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(12) United States Patent (10) Patent No.: US 8,324,179 B2 Chen Et Al USOO8324179B2 (12) United States Patent (10) Patent No.: US 8,324,179 B2 Chen et al. (45) Date of Patent: Dec. 4, 2012 (54) NUCLEOSIDE ANALOGS FOR ANTIVIRAL WO WO-96,07666 A1 3/1996 TREATMENT WO WO-03/073989 A2 9, 2003 WO WO-2004/096286 A2 11/2004 WO WO-2006/015261 A2 2, 2006 (75) Inventors: James M. Chen, San Ramon, CA (US); Alan X. Huang, San Mateo, CA (US); OTHER PUBLICATIONS Richard L. Mackman, Millbrae, CA Lera et al. Organic Letters (2000), vol. 2, pp. 3873-3875.* (US); Jay Parrish, Redwood City, CA Abbas et al. (2000) “An Improved procedure for the synthesis of (US); Jason K. Perry, San Francisco, vinylphosphonate-linked nucleic acids.” Tetrahedron Letters AY 41:4513-4517. CA (US); Oliver L. Saunders, San Abbas et al. (2001) “Commercially Available 5'-DMT Mateo, CA (US); David Sperandio, Palo Phosphoramidites as Reagents for the Synthesis of Alto, CA (US) Vinylphosphonate-Linked Oligonucleic Acids.” Organic Letters 3(21):3365-3367. (73) Assignee: Gilead Sciences, Inc., Foster City, CA Abbas, S. etal (1999) “A Novel Palladium-Catalysed Coupling Strat (US) egy for the Rapid Synthesis of Nucleic Acid Analogues Bearing Modified Backbones.” Synlett 7:1124-1126. c Almer et al. (1991) “Synthesis of a Phosphonomethyl Analogue of (*) Notice: Subject to any disclaimer, the term of this 3'-Deoxy-3'-fluorothymidine.” Acta Cheinica Scandinavica 45:766 patent is extended or adjusted under 35 767. U.S.C. 154(b) by 486 days. Bertram et al. (2002) “Vinylphosphonate Internucleotide Linkages inhibit the Activity of Per A DNA Helicase.” Biochemistry 41:7725 7731. (21) Appl. No.: 12/524,545 Freeman et al. (1992) “3'-Azido-3',5'-dideoxythymidine-5'- 1-1. methylphosphonic Acid Disphosphate: Synthesis and HIV-1 Reverse (22) PCT Filed: Feb. 8, 2008 Transcriptase Inhibitors.” J. Med. Chem 35:3192-3196. Garvey et al. (1998) “Nucleotide and Nucleoside Analogues as (86). PCT No.: PCT/US2O08/OO1743 Inhibitors of Cytosolic 5'-Nucleotidase I from Heart.” Biochemistry 17:9043-9051. S371 (c)(1), Hai et al. (1982) "Species- or isozyme-Specific Enzyme Inhibitors. (2), (4) Date: Nov.30, 2009 7. Selective Effects in Inhibitions of Rat Adenylate Kinase isozymes by Adenosine 5'-Phosphate Derivatives.”.J. Med. Chem. 25:806-812. (87) PCT Pub. No.: WO2008/100447 Hampton et al. (1976) “Evidence for the Conformation About the PCT Pub. Date: Aug. 21, 2008 C(5') -O(5') Bond of AMP Complexed to AMP Kinase: Substrate l ale: Aug. All, Properties of a Vinyl Phosphonate Analog of AMP Bioorganic O O Chemistry 5:31-35. (65) Prior Publication Data International Preliminary Report on Patentability for PCT/US2008/ US 2010/O104532 A1 Apr. 29, 2010 00.1743, issued Aug. 11, 2009. International Search Report and Written Opinion for PCT/US2008/ Related U.S. Application Data 00.1743, mailed May 11, 2008. Jones (1968) “The Synthesis of 6'-Deoxyhomonucleoside-6'- (60) Provisional application No. 60/900,692, filed on Feb. phosphonic Acids,” Journal of the American Chemical Society 90:19 9, 2007. pp. 5337-5338. (51) Int. Cl. (Continued) AOIN 43/04 (2006.01) Primary Examiner — Patrick Lewis A6 IK3I/70 (2006.01) 74). Att Agent, or Fi Fitzpatrick, Cella. H & (52) U.S. Cl. .............. 514/43; 514/44 R: 514/45; 514/49 St. Orney, Agent, or Firm — F1LZpaur1cK, Uella, Harper (58) Field of Classification Search ........................ None See application file for complete search history. (57) ABSTRACT (56) References Cited The invention provides unsaturated phosphonates of Formula I or a tautomer orpharmaceutically acceptable salt thereof, as U.S. PATENT DOCUMENTS described herein, as well as pharmaceutical compositions 5,672,697 A * 9/1997 Buhr et al. ................... 536, 26.7 comprising the compounds, and therapeutic methods com 5,817,647 A 10, 1998 Casara et al. prising administering the compounds. The compounds have 5,892,024 A 4/1999 Chaturvedula et al. anti-viral properties and are useful for treating viral infections 3. A 38. E.aXe ea.s al (e.g. HCV) in animals (e.g. humans). 6,087,490 A 7/2000 Baxter et al. 2003, OOO4345 A1 1/2003 Casara et al. 2004/0023921 A1 2/2004 Hong et al. 5 O (I) 2004/00591.04 A1 3f2004 Cook et al. Ys- B 2006/0074035 A1 4/2006 Hong et al. / \ R1 R6 2 FOREIGN PATENT DOCUMENTS ww. R4 EP O479640 A2 4f1992 R3 R5 EP OS32 423 A1 3, 1993 EP O 618214 A1 10, 1994 EP O 629 633 A2 12, 1994 WO WO-94,22882 A1 10, 1994 22 Claims, No Drawings US 8,324,179 B2 Page 2 OTHER PUBLICATIONS Lera et al. (2001) "An Olefin Cross-Metathesis Approach to Vinylphophonate-Linked Nucleic Acids.” Organis Letters Jung et al. (2000) “Synthesis of Phosphonate Derivatives of Uridine, Cytidine, and Cytosine Arabinoside.” Bioorganic & Medicinal 3(17):2765-2768. Chemistry 8:2501-2509. Montgomery et al. (1979) “Phosphonate Analogue of 2'-Deoxy-5- Kappler et al. (1985) "Use of a Vinyl Phosphonate Analog of ATP as fluorouridylic Acid.” Journal of Medicinal Chemistry 22(1): 109-111. a Rotationally Constrained Probe of the C5'-O5' Torsion Angle in Szabo et al. (1995) “Synthesis and Some Conformational Features of ATP Complexed to Methionine Adenosyl Transferase.” Bioorganic the 5'-Deoxy-5-methylphosphonate Linked Dimmer, 5'-Deoxy-5'-C- Chemistry 13:289-295. (phosphonomethyl)thymidin-3'-yl(Thymidin-5'- Kers et al. (1999) “Preparation of nucleoside 5'-deoxy-5'- yl)methylphosphonate p(CH2)T(CH2)T).” Tetrahedron methylenephosphonates as building blocks for the synthesis of 51(14):4145-4160. methylenephosphonate analogues.” J. Chem. Soc. Perkin Trans I Zhao et al. (1996) “Synthesis and Preliminary Biochemical Studies 2585-1590. with 5'-Deoxy-5'-methylidyne Phosphonate Linked Thymidine Koh et al. (2005) “Design, Synthesis, and Antiviral Activity of Oligonucleotides.” Tetrahedron Letters 37(35):6239-6242. Adenosine 5'-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus.”J Med Chem 48:2867-2875. * cited by examiner US 8,324,179 B2 1. 2 NUCLEOSDE ANALOGS FOR ANTIVIRAL 8, 2501-2509; J. Chem. Soc., Perkins Trans. 1999, 2585 TREATMENT 2590: Synlett 1999, 1124-1126: Biochemistry 1998, 37, 9043-9051; Tetrahedron Lett. 1996, 37, 6239-6242; Tetrahe RELATED APPLICATIONS dron 1995, 51, 4145-4160; Nucleic Acids Research 1995, 23, 893-900; Nucleosides Nucleotides 1995, 14, 871-874; Anti This application claims the benefit of U.S. Provisional viral Chemistry Chemotherapy 1994, 5, 221-228; Tetrahe Application Ser. No. 60/900,692 filed on Feb. 9, 2007, the dron Lett. 1993, 34, 2723-2726; EP 479640; J. Med. Chem. entirety of which is incorporated herein by reference. 1992, 35, 3192-3196: Nucleosides & Nucleotides 1992, 11, 947-956: Acta Chemica Scandinavica 1991, 45, 766–767; FIELD OF THE INVENTION 10 Bioorganic Chemistry 1985, 13, 289-295; J. Med. Chem. The invention relates generally to compounds with antivi 1982, 25, 806-812; J. Med. Chem. 1979, 22, 109-111; and ral activity and more specifically to inhibitors of hepatitis C Bioorganic Chemistry 1976, 5, 31-35. Unsaturated linker virus RNA-dependent RNA polymerase. phosphonate derivatives of purine and pyrimidine com 15 pounds have been reported to be useful as antiviral agents (US BACKGROUND OF THE INVENTION 2003/0004345A1 EP 0532423A1. EP 0618214A1. EP 0701562B1; U.S. Pat. Nos. 5,817,647; 5,922,696; WO The hepatitis C virus (HCV) is the leading cause of chronic 94/22882). liver disease worldwide (Boyer, N. et al. J Hepatol. 32:98 112, 2000). An estimated 170 million persons are infected SUMMARY OF THE INVENTION with HCV worldwide. (Boyer, N. etal, J Hepatol. 32:98-112, 2000). A significant focus of current antiviral research is In one aspect, this invention provides a compound of For directed toward the development of improved methods of mula I: treatment of chronic HCV infections in humans (Di Besceg lie, A. M. and Bacon, B. R., Scientific American, October: 25 80-85, (1999)). A number of HCV treatments are reviewed by Formula I Bymocket al. in Antiviral Chemistry & Chemotherapy, 11:2: 79-95 (2000). Viral serine protease and the RNA-dependent RNA poly merase (RdRp) are the best studied targets for the develop 30 ment of novel HCV therapeutic agents. The NS5B poly merase is a target for inhibitors in early human clinical trials (Sommadossi, J., WO 01/90121 A2). These enzymes have wherein: been extensively characterized at the biochemical and struc A is CR-CR or tural level, with screening assays for identifying selective 35 inhibitors (De Clercq, E. (2001) J. Pharmacol. Exp. Ther. 297:1-10; De Clercq, E. (2001) J. Clin. Virol. 22:73-89). -CEC-: Recent structural work on HCV RdRp has identified catalytic and regulatory nucleotide binding sites (Bressanelli S. et al (2002).J. Virol. 76:3482-92). Since HCV does not replicate in 40 B is a nucleoside base which is optionally substituted; the laboratory, there are difficulties in developing cell-based each R', R. R. R', and R is independently H, OR, assays and preclinical animal systems. N(R), N, CN, NO, SR, halogen, C-C alkyl, C-Cs Currently, there are two primary antiviral compounds, rib Substituted alkyl, C-C alkenyl, C-Cs. Substituted alk avirin and interferon-alpha (C.) (IFN) which are used for the enyl, C-Cs alkynyl, or C-Cs. Substituted alkynyl; or R treatment of chronic HCV infections in humans. Ribavirin 45 and Rare taken together along with the atoms to which alone is not effective in reducing viral RNA levels, has sig they are attached to form a double bond; or R and R. nificant toxicity, and is known to induce anemia. The combi taken together are —O, —NR, or—CRR'; or R and nation of IFN and ribavirin for the treatment of HCV infection R taken together with the carbonatom to which they are has been reported to be effective in the treatment of IFN-naive attached form a 3-7 membered carbocyclic ring wherein patients (Battaglia, A.
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