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(12) United States Patent (10) Patent No.: US 8,871,799 B2 Adonato Et Al

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(12) United States Patent (10) Patent No.: US 8,871,799 B2 Adonato Et Al USOO8871799B2 (12) United States Patent (10) Patent No.: US 8,871,799 B2 adonato et al. (45) Date of Patent: Oct. 28, 2014 (54) IMINOCHROMENE ANTI-VIRAL the action of nucleophilic reagents. 5. Interactions of COMPOUNDS 2-Iminocoumarin-3-carboxamide with anthranilic acid and its derivatives. (2000) Chemistry of Heterocyclic COmpounds, vol. 36. (75) Inventors: Shawn P. Ladonato, Seattle, WA (US); pp. 1026-1031.* Kristin Bedard, Seattle, WA (US) Banerjee, S., et al. (2008) Multi-targeted therapy of cancer by genistein, Cancer Lett 269, 226-242. (73) Assignee: Kineta, Inc., Seattle, WA (US) Barnard, D. L. (2009) Animal models for the study of influenza pathogenesis and therapy, Antiviral Res 82, Al 10-122. (*) Notice: Subject to any disclaimer, the term of this Blight, J.J. et al., (2002) Highly Permissive Cell Lines for patent is extended or adjusted under 35 Subgenomic and Genomic Hepatitis C Virus RNA Replication, J. U.S.C. 154(b) by 55 days. Virology 76:13001-13014. Dafis, S., et al. (2008) Toll-like receptor 3 has a protective role (21) Appl. No.: 13/642,823 against West Nile virus infection, JVirol 82, 10349-10358. Horsmans, Y, et al. (2005) Isatoribine, an agonist of TLR7, reduces (22) PCT Filed: Apr. 20, 2011 plasma virus concentration in chronic hepatitis C infection, Hepatol ogy 42, 724-731. (86). PCT No.: PCT/US2011/033309 Johnson, C. L., and Gale, M., Jr. (2006) CARD games between virus S371 (c)(1), and host get a new player, Trends Immunol 27, 1-4. (2), (4) Date: Oct. 22, 2012 Kato, H., et al. (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses, Nature 441, 101-105. (87) PCT Pub. No.: WO2011/133707 Kawai, T., et al. (2005) IPS-1, an adaptor triggering RIG-I- and MdaS-mediated type I interferon induction, Nat Immunol 6, 981 PCT Pub. Date: Oct. 27, 2011 988. Lee, J., et al. (2006) Activation of anti-hepatitis C virus responses via (65) Prior Publication Data Toll-like receptor 7, Proc Natl Acad Sci U S A 103, 1828-1833. US 2013/OO35382 A1 Feb. 7, 2013 Lescuyer, P. et al. (2003) Progress in the definition of a reference human mitochondrial proteome, Proteomics 3, 157-167. Related U.S. Application Data Li, K., et al. (2005) Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes, J Biol (60) Provisional application No. 61/327.568, filed on Apr. Chem 280, 16739-16747. 23, 2010. Lipinski, C. A., et al. (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery (51) Int. Cl. and development settings, Adv Drug Deliv Rev 46, 3-26. A6 IK3I/352 (2006.01) Loo.Y. M., et al. (2008) Distinct RIG-I and MDA5 signaling by RNA CI2N 5/071 (2010.01) viruses in innate immunity, JVirol 82,335-345. A6IP3L/20 (2006.01) Loo, Y. M., et al. (2006) Viral and therapeutic control of IFN-beta A6IP3L/22 (2006.01) promoter stimulator 1 during hepatitis C virus infection, Proc Natl A6 IK3I/35 (2006.01) Acad Sci U S A 103,6001-6006. A6 IK3I/37 (2006.01) Lutfalla, G. etal. (1995) Mutant U5A cells are complemented by an CO7D 3II/60 (2006.01) interferon-alpha beta receptor Subunit generated by alternative pro (52) U.S. Cl. cessing of a new member of a cytokine receptor gene cluster, EMBO CPC ................. A61 K31/35 (2013.01); A61 K3I/37 J 14, 5100-5108. (2013.01); A61 K3I/352 (2013.01); Meylan, E., et al. (2005) Cardif is an adaptor protein in the RIG-I C07D 31 1/60 (2013.01) antiviral pathway and is targeted by hepatitis C virus, Nature 437. USPC ............................ 514/456; 549/283; 549/388 1167-1172. (58) Field of Classification Search None (Continued) See application file for complete search history. Primary Examiner — Melenie McCormick (56) References Cited Assistant Examiner — Taina D Matos Negron U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Lee & Hayes, PLLC; C. Rachal Winger 5,847,159 A 12/1998 Kai et al. FOREIGN PATENT DOCUMENTS (57) ABSTRACT WO 2007 131350 11, 2006 Disclosed herein are compounds and related compositions for WO 2006/122546 11, 2007 the treatment of viral infection, including RNA viral infec OTHER PUBLICATIONS tion, and compounds that can modulate the RIG-I pathway in Ranjith-Kumar et al. Agonist and Antagonist Recognition by RIG-I. Vertebrate cells, including compounds that can activate the a Cytoplasmic Innate Immunity Receptor. J. Biol. Chem. 2009, RIG-I pathway. 284:1155-1165.* Lippard. The Art of Chemistry, Nature 2002, vol. 416, pp. 587.* Kovalenko et al. Recyclization of 2-imino-2H-1-Benzopyrians under 1 Claim, 1 Drawing Sheet US 8,871,799 B2 Page 2 (56) References Cited Seth, R. B., etal. (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates Nf-kappaB OTHER PUBLICATIONS and IRF3, Cell 122, 669-682. Sumpter, R., et al. (2005) Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a Odaka, M., et al. (1997) Ligand-binding enhances the affinity of cellular RNA helicase, RIG-I, J Virol 79, 2689-2699. dimerization of the extracellular domain of the epidermal growth Suthar, M. S., et al. (2010) IPS-1 is essential for the control of West factor receptor, J Biochem 122, 116-121. Nile virus infection and immunity, PLoS Pathog 6, e1000757. Paterniti, et al. (2010) Evidence for the Role of Peroxisome Prolifera Tan, S. L., et al. (2007) Systems biology and the host response to viral tor-Activated Receptor-beta delta in the Development of Spinal Cord infection, Nat Biotechnol 25, 1383-1389. Injury. Journa 1 of Pharmacology and Experimental Therapeutics, Taylor, S. W., et al. (2003) Characterization of the human heart mitochondrial proteome, Nat Biotechnol 21, 281-286. 333(2), pp. 465-477. Venkataraman, T., et al. (2007) Loss of DExD/H box RNA helicase Philo, J. S., et al. (1996) Dimerization of the extracellular domain of LGP2 manifests disparate antiviral responses, JImmunol 178,6444 the erythropoietin (EPO) receptor by EPO: one high-affinity and one 6455. low-affinity interaction, Biochemistry 35, 1681-1691. Xu, L. G. et al. (2005) Visa is an adapter protein required for virus Philo, J. S., et al. (1996) Human stem cell factor dimer forms a triggered IFN-beta signaling, Mol Cell 19, 727-740. complex with two molecules of the extracellular domain of its recep Yoneyama, M., et al. (2005) Shared and unique functions of the tor, Kit, J Biol Chem 271, 6895-6902. DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate Renard, P. et al. (2001) Development of a sensitive multi-well immunity, JImmunol 175, 2851-2858. colorimetric assay for active NFkappaB. Nucleic Acids Res 29, E21. Yoneyama, M., et al. (2004) The RNA helicase RIG-I has an essential Saito, T., et al. (2007) Regulation of innate antiviral defenses through function in double-stranded RNA-induced innate antiviral responses, a shared repressor domain in RIG-I and LGP2, Proc Natl AcadSci U Nat Immunol 5, 730-737. SA 104, 582-587. Zou, J., et al. (2009) Origin and evolution of the RIG-I like RNA Saito, T., et al. (2008) Innate immunity induced by composition helicase gene family, BMC Evol Biol 9, 85. dependent RIG-I recognition of hepatitis C virus RNA, Nature 454, 523-527. * cited by examiner U.S. Patent Oct. 28, 2014 US 8,871,799 B2 FIGURE 1A KN 5 2.0 -- KEY FO -H siegative COSS: $5. t i.0 s s .5 5. i. 'S 5. drug added FIGURE 1 B interfer 5 2.5 -- SafaN - ---, -H segawa Costii 2. 2. 5. 1.0 e .5 5. t 5 5. drug added US 8,871,799 B2 1. 2 IMINOCHROMENE ANTI-VIRAL SUMMARY OF THE DISCLOSURE COMPOUNDS The compounds and methods disclosed herein shift the STATEMENT OF GOVERNMENT INTEREST focus of viral drug development away from the targeting of viral proteins to the development of drugs that target and This invention was made with government Support under enhance the hosts innate antiviral response. Such com National Institutes of Health Grant No. AIO81335. The gov pounds and methods are likely to be more effective, less ernment has certain rights in the invention. Susceptible to the emergence of viral resistance, cause fewer side effects and be effective against a range of different FIELD OF THE DISCLOSURE 10 viruses (1). The RIG-I pathway is intimately involved in regulating the Compounds and methods disclosed herein are useful for innate immune response to RNA virus infections. RIG-Iago treating viral infection in vertebrates, including RNA viral nists are expected to be useful for the treatment of many infections. 15 viruses including, without limitation, HCV, influenza, and West Nile virus. Accordingly, the present disclosure relates to BACKGROUND OF THE DISCLOSURE compounds and methods for treating viral infection, includ ing infection by RNA viruses, wherein the compounds can As a group, RNA viruses represent an enormous public modulate the RIG-I pathway. health problem in the U.S. and worldwide. Well-known RNA One embodiment includes a pharmaceutical composition viruses include influenza virus (including the avian and Swine comprising a compound having a structure isolates), hepatitis C virus (HCV), West Nile virus, SARS coronavirus, respiratory syncytial virus (RSV), and human immunodeficiency virus (HIV). More than 170 million people worldwide are infected by 25 HCV, and 130 million of those are chronic carriers at risk of developing chronic liver diseases (cirrhosis, carcinoma, and liver failure). As such, HCV is responsible for two thirds of all liver transplants in the developed world.
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