US00787 1991 B2 (12) United States Patent (10) Patent No.: US 7,871,991 B2 Boojamra et al. (45) Date of Patent: Jan. 18, 2011 (54) PHOSPHONATE ANALOGS OF HIV EP O 632 048 3, 2001 INHIBITOR COMPOUNDS RU 21.06353 3, 1998 RU 21882O3 8, 2002 (75) Inventors: Constantine G. Boojamra, San WO WO91, 19721 12/1991 Francisco, CA (US); Kuei-Ying Lin, WO WO-92fOO988 1, 1992 Fremont, CA (US); Richard Mackman, WO WO92, 13869 8, 1992 Millbrae, CA (US); David Y. WO WO-93/24510 12/1993 Markevitch, Los Angeles, CA (US); WO WO94,21604 9, 1994 Oleg V. Petrakovsky, San Mateo, CA WO WO 3.O792O 1995 (US); Adrian S. Ray, San Mateo, CA W WOCS: A * g.. (US); Lijun Zhang, Palo Alto, CA (US) WO WOO3,O90690 11, 2003 WO WOO3,091,264 11, 2003 (73) Assignee: stad Sciences, Inc., Foster City, CA WO WO 2004/096,233 1, 2004 (US) WO WO 2004/096,235 1, 2004 WO WO 2004/096286 1, 2004 (*) Notice: Subject to any disclaimer, the term of this WO WO 2005/O12324 2, 2005 patent is extended or adjusted under 35 WO WO 2005/063751 7/2005 U.S.C. 154(b) by 506 days. WO WO 2006/O15262 2, 2006 (21) Appl.ppl. No.: 11/190,2259 WO WO-2006/11 O157 10, 2006 (22) Filed: Jul. 26, 2005 OTHER PUBLICATIONS (65) Prior Publication Dat Lee, Journal of Medicinal Chemistry (1999), 42(7), 1320-1328.* O DO Moon, Journal of the Chemical Society, Perkin Transactions 1 US 2007/OO497.54 A1 Mar. 1, 2007 (2002), (15), 1800-1804.* Chong J. Med. Chem. 45 (22), 4888-4898, 2002.* Related U.S. Application Data Jeong, J. Med. Chem., 46 (2), 201-203, 2003.* Anan Eva et al. "(2-Iodoethyl)Phosphonic Derivatives.” 53(3):480 (60) Provisional application No. 60/591,811, filed on Jul. 483; J. Gen. Chem. USSR, 1983. 27, 2004. Anderson et al. “2-Chloro-4(R),5(R)-dimethyl-2-oxo-1,3,2- dioxaphospholane, a New Chiral Derivatizing Agent.” 49: 1304 (51) Int. C. 1305; J Org Chem, 1984. C7F 9/656 (2006.01) Asante-Appiah et al.'HIV-1 Integrase: Structural Organization, A6 IK3I/675 (2006.01) Conformational Changes, and Catalysis,” 52:351-369:Advances in A6IP3 L/18 (2006.01) Virus Research, 1999. CO7D 473/40 (2006.01) Alexander et al. "Investigation of (Oxodioxolenyl)methyl Carbam ates as Nonchiral Bioreversible Prodrug Moieties for Chiral Amines.” CO7D 473/34 (2006.01) 39:480-486;J Med Chem, 1996. CO7D 473/30 (2006.01) Balsigeretal."Synthesis of Potential Anticancer Agents. XVIII. Ana (52) U.S. Cl. ......................... 514/81: 544/244; 544/276; logs of Carbamoyl Phosphate.” 24:434-436:JOrg Chem, 1959. 544/264; 54.4/265 Balthazor et al."Nickel-Catalyzed Arbuzov Reaction: Mechanistic (58) Field of Classification Search ................. 544/277, Observations.”45:5425-5426:J Org Chem, 1980. 544/244: 514/81, 263.4 Beusen et al. “Solid-State Nuclear Magnetic Resonance Anlysis of See application file for complete search history. the Conformation of an Inhibitor Bound to Thermolysin' 38: 2742 2747:J Med Chem, 1995. (56) References Cited Bundgaard et al."Design and Application of Prodrugs.” pp. 113 191:Textbook of Drug Design and Development, 1991. U.S. PATENT DOCUMENTS Burger et al. "Monoesters and Ester-amidates of Aromatic 4,816,570 A 3/1989 Farquhar Phosphonic Acids” 79:3575-3579;J Am ChemSoc. 1957. 4,968,788 A 1 1/1990 Farquhar Barre-Sinoussi, Francoise. “HIV as the cause of AIDS.” 348:31-35; 5,663,159 A 9/1997 Starrett, Jr. et al. Lancet, 1996. 5,792,756 A 8/1998 Starrett, Jr. et al. 6,018,049 A 1/2000 Hajima et al. (Continued) 6,312,662 B1 1 1/2001 Erion et al. Primary Examiner Mark L. Berch 7.358,261 B2 * 4/2008 Carson et al. ............... 514,311 2002/0103378 A1 8, 2002 Ellis (74) Attorney, Agent, or Firm Allan Kutzenco 2002/01 19443 A1 8, 2002 Becker et al. 2005/0037925 A1 2/2005 Tsukamoto et al. ......... 504.238 (57) ABSTRACT 2007/0225249 A1* 9, 2007 Shi ............... ... 514,49 2008/0207620 A1* 8, 2008 Desai et al. ..... 514,238.2 The invention is related to phosphorus substituted anti-viral 2009/0012037 A1* 1/2009 Boojamra et al. ............. 514.48 inhibitory compounds, compositions containing Such com 2009/0202470 A1* 8/2009 Boojamra et al. .. ... 424/85.2 pounds, and therapeutic methods that include the administra 2010/0093667 A1* 4/2010 Graetz et al. .................. 514/81 tion of such compounds, as well as to processes and interme diates useful for preparing Such compounds. FOREIGN PATENT DOCUMENTS EP 347852 A2 * 12/1989 18 Claims, No Drawings US 7,871.991 B2 Page 2 OTHER PUBLICATIONS Hottiger et al..."Human Immunodeficiency Virus Type 1 Reverse Transcriptase.”377:97-120: Biol Chem, 1996. Benzaria et al. “Synthesis, InVitro Antiviral Evaluation, and Stability Howell et al.''Antiviral Nucleosides. A Stereospecific, Total Synthe Studies . .39:4958-4965;J Med Chem, 1996. sis of 2'-Fluoro-2'-b-D-arabinofuranosyl Nucleosides.”53:85-88:J Campagne et al. “(1H-Benzotriazol-1- Org Chem, 1988. yloxy)tris(dimethylamino)phosphonium . .” 60(16):5214-5223; J Jacob III. Peyton"Resolution of ()-5-Bromonornicotine. Synthesis Org Chem, 1995. of (R)- and (S)- Nornicotine of High Enantiomeric Purity.”47:4165 Campagne et al. “Synthesis of Mixed Phosphonate Diester Ana 4167:J Org Chem, 1982. logues of Dipeptides Using BOP or PyBOP Reagents' 34:6743 Katz et al. “The Retroviral Enzymes.”63:133-173;Ann Rev 6744; Tet Lett, 1993. Biochem, 1984. Campbell et al. “The Synthesis of Phosphonate Esters, an Extension Kazimierczuk et al. “Synthesis of 2'-deoxytubercidin, of the Mitsunobu Reaction.”57:6331-6335:J Org Chem, 1992. 2"deoxyadenosine, and related 2'-deoxynucleosides ... 106:6379 Carter et al.'"Carbobenzoxy Chloride and Derivatives.”3:167 169:Org Synth Coll, 1965. 6382; JAm ChemSoc. 1984. Casara et al. “Synthesis of Acid Stable 5'-O-Fluoromethyl Khamnei et al"Neighboring Group Catalysis in the Design of Phosphonates of Nucleosides, Evaluation as Inhibitors of Reverse Nucleotide Prodrugs.”39:4109-41 15:J Med Chem, 1996. Transcriptase.” 2:145-148: Bioorg Med Chem Lett, 1992. Khandazhinskaya et al. "Carbocyclic Dinucleoside Casteel et al. "Steric and Electronics Effects in the Aryl Phosphate to Polyphosphonates: Interactions with HIV reverse Transcriptase and Arylphosphonate Rearrangement.”691-693; Synthesis, 1991. Antiviral Activity.”45:1284-1291;J Med Chem,2002. Cavalier et al."New Highly Diastereoselective Synthesis of Konakahara et al.''A Convenient Method for the Synthesis of Acti Phosphoramidates. A Route to Chiral Methyl p-Nitrophenyl vated N-Methylcarbamates.” 103-106:Synthesis, 1993. Alkylphosphonates.” 1:73-75; Synlett, 1998. Kunz et al."71. Synthesis of the Glycopeptide Partial Sequence A Chen et al"Design, Synthesis, and Biochemical Evaluation of 80-A84 of Human Fibroblast Interferon.'68:618-622:Helvetica Phosphonate and Phosphonamidate Analogs of . .” 40(23):3842 Chimica Acta, 1985. 3850;J Med Chem, 1997. Lochmuller et al. "Chromatographic Resolution of Enantiomers Coleman et al. “Synthesis of the aziridino1,2-alpyrrolidine sub Selective Review.”113:283-302:J Chromatog, 1975. structure of the antitumor agents azinomycin A and B.”57(22):5813 Lu Etb Al. “Palladium-Catalyzed Reaction of Aryl 5815;J Org Chem, 1992. Polyfluoroalkanesulfonates with O, O-Dialkyl Phosphonates.”726 Corey et al"Selective Cleavage of Allyl Ethers Under Mild Condi 727:Synthesis, 1897. tions by Transition Metal 38(18):3224; J Org Chem, 1973. Ma et al. “Synthesis and Anti-Hepatitis B Virus Activity of 9-(2- Coe et al. “Synthesis of Some Mimics of Nucleoside Triphosphates' Deosy-2-fluoro-L-arabinofuranosyl)purine Nucleosides.”40:2750 pp. 312-314; J. Chem. Soc. Chem. Commun. 1991. 2754;J Med Chem, 1997. D'Addona et al. "Preparation of carbamates from amines and Maffre-Lafon et al. “Solid Phase Synthesis of Phosphonopeptides alcholols under mind conditions.” 42:5227-5229; Tet Lett, 2001. from Fmoc Phosphonodipeptides.”35:4097-4098;Tet Lett, 1994. Davies et al"Dinucleotide Analogues as Inhibitors of Thymidine Marquez et al. "Acid-stable 2'-fluoro purine dideosynucleosides as Kinase, Thyidylate Kinase, and Ribonucleotide Reductase.”31(7) 1 active agents against HIV” 33:978-985; J Med Chem, 1990. 305-1308;J Med Chem, 1994. Maynard et al. “Organophosphorus Compounds II. Preparation of De Clercq, Erick “New Developments in the Chemotherapy of Phosphonic Acid Esters. Using the Dicyclohexylcarbodi-Imide Lentivirus (Human Immunodeficiency Virus) Infections . ” Reagent” 16:609-612; AustJ Chem, 1963. 724:438-456;Annals of the NY Acad of Sciences, 1994. McKenna et al. "Functional Selectivity in Phosphonate Ester De Lombaert et al. “N-Phosphonomehtyly Dipeptides and Dealkylation with Bromotrimethylsilane'p. 739;JCS Chem Their Phosphonate Prodrugs, a New Generation of Neutral Com, 1979. Endopeptidase . .” 37:498; J Med Chem; 1994. Melvin, LSAn Efficient Synthesis of Effenberger et al."2(1H)-Pyridon als. Austrittsgruppe bei 2-Hydroxyphenylphosphonates.”22:3375-3376:Tet Lett, 1981. Acylierungsreaktionen Anwendungen in der Peptidchemie.” Mikhailopulo etal."Pyrophosphoryl Derivatives of 1-(2-Deoxy-3-O- 118:468-482; Chem Ber, 1985. Phosphonomethyl-B- and—-D-erythro-Pentofuranosyl). .”19(10 Efimov et al. “Synthesis of DNA Analogues with Novel 12): 1885-1909:Nucls & Nuclt, 2000. Carboxamidomethyl Phosphonamide and Glycinamide Mitchell et al.''Bioreversible Protection for the Phospho Group: Internucleoside Linkages'8: 1013-1018: Bioorg Med Chem Lett, Bioactivation of the Dic(4 acyloxybenzyl) . 2345.J Chem Soc 1998. Perkin Trans I. 1992. Esposito et al. “HIV Integrase Structure and Function.”52:319 Mitsunobu, Oyo"The use of Diethyl Azodicarboxylate and 333; Advances in Virus Research, 1999. Triphenlyphosphine in Synthesis and Transformation of Natural Farquhar et al. “Biologically Reversible Phosphate-Protective Products.” 1-28:Synthesis, 1981.