Compounds for treating arenavirus infections

Abstract

Compounds exemplified by Compound A are useful in the treatment of arenavirus infections and viral infections mediated by arenavirus glycoproteins.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application is a continuation-in-part of and claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 776,390, filed on December 6, 2018, which is incorporated herein by reference in its entirety for all purposes.

[0003] STATEMENT REGARDING RIGHTS TO INVENTS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0004] This invention was made with government support under R44 AI112097 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention.

[0005] Annexes to a Sequence Listing, Table or Computer Program Listing Submitted on a Compact Disc

[0006] not applicable Technical Field

[0007] The present invention relates to the use of heterocyclic compounds to inhibit arenavirus infections in humans, other mammals, or in cell culture, methods of treating arenavirus infections such as Lassa hemorrhagic fever, Bolivian hemorrhagic fever, Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, Brazilian hemorrhagic fever, Chapare hemorrhagic fever, and Lujo hemorrhagic fever, methods of inhibiting the replication of arenaviruses, methods of reducing the amount of arenaviruses, and compositions that can be used in such methods. Background Art

[0008] The Arenaviridae family includes a diverse family of 29 (and expanding) negative-strand enveloped RNA viruses. Based on serological, genetic, and geographic data, arenaviruses are divided into two groups, Old World and New World. Old World viruses are found primarily throughout sub-Saharan and West Africa and include the prototype lymphocytic choriomeningitis virus (LCMV), as well as Lassa virus (LASV), Lujo virus (LUJV), Mopeia virus (MOPV), Ippy virus, and Mobala virus (MOBV). Both LASV and LUJV can cause fatal hemorrhagic fever (HF), while LCMV infection is associated with aseptic meningitis. It is estimated that Lassa virus (LASV) alone causes over 300,000 cases of illness per year in West Africa, with 15-20% of hospitalized patients dying, and survivors often suffering from sequelae, including permanent bilateral hearing loss. The larger New World complex group is primarily located in South America and is divided into three clades, A, B, and C, with clade B being important as many viruses in this group can cause fatal HF. Clade B HF viruses include Junin virus (JUNV), Machupo virus (MACV), Guanarito virus (GTOV), Sabia virus (SABV), and Chapare virus, as well as non-HF viruses such as Tacaribe virus (TCRV) and Amapari virus (AMPV). Human infection occurs through contact with the excretions of infected rodents or by inhalation of fine particles contaminated with rodent urine or saliva (airborne transmission). There is also evidence of human-to-human transmission, primarily in institutional settings (e.g., hospitals). The incubation period of the virus is 1-2 weeks, followed by fever, malaise, weakness, sore throat, headache, cough, diarrhea, and vomiting. These general symptoms make it difficult to diagnose arenavirus infection definitively. Symptoms worsen to include pleural effusion, facial edema, neurological complications, and bleeding from mucosal surfaces indicative of a poor prognosis. Current arenavirus treatment is limited to the use of ribavirin, which is only partially effective when given early and is associated with significant side effects. Although a vaccine against Junin virus has been developed, its use is primarily limited to the highest risk group among farm workers in Argentina, and there is no approved vaccine against any other arenavirus. Despite the great need for a prophylactic vaccine, prophylactic vaccines can not always be an effective countermeasure against rapidly emerging, antigenically diverse new viral strains, and existing vaccine development and production strategies are not well equipped to deal with the diverse family of current or emerging arenaviruses. Thus, new broad-spectrum antiviral drugs can provide a first-line therapy and / or prophylaxis not only in endemic areas of arenavirus infection, but also as a prophylactic measure against potential biowarfare agents.

[0009] Arenaviruses consist of a nucleocapsid (NP) surrounded by an envelope and the NP contains two ambisense RNA genome segments L and S that direct the synthesis of two polypeptides. The L segment encodes an RNA-dependent RNA polymerase (RdRp) and a small ring finger protein Z. The S segment encodes a nucleoprotein and a glycoprotein precursor GPC that is cleaved by host proteases and undergoes post-translational modifications into the mature complex consisting of glycoprotein GP1 (binds host proteins at the cell surface), GP2 (directs pH-dependent membrane fusion and release of genomic material into the cytoplasm) and a stable signal peptide (SSP1). The mature glycoprotein complex (GP, or called glycoprotein) forms in the viral envelope and is responsible for mediating viral entry. To enter / endocytose into cells, Old World arenaviruses bind to host d-mannose glycans while New World arenaviruses bind to transferrin receptor 1. Upon binding to cell surface receptors, the virus is endocytosed and directed to an acidic late endosome, from which GP2 mediates pH-dependent membrane fusion and release of genomic material into the cytoplasm for viral replication and transcription. Thus, viral entry inhibitors (e.g. small molecules) that target the viral GP complex or host factors are potential therapeutic / prophylactic methods to treat patients infected with arenavirus infections. Since HF arenavirus species are classified as BSL-4, alternative methods are needed to identify viral entry inhibitors. To facilitate the identification of arenavirus entry inhibitors, arenavirus GP complex can be expressed in a non-pathogenic BSL-2 envelope virus to generate a single round of infectious pseudovirus whose viral entry function is dictated by the heterologous glycoprotein of interest. One viral expression system that can be utilized is the vesicular stomatitis virus (VSV) system whereby the envelope protein of VSV is replaced by the envelope glycoprotein from another virus (e.g. LASV) to mediate entry of the pseudotyped virion. GP pseudotyped VSV viruses have been shown to exhibit cell entry and infection properties for a variety of viruses including HIV, hepatitis B and C, Ebola, Lassa, Hanta, etc. Ogino, M. et al. Use of vesicular stomatitis virus pseudotypes bearing hantaan or seoul virus envelope proteins in a rapid and safe neutralization test. Clin. Diagn. Lab. Immunol. (2003) 10(1): 154-60: Saha, M. N.等人Formation ofvesicular stomatitis virus pseudotypes bearing surface proteins of hepatitisB virus.J.Virol.(2005)79(19):12566-74;Takada,A.等人A system for functionalanalysis of Ebola virus glycoprotein,Proc.Natl.Acad.Sci.(1997)94:14764-69; Garbutt, MProperties of replication-competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses. J. Virol. (2004) 78(10): 5458-65]. The above documents are incorporated by reference in their entirety for all purposes. To monitor pseudovirus infection, a reporter gene such as green fluorescent protein (GFP) or luciferase can be engineered into the pseudovirus genome and optical detection methods (e.g. plate reader) can be used to monitor viral infectivity in mammalian cell lines (e.g. Vero or Hek293) [Cote, M.; Misasi, J.; Ren, T.; Bruchez, A., Lee, K., Filone, C. M.; Hensley, L.; Li, Q.; Ory, D.; Chandran, K.; Cunningham, J., Small molecule inhibitors reveal Niemann-Pick Cl is essential for Ebola virus infection, Nature (2011) 477:344-348; Elshabrawy, H. A. et al. Identification of a broad-spectrum antiviral small molecule against severe scute respiratory syndrome Coronavirus and Ebola, Hendra, and Nipah Viruses by using a novel high-throughput screening assay. J. Virol. (2014) 88:4353-4365]. The above documents are incorporated by reference in their entirety for all purposes. Thus, "pseudovirus" can be used to screen chemical compound libraries to identify inhibitors of arenavirus cell entry while avoiding the difficulties of working with highly pathogenic BSL-4 pathogens.

[0010] The introduction of deuterium (D) into drug molecules is an attractive strategy that can help improve the metabolism, pharmacokinetics, and toxicity profile of drugs. Deuterium is a stable, non-toxic, non-radioactive isotope of hydrogen. Due to its greater atomic mass, deuterium forms stronger bonds with carbon than hydrogen, making carbon-deuterium bonds more difficult to break. In cases where the cleavage of carbon-hydrogen bonds is a partially or fully rate-limiting step in cytochrome P450-mediated drug metabolism, the substitution of hydrogen atoms with deuterium can slow the rate of metabolism, leading to improved half-life, greater tolerability, improved efficacy and dosing regimens, lower side effects, and reduced toxicity [Foster, A. B. Deuterium isotope effects in studies of drug metabolism. Trends in Pharmacological Sciences (1984) 5: 524-527; Anderson, K. E.; Stamler, D.; Davis, M. D.; et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry (2017) 4: 595-604; Harbeson, S.; Morgan, A.; Liu, J.; et al. Altering metabolic profiles of drugs by precision deuteration 2: discovery of a deuterated analog of ivacaftor with differentiated pharmacokinetics for clinical development. J. Pharmacol. Exp. Ther. (2017) 362: 359-367; T.; Feltmann, K.; Konradsson-Geuken, Deuterium-substituted l-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson's disease: comparison with the effects produced by l-DOPA and an M40-B inhibitor. J. Neural. Transm. (Vienna) (2015) 122:259-272; Mutlib, A. E.; Gerson, R. J.; Meunier, P. C. et al. The Species-Dependent Metabolism of Effavirenz Produces a Nephrotoxic Glutathione Conjugate in Rats. Toxicol. Appl. Pharmacol. (2000) 169: 102-113]. The above documents are incorporated herein by reference in their entirety for all purposes. However, in some cases, hydrogen-deuterium exchange can result in the redirection of metabolic sites ("metabolic switching") [Horning, M. G. et al. Metabolic switching of drug pathways as a consequence of drug substitution. Proceedings of the Second International Conference on Stable Isotopes (Klein, E. R. and Klein, P. D. eds) (1976) 41-54; Miwa, G. T.; Lu, A. Y. H. Kinetic isotope effects and'metabolic switching' in cytochrome P450-catalyzed reactions. Bioessays (1987) 7: 215-219]. The above documents are incorporated herein by reference in their entirety for all purposes. Also, deuterium and hydrogen are essentially identical in size and, in most cases, deuterium substitution of a drug will not be expected to affect the biochemical potency or selectivity of the deuterated drug for a biological target. Even when deuterium atoms are incorporated at known metabolic sites, the effect of deuterium modification on drug metabolism and pharmacokinetic properties is unpredictable. The effect of deuterium incorporation on absorption, distribution, metabolism, excretion, and / or toxicity (ADMET) properties can only be determined by making and testing the actual deuterated compound.

[0011] In the present invention, the entry inhibitors are identified using an arenavirus GP pseudovirus screen, and selected compounds are tested against a native non-HF virus TCRV to confirm activity against replicative arenaviruses. Selected superior compounds are then tested against a native LASV to confirm activity against native highly pathogenic human (HF) arenaviruses and to assess initial drug-like properties. SUMMARY

[0012] The present invention relates to the use of heterocyclic compounds to inhibit arenavirus infection in humans, other mammals, or in cell culture, methods of treating arenavirus infection such as Lassa hemorrhagic fever, Bolivian hemorrhagic fever, Argentine hemorrhagic fever, Venezuelan hemorrhagic fever, Brazilian hemorrhagic fever, Chapare hemorrhagic fever, and Lujo hemorrhagic fever, methods of inhibiting replication of arenaviruses, methods of reducing the amount of arenaviruses, and compositions that can be used in such methods.

[0013] In one embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound represented by structural Formula I

[0014]

[0015] or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein

[0016] A is independently selected from C and N;

[0017] G is independently selected from CH, CD, and N;

[0018] E is independently selected from CH, CD, and N;

[0019] J is independently selected from

[0020] and

[0021] R 2 is independently selected from H, D, -OR 3 , -R 4 , -NHR 10 , -CONHR 10 ;

[0022] R 3 is independently selected from H, D, C1to C6alkyl, C2to C6alkenyl, (C3to C 10 )cycloalkyl, (C2to C9)cycloheteroalkyl, -NHC(O)R 4 , -C(O)NHR 10 , and -C(O)R 10wherein each C1to C6alkyl is optionally substituted with D, halogen, -OH, -OR 4 10

[0023] R 4 is independently selected from C1to C6alkyl and (C2to C9)cycloheteroalkyl optionally substituted with D, halogen, -OH, -OR 10 10

[0024] R 5 is independently selected from H, D, C1to C6alkyl, C2to C6alkenyl, C2to C6alkynyl, halogen, -OR 3 10 4 10 10 10 4 10 wherein each C1to C6alkyl is optionally substituted with D;

[0025] R 6 is independently selected from H, D, halogen, -OR 3 4 ;

[0026] R 9 is independently selected from H, D, halogen, C1to C6alkyl, and -OR 10 ;

[0027] R 10 is independently selected from H, D, -OH, C1to C6alkyl, and C2to C6alkenyl;

[0028] and when E is N, CH or CD, then A is C, G is CH or CD, and J is

[0029]

[0030] and when A is N, then J is

[0031]

[0032] with the proviso that the following compounds are excluded:

[0033]

[0034] DETAILED DESCRIPTION

[0035] ​​​​​​​​​​​​In one embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound represented by structural Formula I

[0036]

[0037] or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein

[0038] A is independently selected from C and N;

[0039] G is independently selected from CH, CD, and N;

[0040] E is independently selected from CH, CD, and N;

[0041] J is independently selected from

[0042] and

[0043] R 2 is independently selected from H, D, -OR 3 , -R 4 , -NHR 10 , -CONHR 10 ;

[0044] R 3 is independently selected from H, D, C1to C6alkyl, C2to C6alkenyl, (C3to C 10 )cycloalkyl, (C2to C9)cycloheteroalkyl, -NHC(O)R 4 , -C(O)NHR 10 , and -C(O)R 10 , wherein each C1to C6alkyl is optionally substituted with D, halogen, -OH, -OR 4 , -NHR 10 ;

[0045] R 4 is independently selected from C1to C6alkyl and (C2to C9)cycloheteroalkyl optionally substituted with D, halogen, -OH, -OR 10 , and NHR 10 ;

[0046] R 5 is independently selected from H, D, C1to C6alkyl, C2to C6alkenyl, C2to C6alkynyl, halogen, -OR 3 , -CO2R 10 , -NHC(O)R 4 , -C(O)NHR 10 , -NHR 10 , -CHNHR10 , -CN, -CR 4 and -C(O)R 10 wherein each C1to C6alkyl is optionally substituted with D;

[0047] R 6 is independently selected from H, D, halogen, -OR 3 and R 4 ;

[0048] R 9 is independently selected from H, D, halogen, -OR 10 and C1to C6alkyl;

[0049] R 10 is independently selected from H, D, -OH, C1to C6alkyl, and C2to C6alkenyl;

[0050] and when E is N, CH or CD, then A is C, G is CH or CD, and J is

[0051]

[0052] and when A is N, then J is

[0053]

[0054] with the proviso that the following compounds are excluded:

[0055]

[0056]

[0057]

[0058] In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound or pharmaceutically acceptable salt represented by structural Formula I, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are as defined above and wherein

[0059] J is

[0060] In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound or pharmaceutically acceptable salt represented by structural Formula I, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 3 4 5 6 9 10 as defined above and wherein

[0061] J is

[0062] In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound or pharmaceutically acceptable salt represented by structural Formula I, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, J, R 2 3 4 5 6 9 10 as defined above and wherein

[0063] E is CH or CD.

[0064] In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound or pharmaceutically acceptable salt represented by structural Formula I, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein E, G, J, R 2 3 4 5 6 9 10 as defined above and wherein

[0065] A is C.

[0066] In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound or pharmaceutically acceptable salt represented by structural Formula I, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein E, G, J, R 2 3 4 5 6 9 10 ​​​​​​​​​​​​​​​​​​​​​​​​as defined above and wherein

[0067] A is N.

[0068] In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound or pharmaceutically acceptable salt represented by Structural Formula I, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 9 and R 10 as defined above and wherein

[0069] J is and R6 is or

[0070] In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample an effective amount of a compound or pharmaceutically acceptable salt represented by Structural Formula I, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 9 and R 10 as defined above and wherein

[0071] J is and R6 is or

[0072] In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising a compound selected from the compounds described in Examples Al to A3, B4 to B9, C10 to C26, D27 to D29, and E30, and a pharmaceutically acceptable carrier, diluent, or vehicle.

[0073] In another embodiment, the method comprises administering a pharmaceutically effective amount of a pharmaceutical composition comprising a selected compound of Structural Formula I or a compound as shown above, and a pharmaceutically acceptable carrier, diluent, or vehicle, and a therapeutically effective amount of a therapeutic agent selected from the group consisting of ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNA (siRNA), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors.

[0074] In another embodiment, the present application relates to a compound having the structural Formula I

[0075]

[0076] or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein

[0077] A is independently selected from C and N;

[0078] G is independently selected from CH, CD, and N;

[0079] E is independently selected from CH, CD, and N;

[0080] J is independently selected from

[0081] and

[0082] R 2 is independently selected from H, D, -OR 3 , -R 4 , -NHR 10 , -CONHR 10 ;

[0083] R 3 is independently selected from H, D, C1to C6alkyl, C2to C6alkenyl, (C3to C 10 )cycloalkyl, (C2to C9)cycloheteroalkyl, -NHC(O)R 4 , -C(O)NHR 10 , and -C(O)R 10 , wherein each C1to C6alkyl is optionally substituted with D, halogen, -OH, -OR 4 , -NHR 10 ;

[0084] R 4 is independently selected from C1to C6alkyl and (C2to C9)cycloheteroalkyl optionally substituted with D, halogen, -OH, -OR 10 , and NHR 10 ;

[0085] R 5 is independently selected from H, D, C1to C6alkyl, C2to C6alkenyl, C2to C6alkynyl, halogen, -OR 3 , -CO2R 10 , -NHC(O)R 4 , -C(O)NHR 10 , -NHR 10 , -CHNHR 10 , -CN, -CR4 and -C(O)R 10 wherein each C1to C6alkyl is optionally substituted with D;

[0086] R 6 is independently selected from H, D, halogen, -OR 3 and R 4 ;

[0087] R 9 is independently selected from H, D, halogen, -OR 10 and C1to C6alkyl;

[0088] R 10 is independently selected from H, D, -OH, C1to C6alkyl and C2to C6alkenyl;

[0089] and when E is N, CH or CD, then A is C, G is CH or CD and J is

[0090]

[0091] and when A is N, then J is

[0092]

[0093] with the proviso that the following compounds are excluded:

[0094]

[0095]

[0096]

[0097] In another embodiment, the present application relates to a compound having structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are as defined above and wherein

[0098] J is

[0099] In another embodiment, the present application relates to a compound having structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5R 6 R 9 R 10 as defined above and wherein

[0100] J is

[0101] In another embodiment, the present application is directed to a compound or pharmaceutically acceptable salt of structural formula I, and pharmaceutically acceptable carriers, diluents or vehicles therefor, wherein A, G, J, R 2 R 3 R 4 R 5 R 6 R 9 R 10 as defined above and wherein

[0102] E is CH or CD.

[0103] In another embodiment, the present application is directed to a compound or pharmaceutically acceptable salt of structural formula I, and pharmaceutically acceptable carriers, diluents or vehicles therefor, wherein E, G, J, R 2 R 3 R 4 R 5 R 6 R 9 R 10 as defined above and wherein

[0104] A is C.

[0105] In another embodiment, the present application is directed to a compound or pharmaceutically acceptable salt of structural formula I, and pharmaceutically acceptable carriers, diluents or vehicles therefor, wherein E, G, J, R 2 R 3 R 4 R 5 R 6 R 9 R 10 as defined above and wherein

[0106] A is N.

[0107] In another embodiment, the present application is directed to a compound or pharmaceutically acceptable salt of structural formula I, and pharmaceutically acceptable carriers, diluents or vehicles therefor, wherein A, G, E, R 2 R 3 R 4 R 5 R 9 R 10 as defined above and wherein

[0108] J is and R 6 is or

[0109] In another embodiment, the present application is directed to a compound having structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 9 and R 10 are as defined above and wherein

[0110] J is and R 6 is or

[0111] In another embodiment, the present application is directed to a compound selected from the group consisting of the compounds described in Examples Al to A3, B4 to B9, C10 to C26, D27 to D29, and E30 or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof.

[0112] In another embodiment, the present application is directed to a compound selected from the group consisting of the compounds described in Examples Al to A3, B4 to B9, C10 to C26, D27 to D29, and E30 or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof.

[0113]

[0114]

[0115] Definitions

[0116] As used herein, the terms "comprising" and "including," are used in their open, non- limiting sense.

[0117] The term "halogen" and / or "halo" means fluorine, chlorine, bromine, or iodine.

[0118] The term "(Ci to C6)alkyl" means saturated aliphatic hydrocarbon groups including straight- chain and branched-chain groups having from 1 to 6 carbon atoms. Examples of (Ci to C6)alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl, and the like. As used herein, the terms "Me" and "methyl" mean a -CH3group. As used herein, the terms "Et" and "ethyl" mean a -C2H5group.

[0119] As used herein, the term "(C2to C8)alkenyl" means an alkyl moiety containing 2 to 8 carbon atoms and having at least one carbon-carbon double bond. The carbon-carbon double bond in this radical can be in any position along the 2 to 8 carbon chain to produce a stable compound. Examples of such radicals include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl, and the like. As used herein, the term "allyl" means a -CH2CH=CH2group. As used herein, the term "C(R)=C(R)" represents a carbon-carbon double bond, wherein each carbon atom is substituted with an R group, and includes both E and Z isomers.

[0120] As used herein, the term "(C2to C8)alkynyl" means an alkyl moiety containing 2 to 8 carbon atoms and having at least one carbon-carbon triple bond. The carbon-carbon triple bond in this radical can be in any position along the 2 to 8 carbon chain to produce a stable compound. Examples of such radicals include, but are not limited to, ethynyl, propynyl, 1 -butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, and 3-hexynyl.

[0121] As used herein, the term "(C1to C8)alkoxy" means an O-alkyl group, wherein the alkyl group contains 1 to 8 carbon atoms and is straight-chained, branched, or cyclic. Examples of such radicals include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, cyclopentyloxy, and cyclohexyloxy.

[0122] As used herein, the term "(C6to C 10 )aryl" means a group derived from an aromatic hydrocarbon containing 6 to 10 carbon atoms. Examples of such radicals include, but are not limited to, phenyl or naphthyl. As used herein, the terms "Ph" and "phenyl" mean a -C6H5group. As used herein, the term "benzyl" means a -CH2C6H5group.

[0123] As used herein, “(C2to C9)heteroaryl” means an aromatic heterocyclic radical having a total of 5 to 10 atoms in its ring and containing 2 to 9 carbon atoms and 1 to 4 heteroatoms each independently selected from O, S, and N, and with the proviso that the ring of the radical does not contain two adjacent O atoms or two adjacent S atoms. Heterocyclic radicals include benzo-fused ring systems. Examples of aromatic heterocyclic radicals are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furopyridinyl, benzo-furopyridinyl, benzo-thiophenyl, benzo-thiazolyl, benzo-oxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. (C2to C9)heteroaryl can be C-linked or N-linked where possible. For example, a radical derived from pyrrole can be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Further, a radical derived from imidazole can be imidazol-1-yl (N-linked) or imidazol-3-yl (C-linked).

[0124] As used herein, "(C2 to C9) cycloheteroaryl" means a non-aromatic monocyclic, bicyclic, tricyclic, spirocyclic or tetracyclic group having a total of 4 to 13 atoms in its ring system and containing 5 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from O, S and N, and provided that the ring of the group does not contain two adjacent O atoms or two adjacent S atoms. In addition, such C2 to C9 cycloheteroalkyl groups can contain oxo substituents on any available atom to produce a stable compound. For example, such a group can contain oxo atoms on an available carbon or nitrogen atom. If chemically feasible, such a group can contain more than one oxo substituent. In addition, it should be understood that when such C2 to C9 cycloheteroalkyl groups contain a sulfur atom, the sulfur atom can be oxidized by one or two oxygen atoms to obtain sulfoxide or sulfone. An example of a 4-membered cycloheteroalkyl group is azetidinyl (derived from azetidine). An example of a 5-membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6-membered cycloheteroalkyl group is piperidinyl. Examples of 9-membered cycloheteroalkyl groups are indolinyl. Examples of 10-membered cycloheteroalkyl groups are 4H-quinolizinyl. Other examples of such C2 to C9 cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thiooxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 1-Oxo-2,8,diazaspiro[4.5]dec-8-yl, 2-Oxo-3,4-diazaspiro[4.5]decan-8-yl, 2-Oxo-4,4-diazaspiro[4.5]decan ...

[0125] The term "(C3 to C 10 )Cycloalkyl" means a saturated, monocyclic, fused, spirocyclic or polycyclic ring structure having a total of 3 to 10 carbon ring atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl and adamantyl.

[0126] As used herein, the term "spirocycle" has its conventional meaning, i.e., any compound containing two or more rings in which two rings have one common carbocyclic ring. As defined herein, the rings of a spirocycle independently have from 3 to 20 ring atoms. Preferably, they have from 3 to 10 ring atoms. Non-limiting examples of spirocycle compounds include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

[0127] The term "(C5to C8)cycloalkenyl" means an unsaturated, monocyclic, fused, spirocyclic ring structure having a total of 5 to 8 carbon ring atoms. Examples of such groups include, but are not limited to, cyclopentenyl, cyclohexenyl.

[0128] An "aldehyde" group refers to a carbonyl group -C(O)R, wherein R is hydrogen.

[0129] As defined herein, "alkoxy" means -O-alkyl and -O-cycloalkyl.

[0130] "Alkylsulfonyl" means -SO2alkyl.

[0131] "Alkylsulfonyl" means -SO2alkyl.

[0132] "Amino" means an -NH2or -NRR' group.

[0133] "Aminoalkyl" means an -alkyl-NRR' group.

[0134] "Aminoalkyl" means an -alkyl-NRR' group.

[0135] "Aminocarbonyl" means -C(O)NRR'.

[0136] "Arylalkyl" means -alkylaryl, wherein alkyl and aryl are as defined herein.

[0137] "Aryloxy" as defined herein means -O-aryl and -O-heteroaryl.

[0138] "Aryloxycarbonyl" means -C(O)Oaryl.

[0139] "Arylsulfonyl" means -SO2aryl.

[0140] "C-amido" means a -C(O)NRR' group.

[0141] "Carbonyl" means -C(O)R.

[0142] "C-carboxy" means a -C(O)OR group.

[0143] "Carboxylic acid" group means a C-carboxy group wherein R is hydrogen.

[0144] "Cyano" refers to a -CN group.

[0145] "Dialkylaminoalkyl" refers to a -(alkyl)N(alkyl)2 group.

[0146] "Halo" or "halogen" group means fluoro, chloro, bromo or iodo.

[0147] "Haloalkyl" means an alkyl group substituted by one or more halogen atoms.

[0148] "Heteroaryloxy" refers to a heteroaryl-O- group with the heteroaryl group defined herein.

[0149] "Hydroxy" refers to a -OH group.

[0150] "N-amido" refers to a -R'C(O)NR group.

[0151] "N-carbamoyl" refers to a -ROC(O)NR- group.

[0152] "Nitro" refers to a -NO2 group.

[0153] "N-sulfonamido" refers to a -NR-S(O)2R group.

[0154] "N-thiocarbamoyl" refers to a ROC(S)NR' group.

[0155] "O-carbamoyl" refers to a -OC(O)NRR' group.

[0156] "O-carboxy" refers to a RC(O)O group.

[0157] "O-thiocarbamoyl" refers to a -OC(S)NRR' group.

[0158] "Oxo" group refers to a carbonyl moiety, such that an alkyl group substituted by oxo refers to a keto group.

[0159] "Perfluoroalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced by fluorine atoms.

[0160] "Phosphono" refers to a -P(O)(OR)2 group.

[0161] "Silyl" refers to a -SiR3 group.

[0162] "S-sulfonamido" refers to a -S(O)2NR- group.

[0163] "Sulfinyl" refers to a -S(O)R group.

[0164] "Sulfonyl" refers to a -S(O)2R group.

[0165] "Carboxy" or "carboxyl" means the -C(O)OH group.

[0166] "Trifluoromethane carbonyl" means a Z3CC(O) group, where Z is halogen.

[0167] "Trifluoromethane sulfonyl" means a Z3CS(O)2 group, where Z is halogen.

[0168] "Trifluoromethane sulfonyl" means a Z3CS(O)2 group, where Z is halogen.

[0169] "Trifluoromethane sulfonyl" means a Z3CS(O)2 group, where Z is halogen.

[0170] "C-carboxy" means a -C(O)OR group.

[0171] The term "substituted" means that the designated group or moiety bears one or more substituents.

[0172] The term "unsubstituted" means that the designated group bears no substituents. The term "optionally substituted" means that the designated group is either unsubstituted or substituted with one or more substituents. It should be understood that in the compounds of the application, when a group is said to be "unsubstituted" or "substituted" with fewer than the number of atoms needed to fill the valence of the group in the compound, the remaining valence on the group is filled with hydrogens. For example, if a C6aryl group (also referred to herein as "phenyl") is substituted with another substituent, one of ordinary skill in the art will understand that the group has 4 open positions remaining on the carbon atoms of the C6aryl ring (6 initial positions, minus one position bonded to the remainder of the compound of the application, minus another substituent, leaving 4). In such a case, the remaining 4 carbon atoms are each bonded to a hydrogen atom to fill their valence. Similarly, if a C6aryl group in a compound of the application is said to be "disubstituted", one of ordinary skill in the art will understand that this means that the C6aryl group has 3 unsubstituted remaining carbon atoms. These three unsubstituted carbon atoms are each bonded to a hydrogen atom to fill their valence.

[0173] The term "solvate" is used to describe a molecular complex of a compound of the present application with a solvent molecule. Examples of solvates include, but are not limited to, compounds of the present application in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. When the solvent is water, the term "hydrate" can be used. It is specifically contemplated that, in the present application, one solvent molecule can be associated with one molecule of a compound of the present application, such as a monohydrate. It is further specifically contemplated that, in the present application, more than one solvent molecule can be associated with one molecule of a compound of the present application, such as a dihydrate. In addition, it is specifically contemplated that, in the present application, less than one solvent molecule can be associated with one molecule of a compound of the present application, such as a hemihydrate. Furthermore, solvates of the present application are contemplated to be solvates that retain the biological effectiveness of the non-hydrated form of the compounds of the present application.

[0174] The term "pharmaceutically acceptable salt," as used herein, means a salt of a compound of the present application that retains the biological effectiveness of the free acids and bases of the designated derivatives and is biologically or otherwise

[0175] The term "pharmaceutically acceptable formulation," as used herein, means a combination of a compound of the present application or a salt or solvate thereof and a carrier, diluent, and / or excipient that is compatible with the compound of the present application and not deleterious to the recipient thereof. Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art. For example, the compounds of the present application can be formulated with common excipients, diluents, or carriers and molded into tablets, capsules, and the like. Examples of excipients, diluents, and carriers suitable for use in such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as polyidone, sodium starch glycolate, sodium carboxymethylcellulose, agar-agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface-active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylene glycols. The final pharmaceutical form can be a pill, tablet, powder, lozenge, sachet, cachet, sugar-coated tablet, or sterile packaged powder, and the like, depending on the type of excipient used. In addition, it is specifically contemplated that the pharmaceutically acceptable formulations of the present application can contain more than one active ingredient. For example, such formulations can contain more than one compound according to the present application. Alternatively, such formulations can contain one or more compounds of the present application and one or more additional agents that inhibit an arenavirus.

[0176] As used herein, the term "arenavirus GP-inhibiting amount" refers to the amount of a compound of the application, or salt or solvate thereof, required to inhibit cell entry in vivo, such as in a mammal, a bird, or in vitro. The amount of such compound required to cause such inhibition can be determined without undue experimentation using the methods described herein and methods known to those of ordinary skill in the art.

[0177] As used herein, the term "therapeutically effective amount" means the amount of a compound of the application, or salt thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment as defined herein. Thus, a therapeutically effective amount of a compound of the application, or salt thereof, is an amount that is sufficient to modulate or inhibit the activity of an arenavirus GP protein, such that the cell entry or replication of an arenavirus mediated by the activity of the arenavirus GP protein is reduced or alleviated.

[0178] The term "treat", "treating" or "treatment" with respect to an arenavirus infection in a mammal, particularly a human, includes: (i) preventing the disease or condition from occurring in a subject which can be predisposed to the disease or condition, but has not yet developed the pathology or symptomatology thereof, such that treatment constitutes prophylactic treatment; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving or alleviating the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and / or alleviating the symptoms resulting from the disease or condition.

[0179] Unless otherwise indicated, all references herein to a compound of the application include references to salts, solvates and complexes thereof, including polymorphs, stereoisomers, tautomers and isotopically labeled forms thereof. For example, a compound of the application can be a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate.

[0180] The term "stereoisomer" refers to compounds which have the same chemical constitution, but differ with regard to their arrangement in space. In particular, the term "enantiomer" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. A pure enantiomer can be contaminated with up to about 10% of the opposite enantiomer.

[0181] As used herein, the term "racemic" or "racemic mixture" refers to a 1 : 1 mixture of enantiomers of a particular compound. On the other hand, the term "diastereomer" refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another. According to convention used in the art, the symbol is used in structural formulas herein to depict a bond which is a point of attachment of one moiety or substituent to the core or backbone structure. According to another convention, in some structural formulas herein, carbon atoms and their bonded hydrogen atoms are not explicitly depicted, e.g. represents a methyl group, represents ethyl, represents cyclopentyl, etc.

[0182] The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be represented herein using solid lines (__), solid wedge lines (__), and or dashed wedge The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that only the stereoisomers shown are included. The compounds of the present invention may contain more than one asymmetric carbon atom. In these compounds, the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers are included. For example, unless otherwise indicated, it is expected that the compounds of the present invention may exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of solid lines to depict bonds to one or more asymmetric carbon atoms in the compounds of the present invention and the use of solid or dashed wedges to depict bonds to other asymmetric carbon atoms in the same compound is intended to indicate that a mixture of diastereomers exists.

[0183] Unless otherwise defined, a substituent "R" may be present on any atom of the ring system provided that it replaces a drawn, implied or explicitly defined hydrogen from a ring atom so long as a stable structure results.

[0184] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemic form, for example, by using chiral high pressure liquid chromatography (HPLC). Alternatively, a racemic form (or racemic precursor) can be reacted with a suitable optically active compound (for example, an alcohol) or, where the compound contains an acidic or basic moiety, with an acid or a base such as tartaric acid or 1-phenylethylamine. The resulting mixture of diastereoisomers can be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers can be converted into the corresponding pure enantiomers by means well known to those skilled in the art. Chiral compounds of the application (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on an asymmetric resin, wherein the mobile phase consists of a hydrocarbon (typically heptane or hexane) containing 0% to 50% isopropanol (typically 2% to 20%) and 0% to 5% of an alkylamine (typically 0.1% diethylamine). Concentration of the eluate gives an enriched mixture. The diastereoisomeric assembly can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the disclosure of which is hereby incorporated by reference in its entirety.

[0185] When the compounds of the application contain alkenyl or alkynyl groups, geometric cis / trans (or Z / E) isomers are possible. In cases where the compounds contain, for example, keto or oxime groups or aromatic moieties, tautomerism ("tautomerism") can occur. Examples of tautomers include keto and enol tautomers. A single compound can exhibit more than one type of isomerism. All stereoisomers, geometric isomers and tautomers of the compounds of the application, including mixtures thereof, are within the scope of the present application, alone or as a mixture of one or more thereof. Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0186] The compounds of the present application can be administered as prodrugs. Thus, certain derivatives of compounds of Formula I which can have little or no pharmacological activity themselves can, when administered into a mammal, be converted into compounds of Formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs." A prodrug can be formed, for example, by displacing an appropriate functional group present in a compound of Formula I with certain moieties known to one skilled in the art. See, for example, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (E B Roche, ed., American Pharmaceutical Association). Some examples of such prodrugs include: ester moieties replacing carboxylic acid functions; ether moieties or amide moieties replacing alcohol functions; and amide moieties replacing primary or secondary amino functions. Additional examples of displacing groups are known to those skilled in the art. See, for example, "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety. It is also possible that certain compounds of Formula I can act as prodrugs of other compounds of Formula I themselves.

[0187] The salts of the present application can be prepared in a manner known per se to those skilled in the art. Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate, bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1, 4 diacid, calcium edetate, camphorsulfonate, carbonate, chloride, caproate, caprylate, clavulariate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, ethylenediaminetetraacetate, ethanedisulfonate, estolate, ethanesulfonate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, heptanoate, hexyne-1, 6- diacid, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, gamma- hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methylsulfate, monohydrogenphosphate, mucate, naphthalenesulfonate, naphthalene-1- sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propyne, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, 8-chlorotheophyllinate, tosylate, triethiodode, and valerate.

[0188] Compounds of the present application that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present application as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present application can be prepared by treating the base compound with an essentially equivalent amount of the chosen mineral or organic acid in a water solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by addition of the appropriate mineral or organic acid to the solution.

[0189] Those compounds of the present application which are acidic in nature are capable of forming base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali or alkaline-earth metal salts, and particularly sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents for the preparation of the pharmaceutically acceptable basic salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such nontoxic base salts include those derived from such alkali metals as sodium and potassium, and alkaline earth metals such as calcium and magnesium. These salts can be prepared by treating the acidic compounds of the present invention with an aqueous solution containing the base salt desired, followed by evaporation of the resulting solution to dryness in the presence of a reduced pressure, preferably under a reduced pressure. Alternatively, they can be prepared by mixing a solution of the acidic compound in a lower alcohol with an alkali metal alcoholate, followed by evaporation of the resulting solution to dryness in the same manner as before. In either case, it is preferable to use stoichiometric quantities of the reagents to ensure complete reaction and maximum yield of the desired end product.

[0190] If the compound of the present application is a base, the desired salt can be prepared by any appropriate method available in the art, for example, by treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartamic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, and the like.

[0191] If the compound of the present application is an acid, the desired salt can be prepared by any appropriate method available in the art, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali-metal or alkaline-earth-metal hydroxide; and the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0192] In the case of agents which are solids, it will be understood by one skilled in the art that the compounds, agents, and salts of the present application can exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present application and specified formulas.

[0193] The present application also includes isotopically-labelled compounds of the present application, wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present application include isotopes of hydrogen, such as2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, such as 36 Cl, 35 Cl and 37 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35 S.

[0194] Certain isotopically-labeled compounds of the present invention, for example those incorporating radioactive isotopes, are useful in drug and / or substrate tissue distribution studies. 3 H and carbon-14 14 C is particularly useful for this purpose because of its ease of incorporation and ease of detection. 2 Substitution of H may result in certain therapeutic advantages resulting from greater metabolic stability, e.g. 35 S increases in vivo half-life or reduces dosage requirements and is therefore preferred in some circumstances. Use of positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent originally employed.

[0195] The term "deuterated" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms. Unless otherwise indicated, when a particular position in a compound of the invention is explicitly designated as "D," "deuterium," "deuterated," or "having deuterium" (the element deuterium is represented by the letter "D" in chemical structures and formulas, and by lowercase "d" in chemical names), it is understood that the deuterium at that position is at least 3000 times more abundant than the natural deuterium abundance (which is 0.015%) (i.e., the term "D," "d," or "deuterium" indicates at least 45% deuterium incorporation).

[0196] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance of a specified isotope and the natural abundance.

[0197] In some embodiments, the compounds of the present application have an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each deuterium atom present at a site designated as a deuterium potential site on the compound.

[0198] The compounds of the present application can be formulated into pharmaceutical compositions in any pharmaceutical form as deemed appropriate by the skilled artisan. The pharmaceutical compositions of the present application comprise a therapeutically effective amount of at least one compound of the present application and an inert, pharmaceutically acceptable carrier or diluent.

[0199] For the treatment or prevention of a disease or disorder mediated in whole or in part by an arenavirus infection or a virus expressing an arenavirus glycoprotein, the pharmaceutical compositions of the present application are administered in suitable formulations prepared by combining a therapeutically effective amount (i.e., an arenavirus GP modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present application as the active ingredient with one or more pharmaceutically suitable carriers, which can be chosen, for example, from diluents, excipients, and auxiliaries that facilitate processing of the active compound into the final pharmaceutical preparation.

[0200] The pharmaceutical carrier employed can be a solid or a liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are sugar syrup, peanut oil, olive oil, water and the like. Similarly, the composition of the present application can include time delay or time release materials known in the art such as glycerol monostearate or glycerol distearate, alone or with wax, ethyl cellulose, hydroxypropylmethyl cellulose, methymethacrylate, and the like. Additional additives or excipients can be added to achieve the desired formulation properties. For example, bioavailability enhancers such as Labrasol, Gelucire, and the like; or formulation agents such as CMC (carboxymethylcellulose), PG (propylene glycol), or PEG (polyethylene glycol) can be added. For example, when preparing a capsule formulation, a A semi-solid excipient that protects the active ingredient from light, moisture, and oxidation.

[0201] If a solid carrier is used, the formulation can be tableted or encased in a hard gelatin capsule, or prepared as a sugar or film coated tablet in powder or pellet form. The amount of solid carrier will vary but will typically be from about 25 mg to about 1 g. If a liquid carrier is used, the formulation can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampul or vial, or a non-aqueous liquid suspension. If a semi-solid carrier is used, the formulation can be in the form of a hard and soft gelatin capsule formulation. The compositions of the present application can be prepared in unit dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.

[0202] To obtain a stable aqueous dosage form, a salt of the compound of the present application can be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent can be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include alcohols, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like, in concentrations ranging from 0% to 60% of the total volume. The composition can also be in the form of a solution of the salt form of the active ingredient in an appropriate aqueous vehicle, such as water or isotonic saline or dextrose solution.

[0203] The appropriate formulation depends on the chosen route of administration. For injection, the agent of the compound of the present application can be formulated in an aqueous solution, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

[0204] For transmucosal administration, a permeation agent appropriate to the barrier to be penetrated is used in the formulation. Such permeation agents are generally known in the art.

[0205] For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the application to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained by employing solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as a cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, there can be used concentrated sugar solutions, which can optionally contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active agent.

[0206] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active agents can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions can take the form of tablets or troches formulated in the conventional manner.

[0207] For administration by nasal inhalation or insufflation, the compounds useful according to the present application can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount.

[0208] Capsules and cartridges of gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0209] The compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules as a solution in sterile water, saline or other injectable media. These compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0210] Pharmaceutical formulations for parenteral administration include aqueous solutions of active compounds in water-soluble form. Additionally, suspensions of the active agents can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0211] Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0212] In addition to the formulations described above, the compounds of the present application can also be formulated as depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated in suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as slightly soluble derivatives (for example, as slightly soluble salts). A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system can be a VPD cosolvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v nonpolar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300, made up in absolute ethanol. VPD cosolvent system (VPD:5W) contains VPD diluted 1:1 with 5% dextrose in water. This cosolvent system dissolves hydrophobic compounds well and is itself of low toxicity upon systemic administration. The proportions of the cosolvent system can be varied as appropriate without destroying its solubility and toxicity characteristics. In addition, the identity of the cosolvent components can be varied: for example, other low toxicity nonpolar surfactants can be used instead of polysorbate 80; the size grade of the polyethylene glycol can be varied; other biocompatible polymers, for example polyvinylpyrrolidone, can replace the polyethylene glycol; and other sugars or polysaccharides can replace the dextrose.

[0213] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide can also be employed, but typically at the cost of greater toxicity to the host. Additionally, sustained release systems such as semipermeable matrices of a solid hydrophobic polymer containing the therapeutic agent can be used to deliver the compound. Various sustained release materials have been established and are known to those skilled in the art. Sustained release capsules can release the active ingredient for a few weeks up to over 100 days depending on their chemical nature. Other protein stabilization strategies can be employed depending on the chemical nature and biological stability of the therapeutic agent.

[0214] The pharmaceutical compositions can also contain suitable solid or gel phase carriers or excipients. These carriers and excipients can provide significant improvements in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivates, gelatin and polymers such as polyethylene glycols. In addition, additives or excipients such as and the like.

[0215] In addition, the pharmaceutical compositions can be incorporated into a skin patch for direct delivery of the drug onto the skin.

[0216] It will be appreciated that the actual dose of an agent of the present application will vary according to the particular agent employed, the particular composition formulated, the mode of administration and the particular site, host and disease to be treated. Optimal dosages for a given set of conditions can be determined by routine dosing procedures known in the art. For example, an exemplary daily dose commonly employed can be from about 0.001 to about 1000 mg / kg body weight, with repeat administrations at appropriate intervals depending on the half-life of the compound in the host.

[0217] In addition, the pharmaceutically acceptable formulations of the present application can contain the compound of the present application or a salt or solvate thereof in an amount of about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 10 mg to about 500 mg, or about 25 mg to about 500 mg, or about 50 to about 500 mg, or about 100 mg to about 500 mg.

[0218] Additionally, the pharmaceutically acceptable formulations of the present application can contain the compounds of the present application or salts or solvates thereof in an amount of about 0.5 w / w% to about 95 w / w%, or about 1 w / w% to about 95 w / w%, or about 1 w / w% to about 75 w / w%, or about 5 w / w% to about 75 w / w%, or about 10 w / w% to about 75 w / w%, or about 10 w / w% to about 50 w / w% as a part of the pharmaceutically acceptable formulations.

[0219] The compounds of the present application or salts or solvates thereof can be administered to a mammal (such as a human) suffering from a disorder or disease mediated by an arenavirus or any virus expressing an arenavirus glycoprotein, either alone or in combination with one or more compounds selected from ribavirin, polymerase inhibitors, favipiravir, taribavirin, small interfering RNA (siRNA), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors, once a day, twice a day, three times a day, four times a day, or even more frequently, as a part of a pharmaceutically acceptable formulation.

[0220] A compound of the application, or a salt or solvate thereof, can be administered to a mammal (such as a human) suffering from a disorder or disease mediated by an arenavirus in combination with at least one other agent selected from the group consisting of ribavirin (a viral RNA-dependent RNA polymerase inhibitor) (as shown by Ng KK, Arnold JJ and Cameron CE, Structure-Function Relationships Among RNA-Dependent RNA Polymerases, Curr Top Microbiol Immunol, 2008; 320: 137-156, which is incorporated herein by reference in its entirety), favipiravir (a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase), trelaviru (a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase), small interfering RNA (siRNA) and microRNA (as shown by Carthew RW and Sontheimer EJ, Origins and Mechanisms of miRNAs and siRNAs, Nature, 2009; 136: 642-655, which is incorporated herein by reference in its entirety), vaccines (as shown by Nabel GJ, Designing Tomorrow’s Vaccines, NEJM, 2013; 368: 551-560, which is incorporated herein by reference in its entirety) and immunomodulators (as shown by Patil US, Jaydeokar AV and Bandawane DD, Immunomodulators: A Pharmacological Review, Internatl J Pharmacy and Pharmaceutical Sci, 2012; 4: 30-36, which is incorporated herein by reference in its entirety), either alone or as part of a pharmaceutically acceptable formulation containing other arenavirus inhibitors, once a day, twice a day, three times a day, four times a day or even more frequently.

[0221] It will be understood by one of ordinary skill in the art that the particular pharmaceutical formulation, dose and number of doses administered per day to a mammal in need of such treatment for a compound of the application are all choices within the knowledge of one of ordinary skill in the art and are determined without undue experimentation.

[0222] A compound of the application can be used to modulate or inhibit arenavirus glycoprotein (GP) in vitro and in vivo.

[0223] Accordingly, these compounds are useful for preventing and / or treating a disease state associated with an arenavirus infection or treating a virus expressing an arenavirus glycoprotein.

[0224] The present application also relates to a method for treating an arenavirus infection in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I as defined above or a salt or solvate thereof effective to treat a disease state associated with an arenavirus infection or a virus expressing an arenavirus glycoprotein.

[0225] In the following preparations and examples, "Ac" means acetyl, "Me" means methyl, "Et" means ethyl, "Ph" means phenyl, "Py" means pyridine, "BOC", "Boc" or "boc" means N-tert-butoxycarbonyl, "Ns" means 2-nitrobenzenesulfonyl, "DCM" (CH2Cl2) means dichloromethane or methylene chloride, "dba" means dibenzylideneacetone, "DCE" means dichloroethane or chlorinated ethylene, "D" or "d" means deuterium, "DIAD" means diisopropyl azodicarboxylate, "DIPEA" or "DIEA" means diisopropylethylamine, "DMA" means N,N-dimethylacetamide, "DMF" means N-N- dimethylformamide, "DMSO" means dimethylsulfoxide, "DPPP" means 1,3- bis(diphenylphosphino)propane, "HOAc" means acetic acid, "IPA" means isopropanol, "NMP" means 1-methyl 2-pyrrolidinone, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "DCM" means dichloromethane, "EtOAc" means ethyl acetate, "MgSO4" means magnesium sulfate, "Na2SO4" means sodium sulfate, "MeOH" means methanol, "Et2O" means diethyl ether, "EtOH" means ethanol, "H2O" means water, "HCl" means hydrochloric acid, "POCl3" means phosphorous oxychloride, "SOCl2" means thionyl chloride, "K2CO3" means potassium carbonate, "THF" means tetrahydrofuran, "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene, "LiHMDS" or "LHMDS" means lithium hexamethyldisilazide, "TBME" or "MTBE" means tert-butyl methyl ether, "LDA" means lithium diisopropylamide, "NBS" means N-bromosuccinimide, "NIS" means N-iodosuccinimide, "Xanthphos" means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; "P(Ph3)" means triphenylphosphine, "N" means normal, "M" means molar, "mL" means milliliter, "mmol" means millimole, "μmol" means micromole, "eq." means equivalent, "°C" means degrees Celsius, "Pa" means pascal.

[0226] Preparation method

[0227] The compounds of the application can be prepared using the reaction pathways and synthetic schemes described below, employing techniques available in the art using readily available reagents. The preparation of certain embodiments of the application is described in detail in the following examples, but one of ordinary skill in the art will recognize that the preparations can be readily adapted to prepare other embodiments of the application. For example, the synthesis of unillustrated compounds according to the application can be carried out by modifications obvious to those skilled in the art, for example, by appropriate protection of interfering groups, by substitution of other suitable reagents known in the art, or by routine modification of reaction conditions. Alternatively, it will be recognized that other reactions mentioned herein or known in the art have applicability to the preparation of other compounds of the application.

[0228] Scheme 1 illustrates a method that can be used to synthesize compounds having structural Formula I where G is CH, J is N, E is CH and A is C. Compound 1-1 (X = Cl, Br or I and Y is F, Cl, Br or I) can be reacted with an amine R 2 NH2in the presence of a base such as NaH or Cs2C03in a solvent such as THF or DMF to form compound 1-2. Reduction of the nitro group using a reducing agent such as Fe or SnCl2in a solvent such as THF or methanol can provide aniline 1-3, which can be reacted with formic acid HCO2H or an ortho ester HC(OR)3to form 1-4. Coupling of 1-4 with a boronic acid or boronic ester R 1 B(OR)2in the presence of a base such as K2C03using a catalyst such as [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride in a solvent such as dimethoxyethane can provide a compound having structural Formula I.

[0229] Scheme 1

[0230]

[0231] Scheme 2 illustrates a method to synthesize deuterated aniline 2-4, which can be used to prepare deuterated intermediate 1-2 to synthesize deuterated compounds of the application as described above in Scheme 1. Reaction of phenol 2-1 with deuterated alkyl halide 2-2 (X' = Br or I) in the presence of a base such as K2C03in a solvent such as N,N-dimethylformamide can provide compound 2-3. Reduction of the nitro group using a reducing agent such as hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as methanol can provide aniline 2-4.

[0232] Scheme 2

[0233]

[0234] Scheme 3 illustrates a method for the synthesis of deuterated aniline 3-4, which can be used to prepare deuterated intermediate 1-2 for the synthesis of deuterated compounds of the application as described above in Scheme 1. Arylation of alcohol 3-1 with diaryliodonium salt 3-2 in a solvent such as pentane in the presence of a base such as NaHMDS can provide compound 3-3 [Lindstedt, E.; Stridfeldt, E.; Olofsson, B. Mild synthesis of sterically congested alkyl arylethers. Org. Lett. (2016) 18: 4234-4237]. The above document is incorporated herein by reference in its entirety for all purposes. Reduction of the nitro group using a reducing agent such as hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as methanol can provide aniline 3-4.

[0235] Scheme 3

[0236]

[0237] Scheme 4 illustrates a method that can be used to synthesize compounds of structural formula I where A is N, E is CH and J is C. Compound 4-1 (X = Cl, Br) can be coupled with boronic acid or boronic ester R 1 B(OR)2in the presence of a base such as K2CO3 using a catalyst such as [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride in a solvent such as dimethoxyethane to form 4-2, which can be treated with a halogenating reagent such as bromine or N-bromosuccinimide (NBS) or iodine or N-iodosuccinimide (NIS) to form compound 4-3 (Y = Br, I). Treatment of 4-3 with boronic acid or boronic ester R 2 B(OR)2in the presence of a base such as K2CO3 using a catalyst such as tetrakis(triphenylphosphine)palladium in a solvent such as dioxane to provide a compound of structural formula I. Alternatively, compound 4-4 (X = Cl, Br) can be reacted with boronic acid or boronic ester R 2 B(OR)2in the presence of a base such as K2CO3 using a catalyst such as [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride in a solvent such as dimethoxyethane to form 4-5, which can be reacted with a second boronic acid or boronic ester R 1 B(OR)2in the presence of a base such as K2CO3 using a catalyst such as tetrakis(triphenylphosphine)palladium in a solvent such as dioxane to provide a compound of structural formula I.

[0238] Scheme 4

[0239]

[0240] Scheme 5 illustrates a method that can be used to synthesize compounds having structural Formula I where G is CH, A is C, J is N, and E is N. Compound 5-1 (X = Cl, Br, or I and Y is F, Cl, Br, or I) can be reacted with an amine R 2 NH2in the presence of a base such as NaH or K2CO3in a solvent such as THF or DMF to form compound 5-2. Reduction of the nitro group using a reducing agent such as Fe or SnCl2in a solvent such as THF or methanol can provide aniline 5-3, which can be reacted with nitrous acid to form 5-4. Coupling of 5-4 with a boronic acid or boronic ester R 1 B(OR)2in the presence of a base such as K2CO3using a catalyst such as [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride in a solvent such as dimethoxyethane can provide a compound having structural Formula I.

[0241] Scheme 5

[0242]

[0243] Reaction Schemes 6-8 illustrate methods of synthesizing borane reagents 6-4, 7-4, and 8-4, which can be used to prepare deuterated intermediates and final compounds of the application as described in Schemes 1, 4, and 5 above to incorporate R 1 and / or R 2 substituents.

[0244] Scheme 6 illustrates a method that can be used to synthesize deuterated boronic acid or boronic ester 6-4. Reaction of phenol 6-1 (X = Br or I) with deuterated alkyl halide 6-2 (X' = Br or I) in the presence of a base such as K2CO3in a solvent such as N,N-2-methylformamide can give compound 6-3. Compound 6-3 can be converted to boronic acid or boronic ester 6-4 using standard boronation reaction conditions well known to those skilled in the art. For example, metal-halogen exchange of compound 6-3 with an organolithium reagent such as n-butyllithium followed by treatment with a trialkyl borate B(OR)3can provide boronic ester 6-4, which can be hydrolyzed to give the free boronic acid 6-4 (R = H).

[0245] Scheme 6

[0246]

[0247] Scheme 7 illustrates a method that can be used to synthesize deuterated boronic acids or boronic esters 7-4. Reaction of phenol 7-1 (X = Br or I) with deuterated alkyl bromide 7-2 using a catalyst such as nickel(II) acetylacetonate in the presence of a base such as NaHC03in a solvent such as toluene can provide compound 7-3 [Hodous, B. L. U.S. Patent Application Publication No. US2016 / 0031892, February 4, 2016]. The above patent is incorporated herein by reference in its entirety for all purposes. Compound 7-3 can be converted to boronic acid or boronic ester 7-4 using standard borylation reaction conditions well known to those skilled in the art. For example, metal-halogen exchange of compound 7-3 with an organolithium reagent such as n-butyllithium followed by treatment with a trialkyl borate B(OR)3can provide boronic ester 7-4, which can be hydrolyzed to give the free boronic acid 7-4 (R = H).

[0248] Scheme 7

[0249]

[0250] Scheme 8 illustrates a method that can be used to synthesize deuterated boronic acids or boronic esters 8-4. Metal-halogen exchange of compound 8-1 (X = Br or I) with an organolithium reagent such as n-butyllithium followed by treatment with compound 8-2 in a solvent such as tetrahydrofuran can provide compound 8-3. Compound 8-3 can be converted to boronic acid or boronic ester 8-4 using standard borylation reaction conditions well known to those skilled in the art. For example, coupling of compound 8-3 with a diboron reagent such as bis(pinacolato)diboron using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride in the presence of a base such as potassium acetate in a solvent such as dioxane can provide boronic ester 8-4.

[0251] Scheme 8

[0252]

[0253] Examples

[0254] Preparation of intermediates for Examples A1 to A3.

[0255] 5-bromo-N 1 -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine

[0256]

[0257] To a solution of 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (200 mg, 0.85 mmol) in isopropanol (2 mL) was added 4-isopropoxyaniline (129 mg, 0.85 mmol). The resulting mixture was stirred at 120 °C for 30 min under microwave irradiation. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was dissolved in ethanol (0.6 mL), dioxane (0.6 mL) and water (0.3 mL). To the solution was added iron (476 mg, 8.5 mmol) and NH4CI (457 mg, 8-5 mmol). The reaction was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by Si02column chromatography (hexane / EtOAc = 3:1) to give 198 mg (69.2%) of the product as a white solid. LC / MS m / z: 335.13 79 Br, M+H) + , 337.19( 81 Br, M+H) + , 376.28( 79 Br, M+H+CH3CN) + , 378.25( 81 Br, M+H+CH3CN) + .

[0258] 5-bromo-N1-(4-(tert-butoxy)phenyl)-4-methylbenzene-1,2-diamine

[0259]

[0260] The title compound was prepared in the same manner as described for 5-bromo-N 1 -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine from 1-bromo-5-fluoro-2-methyl-4-nitrobenzene and 4-(tert-butoxy)aniline. LC / MS m / z: 351.24 79 Br, M+H+CH3CN) +

[0261] 6-bromo-5-methyl-1-[4-(propan-2-yloxy)phenyl]-1H-1,3-benzoxazole

[0262]

[0263] To 5-bromo-N 1A solution of (4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine (50.1 mg, 0.15 mmol) in THF (1 mL) was added trimethoxymethane (18.9 mg, 0.18 mmol) followed by formic acid (100 uL). The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by Si02column chromatography (hexane / EtOAc = 1 :1 ) to give 42.1 mg (81.7%) of the product as a white solid. LC / MS m / z: 345.15 (M+H) 79 Bt, M+H) + , 347.21 (M+H) 81 Br, M+H) + , 386.28 (M+H) 79 Br, M+H+CH3CN) + , 388.20 (M+H) 81 Br, M+H+CH3CN) + .

[0264] 6-bromo-1 -(4-(tert-butoxy)phenyl)-5-methyl-1 H-benzo[d]imidazole

[0265]

[0266] The title compound was prepared from 5-bromo-N1 -(4-(tert-butoxy)phenyl)-4- methylbenzene-1,2-diamine in the same manner as described for 6-bromo-5-methyl-1 -[4- (prop-2-yloxy)phenyl]-1 H-1,3-benzodiazole. 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1 H), 7.77 (s, 1 H), 7.74 (s, 1 H), 7.57 (d, 2H), 7.21 (d, 2H), 2.47 (s, 3H), 1.37 (s, 9H). LC / MS m / z: 359.16 (M+H) 79 Br, M+H+CH3CN) + , 361.17 (M+H) 81 Br, M+H+CH3CN) + .

[0267] Example A1 : 2-(4-(1 -(4-(tert-butoxy)phenyl)-5-methyl-1 H-benzo[d]imidazol-6- yl)phenyl)propan-2-ol

[0268]

[0269] To a solution of 6-bromo-l-(4-(tert-butoxy)phenyl)-5-methyl-lH- benzo[d]imidazole (1 g, 2.79 mmol) in 1,4-dioxane (15 mL) was added (4-(2- hydroxypropan-2-yl)phenyl)boronic acid (0.502 g, 2.79 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride (230 mg, 0.279 mmol), potassium carbonate (1.15 g, 8.4 mmol) and water (5 mL). The resulting reaction mixture was degassed with nitrogen for 10 min and then heated to 100 °C overnight. The reaction mixture was then diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by SiO2column chromatography (7:3 to 1:4 hexanes / EtOAc) to give 826 mg of the product as a colorless oil. 1 H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.67 (s, 1H), 7.58 (d, 2H), 7.52 (d, 2H), 7.31 (s, 1H), 7.29 (d, 2H), 7.17 (d, 2H), 5.01 (s, 1H), 2.32 (s, 3H), 1.46 (s, 6H), 1.34 (d, 9H). LC / MS m / z: 415.32 (M+H) +

[0270] Examples A2 to A3 were prepared in the same manner as described above for 2-(4-(l-(4-(tert-butoxy)phenyl)-5-methyl-lH-benzo[d]imidazol-6-yl)phenyl)propan-2- ol (Example Al) using the appropriate aryl halide and the appropriate commercially available boronic acid described above.

[0271]

[0272]

[0273] Preparation of intermediates for Examples B4 to B9

[0274] 6-bromoimidazo[l,2-a]pyridine-7-carbonitrile

[0275]

[0276] To a solution of 2-amino-5-bromoisonicotinonitrile (150 mg, 0.76 mmol) in i-PrOH (2 mL) was added 0.6 mL (1.5 eq) of 2-chloro-l,l-dimethoxyethane. The solution was capped and heated to 1600C in a microwave reactor for 30 min. The mixture was cooled and evaporated in vacuo, the residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3solution and evaporated in vacuo to give 0.47 g of the title compound, which was pure enough for further use. LC / MS m / z: 221.10 (M+H) +

[0277] 6-bromo-3-iodo-7-methylimidazo[l,2-a]pyridine

[0278]

[0279] To a solution of 6-bromo-7-methylimidazo[l,2-a]pyridine (100 mg, 0.47 mmol) in CH2Cl2(1 mL) was added l-iodopyrrolidine-2,5-dione (84 mg, 0.47 mmol) and MeOH (0.1 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by SiO2column chromatography (hexane / EtOAc = 1 : 1) to give 122 mg (77%) of the product as a white solid. LC / MS m / z: 337.00 (M+H) + .

[0280] 6-bromo-3-iodoimidazo[l,2-a]pyridine-7-carbonitrile

[0281]

[0282] The title compound was prepared from 6-bromoimidazo[l,2-a]pyridine-7- carbonitrile and NIS in the same manner as described for 6-bromo-3-iodo-7- methylimidazo[l,2-a]pyridine. LC / MS m / z: 348.01 (M+H) + .

[0283] 6-bromo-3-(4-isopropoxyphenyl)-7-methylimidazo[l,2-a]pyridine

[0284]

[0285] The title compound is prepared from 6-bromo-3-iodo-7-methylimidazo[l,2- a]pyridine and (4-(2-hydroxyprop-2-yl)phenyl)boronic acid in the same manner as described for 2-(4-(l-(4-(tert-butoxy)phenyl)-5-methyl-lH-benzo[d]imidazol-6- yl)phenyl)propan-2-ol (Example Al). LC / MS m / z: 345.10 (M+H) +

[0286] 6-bromo-3-(4-(tert-butoxy)phenyl)-7-methylimidazo[l,2-a]pyridine

[0287]

[0288] The title compound is prepared from 6-bromo-3-iodo-7-methylimidazo[l,2- a]pyridine and (4-(2-hydroxyprop-2-yl)phenyl)boronic acid in the same manner as described for 2-(4-(l-(4-(tert-butoxy)phenyl)-5-methyl-lH-benzo[d]imidazol-6- yl)phenyl)propan-2-ol (Example Al). LC / MS m / z: 345.10 (M+H) +

[0289] 2-(4-(6-bromo-7-methylimidazo[l,2-a]pyridin-3-yl)phenyl)propan-2-ol

[0290]

[0291] The title compound is prepared from 6-bromo-3-iodo-7-methylimidazo[l,2- a]pyridine and (4-(2-hydroxyprop-2-yl)phenyl)boronic acid in the same manner as described for 2-(4-(l-(4-(tert-butoxy)phenyl)-5-methyl-lH-benzo[d]imidazol-6- yl)phenyl)propan-2-ol (Example Al). LC / MS m / z: 345.10 (M+H) +

[0292] Examples B4 to B9 are prepared in the same manner as described above for 2-(4-(l-(4-(tert-butoxy)phenyl)-5-methyl-lH-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example Al), using the appropriate aryl halide and commercially available boronic acid. In the case of compounds with the same substituent for the aryl halide, 2 equivalents of the boronic acid are used.

[0293]

[0294]

[0295]

[0296] Preparation of intermediates for Examples C10 to C26

[0297] 2-bromo-4-((4-isopropoxyphenyl)amino)-5-nitrobenzoic acid methyl ester

[0298]

[0299] in the same manner as described for 5-bromo-N 1 -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine from 2-bromo-4-fluoro-5-nitrobenzoic acid methyl ester and 4-isopropoxyaniline. LC / MS m / z: 381.01 (M+H) + , 421.97 (M+H+CH3CN) +

[0300] 5-bromo-N 1 -(4-isopropoxyphenyl)benzene-1,2-diamine

[0301]

[0302] in the same manner as described for 5-bromo-N 1 -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine from 4-bromo-2-fluoro-1-nitrobenzene and 4-isopropoxyaniline. LCMS m / z: 321.20 79 Br, M+H) + , 323.19 81 Br, M+H) + , 362.20 79 Br, M+H+CH3CN) + , 364.24 81 Br, M+H+CH3CN) + .

[0303] 5-bromo-4-chloro-N1-(4-isopropoxyphenyl)benzene-1,2-diamine

[0304]

[0305] in the same manner as described for 5-bromo-N 1 -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine from 1-bromo-2-chloro-5-fluoro-4-nitrobenzene and 4-isopropoxyaniline. LC / MS m / z: 355.05 79 Br, M+H)+, 357.12 81 Br, M+H) +

[0306] 5-Bromo-6-fluoro-N-(4-isopropoxyphenyl)benzene-1,2-diamine

[0307]

[0308] in the same manner as described for 5-Bromo-N 1 -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine from 1 -bromo-2,3-difluoro-4- nitrobenzene and 4-isopropoxyaniline. LC / MS m / z: 339.13 (M+H) 79 Br, M+H) + , 341.27 (M+H) 81 Br, M+H) +

[0309] 5-Bromo-4-fluoro-N-(4-isopropoxyphenyl)benzene-1,2-diamine

[0310]

[0311] in the same manner as described for 5-Bromo-N 1 -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine from 1 -bromo-2,5-difluoro-4- nitrobenzene and 4-isopropoxyaniline. LC / MS m / z: 339.13 (M+H) 79 Br, M+H) + , 341.22 (M+H) 81 Br, M+H) +

[0312] 5-Bromo-N-(4-isopropoxyphenyl)-6-methylbenzene-1,2-diamine

[0313]

[0314] in the same manner as described for 5-Bromo-N 1 -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine from 1 -bromo-3-fluoro-2-methyl-4- nitrobenzene and 4-isopropoxyaniline. LC / MS m / z: 335.19 (M+H) +

[0315] 5-Bromo-N-(4-isopropoxyphenyl)-4-methoxybenzene-1,2-diamine

[0316]

[0317] in the same manner as described for 5-Bromo-N 1The title compound was prepared in the same manner as described for 6-bromo- 1-[4-(propan-2-yloxy)phenyl]-1H-1,2,3-benzotriazole from 2-bromo-4-((4- isopropoxyphenyl)amino)-5-nitrobenzoic acid methyl ester, sodium nitrite and triphenylphosphine. LC / MS m / z: 390.17 (M+H+CH3CN) +

[0318] 6-bromo-1-[4-(propan-2-yloxy)phenyl]-1H-1,2,3-benzotriazole

[0319]

[0320] To a solution of 5-bromo-N 1 To a solution of 5-bromo-N 79 Br, M+H + , 334.08 (M+H) 81 Br, M+H + , 373.15 (M+H) 79 Br, M+H+CH3CN + , 375.14 (M+H) 81 Br, M+H+CH3CN + .

[0321] 6-bromo-1-[4-(propan-2-yloxy)phenyl]-1H-1,2,3-benzotriazole

[0322]

[0323] The title compound was prepared in the same manner as described for 6-bromo- 1-[4-(propan-2-yloxy)phenyl]-1H-1,2,3-benzotriazole from 2-bromo-4-((4- isopropoxyphenyl)amino)-5-nitrobenzoic acid methyl ester, sodium nitrite and triphenylphosphine. LC / MS m / z: 390.17 (M+H+CH3CN) 79 Br, M+H+CH3CN + , 392.16 (M+H) 81 Br, M+H+CH3CN + .

[0324] 6-bromo-5-chloro-1 -(4-ethoxyphenyl)-1 H-benzo[d][1,2,3]triazole

[0325]

[0326] The title compound is prepared from 5-bromo-4-chloro-N1 -(4- ethoxyphenyl)benzen-1,2-diamine in the same manner as described for 6-bromo-1 - [4-(propan-2-yloxy)phenyl]-1 H-1,2,3-benzotriazole. LC / MS m / z: 368.13 (M+H) + , 408.91 (M+H+CH3CN) +

[0327] 6-bromo-7-fluoro-1 -(4-ethoxyphenyl)-1 H-benzo[d][1,2,3]triazole

[0328]

[0329] The title compound is prepared from 5-bromo-6-fluoro-N1 -(4- ethoxyphenyl)benzen-1,2-diamine in the same manner as described for 6-bromo-1 - [4-(propan-2-yloxy)phenyl]-1 H-1,2,3-benzotriazole. 1 H NMR (500 MHz, DMSO-d6) δ 7.98 (d, 1 H), 7.73-7.68 (m, 3H), 7.16 (d, 2H), 4.78-4.73 (m, 1 H), 1.34 (d, 6H). LC / MS m / z: 351.93 (M+H) +

[0330] 6-bromo-5-fluoro-1 -(4-ethoxyphenyl)-1 H-benzo[d][1,2,3]triazole

[0331]

[0332] The title compound is prepared from 5-bromo-4-fluoro-N1 -(4- ethoxyphenyl)benzen-1,2-diamine in the same manner as described for 6-bromo-1 - [4-(propan-2-yloxy)phenyl]-1 H-1,2,3-benzotriazole. LC / MS m / z: 352.20 (M+H) + , 393.19 (M+H+CH3CN) +

[0333] 6-bromo-1 -(4-ethoxyphenyl)-7-methyl-1 H-benzo[d][1,2,3]triazole

[0334]

[0335] The title compound was prepared from 5-bromo-N1-(4-isopropoxyphenyl)-6-methylbenzene-1,2-diamine in the same manner as described for 6-bromo-1-[4-(propan-2-yloxy)phenyl]-1H-1,2,3-benzotriazole. LC / MS m / z: 346.03 (M+H) +

[0336] 6-Bromo-1-(4-isopropoxyphenyl)-5-methoxy-1H-benzo[d][1,2,3]triazole

[0337]

[0338] The title compound was prepared from 5-bromo-N1-(4-isopropoxyphenyl)-4-methoxybenzene-1,2-diamine in the same manner as described for 6-bromo-1-[4-(propan-2-yloxy)phenyl]-1H-1,2,3-benzotriazole. LC / MS m / z: 362.13 (M+H) +

[0339] Examples C10 to C18 were prepared in the same manner as described above for 2-(4-(1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1) using the appropriate aryl halide described above and the appropriate commercially available boronic acid.

[0340]

[0341]

[0342]

[0343] Example C19: (1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazol-5-yl)methanol

[0344]

[0345] To a solution of 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid methyl ester (86 mg, 1 Eq) in THF (3 mL) was slowly added a 2.6 M solution of lithium aluminum hydride in THF (80 uL, 1 Eq). The mixture was stirred at room temperature for 3 hours, slowly quenched with a cold saturated Na2SO4 solution, and filtered through a pad of celite. The filtrate was concentrated in vacuo, and the residue was purified by SiO2 column chromatography (hexane / EtOAc=7:3 to 6:4) to give 52 mg of the title compound. LC / MS m / z: 418.31 (M+H)+ 835.60 (2M+H) +

[0346] Example C20: 1,6-Bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazole-5- carboxylic acid

[0347]

[0348] To a solution of methyl 1,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazole-5- carboxylate (200 mg, 1 Eq) in 1 :1 MeOH / THF (8 mL) was added 2M aqueous NaOH (4.25 mL). The mixture was stirred overnight, quenched by the addition of 1 M aqueous HC1, extracted with MTBE, and the organic phase evaporated in vacuo. 10 mg of the residue was purified by preparative HPLC to give 2.3 mg of the title compound. LC / MS m / z: 432.35 (M+H) + 473.25 (M+H+CH3CN) +

[0349] Example C21 : 1,6-Bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazole-5- carboxamide

[0350]

[0351] To a solution of 1,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazole-5-carboxylic acid (9.5 mg, 1 Eq) in DMF (0.5 mL) was added diisopropylethylamine (11 uL, 3 Eq) and HATU (12 mg, 1.5 Eq). The mixture was stirred for 1 h, at which point ammonium chloride (5 mg, 4 Eq) was added in one portion. The mixture was stirred overnight, diluted with ethyl acetate, washed twice with 1 M aqueous HC1, and evaporated in vacuo. The residue was purified by preparative HPLC to give 5 mg of the title compound as a white solid. LC / MS m / z: 431.29 (M+H) + 861.54 (2M+H) +

[0352] Example C22: (1,6-Bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazol-5-yl)methanamine

[0353]

[0354] The title compound was prepared from 1,6-bis(4- isopropoxyphenyl)-lH-benzo[d][l,2,3]triazole-5-carboxylic acid in the same manner as described for 1,6-bis(4- isopropoxyphenyl)-lH-benzo[d][l,2,3]triazol-5-yl)methanol (Example C19), but stirred at reflux instead of room temperature. LC / MS m / z: 417.41 (M+H) +

[0355] Example C23: 1,6-bis(4-isopropoxyphenyl)-lH-benzo[d][l,2,3]triazol-5-amine

[0356]

[0357] To a solution of 1,6-bis(4-isopropoxyphenyl)-lH-benzo[d][l,2,3]triazole-5- carboxylic acid (51 mg, 1 Eq) in t-BuOH (0.5 mL) was added triethylamine (33 uL, 2 Eq) and diphenylphosphoryl azide (25 uL, 1 Eq). The mixture was heated to 85 °C and stirred for 6 h, at which point it was diluted with ethyl acetate, washed with saturated aqueous NH4C1 and water, and evaporated in vacuo. The residue was extracted with DCM (1 mL) and TFA (1 mL) was added dropwise. The resulting solution was stirred overnight, then diluted with DCM, washed with saturated aqueous NaHC03, and evaporated in vacuo. The residue was purified by Si02column chromatography (hexanes / EtOAc = 7:3 to 1 :2) to give 7 mg of the title compound as a colorless oil. LC / MS m / z: 403.30 (M+H) + , 444.30 (M+H+CH3CN) +

[0358] Example C24: 4,4'-(5-methoxy-lH-benzo[d][l,2,3]triazole-l,6-diyl)diphenol

[0359]

[0360] To a solution of 1,6-bis(4-isopropoxyphenyl)-5-methoxy-lH-benzo[d][l,2,3]triazole (200 mg, 0.5 mmol) in DCM (4 mL) was added a 1 M solution of BBr3(0.5 mL, 0.5 mmol) at 0 °C. The mixture was allowed to warm to room temperature while stirring overnight, at which point it was quenched by pouring onto ice, extracted twice with ethyl acetate, and evaporated in vacuo. The residue was purified by preparative HPLC to give 13 mg of the title compound. LC / MS m / z: 334.27 (M+H) +

[0361] Example C25: 1,6-Bis(4-isopropoxyphenyl)-5-vinyl-1 H-benzo[d][1,2,3]triazole

[0362] Step 1 : 1,6-Bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazole-5-carbaldehyde

[0363]

[0364] To a solution of (1,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazol-5-yl)methanol (30 mg, 0.072 mmol) was added DCM (0.5 mL) and MnO2(12 mg, 0.14 mmol). The mixture was stirred overnight, filtered through a pad of celite and the filtrate evaporated to give 24 mg of the title compound which was used without further purification. LC / MS m / z: 416.27 (M+H) +

[0365] Step 2: 1,6-Bis(4-isopropoxyphenyl)-5-vinyl-1 H-benzo[d][1,2,3]triazole

[0366]

[0367] To a suspension of methyltriphenylphosphonium iodide (40 mg, 0.1 mmol) in THF (1 mL) was added a 1.6 M solution of n-butyllithium (0.06 mL, 0.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min, at which point a solution of 1,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazole-5-carbaldehyde (24 mg, 0.057 mmol) in THF (0.5 mL) was added and stirring was continued at room temperature for 3 h. The mixture was quenched with aqueous NH4CI, extracted with ethyl acetate and the organics evaporated in vacuo. The residue was purified by preparative HPLC to give 12.9 mg of the title compound. LC / MS m / z: 414.29 (M+H) +

[0368] Example C26: 5-Ethyl-1,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1,2,3]triazole

[0369]

[0370] A solution of 1,6-bis(4-isopropoxyphenyl)-5-vinyl-1 H-benzo[d][1,2,3]triazole (11.5 mg, 0.028 mmol) in MeOH (0.5 mL) was purged of air by vacuum and backfilling with nitrogen twice. Then 10% palladium on carbon (5 mg) was added and the atmosphere was replaced with hydrogen by vacuum and backfilling with a balloon of hydrogen twice. The mixture was stirred overnight, diluted with ethyl acetate, filtered through a pad of celite and the filtrate was evaporated in vacuo to give 10 mg of the title compound which was pure enough to be used without further purification. 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1 H), 7.74 (d, 2H), 7.49 (s, 1 H), 7.29 (d, 2H), 7.15 (d, 2H), 6.98 (d, 2H), 4.70-4.72 (m, 1 H), 4.65-4.67 (m, 1 H), 2.69-2.74 (m, 2H), 1.31 (d, 6H), 1.29 (d, 6H), 1.08 (t, 3H). LC / MS m / z: 416.33 (M+H) +

[0371] Example D27: 3,6-bis(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine

[0372] Step 1 : 6-bromo-7-methylimidazo[1,2-a]pyrimidine

[0373]

[0374] The title compound was prepared in the same manner as described for 6-bromoimidazo[1,2-a]pyridine-7-carbonitrile from 5-bromo-4-methylpyrimidin-2-amine. 1 H NMR (500 MHz, CDCI3) δ 8.57 (s, 1 H), 7.85 (s, 1 H), 7.49 (s, 1 H), 2.79 (s, 3H). LC / MS m / z: 214.25 (M+H) +

[0375] Step 2: 6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine

[0376]

[0377] The title compound is prepared in the same manner as described for 2-(4-(l-(4-(tert- butoxy)phenyl)-5-methyl-lH-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example Al) from 6-bromo-7-methylimidazo[l,2-a]pyrimidine and 4-isopropoxyphenylboronic acid. LC / MS m / z: 268.25 (M+H) +

[0378] Step 3: 3-Iodo-6-(4-isopropoxyphenyl)-7-methylimidazo[l,2-a]pyrimidine

[0379]

[0380] The title compound is prepared in the same manner as described for 6-bromo-3-iodo-7- methylimidazo[l,2-a]pyridine from 6-(4-isopropoxyphenyl)-7-methylimidazo[l,2-a]pyrimidine and NIS. LC / MS m / z: 394.23

[0381] Step 4: 3,6-Bis(4-isopropoxyphenyl)-7-methylimidazo[l,2-a]pyrimidine

[0382]

[0383] The title compound is prepared in the same manner as described for 2-(4-(l-(4-(tert- butoxy)phenyl)-5-methyl-lH-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example Al) from 3-iodo-6-(4-isopropoxyphenyl)-7-methylimidazo[l,2-a]pyrimidine and 4- isopropoxyphenylboronic acid. 1 H NMR (500 MHz, CDC13) δ 8.31 (s, 1H), 7.74 (s, 1H), 7.40 (d, 2H), 7.22 (d, 2H), 6.98 (d, 2H), 6.96 (d, 2H), 4.66-4.56 (m, 2H), 2.55 (s, 3H), 1.38 (d, 6H), 1.36 (d, 6H). LC / MS m / z: 402.36 (M+H) +

[0384] Example D28: 3-(4-(tert-Butoxy)phenyl)-6-(4-isopropoxyphenyl)-7- methylimidazo[l,2-a]pyrimidine

[0385]

[0386] The title compound is prepared from 3-iodo-6-(4- isopropoxyphenyl)-7-methylimidazo[l,2-a]pyrimidine and 4-tert- butoxyphenylboronic acid in the same manner as described for 2-(4-(l-(4-(tert-butoxy)phenyl)-5-methyl-lH- benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example Al). LC / MS m / z: 416.35 (M+H) +

[0387] Example D29: 2-(4-(6-(4-isopropoxyphenyl)-7-methylimidazo[l,2- a]pyrimidin-3-yl)phenyl)propan-2-ol

[0388]

[0389] The title compound is prepared from 3-iodo-6-(4- isopropoxyphenyl)-7-methylimidazo[l,2-a]pyrimidine and (4-(2- hydroxypropan-2-yl)phenyl)boronic acid in the same manner as described for 2-(4-(l-(4-(tert-butoxy)phenyl)-5-methyl-lH- benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example Al). LC / MS m / z: 402.39 (M+H) +

[0390] Example E30: 3-(4-(tert-butoxy)phenyl)-6-(4-(isopropoxy-d7)phenyl)-7- methylimidazo[l,2-a]pyridine

[0391] Step 1: 4-(3-(4-(tert-butoxy)phenyl)-7-methylimidazo[l,2-a]pyridin-6- yl)phenol

[0392]

[0393] To a microwave reactor vial was added 6-bromo-3-(4-(tert-butoxy)phenyl)-7- methylimidazo[l,2-a]pyridine (25 mg, 0.07 mmol), 4-hydroxyphenylboronic acid (11 mg,.083 mmol, 1.2 Eq), Pd(dppf)Cl2(6 mg, 10 mol %), and potassium carbonate (30 mg,.210 mmol, 3 Eq). Then 1.5 mL of 1,4-dioxane and 0.5 mL of water were added and the mixture was degassed by sparging with nitrogen for 5 minutes. The vial was then capped and subjected to microwave irradiation at 80 °C for 1 hour. The resulting mixture was diluted with ethyl acetate and the aqueous layer was extracted with ethyl acetate three times before drying over Na2SO4and evaporation to yield crude product. The crude material was purified using silica gel flash chromatography with 100% ethyl acetate as eluent to give 20 mg of the title compound as a light brown oil. LC / MS m / z: 373.35 (M+H) +

[0394] Step 2: 3-(4-(tert-butoxy)phenyl)-6-(4-(isopropoxy-d7)phenyl)-7- methylimidazo[l,2-a]pyridine

[0395]

[0396] To a solution of 4-(3-(4-(tert-butoxy)phenyl)-7-methylimidazo[l,2-a]pyridin-6- yl)phenol (142 mg, 0.38 mmol) in acetonitrile was added potassium carbonate (0.105 g, 0.76 mmol, 2 Eq). The mixture was stirred at reflux for 30 minutes at which time d7- isopropyl bromide (57 uL, 1.5 Eq) was added in one portion. The mixture was stirred at reflux overnight and then evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water twice, dried over Na2SO4and evaporated to give a crude solid which was purified using silica gel flash chromatography with 3:7 hexanes: ethyl acetate as eluent to give 42 mg of the title compound. LC / MS m / z: 422.33 (M+H) +

[0397] The following examples can be prepared using the appropriate starting materials according to the above Schemes 2, 3, 6-8 and procedures.

[0398]

[0399]

[0400] Arenavirus GP pseudotyping assay.

[0401] Heterocyclic compounds were screened for the ability to inhibit the infectivity of pseudotyped viruses expressing arenavirus glycoproteins (pseudotypes referred to as LASV-p, MACV-p, JUNV-p, GTOV-p and TCRV-p) and a Renilla luciferase reporter using a VSV pseudotyping system (pseudotypes referred to as LASV-p, MACV-p, JUNV-p, GTOV-p and TCRV-p). VSV viruses expressing VSV glycoproteins or pseudotyped with LASV, MACV, JUNV, GTOV and TCRV glycoproteins (LASV-p, MACV-p, JUNV-p, GTOV-p and TCRV-p) were produced in cultured HEK-293T cells (ATCC CRL-3216) and the cells were cultured in 10 cm dishes in DMEM supplemented with 10% FBS, IX penicillin-streptomycin, non-essential amino acids and L-glutamine. When the cells reached approximately 80% confluency, they were transfected with a mixture of 15 μg of pCAGGS plasmid encoding the desired glycoprotein and 45 μl of PEI (polyethylenimine) transfection reagent (PEI MAX, Polysciences Inc., #24765). The cells were incubated with the solution for 5 hours at 37°C in 5% CO2, then washed and the mixture was replaced with supplemented DMEM and incubated at 37°C in 5% CO2 for approximately 16-18 hours. Subsequently, the cells were infected with approximately 50 ul of VSV reporter virus, whereby the VSV glycoprotein was replaced with a luciferase reporter. The cells were infected for 1 hour, then washed once with PBS and incubated in supplemented media. Twenty-four hours post-infection, the supernatant was collected, clarified by centrifugation and filtered through a 0.45 um filter, aliquoted and stored at -80°C. Both VSV-luciferase and arenavirus glycoprotein pseudotypes were titrated for luminescent activity in Vero cells as described in the luciferase assay protocol (below). Vero cells (ATCC: CCL-81) were grown in supplemented DMEM media in clear 384-well plates (3000 cells / well). After overnight incubation at 37°C and 5% CO2, the cells were treated with the desired concentrations of compounds and pseudotypes in assay media. The assay media consisted of 50% Opti-MEM, 50% DMEM, 1% FBS, penicillin-streptomycin, non-essential amino acids and L-glutamine. Each virus supernatant produced was diluted (from 1 : 100 to 1 :2000) to produce similar luminescent signals / background values of >200. The final DMSO concentration in the compound test wells was kept <1% and control wells were treated with assay media and 1% DMSO. The cells were incubated at 37°C and 5% CO2 for 24 hours. The compound-virus mixture was aspirated from the cells 24 hours post-infection and washed once with PBS. The cells were then lysed using 20 μl of lysis buffer from the luciferase kit diluted according to the manufacturer's instructions.After approximately 20 minutes incubation, 5 μΐ of cell lysate was transferred to a white opaque plate and mixed with 12.5 ul of caveolin diluted in buffer. This mixture was incubated at room temperature for 10 minutes on a plate shaker, then luminescence was read using a plate reader (Beckman Coulter DTX 880 Multi-Mode Detector with 535 nm emission). Luminescence signals were obtained for both wells containing compounds and control wells to determine the % activity of each compound (inhibition of luciferase signal).

[0402] Cytotoxicity screen

[0403] The cytotoxicity of active compounds in the pseudotype assay was also evaluated over a 3 day period. Compounds were serially diluted and added to Vero cells (4000 cells / well) with a final DMSO concentration maintained at 1% in growth media consisting of Minimum Essential Medium (MEM) and 1% FBS. Plates were incubated at 37°C for 3 days, then dead cells were removed by washing with phosphate buffered saline (PBS). CPE was assessed by staining cells with neutral red dye for 1 hour, then destained with 50% ethanol / 1% acetic acid solution. Absorbance was read on a Spectramax Plus 384 spectrophotometer at 540 nm and 690 nm. Data was analyzed as (540 nm - 690 nm) then compared to untreated controls to obtain % cell survival.

[0404] Replicon LASV inhibition activity plaque assay

[0405] Cell culture monolayers at confluence or near confluence were prepared in 12-well disposable cell culture plates. Cells were maintained in MEM or DMEM supplemented with 10% FBS. For antiviral assays, the same medium was used but FBS was reduced to 2% or less and supplemented with 1% penicillin / streptomycin. Test compounds were prepared in 2X MEM or 2X DMEM at seven half-logio final concentrations (01-10 μM). Test compounds and positive control compounds (favipiravir or ribavirin) were run in biological triplicate in parallel. Assays were initiated by first removing growth medium from the cells in the 12-well plates, which were challenged with the given concentration of compound and 0.01 MOI of virus or about 50 to 100 plaque forming units (pfu). Cells were incubated for 60 min: 100 μL inoculum / well at 37°C, 5% CO2 with constant gentle shaking. Virus inoculum was removed, cells were washed and overlaid with 1% agarose or 1% methylcellulose diluted 1 : 1 with 2X MEM supplemented with 2% FBS and 1% penicillin / streptomycin and the appropriate drug concentration. Cells were incubated at 37°C and 5% CO2 for 5 days. The overlay was then removed and the plates were stained with 0.05% crystal violet in 10% buffered formalin for approximately 20 min at room temperature. Plates were washed, dried and the number of plaques was counted. The number of plaques in each compound dilution was converted to a percentage relative to the untreated virus control. The 50% effective (EC 50 , viral inhibition) concentration was then calculated by linear regression analysis. The quotient of the EC 50 , divided by the EC 50 gave the selectivity index (Si) value. Compounds showing an SI value > 10 were considered active.

[0406] Replicon LASV virus production reduction assay

[0407] The VYR test is a direct assay of the concentration of test compound that inhibits viral replication. Compounds and virus are added to Vero cells for 3-4 days, at which time the supernatant is removed and tested for infectious particles. On fresh monolayers of Vero cells in 96-well plates, 3 or 4 micro-wells / dilution are used to titrate the supernatant with logio dilutions of virus. After significant CPE is observed, the wells are scored for the presence or absence of virus. The concentration of inhibitor is plotted against the log 10 of virus produced at each concentration. The plot allows the 90% effective concentration to be calculated by linear regression. In addition, the compound is run in parallel at different concentrations on Vero cells in the absence of virus to determine the cytotoxic CC 50 value. The selectivity index (SI) is calculated as the ratio of CC 50 / EC 90 .

[0408] Replicon Tacaribe virus test

[0409] The selected compounds were tested against naturally replicating Tacaribe (TCRV) virus (TRVL-11573, BEI source) using an ELISA-based assay. Vero cells (ATCC: CCL-81) were grown in a 96-well format (5000 cells / well) in supplemented DMEM medium. After overnight incubation, the cells were treated with TCRV and the desired concentration of compound in MEM medium with 1% FBS and supplements. The final DMSO concentration in the compound test wells was kept ≤1%, and the control wells were treated with TCRV or culture medium and 1% DMSO. After incubation for 5 days at 37°C in 5% CO2, the cells were fixed with 2% paraformaldehyde for 45 minutes and then washed with PBS. Subsequently, the cells were permeabilized with 0.25% Triton-X and then TCRV was detected using ELISA using the following protocol. Cells were stained using a monoclonal anti-Junin virus antibody (BEI#NR 41860) that cross-reacts with the TCRV nucleoprotein. After washing, cells were treated with biotin-conjugated secondary antibodies and subsequently with streptavidin-conjugated horseradish peroxidase. TMB substrate was added to the wells and the reaction was terminated using 2M sulfuric acid. Plate reader (Beckman Coulter DTX 880 multi-mode detector with 450nm emission) was used to read absorbance. OD readings for wells and control wells containing compound were obtained to determine the activity % of each compound.

[0410] Microsomal assay

[0411] In addition to the ability of the compounds to exhibit broad inhibitory activity against arenaviruses in vitro, the compounds must also possess certain drug-like properties in order to use them to inhibit arenaviruses and provide methods of treating arenavirus infections in mammals. Such compounds can exhibit drug-like properties including, but not limited to, chemical stability against metabolic degradation by liver microsomal CYP p450 enzymes, cell permeability, and oral bioavailability if the drug is to be delivered orally, and lack of inhibition of the hERG ion channel, which is associated with cardiac safety [Kerns, E. H. Li, D. Drug-like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization, (2008) Academic Press, Burlington MA]. The above publication is incorporated herein by reference for all purposes. To characterize the drug-like properties of the chemical series, example compounds were evaluated for metabolic stability (Table 4) in human, mouse, guinea pig, monkey, rat, mouse, or dog liver microsomal assays and inhibition of the hERG ion channel (Table 5). Compounds that exhibit > 60% parent remaining indicate attractive chemical stability. Good microsomal stability in human and non-human species promotes the ability to test and optimize compounds in preclinical animal studies.

[0412] A reaction premix was set up containing 1 uM of the compound of interest, 1 mg / mL of liver microsomes of the desired species, 2.1 mM MgCl2, and 0.1 M sodium phosphate buffer (pH 7.4). This premix was incubated at 37°C for 30 minutes under gentle agitation to allow the compound to fully dissolve in the mixture. A freshly prepared solution of NADPH in 0.1 M sodium phosphate buffer was then added at a concentration of 2 mM to start the reaction. A "time 0" sample (30 uL) was taken immediately after the addition of NADPH and added to 140 uL of cold acetonitrile containing 1 uM of a pre-determined internal standard. The remaining reaction mixture was incubated at 37°C for the remainder of the time period. The test compound was left in the reaction mixture for 60 minutes, then a "time 60" sample was added to acetonitrile with internal standard. Control compounds (Verapamil for human, monkey, and dog LM, Lidocaine for guinea pig LM, and Benadryl for rat and mouse LM) were incubated in the reaction mixture for 15 minutes, then a "time 15" sample was collected and added to cold acetonitrile with internal standard. The samples were then centrifuged in a centrifuge at 4000 rpm for 10 minutes, the supernatant was collected and mixed with an aliquot of distilled water. These were then analyzed on a Varian 500-MS.

[0413] hERG channel assay

[0414] It has been shown that drugs belonging to different classes are associated with QT prolongation and, in some cases, with serious ventricular arrhythmias. The most common mechanism of these adverse events is the inhibition of one or more cardiac potassium channels, particularly hERG. This current is important for myocardial cell repolarization and is a common target for drugs that prolong the QT interval. Therefore, the test article in this study was characterized to determine its ability to inhibit the hERG channel. Ion channel activity was measured using a Chinese hamster ovary (CHO) cell line expressing hERG mRNA that was stably transfected. The pharmacology of this cloned channel expressed in the CHO cell line is very similar to that observed in native tissue. The cells were cultured in DMEM / F12 containing 10% FBS, 1% penicillin / streptomycin and 500 μg / ml G418. Before testing, cells were harvested using Accumax (Innovative Cell Technologies). For electrophysiological recordings, the following solutions were used: External solution: 2 mM CaCl2; 2 mM MgCl2; 4 mM KCl; 150 mM NaCl; 10 mM glucose; 10 mM HEPES; 305-315 mOsm; pH 7.4 (adjusted with 5 M NaOH); Internal solution: 140 mM KCl; 10 mM MgCl2; 6 mM EGTA; 5 mM HEPES-Na; 5 mM ATP-Mg; 295-305 mOsm; pH 7.25 (adjusted with 1 M KOH). SealChip was used from AVIVA. TMWhole-cell recordings were made using a PX 7000A (Axon Instruments). Cells were voltage clamped at a holding potential of -80 mV. Then, hERG current was activated to -50 mV by a depolarizing step for 300 ms. This first step at -50 mV was used as a baseline to measure the peak amplitude of the tail current. Next, a voltage step to +20 mV for 5 s was applied to activate the channel. Finally, a step back to -50 mV for 5 s removed the activation and the inactivated tail current was recorded. The external solution containing 0.1% DMSO (vehicle) was applied to the cell to establish the baseline. After allowing the current to stabilize for 3 to 10 min, the test article was applied. The test article solution was added to the cell in 4 separate additions. The cell was kept in the test solution until the effect of the test article reached a steady state, up to 12 min. Next, 1 μΜ cisapride (positive control) was added. Finally, a washout with the external solution was performed until the recovered current reached a steady state. Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments), and Origin (OriginLab Corporation) software.

[0415] Table 1. Pseudotype virus activity. Example compounds and their observed inhibitory activity shown as EC50 values against LASV-p, MACV-p, JUNV-p, TCRV-p, and GTOV-p 50 and CC50 values against cellular toxicity. 50 ; nd: not determined.

[0416]

[0417]

[0418] Table 2. Comparison of pseudotype to replicative TCRV inhibitory activity. Example compounds and their observed inhibitory activity (EC50 values) against either pseudotype or replicative TCRV. 50

[0419] Examples TCRV-p EC 50 (nM) TCRV EC 50 (nM) A1 0.24 0.89 A2 0.12 0.33 A3 0.21 0.87 B4 0.16 0.74 B5 0.10 0.88 B6 0.10 0.95 B7 0.20 0.74 B8 0.32 2.16 C11 0.61 0.84 E30 0.2 nd

[0420] A very close correlation between the pseudotype and replicative virus inhibitory activity of the compounds of the present application was surprisingly found.

[0421] Table 3. Inhibition of native Lasota virus. Example compounds and their observed inhibitory activity and selectivity index (SI) in replicative LASV plaque and viral yield reduction (VYR) assays.

[0422] ​ Examples Plaque assay EC 50 (uM) VYR assay EC 90 (uM)]]> SI 90 ]]> B8 ＜.003 ＜0.003 ＞9,000 B7 ＜.003 ＜0.001 ＞11,000 A1 ＜.003 ＜0.001 ＞33,000 A2 ＜.003 ＜0.001 ＞13,000 E30 nd ＜0.014 ＞1,510

[0423] All five compounds, compounds A1, A2, B7, and B8, displayed very potent EC values ​​of less than 1-3 nM in both plaque and VYR assay formats. 50 and EC 90 , and compound E30 displayed an EC of less than 14 nM in the VYR assay format. 90 .SI 90 The values ​​(obtained from the VYR assay data) were > 1510, which clearly indicates that the compound efficacy is due to antiviral activity rather than a cytotoxic effect. The results shown in Tables 1-3 confirm the activity of the compounds against arenaviruses (including replicating LASV) and also strongly validate the method of identifying true HF arenavirus inhibitors by utilizing pseudotyped virus assays.

[0424] Table 4. Multispecies microsomal stability. % parent compound remaining in liver microsomes at 60 min

[0425] Examples nd Mouse Monkey Dog Human Guinea pig A1 82.7 8.6 ＞95 68.3 ＞95 93.8 A2 93.9 53 ＞95 95 ＞95 ＞95 A3 25.4 Rat nd 89.9 67.6 nd B4 37.5 4.9 83.3 88.1 55.45 70.6 B5 16.4 nd nd 86.7 7.4 nd B6 81.7 nd nd 81.5 61.5 nd B7 92.9 22.9 ＞95 ＞95 ＞95 ＞95 B8 77.5 33.7 77.57 87.6 67.7 93 C11 ＞95 nd nd ＞95 ＞95 nd C12 90.3 nd nd ＞95 ＞95 nd C13 nd nd nd 79.5 nd nd C14 ＞95 nd nd ＞95 ＞95 nd C16 57.4 nd nd 72.3 61.9 nd E30 ＞95 74.4 ＞95 ＞95 ＞95 ＞95

[0426] The results of the multi-species microsomal stability studies (Table 4) showed that the deuterated compound E30 exhibited improved metabolic stability in the monkey liver microsomal assay compared to its non-deuterated analog B7, thus showing good microsomal stability in both human and non-human species.

[0427] Table 5: hERG channel assay

[0428] nd Examples A1 ＜10 B7 ＜10 B8 ＜10 C11 ＜10

[0429] These data indicate no hERG channel inhibition, suggesting a good cardiac safety potential.

[0430] Table 6: Pharmacokinetic parameters in mice

[0431]

[0432] Compounds were administered intravenously (3 mg / kg) and orally (30 mg / kg) in mice to determine pharmacokinetic parameters. IV time points included 0.083, 0.25, 0.5, 1, 2, 6, and 24 h, and oral time points included 0.5, 1, 2, 4, 6, 8, and 24 h. Blood was drawn from 3 mice at each time point. Plasma was separated and measured by LC / MS / MS on a Varian 500-LC / MS. Both compounds demonstrated low first-pass liver clearance, which was consistent with the high level of compound remaining after 1 hour in mouse liver microsomes (Table 4). Both compounds demonstrated reasonable oral bioavailability and a long half-life suitable for once-daily dosing. Finally, volume of distribution (Vd) values ​​indicated that the compounds were absorbed into tissues, which further supported the good oral biodistribution of targeting arenavirus infection.

[0433] Mice were able to tolerate daily oral administration of both compounds for 3 days up to at least 100 mg / kg once daily (the highest dose tested). There were no clinical signs of overt toxicity as determined by daily monitoring of body weight, temperature, and behavior. On day 4 (24 hours after the last dose), plasma and liver samples were collected from the administered animals to measure compound levels. The liver was homogenized in 1:1 w / v phosphate buffered saline. Plasma and liver extracts were measured by LC / MS / MS on a Varian 500-MS (Table 7).

[0434] Table 7: Compound concentrations 24 hours after final administration

[0435] % inhibition at 3 uM Examples 24 hr plasma concentration (ug / mL) 24 hr liver concentration (ug / g liver) B7 9.1 63.4 A1 8.8 240.3

[0436] In summary, the results show that the compounds of the present invention exhibit potent broad-spectrum inhibition of HF arenaviruses, as well as attractive drug-like properties for use as treatments for viral infections mediated by arenavirus glycoproteins.

Claims

1. A compound selected from the group consisting of: wherein the term "D" indicates at least 45% deuterium incorporation, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is selected from the group consisting of: wherein the term "D" indicates at least 45% deuterium incorporation, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound is: or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the preparation of a medicament for the treatment of infections associated with viruses of the Arenaviridae family of enveloped viruses or with any virus that expresses an Arenaviral glycoprotein to mediate cell entry.

6. The use according to claim 5, wherein the virus is selected from the New World Arenavirus.

7. The method of claim 6, wherein the New World arenavirus is selected from the group consisting of Junin, Machubo, Guanarito, Sabie, Chapare, Tacaribe and Amapari viruses.

8. The use according to claim 5, wherein the virus is selected from the group consisting of Old World Arenaviruses.

9. The use according to claim 8, wherein the Old World Arenavirus is selected from the group consisting of Lassa, Luyo, Mopea, Ipai and Mobala viruses.

10. The use of claim 8, wherein the Old World Arenavirus is selected from Lassa and Loujo viruses.

11. The use according to any one of claims 5 to 10, wherein the medicament further contains a pharmaceutically acceptable dose of at least one compound selected from the group consisting of ribavirin, viral RNA-dependent RNA polymerase inhibitors, small interfering RNA (siRNA), vaccines, monoclonal antibodies, and immunomodulators.

12. The method of claim 11, wherein the viral RNA-dependent RNA polymerase inhibitor is selected from the group consisting of favipiravir and teriazavirin.

13. A pharmaceutical composition comprising the compound of claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

14. Use of a compound according to claim 3 or a pharmaceutical composition according to claim 13 in the preparation of a medicament for treating an infection associated with a virus of the Arenaviridae family of enveloped viruses or with any virus that expresses an Arenaviral glycoprotein to mediate cell entry.

15. The method of claim 14, wherein the drug further comprises a pharmaceutically acceptable dose of Favipiravir.

16. The use of claim 14, wherein the virus is selected from Lassa virus.

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