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WO 2018/042343 A2 08 March 2018 (08.03.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/042343 A2 08 March 2018 (08.03.2018) W !P O PCT (51) International Patent Classification: (84) Designated States (unless otherwise indicated, for every C07D 403/12 (2006.01) C07D 207/27 (2006.01) kind of regional protection available): ARIPO (BW, GH, C07D 401/12 (2006.01) A61K 31/4155 (2006.01) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, C07D 413/12 (2006.01) A61P 31/00 (2006.01) UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, C07D 417/12 (2006.01) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (21) International Application Number: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, PCT/IB20 17/055206 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (22) International Filing Date: KM, ML, MR, NE, SN, TD, TG). 30 August 2017 (30.08.2017) Declarations under Rule 4.17: (25) Filing Language: English — as to applicant's entitlement to applyfor and be granted a (26) Publication Language: English patent (Rule 4.1 7(H)) — as to the applicant's entitlement to claim the priority of the (30) Priority Data: earlier application (Rule 4.17(Hi)) 62/381,560 30 August 2016 (30.08.2016) US — of inventorship (Rule 4.1 7(iv)) 62/382,410 0 1 September 2016 (01 .09.2016) US Published: (71) Applicant: GLAXOSMITHKLINE INTELLECTUAL — without international search report and to be republished PROPERTY (NO.2) LIMITED [GB/GB] ; 980 Great West upon receipt of that report (Rule 48.2(g)) Road, Brentford Middlesex TW89GS (GB). (72) Inventors: BOTYANSZKI, Janos; 1250 South Col- legeville Road, Collegeville, Pennsylvania 19426 (US). CATALANO, John G.; Five Moore Drive, Research Tri angle Park, North Carolina 27709 (US). CHONG, Pek Yoke; Five Moore Drive, Research Triangle Park, North Carolina 27709 (US). DICKSON, Hamilton; Five Moore Drive, Research Triangle Park, North Carolina 27709 (US). JIN, Qi; 709 Swedeland Road, King of Prussia, Penn sylvania 19406 (US). LEIVERS, Anna; Five Moore Dri ve, Research Triangle Park, North Carolina 27709 (US). MAYNARD, Andrew; Five Moore Drive, Research Tri angle Park, North Carolina 27709 (US). LIAO, Xiang- min; 1250 South Collegeville Road, Collegeville, Penn sylvania 19426 (US). MILLER, John; Five Moore Dri ve, Research Triangle Park, North Carolina 27709 (US). SHOTWELL, John Brad; 1North Waukegan Road, North Chicago, Illinois 60064 (US). TAI, Vincent Wing-Fai; Five Moore Drive, Research Triangle Park, North Caroli na 27709 (US). THALJI, Reema; 1250 South Collegeville Road, Collegeville, Pennsylvania 19426 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, < MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. © 00 o (54) Title: COMPOUNDS THAT INHIBIT 3C AND 3CL PROTEASES AND METHODS OF USE THEREOF (57) Abstract: Compounds, specifically protease inhibitors, more specifically 3C and 3CL protease inhibitors, for the treatment of viral infections, and methods of preparing and using such compounds. Compounds That Inhibit 3C and 3CL Proteases and Methods of Use Thereof FIELD OF THE INVENTION [0001] The present invention relates to compounds, specifically protease inhibitors, for the treatment of viral infections, and methods of preparing and using such compounds. BACKGROUND OF THE INVENTION [0002] Each year viruses are implicated in the deaths of millions of people around the world. (See, e.g., Fact Sheets on HIV/AIDS, Hepatitis C Virus, and Influenza, WORLD HEALTH ORGANIZATION) . The diseases caused by viral infection are numerous and diverse, as are the structures, sizes, genomes, and infection cycles of the viruses that cause them -facts which tend to complicate and fracture research efforts in this area. Despite these difficulties, researchers continue to make advances towards the prevention, control, and treatment of viral diseases. Typically, successful research efforts have focused on viruses of a single species or genus. [0003] One of the most successful broad-spectrum antiviral agents is ribavirin . Ribavirin ( 1-B-D-ribofuranosyl-1 - 1 ,2,4-triazole-3-carboxamide) is a synthetic, non- interferon-inducing , broad spectrum antiviral nucleoside analog sold under the trade name, Virazole®. (THE MERCK INDEX 1304 (Budavari, S., ed. , 11th ed. , 1989). U.S. Pat. Nos. 3,798,209 and RE 29,835 to Wtkowski disclose and claim Ribavirin . Ribavirin is structurally similar to guanosine, and has in vitro activity against several DNA and RNA viruses including Flaviviridae. (Gary L . Davis, 118 GASTROENTEROLOGY S104 (2000)). Ribavirin is indicated for the treatment of severe respiratory syncytial virus (RSV) infection, hepatitis C virus (HCV) infection, and others (including lassa fever, hantavirus, influenza, and rabies). However a major side effect of ribavirin , hemolytic anemia, is so severe that it is reserved for the treatment of only lethal viruses. In addition, ribavirin is a potential teratogen in humans. Accordingly, there exists a serious need for the development of novel therapeutic, antiviral agents, especially broad-spectrum antiviral agents. [0004] Viruses are classified by evaluating several characteristics, including the type of viral genome. Viral genomes can be comprised of DNA or RNA, can be double- stranded or single-stranded (which can further be positive-sense or negative-sense), and can vary greatly by size and genomic organization . Positive-sense, single-stranded RNA viruses ("positive-stand RNA viruses") make up a large superfamily of viruses from many distinct subfamilies. These viruses span both the plant and animal kingdoms causing pathologies ranging from mild phenotypes to severe debilitating disease. The composition of the positive strand RNA virus polymerase supergroup includes, at least, the following families: levi-, narna-, picorna-, dicistro-, marna-, sequi-, como-, poty-, calici-, astro-, noda-, tetra-, luteo-, tombus-, corona-, arteri-, roni-, flavi-, toga-, bromo-, tymo-, clostero-, flexi-, seco-, barna, ifla-, sadwa-, chera-, hepe-, sobemo-, umbra-, tobamo-, tobra-, hordei-, furo-, porno-, peclu-, beny-, ourmia-, and idaeovirus. [0005] Human Rhinoviruses ("HRVs") are Enteroviruses of the Picornaviridae family, and have single-stranded, positive-strand RNA genomes. The naked RNA genome (~8 kb) is surrounded by a capsid composed of sixty copies each of four structural proteins, denoted VP1 - VP4, in an icosahedral configuration. HRVs enter the cell by triggering receptor-mediated endocytosis, with uncoating occurring through endosomes. HRV replication requires viral RNA-dependant RNA polymerase, as well as multiple viruses and host-cell derived accessory proteins. The HRV genome is translated as a single polyprotein, which is first cleaved following translation by virus- encoded proteases into three proteins, which are themselves cleaved to produce at least eleven proteins. Viral genome replication can begin in as little as one hour following infection, and the release of nearly one million fully assembled virus particles at cell death can occur in as little as four hours following cell entry. [0006] Infection with HRVs is a major health problem associated with thirty to fifty percent of all upper respiratory tract infections (common colds), predisposition to acute otitis media and sinusitis, and the development of lower respiratory tract syndromes in individuals with underlying respiratory disorders (like cystic fibrosis), the elderly, and the immunosuppressed. (Gern, 23 PEDIATR. INFECT. DIS . J. S78 (2004); Anzueto et al. , 123 CHEST 1664 (2003); Rotbart, 53 ANTMR. RES . 83 (2002)). In addition, infection with HRVs is responsible for about 50% of asthma exacerbations in adults and is one of the factors that can direct the infant immune system towards an asthmatic phenotype. (D. J. Jackson et al. , 178 A M. J. RESPIR. CRIT. CARE MED . 667 (2008)). HRVs have also been linked to exacerbations of chronic obstructive pulmonary disease (COPD). J-M Perotin et al., vol. 85 J. MED. VIROL . 866 (201 3). [0007] The common cold is one of the most frequently occurring human illnesses and is responsible for substantial morbidity. Although HRV-induced upper respiratory illness is often mild and resolved without medical intervention , the socioeconomic impact is enormous and treatment often includes the inappropriate use of antibiotics. It has been estimated that the common cold accounts for at least twenty-five million absences from work, and nearly as many school absences, annually in the United States. (Rotbart, 53 ANTIVIR. RES. 83 (2002)). Direct and indirect costs from the common cold and related complications in asthmatics alone have been estimated as high as forty billion dollars annually in the United States. (A. M . Fendrick et al. , 163 ARCH. INTERN. MED. 487 (2003). [0008] There are over one hundred distinct serotypes of HRV that have been identified by specific antisera which can be placed into two broad groups based on the cellular receptor through which cell entry is mediated. Approximately ninety percent of HRV serotypes enter host cells through the human intracellular adhesion molecule (ICAM-1 ) , while the remaining approximately ten percent utilize the low-density lipoprotein receptor for cell entry. The differences between the serotypes not only prevent the body from developing cross-immunity, they have greatly impeded the development of vaccines and other virus-specific methods of prevention and treatment.
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