841275 A

[0014] • WO 8853171 A

[0014] • WO 8871785 A

[0014] • WO 8877733 A

[0014] • WO 8889159 A

[0014] • WO 8906880 A

[0014] • WO 8912321 A

[0014] • WO 8957045 A

[0014] 193 EP 4 667 053 A2 • WO 8957046 A

[0014] • WO 9045520 A

[0014] • WO 9085573 A

[0014] • WO 9090642 A

[0014] • WO 9139604 A

[0014] • WO 6908924 A

[0014] • WO 6949522 A

[0014] • WO 7094770 A

[0014] • WO 7211570 A

[0014] • WO 7429572 A

[0014] • WO 7601820 A

[0014] • WO 7638502 A

[0014] • WO 7718790 A

[0014] • WO 7919247 A

[0014] • WO 7964580 A

[0014] • WO 8093380 A

[0014] • WO 8114997 A

[0014] • WO 8173621 A

[0014] • WO 8334270 A

[0014] • WO 8415322 A

[0014] • WO 8481713 A

[0014] • WO 8492539 A

[0014] • WO 8551973 A

[0014] • WO 8580765 A

[0014] • WO 8618076 A

[0014] • WO 8629263 A

[0014] • WO 8633309 A

[0014] • WO 8642756 A

[0014] • WO 8716262 A

[0014] • WO 8716263 A

[0014] • WO 8735345 A

[0014] • WO 8735372 A

[0014] • WO 8735569 A

[0014] • WO 8759510 A

[0014] • WO 8765710 A

[0014] • WO 6660721 A, Hoffman La-Roche

[0014] • WO 6784166 A, Roche

[0014] • WO 7608599 A

[0014] • WO 7608601 A

[0014] • WO 8071567 A

[0014] • WO 8895723 A, Alios BioPharma Inc.

[0014] • WO 8877731 A

[0014] • WO 8871737 A

[0014] • WO 8846896 A

[0014] • WO 8772474 A

[0014] • WO 8980865 A

[0014] • WO 9012427 A

[0014] • US 20150105341 A

[0014] • US 20150011497 A

[0014] • US 20100249068 A

[0014] • US 20120070411 A

[0014] • WO 2015054465 A

[0014] • WO 2014209979 A

[0014] • WO 2014100505 A

[0014] • WO 2014100498 A

[0014] • WO 2013142159 A

[0014] • WO 2013142157 A

[0014] • WO 2013096680 A

[0014] • WO 2013088155 A

[0014] • WO 2010108135 A

[0014] • US 8575119 B, Enanta Pharmaceuticals

[0014] • US 8846638 B

[0014] • US 9085599 B

[0014] • WO 2013044030 A

[0014] • WO 2012125900 A

[0014] • WO 7268119 A, Biota

[0014] • WO 7285658 A

[0014] • WO 7713941 A

[0014] • WO 8119607 A

[0014] • WO 8415309 A

[0014] • WO 8501699 A

[0014] • WO 8802840 A

[0014] • WO 7388002 A, Biocryst Pharmaceuticals

[0014] • WO 7429571 A

[0014] • WO 7514410 A

[0014] • WO 7560434 A

[0014] • WO 7994139 A

[0014] • WO 8133870 A

[0014] • WO 8163703 A

[0014] • WO 8242085 A

[0014] • WO 8440813 A

[0014] • WO 8889701 A, Alla Chem, LLC

[0014] • WO 2015053662 A

[0014] • WO 8759318 A, Inhibitex

[0014] • WO 2012092484 A

[0014] • WO 8399429 A, Janssen Products

[0014] • WO 8431588 A

[0014] • WO 8481510 A

[0014] • WO 8552021 A

[0014] • WO 8933052 A

[0014] • WO 900629 A

[0014] • WO 9012428 A

[0014] • WO 8673926 A

[0014] • WO 8816074 A

[0014] • WO 8921384 A

[0014] • WO 8946244 A

[0014] • WO 8895531 A, RFS Pharma, LLC

[0014] • WO 8859595 A

[0014] • WO 8815829 A

[0014] • WO 7560550 A

[0014] • US 20140066395 A

[0014] • US 20140235566 A

[0014] • US 20100279969 A

[0014] • WO 2010091386 A

[0014]

[0019]

[0021]

[0080] • WO 2012158811 A

[0014] • WO 2014076490 A, University College Cardiff Con- sultants Limited

[0014] • WO 2010081082 A

[0014] • WO 2008062206 A

[0014] • WO 2014169278 A, Achillion Pharmaceuticals, Inc

[0014]

[0160] • WO 2014169280 A

[0014]

[0160] • US 9173893 B, Cocrystal Pharma, Inc

[0014]

[0080]

[0081] • WO 2015158913 A, Katholieke Universiteit Leuven

[0014] 194 EP 4 667 053 A2 • WO 2013090420 A, Catabasis

[0014] • WO 2006004637 A, Regents of the University of Minnesota

[0014] • US 8609627 B

[0019]

[0021]

[0081] • US 8933053 B

[0080] • US 8759318 B

[0080]

[0147] • US 8658616 B

[0080] • US 8263575 B

[0080]

[0147] • US 8119779 B

[0080] • US 7951787 B

[0080] • US 7115590 B

[0080]

[0147] • US 8895723 B

[0080] • US 8871737 B

[0080] • US 8772474 B

[0080]

[0152] • US 7517858 B

[0080] • US 8889658 B

[0080] • US 8846643 B

[0080] • US 8710030 B

[0080] • US 8309565 B

[0080] • US 8008308 B

[0080] • US 7790703 B

[0080] • WO 2014124430 A

[0080] • US 5233031 A

[0147] • US 7547704 B

[0147] • US 7879815 B

[0147] • US 7888330 B

[0147] • US 7902202 B

[0147] • US 7951789 B

[0147] • US 7964580 B

[0147] • US 8071568 B

[0147] • US 8148349 B

[0147] • US 8324179 B

[0147] • US 8334270 B

[0147] • US 8552021 B

[0147] • US 8563530 B

[0147] • US 8580765 B

[0147] • US 8735372 B

[0147] • EP 2120565 A

[0147] • EP 1143995 A

[0147] • EP 6455513 A

[0147] • EP 8334270 A

[0147] • WO 2012040124 A

[0152] • US 20150366888 A

[0186] • WO 2014058801 A

[0186] • WO 2015066370 A

[0186] • WO 2015200219 A

[0186] • US 8859756 B

[0211] • US 8642756 B

[0211] • US 8333309 B, Ross

[0211] • US 7718790 B, Stuyver

[0306] Non-patent literature cited in the description • Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A-Activated Prodrugs (Hep- Direct Prodrugs)Useful for TargetingPhosph(on)ate- Based Drugs to the Liver. J. Am. Chem. Soc., 2004, vol. 126, 5154-5163

[0080] • A. RAY ; K. HOSTETLER. Application of kinase bypass strategies to nucleoside antivirals. Antiviral Research, 2011, 277-291

[0080] • M. SOFIA. Nucleotide prodrugs for HCV therapy. Antiviral Chemistry and Chemotherapy, 2011, 22-23, 49

[0080] • S. PEYROTTES et al. SATE Pronucleotide Ap- proaches: An Overview. Mini Reviews in Medicinal Chemistry, 2004, vol. 4, 395

[0080] • GREENE ; WUTS. Protective Groups in Organic Synthesis. John Wiley and Sons, Inc., 1991

[0143]

[0144] • MADELA ; KAROLINA ; MCGUIGAN. Progress in the development of anti-hepatitis C virus nucleoside and nucleotide prodrugs. Future Medicinal Chemis- try, 2012, vol. 4 (5), 625-650

[0147] • DOMINIQUE ; MCGUIGAN ; BALZARINI. Aryloxy Phosphoramidate Triesters as Pro-Tides. Mini Re- views in Medicinal Chemistry, 2004, vol. 4 (4), 371- 381

[0147] • ANDREW ZHU. New Agents on the Horizon in Hepatocellular Carcinoma. Therapeutic Advances in Medical Oncology, January 2013, vol. 5 (1), 41-50

[0183] • ROSS, B.S. ; REDDY, P.G. ; ZHANG, H.R. ; RACHAKONDA, S. ; SOFIA, M.J. J. Org, Chem., 2011

[0192] • KORBA et al. Antiviral Research, 2008, vol. 77, 56

[0305] • PIERRA et al. Journal of Medicinal Chemistry, 2006, vol. 49, 6614

[0305] (19) *EP004667053A3* (11) EP 4 667 053 A3 (12) EUROPEAN PATENT APPLICATION (88) Date of publication A3: 01.04.2026 Bulletin 2026 / 14 (43) Date of publication A2: 24.12.2025 Bulletin 2025 / 52 (21) Application number: 25196377.3 (22) Date of filing: 07.03.2016 (51) International Patent Classification (IPC): A61K 31 / 7076 (2006.01) C07H 19 / 16 (2006.01) C07H 19 / 20 (2006.01) C07H 19 / 207 (2006.01) A61P 31 / 14 (2006.01) (52) Cooperative Patent Classification (CPC): C07H 19 / 207; A61K 31 / 7076; A61P 31 / 14; C07H 19 / 16; C07H 19 / 20 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR Designated Validation States: MD (30) Priority: 06.03.2015 US 201562129319 P 11.11.2015 US 201562253958 P 08.01.2016 US 201662276597 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 16762325.5 / 3 265 102 (71) Applicant: ATEA Pharmaceuticals, Inc. Boston, MA 02110 (US) (72) Inventors: • SOMMADOSSI, Jean-Pierre Boston, MA 02111 (US) • MOUSSA, Adel Burlington, MA 01803 (US) (74) Representative: Boult Wade Tennant LLP Salisbury Square House 8 Salisbury Square London EC4Y 8AP (GB) (54) BETA‑D‑2’‑DEOXY‑2’ALPHA‑FLUORO‑2’‑BETA‑C‑SUBSTITUTED‑2‑MODIFIED‑N6‑SUBSTI- TUTED PURINE NUCLEOTIDES FOR HCV TREATMENT (57) A compound of the structure: or a pharmaceutically acceptable salt or composition thereof for the treatment of a host infected with or ex- posed to an HCV virus or other disorders more fully described herein. EP 4 66 7 05 3 A 3 Processed by Luminess, 75001 PARIS (FR) (Cont. next page) 2 EP 4 667 053 A3 3 EP 4 667 053 A3 5 10 15 20 25 30 35 40 45 50 55 4 EP 4 667 053 A3 5 10 15 20 25 30 35 40 45 50 55 5 EP 4 667 053 A3 5 10 15 20 25 30 35 40 45 50 55 6 EP 4 667 053 A3 5 10 15 20 25 30 35 40 45 50 55 摘要 本文更充分地描述了用于治疗感染或暴露于 HCV 病毒或其它病 症的宿主的结构的化合物或其药学上可接受的盐或组合物。

Claims

1. A compound of the formula: or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-viral compound selected from a NS3 / 4A protease inhibitor and an NS5B polymerase inhibitor, optionally in a pharmaceutically acceptable carrier, for use to treat hepatitis C virus in a human in need thereof.

2. The compound for use of claim 1, wherein the compound is of the formula 3. The compound for use of claim 1, wherein the compound of the formula:

4. A compound of the formula: or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-viral compound selected from a NS3 / 4A protease inhibitor and an NS5B polymerase inhibitor, optionally in a pharmaceutically acceptable carrier, for use to treat hepatitis C virus in a human in need thereof.

5. The compound for use of claim 4, wherein the compound is of the formula 6. The compound for use of claim 4, wherein the compound is of the formula 7. The compound for use of any one of claims 1-6, wherein the compound is administered orally.

8. The compound for use of any one of claims 1-7, wherein the compound is administered once a day.

9. The compound for use of any one of claims 1-7, wherein the compound is administered twice or three times a day.

10. The compound for use of any one of claims 1-9, wherein the hepatitis C virus is Genotype 1a or 1b.

11. The compound for use of any one of claims 1-9, wherein the hepatitis C virus is Genotype 2a or 2b.

12. The compound for use of any one of claims 1-9, wherein the hepatitis C virus is Genotype 3a.

13. The compound for use of any one of claims 1-9, wherein the hepatitis C virus is Genotype 4a or 4d.

14. The compound for use of any one of claims 1-13, wherein the additional anti-viral compound is an NS3 / 4A protease inhibitor.

15. The compound for use of any one of claims 1-13, wherein the additional anti-viral compound is an NS5B polymerase.

Images