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WO2016160677A1 - Composés pour le traitement d'une infection à arénavirus - Google Patents

Composés pour le traitement d'une infection à arénavirus Download PDF

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Publication number
WO2016160677A1
WO2016160677A1 PCT/US2016/024467 US2016024467W WO2016160677A1 WO 2016160677 A1 WO2016160677 A1 WO 2016160677A1 US 2016024467 W US2016024467 W US 2016024467W WO 2016160677 A1 WO2016160677 A1 WO 2016160677A1
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group
aryl
heteroaryl
cycloheteroalkyi
alkynyl
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Inventor
Micheal PLEWE
Landon WHITBY
Kenneth Mccormack
Gregory Henkel
Eric Brown
Dale Boger
Nadezda Sokolova
Vidyasagar Reddy
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Arisan Therapeutics Inc
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Arisan Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Arenaviridae comprise a diverse family of 29 (and growing) negative stranded enveloped RNA viruses. Arenaviruses are divided into two groups, Old and New World complex, based on serological, genetic and geographical data. Old World viruses are found primarily throughout South and West Africa and include the prototypic lymphocytic choriomeningitis virus (LCMV), along with Lassa (LASV), Lujo (LUJV), Mopeia (MOPV), Ippy and Mobala (MOBV) viruses.
  • LCMV lymphocytic choriomeningitis virus
  • LASV Lassa
  • LJV Lujo
  • MOPV Mopeia
  • Ippy and Mobala (MOBV) viruses Ippy and Mobala
  • LASV and LUJV can cause lethal hemorrhagic fever (HF), while LCMV infection is associated with aseptic meningitis Lassa (LASV) alone is estimated to cause over 300,000 disease cases each year in West Africa of which 15-20% of hospitalized patients die and survivors often suffer sequelae, including permanent bilateral hearing damage.
  • LASV aseptic meningitis Lassa
  • Clade B HF viruses include, Junin (JUNV), Machupo (MACV), Guanarito (GOTV), Sabia (SABV) and Chapare, along with non-HF viruses such as Tacaribe (TACV) and Amapari (AMPV).
  • JUNV Junin
  • MACV Machupo
  • GOTV Guanarito
  • SABV Sabia
  • AMPV Amapari
  • Human infection occurs through contact with the excretions of an infected rodent or by inhalation of tiny particles soiled with rodent urine or saliva (aerosol transmission).
  • TACV Tacaribe
  • AMPV Amapari
  • Arenaviruses consist of a nucleocapsid (NP) surrounded by an envelope membrane, and the NP 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 a small Ring Finger protein Z.
  • the S segment encodes for nucleoprotein and a glycoprotein precursor GPC that is cleaved by host proteases and undergoes post-translational modification into a mature complex composed of glycoproteins GP1 (binds host protein at the cell surface), GP2 (directs pH dependent membrane fusion and release of genomic material in the cytoplasm) and a stable signal peptide (SSP1).
  • GP1 binds host protein at the cell surface
  • GP2 directs pH dependent membrane fusion and release of genomic material in the cytoplasm
  • SSP1 stable signal peptide
  • the mature glycoprotein complex is formed in the viral envelope and is responsible for mediating viral entry.
  • the Old World arenaviruses bind to host -dystroglycan while New World arenaviruses bind to transferrin receptor 1 for entry/endocytosis into cells.
  • the virus Upon binding to cell surface receptors, the virus is endocytosed and directed to acidic late endosomes whereby, GP2 mediates pH dependent membrane fusion and release of genomic material into the cytoplasm for viral replication and transcription. Therefore, viral entry inhibitors (e.g. small molecules) that target virus GP complex or host factors are a potential therapeutic/prophylactic approach in treating patients infected with arenavirus infection. Because the HF arenavirus species are classified as BSL-4 alternative approaches are needed to identify viral entry inhibitors.
  • VSV vesicular stomatitis virus
  • LASV vesicular stomatitis virus
  • the cell entry and infectivity properties of GP pseudotype VSV viruses have been shown for multiple viruses including HIV, Hepatitis B and C, Ebola, Lassa, Hanta and others.
  • a reporter gene such as green fluorescent protein (GFP) or luciferase can be engineered into the pseudovirus genome, and virus infectivity in mammalian cell lines (e.g. Vera or Hek293) can be monitored using optical detection methods (e.g. plate reader).
  • GFP green fluorescent protein
  • the "pseudoviruses" may therefore be used to screen chemical compound libraries to identify inhibitors of arenavirus cell entry while avoiding the complications of working with highly pathogenic BSL4 agents.
  • entry inhibitors described were identified using an arenavirus GP pseudovirus screens.
  • the present invention relates to the use of piperazinones for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers, to methods of inhibiting the replication of arenaviruses, to methods of reducing the amount of arenaviruses, and to compositions that can be employed for such methods.
  • arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I
  • R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Csto C10) cycloalkyl, (C5 to Cio) cycloalkenyl, and (C2 to C9) cycloheteroalkyl, (C6 to C10) aryl, (C2 to C9) heteroaryl, wherein each of the said (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to Cio) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 5 group;
  • R 2 is (Ci to C6) alkyl substituted with a group selected from (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Cs to C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl, wherein
  • each of the said (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 6 group;
  • R 3 is independently selected from hydrogen, halogen, CF3, cyano, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, (C2 .0 C9) heteroaryl, -C(0)R 7 ,-C(0)NR 8a R 8b , -(CH 2 )nC(0)OR 7 , and
  • each of the said (C-, to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 5 group;
  • R 4 is selected from (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkenyl, (Ce to C10) aryl, and (C2 to C9) heteroaryl, wherein
  • each of the said (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkenyl, (Ce to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 5 group;
  • R 5 is independently selected from hydrogen, halogen, cyano , OH, CF3, (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, aryloxy, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, (C2 to C9) heteroaryl, -C(0)R 7 , -C(0)NR 8a R 8b , -NR 8a R 8b , -S(0)mR 7 , -S(0)mNR 8a R 8b , -NR 8a S(0)mR 7 , -(CH 2 )nC(0)OR 7 , -(CH 2 )nC(0)NR 8a R 8b , -OC(0)R 7 ,
  • R 6 is independently selected from hydrogen, halogen, OH, CF3, (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, cyano, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, (C2 to C9) heteroaryl, -C(0)R 7 , -C(0)NR 8a R 8b , -NR 8a R 8b , -S(0)mR 7 , -S(0)mNR 8a R 8b , -NR 8a S(0)mR 7 , -(CH 2 )nC(0)OR 7 , -(CH 2 )nC(0)NR 8a R 8b , -OC(0)R 7 ,
  • each of the R 7 is independently selected from hydrogen, (C ⁇ o C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C 3 to C 0 ) cycloalkyi, (Cs to C10) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl; wherein each of the said (C-, to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to Cio) cydoalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 9 group;
  • each of the R 8a , R 8b , and R 8c are independently selected from hydrogen, (C ⁇ to C 6 ) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 )
  • R 8a and R 8b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyi ring, wherein
  • said 4 to 8 membered cycloheteroalkyi ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein
  • the said 4 to 8 membered cycloheteroalkyi ring is optionally substituted with at least one R 9 group;
  • R 9 is independently selected from hydrogen, halogen, OH, CF3, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Ci to C6) alkoxy, cyano, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C2 to Co) cycloheteroalkyi, (Ce to C10) aryl, (C2 to Co) heteroaryl, -C(0)R 10 , -C(0)NR a R b , -NR a R b -S(0)mR 10 , -S(0)mNR a R b , -NR a S(O)mR 0 , -(CH2)nC(O)OR 10 , -(CH 2 )nC(0)N(R a R b ), -OC(0)R 10 , -NR a C(0)R 10 , and -NR a
  • each of the R 0 is independently selected from hydrogen, (d to C 6 ) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C 3 to C 0 ) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl; wherein
  • each of the said (C-, to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 2 group;
  • each of the R a ,R b and R c are independently selected from hydrogen, (C-, to C 6 ) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 )
  • R a and R b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyi ring, wherein
  • said 4 to 8 membered cycloheteroalkyi ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein
  • the said 4 to 8 membered cycloheteroalkyi ring is optionally substituted with at least one R 2 group;
  • R 2 is independently selected from hydrogen, halogen, cyano , OH, CF3, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Ci to C6) alkoxy, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, and (C2 to C9) heteroaryl,
  • R is not selected from the group consisting of methyl, ethyl, CF 3 , CHF 2 , CH 2 F, cyclopropyl, isopropyl, hydroxymethyl, and methoxymethyl,
  • R 2 is not selected from the group consisting of
  • R 4 is not selected from the group consisting of optionally substituted
  • A is selected from a bond, alkylidene, heterocyclylene, arylene, heteroarylene, -0-, -SO-, and -S0 2 -,
  • R is benzyl or 2-phenylethyl
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula II
  • R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Csto Cio) cycloalkyl, (Cs to Cio) cycloalkenyl, and (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, (C2 to C9) heteroaryl, wherein each of the said (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to Cio) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 5 group;
  • R 2 is (Ci to C6) alkyl substituted with a group selected from (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Cs to C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl, wherein
  • each of the said (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 6 group;
  • R 3 is independently selected from hydrogen, halogen, CF3, cyano, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, (C2 .0 C9) heteroaryl, -C(0)R 7 ,-C(0)NR 8a R 8b , -(CH 2 )nC(0)OR 7 , and
  • each of the said (C-, to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 5 group;
  • R 4 is selected from (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkenyl, (Ce to C10) aryl, and (C2 to C9) heteroaryl, wherein
  • each of the said (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkenyl, (Ce to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 5 group;
  • R 5 is independently selected from hydrogen, halogen, cyano , OH, CF3, (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, aryloxy, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, (C2 to C9) heteroaryl, -C(0)R 7 , -C(0)NR 8a R 8b , -NR 8a R 8b , -S(0)mR 7 , -S(0)mNR 8a R 8b , -NR 8a S(0)mR 7 , -(CH 2 )nC(0)OR 7 , -(CH 2 )nC(0)NR 8a R 8b , -OC(0)R 7 ,
  • R 6 is independently selected from hydrogen, halogen, OH, CF3, (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, cyano, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, (C2 to C9) heteroaryl, -C(0)R 7 , -C(0)NR 8a R 8b , -NR 8a R 8b , -S(0)mR 7 , -S(0)mNR 8a R 8b , -NR 8a S(0)mR 7 , -(CH 2 )nC(0)OR 7 , -(CH 2 )nC(0)NR 8a R 8b , -OC(0)R 7 ,
  • each of the R 7 is independently selected from hydrogen, (C ⁇ o C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C 3 to C 0 ) cycloalkyi, (Cs to C10) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl; wherein each of the said (C-, to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to Cio) cydoalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 9 group;
  • each of the R 8a , R 8b , and R 8c are independently selected from hydrogen, (C ⁇ to C 6 ) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 )
  • R 8a and R 8b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyi ring, wherein
  • said 4 to 8 membered cycloheteroalkyi ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein
  • the said 4 to 8 membered cycloheteroalkyi ring is optionally substituted with at least one R 9 group;
  • R 9 is independently selected from hydrogen, halogen, OH, CF3, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Ci to C6) alkoxy, cyano, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C2 to Co) cycloheteroalkyi, (Ce to C10) aryl, (C2 to Co) heteroaryl, -C(0)R 10 , -C(0)NR a R b , -NR a R b -S(0)mR 10 , -S(0)mNR a R b , -NR a S(O)mR 0 , -(CH2)nC(O)OR 10 , -(CH 2 )nC(0)N(R a R b ), -OC(0)R 10 , -NR a C(0)R 10 , and -NR a
  • each of the R 0 is independently selected from hydrogen, (d to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C 3 to C 0 ) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl; wherein
  • each of the said (C-, to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 2 group;
  • each of the R a ,R b and R c are independently selected from hydrogen, (C-, to C 6 ) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 )
  • R a and R b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyi ring, wherein
  • said 4 to 8 membered cycloheteroalkyi ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein
  • the said 4 to 8 membered cycloheteroalkyi ring is optionally substituted with at least one R 2 group;
  • R 2 is independently selected from hydrogen, halogen, cyano , OH, CF3, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Ci to C6) alkoxy, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, and (C2 to C9) heteroaryl,
  • R is not selected from the group consisting of methyl, ethyl, CF 3 , CHF 2 , CH 2 F, cyclopropyl, isopropyl, hydroxymethyl, and methoxymethyl,
  • R 2 is not selected from the group consisting of
  • A is selected from a bond , alkylidene, heterocyclylene, arylene, heteroarylene, -0-, -S-, , -SO-, and -S0 2 -,
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I II
  • R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Cs to C10) cycloalkyl, (Cs to Cio) cycloalkenyl, and (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, (C2 to C9) heteroaryl, wherein each of the said (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyl, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 5 group;
  • R 2 is (Ci to C6) alkyl substituted with a group selected from (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Cs to C10) cycloalkenyl, (Ce to C10) aryl, and (C2 to C9) heteroaryl, wherein each of the said (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 6 group;
  • R 3 is independently selected from hydrogen, halogen, CF3, cyano, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ceto C10) aryl, (C2 .0 C9) heteroaryl, -C(0)R 7 ,-C(0)NR 8a R 8b , -(CH 2 )nC(0)OR 7 , and - (CH 2 )nC(0)N(R 8a R 8b ), wherein
  • each of the said (C to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 5 group;
  • R 4 is selected from (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Csto C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl, wherein
  • each of the said (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Csto C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 5 group;
  • R 5 is independently selected from hydrogen, halogen, cyano, OH, CF3, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Ci to C6) alkoxy, aryloxy, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ceto C10) aryl, (C2 to C9) heteroaryl, -C(0)R 7 , -C(0)NR 8a R 8b , -NR 8a R 8b , -S(0)mR 7 , -S(0)mNR 8a R 8b , -NR 8a S(0)mR 7 , -(CH 2 )nC(0)OR 7 , -(CH 2 )nC(0)NR 8a R 8b , -OC(0)R 7 ,
  • R 6 is independently selected from hydrogen, halogen, OH, CF3, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Ci to C6) alkoxy, cyano, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ceto C10) aryl, (C2 to C9) heteroaryl, -C(0)R 7 , -C(0)NR 8a R 8b , -NR 8a R 8b , -S(0)mR 7 , -S(0)mNR 8a R 8b , -NR 8a S(0)mR 7 , -(CH 2 )nC(0)OR 7 , -(CH 2 )nC(0)NR 8a R 8b , -OC(0)R 7 ,
  • each of the R 7 is independently selected from hydrogen, (C ⁇ o C 6 ) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C 3 to C 0 ) cycloalkyi, (Csto C10) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl; wherein
  • each of the said (C ⁇ to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 9 group;
  • each of the R 8a , R 8b , and R 8c are independently selected from hydrogen, (C ⁇ to C 6 ) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C 2 to C 9 )
  • cycloheteroalkyi (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl, or R and R may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyi ring, wherein
  • said 4 to 8 membered cycloheteroalkyi ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein
  • the said 4 to 8 membered cycloheteroalkyi ring is optionally substituted with at least one R 9 group;
  • R 9 is independently selected from hydrogen, halogen, OH, CF3, (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, cyano, (C3 to C10) cycloalkyi, (Csto C10) cydoalkenyl, (C2 to Co) cycloheteroalkyi, (Ce to C10) aryl, (C2 to Co) heteroaryl, -C(0)R 10 , -C(0)NR a R b , -NR a R b -S(0)mR 10 , -S(0)mNR a R b , -NR a S(O)mR 0 , -(CH2)nC(O)OR 10 , -(CH 2 )nC(0)N(R a R b ), -OC(0)R 10 , -NR a C(0)R 10 , and -NR a
  • each of the R 0 is independently selected from hydrogen, (d to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C 3 to C 0 ) cycloalkyi, (Csto C10) cydoalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl; wherein
  • each of the said (d to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C 2 to C 9 ) cycloheteroalkyi, (C 2 to C 9 ) heteroaryl, and (C 6 to C 0 ) aryl is optionally substituted with at least one R 2 group;
  • each of the R a ,R b and R c are independently selected from hydrogen, (d to C 6 ) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cydoalkenyl, (C 2 to C 9 )
  • R a and R b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyi ring, wherein
  • said 4 to 8 membered cycloheteroalkyi ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein
  • the said 4 to 8 membered cycloheteroalkyi ring is optionally substituted with at least one R 2 group;
  • R 2 is independently selected from hydrogen, halogen, cyano, OH, CF3, (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C2 to Co) cycloheteroalkyi, (C6 to C10) aryl, and (C2 to Co) heteroaryl,
  • R is not selected from the group consisting of methyl, ethyl, CF 3 , CHF 2 , CH 2 F, cyclopropyl, isopropyl, hydroxymethyl, and methoxymethyl,
  • R 4 is not selected from the group consisting of optionally substituted
  • A is selected from a bond, alkylidene, heterocyclylene, arylene, heteroarylene, -0-, -S-, -CO-, -SO-, and -S0 2 -,
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula III wherein
  • R 2 is (Ci to C6) alkyl substituted with a group selected from (C6 to C10) aryl and (C2 to C9) heteroaryl, wherein
  • each of the said (C6 to C10) aryl and (C2 to C9) heteroaryl is optionally substituted with at least one R 6 group;
  • R 3 is hydrogen or methyl
  • R 4 is selected from (C6 to C10) aryl and (C2 to C9) heteroaryl, wherein
  • each of the said (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R 5 group.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula III, wherein
  • R 2 is methyl substituted with a group selected from (C6 to C10) aryl and (C2 to C9) heteroaryl, wherein
  • each of the said (C6 to C10) aryl and (C2 to C9) heteroaryl is optionally substituted with at least one R 6 group;
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula III, wherein
  • R is selected from benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, aryloxymethyl, and CH 2 NR 8a R 8b , wherein
  • each of the said benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, and aryloxymethyl is optionally substituted with at least one R 5 group.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula III, wherein
  • R 2 is methyl substituted with a (C6 to C10) aryl or (C2 to C9) heteroaryl group selected from the group consisting of
  • each of the said aryl or heteroaryl group is optionally substituted with at least one R 3 group;
  • R 3 is selected selected from hydrogen, halogen, cyano, OH, CF3, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, isopropyl, methoxy, ethoxy, cyclopropyloxy, cyclopropylmethoxy, isopropyloxy, difluoromethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, oxetan-3-yloxy, oxetan-3-yl, 3- hydroxyoxetan-3-yl, 3-fluorooxetan-3-yl, 3-methyloxetan-3-yl, acetyl, ⁇ , ⁇ -dimethylamino, and 1 H- pyrazol-1 -yl.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula III, wherein
  • R 4 is selected from hydrogen, halogen, cyano, OH, CF3, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, isopropyl, methoxy, ethoxy, cyclopropyloxy, isopropyloxy, cyclopropylmethoxy, benzyloxy, oxetan-3-yl, 3-methyloxetan-3-yl, acetyl, ⁇ , ⁇ -dimethylamino, 1 -pyrrolidinyl, 1 -piperidinyl.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula III, wherein
  • R is selected from benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, aryloxymethyl, and CH 2 NR 8a R 8b , wherein
  • each of the said benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, and aryloxymethyl is optionally substituted with at least one R 5 group;
  • R 2 is methyl substituted with a (C6 to C10) aryl or (C2 to C9) heteroaryl group selected from the group consisting of
  • each of the said aryl or heteroaryl group is optionally substituted with at least one R 3 group; 4 is selected from the group consisting of
  • R 3 is selected selected from hydrogen, halogen, cyano, OH, CF3, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, isopropyl, methoxy, ethoxy, cyclopropyl oxy, isopropyloxy, cyclopropylmethoxy, difluoromethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, oxetan-3-yloxy, oxetan-3- yl, 3-hydroxyoxetan-3-yl, 3-fluorooxetan-3-yl, 3-methyloxetan-3-yl, acetyl, ⁇ , ⁇ -dimethylamino, and 1 H-pyrazol-1 -yl;
  • R 4 is selected from hydrogen, halogen, cyano, OH, CF3, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, isopropyl, methoxy, ethoxy, cyclopropyloxy, isopropyloxy, cyclopropylmethoxy, benzyloxy, oxetan-3-yl, 3-methyloxetan-3-yl, acetyl, ⁇ , ⁇ -dimethylamino, 1 -pyrrolidinyl, 1 -piperidinyl.
  • the invention relates to compounds, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, selected from
  • One can treat Arenavirus infection by administering a pharmaceutically effective amount of a pharmaceutical composition comprising a compound selected from structural formulae I, II, and III or a compound as shown above with a pharmaceutically acceptable carrier, dilutant, or vehicle.
  • a therapeutically effective amount of a therapeutic agent selected from the group consisting of Ribavirin, polymerase inhibitors, T-705 (favipiravir), Triazavirin, small interfering RNAs (siRNAs), vaccines, and immunomodulators can be administered with the compound of the invention.
  • halo and/or halogen refer to fluorine, chlorine, bromine or iodine.
  • (CT to C 6 )" alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 6 carbon atoms.
  • Examples of (C ⁇ to C 6 ) alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, / ' so-butyl, fe/ -butyl, pentyl, and the like.
  • Et and “ethyl,” as used herein, mean a - C 2 H 5
  • (C 2 to C 8 ) alkenyl means an alkyl moiety comprising 2 to 8 carbonshaving 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 will result 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.
  • (C 2 to C 8 ) alkynyl means an alkyl moiety comprising 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 will result 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.
  • (C ⁇ to C 8 ) alkoxy means 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, iso-propyloxy, n-butoxy, 5 iso-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.
  • (C 6 to C 0 ) aryl 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.
  • Ph and "phenyl,” as used herein, mean a -C 6 H 5 group.
  • benzyl as used herein , means a -CH 2 C 6 H 5 group.
  • (C 2 to C 9 ) heteroaryl means an aromatic heterocyclic group having a total of from 5 to 10 atoms in its ring, and containing from 2 to 9 carbon atoms and from one to four heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
  • the heterocyclic groups include benzo-fused ring systems.
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyljsoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • the C 2 to C 9 heteroaryl groups may be C-attached or N-attached where such is possible.
  • a group derived from pyrrole may be pyrrol-1 -yl (N- attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1 -yl (N- attached) or imidazol-3-yl (C-attached).
  • (C 2 to C 9 ) cycloheteroalkyl means a non-aromatic, monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic group having a total of from 4 to 13 atoms in its ring system, and containing from 5 to 9 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N , and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
  • such C 2 to C 9 cycloheteroalkyl groups may contain an oxo substituent at any available atom that will result in a stable compound.
  • such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible.
  • a C2 to C9 cycloheteroalkyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone.
  • An example of a 4 membered cycloheteroalkyi group is azetidinyl (derived from azetidine).
  • An example of a 5 membered cycloheteroalkyi group is pyrrolidinyl.
  • An example of a 6 membered cycloheteroalkyi group is piperidinyl.
  • An example of a 9 membered cycloheteroalkyi group is indolinyl.
  • An example of a 10 membered cycloheteroalkyi group is 4/-/-quinolizinyl. Further examples of such C 2 to C 9
  • cycloheteroalkyi groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl,
  • tetrahydrothienyl 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, AH pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothien
  • (C 3 to C 0 ) cycloalkyl group means a saturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 10 carbon 5 ring atoms.
  • groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl.
  • spirocyclic has its conventional meaning , that is, any compound containing two or more rings wherein two of the rings have one ring carbon in common.
  • the rings of a spirocyclic compound, as herein defined independently have 3 to 20 ring atoms. Preferably, they have 3 to 10 ring atoms.
  • Non-limiting examples of a spirocyclic compound include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.
  • (C 5 to C 8 ) cycloalkenyl means an unsaturated, monocyclic, fused, spirocyclic ring strucures having a total of from 5 to 8 carbon ring atoms. Examples of such groups include, but not limited to, cyclopentenyl, cyclohexenyl.
  • cyano refers to a -C ⁇ N group.
  • aldehyde refers to a carbonyl group where R is hydrogen.
  • alkoxy refers to both an -O-alkyl and an -O-cycloalkyl group, as defined herein.
  • alkoxycarbonyl refers to a -C(0)OR.
  • alkylaminoalkyl refers to an -alkyl-NR-alkyl group.
  • alkylsulfonyl refer to a -S0 2 alkyl.
  • amino refers to an -NH 2 or an -NRR'group.
  • aminoalkyl refers to an -alky-NRR' group.
  • aminocarbonyl refers to a -C(0)NRR'.
  • arylalkyl refers to -alkylaryl, where alkyl and aryl are defined herein.
  • aryloxy refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.
  • aryloxycarbonyl refers to -C(0)Oaryl.
  • arylsulfonyl refers to a -S0 2 aryl.
  • a "C-amido” group refers to a -C(0)NRR' group.
  • a “carbonyl” group refers to a -C(0)R.
  • a “C-carboxyl” group refers to a -C(0)OR groups.
  • a “carboxylic acid” group refers to a C-carboxyl group in which R is hydrogen.
  • a "cyano" group refers to a -CN group.
  • a “dialkylamionalkyl” group refers to an— (alkyl)N(alkyl)2 group.
  • halo or halogen group refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl group refers to an alkylgroup substituted with one or more halogen atoms.
  • heteroalicycloxy refers to a heteroalicyclic-O group with heteroalicyclic as defined herein.
  • heteroaryloxyl refers to a heteroaryl-O group with heteroaryl as defined herein.
  • a "hydroxy” group refers to an -OH group.
  • N-amido refers to a -R'C(0)NR group.
  • N-carbamyl refers to a -ROC(0)NR-group.
  • a "nitro” group refers to a -N0 2 group.
  • N-Sulfonamido refers to a -NR-S(0) 2 R group.
  • N-thiocarbamyl refers to a ROC(S)NR' group.
  • An "O-carbamyl” group refers to a -OC(0)NRR' group.
  • An "O-carboxyl” group refers to a RC(0)0 group.
  • O-thiocarbamyl refers to a -OC(S)NRR' group.
  • oxo refers to a carbonyl moiety such that alkyl substituted by oxo refers to a ketone group.
  • a “perfluoroalkyl group” refers to an alkyl group where all of the hydrogen atoms have been replaced with fluorine atoms.
  • a “phosphonyl” group refers to a -P(0)(OR) 2 group.
  • silica refers to a -SiR 3 group.
  • S-sulfonamido refers to a -S(0) 2 NR-group.
  • a “sulfinyl” group refers to a -S(0)R group.
  • a “sulfonyl” group refers to a -S(0) 2 R group.
  • a "trihalomethanecarbonyl” group refers to a Z 3 CC(0) group, where Z is halogen.
  • a "trihalomethanesulfonamido" group refers to a Z 3 CS(0) 2 NR-group.
  • a "trihalomethanesulfonyl” group refers to a Z 3 CS(0) 2 group.
  • a "trihalomethyl” group refers to a -CZ 3 group.
  • a "C-carboxyl” group refers to a -C(0)OR groups.
  • substituted means that the specified group or moiety bears one or more substituents.
  • solvate is used to describe a molecular complex between compounds of the present invention and solvent molecules.
  • examples of solvates include, but are not limited to, compounds of the invention in combination water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • DMSO dimethylsulfoxide
  • hydrate can be used when said solvent iswater. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate.
  • solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.
  • pharmaceutically acceptable salt means a salt of a compound of thepresent invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable.
  • pharmaceutically acceptable formulation means a combination of a compound of the invention, or a salt or solvate thereof, and a carrier, diluent, and/or excipient(s) that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof.
  • compositions can be prepared by procedures known to those of ordinary skill in the art.
  • the compounds of the present invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like.
  • excipients, diluents, andcarriers that are suitable for such formulations include the following: fillers and extenders such as starch.sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as povidone, sodium starch glycolate, sodium
  • compositions of the present invention can contain more than one active ingredient.
  • such formulations may contain more than one compound according to the present invention.
  • such formulations may contain one or more compounds of the present invention and one or more additional agents that reduce abnormal cell growth.
  • Arenavirus GP-inhibiting amount refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit the cell entry of Arenaviruses in vivo, such as in a mammal, birds or in vitro.
  • the amount of such compounds required to cause such inhibition can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
  • terapéuticaally effective amount means an amount of a compound of
  • a therapeutically effective amount of a compound of the present invention, or a salt thereof is a quantity sufficient to modulate or inhibit the activity of the Arenavirus GP protein such that cell entry and replication of arenaviruses that is mediated by activity of the Arenavirus GP protein is reduced or alleviated.
  • treat with reference to arenavirus infection, in mammals, particularly a human, include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition.
  • references herein to the inventive compounds include references to salts, solvates, and complexes thereof, including polymorphs, stereoisomers, tautomers, and isotopically labeled versions thereof.
  • compounds of the present invention can be pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • the term “stereoisomers” refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • the term “stereoisomers” refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • the term “stereoisomers” refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. A pure enantiomer can be contaminated with up to 2% of the opposite enantiomer.
  • racemic or “racemic mixture,” as used herein, refer to a 1 :1 mixture of enantiomers of a particular compound.
  • diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another. In accordance with a convention used in the art, the symbol is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • carbon atoms and their bound hydrogen atoms are not explicitly depicted, 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 may be depicted herein using a solid line (— ), a solid wedge (— ), or a dotted wedge ( ).
  • the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.
  • the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom.
  • a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
  • 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 bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid ordotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
  • Chiral compounds of the invention may be obtained in enantiomerically- enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typicallyO.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.
  • a compound of the invention contains an alkenyl or alkenylene group
  • geometric cis/trans (or Z/E) isomers are possible.
  • the compound contains, for example, a keto or oxime group or an aromatic moiety
  • tautomeric isomerism ('tautomerism') can occur.
  • Examples of tautomerism 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 stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, 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 present invention may be administered as prodrugs.
  • certain derivatives of compounds of Formulae I, II, or III which may have little or no pharmacological activity themselves can, when administered to a mammal, be converted into a compound of Formula I, II, or III having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as "prodrugs”.
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compound of Formulae la and lb with certain moieties known to those skilled in the art. See, e.g. "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 (ed.
  • prodrugs include: an ester moiety in the place of a carboxylic acid functional group; an ether moiety or an amide moiety in place of an alcohol functional group; and an amide moiety in place of a primary or secondary amino functional group.
  • replacement groups are known to those of skill in the art. See, e.g. "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 Formulae I, II, or III may themselves act as prodrugs of other compounds of Formulae I, II, or III.
  • Salts of the present invention can be prepared according to methods known to those of skill in the art.
  • Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1 ,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, he
  • the acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
  • Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the desired salt may 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 and the like, or with an organic acid, suchas acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamicacid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid, hydro
  • the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and terti
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as C, 3 C and 4 C, chlorine, such as 36 CI, fluorine, such as 8 F, iodine, such as 23 l and 25 l, nitrogen, such as 3 N and 5 N, oxygen, such as 5 0, 7 0 and 8 0, phosphorus, such as 32 P, and sulfur, 30 such as 35 S.
  • isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3 H, and carbon-14, 4 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, 35 S increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as C, 8 F, 5 0 and 3 N can be useful in Positron Emission Topography (PET) studies for examining 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 analogous to those described herein, using
  • compositions of the invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., an arenavirus GP modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • a therapeutically effective amount i.e., an arenavirus GP modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy
  • one compound of the present invention as an active ingredient
  • pharmaceutically suitable carriers which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • the pharmaceutical carriers employed 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.
  • the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like.
  • Further additives or excipients may be added to achieve the desired formulation properties.
  • a bioavailability enhancer such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG
  • polyethyleneglycol polyethyleneglycol
  • Gelucire® a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
  • 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 may vary, but generally will be from about 25 mg to about 1 g.
  • the preparation may be in theform of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
  • a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations.
  • the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.
  • a salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid.
  • the agent may be dissolved in a suitable co-solvent or combinations of co-solvents.
  • suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume.
  • a compound of the present invention is dissolved in DMSO and diluted with water.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • the agents of the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the presentinvention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of gelatin for use in an inhaler or insufflator and 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 in multi-dose containers, with an added preservative.
  • the compositions may take such 35 forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions 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 that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • the compounds of the present invention may also be formulated as a depot preparation.
  • Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the co-solvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD: 5W) contains VPD diluted 1 :1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a cosolvent system may be suitably varied without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • the pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients.
  • These carriers and excipients may provide marked 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 glycols.
  • additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, Peceol® Transcutol® and the like may be used.
  • the pharmaceutical composition may be incorporated into a skin patch for delivery of thedrug directly onto the skin.
  • an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
  • the pharmaceutically acceptable formulations 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 from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500mg.
  • the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount from about 0.5 w/w% to about 95 w/w%, or from about 1 w/w% to about 95 w/w%, or from about 1 w/w% to about 75 w/w%, or from about 5 w/w% to about 75 w/w%, or from about 10 w/w% to about 75 w/w%, or from about 10 w/w% to about 50 w/w%.
  • the compounds of the present invention may be administered to a mammal, such as a human, suffering from a condition or disease mediated by arenavirus, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, four times a day, or even more frequently.
  • the compounds of the present invention may be administered to a mammal, such as a human, suffering from a condition or disease mediated by arenavirus in combination with at least one other agent used for treatment of arenavirus selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors as shown by Ng KK, Arnold JJ and Cameron CE, Structure-Function Relationships Among RNA-Dependent RNA Polymerases, Curr Top Microbiol Immunol, 2008; 320: 137-156, incorporated herein by reference in its entirety, Favipiravir , a broad-spectrum inhibitor of viral RNA-Dependent RNA Polymerases, Triazavirin, a broad-spectrum inhibitor of viral RNA-Dependent RNA Polymerases, small interfering RNAs (siRNAs) and microRNAs as shown by Carthew RW and Sontheimer EJ, Origins and Mechanisms ofmiRNAs
  • the compounds of the present invention are useful for modulating or inhibiting arenavirus GP.
  • these compounds are useful for the prevention and/or treatment of disease states associated with arenavirus infection.
  • This invention also relates to a method for the treatment of arenavirus infection including a human comprising administering to said mammal an amount of a compound of the Formula (I), as defined above, or a salt or solvate thereof, that is effective in treating disease states associated with Arenavirus infection.
  • DIPEA diisopropylazadicarboxylate
  • DIPEA diisopropyl ethyl amine
  • DMA means N,N- dimethylacetamide
  • DF means N-N-dimethyl formamide
  • DMSO dimethylsulfoxide
  • DPPP means 1 ,3-bis(diphenylphosphino)propane
  • HOAc means acetic acid
  • IPA means isopropyl alcohol
  • NMP means 1 -methyl 2-pyrrolidinone
  • TAA means triethyl amine
  • TFA trifluoroacetic acid
  • DCM means dichloromethane
  • EtOAc means ethyl acetate
  • MgS0 4 means magnesium sulphate
  • Na 2 S0 4 means sodium sulphate
  • MeOH means methanol
  • Et 2 0 means diethyl ether
  • the amino acid 1 -4 can be reduced to the amino alcohol 1 -7 with a reducing agent such as LiAIH 4 or Borane in solvent such as THF, or NaBH 4 in a solvent such as methanol.
  • a reducing agent such as LiAIH 4 or Borane in solvent such as THF, or NaBH 4 in a solvent such as methanol.
  • Reductive alkylation of aminoalcohol 1 -7 with aldehyde 1 -8 can provide secondary aminoalcohol 1 -9.
  • Tetrahedron Lett. 1995, 36, 6373-74) can provide compound 2-3.
  • the nosyl group in 2-3 can be cleaved with thiophenol under basic conditions using a base such as K 2 C0 3 to yield the secondary amine 2-4, which can be coupled with a carboxylic acid 2-5 using a coupling reagent such as EDCI, HOAt in the presence of a base such as 2,6-lutidine in a suitable solvent such as DMF to give the tertiary amide 2-6.
  • Hydrolysis of the f-butyl ester and the Boc group can be achieved under acidic conditions using an acid such as TFA in a solvent such as CH 2 CI 2 to provide the amino acid 2-7 as the TFA salt.
  • Reductive alkylation of 2-7 using sodium triacetoxyborohydride as the reductant (Et 3 N, CICH 2 CH 2 CI), with aldehyde 2-8 component can provide 2-9 which can be converted to piperazinone I on treatment with a coupling reagent such as EDCI.
  • Scheme 3 depicts an alternative method for preparation of compounds of formula I .
  • Fukuyama -Mitsunobu conditions conditions can provide compound 3-3. Removal of the Boc group and cleavage of the tert-butyl ester under acidic condition will provide free amine 3-4 which can react with an aldehyde 3-5 under reductive alkylation conditions using a reducing agent such as sodium triacetoxyborohydride in s solvent such as dichloroethane to form secondary amine 3-6. Ring closure to piperazinone 3-7 can be accomplished using a coupling reagent such as EDCI.
  • a coupling reagent such as EDCI.
  • the nosyl group in 3-8 can be cleaved with thiophenol (ref.) under basic conditions using a base such as K 2 C0 3 to yield the secondary amine 3-8, which can be coupled with a carboxylic acid using a coupling reagent such as EDCI, HOAt in the presence of a base such as 2,6-lutidine in a suitable solvent such as DMF to give the tertiary amide 1
  • Scheme 4 depicts an alternative method for preparation of compounds of formula I. Alkylation of the t- butyl ester of N-nosyl protected amino acid 4-1 with a Boc protected aminoalcohol 4-2 under
  • Fukuyama -Mitsunobu conditions conditions (Fukuyama, T.; Cheung, M., Kan, T. Tetrahedron Lett. 1995, 36, 6373) can provide compound 4-3.
  • Acylation with indole carboxylic acid 4-5 using a coupling reagent such as EDCI, HOAt in the presence of a base such as 2,6-lutidine in a suitable solvent such as DMF can provide amide 4-6.
  • Cleavage of the t-butyl ester with a base such as LiOH can provide acid 4-7 which can form 1 /-/,2/-/,3/-/,4/-/-pyrazino[1 ,2-a]indole-1 ,4-dione 4-8 on treatment with a coupling reagent such as as EDCI, HOAt in the presence of a base such as 2,6-lutidine in a suitable solvent such DMF.
  • a coupling reagent such as as EDCI, HOAt
  • a base such as 2,6-lutidine
  • DMF suitable solvent
  • Removal of the Boc group under acidic condition will provide free amine 4-9 which can react with an aldehyde 4-11 under reductive alkylation conditions using a reducing agent such as sodium triacetoxyborohydride in s solvent such as dichloroethane to form secondary amine 4-11.
  • Ring opening under basic condition can provide free acid 4-12 which on treatment with a coupling reagent such as EDCI, HOAt in the presence of a base such as 2,6-lutidine in a suitable solvent such as DMF can provide piperazinone 4-13.
  • a coupling reagent such as EDCI, HOAt
  • a base such as 2,6-lutidine
  • a suitable solvent such as DMF
  • Step 1 fe/f-butyl (S)-/V-(2-((fe/ -butoxycarbonyl)amino)-4-phenylbutyl)-/V-((2-nitrophenyl)sulfonyl) glycinate
  • Step 2 fe/f-butyl (S)-(2-( fe/f-butoxycarbonyl)amino)-4-phenylbutyl)glycinate
  • Te/f-butyl (S)-N-(2-((tert-butoxycarbonyl)amino)-4-phenylbutyl)-N-((2-nitrophenyl)sulfonyl)glycinate (3.2 g, 5.6 mmols) was dissolved in DMF (15 ml_) in a 50 ml_ round-bottom flask and K 2 C0 3 (1 .6 g, 1 1 .5 mmol) was added. Thiophenol (900 mg, 8.1 mmol) was added and the reaction was stirred for 3 h and then diluted with ethyl acetate and washed with H 2 0 and saturated aq. NaHC0 3 .
  • Step 3 fe/f-butyl (S)-/V-(2-((fe/f-butoxycarbonyl)amino)-4-phenylbutyl)-/V-(4-methoxybenzoyl)glycinate
  • Te/f-butyl (S)-(2-((tert-butoxycarbonyl)amino)-4-phenylbutyl)glycinate (1 .4 g, 3.7 mmol) was dissolved in DMF (12 mL) in a 50 mL round-bottom flask and 1 -Hydroxy-7-azabenzotriazole (HOAt, 700 mg, 5.1 mmol), 2,6-lutidine (1 .3 mL, 1 1 .1 mmol), and 4-methoxybenzoic acid (563 mg, 3.7 mmols) were added. EDC was then added and the reaction was stirred overnight and then diluted with ethyl acetate.
  • HOAt 1 -Hydroxy-7-azabenzotriazole
  • Step 4 (S)-/V-(2-amino-4-phenylbutyl)-/V-(4-methoxybenzoyl)glycine
  • Step 5 General procedure A for synthesis of examples A-1 to A-49.
  • Step 1 2-[(2-nitrobenzene)sulfonamido]acetic acid
  • Method 1 A 1 L flask was charged with the 2-[(2-nitrobenzene)sulfonamido]acetic acid from step 1 and SOCI 2 (150 ml_) was added. The reaction was heated at 80 °C until the material fully dissolved ( ⁇ 1 hr) and then was heated for an additional 1 .5 hrs. The reaction was brought to room temperature and was put under a stream of N 2 for 15 hrs to remove the SOCI 2 and provide a brown solid. The solid was then put under high vacuum for 15 hrs to provide the final product (13.5 g).
  • Method 2 A round bottom flask was charged with 2-[(2-nitrobenzene)sulfonamido]acetic acid and SOCI 2 (40 ml_) was added. The reaction was heated at 80 °C until the material fully dissolved ( ⁇ 1 h) and then was heated for an additional 1 .5 h. The reaction was brought to room temperature, and excess SOCI 2 was removed under vacuum ro provide a brown solid which was used without further purification in the next step.
  • Step 4 A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-2-[(2-nitrobenzene)sulfonamido]-N- ⁇ [3-(trifluoromethyl) phenyl]methyl ⁇ acetamide
  • Step 7 General Procedure B for formation of examples A-50 to A-143:
  • a 1/2 dram vial was charged with the desired carboxylic acid (22 ⁇ ) and 200 ⁇ _ of a DMF solution containing the (6S)-6-(2-phenylethyl)-1 - ⁇ [3-(trifluoromethyl)phenyl]methyl ⁇ piperazin-2-one (8 mg, 22 ⁇ ), 2,6-lutidine (7 mg, 66 ⁇ ), and 1 -hydroxy-7-azabenzotriazole (3 mg, 22 ⁇ ) was added. EDC (6 mg, 33 ⁇ ) was then added to the reaction and the vial was capped and put on a rotary shaker for 14 hrs.
  • reaction was then diluted with ethyl acetate and washed twice with 1 N aqueous HCI and twice with saturated aqueous NaHC0 3 and the organics were dried over Na 2 S0 4 .
  • the solvents were removed under a stream of N 2 and further under high vacuum to provide the title compounds (examples A50 to A-143).
  • Step 1 3-( ⁇ [(2S)-1 -hydroxy-4-phenylbutan-2-yl]amino ⁇ methyl)phenol
  • Step 2 A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-N-[(3-hydroxyphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido]acetamide
  • Step 3 (6S)-1 -[(3-hydroxyphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2- one
  • Step 4 (6S)-1 -[(3-hydroxyphenyl)methyl]-6-(2-phenylethyl)piperazin-2-one
  • Step 1 (2S)-2- ⁇ [(3-methylphenyl)methyl]amino ⁇ -4-phenylbutan-1 -ol
  • Step 2 N-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-N-[(3-methylphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido]acetamide
  • Step 3 (6S)-1 -[(3-methylphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2-one
  • Step 4 (6S)-1 -[(3-methylphenyl)methyl]-6-(2-phenylethyl)piperazin-2-one
  • the desired products were prepared using General Procedure B using (6S)-1 -[(3-methylphenyl) methyl]-6-(2-phenylethyl)piperazin-2-one instead of (6S)-6-(2-phenylethyl)-1 - ⁇ [3- (trifluoromethyl)phenyl]methyl ⁇ piperazin-2-one.
  • Step 1 (2S)-2- ⁇ [(3-methoxyphenyl)methyl]amino ⁇ -4-phenylbutan-1 -ol
  • Step 2 A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-N-[(3-methoxyphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido]acetamide
  • Step 3 (6S)-1 -[(3-methoxyphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2- one
  • Step 4 (6S)-1 -[(3-methoxyphenyl)methyl]-6-(2-phenylethyl)piperazin-2-one
  • Step 5 examples A-156 to A-158 and examples B-1 to B-25
  • diethylazodicarboxylate solution (40 wt% in toluene, 6.9 mL, 15.2 mmol) was added dropwise over 10 minutes, and the reaction stirred for 3 hours or until all starting material has been consumed by TLC.
  • the mixture was evaporated to a final volume of about 10 mL and the syrup purified by flash chromatography using 4:1 hexanes:ethyl acetate as eluent, yielding 4.2g (70%) of the title compound as a viscous oil.
  • the title compound was obtained from 3-bromoacetophenone using the procedure described in WO 2000/02616.
  • the title compound was prepared from ethyl 5-hydroxy-1 /-/-indole-2-carboxylate and 2-bromopropane using the method described for 5-(cyclopropylmethoxy)-1 /-/-indole-2-carboxylic acid.
  • the title compound was prepared from ethyl 4-hydroxy-1 /-/-indole-2-carboxylate using the method described for 5-(cyclopropylmethoxy)-1 /-/-indole-2-carboxylic acid.
  • the title compound was prepared from methyl 4-hydroxybenzoate using the method described for 5- (cyclopropylmethoxy)-1 /-/-indole-2-carboxylic acid above.
  • Example B-74 (6R)-6-(Hydroxymethyl)-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-1 -[(3-methoxyphenyl) methyl] piperazin-2-one
  • Example B-75 (6S)-6-[(4-Hydroxyphenyl)methyl]-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-1 -[(3-methoxy phenyl)methyl]piperazin-2-one
  • Example B-76 (6S)-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-6- ⁇ [4-(2-methoxyethoxy)phenyl] methyl ⁇ -1 - [(3-methoxyphenyl)methyl]piperazin-2-one
  • Example B-77 (6S)-4-[(5-methoxy-1 H-indol-2-yl)carbonyl]-1 -[(3-methoxyphenyl)methyl]-6-( ⁇ 4-[2- (morpholin-4-yl)ethoxy]phenyl ⁇ methyl)piperazin-2-one
  • Examples B-78 to B-104 The following title compounds were prepared from (6S)-6-dibenzyl piperazin-2-one and the appropriate carboxylic acid using General Procedure B.
  • Examples B-1 1 1 to B-1 14 The following title compounds were prepared from (6S)-6-(2-phenylethyl)- 1 - ⁇ [3-(propan-2-yloxy)phenyl]methyl ⁇ piperazin-2-one and the appropriate carboxylic acid using General Procedure B.
  • Examples B-1 15 to B-1 18 The following title compounds were prepared from (6S)-1 -benzyl-6-(2- phenylethyl)piperazin-2-one and the appropriate carboxylic acid using General Procedure B.
  • Examples B-1 19 to B-142 The following title compounds were prepared from (6S)-6-benzyl-1 -[(3- methoxyphenyl)methyl]piperazin-2-one and the appropriate carboxylic acid using General Procedure B.
  • Examples B-144 to B-156 The following title compounds were prepared from (6S)-6-benzyl-1 - ⁇ [3- (difluoromethoxy)phenyl]methyl ⁇ piperazin-2-one and the appropriate carboxylic acid using General Procedure B.
  • Examples B-157 to B-161 The following title compounds were prepared from (6R)-1 -benzyl-6- [(benzyloxy)methyl]piperazin-2-one and the appropriate carboxylic acid using General Procedure B.
  • Example B-162 3- ⁇ [(2S)-2-benzyl-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-6-oxopiperazin-1 -yl]methyl ⁇ benzoic acid
  • Step 1 fe/f-butyl 2- ⁇ [(2S)-2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -3-phenylpropyl]amino ⁇ acetate
  • Step 2 fe/f-butyl 2- ⁇ /V-[(2S)-2- ⁇ [(fe t-butoxy)carbonyl]amino ⁇ -3-phenylpropyl]-1 -(5-methoxy-1 H-indol-2- yl)formamido ⁇ acetate
  • Step 3 2- ⁇ /V-[(2S)-2- ⁇ [(fe/f-butoxy)carbonyl]amino ⁇ -3-phenylpropyl]-1 -(5-methoxy-1 H-indol-2-yl) formamido ⁇ acetic acid
  • Step 4 fe/f-butyl A/-[(2S)-1 - ⁇ 1 ,4-dioxo-1 H,2H,3H,4H-pyrazino[1 ,2-a]indol-2-yl ⁇ -3-phenylpropan-2-yl] carbamate
  • Step 5 2-[(2S)-2-amino-3-phenylpropyl]-1 H,2H,3H,4H-pyrazino[1 ,2-a]indole-1 ,4-dione
  • Step 6 General Procedure D for formation of intermediates 1-1 to 1-31
  • Step 6 General Procedure E for formation of examples B-168 to B-196 and intermediate J-1 .
  • Step 1 fe/ -Butyl 2- ⁇ /V-[(2S)-2- ⁇ [(fe/ -butoxy)carbonyl]amino ⁇ -3-phenylpropyl]-1 -(5-methyl-1 H-indol-2- yl) formamido ⁇ acetate
  • Step 2 2- ⁇ /V-[(2S)-2- ⁇ [(fe/ -butoxy)carbonyl]amino ⁇ -3-phenylpropyl]-1 -(5-methyl-1 H-indol-2- yl)formamido ⁇ acetic acid
  • Step 3 fe/f-butyl A/-[(2S)-1 - ⁇ 8-methyl-1 ,4-dioxo-1 H,2H,3H,4H-pyrazino[1 ,2-a]indol-2-yl ⁇ -3- phenylpropan-2-yl]carbamate
  • Step 4 2-[(2S)-2-amino-3-phenylpropyl]-8-methyl-1 H,2H,3H,4H-pyrazino[1 ,2-a]indole-1 ,4-dione
  • Examples B-199 to B-207 The compounds were prepared from intermediates I-32 to I-40 using General Procedure E.
  • Step 1 fe/f-butyl 2- ⁇ N-[(2S)-2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -3-phenylpropyl]-1 -(5-cyclopropyl-1 /-/- indol-2-yl)formamido ⁇ acetate
  • Step 2 2- ⁇ N-[(2S)-2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -3-phenylpropyl]-1 -(5-methyl-1 H-indol-2- yl)formamido ⁇ acetic acid
  • Step 4 2-[(2S)-2-amino-3-phenylpropyl]-8-methyl-1 H,2H,3H,4H-pyrazino[1 ,2-a]indole-1 ,4-dione
  • Example B-208 to B-216 The compounds were prepared from intermediates 1-41 to I-49 using General Procedure E.
  • 0-(tert-butyl)-L-serine (5.0 g, 31 .01 mmol) was cooled to 0°C using an ice bath. Then aq. 2M NaOH (34.10 mL, 68.20 mmol) followed by benzoyl chloride (3.58 mL, 31 .01 mmol) were added. The reaction mixture was stirred at 0°C for 1 h and then at room temperature for additional 1 h. It was acidified with conc.HCI, then extracted with ethyl acetate (2 x 80 mL), and washed with water (1 x 100 mL).
  • Step 2 (R)-2-(benzylamino)-3-(fe/ -butoxy)propan-1 -ol
  • Step 3 (R)-/V-benzyl-/V-(1 -(fe/ -butoxy)-3-hydroxypropan
  • Step 4 (R)-1 -benzyl-6-(fe/ -butoxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one
  • Step 5 (R)-1 -benzyl-6-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one
  • Step 6 (R)-(1 -benzyl-4-((2-nitrophenyl)sulfonyl)-6-oxopiperazin-2-yl)methyl trifluoromethanesulfonate
  • Step 7 General Procedure F for formation of Intermediates I-58 to I-79.
  • Step 8 General Procedure G for preparation Examples B-215 to B-254
  • Example B-255 (6f?)-6-((6-azaspiro[2.5]octan-6-yl)methyl)-1 -benzyl-4-(5-methoxy-1 H-indole-2- carbonyl) piperazin-2-one.
  • Example B-256 (6R)-1 -benzyl-4-(5-methoxy-1 /-/-indole-2-carbonyl)-6-(piperidin-1 -ylmethyl)piperazin- 2-one.
  • Step 1 (2S)-3-(fe/ -butoxy)-2- ⁇ [3-(difluoromethoxy)phenyl]formamido ⁇ propanoic acid
  • Step 2 (2R)-3-(fe/ -butoxy)-2-( ⁇ [3-(difluoromethoxy)phenyl]methyl ⁇ amino)propan-1 -ol
  • Step 3 A/-[(2f?)-1 -(fe/ -butoxy)-3-hydroxypropan-2-yl]-/V- ⁇ [3-(difluoromethoxy)phenyl]methyl ⁇ -2-[(2- nitrobenzene)sulfonamido]acetamide
  • Step 5 (6R)-1 - ⁇ [3-(difluoromethoxy)phenyl]methyl ⁇ -6-(hydroxymethyl)-4-[(2-nitrobenzene)sulfonyl] piperazin-2-one
  • Step 6 [(2R)-1 - ⁇ [3-(difluoromethoxy)phenyl]methyl ⁇ -4-[(2-nitrobenzene)sulfonyl]-6-oxopiperazin-2-yl] methyl trifluoromethanesulfonate
  • the intermediates 1-80 to 1-87 were prepared from [(2R)-1 - ⁇ [3-(difluoromethoxy)phenyl]methyl ⁇ -4-[(2- nitrobenzene)sulfonyl]-6-oxopiperazin-2-yl] methyl trifluoromethanesulfonate and the appropriate amine using General Procedure F.
  • Step 8 Preparation Examples B-257 to B-264.
  • Protocol A Arenavirus GP Pseudotype Assay.
  • Vera cells ATCC: CCL-81 were grown in clear 384 well plates (3000 cells/well) in DMEM media with 10% FBS, 1X Pen-Strep, non-essential amino acids and L-glutamine. After incubating overnight at 37°C and 5% C0 2 , cells were treated with compounds at desired concentrations and pseudotyped virus in assay media.
  • VSV viruses expressing the VSV glycoprotein as well as the LASV, MACV and JUNV pseudotyped VSV viruses were generated in cultured HEK-293T cells (ATCC CRL-3216), which were grown in 10 cm dishes in DMEM supplemented with 10% FBS, 1X Pen-Strep, non-essential amino acids, L-glutamine and 500 ⁇ g/mL G418 antibiotic. When cells reached approximately 80% confluency, they were transfected with a mixture of 15 ⁇ g of the pCAGGS plasmid encoding the desired glycoprotein and 45 ⁇ of PEI (polyethylenimine) transfection reagent. The cells were incubated with the solution for 5 hours at 37°C at 5% C0 2 .
  • PEI polyethylenimine
  • the cells were then washed and the mixture replaced with supplemented DMEM and incubated at 37°C at 5% C0 2 for approximately 16- 18 hours. Subsequently cells were infected with approximately 50 ⁇ of VSV parent pseudotype virus lacking VSV glycoprotein and containing the gene for luciferase or GFP. The cells were infected for 1 hour, then washed 1X with PBS and incubated in supplemented media. 24 hours post-infection, supernatant was collected, aliquoted and stored at -80°C.
  • VSV-Luciferase pseudotypes For VSV-Luciferase pseudotypes, one aliquot was thawed and tested in a serial dilution for luminescence activity in Vera cells as described in the Luciferase assay protocol (below). Each of the viral supernatants generated was diluted (from 1 :100 to 1 :2000) to give similar luminescence signal / background values of > 200 and stored at -80°C as aliquots for later use.
  • Assay media consisted of 50% Opti-MEM, 50% DMEM, with 1 % FBS, Pen- Strep, non-essential amino acids and L-glutamine. Final DMSO concentration in the compound testing wells was kept ⁇ 1 % and control wells were treated with assay media and 1 % DMSO.
  • Cells were incubated for 24 hours at 37°C and 5% C0 2 .
  • the compound-virus mixture was aspirated off the cells 24 hours post-infection and washed 1X with PBS.
  • Cells were then lysed using 20 ⁇ of lysis buffer from a Luciferase kit diluted according to manufacturer's instructions. After incubating for approximately 20 minutes, 5 ⁇ of cell lysate was transferred to an opaque white plate, and mixed with 12.5 ⁇ of Coelenterazine diluted in buffer.
  • Luminescence signals were obtained for compound containing and control wells to determine % activity (inhibition of luciferase signal) for each compound.
  • a small library collection of compounds was initially tested at 10OnM concentration against the LASV pseudotype virus and those compounds found to decrease the luciferase activity >25% then tested against the MACV and JUNV pseudotype virus to facilitate identification of potential broad- spectrum arenavirus inhibitors.
  • Those compounds exhibiting significant activity against all three pseudotype viruses (>50%) were then retested against the the LASV, MACV and JUNV pseudotype viruses at 1 , 5 and 25 nM as well as against the parent VSV virus (expressing the same luciferase gene with the native VSV glycoprotein) at 1 uM as a control to confirm that compound activity was related to cell entry via arenavirus glycoproteins rather than replication of VSV viruses.
  • Table 1 we identified a number of compounds exhibiting specific inhibition of arenavirus pseudotyped viruses that did not inhibit the VSV-GP pseudotype virus control.
  • Protocol B Tacaribe live virus CPE assay:
  • Vera cells were seeded in a 96 well plate at a density of 4000 cells/well and incubated overnight at 37C, 5% C0 2 . The next day, desired compound dilutions were prepared in DMSO at 100X dilution (30uM, 10uM etc). Required Tacaribe virus (TCRV) dilutions were prepared in minimal essential media (MEM) with 2% FBS. The virus dilutions used for the assay were determined so that cytopathic effect (CPE) was observed in all replicates at 7 days post infection. Compounds tested in TCRV assay were serially diluted in media with DMSO final concentration maintained at 1 %.
  • TCRV live virus CPE assay is run for seven (7) days compounds were tested for cytotoxicity over the same time period of 7 days.
  • Compounds were serially diluted and added to Vera cells (4000 cells/well) with final DMSO concentration maintained at 1 % in growth media consisting of minimal essential media (MEM) with 2% FBS. The plates were incubated at 37C for 7 days, and then dead cells were revomed by washing with Phosphate buffered saline (PBS). CPE was assessed by staining cells with neutral red dye for 1 hour and then de-staining with a solution of 50% ethanol/ 1 % acetic acid solution.
  • PBS Phosphate buffered saline
  • pseudotype viruses LASV, MACV, JUNV, GTOV
  • Example compounds and their observed inhibitory activities against the indicated pseudotype viruses (LASV, MACV, JUNV), VSV control, or in cellular cytotoxicity assays;
  • Example compounds and their observed inhibitory activities against the indicated pseudotype viruses (LASV, MACV, JUNV, TCRV), VSV control, or in cellular cytotoxicity assays; shown is % Inh. at 5 nM for LASV, MACV; % Inh. for VSV at 1 uM ; EC 50 for TCRV, CC 50 for cytotoxicity.

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Abstract

La présente invention se rapporte à l'utilisation de pipérazinones pour inhiber une infection à arénavirus chez l'homme, d'autres mammifères, ou dans une culture de cellules, à des procédés de traitement d'une infection à arénavirus telles que les fièvres hémorragiques de Lassa, de Bolivie, d'Argentine, du Venezuela, du Brésil, de Chapare et de Lujo, à des procédés d'inhibition de la réplication d'arénavirus, à des procédés de réduction de la quantité d'arénavirus, et à des compositions qui peuvent être utilisées pour de tels procédés.
PCT/US2016/024467 2015-04-01 2016-03-28 Composés pour le traitement d'une infection à arénavirus Ceased WO2016160677A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3815689A4 (fr) * 2018-06-27 2022-04-20 National University Corporation Hokkaido University Inhibiteur de la croissance d'arénavirus comprenant un dérivé de carbamoylpyridone polycyclique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011041713A2 (fr) * 2009-10-02 2011-04-07 Glaxosmithkline Llc Agents anti-viraux à base de pipérazinyle

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011041713A2 (fr) * 2009-10-02 2011-04-07 Glaxosmithkline Llc Agents anti-viraux à base de pipérazinyle

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Title
WHITBY ET AL.: "Characterization of Lassa Virus Cell Entry Inhibitors: Determination of the Active Enantiomer by Asymmetric Synthesis", BIOORG MED CHEM LETT., vol. 19, no. 14, 15 July 2009 (2009-07-15), pages 3771 - 3774, XP026281672 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3815689A4 (fr) * 2018-06-27 2022-04-20 National University Corporation Hokkaido University Inhibiteur de la croissance d'arénavirus comprenant un dérivé de carbamoylpyridone polycyclique
US11492352B2 (en) 2018-06-27 2022-11-08 National University Corporation Hokkaido University Arenavirus growth inhibitor comprising polycyclic carbamoylpyridone derivative
US12098151B2 (en) 2018-06-27 2024-09-24 National University Coporation Hokkaido University Arenavirus growth inhibitor comprising polycyclic carbamoyl pyridone derivative

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