TW200942245A - HCV nucleoside inhibitor - Google Patents

Abstract

4-Amino-1-((2R, 3S, 4S, 5R)-5-azido-4-hydroxy-5-hydroxymethyl-3- methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (22) and prodrugs thereof are hepatitis C (HCV) polymerase inhibitors. Also disclosed are compositions and methods for inhibiting HCV and treating HCV-mediated diseases, processes for making the compounds and synthetic intermediates employed in the process.

Description

200942245 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention provides nucleoside compounds and certain derivatives thereof, which are inhibitors of RNA-dependent RNA viral polymerases. These compounds are RNA-dependent inhibitors of RNA viral replication and are useful for the treatment of RNA-dependent RNA viruses and infections. It is especially useful as an inhibitor of hepatitis C virus (HCV) NS5B polymerase, as an inhibitor of HCV replication, and for the treatment of hepatitis C infection. Ο The present invention relates to nucleoside inhibitors of HCV replicon RNA replication. In particular, the present invention relates to the use of pyrimidine nucleoside compounds as inhibitors of subgenomic HCV RNA replication and pharmaceutical compositions containing such compounds. [Prior Art] Hepatitis C virus is the leading cause of chronic liver disease worldwide. (Boyer, N. et al. J. Ugly 叩 / / 2000 32:98-112). Patients infected with HCV have a risk of developing cirrhosis and subsequent hepatocellular carcinoma. Therefore, HCV is the main indication for liver transplantation. HCV has been classified as a member of the Flaviviridae family of viruses, including the flavivirus, prion, and hepatitis C virus including the hepatitis C virus (Rice, CM, F/aWWWi/ote·· 77ze viruses and their replication, in: Fields Virology, Editors:

Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., Chapter 30, 931-959, 1996). HCV is an envelope disease containing approximately 9.4 kb of a single-stranded RNA genome 130152.doc 200942245. The viral genome consists of a 5'-untranslated region (UTR), a long open reading frame encoding a polymeric protein precursor of about 3011 amino acid, and a short 3' UTR. The 5' UTR is the most conserved part of the HCV genome and is important for initiating and controlling the translation of polymeric proteins. 'Genetic analysis of HCV has identified six major genotypes with more than 30% difference in DNA sequence Γ. More than 30 subtypes have been identified. In the United States, approximately 70% of infected individuals have la-type and lb-type infections. The lb type is the most popular subtype in Asia. (X. Forns and J. Bukh, C7z·, 'cs ❹ 1999 3: 693-716; J. Bukh et al., Sewk. Ζζ·ν·Db. 1995 15:41-63). Unfortunately, type 1 infection is more resistant to treatment than type 2 or type 3 genotypes. (N. N. Zein, 2000 13: 223-235).

Viral structural proteins include nuclear core protein (C) and two envelope glycoproteins E1 and E2. HCV also encodes two proteases: a zinc-dependent metalloproteinase encoded by the NS2-NS3 region and a serine protease encoded in the NS3 region. These proteases are required for the cleavage of specific regions of the precursor polymeric protein into mature peptides. The carboxyl portion of non-structural protein 5 (NS5B) contains an RNA-dependent RNA ❹ polymerase. The function of the remaining non-structural proteins NS4A and NS4B and the function of NS5A (the amino terminal portion of non-structural protein 5) are still unknown. Xianxin. Most of the non-structural proteins encoded by the HCV RNA genome are involved in RNA replication. : There are currently a limited number of approved therapies available for the treatment of HCV infection. Novel and existing treatments for the treatment of HCV and inhibition of HCV NS5B polymerase have been reviewed in the following literature: RG Gish, /Sem. £)/?, 1999 19:5; Di Besceglie, AM and Bacon, BR, 130152.doc 200942245

Scientific American, October: 1999 80-85; G. Lake-Bakaar, Current and Future Therapy for Chronic Hepatitis C Virus Liver Disease, Curr. Drug Targ. Infect Dis. 2003 3(3): 247-253; P. Hoffmann et al. People, patents on experimental

Therapy for hepatitis C virus infection (1999-2002), Exp. Opin. Ther. Patents 2003 13(11): 1707-1723; Μ. P. Walker et al. Promising Candidates for the treatment of chronic hepatitis C, Exp. Opin. Investing. Drugs 2003 12(8):1269-1280; S.-L. Tan et al., Hepatitis C Therapeutics: Current

Status and Emerging Strategies, Nature Rev. Drug Discov. 2002 1:867-881 〇

La: R = C(=0)NH2 lb: R = C(=NH+)NH2 ❿ Ribavirin (11 & 乂11^11) (13; 1-((211,311,48,511)-3,4 -dihydroxy- 5-hydroxyindolyl-tetrahydro-furan-2-yl)·1Η-[1,2,4]triazole-3-carboxylic acid decylamine; virus °Virazole) for synthetic non-interference A broad-spectrum antiviral nucleus induced by priming: a glycoside analog. Ribavirin has in vitro activity against several DNA and RNA diseases including the Flaviviridae (Gary L. Davis, Gasiroe price ero/og_y 2000 118:S104-S114). In monotherapy, ribavirin reduced serum aminotransferase levels to normal in 40% of patients, but it did not reduce the jk clearance of HCV-RNA. Ribavirin also exhibits significant toxicity and is known to induce stagnation of 130152.doc 200942245 blood. Vera carbamide lb is a drug that is converted to la in hepatocytes. Interferon (IFN) has been used to treat chronic hepatitis in the last decade. IFN is a glycoprotein produced by infection with an immune cell reactive virus. Two different types of interferon have been identified: Type 1 includes several interferon alpha and one interferon beta, and type 2 includes interferon y. Type 1 interferons are produced primarily by infected cells and protect adjacent cells from reinfection. IFN inhibits viral replication of many viruses including HCV, and when used alone as a treatment for hepatitis C infection, IFN inhibits serum HCV-RNA to an undetectable level. In addition, IFN normalizes serum amino-based transferase levels. Unfortunately, the effects of IFN are short-lived. Stop treatment resulted in a 70% relapse rate and only 10-15% showed a sustained viral response to normal serum alanine transferase levels (L.-B. Davis, supra). One limitation of early IFN therapy is the rapid clearance of proteins in the blood. The chemical derivatization of IFN with polyethylene glycol (PEG) results in a pharmacokinetic profile of the protein that is substantially improved. PEGASYS® is a combination of interferon a-2a and 40 kD branched monomethoxy PEG and PEG-INTRON® is a combination of interferon a-2b and 12 kD monomethoxy PEG. (BA Luxon et al, Therap. 2002 24(9): 13631383; A. Kozlowski and JM Harris, "/. Coniro/. 2001 72:217-224) 〇. Currently using ribavirin and interferon-a Combination therapy with HCV represents the best therapy. Combination ribavirin with PEG-IFN (below) leads to a sustained viral response in 54-56% of patients. For Type 2 and Type 3 HCVs, the SVR is 80%. (Walker, above). Unfortunately, this combination also produces side effects that pose clinical challenges. Inhibition of flu, flu-like symptoms and skin reactions are associated with subcutaneous IFN-α and hemolytic anemia is associated with continued treatment with ribavirin 130152.doc 200942245. Many potential molecular targets currently identified for drug development such as anti-HCV therapy include, but are not limited to, NS2-NS3 autologous protease, N3 protease, N3 helicase, and NS5B polymerase. RNA-dependent RNA polymerase 'is absolutely necessary for single-strand, sense, and replication of the RNA genome. This enzyme has aroused strong interest from pharmaceutical chemists. Both nucleoside and non-nucleoside inhibitors of NS5B are known. Nucleoside inhibitors can be used as chain terminators or as competitive inhibitors that interfere with the binding of nucleotides to polymerase ® . For use as a chain terminator, the nucleoside analog must be taken up by the cell and converted in vivo to a triphosphate to compete for the binding site of the polymerase nucleotide. This conversion to the triphosphate is typically mediated by cellular kinases that confer additional structural requirements on the potential nucleoside polymerase inhibitor. Furthermore, this direct restriction of nucleosides as inhibitors of HCV replication is limited to cell-based assays capable of in situ acidification. In WO 01 90121, published on Nov. 29, 2001, J.-P. Sommadossi and Ρ La Colla disclose and exemplify the anti-HCV of 1'-alkyl- and 2'-alkyl nucleosides of formulas 2 and 3. Polymerase activity. In WO 0 1/92282, published on Dec. 6, 2001, J.-P. Sommadossi and P. Lacolla disclose and exemplify the treatment of oxime-alkyl- and 2'-alkyl nucleosides of formulas 2 and 3. Flavivirus and prion. In WO 03/026675 and WO 03/026589, both of which are hereby incorporated by reference in its entirety, the entire disclosure of the disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of The method of the virus. J.-P. Sommadossi et al. disclose Γ-, 2'-, 3'- and 4·-substituted β-D and β-L in WO 2004003000 and WO 2004002999, both of which are published on Jan. 8, 2004. Pre-nucleoside drug. J.-P. Sommadossi et al. disclose 3'-C-methyl-ribofuranosylcytosine 3i_〇_L in WO 04/002422, published on the Japanese Patent Publication No. 130152.doc -10- 200942245. _Propylamine and its use for the treatment of HCV.

Idenix has been reported as a clinical trial of the related compound NM283 of the tranexamic acid 'ester 5' of the nucleoside analog 2 (b = cell carcinoma bite). Further, Idenix: Pharmaceuticals, Ltd. also discloses in WO 04/04633 1 a biologically active 2'-branched chain β-D or β-L nucleoside or a pharmaceutically acceptable salt or prodrug thereof Caused by the Flaviviridae mutation.

η ηο^Λη ho oh ηο^Λη ^ i-Pr 2 3 4 5 B=Adenine, thymidine, uracil, cytidine, guanine and hypoxanthine were released on July 25, 2002 In WO 02/057425, SS Carroll et al. disclose a nucleoside inhibitor of a chemically modified RNA-dependent RNA-polymerase of a carbohydrate subunit. In WO 02/05787, published July 25, 2002, SS Carroll et al. disclose related 2α-methyl and 2β-mercapto ribose derivatives in which the base is optionally substituted 7Η-pyrrole And [2,3-d]pyrimidine, base 6. This same application discloses an example of a 3?-mercapto nucleoside. S.S·

Carroll et al. (/. Chronicles/. Chm. 2003 278(14): 11979-11984) revealed the inhibitory effect of '2-0-methylcytosine nucleoside (6a) on HCV polymerase. In US Publication No. 2004/0259934, published on Dec. 23, 2004, DB Olsen et al. disclose the use of nucleoside compounds to inhibit ConovaWr/i/ae virus replication in the Coronavirus family and to treat coronavirus infections. 130152.doc 200942245 Act.

No\〇fiS H HO OH HO 〇Me 6 6a r In WO 02/100415 (US 2003/0236216 . A1) published on December 19, 2002, R. R. Devos et al. disclose 4 showing HCV activity, - a substituted nucleoside compound. The four compounds are clearly identified to include 4'-azido compound 7a, 4'-ethynyl compound 7b, 4'-ethoxy compound 7c and 4'-acetyl group 7d. Modifications to the ribose moiety exemplified include 2·-deoxy derivatives 8a, 3'-deoxy derivatives 8b, 3'-methoxy derivatives 8e, 3'-fluoro derivatives 8c and 2', 2' - a difluoro derivative 8d. In WO 2004/046159 (US 2004121980), published June 3, 2004, J. A. Martin et al. disclose a pre- 7a drug suitable for the treatment of HCV-mediated diseases. Both U.S. applications are hereby incorporated by reference in their entirety.

7a: R = =n3 8a: R1 = OH, R2 = R3 = R4 = H 7b: R = = ethynyl 8b: R3 = ΟΗ, ^=Κ2 = Κ4 = Η 7c: R = = OEt 8c: R3 = OH9R2 = F,R}=Ra=H 7d:R ==C(=0)Me Sd: R1 = R2 = H,R3 = R4 = F 8c: R1 =OMe, R3 = OH, R2 = R4 = H

US Application No. 10/167,106, filed on June 11, 2002, entitled "4'-Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication", and US 130152.doc, filed on November 19, 2003 The compounds related to the present invention are disclosed in Application No. 10/71 7,260. Both of these applications are hereby incorporated by reference in their entirety. Y.-H. Yun^- K{Arch. Pharm. Res. 1985 18(5):364-35)^3⁄4 shows 4'-azido-2'-deoxy-2'-fluoro-arabinofuranose Synthesis and antiviral activity of nucleosides (9: R = H, Me and Cl).

❹ G·S. Jeon and V. Nair (7Wri?/zei/rcm 1996 52(39): 12643-50) reveal the synthesis of 4'-azidomethyl-2',3'-deoxyribonucleoside 10 (B = adenine, thymine, and uracil) as an HIV reverse transcriptase inhibitor. Several computational studies have been reported for 4'-azidonucleosides: D, Galisteo et al., J. Mol. 1996 384(1): 25-33; J. Pepe et al., Ewr. 乂Met/. CTzem. 1996 32(10): 775-786; E. Estrada et al., silico studies towards the discovery of New Anti HIV Nucleoside, J. Chem. Info. Comp. Sci. 2002 42(5): 1194-1203. I. Sugimoto et al. revealed the synthesis of 4'-ethynyl-2'-deoxycytidine nucleoside (11) and other two-carbon substituents at the 4'-position and HIV and herpes simplex (/Λ siwp/ex Bioassay (Nucleosides and Nucleotides. 183. Synthesis of 4' β-Branched Thymidines as a New Type of Antiviral Agent, Bioorg. Med. Chem. Lett. 1999 9:385-130152.doc 13 200942245 88). T. Wada et al. (TVMc/eoiWe.? iVMc/eoiii/e.? 1996 15(1-3): 287-304) disclose the synthesis and anti-HIV activity of 4匕C-methyl nucleosides. In WO 01/32153, published May 10, 2001, R. Storer discloses a method of treating or preventing Flaviviridae-infection by administering a dioxolan analog of a nucleoside. In WO 02/18404, published March 7, 2002, R. Devos et al. disclose novel and known purine and pyrimidine nucleoside derivatives and their use as inhibitors of subgenomic HCV replication and contain the same A pharmaceutical remedy for a nucleoside derivative. The disclosed compounds consist of a nucleoside having a substituted purine and a bite test. EPA Publication No. 0 352 248 discloses various types of L-ribofuranosyl nucleosides for the treatment of HIV, herpes and hepatitis. A similar description can be found in WO 88/0900 1 filed by Aktiebolaget Astra. K. Kitano et al. 1997 53(39): 13315-13322) reveals the synthesis of 4'-fluoroindolyl 2-deoxy-D-erythro, ritual- and V-inhibited biting and anti-cellulite赘Bioactive β It has been demonstrated that non-nucleoside ectopic inhibitors of HIV reverse transcriptase are used alone or in combination with nucleoside inhibitors and with protease inhibitors. Described as a non-nucleoside HCV NS5B inhibitor currently in various stages of development

Dry species include: benzimidazoles (H. Hashimoto et al. WO 01/47833, 'H. Hashimoto et al. WO 03/000254, PL Beaulieu et al. WO 03/020240 A2; PL Beaulieu # AUS 6,448,281 Bl; PL Beaulieu et al. Human WO 03/007945 A1); steroids (PL Beaulieu et al. WO 03/0010141 A2); benzothiadiazines, for example 1, (D. 130152.doc -14- 200942245

Dhanak et al., May 10, 2001, application for w〇01/85172 A1; D. Chai et al., application dated June 7, 2002, w〇2002098424, D. Dhanak et al., application dated October 28, 2002 03/03 7262 A2; KJ Duffy et al., application dated May 23, 2003, w〇03/099801 A1, MG Darcy et al., October 28, 2002, application WO 2003059356; D. Chai et al. June 24, 2004 W 〇 2004052312, D. Chai et al., WO 2004052313, filed on December 13, 2003; DM Fitch et al., filed on December 11, 2003, w〇2004058150; DK Hutchinson et al., application dated August 19, 2004 WO 2005019191; J. Κ Pratt et al., filed on October 31, 2003, w〇2004/041818 Al);

❹

Thiophenes such as 2' (C. K. Chan et al. WO 02/100851 A2); benzothiophenes (DC Young and TR Bailey WO 00/18231); β-ketopyruvate (S. Attamura et al. US 6,492,423 Bl, A. Attamura et al. WO 00/06529); pyrimidines (C. Gardelli et al. WO 02/06246 Al); pyrimidinediones (TR Bailey and DC Young WO 00/13708); triazines ( K.-H. Chung et al. WO 02/079187 Al); rhodamine derivatives (TR Bailey and DC Young WO 00/10573, JC Jean et al. WO 01/77091 A2); 2,4-di- oxy oxyperazine Ran (RA Love et al. EP 25 6628 A2); phenylalanine derivatives (M. Wang et al. / 130152.doc -15- 200942245 5b/. C/2em. 2003 278:2489-2495). The thiazide which inhibits HCV NS5B has been disclosed in U.S. Patent No. 20060040927, filed on Jan. 22, 2005. Inhibitors of HCV protease required for viral replication have also been revealed (F. McPhee^ A > Drugs of the Future 2003 28(5): 465-488; YS Tsantrizos et al., C/zem. V. wg·· 2003 42 (12): 13 56-1360). The nucleoside compounds of the invention can be used in combination with these and other polymerases and protease inhibitors. The results of these efforts have been reviewed (J. Z. Chen and Z_ Hong, Targeting NS5B RNA-Dependent RNA Polymerase for Anti-HCV Chemotherapy, Curr. Drug Targ. Inf. Dis. 2003 3(3): 207-219) . These non-nucleoside inhibitors are not relevant to the present invention. SUMMARY OF THE INVENTION It is an object of the present invention to provide novel nucleoside compounds for use in methods and compositions for treating a host infected with hepatitis C virus. Current currently approved therapies for hepatitis C virus (HCV) without prophylactic treatment and only for HCV are limited. It is necessary to design and develop novel pharmaceutical compounds. Surprisingly, 2'-deoxy-2'-[beta]-methyl-4'-azido-cytosine or its esters are useful for the treatment of HCV and exhibit less toxicity when administered to a host. The invention also provides a pharmaceutical composition of the compound with at least one pharmaceutically acceptable carrier, excipient or diluent. Combination therapies have been shown to be useful in the treatment of viral diseases and novel compounds potentiate other approved and studied HCV therapeutics and the present invention provides the use of the above-mentioned inventions 130152.doc -16- 200942245, or the medicinal An acceptable salt for use in combination with or alternation with one or more other effective antiviral or immunomodulatory agents (i) includes, where appropriate, a pharmaceutically acceptable carrier, excipient or diluent) for the treatment of HCV. : 0)

NCK RO Me φ The present invention provides a nucleoside of the formula i, or a pharmaceutically acceptable salt thereof, and the use of the same for treating a host infected with HCV, wherein: R1, R2 and R3 are independently selected from the group consisting of Groups: hydrogen, COR4, C(=0)0R4, and c(=〇)chrSnhr6; R4 is independently selected from the group consisting of: (a) Ci i8 non-branched or branched alkyl, (Wc^8 Haloalkyl, (c) C38 cycloalkyl, (d) Ci 1 oxaalkyl and 0) phenyl, which are optionally independently selected from Gy alkyl, Cl-3 alkoxy by one or three Substituted with a halogen, cyano or nitro group; ® R is wind, Ci_1() alkyl, phenyl or (^-3 phenyl), which is optionally selected from one or three Substituents of groups of each group consisting of: halogen, hydroxy, Cw alkoxy, Cw alkyl, cyano and nitro; R6 is hydrogen or Cw alkoxy; or; acid addition salt thereof. Formula I or pharmaceutically acceptable in combination with other effective antiviral agents for the treatment of HCV infection and optionally including at least one pharmaceutically acceptable carrier, excipient or diluent The use of the salt in the manufacture of a medicament for the treatment or prevention of Hcv in a host 130152.doc -17- 200942245. Without wishing to be bound by theory, it is believed that the compound of the invention is continuously phosphorylated by a kinase in human cells. 5,-〇-monophosphate, 5|_〇_bisphosphate and eventually becomes the antiviral active metabolite 5,-〇·triphosphate. Therefore, another aspect of the present invention provides such 5,_〇 Phosphorylated material, ie, compound 'where R and R are oxime and R is a monophosphate, diphosphate or triphosphate. The antiviral activity of a nucleoside inhibitor is usually the absorption of a nucleoside into a host cell, nuclear transformation The result of a combination of the activity of the active triphosphate, the intracellular stability of the triphosphate, and the ability of the sirolimus to interfere with the rNA synthesis activity of the viral polymerase. As shown in the biological examples below, the compounds of the invention are readily scalarized in vivo to The active triphosphate has a long intracellular triphosphate half-life, thus allowing for a sustained and high concentration of the antiviral active substance. [Embodiment] In one embodiment of the present invention, a compound of the formula or a pharmaceutical thereof is provided. An acceptable salt, wherein R1, R2, R3, R4, 5 and R6 are as defined above. The phrase "as defined above" refers to the groups provided in the definition of the formula given above. The most broad definition of the group. In the other examples provided below, the substituents that are not explicitly defined in the examples remain the broadest definitions provided in [Summary of the Invention]. Another embodiment of the invention Provided is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 are hydrogen. In another embodiment, a compound of formula I is provided wherein Ri and R3 are Η and R2 is monophosphate Ester, diphosphate or triphosphate. In a further embodiment of the invention 'providing a compound of formula I or a physician thereof 130152.doc -18 - 200942245 are each independently a pharmaceutically acceptable salt of nitrogen, wherein R1, R2, R3 C〇R4 or c(= 0) 〇R4 and R4 are as described above.

In a further embodiment of the invention, there is provided a compound of the formula I or a therapeutically acceptable salt thereof, wherein r!, r2, r3 are each independently hydrogen, or C(〇)〇R and R4 is an unbranched chain or a branching key Cl]. The base, such as a low carbon burn group, is especially methyl, ethyl, isopropyl or tert-butyl. In a further embodiment of the invention there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen; R2 and R3 are COR, + in a further embodiment of the invention, provided A compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen; R2 and R3 are COR4, and R4 is a non-branched or branched Cnig alkyl group, such as a lower alkyl group, especially a methyl ethyl group. , isopropyl or tert-butyl. When a compound contains two R4 moieties, it is generally the same for convenience of synthesis. In still another embodiment of the present invention, there is provided a compound of formula j, or a pharmaceutically acceptable salt thereof, wherein is hydrogen; R2 is C〇R4, C(=0)0R4 or COCH(r5)nhr6; and r4 And r6 are as defined above. In still another embodiment of the present invention, there is provided a compound of formula j or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are hydrogen; and R3 is C〇r4, C(= 0) 〇R4 or C0CH(Rs)NHR6; and r4, RS and r6 are as defined above. In another embodiment of the invention, there is provided a compound of formula I, wherein R2 is COCH(Rs)NHR6, RS is different a propyl group, an isobutyl group or a second butyl group and R6 is hydrogen. In a preferred configuration of this embodiment, the space configuration of the group 130152.doc -19· 200942245 is (S), that is, R2 is L The aliphatic amino acid residue ^ Ri is generally ruthenium in this embodiment, and R3 is ruthenium or COCH(Rs)NHR6, which is isopropyl, isobutyl or second butyl and R6 is hydrogen. When having two such COCH(Rs) NHR6 moieties, it is typically a phase, homo-amino acid for ease of synthesis. : ' In another embodiment of the invention 'provides a compound of formula I, wherein R3 Is COCH(R5)NHR6, RS is isopropyl, isobutyl or second butyl and R is hydrogen. In a preferred configuration of this embodiment, the 'space configuration of the RS group' is (S), That is, R3 is an L-aliphatic amino acid residue. R1 is usually hydrazine in this embodiment. In still another embodiment of the present invention, there is provided a compound of formula j or a pharmaceutically acceptable salt thereof, wherein R1 And R3 is hydrogen; R2 is C〇R4; and r4 is as defined above. In another embodiment of the invention, there is provided a compound of formula j, or a pharmaceutically acceptable salt thereof, wherein R1 and R3 are hydrogen; R2 is C〇R4; and R4φ is a Cl-1Q non-branched or branched alkyl group, such as a lower alkyl group, especially a methyl, ethyl, isopropyl or tert-butyl group. In one embodiment, a method of treating a disease mediated by a hepatitis C virus (HCV) virus, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable compound thereof Accepted salts, wherein, only 2, 3, 4, 5 and only 6 are as defined above. In another embodiment of the invention, a treatment is provided by a liver A method of prion (HCV) virus mediated disease comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula j or a pharmaceutically acceptable salt of 130152.doc -20-200942245, wherein R1 R2 and R3 are hydrogen. In another embodiment of the invention, there is provided a method of treating a disease mediated by a hepatitis C virus (HCV) virus, comprising administering to a mammal in need thereof therapeutically effective A compound of the formula "a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen; r\r3 is each c〇r4; and only 4 is selected from the group consisting of a non-branched chain or a branched lower alkyl group.

In another embodiment of the present invention, there is provided a method of treating a disease mediated by a hepatitis C virus (HCV) virus, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the formula or s pharmaceutically acceptable salt, wherein R1 and R3 are hydrogen; rule 2 is (: 〇114 or c〇ch(rS)nhr6; R is selected from the group consisting of Cmo# branched or branched low carbon alkyl rS and R6 are as defined above. In another embodiment of the invention 'providing a method of treating a disease mediated by a hepatitis C virus (HCV) virus, comprising administering to a mammal in need thereof The dose is between (9) mg of the compound of formula I or a pharmaceutically acceptable salt thereof per kg of patient body weight per day, wherein r1, r2, r3, R4, R5 and R6 are as defined above. In an embodiment, a method of treating a disease mediated by a hepatitis C virus (HCV) virus comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable compound thereof Salt, where ~, 仏... and ~ are defined by the text: and at least one immune system An agent and/or at least one antiviral agent that inhibits Hcv replication. In another embodiment of the present invention, a disease method for treating a disease caused by (IV) hepatitis 130152.doc -21 · 200942245 virulence (HCV) virus is provided. And a therapeutically effective amount of a compound of formula j, or a pharmaceutically acceptable salt thereof, is administered to a mammal in need thereof, wherein it is as defined above: and at least one selected from the group consisting of interference Immune system modulators of leucine, interleukin, tumor necrosis factor or community stimulating factor. Those skilled in the art will appreciate that such immune system molecules may be in their natural form or they may be chemically derivatized to confer beneficial pharmacokinetics. In another embodiment of the invention, a method of treating a disease mediated by a hepatitis virus (HCV) virus, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt, wherein R1, R2, R3, R4 are as defined above; and interferon or chemically derived interferon. In another embodiment of the invention, a treatment is provided by type C A method of mediated by a hepatitis virus (HCV) virus comprising administering to a mammal in need thereof a therapeutically effective amount of a guanidine compound or a pharmaceutically acceptable salt thereof, wherein 1^, 1^, 1 ^, 1^, 1^ are as defined above; and at least one other antiviral agent. In another embodiment of the invention, a method of treating a disease mediated by a hepatitis C virus (HCV) virus is provided, A method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein, as defined above, and at least one other HCV protease inhibits Agent, another nucleoside HCV polymerase inhibitor, a non-nucleoside HCV polymerase inhibitor, an HCV helicase inhibitor, an HCV priming enzyme inhibitor, or an HCV fusion inhibitor. 130152.doc -22- 200942245 In one embodiment of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of at least one pharmaceutically acceptable carrier, diluent or excipient = A compound or a pharmaceutically acceptable salt thereof, wherein R, R, R3, R4, R5 and R6 are as defined above. In another embodiment of the present invention, there is provided a pharmaceutical composition comprising 500-1500 mg of a compressed tablet containing 35-75 wtws of a compound or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Di 5 and R6 as above

As defined; and the remainder comprises at least one pharmaceutically acceptable carrier, diluent or excipient. In another embodiment of the present invention, there is provided a pharmaceutical composition comprising 500-1500 mg of a compressed tablet containing 40-60% by weight of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, r3 R4, ... and R6 are as defined above; and the balance comprises at least one pharmaceutically acceptable carrier, diluent or excipient. The phrase "a", as used herein, refers to one or more such entities; for example, a compound refers to one or more compounds or at least one compound. Similarly, the terms "a", "and", "and" and "at least one of" are used interchangeably herein. The phrase "as defined above" means each as provided in the definition of Formula I. The first definition of the group. The term "optional" or "as appropriate" as used herein means that the described event or circumstance may or may not occur' and that the description includes instances where the event or circumstance occurs and instances where it does not occur, e. And "optionally substituted phenyl" means that the phenyl group may be substituted or unsubstituted, and the description includes a phenyl group substituted with 130152.doc 23-200942245 and a substituted phenyl group thereof. The compounds of the invention may have a symmetry center on the side chain of the carboxylate, guanamine or carbonate moiety attached to the core to produce the diastereomer. All stereoisomers of the side chains of the compounds of the invention, whether in the form of a mixture or in pure or substantially pure form, are contemplated. The definition of a compound of the invention includes all isolated optical isomer enantiomers and mixtures thereof, including racemic forms. Pure optical isomers may be prepared by stereospecific synthesis from a_D_ribose or by racemic forms by physical methods (eg, fractional crystallization, separation or crystallization of diastereomeric derivatives or by palms) Separate by column chromatography to separate. Individual optical isomers can be obtained from the racemate by conventional methods (e.g., formation of a salt with an optically active acid followed by crystallization). The term "alkyl" as used herein denotes a non-branched or branched chain hydrocarbon group containing from 1 to 18 carbon atoms. The term "lower alkyl" denotes an unbranched or branched chain hydrocarbon group containing from 1 to 6 carbon atoms. Representative lower alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl. When the term "alkyl" is used as the suffix of another term, as in "phenylalkyl" or "hydroxyalkyl", this is intended to indicate one to two groups selected from other specific nomenclature. An alkyl group as defined above substituted with a substituent. Thus, for example, "phenylalkyl" refers to an alkyl group having one to two phenyl substituents and thus includes benzyl, phenylethyl and biphenyl. "Alkylaminoalkyl" is an alkyl group having one to two alkylamino substituents. The term "ialkyl" as used herein denotes an unbranched or branched chain as defined above. The base 'in which 1, 2, 3 or more hydrogen atoms are substituted by halogen. Examples are 1-fluoromethyl, 1-methylmethyl, 1-bromoindolyl, iodomethyl 130152.doc -24· 200942245, difluoromethyl, trimethylmethyl, tribromomethyl, triiodomethyl Base, 1-fluoroethyl, 1-haloethyl, 1_fluorenylethyl, b-ethyl, ethyl, 2-methoxyethyl, 2-bromoethyl, 2-iodoethyl, 2 2_2 Gas ethyl, % bromopropyl or 2,2,2-trifluoroethyl. The term "cycloalkyl" as used herein denotes a saturated carbocyclic ring containing from 3 to 8 carbon atoms, meaning cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. . The term "cycloalkylalkyl" as used herein refers to a group R,R,, wherein R' is cycloalkyl as defined herein, and R" is alkyl as defined herein. It should be understood that the point of attachment of the cycloalkylalkyl moiety will be on the alkyl group. Examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl. CM ring Alkyl_Cl.3 alkyl refers to the group R, R", wherein the ruthenium is C3.7 cycloalkyl and 11" is (:1-3 alkyl), as defined herein. Unless otherwise stated, Otherwise the term "alkylene" as used herein denotes a divalent saturated straight chain hydrocarbon group having 1 to 8 carbon atoms or a branched chain saturated divalent hydrocarbon group having 3 to 8 carbon atoms. Including, but not limited to, anthracenylene, ethylidene, propyl, 2, fluorenyl, butyl, 2-ethylethyl butyl. The term "alkenyl" as used herein means having 2 An unsubstituted [or substituted] hydrocarbon chain having up to 18 carbon atoms, preferably 2 to 4 carbon atoms, having one or two olefinic double bonds, preferably an olefinic double bond Examples are vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl (crotonyl). As used herein, the term "fast radical" means having from 2 to 18 carbon atoms [ Preferably 2 to 4 carbon atoms], and having one or, if possible, two unbonded hydrocarbon chain groups of the two reference bonds [preferably 130152.doc -25 - 200942245 a reference bond]. Examples are ethynyl groups, a propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl group. The term "alkoxy" as used herein denotes an unsubstituted non-branched chain. Or a branched alkyloxy group, wherein the "alkyl" moiety is as defined above, such as decyl, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyl Oxyl, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, including isomers thereof. As used herein, "lower alkoxy" means having the meaning as defined above "Lower alkyl" alkoxy. The term "alkylthio" or "sulfanyl" as used herein denotes an unbranched or branched (alkyl) S- group, The "alkyl" moiety is as defined above. Examples are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butyl. Sulfhydryl. The term "alkylsulfinyl" and "arylsulfinyl" as used herein, and a radical of the formula -S(=0)R, wherein R is alkyl or aryl, respectively. Alkyl and aryl are as defined herein. The terms "alkylsulfonyl" and "arylsulfonyl" as used herein mean a radical of the formula -S(=0)2R wherein R is independently alkane. Alkyl or aryl and alkyl and aryl are as defined herein. The term "aryl" as used herein denotes optionally substituted monocyclic or polycyclic aromatic groups containing carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl and naphthyl (e.g., 1-naphthyl or 2-naphthyl). Suitable substituents for the aryl group are selected from the group consisting of alkyl, alkenyl, alkynyl, aryloxy, cyclo, aryl, arylamino, alkoxy, amine, alkyl Amine group, dialkylamino group, ruthenium, halogen group, thiol group, Schopent group and cyano group. 130152.doc -26- 200942245 The term "mercapto" ("alkylcarbonyl") as used herein denotes a group of the formula c(=〇)R where R is hydrogen and contains from 1 to 7 carbon atoms Non-branched bond or branched chain alkyl group or phenyl group. The terms "alkoxycarbonyl" and "aryloxy" as used herein mean a radical of the formula -C(=0)OR wherein R is alkyl or aryl, respectively, and alkyl and aryl are as As defined herein, the term halogen means fluorine, chlorine, bromine or moth, preferably fluorine, gas, and moisture.

The term "chemicalizing agent" as used herein refers to an anhydride of a carboxylic acid, a hydrazine-based tooth or other activated derivative. The term "anhydride" as used herein refers to a structure of the formula RC(0)-0. a compound of -C(0)R' wherein r is as defined in the above paragraph. The term "indenyl halide" as used herein refers to the group RC(〇)x, where X is bromine or gas. As used herein, the term "activated derivative" refers to a transiently reactive form of an initial compound that activates a compound in a desired chemical reaction, wherein the initial compound is only moderately reactive or non-reactive. A chemical group having a higher free energy content than the starting compound in the derivative or molecule to effect activation, which makes the activated form easier to react with another reagent. In the context of the present invention, activation of the carboxyl group is particularly important as herein The term brewing agent used additionally includes a reagent which produces carbonate 0C(=0)0R4 wherein R4 is as defined above. The term "protecting group" as used herein means (a) protecting a reactive group. Participation in unwanted chemical reactions; and (8) chemical groups that are easily removed after protection of reactive groups are no longer needed. For example, a three-base base is a protecting group for the first hydroxyl function and a acetonide is adjacent. The protecting group of the diol. In the illustration of the compound given in this application, the thickening 130152.doc •27· 200942245 the wedge key indicates the asymmetric carbon The substituent above the ring plane (also denoted by p) and the wedge-shaped bond of the dotted line indicates the substituent below the ring plane to which the asymmetric carbon belongs (also denoted by α). The term "combination" as used herein "combination therapy" refers to a plurality of drugs that are administered simultaneously or sequentially at the same time or at different times. : As used herein, chemically derived interferon, refers to a covalently linked + interferon molecule of a polymer that alters the physical and/or pharmacokinetic properties of the interferon. A non-limiting list of such polymers includes polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycol (ppG), polyoxyethylated polyols (P〇iyoxyethylenated p〇ly〇1) ), its copolymer and its block copolymer, the restriction is to maintain the water solubility of the block copolymer. Those skilled in the art will appreciate a number of methods for linking polymers to interferons (see, for example, A. Kozlowski and j. M. HarHs / 〇 〇 / pure (4) 2001 72(1-3): 217-24). A non-limiting list of chemically derived FNas covered by this patent includes peginterferon-cardiac 2a (PEGASYS®) and peginterferon-a-2b (PEGINTR〇N8). . The compounds of formula I exhibit tautomerism. The tautomeric compound may exist in the form of two or more substances which are mutually converted. Proton mobility tautomerism; (iv) The migration of a covalently bonded hydrogen atom between two atoms. Tautomers are generally present in equilibrium and the attempt to separate individual tautomers is usually a mixture of chemical and physical properties and a mixture of compounds. The position of the equilibrium depends on the chemical characteristics of the molecule. For example, in many fat secrets

^ Caps such as ) )), the main style, and in the hope, sterol-based. Common proton mobile tautomers include ketone/dilute alcohols (_c (which CM 130152.doc -28- 200942245 C(-OH)=CH-), decylamine/hydrazine imidate (-C(=0)-NH) -i?-C(-0H)=N_) and 脒(-C(=NR)-NH-SC(-NHR)=N-) tautomers. The latter two are especially in heteroaryl and heterocycles. Common, and the invention includes all tautomeric forms of the compounds. Commonly used abbreviations include: acetamido (Ac), azo-bis-isobutyl decyl nitrile (AIBN), atmospheric (Atm), tert-butoxycarbonyl ( Boc), di-tert-butyl or dibutoxycarbonyl anhydride (B0C20), benzyl (Bn), butyl (Bu), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI) ), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diaza Bicyclo [5.4.0] undec-7-ene (DBU), N,N,-dicyclohexylcarbodiimide (DCC), 1,2-dioxaethane (DCE), dichloromethane (DCM) , diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), diisobutylaluminum hydride (DIB AL or DIB AL-H), diisopropylethylamine (DIPEA) ,N,N-dimethylacetamide (DMA), 4-N,N-didecylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl hydrazine (DMSO), 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethyl lactyl-2 wahlin-1 - decanoic acid S (EEDQ) 'Ethylene bond (Et2〇) 'Six-gas sulphate-(7-azabenzotriazol-1-yl)-fluorene, hydrazine, Ν'Ν'-tetramercaptopurine (HATU) , acetic acid (HOAc), 1-indole-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), hexamethyl diazepine (LiHMDS), methanol (MeOH), melting point (mp ), MeS02-(sulfonyl or Ms), mercapto (Me), acetonitrile (MeCN), meta-benzoic acid (MCPBA), mass spectrometry (ms), mercapto tert-butyl ether (MTBE), N -bromosuccinimide (NBS), N-carboxyanhydride (NCA), N-130152.doc -29- 200942245 Chloroamyl succinimide (NCS), hydrazine-mercaptomorpholine (NMM), N-fluorenyl Pyrrolidone (NMP), picochromic pyridinium (PCC), dichromate pyrene (PDC), phenyl (Ph), propyl (Pr), ginger propyl (/-Pr), pounds per square inch (psi) ), "bipyridine (pyr), room temperature (rt or RT), Butyldimethylmethylalkyl or BuBu2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), trifluoromethanesulfonic acid or CF3S02-(Tf), trifluoroacetic acid (TFA), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethyldecyl or Me3Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or © pTsOH ), 4-Me-C6H4S02- or fluorene sulfonyl (Ts), N-amino phthalate-N-carboxy anhydride (UNC A). When used in the alkyl moiety, the conventional nomenclature including the prefix («), its (z_-), the second, the third and the new ("deduction" has its conventional meaning (J. Rigaudy and D. Klesney, iVowewc/aiMre IUPAC 1979 Pergamon Press, Oxford.) The compounds of the invention can be prepared by a variety of methods as described in the illustrative synthetic schemes shown and described below. Starting materials for the preparation of such compounds And reagents are generally commercially available from suppliers such as Aldrich Chemical Co., or by methods known to those skilled in the art, according to the procedures described in the following references, such as: , /or Orgam'c Wiley & Sons: New York, Volumes 1-21', KC hdiKock, Comprehensive Organic Transformations, 2nd Edition Wiley-VCH, New York 1999 ί Comprehensive Organic • Syw/zes/i, B. Trost and I. Fleming (Editor Volumes 1-9, Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, AR Katritzky and CW Rees (ed.) Pergamon, Oxford 130152.doc -30- 200942245 19S4, Volume Ί-9,, Comprehensive Heterocyclic Ch Emistry II, AR Katritzky and CW Rees (ed.) Pergamon, Oxford 1996, vol. 1-11; and Orgam.c iieaciz'cm·?, Wiley & Sons: New York, 1991, vol. 1-40. The reaction schemes are merely illustrative of certain methods by which the compounds of the present invention can be synthesized, and various modifications can be made to such synthetic reaction schemes and such modifications can be suggested to those skilled in the art with reference to the disclosure contained in this application. If necessary, the starting materials and intermediates of the synthetic reaction scheme can be separated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These materials can be used including physics. The constant and spectral data are characterized by conventional methods. Unless stated to the contrary, the reactions described herein are preferably in an inert atmosphere, at atmospheric pressure, from about -78 ° C to about 150 ° C, more preferably from about 〇 ° C to about The reaction temperature range of 125 ° C, and most preferably and suitably, is carried out at a temperature of about room temperature (or ambient), for example, about 20 ° C. The chemical modification of the 2' and 3'-positions of nucleosides has been studied, and the modification of the 4'-position has been less popular, most likely due to the additional synthetic challenges associated with its synthesis. Maag et al. (Anti-HIV Activity of 4'-Azido and 4'-Methoxynucleosides, J. Med Chem. 1992 3 5 :1440-145 1) reveal 4'-azido-2-deoxyribonucleosides and 4 - Synthesis of azido nucleosides. C. O'Yang, k [Tetrahedron Lett. 1992 33(1): 37-40 and 33(1 ): 41-44) reveals the synthesis of 4'-cyano, 4'-hydroxyindenyl- and 4' a nucleoside substituted with a thiol nucleoside compound. These compounds have been evaluated as anti-HIV compounds. Maag et al. (supra) teach that 4'-azidonucleoside 16c can be added to 5-methylene-tetrahydro-furan-2-yl nucleoside 15 by azide 130152.doc -31 - 200942245 iodine To prepare, wherein B is thymine, uracil, adenine or guanosine. An improved process for the preparation of 4'-azido nucleosides is disclosed in U.S. Patent Publication No. 20050038240, issued Feb. 17, 2005, to T. J. Connolly et al.

HO

RO Η (15)

16a: X = I; R = H

16b: X = 0C(0)-m-Cl-C6H4Cl; R = COPh 16c: X = OH; R = H

In WO 02/100415, R. Devos et al. disclose a novel 4'-substituted nucleoside derivative that inhibits the HCV NS5B viral DNA polymerase. The addition of azide iodine is most effective in the urinary mouth. Determination of nucleoside 15 (B = urinary sputum), urinary sputum sputum 15 can be used by AD Borthwick et al. (··· Met/· Chem. 1990 33(1): 179; see also KJ Divakar And CB Reese J. Chem • Soc., PerHn / 1982 11 71-1 1 76) The method described is converted to the corresponding cytosine nucleoside.

Process A

.—18a:X = OH 19 at ε» 4 ι— 20a: X = I »-► 18b: X = I ^ Na匕20b: X = m-ClC6H4COz-

Using the procedure of Maag et al. (see above) (Scheme A), from 1-(4-hydroxy-130152.doc-32-200942245 5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl Preparation of 4-amino-1-(5-azido-4-alkyl-5-ylamino-3-methyl-tetrahydrol)-1-purine-pyrimidine-2,4-dione (18a) -furan-2-yl)-1 -pyrimidin-2-one (22) (D. Ο. Cicero et al., "Stereoselective synthesis of novel analogs of 2'-deoxy- and 2',3'-dideoxynucleosides with potential Antiviral activity", Bioorg. Med. Chem. Lett. 1994 4(7):861-6; A. Iribarren, published on June 16, 1993 entitled "Preparation of new (2'R)- and (2'S -2'-deoxy-2'-C-hydrocarbyl antisense oligonucleotides useful in scientific research, therapeutics and diagnostics" (EP547008 Al). In the cell-based replicon assay for HCV polymerase activity, 4-amino-1-(5-azido-4-hydroxy-5-hydroxyindolyl-3-indolyl-tetrahydro-furan-2- The base-1-pyrimidin-2-one (22) exhibited good activity (Table I). In addition, the compound exhibited a low degree of cytotoxicity in the assay. Table I Maximum inhibition of HCV polymerase by compound / 〇 (100 μΜ) Maximum cytotoxicity % (100 μΜ) 22 98.58 9.48 Nucleoside derivatives are often effective antiviral agents (eg HIV, HCV, herpes simplex, CMV) and anticancer Chemotherapeutic agent. Unfortunately, its practical utility is often limited to two factors. First, adverse pharmacokinetic properties often limit the absorption of nucleosides through the digestive tract and the intracellular concentration of nucleoside derivatives, and the second 'second best physical property limit can be used to enhance the choice of formulation for delivery of active ingredients. Albert introduces the term prodrug to describe a compound that lacks intrinsic biological activity but is capable of transforming into a 14 drug (A. Albert, Tbja.c/iy,

Chapman and Hall, L〇ndon, wn). A recent review of prodrugs (p. Ettmayer et al.' j. j 2004 47 (i〇): 2393-2404; K.

Beaumont# A » Qurr Drug Metab 2〇〇3 4:461-485 ; H. Bundgaard, Design 〇j· pro^rUgS: Bioreversible derivatives : for various functional groups and chemical entities in

Design of Prodrugs, H. Bundgaard (ed) Elsevier Science Publishers, Amersterdam 1985; G. M. Pauletti et al. Jc/v. © Drug Deliv. Rev. 1997 27:235-256 ; R. J. Jones and N.

Bischofberger, Jwii'Wra/1995 27, 1-15 and C. R. Wagner et al., A/W. Heart v. 2000 20: 417-45). Metabolic transformation can be catalyzed by a specific enzyme (often a hydrolase) and the active compound can also be regenerated by non-specific chemical methods. A pharmaceutically acceptable prodrug is a compound that is metabolized (e.g., hydrolyzed or oxidized) in a host to form a compound of the invention. Biotransformation should avoid the formation of fragments with toxicological tendencies. Typical examples of prodrugs include compounds having a biolabile protecting group attached to a functional moiety of the active compound. Alkylation, thiolation or other lipophilic modification of the hydroxyl group on the sugar moiety is used in the design of the positive nucleotide. These positive nucleotides can be hydrolyzed or dealkylated in vivo to form the active compound. * The factors limiting oral bioavailability are often the first time the gastrointestinal tract is absorbed and the digestive tract and liver are excreted. The intercellular absorption through the gastrointestinal tract preferably requires a D greater than 0 (7.4). However, the optimization of the partition coefficient does not guarantee success. Prodrugs may have to avoid active efflux transporters in intestinal epithelial cells. Intestine 130152.doc •34- 200942245 The intracellular metabolism of the skin and cells can be passively transported or lived by the outflow pump. ·Transportation return> Xiaohuao cavity must also resist the biological transformation of blood before it reaches the sister (four) receptor. Although it is sometimes possible to presume a pre-drug based on the molecule, the chemical modification of the chemical functional group in the rational design of the character can be displayed in the parent: non-existent undesired physical, chemical and A completely novel knife entity with biological properties. Metabolites if multiple pathways produce multiple metabolites

The need for the system can cause challenges. _, the identification of prodrugs is still inaccurate and ', challenging practice. In addition, the assessment of the pharmacokinetic properties of possible drugs may be challenging and expensive. (d) The pharmacokinetics of animal models can be difficult to extrapolate to humans. In U.S. Patent No. 6,846,81, issued Jan. 25, 2005, D. A. Martin et al. show that deuterated 4,-azido nucleosides have been found to be effective prodrugs. The one of the thiol derivatives 23 can be prepared by the hydrazine reaction of the parent nucleoside. The compound of the present invention is suitably prepared in one step in an aqueous organic solvent by a hydrazine reaction of 22. The solvent can be a homogeneous aqueous solution or a two phase solution. The pH of the aqueous organic solvent is maintained at 7.5 or more by neutralizing the acid generated by the deuteration reaction by adding a base. The test may be an alkali metal hydroxide or a third amine. The reaction is carried out in the presence of DMAP known in the art as a catalyst for the deuteration reaction. One of the advantages of this method is that the desired product can be obtained in the absence of a deuteration reaction of the heterocyclic base. Alternatively, the deuteration reaction is suitably between -20 and 200 ° C, but preferably at a temperature of -ίο and 160 ° C, such as DCM, gas, four carbonized carbon, B 130152.doc -35· 200942245 Ether, THF, dioxane, benzene, toluene, MeCN, DMF, sodium hydroxide solution or cyclobutane solvent, optionally in the presence of an inorganic base or an organic base with the corresponding fluorenyl tooth or anhydride. The deuteration reaction can also be carried out in a two-phase organic-aqueous medium in the presence of a phase transfer catalyst and DMAP under Schotten Baumann conditions. : Selective deuteration of hydroxyl groups can be achieved. Alternatively, the N-fluorenyl group of the N,0,0-tridecyl nucleoside can be selectively decomposed by bromination to form a protected diindenyl compound (R. KAerzek et al. Tetrahedron Lett. 1981 22(38): 3762 -❹ 64). The selective deuteration of a particular hydroxyl group on the carbohydrate group can be conveniently achieved by an enzymatically catalyzed deuteration or de-masting reaction. Enzyme catalysis provides mild selection conditions for organic conversion. S. M. Roberts has reviewed preparative biotransformation 4t (J. Chem. Soc. Perkin 1, 2001, 1475; 2000 611; 1999, 1 and 1998 157). M. Mahmoudian et al. Appl. jBz'ac/zem. 1999 29:229-233) reported the use of Novozyme 435, an immobilized preparation of Candida antarctica (Co^山·ΰ?α imiarchca) lipase, _ selection The 5'-position of 2-amino-9-PD-arabinofuranosyl-6-methoxy-9H-indole is deuterated. Other enzymes reported to selectively degenerate the 5'-hydroxyl group include: ground, Bacillus licheniformis, immobilized lipase IM (Lipozyme IM, immobilized Mwcor mie/zei fat; enzyme), CLEC -BL (Bacillus licheniformis), Savinase (Bacillus sp.), Novozyme-243 (Bacillus licheniformis), bacteriophage π·) Lipase and Lipolipase (lipolase) , Novo). 130152.doc -36 - 200942245 The Lipolase® enzyme preparation (lipase from thermophilic fungi, Sigma catalog number L 0777) was found to selectively hydrolyze the 5'-mercapto group of the tridecyl derivative to give 2',3'-di Mercapto compound. In WO 2004043894, G. G. Heraldsson et al. disclose the use of thermophilic fungal lipases for the esterification of marine oils. N. Weber et al. (five J. 〇/

Tfec/mo/. 2003 105(10): 624-626) reveals the transesterification of methyl oleate catalyzed by thermophilic bacteria. V. Bodai et al. (Op. C. 2003 345 (6 and 7): 811-818) describe novel hydrolases from thermophilic filamentous fungi that can be used for selective biotransformation. Other reports of position-selective enzymatic ester hydrolysis include: R. Hanson et al. A > Bioorg. and Med. Chem. 2000, 2681-2687 (synthesis of a lobucavir prodrug via regioselective acylation and hydrolysis); R, Pfau et al. Leii 1999, 1817-1819 (selective hydrolysis of carbohydrate ester); A. Bianco et al, J. 〇 / Mo /. Cai. B · 1997 209-212 (regioselective acylation and hydrolysis for synthesis of sialic acid gins derivatives); Y. Ota et al, Bioscience, Biotechnology,

Biochemistry (1997), 166-167 (regioselective ester hydrolysis of 1,2,3-trihexanolylglycerol); U. T. Bornscheuer et al., Enzyme

Microbial Technol. 1995, 578-86 (lipase catalyzed syntheses of · 'monoacylglycerol; review); CT Goodhue et al. WO 9403625 (regioselective process for resolution of carbohydrate monoesters); NW Boaz, WO 9115470 (Separation of alcohol-ester mixture by selective Enzymatic hydrolysis); 130152.doc -37- 200942245 YS Sanghvi et al US2002142307 (regioselective hydrolysis of 3', 5'-di-0-levulinylnucleosides); J. Garcia et al. /. Org. Chem. 2002, 4513-4519 (regioselective hydrolysis of 3',5'-di-O-levulinylnucleosides); 0· Kirk et al. k Biocat and

Biotransformation (1995) 91-7 (lipase catalyzed regioselective acylation and deacylation of glucose derivatives) 熟 Those skilled in the art will recognize that selective esterification can also be achieved by standard chemical methods. The selective protection of the 5,-hydroxyl group (which allows for direct esterification of the 2·- vial) or the incorporation of a second protecting group (which allows for deprotection and selective brewing of the first alcohol) has been described. The compounds of the invention may be formulated into a variety of oral dosage forms and carriers. Oral dosage forms can be in the form of lozenges, coated lozenges, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. In the administration route, the compound of the present invention is effective when administered by a suppository administration form. The most convenient way to administer medication is usually oral administration using a convenient daily dosing regimen that can be adjusted depending on the severity of the disease and the patient's response to the antiviral drug. The compounds of the present invention, as well as pharmaceutically acceptable salts thereof, are placed in the form of pharmaceutical compositions and unit dosages together with one or more conventional excipients, carriers or diluents. The pharmaceutical compositions and unit dosage forms may contain conventional ingredients in the ordinary proportions with or without additional active compounds, and the unit dosage form may contain any suitable effective amount of activity commensurate with the intended daily dosage range to be used. Ingredients. The pharmaceutical composition may be in the form of a lozenge or a filled solid, semi-solid, powder, sustained release formulation or a liquid such as a suspension, an emulsion or a filled capsule for oral administration in the rectum or vagina 130152.doc-38 - 200942245 The use of suppository in the form of music. A typical preparation will contain from about 5% to about (iv) active compound (W/W). The term "formulation,", or "dosage form" is intended to include both solids of the active person and (iv) formulations and those skilled in the art will appreciate that the active filaments may be present in different formulations depending on the desired dosage and pharmacokinetic parameters. ❹ ❹ The term "excipient" as used herein refers to a compound that is used to prepare a pharmaceutical composition and is generally safe and non-toxic and neither biologically nor otherwise undesirable, and includes veterinary use as well as human pharmaceutical materials. All acceptable excipients. The compounds of the invention may be administered alone, but are usually administered in admixture with one or more suitable pharmaceutical agents, diluents or carriers selected in accordance with the intended pharmaceutical practice. The "pharmaceutically acceptable salt" form of the active ingredient may also initially impart the desired pharmacokinetics of the active ingredient in the non-salt form, and may even actively modulate the active ingredient with respect to it. Pharmacodynamics of therapeutic activity in vivo. As used herein, the phrase "pharmaceutically acceptable salt" means pharmaceutically acceptable and has the desired parental combination. Pharmacologically active salt. The continuation salt includes: (1) an acid addition salt formed with an inorganic acid such as hydrochloric acid, hydrogen desert acid, sulfuric acid, nitric acid, or acid: an acid similar to an acid; or with, for example, glycolic acid, pyruvic acid, Lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-benzopyridinyl)benzoic acid, meat diacid, mandelic acid, methylsulfonate Acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, acetyl acid, benzoic acid, 4_gas benzene, 2_naphthoic acid, 4_toluene acid, camphor acid, lauryl sulfate An acid addition salt formed from an organic acid of gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like. It is understood that all pharmaceutically acceptable salts include the same acid addition salts as defined herein. Solubility 130152.doc -39· 200942245 Additive form (solvate) or crystalline form (polymorph)^ 固体 Solid form preparations include powders, lozenges, pills, knee capsules, suppositories and knives. Solids The carrier may be one or more, and may also be used as a diluent, a flavoring agent, a solubilizer, a lubricant, a suspending agent, a binder, and a preservative. A substance of a tablet disintegrating or encapsulating material. In the form of a powder, the carrier is usually a finely divided solid which forms a mixture with the finely divided active ingredient. In the tablet form, the Z component is usually suitable The ratio of the carrier with the necessary bonding ability is blended into the desired shape and size. Suitable carriers include, but are not limited to, magnesium analate, stearic acid, talc powder, sugar, lactose, fruit knee, paste Fine, starch, gelatin, scutellaria, methyl cellulose, sodium carboxymethyl cellulose, low melting point 2, fat and its analogues. Solid form preparations can also be colored in addition to the active ingredients. Agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like. Also suitable for oral liquid formulations include emulsions, syrups, elixirs and aqueous suspensions. Liquid formulation. This includes solid form preparations which are intended to be converted into liquid form preparations just prior to use. The emulsion can be prepared, for example, in the aqueous solution of aqueous propylene glycol 4 liquid or can contain, for example, lecithin, sorbitol oleate or arabic, and the liquid can be floated. The fine powdery active ingredient is dispersed in water by using a viscous substance such as a day = a = knee, a resin, a methyl cellulose, a slow methyl fiber, and a well-known suspension agent: =: The suppository is administered in the form of a suppository. First, the low melting point (4) of a mixture such as fatty acid glycerin or cocoa butter is used to disperse the active components by (iv). The melted homogeneous phase 130152.doc 200942245 is then poured into a convenient size mold which is allowed to cool and solidify. The compounds of the invention may be formulated for vaginal administration. Carriers other than the active ingredient, such as uterus, hemostatic cotton balls, creams, gels, pastes, foams or sprays, are also suitable in the art. Suitable formulations, along with pharmaceutical carriers, diluents and excipients, are described in the following text: Remington: The Science and Practice of 1995, edited by E. W. Martin, Mack Publishing

Company, 19th edition, Pennsylvania. Skilled deployment of scientists can

Modifications of the formulations in the teachings of the present specification provide a variety of formulations for the particular route of administration without destabilizing or compromising the therapeutic activity of the compositions of the present invention. Modification of the compounds of the invention renders them more soluble in water or other vehicles which can be readily achieved by, for example, minor changes (e.g., salt formulations) which are well within the ordinary skill. It is also within the ordinary skill to alter the route of administration and dosing regimen of a particular compound in order to control the pharmacokinetics of the compounds of the invention to maximize benefit to the patient. The term "therapeutically effective amount" as used herein means the amount required to reduce the symptoms of a disease in an individual. The dosage may be adjusted according to individual needs in each particular case. The dose may be determined, for example, the severity of the disease to be treated, the age of the patient, the general health condition, other agents used in the treatment of the patient, the route of administration, and 4 and the medical practitioner involved. There are many factors of preference and experience that vary over a wide range. For oral administration, between about 40 and (4) g per day should be appropriate in monotherapy and/or combination therapy. Preferably, the dosage is between 5 and about 7.5 g of the mother rail, preferably between (1) and about 130152.doc -41 - 200942245. In general, treatment begins with a large onset, and the impact dose begins to rapidly reduce or eliminate the virus, and then reduces the dose to a level sufficient to prevent recurrence of the infection. For a given disease and patient, the general practitioner of the treatment of the diseases described herein will be able to determine the therapeutically effective amount of the compound of the invention, without undue experimentation, relying on personal knowledge, experience and disclosure of the present application. Therapeutic efficacy can be determined from liver function tests including, but not limited to, serum proteins such as albumin, coagulation factors, alkaline phosphatase, amines

Protein content of basal transferase (eg, alanine transaminase, aspartate transaminase, 5·_ nucleosidase, γ-glutamate thiol transpeptidase, etc.), synthetic cholesterol of bilirubin Synthesis and synthesis of bile acids; liver metabolic functions include, but are not limited to, carbohydrate metabolism, amino acids, and ammonia metabolism. Or the therapeutic effect can be monitored by measuring HCV_RNA. The results of these tests allow the dosage to be optimized. In the examples of the present month, the active compound or salt may be combined with another antiviral agent such as ribamycin, another nucleoside Hcv polymerase inhibitor, an HCV non-nuclear budase polymerase inhibitor, an HCV protease inhibitor, (10) A combination of a helicase inhibitor or an HCV fusion inhibitor. When the active compound or a derivative or salt thereof is administered in combination with another antiviral agent, the activity may increase beyond the parent: when the treatment is a combination therapy, the administration may be carried out simultaneously or continuously with respect to the nucleoside derivative. Therefore, as in this article at the same time or at different times, it is included in the four doses. Two doses are administered at the same time: the tincture can be prepared by containing two or more active ingredients. Formulations can be achieved by administering a dosage form of the two active agents substantially simultaneously. Having an early 130152.doc • 42· 200942245 It should be understood that the treatments referred to herein extend to the prevention and treatment of existing conditions. Further, as used herein The term "HCV-infected, therapeutic" also includes the treatment or prevention of a disease or condition associated with HCV infection or mediated by HCV infection or its clinical symptoms. Example 1 Step 1 - 18a (2.17 g, 8.96 mmol, 1 Equivalent), imidazole (732 mg, 10.7 mmo, 1.2 equivalents) and a solution of ph3P (2.82 g, 1〇7 mm〇h L2 eq.) in anhydrous THF (30 mL) were cooled on ice water bath over 10 min A solution of angstrom (2.50 g, 9.85 mmol, 1.1 eq.) in anhydrous THF (10 mL) was evaporated. The mixture was stirred for 1 hr. 〇h. Dilute the reaction mixture with DCM (200 mL) The aqueous layer was washed with a solution of EtOAc (aq. EtOAc) (EtOAc). The residue was purified by EtOAc/EtOAc (EtOAc) elut elut elut elut elut elut elut eluting eluting (br s,1H), 7.59 (d,1H), 6.19 (d, 1H) ' 5.75 (dd,1H), 3.79 (m, 1H), 3.65 (m,1Η), 3.57 (dd, 1H) ' 3.47 (dd, 1H), 2_69 (m, 1H), 2.13 (d, 1H), 1.00 (d, 3H). Step 2 - 18b (1.84 g ' 5.22 mmol) and 0.4 M sodium methoxide

The solution in MeOH (81 mL) was stirred at 6 <RTI ID=0.0>(</RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; And prepared by washing with Me〇H before use) 130152.doc •43· 200942245 until the pH of the solution is neutral (5-6 g total). The ice water bath was removed and the mixture was stirred at RT for 5 minutes. Residues were washed with MeOH (100 mL). EtOAc (EtOAc) * (80%) 19, pure enough for use in the next step: Step 3 - Gasification of benzyltriethylammonium (1.91 g, 8.4 mmol, 2 eq.) and gassing sodium (546 mg, 8.4 mmol) , 2 equivalents), suspended in anhydrous MeCN (32 mL) and sonicated for a few minutes. The resulting fine suspension was stirred at RT for 3 h, and then filtered under N2 to compound 19 (942 mg, 4.2 mmol, 1 equivalent) in anhydrous THF solution (30 mL). NMM (140 μM, 0.106 mmol, 0.3 eq.) was added and the solution was cooled on ice water bath and added dropwise over 1 h (1.8 1 g, 7.14 mmo 1,1.7 eq.) in anhydrous THF (39 mL). The obtained mixture was stirred for 2 h at 0-5 ° C. iV-ethyl- s-l-cysteamine was added. Acid (69 mg, 0.035 mmol, 0.1 eq.) and mix the solution until the bubbles subsided. Add NMM (2.3 1 m b 21.0 mmo b 5 eq.) and DMAP (513 mg, 4.2 mmol, 1 eq.), then add benzene dropwise Formazan chloride (1.1 mL, 9.24 mmol, 2.2 eq.). The reaction mixture was stirred at 0-5 ° C for 30 min then then stored in a refrigerator overnight. TLC and LC-MS analysis showed the reaction was complete. 5 mL) and after a few minutes the solvent was concentrated on a rotary evaporator to a &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& 150 ml) The mixture was extracted and the aqueous layer was extracted twice with DCM (50 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated. </ RTI> 130152.doc -44 - 200942245 extracted with 5% citric acid The organic phase was washed twice with EtOAc (EtOAc)EtOAc. The residue was taken up in a step-wise EtOH / DCM gradient (eluent, 0.5, 0.75, 1.0, 1.5, and 2.0% EtOH) and purified by EtOAc to yield 1.72 g (83%) 20a: h-NMR data (CDC13, 25. 〇: δ 8.22-7.46 (7Η) ' 6.49-6.39 (1Η), 5.84 (dd, 1Η), 5.55-5.47 (1Η), 3.85 (d,1H) ' 3.74 (d,1H), 3.18 (m , 1H), 1.09 (d, 3H). Step 4 - a solution of compound 20a (1.72 g, 3.47 mmol, 1 eq.) in DCM (155 mL) with EtOAc (EtOAc, EtOAc, And a mixture of m-chlorobenzoic acid (359 mg, 2.29 mmol, 0.66 eq.) in 1.75 M K2HP 〇4 aqueous solution (55 mL). The two-phase system was vigorously stirred at RT and two portions were added at 1.5 h intervals. 55% MCPBA, 10% methane acid and 35% Η20 (2χ3·57 g, equivalent to 2x16.5 mmol or 2x3.28 equivalent MCPBA and 2x3.3 mmol or 2x0.66 equivalent m-benzoic acid) The reagent mixture was sold. The mixture was stirred vigorously for a further 18 h at RT. LC-MS analysis showed &gt;96% of the reaction. A solution of Na2S20.sup. Play After stirring for 30 minutes, the organic layer was separated and washed with EtOAc EtOAc (EtOAc m. Na2S04), filtered and concentrated. The residue was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc 〇: δ 8.19 (br s, 1H), 8.07-7.88 (4H), 7.65-7.36 (6H), 6·57-6·45 130152.doc -45- 200942245 (1H), 5.64 (dd, 1H) , 5.51-5.42 (1H), 4.80 (m, 2H), 3.24 (m, 1H), 1.09 (d, 3H). Step 5 - a vinegar 20b (100 mg, 0.19 mm 〇i, i equivalent) and i, 2, 4_

Triazole (131 mg, i.9 mm 〇 1,1 〇 equivalent) was co-evaporated from anhydrous pyridine and redissolved in anhydrous pyridine mL). The solution was cooled in an ice water bath and a solution of &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred for another 5 minutes under 0-5t: and then stirred at RT for 3 h. The reaction mixture was concentrated to a half volume on a rotary evaporator then applied to sat. NH3 &lt;&quot;&gt;&gt; The residue was taken up in a stepwise EtOH/DCM gradient (6, 10, 15 and 20% v/v EtOH) and purified by SiO 2 chromatography to afford 0.036 g (66%) of 22, which was determined by LCMS. Purine purity (about 2.0% of the impurities are 2'-alpha isomers). This reaction was repeated with 900 mg of compound 20b. After chromatography, 270 mg (54 ° /., 97% purity) of 22 was obtained: 11-NMR (DMSO-d6, 25. 〇: δ 7.69 (d, 1H), 7.14 (d,2H), 6.32 (br s,1H), 5.72 (d,1H), 5.78 (br s, 2H), 3.89 (br s, 1H), 3.74 (d,d,d,2H) ' 2.54 ( m, 1H), 0.77 (d, 3H). Example 2 Isobutyric acid (211,35,48,511)-5-(4-amino-2-oxo-2,dan-pyrimidin-1-yl)-2 -isobutyl decyloxymethyl-4-mercapto-tetrahydro-furan-3-ester (25)

130152.doc -46· 200942245

The pH of the solution of 22 (0.700 §, 2.48 111111〇1) in 1'1^(7 111[) and dilute brine (7 111 [) was adjusted to about 11 with a dilute aqueous KOH solution. Slowly (dropwise) Isobutyl hydrazine (1.0 g) was added to the ice-cold stirred biphasic reaction mixture while maintaining the pH at about 11 by adding a dilute aqueous KOH solution if necessary. The extent of the reaction was monitored by HPLC. The addition of an additional 1 equivalent of isobutylphosphonium chloride under HPLC indicates near complete conversion. The reaction mixture was allowed to stand at RT overnight. The solution was diluted with EtOAc (50 mL) and the pH of aqueous was adjusted to approximately 7.5 with concentrated HCl. The phases were separated and the organic phase was washed 3 times with water and evaporated to dryness to afford 25. Example 3 Valeric acid (2R,3S,4S,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-4-hydroxy-2-hydroxyl Methyl-tetrahydro-furan-3-ester (27)

27 bismuth citrate 26 (R&quot;=«-C4H9, 1.9 g, 3.46 mmol) in MTBE (13 mL) and phosphate buffer (15 mL, adjusted to pH 6.5 of 5 mM sodium phosphate and 0.1 M NaCl (about 2 mL) of Lipolase® (lipase from thermophilic fungi, Sigma catalog number L 0777) was added to the suspension. The reaction mixture was warmed to 35 ° C and stirred for 2 h, and the pH of the reaction mixture was maintained at 6.5 by the addition of NaHC03. After 2 h, the reaction was carried out until completion of 8%. Add an additional 2 mL of Lipolase® and continue to scramble for 6 h, add an additional 2 mL of this aliquot of the enzyme after 130152.doc -47-200942245 and stir the reaction for an additional 24 h. To the solution were added acetone (10 mL), MTBE (20 mL) and brine (10 mL) and the reaction warmed to 50 °C. The phases were separated and the organic phase was extracted twice with warm MTBE. The combined organic phases were washed twice with hot brine and dried (Na2EtOAc) Example 4 Tetradecanic acid (211, 38, 48, 511)-5-(4-amino-2-yloxy-21--pyrimidin-1-yl)-2-azido-3-butanyloxy -4-methyl-four wind-0 husband c south-2-yl vinegar (28)

29 (1.0 g, 3.52 mmol), tetraethyl sulphate S (1.2 g, 4.57 mmol), Candida antarctica lipase G (0.30 g; from Novosome, Sigma catalog number) immobilized on polyacrylate resin The suspension of L4777) and THF (20 mL) was warmed to 60 ° C overnight. HPLC analysis indicated that the reaction was about 33% complete and an additional 2.4 mL of vinyltetradecanoate and 0.3 g of lipase were added. After -· another 48 h, the reaction was completed 50% and an additional 0.3 g of enzyme and 3 mL of vinyl vinate was added. After about 80 h (total reaction time), the conversion to the single S is complete. The crude reaction mixture was filtered through CELITE® and the filter pad was washed with THF. The combined organic phases were evaporated. The residue was dissolved in MeOH (50 mL)EtOAc. The methanol solution was evaporated and the residue was dissolved in 130152.doc -48- 200942245

The mixture was washed with EtOAc EtOAc (EtOAc) (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Chromatography to purify. Example 5 3',5·-0-bis(L-proline)-4'-azido-2,-,C-mercapto-2'-deoxygenated nucleoside (34)

Indole-[(didecylamino)methylene]-4,-azido-2,-; 0-C-methyl·2'-deoxycytidine (32).

A solution of 22 (1.81 g, 6.42 mmol) in DMF (30 ml) was taken from EtOAc (EtOAc) The solution was evaporated under reduced pressure and co-evaporated with ethanol. Crystallization from ethanol/diethyl ether gave the title compound 32 ° 3',5|-〇-bis[#-(t-butoxycarbonyl)-[-valine-amino]-'-[(didecylamino) Mercapto]-4,-azido-21-C-methyl-2,-deoxycytidine nucleoside (33). Boc-Vai-OHU.62 g, 7.48 130152.doc -49- 200942245 mmol) was continuously added to a solution of 32 (1.26 g, 3.74 mmol) in a mixture of anhydrous acetonitrile (30 ml) and DMF (15 ml). EDC (1.43 g, 7.48 mmol), hydrazine (1.04 ml, 7.48 mmol) and DMAP (0.1 g). The resulting mixture was stirred at room temperature. The progress of the reaction was followed by HPLC and the reaction mixture was further fed with 8 〇〇 &amp; 1-OH (0.63 g), EDC (0.72 g), hydrazine (0. 52 ml) and DMAP (0.05 g). After the starting material was completely consumed, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. Purification by oxime column chromatography (5-40% EtOAcEtOAcEtOAc) elute Base-2'-yS-C-methyl-2'-deoxycytidine nucleoside (trihydrochloride, 34). A solution of 13 ml of 1 M HCl in EtOH was slowly added to a concentrated solution of 33 (1.6 g, 2.17 mmol) in EtOH. The reaction mixture was stirred at room temperature for 4 h and diluted with diethyl ether. The precipitate was filtered and washed with ether to give the title compound 34 in the form of tris. Example 6 Another method for the preparation of 3',5'-0-bis(isobutiryl)-4'-azidodecyl-2·-deoxycytidine nucleoside. (Isobutyric acid (2R,3S,4S,5R)-2-(4-amino-2-oxo-2//-pyrimidin-1-yl)-2-isobutylcarbonyloxycarbonyl- 4_mercapto-tetrazine s-ofran-3-S) (25).

130152.doc -50- 200942245 3',5|-0-bis(isobutylguanidino)_4,_azido- 2 k-methyl-2,-de-cytosine nucleoside (25). Isobutyric anhydride (1.77 g, u.2 mm 〇 1) was added to a solution of 22 (1.26 g, 3.74 mmol) in anhydrous n-pyridine (25 ml). The reaction was followed by HpLc and the reaction was quenched with water when complete to discard excess isobutyric anhydride and remove ^-protection. The solvent was evaporated under reduced pressure and co-evaporated with ethanol. The residue was dissolved in ethyl acetate and washed with NaHC.sub.3, brine. Purification by gel column chromatography (gradient 10-40% EtOAc in hexanes) Example 7 4'-Laminated-3'-indole-(l-prolinyl)-2'-,C-mercapto-2·-deoxycytosine nucleoside (37)

Bis(monomethoxytrityl hydrazine 1-azido-2,-,C-fluorenyl-deoxycytosine nuclear (35). 130152.doc -51 · 200942245 22 at 80 ° C 2.82 g, 10 mmol) and MMTrCl (9.15 g, 30 mmol) were mixed overnight at a ratio of 17 (50 ml). After adding MeOH (5 ml) and stirring for 2 h, the solvent was evaporated. The residue was partitioned between EtOAc EtOAc (EtOAc m. , 5'-0-bis(monomethoxytriphenylmethyl)-4·-azido-3'-[7V-(t-butoxycarbonyl)-L-prolinyl]mercapto- 2'-deoxycytidine nucleoside (36). To a solution of 35 (3.09 g, 3.74 mmol) in a mixture of anhydrous acetonitrile (30 ml) and DMF (15 ml), Boc-Val-OH (0.8) 1 g, 3.74 mmol), EDC (0.72 g, 3.74 mmol), hydrazine (0.52 ml, 3.74 mmol) and DMAP (0.07 g). The mixture was stirred at room temperature. The progress of the reaction was followed by HPLC and in the reaction mixture. Re-feed 6〇〇¥&amp;1-OH (0.4 g), EDC (0.36 g), TEA (0.26 ml) and DMAP (0.04 g) When the starting material is completely consumed, the solvent is removed under reduced pressure. The residue is taken in ethyl acetate and washed with water and brine. Purified in EtOAc) to give the title compound 36. 41 - ablate - 3'-(9-(L- sylamino)-21-C-methyl-2'-de-nosed bite Hydrochloric acid, 37). To a solution of 36 (2.4 g, 2.34 mmol) in EtOAc EtOAc. The precipitate was filtered and washed with diethyl ether to give the title compound (37) as the dihydrochloride salt. Example 8 130152.doc -52 - 200942245 4'-azido-3'-(9-isobutylmethyl-2'-^-C -Methyl-2'-deoxycytidine nucleoside (38).

Q V-azido-3'-0-isobutylindol-2'-G-C-methyl-2'-deoxycytidine nucleoside (38) at 35 °C (3.09 g, 3.74 mmol) Isobutyric anhydride (0.89 g, 5.61 mmol) was added to a solution of anhydrous pyridine (25 ml). The reaction was traced by HPLC and when completed, the reaction was quenched with water to discard excess isobutyric anhydride. The solvent was evaporated under reduced pressure and co-evaporated with ethanol. The residue was dissolved in ethyl acetate, washed with NaHC03, brine and evaporated. The crude MMTr protected 3'-isobutyl decyl derivative was dissolved in 80% AcOH at 50 ° C and stirred until 〇 completely removed the protection of the MMTr group. The solvent was evaporated and the residue was purified eluting elut elut elut elut elut elut elut 'Example 9;. 5'-0-(L-proline)-4'-azidomethyl-2'-deoxycytosine nucleoside (43) 130152.doc -53- 200942245

43 5^0-t-butyldimethylmethylalkyl-4'-azido-2'-, C-methyl-2'-deoxycytidine nucleoside (39). To a solution of 22 (2.82 g, 10 mmol) in DMF (5 mL), EtOAc (l. The reaction mixture was quenched with MeOH (1 mL) and partitioned between ethyl acetate and water. The organic phase was washed with water and brine and evaporated. The residue was purified by EtOAc EtOAc EtOAc elutcd 5'-0-Terbutyl dimethyl decyl-4'-azido-7V4,3'-0-bis(monomethoxytriphenyl)-2'-, C-fluorenyl- 2^Deoxycytidine nucleoside (40). 39 (3.7 g, 9.34 mmol) and MMTrCl (8.63 g, 28 mmol) were dried at 80 °C. The mixture in the lake (50 ml) was scrambled overnight. Add 130152.doc -54- 200942245

After MeOH (5 ml) and EtOAc (EtOAc)EtOAc. The organic phase was washed with water, brine and evaporated. Purification of the title compound 40 by hydrazine column chromatography (0-5% MeOH in DCM). • 4'-azido-iV4,3'-&lt;9-bis(monomethoxytriphenyl)-2-, C-methyl-2-deoxycytidine sigma nucleoside (41 ). A solution of 40 (5.3 g, 5.64 mmol) in THF (20 mL) was obtained from EtOAc EtOAc. The reaction mixture was diluted with ethyl acetate, washed with water and brine and evaporated. Chromatography (0-5% ethyl acetate in CH.sub.3) afforded the title compound 41 〇5i-[7V-(t-butoxycarbonyl)-L-proline acid group]-iV4,3,-0- Bis(monomethoxytrityl)-4'-azido-21-C-mercapto-2'-deoxycytidine nucleoside (42) 〇41 (3.09 g, 3.74 mmol) in anhydrous Boc-Val-OH (0.81 g, 3.74 mmol), EDC (0.72 g, 3.74 mmol), hydrazine (0.52 ml, 3.74 mmol) was continuously added to a solution of a mixture of acetonitrile (30 ml) and DMF (15 ml). And DMAP (0.07 g). The resulting mixture was stirred at room temperature. The progress of the reaction was followed by HPLC, and Boc-Val-OH (0.4 g), EDC (0.36 g), hydrazine (0.26 ml) and DMAP (0.04 g) were further fed into the reaction mixture. ' When the starting material is completely consumed, remove the solvent under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. Purification by column chromatography (5-40% EtOAcEtOAcEtOAc) 5'-0-(L-proline)-4'-azido-2'-homo-C-mercapto-2'-deoxycytosine 130152.doc -55- 200942245 nucleoside (di-salt Acid salt, 43). A solution of 13 ml of 1 M HCl in EtOH was slowly added to a concentrated solution of 42 (2.4 g, 2.34 mmol) in EtOH. The reaction mixture was stirred at room temperature for 4 h and diluted with diethyl ether. The precipitate was filtered and washed with diethyl ether to give the title compound 43. Example 10 5'-Ο-Isobutyl-based-41-azidomethyl-2'-de-emulsion. Denucleoside (44)

5'-0-Isobutylguanidino-4'-azido-2'-A-C-methyl-2'-deoxycytidine nucleoside (44). To a solution of 41 (3.09 g, 3.74 mmol) in anhydrous pyridine (25 ml) was added isobutyric anhydride (0.89 g, 5.61 mmol) at EtOAc. The reaction was followed by HPLC and the reaction was quenched with water when complete to discard excess isobutyric anhydride. The solvent was evaporated under reduced pressure and co-evaporated with ethanol. The residue was dissolved in ethyl acetate (t. &quot; ester, washed with NaHC03, brine and evaporated. The crude MMTr protected 3'-isobutyl decyl derivative was dissolved in 80% AcOH at 50 ° C and stirred until the protection of the MMTr group was completely removed. The solvent was evaporated and the residue was purified EtOAcjjjjjjjj 130152.doc -56- 200942245 Example 11 Renilla luciferin assay This assay quantifies the ability of a compound of formula I to inhibit HCV RNA replication and its potential for treating HCV infection. This assay uses the reporter - (reporter) as a simple reader for the intracellular HCV replicon RNA content. - Introduction of the Renilla luciferase gene into the first open reading frame of the replicon construct NK5.1 immediately after the internal ribosome entry site (IRES) sequence (Krieger et al., J. Wro/. 75:46M) And fusion with the self-cleaving peptide 2A from the foot-and-mouth disease virus and the neomycin phosphotransferase (NPTII) gene (Ryan &amp;

Drew, EMBO Vol 13:928-93 3). After in vitro transcription, RNA was electroporated into human liver tumor Huh7 cells and the anti-G41 8 population was isolated and expanded. The stably selected cell line 2209-23 contains a replicative HCV subgenomic RNA, and the activity of Renilla luciferase expressed by the replicon in the cell reflects its RNA content. The assay is performed in a double plate, one being opaque white and the other being transparent to measure the antiviral activity and cytotoxicity of the compound while ensuring that the observed activity is not due to reduced cell proliferation. Sea luciferase HCV replicon cells (2209-23) cultured in Dulbecco's MEM (GibcoBRL Cat # 31966-021) with 5% fetal bovine serum (FCS, Gibco BRL Cat. No. 10106-169) per well 5000 cells were plated on 96-well plates and incubated overnight. After 24 hours, different dilutions of the compounds in the growth medium were added to the cells, which were then incubated for an additional three days at 37 °C. At the end of the incubation period, cells in the white plate were collected and assayed for luciferase activity by using the dual luciferase reporter assay system (Promega Cat. No. 130152.doc - 57 - 200942245 E1960). All reagents described in the following paragraphs are included in the manufacturer's kit and are accompanied by the manufacturer's instructions for the preparation of such reagents. The cells were washed with 200 μM phosphate buffered saline (pH 7.0) (PBS) in each well and incubated for 2 min at room temperature after lysing the cells with 25 μl of 1 χ passive lysis buffer. Add 1 μl of microliter LAR π reagent to each well. The plates were then inserted into a LB 96V micro-quantitative plate luminometer (MicroLumatP1us ' Berthold) and 100 μΐ Stop &amp; Glo® reagent was injected into each well and the signal was measured using a 2 second delay, 1 sec measurement procedure. ICw is the concentration of drug required to reduce the replicon content of 50% associated with untreated cell control values, as calculated from the percent reduction in luciferase activity versus drug concentration. The WST-1 reagent from Roche Diagnostic (catalog number 1644807) was used for cytotoxicity assays. A microliter of WST-1 reagent was added to each well, including wells containing only medium as a blank. The cells were then incubated at 37t: for 1 to 1.5 hours&apos; and the 〇D value was measured by a 96-well plate reader at 450 nm (reference ferrite at 650 nm). Furthermore, CCm is a drug concentration required to reduce cell proliferation by 50% associated with untreated cell control values, which can be calculated from a percentage of the decrease in WST-1 value versus drug concentration. Example 12 MT4/XTT Assay The activity of the compounds of the invention against concurrent infection can also be assayed. For example, individuals at risk of blood-borne infections such as HCV are sometimes infected with HIV. For example, a variety of assays using sputum in ΜΤ-4 cells are used to characterize the HIV activity of a compound (Weislow et al, J Nat Cancer Inst 1989, pp. 8 1 130152.doc -58 - 200942245, Vol. 8, 577, et al. Etc.) preferably comprises an assay in the presence of 40-50% human serum to account for the effect of protein binding. Briefly, a typical XTT assay uses human T cell line MT4 cells grown in RPMI 1640 medium supplemented with 10% fetal bovine serum (or 40-50% human-like serum if appropriate), penicillin and streptavidin , cells were seeded in 96-well microplates (2.104 cells/well), each well infected with 10-20 TCID50 of HIV-1丨IIB (wild type) or such as with RT lie 100, Cys 181 or Asn 103 Mutant mutant virus. Serially diluted test compounds were added to individual wells and the cultures were incubated at 37 °C in a CO2-rich atmosphere and the viability of the cells was determined on day 5 or 6 with XTT live dye. Usually the result is expressed as ED50 μΜ. The compound of Example 1 exhibited an ED50 of about 0.6 μΜ in the XTT assay. EXAMPLE 13 Intracellular Triphosphate Concentration and Half-Life Estimated The active substance of the compound of the present invention is β-ϋ-2'-deoxy-2'-PC-methyl-4'-azidocytosine triphosphate . Fresh human primary hepatocytes pre-incubated with deuterated parent compound (CellzDirect or In Vitro ❹

The stability of the triphosphate was determined in Technologies). Hepatocytes were typically cultured at 1.5 million cells/well on 6-well collagen coated plates (BD Biosciences) using serum-containing medium (CellzDirect or In Vitro Technologies) / 37 °C / 5% CO 2 . Various hepatocyte cell lines such as Hu497, MHL-091806 and Hu504 can be used, and are therefore suitable for testing these cell lines simultaneously and calculating the average value from a range of cell lines. It is usually pre-incubated with 2 μΜ 10 g C/ml of the deuterated precursor for 24 hours. At t〇, the cell monolayer was washed with cell culture medium to remove the extracellular matrix compound 130152.doc -59- 200942245, and the cell culture was re-incubated with fresh cell culture medium. The intracellular triphosphate concentration was quantified at different time points (up to 72 hours). Convenient time points are 0, 0_5, 1, 2, 4, 6, 8, 24, 48, and 72 hours, with duplicate cell cultures at each time point. At appropriate time, cells are harvested by pumping the cell culture medium and The cells were washed with cold PBS. The cells were scraped into an extraction medium, such as 预w pre-cooled 60% (Wv) methanol, and extracted into methanol at _2 (rc) for 24 h. The extracted sample was centrifuged to remove cell debris. The supernatant was removed. Transfer to fresh tube, evaporate and store in liquid nitrogen for analysis. Dry cell pellet extract / combined in water and passed through a nanometer (eg nan〇Sep centrifuge, ρα Life Sciences). Prior to analysis, the sample is spiked with the parent and its unlabeled reference standards in the form of monophosphates, di-salts, and triphosphates. Typical HPLC systems use a radiometric detector (such as beta-RAM) , IN/US Systems lnc) Ion exchange hplC of Whatman partisil 10SAX (4.6x250 mm) column coupled. The known mobile phase linear gradient is: 0% aqueous buffer to a flow rate such as 1ml/min to 1〇〇 % Potassiumate buffer (eg 0.5M ΚΗ2Ρ〇4/〇·8Μ KC1). For the detection of radiolabeled substances in β-RAM, a 5:1 ratio of n〇Scint IV or UltimaFloAP (Perkin Elmer) can be used. ) with the column leaching agent. By comparing the lag of intracellular substances in the radioactive chromatogram The retention time and retention time of the non-radioactive reference standard in the cell extraction sample are used to identify maternal and intracellular metabolites and are detected by UV absorption, usually at 27 〇 nm. Measurement of uptake and scalification in a similar manner The time course is used to culture human primary cells 130152.doc -60· 200942245 hepatocytes with, for example, 2 μΜ and 10 μ(Μ/ηι1 of the present invention. The appropriate time course is added before cell collection. In the aliquot culture of the compound at 72, 48 'Μ, 16, 6 and 丨 hours. For the determination of the dose response of the phosphorylation of the compound of the invention, for example, in 〇, 2, 10, 25, 50, 100 and 25 〇μΜτ of the sputum test compound were incubated in human 'suppressed liver 7 cells for 24 hours. By supplementing the non-radiolabeled test compound to: final concentration of force. Usually double cell cultures were collected after 24 hours of incubation. The average triphosphate half-life of the compounds of the invention in these assays was 21.4 hours (standard deviation 4.22 hours). The steady-state tri- 4 vinegar content was about 15 ρ Μ / million cells at 2 _ for 24 hours. 3 μΐ was used as Humanity The average volume of parenchymal cells, the concentration of three-disc vinegar is equivalent to a value substantially exceeding the Ki of the parent compound. The long half-life and high concentration of the triphosphate indicate that the antiviral activity of the active substance will be present in the HCV-infected cell towel. After a long time, the minimum daily minimum content will remain high, even when QD is administered, thereby minimizing the chance of suboptimal exposure to the drug, leading to the development of drug escape mutation. &amp; Similar to the long half-life of the diceramide of the present invention, similar to methylation: PSI 6130 (pD-2'-deoxy-2,-fluoromethyl cytosine nucleoside, one of the phospho-S 曰 half-lives ( The following is only 4 hours, and the steady-state triphosphate concentration is only UpM/million cells at 24 hours.

PSI-6130 130152.doc -61 - 200942245 Example 14 A pharmaceutical composition of a compound of the invention administered via several routes was prepared as described in the Examples. Composition for oral administration (A) Ingredient % wt./wt. Active ingredient 20.0% ~ Lactose 79.5% Magnesium stearate 0.5% ❹ Mix and distribute the ingredients in capsules each containing about 500 to 1000 mg. Oral composition (B) Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate 0.5% Cross-linked carboxymethyl cellulose sodium 2.0% Lactose 76.5% P VP (polyethyl hydrazine ° ratio 11 ketones) 1.0% ® combines ingredients and uses a solvent such as sterol to granulate. The formulation is then dried and formed into a tablet (containing about 20 mg of active compound) using a suitable tablet machine. Composition for oral administration (C) Ingredient % wt./wt. Active compound lo g Fumaric acid 0.5 g Gasified sodium 2.0 g P-hydroxybenzoic acid decyl ester 0.15 g Propyl hydroxybenzoate 0.05 g 130152 .doc -62- 200942245 Sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring agent 0.035 ml Coloring agent 0.5 mg Distilled water up to 100 ml These ingredients are mixed to form Oral suspension. Parenteral formulation (D) Ingredients % wt./wt. Active ingredient 0.25 g Sodium chloride Appropriate amount to make it isotonic Water for injection 100 ml

The active ingredient is dissolved in one part of the water for injection. A sufficient amount of sodium vapor is then added while stirring to make the solution isotonic. The solution was prepared and weighed together with the rest of the water for injection, filtered through a 0.2 micron filter membrane and packaged under sterile conditions. Suppository Formulation (E) Ingredient % wt./wt. Active Ingredient 1.0% Polyethylene Glycol 1000 74.5% Polyethylene Glycol 4000 24.5% The ingredients are melted together and mixed on a steam bath and poured into a total weight of 2.5 g. In the mold. The above invention has been described in detail by way of illustration and example embodiments Those skilled in the art will appreciate that variations and modifications can be made in the scope of the accompanying claims. Therefore, the above description is intended to be illustrative, and not restrictive. Therefore, the scope of the present invention should not be referred to the above description to confirm 130152.doc -63 - 200942245 'and should be accompanied by the authorized Shishi Quan Fan bee reference to the following two attached = the equivalent form of the patent scope Determined by the scope of the patent. For all purposes, all patents, patent claims, and publications cited in this application are incorporated herein by reference. Sexual quests are reported in the A% case or the public case.

❹ 130152.doc -64·

Claims (1)

200942245 X. Patent application scope: 1. A compound of formula I (D where: R1, R2 and R3 are independently selected from the group consisting of hydrogen, C〇R4, C(=〇)or4 and C(=0)CHRsNHR6; or R1 and ... are! ^ R is a monophosphate, diphosphate or triphosphate; R is independently selected from the group consisting of (a) Ci 18 non-branched or branched alkyl, haloalkyl, (〇3: 3-8 a cycloalkyl group, (d) a Ciioxaalkyl group, and (e) a phenyl group, wherein the phenyl group is optionally selected from one to three independently selected from the group consisting of a C3 alkyl group, a ci-3 alkoxy group, a halogen, a cyano group or a nitro group. Substituting a group; R is hydrogen, alkyl, phenyl or cN3 phenylalkyl, and the phenyl group is optionally substituted by one to three groups independently selected from the group consisting of halogen, hydroxy, Cw alkane An oxy group, a Cw alkyl group, a cyano group and a nitro group; r6 is hydrogen or a CN6 alkoxy group; or an acid addition salt thereof. 2. The compound of claim 1 wherein R1, R2 and R3 are each hydrogen. The compound of the present invention, wherein R1, R2 and R3 are each independently hydrogen, COR4 or C(=〇)〇R4. 4. The compound of claim 3, wherein r4 is a non-branched chain or a branched chain Cii. 130152.doc 200942245 5. 6. • 7. 8. 〇9. 10. 11. 12. ❹ For the compound of claim 1, wherein R1 is hydrogen and ... and therefore 3 is c〇R4. Compound or its medicine An acceptable salt, wherein R1 is hydrogen, R2 and R3 are COR4 and R4 is a non-branched or branched chain octadecyl. The compound of claim 1, wherein R1 and R3 are hydrogen and R2 is selected from COR4, c (=〇) group of 〇r4 and c〇ch(rS)nhr6. For example, the compound of claim 7 wherein R2 is COCH(R5)NHR6, and R5 is isopropyl, isobutyl or t-butyl and R6 is hydrogen. The compound of claim 8 wherein Rs has the stereochemistry of L-amino acid. For example, the compound of δ δ, wherein R2 is COR4. The compound of claim 10, wherein R4 is Cl_1G non- A branched or branched alkyl group. The compound of claim 1 is selected from the group consisting of: 3 '5 bis(isobutyl)- 4'-azido-decyl deoxycytosine nucleus, 3',5'-〇_bis(L_valeric acid)_4,_azido-2-κ_methyl·2,·deoxycytidine, 4'-azido-3i-0- (L-proline group)_2, _, C_methyl_2, _ deoxygenated cell nucleus, 4'-azido-3,-0-isobutyl decyl-methyl-2, deoxygenated Cytosine bud, 5'-〇·α-prolinyl)-4,-azido_2,-,C- Methyl-2,_deoxycytosine 130152.doc 200942245 pyridine nucleoside, 5·-0-isobutyl fluorenyl _4,-azido K-C1-methyl_2· nucleoside; or pharmaceutically acceptable Accepted salt 13. Use of the compound of claim 1 for the treatment of a disease mediated by the hepatitis C virus (HCV) virus or for the preparation of a hepatitis C virus (HCV) virus for treatment A medicinal agent that mediates disease. 14. The use of claim 13, wherein the compound is delivered at a dose between 1 and 100 mg per kg of patient body weight per day. 15. The use of claim 13, wherein the treatment or agent additionally comprises at least one immune system modulator and/or at least one antiviral agent that inhibits HcV replication. 16. The use of claim 15, wherein the immune system modulator is interferon, interleukin, tumor necrosis factor or community stimulating factor. Deoxycytosine 17. The material of claim 16, wherein the immune system modulator is interferon 化学 chemically derived interferon. The use of claim 15 wherein the treatment or agent additionally comprises at least one other antiviral agent. [19] The use of the item 18, wherein the antiviral compound is selected from the group consisting of HCV protease inhibitors, another nuclear bitter poly(ase inhibitor), non-nuclear (tetra)v polymerase inhibitor, Hcv helicase Formulations, HCV-priming enzyme inhibitors and Hcv fusion inhibitors. 2A. A pharmaceutical composition comprising a therapeutically effective amount of a chemical substance as claimed in claim i and at least one drug, a carrier, a diluent or a formulation of 130152.doc 200942245. A pharmaceutical composition of the lapse of 20 comprising 500-1 500 mg of a compressed tablet containing 35 to 75 Wt/° of a compound of claim 1 and the balance comprising y of a pharmaceutically acceptable carrier, Thinner or job form 22, as claimed in claim 21, which contains 5 〇〇·ΐ5 60 wt%, such as please ash into g 3, 40--the compression of the compound of the moon clothing item 1 The ingot is less pharmaceutically acceptable and the remainder contains an acceptable carrier, diluent or topical agent. 130152.doc 200942245 VII. Designation of representatives: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 0) 130152.doc