JP7675009B2 - Compounds for the treatment of arenavirus infections - Patents.com - Google Patents

Description

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

STATEMENT AS TO RIGHTS TO INVENTS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under R44 AI112097 awarded by the National Institutes of Health. The Government has certain rights in this invention.

FIELD OF THEINVENTION The present invention relates to the use of heterocyclic compounds to inhibit arenavirus infection in humans, other mammals, or cell cultures, methods of treating arenavirus infections such as Lassa, Bolivian, Argentinian, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers, methods of inhibiting arenavirus replication, methods of reducing the amount of arenavirus, and compositions that can be used for such methods.

2. Background of the Invention The Arenaviridae family comprises a diverse family of 29 (and growing) negative-stranded enveloped RNA viruses. Arenaviruses are divided into two groups, Old World and New World, based on serological, genetic and geographic data. Old World viruses are found primarily throughout South and West Africa and include the prototype lymphocytic choriomeningitis virus (LCMV), along with Lassa (LASV), Lujo (LUJV), Mopeia (MOPV), Yippee and Mobara (MOBV) viruses. Both LASV and LUJV can cause fatal hemorrhagic fever (HF), and LCMV infection is associated with aseptic meningitis. Lassa (LASV) alone is estimated to cause over 300,000 cases of disease annually in West Africa, of which 15-20% of hospitalized patients die, and survivors often suffer from sequelae including permanent bilateral hearing loss. The large New World arenavirus group, located mainly in the South American continent, is divided into three clades A, B, and C, with clade B being important because many of the viruses in this group can cause fatal HF. Clade B HF viruses include Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabia (SABV), and Chapare, along with non-HF viruses such as Tacaribe (TCRV) and Amapari (AMPV). Human infection occurs by contact with infected rodent excreta or by inhalation of small particles contaminated with rodent urine or saliva (aerosol infection). There is also evidence of person-to-person transmission, primarily in nosocomial settings (e.g., hospitals). The incubation period of the virus is 1-2 weeks, followed by fever, general malaise, weakness, sore throat, headache, cough, diarrhea, and vomiting. These systemic symptoms make it difficult to differentially diagnose arenavirus infections. As symptoms worsen, poor prognosis has been shown to include pleural effusion, facial edema, neurological complications, and bleeding from mucosal surfaces. Current arenavirus treatment is limited to the use of ribavirin, which is only partially effective if given early and is associated with significant side effects. A vaccine for Junin virus has been developed, but its use is primarily restricted to the most at-risk population of farm workers in Argentina, and no vaccines have been approved for other arenaviruses. A highly desirable prophylactic vaccine would not necessarily be an effective countermeasure against the rapidly emerging, antigenically distinct new virus strains, but existing vaccine development and production strategies cannot adequately respond to the diverse family of current or emerging arenaviruses. Thus, new broad-spectrum antivirals could provide first-line treatment and/or prophylaxis as a means of protection against endemic areas of arenavirus infection as well as potential biological warfare agents.

Arenaviruses consist of a nucleocapsid (NP) surrounded by an envelope membrane, which contains two ambisense RNA genome segments, L and S, that direct the synthesis of two polypeptides. The L segment encodes the RNA-dependent RNA polymerase (RdRp) and the small ring finger protein Z. The S segment encodes the nucleoprotein and glycoprotein precursor GPC, which is cleaved by host proteases and post-translationally modified into a mature complex composed of glycoproteins GP1 (which binds host proteins at the cell surface), GP2 (which directs pH-dependent membrane fusion and release of genomic material in the cytoplasm) and a stable signal peptide (SSP1). The mature glycoprotein complex (GP, or termed glycoprotein) is formed within the viral envelope and is responsible for mediating viral entry. Old World arenaviruses bind to host α-dystroglycan, whereas New World arenaviruses bind to transferrin receptor 1 for cell entry/endocytosis. Upon binding to the cell surface receptor, the virus is endocytosed and directed to acidic late endosomes, where 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 viral GP complexes or host factors are potential therapeutic/prophylactic approaches in treating patients with arenavirus infections. Because HF arenavirus species are classified as BSL-4, alternative approaches are needed to identify viral entry inhibitors. To facilitate the identification of arenavirus entry inhibitors, arenavirus GP complexes can be expressed within a non-pathogenic BSL-2 enveloped virus to produce in one round an infectious pseudovirus whose viral entry function is determined 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 with an envelope glycoprotein from another virus, e.g., LASV, to mediate the entry of the pseudovirion. The cell entry and infection properties of GP pseudo-VSV viruses have been demonstrated against several 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. et al. N. et al. Formation of vesicular stomatitis virus pseudotypes bearing surface proteins of hepatitis B virus. J. Virol. (2005) 79(19):12566-74; Takada, A. et al. A system for functional analysis of Ebola virus glycoprotein. Proc. Natl. Acad. Sci. (1997) 94:14764-69; Garbutt, M. et al. Properties of replication-competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses J. Virol. (2004) 78(10):5458-65]. The above articles are incorporated herein by reference for all purposes. To monitor pseudovirus infection, reporter genes such as green fluorescent protein (GFP) or luciferase can be introduced into the pseudovirus genome and viral infectivity in mammalian cell lines (e.g., Vero or Hek293) can be monitored using optical detection methods (e.g., plate readers) [Cote, M.; Missasi, J.; Ren, T.; Bruchez, A., Lee, K., Fillone, C. M.; Hensley, L.; Li, Q.; Ory, D.; Chandran, K.; Cunningham, J. , Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection, Nature (2011) 477: 344-348, Elshabrawy, H. A. Identification of a broad-spectrum antiviral amall molecule against severe acute 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 articles are incorporated herein by reference in their entireties for all purposes. Thus, the "pseudovirus" can be used to screen chemical compound libraries to identify arenavirus cell entry inhibitors while avoiding the complications of the concomitant use of highly pathogenic BSL-4 agents.

Introduction of deuterium (D) into drug molecules is an attractive strategy to help improve the metabolism, pharmacokinetics, and toxicity profile of drugs. Deuterium is a stable, non-toxic, non-radioactive isotope of hydrogen. Due to its large atomic mass, deuterium bonds more tightly with carbon than hydrogen, making the carbon-deuterium bond more difficult to break. In cases where the disruption of the carbon-hydrogen bond is a partial or complete rate-limiting step in cytochrome P450-mediated drug metabolism, replacement of the hydrogen atom(s) with deuterium may slow the rate of metabolism, leading to improved half-life, increased tolerance, improved efficacy and dosing regimens, reduced side effects, and decreased 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. Deuterabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomized, 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; Malmlov, T. ; Feltmann, K. Konradsson-Geuken, A. et al. 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 MAO-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 Efavirenz Produces a Nephrotoxic Glutathione Conjugate in Rats. Toxicol. Appl. Pharmacol. (2000) 169:102-113. The above articles are incorporated herein by reference in their entirety for all purposes. However, in some cases, hydrogen-deuterium exchange can lead to a redirection of sites of metabolism ("metabolic switching"). [Homing, 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. 'Metabolic switching' in cytochrome P450-catalyzed reactions) Bioessays (1987) 7:215-219]. The above article is incorporated herein by reference in its entirety for all purposes. At the same time, deuterium and hydrogen are essentially the same size, and in most cases deuterium in a drug is not thought to affect the biochemical potency or selectivity of the deuterated drug for a biological target compared to the non-deuterated analog. The effect of deuterium modification on the metabolic and pharmacokinetic properties of a drug cannot be predicted even if the deuterium atom is incorporated at a known site of metabolism. Only by preparing and testing the actual deuterated compound can the effect of deuterium incorporation on absorption, distribution, metabolism, excretion and/or toxicity (ADMET) properties be determined.

In the present invention, the arenavirus GP pseudovirus screen was used to identify the described entry inhibitors and to confirm activity against replicating arenaviruses, selected compounds were tested against the natural non-HF virus TCRV. The top selected compounds were then tested against natural LASV to confirm activity against natural highly pathogenic human (HF) arenaviruses and to evaluate initial drug-like properties.

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

In one embodiment, the method comprises the step of preparing a compound of formula I
(Wherein,
A is independently selected from C and N;
G is independently selected from CH, CD, and N;
E is independently selected from CH, CD, and N;
J is independent

Selected from:
R ² is independently selected from H, D, —OR ³ , —R ⁴ , —NHR ¹⁰ , —CONHR ¹⁰ ;
R ³ is independently selected from H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )cycloheteroalkyl, -NHC(O)R ⁴ , -C(O)NHR ¹⁰ , and -C(O)R ¹⁰ , wherein each C ₁ -C ₆ alkyl is optionally substituted with D, halogen, -OH, -OR ⁴ , -NHR ¹⁰ ;
R ⁴ is independently selected from C ₁ -C ₆ alkyl and (C ₂ -C ₉ )cycloheteroalkyl optionally substituted with D, halogen, —OH, —OR ¹⁰ , and NHR ¹⁰ ;
R ⁵ is independently selected from H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, -OR ³ , -CO ₂ R ¹⁰ , -NHC(O)R ⁴ , -C(O)NHR ¹⁰ , -NHR ¹⁰ , -CHNHR ¹⁰ , -CN, -CR ⁴ , and -C(O)R ¹⁰ , wherein each C ₁ -C ₆ alkyl is optionally substituted with D;
R ⁶ is independently selected from H, D, halogen, —OR ³ , and R ⁴ ;
R ⁹ is independently selected from H, D, halogen, C ₁ -C ₆ alkyl, and —OR ¹⁰ ;
R ¹⁰ is independently selected from H, D, —OH, C ₁ -C ₆ alkyl, and C ₂ -C ₆ alkenyl;
When E is N, CH or CD, A is C, G is CH or CD and J is
and
If A is N, J is
and
However, the following compounds are excluded:
or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier, diluent or vehicle to a human, other mammal, cell culture, or biological sample.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In one embodiment, the method comprises the step of:
I
(In the formula,
A is independently selected from C and N;
G is independently selected from CH, CD, and N;
E is independently selected from CH, CD, and N;
J is independent
Selected from:
R ² is independently selected from H, D, —OR ³ , —R ⁴ , —NHR ¹⁰ , —CONHR ¹⁰ ;
R ³ is independently selected from H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )cycloheteroalkyl, -NHC(O)R ⁴ , -C(O)NHR ¹⁰ , and -C(O)R ¹⁰ , wherein each C ₁ -C ₆ alkyl is optionally substituted with D, halogen, -OH, -OR ⁴ , -NHR ¹⁰ ;
R ⁴ is independently selected from C ₁ -C ₆ alkyl and (C ₂ -C ₉ )cycloheteroalkyl optionally substituted with D, halogen, —OH, —OR ¹⁰ , and NHR ¹⁰ ;
R ⁵ is independently selected from H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, -OR ³ , -CO ₂ R ¹⁰ , -NHC(O)R ⁴ , -C(O)NHR ¹⁰ , -NHR ¹⁰ , -CHNHR ¹⁰ , -CN, -CR ⁴ , and -C(O)R ¹⁰ , wherein each C ₁ -C ₆ alkyl is optionally substituted with D;
R ⁶ is independently selected from H, D, halogen, —OR ³ , and R ⁴ ;
R ⁹ is independently selected from H, D, halogen, —OR ¹⁰ , and C ₁ -C ₆ alkyl;
R ¹⁰ is independently selected from H, D, —OH, C ₁ -C ₆ alkyl, and C ₂ -C ₆ alkenyl;
When E is N, CH or CD, A is C, G is CH or CD and J is
and
If A is N, J is
and
However, the following compounds are excluded:
or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier, diluent or vehicle to a human, other mammal, cell culture, or biological sample.

In another 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, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, E, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are defined above, and J is
It is.

In another 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, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, E, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are defined above, and J is
It is.

In another 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, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, J, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are defined above, and E is CH or CD.

In another 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, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein E, G, J, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are defined above, and A is C.

In another 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, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein E, G, J, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are defined above, and A is N.

In another 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, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, E, ^R2 , ^R3 , ^R4 , ^R5 , ^R9 , and ^R10 are defined above, and J is
and ^R6 is
It is.

In another 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, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, E, ^R2 , ^R3 , ^R4 , ^R5 , ^R9 , and ^R10 are defined above, and J is
and ^R6 is
It is.

In another embodiment, the method comprises administering to a human, other mammal, cell culture, or biological sample a pharma- ceutical composition comprising a compound selected from the group of compounds described in Examples A1-A3, B4-B9, C10-C26, D27-D29, and E30 in a pharma- ceutical effective amount in combination with a pharma- ceutical acceptable carrier, diluent, or vehicle.

In another embodiment, the method comprises administering a pharma- ceutical effective amount of a pharmaceutical composition comprising a compound selected from structural formula I or the compounds shown above, together with a pharma- ceutical acceptable carrier, diluent, or vehicle, and together with a therapeutically effective amount of an additional 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.

In another embodiment, the present invention provides a compound represented by structural formula I
(Wherein,
A is independently selected from C and N;
G is independently selected from CH, CD, and N;
E is independently selected from CH, CD, and N;
J is independent
Selected from:
R ² is independently selected from H, D, —OR ³ , —R ⁴ , —NHR ¹⁰ , —CONHR ¹⁰ ;
R ³ is independently selected from H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )cycloheteroalkyl, -NHC(O)R ⁴ , -C(O)NHR ¹⁰ , and -C(O)R ¹⁰ , wherein each C ₁ -C ₆ alkyl is optionally substituted with D, halogen, -OH, -OR ⁴ , -NHR ¹⁰ ;
R ⁴ is independently selected from C ₁ -C ₆ alkyl and (C ₂ -C ₉ )cycloheteroalkyl optionally substituted with D, halogen, —OH, —OR ¹⁰ , and NHR ¹⁰ ;
R ⁵ is independently selected from H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, -OR ³ , -CO ₂ R ¹⁰ , -NHC(O)R ⁴ , -C(O)NHR ¹⁰ , -NHR ¹⁰ , -CHNHR ¹⁰ , -CN, -CR ⁴ , and -C(O)R ¹⁰ , wherein each C ₁ -C ₆ alkyl is optionally substituted with D;
R ⁶ is independently selected from H, D, halogen, —OR ³ , and R ⁴ ;
R ⁹ is independently selected from H, D, halogen, —OR ¹⁰ , and C ₁ -C ₆ alkyl;
R ¹⁰ is independently selected from H, D, —OH, C ₁ -C ₆ alkyl, and C ₂ -C ₆ alkenyl;
When E is N, CH or CD, A is C, G is CH or CD and J is
and
If A is N, J is
and
However, the following compounds are excluded:
or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, diluent or vehicle.

In another embodiment, the present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, E, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are defined above, and J is
It is.

In another embodiment, the present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, E, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are defined above, and J is
It is.

In another embodiment, the present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, J, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are as defined above, and E is CH or CD.

In another embodiment, the present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein E, G, J, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are as defined above, and A is C.

In another embodiment, the present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein E, G, J, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R9 , and ^R10 are as defined above, and A is N.

In another embodiment, the present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, E, ^R2 , ^R3 , ^R4 , ^R5 , ^R9 , and ^R10 are defined above, and J is:
and ^R6 is
It is.

In another embodiment, the present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle, wherein A, G, E, ^R2 , ^R3 , ^R4 , ^R5 , ^R9 , and ^R10 are defined above, and J is:
and ^R6 is
It is.

In another embodiment, the present invention relates to a compound selected from the group consisting of the compounds set forth in Examples A1-A3, B4-B9, C10-C26, D27-D29, and E30, or a pharma- ceutically acceptable salt thereof, and a pharma-ceutically acceptable carrier, diluent, or vehicle.

In another embodiment, the present invention provides
or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or vehicle.

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

The terms "halo" and/or "halogen" refer to fluorine, chlorine, bromine or iodine.

The term "(C ₁ -C ₆ )" alkyl refers to saturated aliphatic hydrocarbon radicals including straight and branched chain groups of 1 to 6 carbon atoms. Examples of (C ₁ -C ₆ ) alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tertbutyl, pentyl, and the like. As used herein, the terms "Me" and "methyl" refer to a -CH ₃ group. As used herein, the terms "Et" and "ethyl" refer to a -C ₂ H ₅ group.

The term "( _C2 - _C8 )alkenyl" as used herein means an alkyl moiety containing 2 to 8 carbons with at least one carbon-carbon double bond. The carbon-carbon double bond in such a group may be anywhere along the 2 to 8 carbon chain that results in a stable compound. Such groups include both the E and Z isomers of said alkenyl moiety. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl. The term "allyl" as used herein means the group _-CH2CH = _CH2 . The term "C(R)=C(R)" as used herein represents a carbon-carbon double bond where each carbon is replaced by an R group and includes both the E and Z isomers.

The term "(C ₂ -C ₈ )alkynyl" as used herein means an alkyl moiety containing from 2 to 8 carbon atoms and having at least one carbon-carbon triple bond. The carbon-carbon triple bond in such a group may be anywhere along the 2 to 8 carbon chain that results in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, and 3-hexyne.

The term "(C ₁ -C ₈ )alkoxy" as used herein refers to an O-alkyl group, wherein said alkyl group contains from 1 to 8 carbon atoms and is straight, branched, or cyclic. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, isobutoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.

The term "(C ₆ -C ₁₀ )aryl" as used herein means a group derived from an aromatic hydrocarbon containing from 6 to 10 carbon atoms. Examples of such groups include, but are not limited to, phenyl or naphthyl. The terms "Ph" and "phenyl" as used herein mean a -C ₆ H ₅ group. The term "benzyl" as used herein means a -CH ₂ C ₆ H ₅ group.

As used herein, "( _C2 - _C9 )heteroaryl" means an aromatic heterocyclic group having a total of 5 to 10 atoms in its rings, containing 2 to 9 carbon atoms and containing 1 to 4 heteroatoms, each independently selected from O, S and N, with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. Heterocyclic groups include benzo-fused ring systems. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. ( _C2 - _C9 )Heteroaryl groups may be C-attached or N-attached where such is possible. For example, the group derived from pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached), and the group derived from imidazole can be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).

As used herein, "(C ₂ -C ₉ )cycloheteroalkyl" refers to a non-aromatic, monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic group having a total of 4 to 13 atoms in its ring system, containing 5 to 9 carbon atoms and containing 1 to 4 heteroatoms, each independently selected from O, S, and N, with the proviso that the rings of said group do not contain two adjacent O atoms or two adjacent S atoms. Furthermore, such C ₂ -C ₉ cycloheteroalkyl groups may contain an oxo substituent at any available atom that results in a stable compound. For example, such groups may contain an oxo atom at an available carbon or nitrogen atom. Such groups may contain two or more oxo substituents, if chemically feasible. Additionally, it is understood that when such C ₂ -C ₉ cycloheteroalkyl groups contain a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to provide either a sulfoxide or a 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. An example of a 9-membered cycloheteroalkyl group is indolinyl. An example of a 10-membered cycloheteroalkyl group is 4H-quinolidinyl. Further examples of _C2 - _C9 cycloheteroalkyl groups include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- Examples include, but are not limited to, pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolylquinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo-2,8,diazaspiro[4.5]dec-8-yl.

The term "( _C3 - _C10 )cycloalkyl group" means a saturated monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of three to ten carbon ring atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl.

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

The term "(C ₅ -C ₈ )cycloalkenyl" means an unsaturated monocyclic, fused, or spirocyclic ring structure having a total of five to eight carbon ring atoms. Examples of such groups include, but are not limited to, cyclopentenyl, cyclohexenyl.

An "aldehyde" group refers to a carbonyl group -C(O)R, where R is hydrogen.

An "alkoxy" group refers to both -O-alkyl and -O-cycloalkyl groups as defined herein.

"Alkoxycarbonyl" refers to -C(O)OR.

An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group.

An "alkylsulfonyl" group refers to an _-SO2alkyl .

An "amino" group refers to an _--NH2 or --NRR' group.

An "aminoalkyl" group refers to an -alkyl-NRR' group.

"Aminocarbonyl" refers to -C(O)NRR'.

An "arylalkyl" group refers to an -alkylaryl, where alkyl and aryl are defined herein.

An "aryloxy" group refers to both an -O-aryl group and an -O-heteroaryl group as defined herein.

"Aryloxycarbonyl" refers to -C(O)Oaryl.

An "arylsulfonyl" group refers to _-SO2aryl .

A "C-amido" group refers to a -C(O)NRR' group.

A "carbonyl" group refers to -C(O)R.

A "C-carboxyl" group refers to the -C(O)OR group.

A "carboxylic acid" group refers to a C-carboxyl group where R is hydrogen.

The "cyano" group refers to the -CN group.

A "dialkylaminoalkyl" group refers to a -(alkyl)N(alkyl) ₂ group.

A "halo" or "halogen" group refers to fluorine, chlorine, bromine, or iodine.

A "haloalkyl" group refers to an alkyl group substituted with one or more halogen atoms.

A "heteroaryloxyl" group refers to a heteroaryl-O group, with heteroaryl as defined herein.

A "hydroxy" group refers to an -OH group.

An "N-amido" group refers to the -R'C(O)NR group.

An "N-carbamyl" group refers to the -ROC(O)NR- group.

A "nitro" group refers to a _-NO2 group.

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

An "N-thiocarbamyl" group refers to the ROC(S)NR' group.

An "O-carbamyl" group refers to the -OC(O)NRR' group.

An "O-carboxyl" group refers to the RC(O)O group.

An "O-thiocarbamyl" group refers to the -OC(S)NRR' group.

An "oxo" group refers to a carbonyl moiety such that an alkyl substituted by oxo refers to a ketone group.

"Perfluoroalkyl group" refers to an alkyl group in which all hydrogen atoms have been replaced with fluorine atoms.

A "phosphonyl" group refers to a -P(O)(OR) _group .

A "silyl" group refers to a -SiR3 _group .

An "S-sulfonamido" group refers to a -S(O) ₂ NR- group.

A "sulfinyl" group refers to the -S(O)R group.

A "sulfonyl" group refers to a -S(O) _2R .

A "thiocarbonyl" group refers to the -C(=S)-R group.

A "trihalomethanecarbonyl" group refers to a Z ₃ CC(O) group where Z is a halogen.

A "trihalomethanesulfonamido" group refers to a Z ₃ CC(O) ₂ NR-- group where Z is a halogen.

A "trihalomethanesulfonyl" group refers to a _Z3CS (O) ₂ group where Z is a halogen.

A "trihalomethyl" group refers to a _-CZ3 group where Z is a halogen.

A "C-carboxyl" group refers to the -C(O)OR group.

The term "substituted" means that the specified group or moiety bears one or more substituents.

The term "unsubstituted" means that the specified group does not bear any substituents. The term "optionally substituted" means that the specified group is not substituted or is substituted by one or more substituents. In the compounds of the present invention, when a group is said to be "unsubstituted" or "substituted" with fewer groups than fill all the valences in the compound, it is understood that the remaining valences of such group are filled by hydrogen. For example, when a _C6 aryl group, also referred to herein as "phenyl", is substituted with one additional substituent, one skilled in the art will understand that such a group has four open positions remaining on the carbon atoms of the _C6 aryl ring (subtract one from the six initial positions and subtract the additional substituent from those to which the remainder of the compounds of the present invention are attached, leaving four). In such a case, the remaining four carbon atoms are each bonded to one hydrogen atom to fill their valences. Similarly, when a _C6 aryl group in the compounds is said to be "disubstituted", one skilled in the art will understand that this means that the _C6 aryl has three carbon atoms remaining unsubstituted. Each of the three unsubstituted carbon atoms is bonded to one hydrogen atom to satisfy its valence.

The term "solvate" is used to describe a molecular complex between a compound of the present invention and a solvent molecule. Examples of solvates include, but are not limited to, a compound of the present invention in combination with water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or a mixture thereof. The term "hydrate" can be used when the solvent is water. It is specifically contemplated in the present invention that one solvent molecule can be associated with one molecule of a compound of the present invention, such as a hydrate. It is further specifically contemplated in the present invention that two or more solvent molecules can be associated with one molecule of a compound of the present invention, such as a dihydrate. It is further specifically contemplated in the present invention that less than one solvent molecule can be associated with one molecule of a compound of the present invention, such as a hemihydrate. In addition, the solvates of the present invention are contemplated as solvates of the compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compound.

As used herein, the term "pharmaceutical acceptable salts" refers to salts of the compounds of the present invention that retain the biological effectiveness of the free acids and free bases of the specified derivatives and that are biologically or otherwise undesirable.

As used herein, the term "pharmaceutical acceptable formulation" refers to a combination of a compound of the invention or a salt or solvate thereof with a carrier, diluent and/or excipient(s) that is compatible with the compound of the invention and not deleterious to the recipient thereof. Pharmaceutical formulations can be prepared by procedures known to those skilled in the art. For example, the compounds of the invention can be formulated with common excipients, diluents, or carriers and formed into tablets, capsules, and the like. Examples of excipients, diluents and carriers suitable for such formulations include: fillers and extenders such as starch, sugar, mannitol and silicic acid derivatives; binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants such as glycerol; disintegrants such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate and sodium bicarbonate; agents that delay dissolution such as paraffin; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol and glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycol. The final pharmaceutical form may be pills, tablets, powders, troches, sachets, cachets, dragees or sterile packaged powders, depending on the type of excipients used. In addition, the medicament acceptable formulation of the present invention may contain two or more active ingredients. For example, such formulations may contain two or more compounds according to the present invention. Alternatively, such formulations may contain one or more compounds of the invention and one or more additional agents that inhibit arenaviruses.

As used herein, the term "arenavirus GP inhibitory amount" refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit arenavirus cell entry in vivo in a mammal, bird, etc., 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 known to those of skill in the art.

As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the invention or a salt thereof that, when administered to a mammal in need of such treatment, is sufficient to affect treatment as defined herein. Thus, a therapeutically effective amount of a compound of the invention or a salt thereof is an amount sufficient to modulate or inhibit the activity of an arenavirus GP protein such that cellular entry and replication of arenaviruses mediated by the activity of the arenavirus GP protein is reduced or ameliorated.

The terms "treat", "treating" and "treatment" in relation to arenavirus infections in mammals, particularly humans, include (i) preventing the occurrence of a disease or condition in a subject that may be susceptible to the pathology, such that the treatment constitutes a prophylactic treatment for a pathological condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its onset; (iii) alleviating the disease or condition, i.e., causing regression of the disease or condition; or (iv) alleviating and/or relieving the disease or condition or symptoms resulting from the disease or condition.

Unless otherwise indicated, all references herein to the compounds of the invention include references to their salts, solvates, and complexes, including polymorphs, stereoisomers, tautomers, and isotopically labeled versions thereof. For example, the compounds of the invention may be pharma- ceutically acceptable salts and/or pharma-ceutically acceptable solvates.

The term "stereoisomers" refers to compounds that have identical chemical structure but differ with respect to the arrangement of their atoms or groups in space. In particular, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. Pure enantiomers may be contaminated with up to about 10% of the opposite enantiomer.

As used herein, the term "racemic" or "racemic mixture" refers to a 1:1 mixture of enantiomers of a particular compound. The term "diastereomer," on the other hand, refers to the relationship of a pair of stereoisomers that contain two or more asymmetric centers and are not mirror images of each other. In accordance with the conventions used in the art, this symbol is used herein in structural formulae to depict the bond that is the point of attachment of a moiety or substituent to a core or backbone structure. In accordance with another convention, the carbon atoms and hydrogen atoms attached thereto in some structural formulae are not explicitly shown, e.g.,
represents a methyl group,
represents an ethyl group,
represents a cyclopentyl group, etc.

The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention are represented by solid lines (
), dark wedge (

), dotted wedge (
) can be depicted herein. The use of a solid line to depict a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers of that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of either a solid wedge or a dashed wedge to depict a bond to an asymmetric carbon atom is meant to indicate that only the stereoisomer depicted is meant to be included. The compounds of the present invention may contain two or more asymmetric carbon atoms. In those compounds, the use of a solid line to depict a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included. For example, unless otherwise indicated, it is intended that the compounds of the present invention can exist as enantiomers and diastereomers, or as racemates and mixtures thereof. The use of a solid line to depict a bond to one or more asymmetric carbon atoms in a compound of the present invention and a solid or dashed wedge to depict a bond to another asymmetric carbon atom in the same compound is meant to indicate that a mixture of diastereomers is present.

Unless otherwise defined, the substituent "R" may be present on any atom of the ring system provided that a stable structure is formed assuming replacement of a hydrogen on one of the depicted, implied, or explicitly defined ring atoms.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis or resolution of the racemate from a suitable optically pure precursor, for example using chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, if the compound has an acidic or basic moiety, an acid or base, such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization, and one or both of the diastereoisomers may be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. The chiral compounds of the invention (and their chiral precursors) may be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin, the mobile phase of which consists of 0-50% isopropanol, typically 2-20%, and a hydrocarbon, typically heptane or hexane, containing 0-5% alkylamine, typically 0.1% diethylamine. Concentration of the eluate gives the enriched mixture. Stereoisomeric conglomerates may 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 incorporated herein by reference in its entirety.

When the compounds of the invention contain alkenyl or alkenylene groups, geometric cis/trans (or Z/E) isomers are possible. When the compounds contain, for example, keto or oxime groups or aromatic moieties, tautomeric isomerism ("tautomerism") may occur. Examples of tautomers include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomeric, geometric and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism and mixtures of one or more thereof. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

The compounds of the invention may be administered as prodrugs. Thus, certain derivatives of compounds of formula I may have little or no pharmacological activity and, when administered to a mammal, may be converted, for example, by hydrolytic cleavage, to compounds of formula (I) having the desired activity. Such derivatives are referred to as "prodrugs." Prodrugs can be generated, for example, by replacing appropriate functionality present in compounds of formula I with certain moieties known to those of skill in the art. See, for example, "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T Higuchi and W Stella), and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E B Roche (ed.), American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties. Some examples of such prodrugs include an ester moiety in place of the carboxylic acid functional group; an ether or amide moiety in place of the alcohol functional group; and an amide moiety in place of a primary or secondary amino functional group. Further examples of substituents will be known to those of skill 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 may act as prodrugs of other compounds of formula I.

The salts of the present invention can be prepared according to methods known to those skilled in the art. Examples of salts include acetates, acrylates, benzenesulfonates, benzoates (such as chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, etc.), bicarbonates, hydrogen disulfates, hydrogen tartrates, hydrogen sulfites, borates, bromides, butyne-1,4-dioate, calcium edetate, camsylates, carbonates, chlorides, caprates, caprylates, clavulanates, citrates, decanoates, Dihydrochloride, dihydrogen phosphate, edetate, edisylate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, gamma-hydroxybutyrate, iodide, isopropyl alcohol, ethyl ester ... These include, but are not limited to, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate/diphosphate, polygalacturonate, propanesulfonate, propionate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate.

The compounds of the present invention are basic in nature and can form a wide variety of different salts with various inorganic and organic acids. Such salts must be pharma- ceutically acceptable for administration to animals, but in practice it is often desirable to first isolate the compounds of the present invention from the reaction mixture as pharma- ceutically unacceptable salts, then simply convert the latter back to the free base compounds by treatment with alkaline reagents, and then convert the latter free bases to pharma-ceutically acceptable acid addition salts. Acid addition salts of basic compounds of the present invention can be prepared by treating the basic compounds with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent medium or 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 adding the appropriate mineral or organic acid to the solution.

The compounds of the present invention are acidic in nature and can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly sodium and potassium salts. All of these salts are prepared by conventional techniques. The chemical bases used as reagents to prepare the pharma- ceutical acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium. These salts can be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can be prepared by mixing the acidic compound with a low alkaline solution of the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in a manner similar to that before. In either case, stoichiometric amounts of reagents are preferably used to ensure completeness of reaction and maximum yield of the desired end product.

When the compound of the invention is a base, the desired salt can be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or 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, pyranosidyl acids, such as glucuronic acid or galacturonic acid, alpha-hydroxy acids, such as citric acid or tartaric acid, amino acids, such as aspartic acid or glutamic acid, aromatic acids, such as benzoic acid or cinnamic acid, or sulfonic acids, such as p-toluenesulfonic acid or ethanesulfonic acid.

When the compound of the invention is an acid, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, or an organic base. 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, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

For drugs that are solids, those of skill in the art will appreciate that the compounds, drugs and salts of the invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the invention and the specified formulas.

The present invention also includes isotopically labeled compounds of the present invention, in which one or more atoms are replaced with an atom having the same atomic number, but with a different atomic mass or mass number than that usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen such as ^2H and ^3H , carbon such as ^11C , ^13C and ^14C , chlorine such as ^36Cl , ^{35Cl and 37Cl ,} fluorine such as ^18F , iodine such as ^123I and ^125I , nitrogen such as ^13N and ^15N , oxygen such as ^15O , ^17O and ^18O , phosphorus such as 32P, and sulfur such ^{as 35S .}

Certain isotopically labeled compounds of the invention, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium ³ H and carbon-14 ¹⁴ C are particularly useful for this purpose in view of their ease of incorporation and rapid means of detection. Substitution with heavier isotopes, such as deuterium ² H, may offer certain therapeutic advantages due to greater metabolic stability. For example, ³⁵ S may be preferred in some circumstances to increase in vivo half-life or reduce dosage requirements. Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful 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 processes similar to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent otherwise used.

The term "deuterated" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms. Unless otherwise specified, when a particular position in a compound of the invention is specifically designated as "D", "deuterium", "deuterated", or "having deuterium" (the element deuterium is represented in chemical structures and formulas by the letter "D" and in chemical names by the lower case letter "d"), it is understood that the position has deuterium in an abundance of at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the terms "D", "d" or "deuterium" indicate at least 45% incorporation of deuterium).

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

In some embodiments, the compounds of the invention have an isotopic enrichment factor for each deuterium present at a site designated as a potential site for deuterium on the compound 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).

The compounds of the present invention may be formulated into pharmaceutical compositions, as described below, in any pharmaceutical form that one of skill in the art would recognize as appropriate. Pharmaceutical compositions of the present invention comprise a therapeutically effective amount of at least one compound of the present invention and a pharma- ceutical acceptable carrier or diluent.

For treating or preventing an arenavirus infection or a disease or condition mediated in whole or in part by a virus expressing an arenavirus glycoprotein, the pharmaceutical compositions of the invention are administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., an amount that modulates, controls or inhibits arenavirus GP effective to achieve a therapeutic effect) of at least one compound of the invention (as an active ingredient) with one or more pharma- ceutical suitable carriers, which may be selected, for example, from diluents, excipients and adjuvants that facilitate processing of the active compound into a final pharmaceutical preparation.

The pharmaceutical carriers used may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the compositions of the present invention may include time-delay or time-release materials known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate, and the like. Additional additives or excipients may be added to achieve the desired formulation properties. For example, bioavailability enhancers such as Labrasol, Gelucire, or formulators such as CMC (carboxymethylcellulose), PG (propylene glycol), or PEG (polyethylene glycol) may be added. For example, Gelucire, a semi-solid vehicle that protects the active ingredient from light, moisture, and oxidation, may be added when preparing a capsule formulation.

When a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier can vary, but will generally be from about 25 mg to about 1 g. When a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid or a suspension in an ampoule or vial or a non-aqueous liquid suspension. When a semi-solid carrier is used, the preparation can be in the form of hard and soft gelatin capsule formulations. The compositions of the present invention are prepared in unit dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.

To obtain a stable water-soluble dosage form, the salt of the compound of the invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic or citric acid. If a soluble salt form is not available, the drug may be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, etc., in concentrations ranging from 0-60% of the total volume. The composition may also be in the form of a solution of the salt form of the active ingredient in a suitable aqueous vehicle, such as water or isotonic saline or dextrose solution.

Appropriate formulations will depend on the route of administration chosen. For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated by combining the active compounds with pharma- ceutical acceptable carriers known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by the subject. Pharmaceutical preparations for oral use can be obtained using solid excipients mixed with the active ingredient (drug), optionally milling the resulting mixture, and processing the granular mixture after adding suitable auxiliary agents to obtain tablet or dragee cores, if desired. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; as well as cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, optionally containing gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or characterization of different combinations of active agents.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler, such as lactose, a binder, such as starch, and/or a lubricant, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agent can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. All preparations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner.

For intranasal or inhalation administration, the compounds for use according to the invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer using a suitable propellant, for example, 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.

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

The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.

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

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

In addition to the above formulations, the compounds of the present invention may also be formulated as depot preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds may be formulated in suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. The 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 may be the VPD cosolvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume with absolute ethanol. The VPD cosolvent system (VPD:5W) comprises VPD diluted 1:1 with 5% dextrose in water. This co-solvent system dissolves hydrophobic compounds well and itself produces low toxicity upon systemic administration. The proportions of the co-solvent system can be varied as appropriate without destroying its solubility and toxicity properties. Additionally, the identity of the co-solvent components can be varied: for example, other low toxicity non-polar surfactants can be used in place of polysorbate 80. The fraction size of the polyethylene glycol can be varied. Other biocompatible polymers can replace the polyethylene glycol, e.g., polyvinylpyrrolidone. And other sugars or polysaccharides can be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide may also be used, although usually at the expense of higher toxicity due to the toxicity of DMSO. Furthermore, the compounds may be delivered using sustained-release systems such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. A variety of sustained-release materials have been established and are known to those skilled in the art. Sustained-release capsules may release the compound for a period of several weeks up to 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization may be used.

The pharmaceutical compositions may also include suitable solid or gel phase carriers or excipients. These carriers and excipients may provide significant improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. Additionally, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, (registered trademark), Transcutol®, etc. may also be used.

The pharmaceutical composition may also be incorporated into a skin patch to deliver the drug directly onto the skin.

It is understood that the actual dosage of the agents of the invention will vary depending on the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host and disease being treated. Those skilled in the art can ascertain optimal dosages for a given set of conditions using conventional dosage determination tests in view of the experimental data for a given compound. For oral administration, exemplary daily doses in general use are from about 0.001 to about 1000 mg per kg of body weight, with courses of treatment repeated at appropriate intervals.

Furthermore, a medicamentously acceptable formulation of the present invention may contain a compound of the present invention, 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, 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.

Furthermore, a medicamentously acceptable formulation of the present invention may contain a compound of the present invention, or a salt or solvate 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%.

The compounds of the invention, or salts or solvates thereof, may be administered once daily, twice daily, three times daily, four times daily, or even more frequently, alone or in combination with one or more compounds selected from ribavirin, polymerase inhibitors, favipiravir, triazavirin, small interfering RNA (siRNA), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors, as part of a pharmacologic acceptable formulation, to a mammal, such as a human, suffering from a condition or disease mediated by an arenavirus or any virus expressing an arenavirus glycoprotein.

The compounds of the present invention, or salts or solvates thereof, may be administered alone or as part of a medicament containing other arenavirus inhibitors to mammals, such as humans, suffering from a pathology or disease mediated by an arenavirus. Ng KK, Arnold JJ and Cameron CE, Structure-Function Relationships Among RNA-Dependent RNA Polymerases, Curr Top Microbiol, 1999, 143, 1111-1152, the entire contents of which are incorporated herein by reference. Ribavirin, a viral RNA-dependent RNA polymerase inhibitor as shown by Immunol, 2008; 320:137-156; favipiravir, a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase; triazavirin, a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase; small interfering RNA (siRNA); and microRNA as shown by Carthe 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; Nable GJ, Designing Tomorrow's Vaccines, as shown by Carthew RW and Sontheimer EJ, Origins and Mechanisms of miRNAs and siRNAs, Nature, 2009; Vaccines, NEJM, 2013; 368: 551-560, and immunomodulators, Patil US, Jaydeokar AV and Bandawane DD, Immunomodulators: A Pharmacological Review, International J Pharmacy and Pharmaceutical Sci, 2012; 4: 30-36, the entire contents of which are incorporated herein by reference, may be administered once a day, twice a day, three times a day, four times a day, or even more frequently in combination with at least one other agent used in the treatment of arenaviruses selected from the group consisting of vaccines, as described by Patil US, Jaydeokar AV and Bandawane DD, Immunomodulators: A Pharmacological Review, International J Pharmacy and Pharmaceutical Sci, 2012; 4: 30-36, the entire contents of which are incorporated herein by reference.

Those of skill in the art will appreciate that with respect to the compounds of the present invention, the particular pharmaceutical formulations, dosage amounts, and number of doses given per day to a mammal in need of such treatment are all selectable and within the knowledge of those of skill in the art and can be determined without undue experimentation.

The compounds of the present invention are useful for modulating or inhibiting arenavirus glycoproteins (GPs) both in vitro and in vivo.

These compounds are therefore useful for the prevention and/or treatment of disease states associated with arenavirus infections or for the treatment of viruses expressing arenavirus glycoproteins.

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

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-nitrophenylsulfonyl, "DCM" (CH ₂ Cl ₂ ) means dichloromethane or methylene chloride, "dba" means dibenzylideneacetone, "DCE" means dichloroethane or ethylene chloride, "D" or "d" means deuterium, "DIAD" means diisopropylazadicarboxylate, "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 isopropyl alcohol, "NMP" means 1-methyl-2-pyrrolidinone, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "DCM" means dichloromethane, "EtOAc" means ethyl acetate, "MgSO ₄ " 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 phosphorus oxychloride, " _SOCl2 " means thionyl chloride, " _{K2CO3 "} means tetrahydrofuran, and " 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(Ph ₃ )" means triphenylphosphine, "N" means normal, "M" means molar, "mL" means milliliters, "mmol" means millimole, "μmol" means micromole, "eq" means equivalent, "° C." means degrees Celsius, and "Pa" means pascals.

Methods of Preparation The compounds of the present invention can be prepared using the reaction pathways and synthesis schemes described below, using techniques available in the art with readily available starting materials. The preparation of certain embodiments of the present invention is detailed in the following examples, but those skilled in the art will recognize that the described preparations can be easily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplary compounds according to the present invention can be carried out by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine changes to reaction conditions. Alternatively, it will be recognized that other reactions mentioned herein or known in the art have applicability for preparing other compounds of the present invention.

Scheme 1 shows a method useful for the synthesis of compounds of 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 NH ₂ in the presence of a base such as NaH or Cs ₂ CO ₃ in a solvent such as THF or DMF to form compound 1-2. Reduction of the nitro group with a reducing agent such as Fe or SnCl ₂ in a solvent such as THF or methanol can provide the aniline 1-3, which can be reacted with formic acid HCO ₂ H or orthoester HC(OR) ₃ to form 1-4. Coupling of 1-4 with a boronic acid or boronic ester R ¹ B(OR) 2 using a catalyst such as [1,1- _bis (diphenylphosphino)ferrocene]palladium(II) dichloride in the presence of a base such as K ₂ CO ₃ in a solvent such as dimethoxyethane can provide compounds of structural formula I.

Scheme 1

Scheme 2 illustrates a method for the synthesis of deuterated anilines 2-4, useful for preparing deuterated intermediates 1-2 for the synthesis of deuterated compounds of the invention described in Scheme 1 above. Reaction of deuterated alkyl halides 2-2 (X' = Br or I) with phenols 2-1 in the presence of a base such as _K2CO3 in a solvent such as _N ,N-dimethylformamide can provide compounds 2-3. Reduction of the nitro group with 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 anilines 2-4.

Scheme 2

Scheme 3 shows a method for the synthesis of deuterated anilines 3-4, useful for preparing deuterated intermediates 1-2 for the synthesis of deuterated compounds of the invention described in Scheme 1 above. Arylation of alcohols 3-1 with diaryliodonium salts 3-2 in the presence of a base such as NaHMDS in a solvent such as pentane can provide compounds 3-3 [Lindstedt, E.; Stridfeldt, E.; Olofsson, B. Mild synthesis of sterically congested alkyl aryl ethers. Org. Lett. (2016) 18:4234-4237. The above paper is incorporated by reference in its entirety for all purposes. Reduction of the nitro group with 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 the aniline 3-4.

Scheme 3

Scheme 4 illustrates a method useful for the synthesis of 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 a boronic acid or boronic ester R ¹ B(OR) ₂ using a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride in the presence of a base such as K ₂ CO ₃ in a solvent such as dimethoxyethane to form 4-2, which can be treated with a halogenating agent 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 a boronic acid or boronic ester R ² _B (OR) ₂ using a catalyst such as tetrakis(triphenylphosphine)palladium in the presence of a base such as K 2 CO 3 in a solvent such as dioxane can provide compounds of structural formula I. Alternatively, compound 4-4 (X = Cl, Br) can be reacted with a boronic acid or boronic ester R ² B(OR) _{2 using a catalyst such as tetrakis(triphenylphosphine)palladium in the presence of a base such as K 2 CO 3 in a solvent such as dioxane to provide compound 4-5, which can be reacted with a second boronic acid or boronic ester R 1 B(OR) 2 using a} catalyst such as [ ^1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloride in the presence of a base such as K _{2 CO 3} in a solvent such as dimethoxyethane to provide a compound of structural formula I.

Scheme 4

Scheme 5 illustrates a method useful for the synthesis of compounds of 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 NH ₂ in the presence of a base such as NaH or K ₂ CO ₃ in a solvent such as THF or DMF to form compound 5-2. Reduction of the nitro group with a reducing agent such as Fe or SnCl ₂ in a solvent such as THF or methanol can provide the 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) ₂ using a catalyst such as [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride in the presence of a base such as K ² CO ₃ in a solvent such as dimethoxyethane can provide compounds of structural formula I.
Scheme 5

Reaction Schemes 6-8 provide methods for the synthesis of borane reagents 6-4, 7-4, and 8-4, which are useful for preparing deuterated intermediates and final compounds of the invention described above in Schemes 1, 4, and 5 for introducing ^R1 and/or ^R2 substituents.

Scheme 6 illustrates a method useful for the synthesis of deuterated boronic acids or boronic esters 6-4. Reaction of deuterated alkyl halides 6-2 (X' = Br or I) with phenols 6-1 (X = Br or I ₎ in the presence of a base such as _K2CO3 in a solvent such as N,N-dimethylformamide can provide compounds 6-3. Compounds 6-3 can be converted to boronic acids or boronic esters 6-4 using standard boronation reaction conditions well known to those skilled in the art. For example, metal halide exchange of compound 6-3 with an organolithium reagent such as n-butyllithium, followed by treatment with trialkylborate B(OR) ₃ can provide the boronic esters 6-4, which can be hydrolyzed to provide the free boronic acids 6-4 (R = H).

Scheme 6

Scheme 7 shows a method useful for the synthesis of deuterated boronic acids or boronic esters 7-4. Reaction of deuterated alkyl bromides 7-2 with phenols 7-1 (X=Br or I) using a catalyst such as nickel(II) acetylacetonate in the presence of a base such as NaHCO ₃ in a solvent such as toluene can provide compounds 7-3 [Hodous, B. L. US Patent Application Publication No. 2016/0031892, Feb. 4, 2016], which is incorporated herein by reference in its entirety for all purposes. Compounds 7-3 can be converted to boronic acids or boronic esters 7-4 using standard boronation 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 trialkylborate B(OR) ₃ can provide the boronic esters 7-4, which can be hydrolyzed to provide the free boronic acids 7-4 (R=H).

Scheme 7

Scheme 8 illustrates a method useful for the synthesis of deuterated boronic acids or boronic esters 8-4. Metal halide 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 acids or boronic esters 8-4 using standard boronation reactions well known to those skilled in the art. For example, coupling of compound 8-3 with a diboronyl 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 the boronic acid ester 8-4.

Scheme 8

Working Example
Preparation of intermediates for Examples A1-A3
5-Bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine

To a solution of 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (200 mg, 0.85 mmol) in i-propanol (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 NH ₄ Cl (457 mg, 8.5 mmol). The reaction was stirred at 80° C. for 2 h. After cooling to room temperature, the reaction was filtered through a celite pad. 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 Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by SiO2 column chromatography (hexane/EtOAc=3:1) to give 198 mg (69.2%) of the product as a white solid. LC/MS m/z: 335.13 ( ^79Br , M+H) ⁺ , 337.19 ( ^81Br , M+H) ⁺ , 376.28 ( ^79Br , M+H+ _CH3CN ) ⁺ , 378.25 ( ^81Br , M+H+ _CH3CN ) ⁺ .

5-Bromo-N1-(4-(tert-butoxy)phenyl)-4-methylbenzene-1,2-diamine
The title compound was prepared from 1-bromo-5-fluoro-2-methyl-4-nitrobenzene and 4-(tert-butoxy)aniline in the same manner as described for 5-bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine. LC/MS m/z: 351.24 ( ⁷⁹ Br, M+H+CH ₃ CN) ⁺ .

6-Bromo-5-methyl-1-[4-(propan-2-yloxy)phenyl]-1H-1,3-benzodiazole
To a solution of 5-bromo-N ¹ -(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 μL). 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 Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by SiO ₂ column 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 ( ⁷⁹ Br, M+H) ⁺ , 347.21 ( ⁸¹ Br, M+H) ⁺ , 386.28 ( ⁷⁹ Br, M+H+CH ₃ CN) ⁺ , 388.20 ( ⁸¹ Br, M+H+CH ₃ CN) ⁺ .

6-Bromo-1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazole
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-(propan-2-yloxy)phenyl]-1H-1,3-benzodiazole.¹H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.57 (d, 2H), 7.21 (d, 2H), 2.47 (s, 3H), 1.37 (s, 9H). LC/MS m/z: 359.16 (⁷⁹Br, M+H+CH₃CN)⁺, 361.17 (⁸¹Br, M+H+CH₃CN)⁺.

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



To a solution of 6-bromo-1-(4-(tert-butoxy)phenyl)-5-methyl-1H-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 minutes 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 Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by _SiO2 column chromatography (Hexane/EtOAc 7:3 to 1:4) to give 826 mg of product as a colorless oil. ^1H 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) ⁺ .

Examples A2-A3 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.

Preparation of intermediates for Examples B4 to B9 6-Bromoimidazo[1,2-a]pyridine-7-carbonitrile

To a solution of 2-amino-5-bromoisonicotinonitrile (150 mg, 0.76 mmol) in i-PrOH (2 mL) is added 0.6 ml (1.5 eq) of 2-chloro-1,1-dimethoxyethane. The solution is tightly capped and heated to 160° C. in a microwave reactor for 30 minutes. The mixture is cooled, evaporated in vacuo, and the residue dissolved in ethyl acetate, washed with saturated aqueous NaHCO ₃ and evaporated in vacuo to give 0.47 g of the title compound, sufficiently pure for later use. LC/MS m/z: 221.10 (M+H) ⁺ .

6-Bromo-3-iodo-7-methylimidazo[1,2-a]pyridine
To a solution of 6-bromo-7-methylimidazo[1,2-a]pyridine (100 mg, 0.47 mmol) in CH ₂ Cl ₂ (1 mL) was added 1-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 Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by SiO ₂ column 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) ⁺ .

6-Bromo-3-iodoimidazo[1,2-a]pyridine-7-carbonitrile
The title compound was prepared from 6-bromoimidazo[1,2-a]pyridine-7-carbonitrile in the same manner as described for 6-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine. LC/MS m/z: 348.01 (M+H) ⁺ .

6-Bromo-3-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine
The title compound was prepared from 6-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine and 4-isopropoxyboronic acid in the same manner as described for 2-(4-(1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1). LC/MS m/z: 345.20 (M+H) ⁺ .

6-Bromo-3-(4-(tert-butoxy)phenyl)-7-methylimidazo[1,2-a]pyridine
The title compound was prepared from 6-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine and (4-(tert-butoxy)phenyl)boronic acid in the same manner as described for 2-(4-(1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1). LC/MS m/z: 359.22 (M+H) ⁺ .

2-(4-(6-bromo-7-methylimidazo[1,2-a]pyridin-3-yl)phenyl)propan-2-ol
The title compound was prepared from 6-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid in the same manner as described for 2-(4-(1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1). LC/MS m/z: 345.10 (M+H) ⁺ .

Examples B4 to B9 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 and commercially available boronic acid. In the case of compounds with the same substitution of the aryl halide, two equivalents of boronic acid are used.

Preparation of intermediates for examples C10 to C26 Methyl 2-bromo-4-((4-isopropoxyphenyl)amino)-5-nitrobenzoate
The title compound was prepared from methyl 2-bromo-4-fluoro-5-nitrobenzoate and 4-isopropoxyaniline in the same manner as described for 5-bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine. LC/MS m/z: 381.01 (M+H) ⁺ , 421.97 (M+H+CH ₃ CN) ⁺ .

5-Bromo-N ¹ -(4-isopropoxyphenyl)benzene-1,2-diamine
The title compound was prepared from 4-bromo-2-fluoro-1-nitrobenzene and 4-isopropoxyaniline in the same manner as described for 5-bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine. LCMS m/z: 321.20 ( ⁷⁹ Br, M+H) ⁺ , 323.19 ( ⁸¹ Br, M+H) ⁺ , 362.20 ( ⁷⁹ Br, M+H+CH ₃ CN) ⁺ , 364.24( ⁸¹ Br, M+H+CH ₃ CN) ⁺ .

5-bromo-4-chloro-N1-(4-isopropoxyphenyl)benzene-1,2-diamine
The title compound was prepared from 1-bromo-2-chloro-5-fluoro-4-nitrobenzene and 4-isopropoxyaniline in the same manner as described for 5-bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine. LC/MS m/z: 355.05 ( ⁷⁹ Br, M+H) ⁺ , 357.12 ( ⁸¹ Br, M+H) ⁺ .

5-bromo-6-fluoro-N1-(4-isopropoxyphenyl)benzene-1,2-diamine
The title compound was prepared from 1-bromo-2,3-difluoro-4-nitrobenzene and 4-isopropoxyaniline in the same manner as described for 5-bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine. LC/MS m/z: 339.13 ( ⁷⁹ Br, M+H) ⁺ , 341.27 ( ⁸¹ Br, M+H) ⁺ .

5-bromo-4-fluoro-N1-(4-isopropoxyphenyl)benzene-1,2-diamine
The title compound was prepared from 1-bromo-2,5-difluoro-4-nitrobenzene and 4-isopropoxyaniline in the same manner as described for 5-bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine. LC/MS m/z: 339.13 ( ⁷⁹ Br, M+H) ⁺ , 341.22 ( ⁸¹ Br, M+H) ⁺ .

5-Bromo-N1-(4-isopropoxyphenyl)-6-methylbenzene-1,2-diamine
The title compound was prepared from 1-bromo-3-fluoro-2-methyl-4-nitrobenzene and 4-isopropoxyaniline in the same manner as described for 5-bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine. LC/MS m/z: 335.19 (M+H) ⁺ .

5-Bromo-N ¹ -(4-isopropoxyphenyl)-4-methoxybenzene-1,2-diamine
The title compound was prepared from 1-bromo-5-fluoro-2-methoxy-4-nitrobenzene and 4-isopropoxyaniline in the same manner as described for 5-bromo-N ¹ -(4-isopropoxyphenyl)-4-methylbenzene-1,2-diamine. LC/MS m/z: 418.30 (M+H) ⁺ .

6-Bromo-1-[4-(propan-2-yloxy)phenyl]-1H-1,2,3-benzotriazole
To a solution of 5-bromo-N ¹ -(4-isopropoxyphenyl)benzene-1,2-diamine (100 mg, 0.3 mmol) in acetic acid (3 mL) is added PPh ₃ (81.6 mg, 0.3 mmol) followed by sodium nitrite (25.8 mg, 0.36 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by SiO ₂ column chromatography (hexanes/EtOAc=2:1) to give 98 mg (95%) of the product as a white solid. LC/MS m/z: 332.07 ( ⁷⁹ Br, M+H) ⁺ , 334.08 ( ⁸¹ Br, M+H) ⁺ , 373.15 ( ⁷⁹ Br, M+H+CH ₃ CN) ⁺ , 375.14 ( ⁸¹ Br, M+H+CH ₃ CN) ⁺ .

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

6-Bromo-5-chloro-1-(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole
The title compound was prepared from 5-bromo-4-chloro-N1-(4-isopropoxyphenyl)benzene-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: 368.13 (M+H) ⁺ , 408.91 (M+H+CH ₃ CN) ⁺ .

6-Bromo-7-fluoro-1-(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole
The title compound was prepared from 5-bromo-6-fluoro-N1-(4-isopropoxyphenyl)benzene-1,2-diamine in the same manner as described for 6-bromo-1-[4-(propan-2-yloxy)phenyl]-1H-1,2,3-benzotriazole. ¹ H NMR (500 MHz, DMSO-d6) δ 7.98 (d, 1H), 7.73-7.68 (m, 3H), 7.16 (d, 2H), 4.78-4.73 (m, 1H), 1.34 (d, 6H). LC/MS m/z: 351.93 (M+H) ⁺ .

6-Bromo-5-fluoro-1-(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole
The title compound was prepared from 5-bromo-4-fluoro-N1-(4-isopropoxyphenyl)benzene-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: 352.20 (M+H) ⁺ , 393.19 (M+H+CH ₃ CN) ⁺ .

6-Bromo-1-(4-isopropoxyphenyl)-7-methyl-1H-benzo[d][1,2,3]triazole
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) ⁺ .

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

Examples C10-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 above and the appropriate commercially available boronic acid.

Example C19: (1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazol-5-yl)methanol
To a solution of methyl 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (86 mg, 1 equiv.) in THF (3 mL) was slowly added a solution of 2.6 M lithium aluminum hydride in THF (80 μL, 1 equiv.). The mixture was stirred at room temperature for 3 h, slowly quenched with cold saturated Na ₂ SO ₄ solution, and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by SiO ₂ column chromatography (Hexanes/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) ⁺ .

Example C20: 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid
To a solution of methyl 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (200 mg, 1 eq.) in 1:1 MeOH/THF (8 mL) is added 2M aqueous NaOH (4.25 mL). The mixture is stirred overnight, quenched by addition of 1M aqueous HCl, extracted with MTBE, and the organic phase is evaporated in vacuo. 10 mg of the residue is 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+CH ₃ CN) ⁺ .

Example C21: 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxamide
To a solution of 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (9.5 mg, 1 equiv.) in DMF (0.5 mL) is added diisopropylethylamine (11 μL, 3 equiv.) and HATU (12 mg, 1.5 equiv.). The mixture is stirred for 1 h at which time ammonium chloride (5 mg, 4 equiv.) is added in one portion. The mixture is stirred overnight, diluted with ethyl acetate, washed twice with 1M aqueous HCl, and evaporated in vacuo. The residue is 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) ⁺ .

Example C22: (1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazol-5-yl)methanamine
The title compound was prepared from 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-yl)methanol in the same manner as described for (1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazol-5-yl)methanol (Example C19), but stirred at reflux instead of room temperature. LC/MS m/z: 417.41 (M+H) ⁺ .

Example C23: 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazol-5-amine
To a solution of 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxamide (51 mg, 1 equiv.) in t-BuOH (0.5 mL) are added triethylamine (33 μL, 2 equiv.) and diphenylphosphoryl azide (25 μL, 1 equiv.). The mixture is heated to 85° C. and stirred for 6 h, at which time it is diluted with ethyl acetate, washed with saturated aqueous NH ₄ Cl and water, and evaporated in vacuo. The residue is taken up in DCM (1 mL) and TFA (1 mL) is added dropwise. The resulting solution is stirred overnight, diluted with DCM, washed with saturated NaHCO ₃ , and evaporated in vacuo. The residue is purified by SiO ₂ column 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+CH ₃ CN) ⁺ .

Example C24: 4,4'-(5-methoxy-1H-benzo[d][1,2,3]triazole-1,6-diyl)diphenol
To a solution of 1,6-bis(4-isopropoxyphenyl)-5-methoxy-1H-benzo[d][1,2,3]triazole (200 mg, 0.5 mmol) in DCM (4 mL) at 0° C. is added a 1 M solution of BBr ₃ (0.5 mL, 0.5 mmol). The mixture is allowed to warm to room temperature with stirring overnight, at which time it is quenched by pouring onto ice, extracted twice with ethyl acetate, and evaporated in vacuo. The residue is purified by preparative HPLC to give 13 mg of the title compound. LC/MS m/z: 334.27 (M+H) ⁺ .

Example C25: 1,6-bis(4-isopropoxyphenyl)-5-vinyl-1H-benzo[d][1,2,3]triazole Step 1: 1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carbaldehyde
To a solution of (1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazol-5-yl)methanol (30 mg, 0.072 mmol) is added DCM (0.5 mL) and MnO ₂ (12 mg, 0.14 mmol). The mixture is stirred overnight, filtered through a celite pad and the filtrate is evaporated to give 24 mg of the title compound which is not further purified. LC/MS m/z: 416.27 (M+H) ⁺ .

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

Example C26: 5-ethyl-1,6-bis(4-isopropoxyphenyl)-1H-benzo[d][1,2,3]triazole
A solution of 1,6-bis(4-isopropoxyphenyl)-5-vinyl-1H-benzo[d][1,2,3]triazole (11.5 mg, 0.028 mmol) in MeOH (0.5 mL) is purged of air by pulling a vacuum and filling with nitrogen twice. 10% palladium on carbon (5 mg) is then added and the atmosphere is replaced with hydrogen by pulling a vacuum and filling with a hydrogen balloon twice. The mixture is stirred overnight, diluted with ethyl acetate, filtered through a celite pad, and the filtrate is evaporated in vacuo to give 10 mg of the title compound pure enough to be used without further purification. ¹ H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.74 (d, 2H), 7.49 (s, 1H), 7.29 (d, 2H), 7.15 (d, 2H), 6.98 (d, 2H), 4.70-4.72 (m, 1H), 4.65-4.67 (m, 1H), 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) ⁺ .

Example D27: 3,6-bis(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine Step 1: 6-bromo-7-methylimidazo[1,2-a]pyrimidine
The title compound was prepared from 5-bromo-4-methylpyrimidin-2-amine in the same manner as described for 6-bromoimidazo[1,2-a]pyridine-7-carbonitrile. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 7.85 (s, 1H), 7.49 (s, 1H), 2.79 (s, 3H). LC/MS m/z: 214.25 (M+H) ⁺ .

Step 2: 6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine
The title compound was prepared from 6-bromo-7-methylimidazo[1,2-a]pyrimidine and 4-isopropoxyphenylboronic acid in the same manner as described for 2-(4-(1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1).

Step 3: 3-iodo-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine
The title compound was prepared from 6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyridine in the same manner as described for 6-bromo-3-iodo-7-methylimidazo[1,2-a]pyridine.

Step 4: 3,6-bis(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine
The title compound was prepared from 3-iodo-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine and 4-isopropoxyphenylboronic acid in the same manner as described for 2-(4-(1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1). ¹ H NMR (500 MHz, CDCl ₃ ) 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) ⁺ .

Example D28: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine
The title compound was prepared from 3-iodo-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine and 4-tert-butoxyphenylboronic acid in the same manner as described for 2-(4-(1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1). LC/MS m/z: 416.35 (M+H) ⁺ .

Example D29: 2-(4-(6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl)propan-2-ol
The title compound was prepared from 3-iodo-6-(4-isopropoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid in the same manner as described for 2-(4-(1-(4-(tert-butoxy)phenyl)-5-methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1). LC/MS m/z: 402.39 (M+H) ⁺ .

Example E30: 3-(4-(tert-butoxy)phenyl)-6-(4-(isopropoxy-d ₇ )phenyl)-7-methylimidazo[1,2-a]pyridine Step 1: 4-(3-(4-(tert-butoxy)phenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)phenol

A microwave reactor vial is charged with 6-bromo-3-(4-(tert-butoxy)phenyl)-7-methylimidazo[1,2-a]pyridine (25 mg, 0.07 mmol), 4-hydroxyphenylboronic acid (11 mg, 0.083 mmol, 1.2 equiv), Pd(dppf)Cl ₂ (6 mg, 10 mol %), and potassium carbonate (30 mg, 210 mmol, 3 equiv). 1.5 mL of 1,4-dioxane and 0.5 mL of water are then added and the mixture is degassed by bubbling nitrogen for 5 min. The vial is then tightly capped and subjected to microwave irradiation at 80° C. for 1 h. The resulting mixture is diluted with ethyl acetate and the aqueous layer is extracted three times with ethyl acetate followed by drying over Na ₂ SO ₄ and evaporation to give the crude product. The crude material is purified using silica gel flash chromatography with 100% ethyl acetate as the eluent to give 20 mg of the title compound as a light brown oil. LC/MS m/z: 373.35 (M+H) ⁺ .

Step 2: 3-(4-(tert-butoxy)phenyl)-6-(4-(isopropoxy-d ₇ )phenyl)-7-methylimidazo[1,2-a]pyridine
To a solution of 4-(3-(4-(tert-butoxy)phenyl-7-methylimidazo[1,2-a]pyridin-6-yl)phenol (142 mg, 0.38 mmol) in acetonitrile is added potassium carbonate (0.105 g, 0.76 mmol, 2 equiv). This mixture is stirred at reflux for 30 minutes at which time d7-isopropyl bromide (57 μL, 1.5 equiv) is added in one portion. The mixture is stirred at reflux overnight and then evaporated to dryness. The residue is dissolved in ethyl acetate, washed twice with water, dried over Na ₂ SO ₄ , and evaporated to give a crude solid which was purified using silica gel flash chromatography with 3:7 hexanes:ethyl acetate as the eluent to give 42 mg of the title compound. LC/MS m/z: 422.33 (M+H) ⁺ .

Following Schemes 2, 3, 6-8 and the procedures described above using appropriate starting materials, the following examples can be made.

Arenavirus GP Pseudotype Assay Utilizing a VSV pseudotype system expressing arenavirus glycoproteins (pseudoviruses referred to herein as LASV-p, MACV-p, JUNV-p, GTOV-p, and TCRV-p) and a Renilla luciferase reporter gene heterocyclic compound, we screened to identify individual compounds that inhibit infection of the pseudoviruses but not the native VSV virus expressing the VSV glycoprotein. VSV viruses expressing VSV glycoproteins or pseudoviruses carrying LASV, MACV, JUNV, GTOV and TCRV glycoproteins (LASV-p, MACV-p, JUNV-p, GTOV-p and TCRV-p) were produced in cultured HEK293T cells (ATCC CRL-3216) and grown in 10 cm dishes in DMEM supplemented with 10% FBS, 1× Pen-Strep, non-essential amino acids and L-glutamine. When cells reached approximately 80% confluence, they were transfected with a mixture of 15 μg of pCAGGS plasmid encoding the desired glycoprotein and 45 μl of PEI (polyethyleneimine) transfection reagent (PEI MAX, Polysciences, #24765). Cells were incubated with the solution for 5 hours at 37°C with 5% _CO2 , then washed and the mixture was replaced with supplemented DMEM and incubated for approximately 16-18 hours at 37°C with 5% _CO2 . Cells were then infected with approximately 50 μl of VSV reporter virus, replacing the VSV glycoprotein with a luciferase reporter gene. Cells were infected for 1 hour, then washed once with PBS and incubated in supplemented medium. 24 hours after infection, supernatants were collected, clarified by centrifugation and filtration through a 0.45 μm filter, and stored at -80°C. Both VSV-luciferase and arenavirus glycoprotein pseudotypes were titrated for luminescence activity in Vero cells as described in the luciferase assay protocol (below). Vero cells (ATCC: CCL-81) were grown in supplemented DMEM medium in clear 384-well plates (3000 cells/well). After overnight incubation at 37°C, 5% _CO2 , cells were treated with desired concentrations of compounds and pseudovirus in assay medium. Assay medium consisted of 50% Opti-MEM, 50% DMEM, 1% FBS, Pen-Strep, non-essential amino acids and L-glutamine. Each of the resulting viral supernatants was diluted (1:100-1:2000) to obtain similar luminescence signal/background values of 200 or greater. Final DMSO concentrations in compound test wells were kept below 1%, and control wells were treated with assay medium and 1% DMSO. Cells were incubated for 24 hours at 37°C, 5% _CO2 . Compound-virus mixtures were aspirated from cells 24 hours post-infection and washed once with PBS. Cells were then lysed using 20 μl of lysis buffer from the luciferase kit diluted according to the manufacturer's instructions. After about 20 minutes of incubation, 5 μl of cell lysate was transferred to an opaque white plate and mixed with 12.5 μl of coelenterazine diluted in buffer. The mixture was incubated for 10 minutes at room temperature on a plate shaker, and then luminescence was read using a plate reader (Beckman Coulter DTX 880 multimode detector with 535 nm emission). Luminescence signals of compound-containing and control wells were obtained, and the % activity (inhibition of luciferase signal) of each compound was determined.

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

Inhibitory activity of replicating LASV Plaque assay Confluent or near-confluent cell culture monolayers 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 with FBS reduced to 2% or less and supplemented with 1% penicillin/streptomycin. Test compounds were prepared at seven half-log10 final concentrations (01-10 μM) in 2×MEM or 2×DMEM. Test compounds and positive control compounds (favipiravir or ribavirin) were examined in parallel in biological triplicates. The assay was initiated by first removing growth medium from 12-well plates of cells and loading with the indicated concentration of compound and virus at an MOI of 0.01 or approximately 50-100 plaque forming units (pfu). Cells were incubated for 60 min: 100 μL inoculum/well, 37° C., 5% CO ₂ , constant gentle rocking. The virus inoculum was removed, cells were washed, diluted 1:1 with 2×MEM, and overlaid with either 1% agarose or 1% methylcellulose supplemented with 2% FBS and 1% penicillin/streptomycin along with the corresponding drug concentrations. Cells were incubated for 5 days at 37° C., 5% CO ₂ . The overlay was then removed and 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 set of compound dilutions was converted to a percentage relative to the untreated virus control. The 50% effective (EC ₅₀ , virus inhibition) concentration was then calculated by linear regression analysis. The quotient of CC ₅₀ divided by EC ₅₀ gives the selection index (SI) value. Compounds exhibiting an SI value of 10 or greater were considered active.

The replicating LASV virus yield reduction assay VYR test directly determines the concentration of test compound that inhibits virus replication. Compounds and virus were added to Vero cells for 3-4 days, at which time the supernatant was removed and tested for infectious particles. Supernatants were titrated log10 dilutions of virus onto fresh monolayers of Vero cells in 96-well plates, using 3 or 4 microwells per dilution. Wells were scored for the presence or absence of virus after a discrete CPE was observed. Plotting the inhibitor concentration against the log10 of virus obtained at each concentration allowed the calculation of the 90% effective concentration by linear regression. In addition, compounds were tested at different concentrations in parallel on virus-free Vero cells to determine cytotoxicity _CC50 values. Selectivity index (SI) was calculated as the ratio _CC50 / _EC90 .

Replicating Tacaribe Virus Testing Selected compounds were tested against native replicating Tacaribe (TCRV) virus (TRVL-11573, BEI Resources) using an ELISA-based assay. Vero cells (ATCC: CCL-81) were grown in supplemented DMEM medium in a 96-well format (5000 cells/well). After overnight incubation, cells were treated with TCRV and desired concentrations of compounds in MEM medium with 1% FBS and supplements. Final DMSO concentrations in compound test wells were kept below 1%, while control wells were treated with TCRV or medium and 1% DMSO. After 5 days of incubation at 37°C with 5% CO ₂ , cells were fixed with 2% paraformaldehyde for 45 minutes and then washed with PBS. Afterwards, cells were permeabilized with 0.25% Triton-X and then TCRV was detected using ELISA according to the following protocol: Cells were stained with a monoclonal anti-Junin virus antibody (BEI number NR 41860) that cross-reacts with TCRV nucleoprotein. After washing, cells were treated with a biotin-conjugated secondary antibody followed by streptavidin-conjugated horseradish peroxidase. TMB substrate was added to the wells and the reaction was stopped with 2M sulfuric acid. Absorbance was read using a plate reader (Beckman Coulter DTX 880 Multimode detector with 450 nm emission). OD readings were obtained for compound-containing and control wells to determine the % activity of each compound.

In addition to the ability of a compound to demonstrate broad inhibitory activity against arenaviruses in vitro in a microsomal assay , the compound must also possess certain drug-like properties to be used to inhibit arenaviruses and provide a method of treating arenavirus infections in mammals in vivo. Such compounds may exhibit drug-like properties including, but not limited to, chemical stability against metabolic degradation by hepatic microsomal CYP p450 enzymes, cell permeability and oral bioavailability (if the drug is 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 publications are incorporated herein by reference for all purposes. To characterize the drug-like properties of the chemical series, example compounds were evaluated for metabolic stability in human, mouse, guinea pig, monkey, rat, mouse, or dog liver microassays (Table 4) and for inhibition of the hERG ion channel (Table 5). Compounds showing greater than 60% survival of the parent indicate attractive chemical stability. Demonstration of good microsomal stability in human and non-human species facilitates the ability to test and optimize compounds in preclinical animal studies.

A reaction premix is set up containing 1 μM of the compound of interest, 1 mg/mL liver microsomes of the desired species, 2.1 mM _MgCl2 , and 0.1 M sodium phosphate buffer, pH 7.4. This premix is incubated at 37° C. for 30 minutes with gentle agitation to allow complete dissolution of the compound in the mixture. A freshly prepared solution of NADPH in 0.1 M sodium phosphate buffer is then added at a concentration of 2 mM to initiate the reaction. A “time 0” sample (30 μL) is removed immediately after the addition of NADPH and added to 140 μL of cold acetonitrile containing a pre-determined 1 μM internal standard. The remaining reaction mixture is incubated at 37° C. for the remaining period. The test compound was left in the reaction mixture for 60 minutes, and a “time 60” sample was added to acetonitrile along with the internal standard. Control compounds (verapamil for human, monkey and dog LM, lidocaine for guinea pig LM, diphenhydramine for rat and mouse LM) were incubated in the reaction mixture for 15 minutes and a "time 15" sample was collected and spiked into cold acetonitrile along with the internal standard. The samples were then spun in a centrifuge at 4000 rpm for 10 minutes and the supernatant was collected and mixed with an equal portion of distilled water. They were then analyzed on a Varian 500-MS.

hERG Channel Assay Drugs belonging to different classes have been shown to be associated with QT prolongation and, in some cases, severe 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 cardiomyocyte repolarization and is a common target of drugs that prolong the QT interval. Therefore, the test articles in this study were characterized to determine their ability to inhibit the hERG channel. Ion channel activity was measured using a stably transfected Chinese Hamster Ovary (CHO) cell line expressing hERG mRNA. The pharmacology of this cloned channel expressed in the CHO cell line closely resembles that observed in the native tissue. Cells were cultured in DMEM/F12 containing 10% FBS, 1% penicillin/streptomycin and 500 μg/ml G418. Prior to testing, cells were harvested using an Accumax (Innovative Cell Technologies). For electrophysiological recordings, the following solutions were used: External solution: 2 mM CaCl ₂ ; 2 mM MgCl ₂ ; 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 MgCl ₂ ; 6 mM EGTA; 5 mM HEPES-Na; 5 mM ATP-Mg; 295-305 mOsm; pH 7.25 (adjusted with 1 M KOH). Whole-cell recordings were made with a PX7000A (Axon Instruments) using AVIVA's SealChip® technology. Cells were voltage clamped at a holding potential of -80 mV. The hERG current was then activated with a depolarizing step to -50 mV for 300 ms. This first step to -50 mV was used as a baseline for measuring the peak amplitude of the tail current. A voltage step to +20 mV was then applied for 5 s to activate the channel. Finally, a step back to -50 mV for 5 s removed activation and the non-activated tail current was recorded. An external solution containing 0.1% DMSO (vehicle) was added to the cells to establish a baseline. The current was allowed to stabilize for 3-10 min before the addition of the test article. The test article solution was added to the cells in four separate additions. The cells were kept in the test solution for up to 12 min until the effect of the test article reached steady state. 1 mM cisapride (positive control) was then added. Finally, a wash with external solution was performed until the recovery current reached steady state. Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments) and Origin (OriginLab Corporation) software.

Table 1. Pseudovirus activity. Example compounds and their observed inhibitory activity are shown as EC ₅₀ values for LASV-p, MACV-p, JUNV-p, TCRV-p and GTOV-p (VSV-p EC 50 values were all above 10 μM) and CC ₅₀ for cytotoxicity; nd: not determined.

Table 2. Comparison of inhibitory activity of mock versus replicated TCRV. Example compounds and their observed inhibitory activity ( _EC50 ) against mock or replicated TCRV.

Surprisingly, a very close correlation was found between the pseudovirus inhibitory activity and replicating virus inhibitory activity of the compounds of the present invention.

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

All five compounds demonstrated highly potent _EC50 and _EC90 values of <1-3 nM for compounds A1, A2, B7, and B8 in plaque assay and VYR assay formats, and an _EC90 of <14 nM for compound E30 in the VYR assay format. _SI90 values (derived from VYR assay data) were >1510, clearly indicating that the efficacy of the compounds was due to antiviral activity and not due to cytotoxic effects. The results shown in Tables 1-3 confirm the activity of the compounds against arenaviruses, including replicating LASV, and also strongly validate the approach to identify bona fide HF arenavirus inhibitors through the use of pseudovirus assays.

Table 4. Multispecies microsomal stability. Percentage of parent compound remaining in liver microsomes at 60 min.

Results of the multi-species microsomal stability study (Table 4) demonstrated that deuterated compound E30 demonstrated improved metabolic stability in monkey liver microsomal assays compared to the non-deuterated analogue B7, and therefore showed good microsomal stability in both human and non-human species.

TABLE 5 hERG Channel Assays

These data demonstrate a lack of hERG channel inhibition, suggesting good potential for cardiac safety.

Table 6. Pharmacokinetic parameters in mice

Compounds were administered to mice by intravenous (3 mg/kg) and oral (30 mg/kg) routes to determine pharmacokinetic parameters. IV time points included 0.083, 0.25, 0.5, 1, 2, 6, and 24 hours, and oral time points included 0.5, 1, 2, 4, 6, 8, and 24 hours. Three mice were bled per time point. Plasma was isolated and measured by LC/MS/MS on a Varian 500-LC/MS. Both compounds demonstrated low first-pass hepatic clearance, consistent with high levels of compound remaining in mouse liver microsomes after 1 hour (Table 4). Both compounds demonstrate reasonable oral bioavailability and long half-lives suitable for once-daily dosing. Finally, volume of distribution (Vd) values indicate that the compounds are taken up into tissues, further supporting good oral biodistribution to target arenavirus infections.

Mice were able to tolerate both compounds administered orally once daily for three days at a maximum of at least 100 mg/kg (highest dose tested). There were no clinical signs of undue 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 taken from treated animals to measure compound levels. Livers were homogenized in 1:1 w/v phosphate buffered saline. Both plasma and liver extracts were measured by LC/MS/MS on a Varian 500-MS (Table 7).

Table 7: Compound concentrations 24 hours after last dose

Collectively, the results demonstrate that the compounds of the present invention exhibit potent, broad-spectrum inhibition of HF arenavirus and exhibit drug-like properties that make them attractive for use as therapeutics for viral infections mediated by arenavirus glycoproteins.

Claims (13)

is selected from the group consisting of
D is a compound , or a solvate, hydrate or pharma- ceutically acceptable salt thereof , exhibiting at least 45% deuterium incorporation . The compound is
2. The compound of claim 1 , selected from the group consisting of: The compound is
3. The compound of claim 2 , wherein: or a solvate, hydrate, or pharma- ceutical acceptable salt thereof, selected from the group consisting of: The compound is
5. The compound of claim 4, wherein: A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 , or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier, diluent or vehicle. A pharmaceutical composition according to claim 6 for use as a medicament. 7. The pharmaceutical composition according to claim 6 for use in a method for treating an infection associated with a virus of the Arenaviridae enveloped virus family. A pharma- ceutically acceptable dose of a compound according to any one of claims 1 to 5 ,
9. The pharmaceutical composition of claim 6 for use in a method for treating an infection as described in claim 8, administered together with a pharma- ceutically acceptable dose of at least one compound selected from ribavirin, a polymerase inhibitor, favipiravir, triazavirin , a small interfering RNA (siRNA), a vaccine, a monoclonal antibody, and an immunomodulatory agent. 4. A pharmaceutical composition comprising a compound according to claim 3 , or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent or vehicle. 11. The pharmaceutical composition of claim 10 for use in a method for treating an infection associated with a virus of the Arenaviridae enveloped virus family. 12. The pharmaceutical composition of claim 10 for use in a method for treating an infection as described in claim 11 , wherein a pharma- ceutical acceptable dose of a compound of claim 3 is administered together with a pharma- ceutical acceptable dose of favipiravir . 11. A pharmaceutical composition according to claim 6 or 10 for use in a method for treating an infection associated with Lassa virus.