WO2016160677A1

WO2016160677A1 - Compounds for the treatment of arenavirus infection

Info

Publication number: WO2016160677A1
Application number: PCT/US2016/024467
Authority: WO
Inventors: Micheal PLEWE; Landon WHITBY; Kenneth Mccormack; Gregory Henkel; Eric Brown; Dale Boger; Nadezda Sokolova; Vidyasagar Reddy
Original assignee: Arisan Therapeutics Inc
Current assignee: Arisan Therapeutics Inc
Priority date: 2015-04-01
Filing date: 2016-03-28
Publication date: 2016-10-06
Anticipated expiration: 2017-10-01

Abstract

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, Bolivian, 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.

Description

COMPOUNDS FOR THE TREATMENT OF ARENAVIRUS INFECTION

CROSS REFERENCES TO RELATED APPLICATIONS

This patent application claims the benefit of priority to United States Provisional Patent Application serial number 62/141 ,605, filed April 1 , 2015, the contents of which are incorporated herein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

This invention was made with government support from the U.S. National Institutes of Health, grant number 1 R43AI112097 (Michael Bruno Plewe, Ken McCormack). Accordingly, the United States Govermnent may have certain rights in the invention described herein.

BACKGROUND OF THE INVENTION

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. Both 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. The larger New World complex primarily located in the South American continent, is divided into 3 clades, A, B, and C, with clade B being important as many of the viruses in this group can cause lethal HF. 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). 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). There is also evidence of human-to-human spread primarily in nosocomial settings (e.g. hospitals). Incubation period of virus is 1 -2 weeks followed by fever, general malaise, weakness, sore throat, headache, cough, diarrhea, and vomiting. These general symptoms make it difficult to differentially diagnose arenavirus infection. Poor prognosis is indicated as symptoms worsen to include pleural effusions, facial edema, neurological complications and bleeding from mucosal surfaces. Current arenavirus treatment is limited to the use of ribavirin, which is only partially effective if given early and associated with significant side effects. Although a vaccine has been developed for Junin virus its usage is primarily restricted to the most at risk populations of farm workers in Argentina and there are no approved vaccines for any other arenaviruses. Although highly desirable, prophylactic vaccines may not always be effective countermeasures against rapidly emerging, antigenically distinct new virus strains and the existing vaccine development and production strategies cannot adequately respond to the diverse family of current or emergent arenaviruses. Novel broad- spectrum antiviral drugs could therefore, provide a first line therapy and/or prophylactic not only for endemic regions of arenavirus infection but also as a safeguard against potential biological warfare.

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). 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. 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. To facilitate the identification of arenavirus entry inhibitors one may express arenavirus GP complex in nonpathogenic BSL-2 envelope viruses, to produce single round infectious pseudoviruses whose viral entry functions are determined by the heterogeneous glycoprotein of interest. One viral expression system that may be utilized is the vesicular stomatitis virus (VSV) system, whereby the envelope protein of VSV is substituted with an envelope glycoprotein from another virus, e.g., LASV, to mediate entry of the pseudotype virion. 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. To monitor pseudovirus infection, 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). 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. In the present invention, entry inhibitors described were identified using an arenavirus GP pseudovirus screens.

BRIEF SUMMARY OF THE INVENTION

In one embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I

I

or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein:

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 R⁵ group;

R² 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 R⁶ group;

R³ 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)R⁷,-C(0)NR^8aR^8b, -(CH₂)nC(0)OR⁷, and

-(CH₂)nC(0)N(R^8aR^8b), wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁵ group;

R⁴ 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 R⁵ group;

R⁵ 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)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C^ to C₆) 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, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

R⁶ 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)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Cs to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

each of the R⁷ is independently selected from hydrogen, (C^o C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C₃ to C ₀) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to Cio) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

each of the R^8a, R^8b, and R^8c are independently selected from hydrogen, (C^ to C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉)

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

or 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 R⁹ group;

R⁹ 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)R¹⁰, -C(0)NR ^aR ^b, -NR ^aR ^b -S(0)mR¹⁰, -S(0)mNR ^aR ^b, -NR ^aS(O)mR ⁰, -(CH2)nC(O)OR¹⁰, -(CH₂)nC(0)N(R ^aR ^b), -OC(0)R¹⁰, -NR ^aC(0)R¹⁰, and -NR ^acC(0)N(R ^aR ^b), wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R ² group;

each of the R ⁰ is independently selected from hydrogen, (d to C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C₃ to C ₀) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ 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 C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉)

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

or 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

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,

with the proviso that R is not selected from the group consisting of methyl, ethyl, CF₃, CHF₂, CH₂F, cyclopropyl, isopropyl, hydroxymethyl, and methoxymethyl,

and with the proviso that

R² is not selected from the group consisting of

and with the proviso that R⁴ is not selected from the group consisting of optionally substituted

■ wherein

A is selected from a bond, alkylidene, heterocyclylene, arylene, heteroarylene, -0-, -SO-, and -S0₂-,

and with the proviso when

R is benzyl or 2-phenylethyl, and

2 is selected from the group consisting of

4 is not selected fro

disclosed in Lee A. et al. J. Biol. Chem. 2008, 283, 18734 - 18742, incorporated herein by reference in its entirety.

In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula II

II

or a pharmaceutically acceptable salt thereof, wherein

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 R⁵ group;

-(CH₂)nC(0)N(R^8aR^8b), wherein

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

each of the R ⁰ is independently selected from hydrogen, (d to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C₃ to C ₀) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

and with the proviso that

R² is not selected from the group consisting of

and with the proviso that

4 is not selected from the group consisting of optionally substituted

^■ wherein

A is selected from a bond , alkylidene, heterocyclylene, arylene, heteroarylene, -0-, -S-, , -SO-, and -S0₂-,

and with the proviso that the following compound is excluded: (6S)-4-[(1 -benzofuran-2- l)carbonyl]-6-benzyl-[(4-methylphenyl)methyl]piperazin-2-one

In another embodiment, 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

III

or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein :

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 R⁵ group;

R² 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 R⁶ group;

R³ 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)R⁷,-C(0)NR^8aR^8b, -(CH₂)nC(0)OR⁷, and - (CH₂)nC(0)N(R^8aR^8b), wherein

each of the said (C to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁵ group;

R⁴ 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 R⁵ group;

R⁵ 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)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C^ to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, aryloxy, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

R⁶ 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)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Csto C10) cycloalkyi, (Csto C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

each of the R⁷ is independently selected from hydrogen, (C^o C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C₃ to C ₀) cycloalkyi, (Csto C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

each of the said (C^ to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

each of the R^8a, R^8b, and R^8c are independently selected from hydrogen, (C^ to C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C₂ to C₉)

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ 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

R⁹ 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)R¹⁰, -C(0)NR ^aR ^b, -NR ^aR ^b -S(0)mR¹⁰, -S(0)mNR ^aR ^b, -NR ^aS(O)mR ⁰, -(CH2)nC(O)OR¹⁰, -(CH₂)nC(0)N(R ^aR ^b), -OC(0)R¹⁰, -NR ^aC(0)R¹⁰, and -NR ^acC(0)N(R ^aR ^b), wherein

each of the said (d to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Csto C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R ² group;

each of the R ⁰ is independently selected from hydrogen, (d to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C₃ to C ₀) cycloalkyi, (Csto C10) cydoalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

each of the said (d to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ 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 C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cydoalkenyl, (C₂ to C₉)

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

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,

with the proviso that

R is not selected from the group consisting of methyl, ethyl, CF₃, CHF₂, CH₂F, cyclopropyl, isopropyl, hydroxymethyl, and methoxymethyl,

and with the proviso that

2 is not selected from the group consisting of

■ wherein

A is selected from a bond, alkylidene, heterocyclylene, arylene, heteroarylene, -0-, -S-, -CO-, -SO-, and -S0₂-,

and with the proviso that the following compound is excluded: (6S)-4-[(1 -benzofuran-2- carbonyl]-6-benzyl-[(4-methylphenyl)methyl]piperazin-2-one

In another embodiment, 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

R² 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 R⁶ group;

R³ is hydrogen or methyl;

R⁴ 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 R⁵ group.

In another embodiment, 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

R² is methyl substituted with a group selected from (C6 to C10) aryl and (C2 to C9) heteroaryl, wherein

R is selected from benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, aryloxymethyl, and CH₂NR^8aR^8b, wherein

each of the said benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, and aryloxymethyl is optionally substituted with at least one R⁵ group. In another embodiment, 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

R² is methyl substituted with a (C6 to C10) aryl or (C2 to C9) heteroaryl group selected from the group consisting of

, wherein

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, Ν,Ν-dimethylamino, and 1 H- pyrazol-1 -yl.

4 is selected from the group consisting of

, 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, Ν,Ν-dimethylamino, 1 -pyrrolidinyl, 1 -piperidinyl.

each of the said benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, and aryloxymethyl is optionally substituted with at least one R⁵ group;

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, Ν,Ν-dimethylamino, and 1 H-pyrazol-1 -yl;

In another embodiment, the invention relates to compounds, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, selected from

et y pperazn- -one

met y pperazn- -one

carbonyl]piperazin-2-one

piperazin-2-one

piperazin-2-one

- - -

piperazin-2-one

piperazin-2-one

2-yl)piperidin-1 -yl)methyl)piperazin-2-one

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.

Additionally 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.

DETAILED DESCRIPTION OF THE INVENTION

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

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

The term "(CT to C₆)" 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 C₆) alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, /^'so-butyl, fe/ -butyl, pentyl, and the like. The terms "Me" and "methyl," as used herein, mean a -CH₃ group. The terms "Et" and "ethyl," as used herein, mean a - C₂H₅

group.

The term "(C₂ to C₈) alkenyl", as used herein, 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. The term "allyl," as used herein , means a -CH₂CH=CH₂group.

The term, "C(R)=C(R)," as used herein, represents a carbon-carbon double bond in which each carbon is substituted by an R group.

As used herein, the term "(C₂ to C₈) 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.

The term "(C^ to C₈) alkoxy", as used herein, 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.

The term "(C₆ to C ₀) aryl", as used herein, means a group derived from an aromatic hydrocarbon containing from 6 to 10 carbon atoms. Examples of such groups include, but are not limited to, phenyl or naphthyl.

The terms "Ph" and "phenyl," as used herein, mean a -C₆H₅ group. The term "benzyl," as used herein , means a -CH₂C₆H₅ group.

The term "(C₂ to C₉) heteroaryl", as used herein, 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. Examples of 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, quinoxalinyl, naphthyridinyl, and furopyridinyl. The C₂ to C₉ heteroaryl groups may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1 -yl (N- attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1 -yl (N- attached) or imidazol-3-yl (C-attached).

The term "(C₂ to C₉) cycloheteroalkyl", as used herein, 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. Furthermore, such C₂ to C₉ cycloheteroalkyl groups may contain an oxo substituent at any available atom that will result in a stable compound. For example, 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. In addition, it is to be understood that when such 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 C₂ to C₉

cycloheteroalkyi groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl,

tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, AH pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1 .0]hexanyl, 3-azabicyclo[4.1 .0]heptanyl, 3H-indolyl quinolizinyl, 3-oxopiperazinyl, 4- methylpiperazinyl, 4-ethylpiperazinyl, and 1 -oxo-2,8,diazaspiro[4.5]dec-8-yl.

The term "(C₃ to C ₀) cycloalkyl group" , as used herein , means a saturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 10 carbon 5 ring atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl.

The term "spirocyclic", as used herein, 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.

The term "(C₅ to C₈) 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.

The term cyano" refers to a -C≡N group.

An "aldehyde" group refers to a carbonyl group where R is hydrogen.

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

An "alkoxycarbonyl" refers to a -C(0)OR.

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

An "alkylsulfonyl" group refer to a -S0₂alkyl.

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

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

An "aminocarbonyl" refers to a -C(0)NRR'.

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

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

An "aryloxycarbonyl" refers to -C(0)Oaryl.

An "arylsulfonyl" group refers to a -S0₂aryl.

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.

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

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

A "heteroalicycloxy" group refers to a heteroalicyclic-O group with heteroalicyclic as defined herein.

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

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

An "N-amido" group refers to a -R'C(0)NR group.

An "N-carbamyl" group refers to a -ROC(0)NR-group.

A "nitro" group refers to a -N0₂ group.

An "N-Sulfonamido" group refers to a -NR-S(0)₂R group.

An "N-thiocarbamyl" group 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.

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

An "oxo" group 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.

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

An "S-sulfonamido" group refers to a -S(0)₂NR-group.

A "sulfinyl" group refers to a -S(0)R group.

A "sulfonyl" group refers to a -S(0)₂R group.

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

A "trihalomethanecarbonyl" group refers to a Z₃CC(0) group, where Z is halogen.

A "trihalomethanesulfonamido" group refers to a Z₃CS(0)₂NR-group.

A "trihalomethanesulfonyl" group refers to a Z₃CS(0)₂ group.

A "trihalomethyl" group refers to a -CZ₃ group.

A "C-carboxyl" group refers to a -C(0)OR groups.

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

The term "unsubstituted," means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more

substituents. It is to be understood that in the compounds of the present invention when a group is said to be "unsubstituted," or is "substituted" with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen. For example, if a C₆ aryl group, also called "phenyl" herein, is substituted with one additional substituent, one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C₆ aryl ring (6 initial positions, minus one to which the remainder of the compound of the present invention is bonded, minus an additional substituent, to leave 4). In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies. Similarly, if a C₆ aryl group in the present compounds is said to be "disubstituted," one of ordinary skill in the art would understand it to mean that the C₆ aryl has 3 - 5 carbon atoms remaining that are unsubstituted. Those three unsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies.

The term "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. The term "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. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, 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.

The term "pharmaceutically acceptable salt," as used herein, 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.

The term "pharmaceutically acceptable formulation," as used herein, 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.

Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art. For example, the compounds of the present invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like. Examples of 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

carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. Final pharmaceutical forms may be pills, tablets, powders, lozenges, saches, cachets, or sterile packaged powders, and the like, depending on the type of excipient used. Additionally, it is specifically contemplated that pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient. For example, such formulations may contain more than one compound according to the present invention. Alternatively, such formulations may contain one or more compounds of the present invention and one or more additional agents that reduce abnormal cell growth.

The term "Arenavirus GP-inhibiting amount" as used herein, 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.

The term "therapeutically effective amount," as used herein, means an amount of a compound of

the present invention, or a salt thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, a therapeutically effective amount of a compound of the 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.

The terms "treat", "treating", and "treatment" 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.

Unless indicated otherwise, all references herein to the inventive compounds include references to salts, solvates, and complexes thereof, including polymorphs, stereoisomers, tautomers, and isotopically labeled versions thereof. For example, compounds of the present invention can be pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates.

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. In particular, the term

"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.

The terms "racemic" or "racemic mixture," as used herein, refer to a 1 :1 mixture of enantiomers of a particular compound. The term "diastereomers", on the other hand, 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. In accordance with another convention, in some structural formulae herein the 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. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of the present invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict 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.

(R) then, unless otherwise defined, a substituent "R" may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the reacemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenyl ethyl amine. The resulting diastereomeric mixture may be separated by

chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) 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.

Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where 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. Thus 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. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties. Some examples of such prodrugs include: an ester moiety in 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. Further examples of 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, hexyne-1 ,6- dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methyls ulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate.suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.

The compounds of the present invention that are basic in nature are capable of forming a wide

variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolatethe compound of the present invention from the reaction mixture as a pharmaceutically unacceptable saltand then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. 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. Examples of 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. These 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. Alternatively, 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. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

If the inventive compound is a base, 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.

If the inventive compound is an acid, 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. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.

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. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as C, ³C and ⁴C, chlorine, such as ³⁶CI, fluorine, such as ⁸F, iodine, such as ²³l and ²⁵l, nitrogen, such as ³N and ⁵N, oxygen, such as ⁵0, ⁷0 and ⁸0, phosphorus, such as ³²P, and sulfur, 30 such as ³⁵S.

Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, ³H, and carbon-14, ⁴C, 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, ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, ³⁵S 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, ⁸F, ⁵0 and ³N, 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

an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

The compounds of the present invention may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical 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.

To treat or prevent diseases or conditions mediated in part or whole by arenavirus infection, 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.

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. Similarly, 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. For example, a bioavailability enhancer, such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG

(polyethyleneglycol), may be added. Gelucire®, a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.

If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, 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. If 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.

To obtain a stable water-soluble dose form, 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. If a soluble salt form is not available, the agent may be dissolved in a suitable co-solvent or combinations of co-solvents. Examples of 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. In an exemplary embodiment, 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.

Proper formulation is dependent upon the route of administration selected. For injection, 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.

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

For oral administration, the compounds can be formulated by combining the active compounds with 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). If desired, 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. 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.

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

Pharmaceutical formulations 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.

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

In addition to the formulations described above, 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. Thus, for example, 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. Furthermore, the identity of the 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.

Alternatively, other delivery systems for 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. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various 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. Depending on the chemical nature and the biological stability of the therapeutic reagent, 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. Furthermore, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, Peceol® Transcutol® and the like may be used.

Further, the pharmaceutical composition may be incorporated into a skin patch for delivery of thedrug directly onto the skin.

It will be appreciated that the actual dosages of the agents of this invention will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions. For oral administration, 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. Furthermore, 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.

Additionally, 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, or salts or solvates thereof, 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, or salts or solvates thereof, 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 and siRNAs, Nature, 2009; 136: 642-655, incorporated herein by reference in its entirety, vaccines as shown by Nablel GJ, Designing Tomorrow's Vaccines, NEJM, 2013; 368: 551 -560, incorporated herein by reference in its entirety, and immunomodulators as shown by Patil US, Jaydeokar AV and Bandawane DD, Immunomodulators: A Pharmacological Review, Internatl J Pharmacy and

Pharmaceutical Sci, 2012; 4: 30-36, incorporated herein by reference in its entirety], 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.

Those of ordinary skill in the art will understand that with respect to the compounds of the present invention, the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment, are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.

The compounds of the present invention are useful for modulating or inhibiting arenavirus GP.

Accordingly, 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.

In the following Preparations and Examples, "Ac" means acetyl, "Me" means methyl, "Et" means ethyl, "Ph" means phenyl, "Py" means pyridine, "BOC", "Boc" or "boc" means N-tert- butoxycarbonyl, "Ns" means 2-Nitrophenylsulfonyl, "DCM" (CH₂CI₂) means dichloromethane or methylene chloride, "DCE" means dichloroethane or ethylene chloride, "DIAD" means

diisopropylazadicarboxylate, "DIPEA" or 'OIEA" means diisopropyl ethyl amine, "DMA" means N,N- dimethylacetamide, "DMF" means N-N-dimethyl formamide, "DMSO" means dimethylsulfoxide, "DPPP"means 1 ,3-bis(diphenylphosphino)propane, "HOAc" means acetic acid, "IPA" means isopropyl alcohol, "NMP" means 1 -methyl 2-pyrrolidinone, "TEA" means triethyl amine, "TFA" means trifluoroacetic acid, "DCM" means dichloromethane, "EtOAc" means ethyl acetate, "MgS0₄" means magnesium sulphate, "Na₂S0₄" means sodium sulphate, "MeOH" means methanol, "Et₂0" means diethyl ether, "EtOH" meansethanol, "H₂0" means water, "HCI" means hydrochloric acid, "POCI₃" means phosphorus oxychloride,"SOCI₂" means thionylchloride, "K₂C0₃" means potassium carbonate, "THF" means tetrahydrofuran, "DBU" means 1 ,8-diazabicyclo[5.4.0]undec-7-ene, "LiHMDS" or "LHMDS" means lithium hexamethyldisilazide, "TBME" or"MTBE" means fe/ -butyl methyl ether, "LDA" means lithium diisopropylamide, "N" means Normal, 'M'means molar, "mL" means millilitre, "mmol" means millimoles, "μπΊθΓ means micromoles, "eq." meansequivalent, "°C" means degrees Celsius, "Pa" means pascals, "Xanthphos" means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "rt" means room temperature

Methods of Preparation.

Compounds of the present invention may be prepared using the reaction routes and synthetic schemes described below, employing the techniques available in the art using starting materials that are readily available. The preparation of certain embodiments of the present invention is described in detail in the following examples, but those of ordinary skill in the art will recognize that the preparations described may be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplified compounds according to the invention may be performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions referred to herein or known in the art will be recognized as having adaptability for preparing other compounds of the invention.

The synthesis of compound I is depicted in Scheme 1 using a sequence similarly to a route disclosed in patent application US2004/0224957. Amino acid 1 -1 can be converted to the /V-nosyl protected amino acid 1 -2 using nosylchloride in the presence of a base such as triethyl amine and then treated with thionylchloride to provide the acid chloride of /V-nosyl protected amino acid 1 -3. Acylation of amino acid 1 -7 under with acylchloride 1 -5 under Schotten-Baumann conditions can provide amide 1 - 6 which can be reduced to the secondary aminolacohol 1 -9 using a reducing agent such as LiAIH4. Alternatively, the amino acid 1 -4 can be reduced to the amino alcohol 1 -7 with a reducing agent such as LiAIH₄ or Borane in solvent such as THF, or NaBH₄ in a solvent such as methanol. Reductive alkylation of aminoalcohol 1 -7 with aldehyde 1 -8 can provide secondary aminoalcohol 1 -9.

Subsequent N-acylation of 1 -9 with of acid chloride 1 -3 in the presence of a base such as triethyl amine, or MgO can provide compound 1 -10. The 6-membered ring can be closed under Mitsunobu conditions (PPh₃, DIAD, THF) to give 1 -11. Nosyl deprotection can be achieved with thiophenol in the presence of a base such as K₂C0₃ to provide piperazinone 1 -12. Subsequent acylation of the free amine with carboxylic acid 1 -13 using a coupling reagent such as EDCI, HOAt in the presence of a base such as 2,6-lutidine can furnish compound of general formula I. Scheme 2

An alternative method for the synthesis of compound of general formula I is depicted in scheme 2. The Alkylation of the t-butyl ester of N-nosyl protected amino acid 2-1 with a Boc protected aminoalcohol 2-2 under Fukuyama-Mitsunobu conditions (Fukuyama, T.; Cheung, M., Kan, T.

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 K₂C0₃ 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 CH₂CI₂ to provide the amino acid 2-7 as the TFA salt. Reductive alkylation of 2-7 using sodium triacetoxyborohydride as the reductant (Et₃N, CICH₂CH₂CI), 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

3-6 3-7 3-8 I

Scheme 3 depicts an alternative method for preparation of compounds of formula I . Alkylation of the t- butyl ester of N-nosyl protected amino acid 3-1 with a Boc protected aminoalcohol 3-2 under

Fukuyama -Mitsunobu conditions conditions (Fukuyama, T.; Cheung, M., Kan, T. Tetrahedron Lett. 1995, 36, 6373) 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. The nosyl group in 3-8 can be cleaved with thiophenol (ref.) under basic conditions using a base such as K₂C0₃ 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

4-12 4-13

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. 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.

5-9 5-10 5-12

The synthesis of compounds of general formula I (R = CH₂NR^8aR^8b, 5-12) can be accomplished as shown in Scheme 5. 0-(tert-butyl)-serine 5-1 can be converted to the /V-acyl derivative 5-3 using acylchloride 5-2. LAH reduction can provide the amino alcohol 5-4. Acylation of amino alcohol 5-4 with N-nosyl glycine chloride 1 -3 can yield the corresponding amide 5-5. Under Mitsunobu reaction conditions amide 5-5 can be cyclized to give piperazinone derivative 5-6. The fe/ -butyl group of piperazinone derivative 5-6 can be removed using 4N HCI/1 ,4-dioxane to give alcohol 5-7. The alcohol 1 -7 can be converted to triflate derivative 5-8, which upon reacting with amines NHR^8aR^8b can provided amine derivative 5-9. Removal of the nosyl group in 5-9 can be accomplished with

PhSH/K₂C0₃ in DMF to afford amine derivative 5-10. Acylation of the amine derivative 5-10 with carboxylic acid (5-11) using EDCI, 2,6-lutidine can compound of general formula I (R = CH₂NR^8aR^8b, 5-12). Examples A-1 to A-49

Step 1 : fe/f-butyl (S)-/V-(2-((fe/ -butoxycarbonyl)amino)-4-phenylbutyl)-/V-((2-nitrophenyl)sulfonyl) glycinate

A dry 250 ml_ round-bottom flask was charged with fe/f-butyl (S)-(1 -hydroxy-4-phenylbutan-2-yl) carbamate (4.2 g, 15.8 mmol) and anhydrous THF (70 ml_). Te/f-butyl ((2- nitrophenyl)sulfonyl)glycinate (3.85 g, 12.2 mmol) was then added, followed by triphenylphosphine (4.15 g, 15.8 mmol). The diisopropyl azodicarboxylate (3.4 g, 16.8 mmols) was then added dropwise over a 30 minute period using a syringe. The reaction was allowed to stir for 2 h, and then diluted with ethyl acetate and washed with H₂0. The organics were dried (Na₂S0₄) and concentrated. The product was purified by Si0₂ flash chromatography using 3:1 hexanes/ethyl acetate. The solvents were then removed in vacuo to provide the product as a viscous yellow oil (3.2 g, 5.6 mmol, 46% yield). MS-ESI (m/z) calculated for C₂₇H38N₃0₈S [M+H]⁺ 564.2; found 564.2.

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 K₂C0₃ (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 H₂0 and saturated aq. NaHC0₃. The organics were dried over Na₂S0₄ and the product was purified by Si0₂ flash chromatography using a gradient of 3:1 to 1 :1 hexanes/ethyl acetate. The solvents were removed in vacuo to provide the title compound as a light yellow oil (1 .4 g, 3.7 mmol, 71 %). MS-ESI (m/z) calculated for C₂ H₃₅N₂0₄ [M+H]⁺ 379.3; found 379.2.

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. The reaction was washed with 1 N aq. HCI and saturated aq. NaHC0₃ and the organics were dried over Na₂S0₄ and the solvent removed to provide the title compound as a yellow oil (1 .5 g, 2.9 mmols, 80% yield). MS-ESI (m/z) calculated for C₂9H4i N₂0₆ [M+H]⁺ 513.3; found 513.3.

Step 4: (S)-/V-(2-amino-4-phenylbutyl)-/V-(4-methoxybenzoyl)glycine

A 10 dram vial was charged with fe/f-butyl (S)-/V-(2-((fe/ -butoxycarbonyl)amino)-4-phenylbutyl)-N-(4- methoxybenzoyhglycinate (1 .1 g, 2.1 mmol) and CH₂CI₂ (12 mL) and TFA (6 mL) were added. The vial was capped and stirred for 17 hrs and then put under a stream of N₂ to remove the volatiles and provide the crude product. The crude material was purified over a small column of Si0₂ using 9:1 CH₂CI₂/MeOH to provide the product (745 mg, 1 .6 mmols) as a white solid. MS-ESI (m/z) calculated for C₂oH₂₅N₂0₄ [M+H]⁺ 357.2; found 357.2.

Step 5: General procedure A for synthesis of examples A-1 to A-49.

A 1/2 dram vial was charged with the desired aldehyde (25 μηιοΙ) and then the (S)-/V-(2-amino-4- phenylbutyl)-/V-(4-methoxybenzoyl)glycine (1 1 mg, 25 μηιοΓ) as a solution in 1 ,2-dichloroethane (150 μί) and NEt₃ (3.5 μί) was added. Sodium triacetoxyborohydride (10.5 mg, 50 μηιοΓ) was then added and the vial was capped and put on a rotary shaker for 18 hrs. The reaction was then diluted with CH₂CI₂ (1 .2 mL) and NaHC0₃ (7 mg) was added, followed by the addition of EDC (14 mg, 75 μη-iols). The sample was then capped and put on a rotary shaker for 8 additional hours. The reaction volume was then reduced under a stream of N₂ and the product was purified by PTLC using 9:1

CH₂CI₂/MeOH.

piperazin-1 -yl]methyl} benzonitrile

Examples A-50 to A-143

Step 1 : 2-[(2-nitrobenzene)sulfonamido]acetic acid

Ns-CI

Glycine (5.3 g, 71 mmol) was dissolved in 1 :1 dioxane/H₂0 (200 mL). NaOH pellets (6.2 g, 155 mmol) were added and the mixture stirred until the pellets dissolved. The reaction was then brought to 0 °C and 2-nitrobenzene sulfonyl chloride (17.2 g, 78 mmol) was added. The ice bath was removed and the reaction was stirred for 3 hrs at room temperature and then diluted with EtOAc and washed with 1 N aqueous HCI (2X). The organics were dried over Na₂S0₄ then removed to provide the product, which was taken to the next step without further purification. MS-ESI (m/z) calculated for C₈H₇N₂0₆S [M-H]^" 259.0; found 259.0.

Step 2: 2-[(2-nitrobenzene)sulfonamido]acetyl chloride

Method 1 : A 1 L flask was charged with the 2-[(2-nitrobenzene)sulfonamido]acetic acid from step 1 and SOCI₂ (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 N₂ for 15 hrs to remove the SOCI₂ 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 SOCI₂ (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 SOCI₂ was removed under vacuum ro provide a brown solid which was used without further purification in the next step.

Step 3: (2S)-4-phenyl-2-({[3-(trifluoromethyl)phenyl]methyl}amino)butan-1 -ol

L-Homophenylalaninol (1 .4 g, 8.5 mmol) was dissolved in MeOH (40 ml_). 3-(trifluoromethyl) benzaldehyde (1 .5 g, 8.5 mmol) was added and the reaction was stirred at room temperature for 1 hr. The reaction was then brought to 0 °C and NaBH₄ (386 mg, 10.2 mmol) was added at once and the reaction was allowed to warm to room temperature and stir for 2 additional hrs. The reaction was then diluted with EtOAc and washed with saturated aqueous NaHC0₃ (2X). The organics were dried over Na₂S0₄ and removed to provide the product as a viscous oil (2.6 g, 8.2 mmol, 95% yield). MS- ESI (m/z) calculated for C₁₈H₂₁F₃NO [M+H]⁺ 324.2; found 324.2.

Step 4: A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-2-[(2-nitrobenzene)sulfonamido]-N-{[3-(trifluoromethyl) phenyl]methyl}acetamide

(2S)-4-Phenyl-2-({[3-(trifluoromethyl)phenyl]methyl}amino)butan-1 -ol (2.6 g, 8.2 mmol) was dissolved in CH₂CI₂ (150 mL) in a 500 mL round-bottom flask and NaHC0₃ (5 g, 59 mmols) was added. ((2- Nitrophenyl)sulfonyl)glycinoyl chloride (2 g, 7.2 mmols) was then added in 250 mg portions over 2 hrs and the reaction was allowed to stir for 1 additional hr. The reaction was then diluted with ethyl acetate and washed with saturated aq. NaHC0₃ and the organics were dried over Na₂S0₄ and then removed in vacuo to provide the product, which was taken to the next step without further purification. MS-ESI (m/z) calculated for C₂₆H₂₇F₃N₃0₆S [M+H]⁺ 566.1 ; found 566.0.

Step 5: (6S)-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)-1 -{[3-(trifluoromethyl)phenyl]methyl} piperazin-2-one

A/-[(2S)-1 -Hydroxy-4-phenylbutan-2-yl]-2-[(2-nitrobenzene)sulfonamido]-N-{[3-(trifluoromethyl) phenyl]methyl}acetamide was dissolved in anhydrous THF (200 ml_) and PPh₃ (2.6 g, 10 mmol) was then added. Diisopropyl azodicarboxylate (2.3 g, 1 1 mmol) was added dropwise over 30 minutes and the reaction was then stirred for 1 hr. The reaction was concentrated on a rotary evaporator and the product was purified by Si0₂ flash column chromatography using a gradient of 2:1 to 1 :2

hexanes/ethyl acetate to provide the product (1 .5 g, 2.7 mmol, 33% yield over two steps). MS-ESI (m/z) calculated for C₂₆H₂5F₃N₃0₅S [M+H]⁺ 548.1 ; found 548.1 .

Step 6: (6S)-6-(2-phenylethyl)-1 -{[3-(trifluoromethyl)phenyl]methyl}piperazin-2-one

(6S)-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)-1 -{[3- (trifluoromethyl)phenyl]methyl}piperazin-2- one (1 .5 g, 2.7 mmol) was dissolved in DMF (10 ml_) and K₂CO₃750 mg, 5.4 mmol) was added, followed by thiophenol (327 mg, 3 mmol). The reaction was stirred at room temperature for 3 hrs and then diluted with ethyl acetate and washed with saturated aqueous NaHC0₃ (2X). The organic extracts were dried over Na₂S0₄ and concentrated. The product was purified by Si0₂ flash column chromatography using a gradient 1 :1 to 1 :2 hexanes/ethyl acetate to provide the product (833 mg, 2.3 mmol, 85% yield). MS-ESI (m/z) calculated for C₂₀H₂₂F₃N₂O [M+H]⁺ 363.2; found 363.2

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 μηιοΐε) and 200 μΙ_ of a DMF solution containing the (6S)-6-(2-phenylethyl)-1 -{[3-(trifluoromethyl)phenyl]methyl}piperazin-2-one (8 mg, 22 μηιοΐε), 2,6-lutidine (7 mg, 66 μηιοΐε), and 1 -hydroxy-7-azabenzotriazole (3 mg, 22 μηιοΐε) was added. EDC (6 mg, 33 μηιοΐε) was then added to the reaction and the vial was capped and put on a rotary shaker for 14 hrs. The reaction was then diluted with ethyl acetate and washed twice with 1 N aqueous HCI and twice with saturated aqueous NaHC0₃ and the organics were dried over Na₂S0₄. The solvents were removed under a stream of N₂ and further under high vacuum to provide the title compounds (examples A50 to A-143).

Examples A-144 to A-149

Step 1 : 3-({[(2S)-1 -hydroxy-4-phenylbutan-2-yl]amino}methyl)phenol

The title compound was prepared in the same manner as described in step 3 for examples A-50 to A- 143 using 3-hydroxybenzaldehyde instead of 3-trifluoromethylbenzaldehyde. MS-ESI (m/z) calculated for C₁₇H₂₂N0₂ [M+H]⁺ 272.2; found 272.2.

Step 2: A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-N-[(3-hydroxyphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido]acetamide

The title compound was prepared in the same manner as described in step 4 for examples A-50 to A- 143 using 3-({[(2S)-1 -hydroxy-4-phenylbutan-2-yl]amino}methyl)phenol instead of (2S)-4-phenyl-2- ({[3-(trifluoromethyl) phenyl]methyl}amino)butan-1 -ol. MS-ESI (m/z) calculated for C25H28N3O7S

[M+H]⁺ 514.2; found 514.1 .

Step 3: (6S)-1 -[(3-hydroxyphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2- one

The title compound was prepared in the same manner as described in step 5 for examples A-50 to A- 143 using A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-N-[(3-hydroxyphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido] acetamide instead of A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-2-[(2-nitrobenzene) sulfonamido]-N-{[3-(trifluoromethyl) phenyl]methyl}acetamide. MS-ESI (m/z) calculated for

C₂5H26N₃0₆S [M+H]⁺ 496.1 ; found 496.0.

Step 4: (6S)-1 -[(3-hydroxyphenyl)methyl]-6-(2-phenylethyl)piperazin-2-one

The title compound was prepared in the same manner as described in step 6 for examples A-50 to A- 143 using (6S)-1 -[(3-hydroxyphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2- one instead of (6S)-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)-1 -{[3-(trifluoromethyl)phenyl]methyl} piperazin-2-one. MS-ESI (m/z) calculated for C₁₉H₂₃N₂0₂ [M+H]⁺ 31 1 .2; found 31 1 .2.

Step 5:

The desired products were prepared using General Procedure B using (6S)-1 -[(3- hydroxyphenyl)methyl]-6-(2-phenylethyl)piperazin-2-one instead of (6S)-6-(2-phenylethyl)-1 -{[3- (trifluoromethyl)phenyl]methyl} piperazin-2-one.

13.8, 8.3 Hz, 0.5H), 2.16 (tdd, J = 13.5, 8.2, 5.0 Hz,

0.5H), 2.06 - 1 .91 (m, 2H). MS m/z: 466.2 [M+H]⁺

Examples A-150 to A-155

Step 1 : (2S)-2-{[(3-methylphenyl)methyl]amino}-4-phenylbutan-1 -ol

The title compound was prepared in the same manner as described in step 3 for examples A-50 to A- 143 using 3-methylbenzaldehyde instead of 3-trifluoromethylbenzaldehyde. MS-ESI (m/z) calculated for C₁₈H₂₃NO [M+H]⁺ 270.2; found 270.2.

Step 2: N-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-N-[(3-methylphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido]acetamide

The title compound was prepared in the same manner as described in step 4 for examples A-50 to A- 143 using (2S)-2-{[(3-methylphenyl)methyl]amino}-4-phenylbutan-1 -ol instead of (2S)-4-phenyl-2-({[3- trifluoro methyl)phenyl]methyl}amino)butan-1 -ol. MS-ESI (m/z) calculated for C26H₃oN₃0₆S [M+H]⁺ 512.2; found 512.1 .

Step 3: (6S)-1 -[(3-methylphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2-one

The title compound was prepared in the same manner as described in step 5 for examples A-50 to A- 143 using N-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-N-[(3-methoxyphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido acetamide instead of N-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-2-[(2-nitrobenzene) sulfonamido]-N-{[3-(trifluoromethyl)phenyl]methyl}acetamide. MS-ESI (m/z) calculated for C₂₆H₂₈N₃0₅S [M+H]⁺ 494.2; found 494.1 .

Step 4: (6S)-1 -[(3-methylphenyl)methyl]-6-(2-phenylethyl)piperazin-2-one

The title compound was prepared in the same manner as described in step 6 for examples A-50 to A- 143 using (6S)-1 -[(3-methylphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2- one instead of (6S)-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)-1 -{[3-(trifluoromethyl)phenyl] methyl}piperazin-2-one MS-ESI (m/z) calculated for C20H25N2O [M+H]⁺309.2; found 309.2.

Step 5:

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.

Ex. Structure/Name Analytical Data

A- 150 Ή NMR (400 MHz, Chloroform-d) δ 7.41 - 7.38 (m,

2H), 7.35 - 7.06 (m, 7H), 6.87 (m, 2H), 6.69 (d, J = 8.9 Hz, 2H), 5.30 (d, J = 14.3, 1 H), 4.63 ( br s, 2H), 4.17 (d, J = 18.3 Hz, 1 H), 3.70 (d, J = 14.6 Hz, 1 H), 3.20 (d, J = 5.9 Hz, 2H), 3.03 (s, 6H), 2.81 (d, J = 33.9

Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.32 (q, J = 0.5 Hz,

(6S)-4-{[4(dimethylamino)phenyl]

3H), 1 .91 (td, J = 9.2, 8.7, 5.6 Hz, 2H). MS m/z: 456.4 carbonyl}-1 -[(3-methylphenyl) methyl]- [M+H]⁺

6-(2-phenylethyl)piperazin-2-one

H NMR (400 MHz, Chloroform-d) δ 8.32 (dd, J = 8.6,

0.9 Hz, 1 H), 8.18 - 8.02 (m, 1 H), 7.92 - 7.84 (m, 2H), 7.78 (dddd, J = 20.0, 8.5, 6.9, 1 .5 Hz, 1 H), 7.69 - 7.61 (m, 1 H), 7.38 - 7.31 (m, 1 H), 7.30 - 7.05 (m, 5H), 7.00 - 6.96 (m, 1 H), 6.89 (d, J = 5.1 Hz, 2H), 5.42 - 5.24 (m, 1 H), 5.01 - 4.77 (m, 2H), 4.52 (d, J = 18.5

(6S)-1 -[(3-methylphenyl)methyl]-6-(2- Hz, 0.5H), 4.21 (d, J = 19.3 Hz, 0.5H), 3.73 (dd, J = phenylethyl)-4-[(quinolin-2- 14.6, 4.3 Hz, 1 H), 3.42 (m, 1 H), 3.26 - 3.1 1 (m, 1 H), yl)carbonyl] piperazin-2-one

3.00 (dt, J = 13.6, 6.6 Hz, 1 H), 2.72 - 2.59 (m, 1 H), 2.34 - 2.28 (m, 3H), 2.07 - 1 .92 (m, 1 H). MS m/z: 464.4 [M+H]⁺

Examples A-156 to A-161 and examples B-1 to B-25

Step 1 : (2S)-2-{[(3-methoxyphenyl)methyl]amino}-4-phenylbutan-1 -ol

The title compound was prepared in the same manner as described in step 3 for examples A-50 to A- 143 using 3-methoxybenzaldehyde instead of 3-trifluoromethylbenzaldehyde. MS-ESI (m/z) calculated for C₁₈H₂₄N0₂ [M+H]⁺ 286.2; found 286.2.

Step 2: A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-N-[(3-methoxyphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido]acetamide

The title compound was prepared in the same manner as described in step 4 for examples A-50 to A- 143 using (2S)-2-{[(3-methoxyphenyl)methyl]amino}-4-phenylbutan-1 -ol instead of (2S)-4-phenyl-2- ({[3-(trifluoromethyl)phenyl]methyl}amino)butan-1 -ol. MS-ESI (m/z) calculated for C₂₆H29N₃0₇S [M+H]⁺ 528.2; found 528.1 .

Step 3: (6S)-1 -[(3-methoxyphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2- one

To a solution of A/-[(2S)-1 -hydroxy-4-phenylbutan-2-yl]-/V-[(3-methoxyphenyl)methyl]-2-[(2- nitrobenzene)sulfonamido] acetamide (1 g, 1 .9 mmol) and diphenyl-2-pyridylphosphine (1 .75 g, 6.64 mmol) in anhydrous THF (25 ml_) cooled in an ice-bath was added DIAD (1 .31 ml_, 6.6 mmol) dropwise over 30 minutes. The mixture was stirred in an ice-bath for 1 h, and at rt for 2 h. Finally, silica gel is added and the mixture evaporated to dryness. The adsorbed mixture is purified by flash chromatography using a 1 :1 to 1 :2.5 hexanes:ethyl acetate gradient to provide the title compound (.415 g, 43%) as a viscous oil. LC/MS m/z: 510.18 (M+H)⁺, 551 .30 (M+H+CH₃CN)⁺

Step 4: (6S)-1 -[(3-methoxyphenyl)methyl]-6-(2-phenylethyl)piperazin-2-one

(6S)-1 -[(3-Methoxyphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2-one (448 mg, 0.88 mmol) was dissolved in DMF (6 ml_), under N₂ and K₂C0₃ (425mg, 3.1 mmol) was added, followed by thiophenol (290 mg, 2.64 mmol). The reaction was stirred at room temperature overnight and then diluted with EtOAc and washed with saturated aqueous NaHC0₃ (2X). The organic extracts were dried (Na₂S0₄) and concentrated. The product was purified by flash column chromatography using a gradient of 2% to 10% MeOH in CH₂CI₂ to provide the product (227 mg, 82% yield). LC/MS m/z: 325.35 (M+H)⁺ , 366.30 (M+H+CH₃CN)⁺

Step 5: examples A-156 to A-158 and examples B-1 to B-25

The desired products were prepared from (6S)-1 -[(3-methoxyphenyl)methyl]-6-(2-phenylethyl) piperazin-2-one and the appropriate carboxylic acid using General Procedure B.

B-25 Ή NMR (600 MHz, Chloroform-d) δ 9.68 (s, 1 H),

8.39 (s, 1 H), 8.01 (d, J = 8.7 Hz, 1 H), 7.50 (dd, J = 8.8, 1 .9 Hz, 1 H), 7.26 - 6.92 (m, 8H), 6.88 - 6.82 (m, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 6.69 (d, J = 7.5 Hz, 1 H), 5.32 (d, J = 14.6 Hz, 1 H), 4.96 (s, 2H), 4.58 (s, 1 H), 3.84 (dd, J = 14.9, 1 .9 Hz, 1 H), 3.82 -

(6S)-4-[(5-acetyl-1 H-indol-2- 3.79 (m, 3H), 3.37 (d, J = 10.3 Hz, 1 H), 3.21 (s, yl)carbonyl]-1 -[(3-methoxyphenyl) 1 H), 2.91 (d, J = 1 .9 Hz, OH), 2.73 - 2.67 (m, 3H), methyl]-6-(2-phenylethyl) piperazin-2- 2.64 - 2.48 (m, 1 H), 1 .97 (q, J = 10.4, 9.3 Hz, 1 H), one 1 .89 (dd, J = 15.1 , 9.6 Hz, 1 H). LC/MS m/z: 510.26

(M+H)^{+ 1} 551 .25 (M+H+CH₃CN)⁺

The following intermediates were prepared in the same manner as described in step 1 for examples A-50 to A-143 using the appropriate starting material.

The following intermediates were prepared in the same manner as described in step 2 for examples A-50 to A-143 using the appropriate starting materials.

Methyl (2S)-3-phenoxy-2-[(triphenylmethyl)amino]propanoate

/V-trityl serine methyl ester (5.0 g, 13.8mmol), triphenylphosphine (3.98g, 15.2 mmol), phenol (1 .95 g, 20.7 mmol) and toluene (125 mL) was added to a flask with stirring under dry N₂. Next,

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. LC/MS m/z: 438.24 (M+H)⁺

Methyl (2S)-2-amino-3-phenoxypropanoate

Methyl (2S)-3-phenoxy-2-[(triphenylmethyl)amino]propanoate (4.36 g, 9.98 mmol) was dissolved in methanol (50 mL) and 0.92 mL(10.97 mmol) of concentrated HCI was added in one portion. The mixture was stirred unil TLC indicates completion. Next, all volatiles were evaporated leaving behind a white solid which is triturated twice with hexanes to provide 2.187g (95%) of the title compound as a white HCI salt. LC/MS m/z: 237.19 (M+H)⁺

Methyl (2S)-3-phenoxy-2-(phenylformamido)propanoate

Methyl (2S)-2-amino-3-phenoxypropanoate hydrochloride (2.187 g, 9.47 mmol), dichloromethane (50 mL), triethylamine (3.28 mL, 23.68 mmol), and 10 mg of 4-dimethylaminopyridine were combined with stirring and cooled to 0°C in an ice bath. Next, benzoyl chloride (1 .21 mL, 10.42 mmol) was added dropwise over 5 minutes, and stirring continued for 2 hours. The mixture was diluted with

dichloromethane and washed with NaHC0₃ (1 x 30ml), 1 M HCI (1 x 30ml), brine (1x 30ml), dried (Na₂S0₄), and concentrated under vacuum. The crude residue was purified by flash chromatography using 4:1 hexanes:ethyl acetate as eluent to give 2.15g (76%) of the title compound as a white foam. LC/MS m/z: 300.17 (M+H)⁺, 599.18 (2M+H)⁺

(2S)-3-Cyclohexyl-2-[(3-methoxyphenyl)formamido]propanoic acid

L-Cyclohexylalanine (2.0 g, 1 1 .6 mmol) was dissolved in 2N NaOH (17.5 mL) and cooled to 0°C in an ice-bath. 3-Methoxybenzoyl chloride (1 .65 mL, 2.0 g, 1 1 .6 mmol) was added to the solution in ten equal portions during a period of 30 min. The mixture was stired at rt for 1 h, cooled to 0°C in an ice- bath, and acidified with cone HCI to pH 2. After stirring at rt for 1 h, the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (2 x 20 mL), brine (20 mL), dried (Na₂S0₄), and concentrated to provide the title product as a white solid (4.3 g). LC/MS m/z: 306.26 (M+H)⁺, 323.26 (M+NH₄)⁺

The following intermediates were prepared in the same manner as described above for (2S)-3- cyclohexyl-2-[(3-methoxyphenyl)formamido]propanoic acid using the appropriate amino acid and the appropriate acylchloride as starting material.

benzoyl chloride

(2S)-3-[4-(Benzyloxy)phenyl]-2-[(3-methoxyphenyl)formamido]propanoic acid

A solution of O-benzyl-L-tyrosine (5.0 g, 18.6 mmol) in 2N NaOH (28 mL) and dioxane (20 mL) was cooled to 0°C in an ice-bath. 3-Methoxybenzoyl chloride (2.62 mL, 3.17 g, 18.6 mmol) was added to the solution in ten equal portions during a period of 45 min. The mixture was stired at rt for 1 h, cooled to 0°C in an ice-bath, and acidified with cone HCI to pH 4. The precipitate was collected by vaccum filtration, to provide the title compound as colorless solid (7.95 g). LC/MS m/z: 406.19 (M+H)⁺

(2S)-2-[(3-methoxyphenyl)formamido]-3-(pyridin-2-yl)propanoic acid

L-2-Pyridylalanine (3.0 g, 18 mmol) was dissolved in 2N NaOH (28 mL) and cooled to 0°C in an ice- bath. 3-Methoxybenzoyl chloride (2.55 mL, 3.07 g, 18 mmol mmol) was added to the solution in ten equal portions during a period of 30 min. The mixture was stired at rt for 1 h, cooled to 0°C in an ice- bath, and acidified with cone HCI to pH 4. After stirring at rt for 1 h, the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (2 x 20 mL), brine (20 mL), dried (Na₂S0₄), and concentrated to provide the title product as brown oil (2.0 g). LC/MS m/z: 306.26 (M+H)⁺, 323.26 (M+NH₄)⁺ After 16 a precipitate formed in the aqueous layer which was filtered off providing additional 1 .77 g of product. LC/MS m/z: 301 .20 (M+H)⁺. (2S)-2-{[(3-Methoxyphenyl)methyl]amino}-3-(pyridin-2-yl)propan-1 -ol

To suspension of LiAIH₄ (623 mg, 16.4 mmol) in THF (16 mL) was added drowpwise a suspension of (2S)-2-[(3-methoxyphenyl)formamido]-3-(pyridin-2-yl)propanoic acid (2.46 g, 8.2 mmol) in THF (40 mL). The mixture was heated to reflux for 16 h. It was cooled in an ice-bath, and water (0.6 mL), 15% NaOH solution (0.6 mL), water (1 .8 mL) was added successively. After stirring for 30 min, MgS0₄ was added, and the mixture was stirred for 30 min. The mixture was filtered through Celite, and the filtrate was concentrated to provide a colorless oil (2.03 g). LC/MS m/z: 273.15 (M+H)⁺

(2S)-3-Cyclohexyl-2-{[(3-methoxyphenyl)methyl]amino}propan-1 -ol

To suspension of LiAIH₄ (1 .07 g, 28 mmol) in THF (28 mL) was added drowpwise a solution of (2S)-3- cyclohexyl-2-[(3- methoxyphenyhformamido] propanoic acid ( 4.3 g, 14 mmol) in THF (15 mL). The mixture was heated to reflux for 16 h. It was cooled in an ice-bath, and water (1 .1 mL), 15% NaOH solution (1 .1 mL), water (3.3 mL) was added successively. After stirring for 30 min, the mixture was filtered through Celite, and the filtrate was concentrated to provide a colorless oil that crystallized (2.03 g). LC/MS m/z: 278.23 (M+H)⁺.

The following intermediates were prepared in the same manner as described above for the preparation of (2S)-3-cyclohexyl-2-{[(3-methoxyphenyl)methyl]amino}propan-1 -ol using the appropriate precursor.

(2S)-2-{[(3-Methoxyphenyl)methyl]amino}-2-phenylethan-1 -ol

The title compound was prepared in the same manner as described in step 3 for examples 1 to 22 using of (6S)-1 -[(3-Methoxyphenyl)methyl]-4-[(2-nitrobenzene)sulfonyl]-6-(2-phenylethyl)piperazin-2- one. LC/MS m/z: 258.28 (M+H)⁺

(2S)-2-{[(3-Methoxyphenyl)methyl]amino}-2-phenylethan-1 -ol

To a solution of L-phenylalaninol (2.35 g, 15.5 mmol) in EtOH (20 mL) was added 3-methoxymethyl benzaldehyde (2.1 1 g, 15.5 mmol). The mixture was stirred at room temperature for 1 h, and NaBH₄ (590 mg, 15.5 mmol) was added at once. After stirring for 16 h at rt, the mixture was diluted with EtOAc (20 mL), and washed with saturated aqueous NaHC0₃ (2 X 20 mL). The organic layer was dried (Na₂S0₄₎ and concentrated to provide the title product as a viscous oil (3.74 g). LC/MS m/z: 272.24 (M+H)⁺(2f?)-3-(Benzyloxy)-2-{[(3-methoxyphenyl)methyl]amino}propan-1 -ol

The title compound was prepared in the same manner as described above for the preparation (2S)-2- {[(3-methoxyphenyl)methyl]amino}-2-phenylethan-1 -ol using (2R)-2-amino-3-(benzyloxy)propan-1 -ol instead of L-phenylalaninol. LC/MS m/z: 302.25 (M+H)⁺ fe/ -butyl A/-[(2S)-1 -hydroxy-3-(pyridin-2-yl)propan-2-yl]carbamate

HBOC

To a solution of Boc-L-2-Pyridylalanine (1 g, 3.7 mmol) in THF (10 mL) was added dropwise 1 M solution of L1AIH₄ in THF (3.7 mL) at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h. It was cooled in an ice-bath, and quenched with saturated aqueous Na₂S0₄ solution (2 mL). After stirring for 1 h, the mixture was filtered through Celite, and washed with 2-propanol. The filtrate was concentrated, and the crude product was purified by column chromatography using EtOAc, then a 50:1 to 10:1 CH₂CI₂ / MeOH gradient to provide the title compound as a white solid (0.5 g, 53%). LC/MS m/z: 197.24 (M - ferf-butyl+H)⁺, 253.26 (M+H)⁺.

(2S)-2-amino-3-(pyridin-2-yl)propan-1 -ol

H

To a solution of fe/f-butyl N-[(2S)-1 -hydroxy-3-(pyridin-2-yl)propan-2-yl]carbamate (0.33 g, 1 .3 mmol) in CH₂CI₂ (6 ml_) was added dropwise trifluoroacetic acid (2 ml_). The mixture was stirred at rt for 2 h, then concentrated in vacuo. The residue was dissolved in methanol and filtered through an Agilent Stratopheres PL-HC0₃ ion exchange resin. The filtrate was concentrated to provide the title compound as its freebase (0.2 g, 100%).

(2S)-2-(benzylamino)-3-(pyridin-2-yl)propan-1 -ol

To a solution of (2S)-2-amino-3-(pyridin-2-yl)propan-1 -ol (200 mg, 1 .3 mmol) in MeOH (5 ml_) was added benzaldehyde (140 mg, 1 .3 mmol). The reaction mixture was stirred at rt for 1 h. It was cooled in an ice-bath, and NaBH₄ (75 mg, 1 .97 mmol) was added at once. The reaction mixture was stirred at ambient temperature for 2 h, then diluted with EtOAc and washed with saturated aqueous NaHC0₃ solution. The organic phase was dried over Na₂S0₄ and concentrated. The residue was dissolved in EtOAc and extracted with 1 N HCI. The aqueous phase was basified with 2N NaOH solution, and extracted with EtOAc. The organic phase was dried over Na₂S0₄ and concentrated to provide the product as a yellow viscous oil (200 mg, 63%) which was used in the next step without further purification. LC/MS m/z: 243.22 (M+H)⁺.

The following intermediates were prepared in the same manner as described in step 4 for examples A-50 to A-143 using the appropropriate amino alcohols and appropriate acyl chlorides as starting materials

A/-[(2S)-1 -Hydroxy-3-phenylpropan-2-yl]-/V-[(3-methoxyphenyl)methyl]-2-[(2-nitrobenzene) sulfonamido] acetamide

To as solution of (2S)-2-{[(3-methoxyphenyl)methyl]amino}-2-phenylethan-1 -ol (3.58 g, 13.2 mmol) in a mixture of THF (80 mL) and water (20 mL) was added MgO (2.66 g, 66 mmol). The mixture was stirred at rt for 30 min. A solution of 2-[(2-nitrobenzene)sulfonamido]acetyl chloride (4.4 g, 15.8 mmol) in THF (40 mL) was added dropwise during a period of 30 min. The mixture was stirred at rt for 4 h, and filtered through Celite. The filtrate was diluted with EtOAc (50 mL), washed with NaHC0₃ solution (3 x 10 mL), 1 N HCI (3 x 10 mL), brine (10 mL), dried (MgS0₄), and concentrated. The crude product was purified by flash column chromatography using a 1 :1 to 1 :2 hexanes/EtOAc gradient to provide the title compound as a white foam (5.06 g). LC/MS m/z: 514.19 (M+H)⁺.

The following intermediates were prepared in the same manner as described above for A/-[(2S)-1 - hydroxy-3-phenylpropan-2-yl]-/V-[(3-methoxyphenyl)methyl]-2-[(2-nitrobenzene)sulfonamido] acetamide using the appropriate amino alcohol as starting material

The title compounds were was prepared in the same manner as described in step 5 for examples A- 50 to A-143 using the appropriate starting materials.

(R)-1 -Benzyl-6-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one

To (R)-1 -benzyl-6-(tert-butoxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one (2 g, 4.34 mmol) was added 4N HCI/1 ,4-dioxane (5 mL, 20 mmol). The resulting reaction mixture was stirred at 70 °C for 4 h. Evaporation of solvent under vacuum gave crude residue which was treated with saturated aqueous NaHC0₃ solution (10 mL), then extracted with ethyl acetate (2 x 100 mL). Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave the crude residue which was purified on Si0₂ column chromatography to give the title compound as pale yellow syrup. Yield : 0.984 g (56%). LC/MS m/z: 406.14 (M+H)⁺.

(6R)-1 -Benzyl-6-(4-fluorophenoxymethyl)-4-[(2-nitrobenzene)sulfonyl]piperazin-2-one

The title compound was prepared using the same procedure as decribed for methyl (2S)-3-phenoxy- 2-[(triphenylmethyl)amino]propanoate using (R)-1 -benzyl-6-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl) piperazin-2-one instead of /V-trityl serine methyl ester and 4-fluorophenol instead of phenol. LC/MS m/z: 488.21 (M+H)⁺ fe/f-Butyl 2-[(2-nitrobenzene)sulfonamido]acetate

To a suspension of fe/f-butyl glycinate hydrochloride (10.0 g, 60 mmol) in CH₂CI₂ (120 mL) was added 2-nitrobenzenesulfonyl chloride (13.2 g, 60 mmol). The mixture was cooled in an ice-bath, and N- methylmorpholine (16.3 mL, 15.0 g, 150 mmol) was added dropwise during a period of 30 min. The mixture was stirred at rt for 2 h, washed with dilute NaHC0₃ solution (2 x 50 mL), water (50 mL), brine (50 mL), dried (MgS0₄), and concentrated to provide colorless crystals (17.6 g). LC/MS m/z: 334.17 (M+NH₄)⁺, 633.1 1 (2M+H)⁺, 650.18 (2M+Na)⁺ fe/f-Butyl 2-{/V-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl](2- nitrobenzene)sulfonamido}acetate

To a solution of fe/f-butyl 2-[(2-nitrobenzene)sulfonamido]acetate, (9.49 g, 30 mmol) Boc-L- phenylalaninol (7.53 g, 30 mmol) and triphenylphosphine (1 1 .8 g, 45 mmol) in anhydrous THF (60 mL) under N₂ cooled in ice-bath was added DIAD (9.1 g, 8.9 mL, 45 mmol) dropwise over 30 minutes. The mixture was stirred at rt for 2 h, filtered, and concentrated. Purification by flash column chromatography using a gradient of 80:20 to 75:25 Hexanes/EtOAc provided the title compound product (1 1 .3 g). LC/MS m/z: 394.21 (M - fe/f-butyl - Boc)⁺, 438.13 (M - 2 fe/f-butyl)⁺, 550.09 (M+H)⁺ tert-Butyl 2-{/V-[(2S)-2-amino-3-phenylpropyl](2-nitrobenzene)sulfonamido}acetate

fe/ -Butyl 2-{/V-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl](2- nitrobenzene)sulfonamido}acetate (200 mg, 0.36 mmol) is dissolved in 1 ml dichloromethane and 1 ml of trifluoroacetic acid is added. The mixture is stirred until LC/MS indicates completion, and all volatiles are evaporated. The residue is dissolved in methanol and filtered through an Agilent Stratopheres PL-HC0₃ ion exchange resin. The filtrate is evaporated under vacuum to provide the title compound as its freebase (160 mg, 98%). LC/MS m/z: 450.18 (M+H)⁺

3-(2-Methyl-1 ,3-dioxolan-2-yl)benzaldehyde

The title compound was obtained from 3-bromoacetophenone using the procedure described in WO 2000/02616.

(S)-tert-Butyl 2-(/V-(2-((3-(1 /-/-pyrazol-1 -yl)benzyl)amino)-3-phenylpropyl)-2-nitrophenylsulfonamido) acetate

fe/ -Butyl 2-{/V-[(2S)-2-amino-3-phenylpropyl](2-nitrobenzene)sulfonamido}acetate (390 mg, 0.87 mmol), aldehyde (157 mg, 0.91 mmol), and 1 ,2-dichloroethane (3 ml) are combined with a spoonful of 4A molecular sieves and stirred for 12 hours. NaBH₃CN (.083 g, 1 .32 mmol) is added in one portion and the reaction stirred a further 12 hours. The reaction is diluted with dichloromethane, washed with saturated NaHC0₃ (1 x 10 ml), brine (1 x 10 ml) and dried (Na₂S0₄). After evaporation of the organics under vacuum, the residue is purified by flash chromatography using 1 :1 hexanes:ethyl acetate as eluent to provide the title compound as a viscous oil (139 mg, 26%). LC/MS m/z: 606.28 (M+H)⁺. The following title compounds were prepared using above procedure using the appropriate aldehyde.

S)-1 -(3-(1 H-Pyrazol-1 -yl)benzyl)-6-benzyl-4-((2-nitrophenyl)sulfonyl)piperazin-2-one

To (S)-fe/ -butyl 2-(N-(2-((3-(1 H-pyrazol-1 -yl)benzyl)amino)-3-phenylpropyl)-2-nitrophenylsulfonamido) acetate (139 mg, 0.23 mmol) was added dichloromethane (1 mL) and trifluroacetic acid (1 mL). The mixture is stirred overnight. HCI (1 .25 M in EtOH, 0.4 mL) was added and the volatiles were evaporated leaving behind a white HCI salt. DMF (2 mL) and 2,6-lutidine (82 uL, 0.7 mmol) were added, followed by EDCI*HCI (59 mg, 0.308 mmol). The mixture was stirred one hour, then diluted with ethyl acetate, washed with water (1 x 5 mL), brine (1 x 5 mL), and dried (Na₂S0₄). The organics were evaporated under reduced pressure and the residue waspurified by flash chromatography using 3:7 hexanes:ethyl acetate as eluent to provide the title compound (122 mg, 100%). LC/MS m/z:

532.26 (M+H)⁺

The following title compounds were prepared using above procedure using the appropriate starting material.

\__ piperazin-2-one -2-(A/-(2-Amino-3-phenylpropyl)-2-nitrophenylsulfon acid

fe/ -Butyl 2-{N-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl](2-nitrobenzene)

sulfonamido}acetate (200 mg, 0.36 mmol) is dissolved in 1 ml dichloromethane and 1 ml of trifluoroacetic acid is added. The mixture is stirred until LC/MS indicates completion, and all volatiles are evaporated. The crude TFA salt is used without further purification . LC/MS m/z 394.10 (M+H)⁺

(S)-6-Benzyl-1 -(3-methylbenzyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one

(S)-2-(/V-(2-amino-3-phenylpropyl)-2-nitrophenylsulfonamido)acetic acid (250 mg, 0.49 mmol) and 3- methylbenzaldehyde (88 uL, 0.74 mmol) are dissolved in dichloroethane (3 ml) and stirred for 30 min, after which sodium triacetoxyborohydride (263 mg, 1 .24 mmol) is added and the mixture stirred for a further 12 h. Next, 1 M HCI (2 ml) is added and the mixture evaporated to dryness under vacuum. The residue is dissolved in DMF (5 ml) and 2,6-lutidine (171 uL, 1 .48 mmol), HOAT (80 mg, 0.59 mmol), and EDCI (1 13 uL, 0.64 mmol) are added and the mixture stirred a further 1 h. The mixture is then diluted with ethyl acetate, washed with water (1 x 2 ml), 1 M HCI (1 x 2ml), and brine (1 x 5ml), dried (Na₂S0₄), and evaporated under vacuum. The crude product is purified by flash chromatography with 3:7 hexanes:ethyl acetate as eluent to afford the title compound (80 mg, 34%). LC/MS m/z: 480.21 (M+H)⁺ , 521 .24 (M+H+CH₃CN)⁺

The title compounds were was prepared in the same manner as described in step 6 for examples A- 50 to A-143 usin the appropriate starting materials.

(6S)-6-Benzyl-1 -[(6-0X0-1 ,6-dihydropyridin-2-yl)methyl]piperazin-2-one

To (S)-6-benzyl-1 -((6-methoxypyridin-2-yl)methyl)piperazin-2-one (20 mg, 0.064 mmol) in a pressure tube is added 2 mL dioxane and 0.25 mL of a 4N HCI/dioxane solution. The tube was capped and heated to 90°C for 3 hours. After cooling to room temperature, the solution was evaporated under reduced pressure to give 18 mg of the title compound as a light pink HCI salt, which is used immediately without further purification. LC/MS m/z: 298.24 (M+H)⁺, 595.18 (2M+H)⁺

Ethyl 5-(cyclopropylmethoxy)-1 H-indole-2-carboxylate

To a solution of ethyl 5-hydroxy-1 H-indole-2-carboxylate (0.25g, 1 .22 mmol) in acetone (3ml_) was added K₂C0₃ (0.51 g, 3.66 mmol) and cyclopropylmethyl bromide (.24ml_, 2.44 mmol). The mixture was heated to reflux overnight. After cooling, the mixture wasfiltered through celite and concentrated under reduced pressure. The crude product was purified using flash chromatography on silica gel with 8:2 hexanes/ethyl acetate as eluent to give 131 mg of the title compound.

5-(Cyclopropylmethoxy)-1 H-indole-2-carboxylic acid

To ethyl 5-(cyclopropylmethoxy)-1 /-/-indole-2-carboxylate (131 mg) was added 2 mL dioxane and 1 mL 1 M aqueous LiOH. The mixture is stirred overnight, and then evaporated to dryness under reduced pressure. The residue is resuspended in water, and concentrated HCI is added until a precipitate forms. The solid is filtered off, washed 1X with 1 M HCI, and dried at 80°C under strong vacuum to give 103 mg of the title compound as a white solid.

5-(Propan-2-yloxy)-1 /-/-indole-2-carboxylic acid

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.

4-(Cyclopropylmethoxy)-1 H-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.

4-(Propan-2-yloxy)-1 /-/-indole-2-carboxylic acid

The title compound was prepared from ethyl 4-hydroxy-1 /-/-indole-2-carboxylate and 2-bromopropane using the method described for 5-(cyclopropylmethoxy)-1 H-indole-2-carboxylic acid above. 4-(Cyclopropylmethoxy)benzoic acid

The title compound was prepared from methyl 4-hydroxybenzoate using the method described for 5- (cyclopropylmethoxy)-1 /-/-indole-2-carboxylic acid above.

5-Cyclopropyl-1 /-/-indole-2-carboxylic acid

To 1 -(fe/ -butyl) 2-ethyl 5-cyclopropyl-1 /-/-indole-1 ,2-dicarboxylate [prepared following the procedure in WO2013/171712] was added (600 mg) 1 ml_ TFA and 1 mL DCM. The mixture was stirred until TLC indicates completion, and all volatiles were evaporated. The crude material was then dissolved in THF (5 mL) and water (1 mL) and 40mg of LiOH was added. When TLC indicates complete saponification, the mixture was evaporated to dryness and resuspended in water. Concentrated HCI was then added dropwise until a precipitate forms, which was filtered off, washed with 1 M HCI, and dried under vacuum at 80°C, yielding 282 mg of the title compound as a light brown solid.

Methyl-4-cyclopropoxybenzoate

To methyl-4-hydroxybenzoate (0.2g, 1 .32 mmol) in a pressure tube was added N,N- dimethylacetamide (4 mL) and Cs₂C0₃ (1 .07 g, 3.3 mmol). The mixture was stirred for 10 minutes and then cyclopropyl bromide (0.53 mL, 6.58 mmol) was added in one portion and the pressure tube was capped and heated to 150°C overnight. After cooling, the reaction was filtered through celite and the filter cake washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed 2X with water, brine 1X, and dried over Na₂S0₄. After removal of the solvents under reduced pressure, the crude product was purified with flash chromatography on silica gel using 8:2 hexanes:ethyl acetate as eluent, yielding 27 mg of the title compound.

4-Cyclopropoxybenzoic acid

To methyl-4-cyclopropoxybenzoate (24 mg) was added 1 mL THF, 1 mL water, and 10 mg of LiOH. The mixture was stirred overnight, after which time all volatiles were evaporated. The crude residue is resuspended in 1 mL water, and concentrated HCI is added dropwise until a precipitate forms. The solid is filtered off, washed 1X with 1 M HCI, and dried under vacuum at 80°C yielding 1 1 mg of the title compound as a white solid.

6-Methylindolizine-2-carboxylic acid and 7-methylindolizine-2-carboxylic acid

The title compounds were prepared as described in WO201 1/038086.

The following title compounds were prepared from the corresponding piperazinone and carboxylic acid using General Procedure B.

7.28

(d, J 1 H), (s,

J = J = Hz, 4.4

6.99 Hz, 1 H), 3.84 H), (s,

(d, Hz, J = 2H), 5.49 Hz, (d, J =

(d, J 1 H), H), (d, J (d, J = = 69.4 -

(dd, J

1 .9 = 1 H),

J =

Hz, J = J = 15.0 9.8 Hz, = 12.4

= 8.6, 4.97 (d, 2H),

methyl)piperazin-2-one

Methyl 6-methyl-1 ,3-benzoxazole-2-carboxylate

The title compound was obtained from 2-amino-5-methylphenol according to the procedures described for the synthesis of methyl benzoxazole-2-carboxylate in US 2015/0289512.

Methyl 5-methyl-1 ,3-benzoxazole-2-carboxylate

The title compound was obtained from 2-amino-4-methylphenol according to the procedures described for the synthesis of methyl benzoxazole-2-carboxylate in US 2015/0289512.

Example: B-72: (6S)-6-(cyclohexylmethyl)-1 -[(3-methoxyphenyl)methyl]-4-[(6-methyl-1 ,3-benzoxazol- 2-yl)carbonyl]piperazin-2-one

To a solution of (6S)-6-(cyclohexylmethyl)-1 -[(3-methoxyphenyl)methyl]piperazin-2-one (30 mg, 0.095 mmol) in DMF (1 mL) was added methyl 6-methyl-1 ,3-benzoxazole-2-carboxylate (37 mg, 0.19 mmol), 1 ,2,4-triazole (1 .3 mg, 0.02 mmol), and DBU (3 mg, 0.02 mmol) (X. Yang and V. B. Birman, Org. Lett. 2009, 11, 1499-1502.). The reaction mixture was stirred at 75 °C overnight, then concentrated. The residue was purified by preparative HPLC to afford the title compound as a viscous oil (25 mg, 55% yield). LC/MS m/z: 476.34 (M+H)⁺, 517.4 (M+H+CH₃CN)⁺, 951 .7 (2M+H)⁺ Example B-73: (6S)-6-(cyclohexylmethyl)-1 -[(3-methoxyphenyl)methyl]-4-[(5-methyl-1 ,3-benzoxazol- 2-yl)carbonyl]piperazin-2-one

The title compound was obtained using the procedure described above for (6S)-6-(cyclohexylmethyl)- 1 -[(3-methoxyphenyl)methyl]-4-[(5-methyl-1 ,3-benzoxazol-2-yl)carbonyl]piperazin-2-one. LC/MS m/z: 476.34 (M+H)⁺, 517.36 (M+H+CH₃CN)⁺, 951 .63 (2M+H)⁺.

Example B-74: (6R)-6-(Hydroxymethyl)-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-1 -[(3-methoxyphenyl) methyl] piperazin-2-one

To a solution of (6R)-6-[(benzyloxy)methyl]-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-1 -[(3- methoxyphenyl) methyl]piperazin-2-one (210 mg, 0.40 mmol) in EtOH (5 ml_) was added Pd/C (10% Pd) (40 mg). The flask was evacuated and flushed with hydrogen gas. After stirring under a hydrogen atmosphere for 5 d, the mixture was filtered through Celite, and the filtrate was concentrated.

Purification by flash chromatography with 3:7 hexanes:ethyl acetate as eluent allowed recovery of unreacted starting material and provided the title compound (25mg, 14%). LC/MS m/z: 424.18 (M+H)⁺, 847.37 (2M+H)⁺

Example B-75: (6S)-6-[(4-Hydroxyphenyl)methyl]-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-1 -[(3-methoxy phenyl)methyl]piperazin-2-one

To a solution of (6S)-6-{[4-(benzyloxy)phenyl]methyl}-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-1 -[(3- methoxyphenyl) methyl]piperazin-2-one (120 mg, 0.20 mmol) in EtOH (10 mL) was added Pd/C (10% Pd) (20 mg). The flask was evacuated and flushed with hydrogen gas. After stirring under a hydrogen atmosphere for 16 h, the mixture was filtered through Celite, and the filtrate was concentrated.

Purification by flash chromatography using a gradient of 4:6 hexanes:ethyl acetate to 100% ethyl acetate provided the title compound (95 mg, 94%). H NMR (600 MHz, Chloroform-d) δ 9.30 (s, 1 H), 7.33 - 7.27 (m, 2H), 7.21 - 6.92 (m, 3H), 6.90 - 6.83 (m, 2H), 6.82 (s, 1 H), 6.72 (s, 3H), 6.1 1 (s, 1 H), 5.41 (d, J = 14.8 Hz, 1 H), 4.89 (d, J = 17.1 Hz, 1 H), 4.64 (s, 1 H), 4.47 (s, 1 H), 3.89 - 3.76 (m, 7H), 3.53 - 3.45 (m, 1 H), 3.13 (s, 1 H), 2.92 (d, J = 42.2 Hz, 1 H), 2.85 (dd, J = 13.9, 3.9 Hz, 1 H), 2.69 (s, 1 H).LC/MS m/z: 500.17 (M+H)⁺, 541 .23 (M+H+CH₃CN)⁺

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

To (S)-6-(4-hydroxybenzyl)-4-(5-methoxy-1 H-indole-2-carbonyl)-1 -(3-methoxybenzyl)piperazin-2-one (15 mg,0 .030 mmol) was added acetonitrile (1 mL), potassium carbonate (10 mg, 0.066 mmol), and 1 -bromo-2-methoxyethane (4 uL, 0.036 mmol). The mixture was brought to reflux overnight. After cooling, all solids were filtered off and the organics evaporated. The crude product waspurified via flash chromatography on silica gel with 3:7 hexanes:ethyl acetate as eluent to afford 4.6 mg of the title compound as a viscous oil. H NMR (300 MHz, Chloroform-d) δ 9.35 (s, 1 H), 7.41 -7.28 (m, 2H), 7.2- 6.95 (m, 4H), 6.86 (t, 4H), 6.76 (br:s, 2H), 5.44 (d, 1 H), 4.91 (d, 1 H), 4.77-4.30 (m, 2H), 4.02-3.75 (m, 8H), 3.69 (t, 2H), 3.53 (br:s, 1 H), 3.44 (s, 3H), 3.0-2.59 (m, 2H), 1.28 (t, 2H). LC/MS m/z: 558.36 (M+H)⁺

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

The title compound was prepared from (S)-6-(4-hydroxybenzyl)-4-(5-methoxy-1 /-/-indole-2-carbonyl)- 1-(3-methoxybenzyl)piperazin-2-one and 4-(2-chloroethyl)morpholine using the procedure for (6S)-4- [(5-methoxy-1 /-/-indol-2-yl)carbonyl]-6-{[4-(2-methoxyethoxy)phenyl] methyl}-1-[(3-methoxyphenyl) methyl] piperazin-2-one found above. LC/MS m/z: 613.41 (M+H)⁺

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.

1H), (s, m/z:

1H), (m, 1H),

piperazin-2-one

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.

phenyl]methyl}piperazin-2-one

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.

carbonyl) piperazin-2-one

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.

B-156 1 H- LC/MS m/z: 491 .31 (M+H)^÷ pyrrolo[3,2- b]pyridine-5- carboxylic acid

(6S)-6-benzyl-1 -{[3-(difluoro

methoxy)phenyl] methyl}-4-({1 H- pyrrolo[3,2-b]pyridin-5-yl}

carbonyl) piperazin-2-one

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.

one

Example B-162: 3-{[(2S)-2-benzyl-4-[(5-methoxy-1 /-/-indol-2-yl)carbonyl]-6-oxopiperazin-1 -yl]methyl} benzoic acid

To methyl (S)-3-((2-benzyl-4-(5-methoxy-1 /-/-indole-2-carbonyl)-6-oxopiperazin-1 -yl)methyl)benzoate (157 mg, 0.31 mmol) was added 1 mL methanol and 0.5 mL 2M lithium hydroxide solution. The mixture was stirred until LC/MS indicates saponification is complete. After completion, the mixture was evaporated to dryness under reduced pressure and resuspended in 5 mL of water. Concentrated aqueous HCI was then added dropwise until a precipitate formed which was filtered off, washed with 1 M aqueous HCI, and dried at 80°C under reduced pressure on a rotary evaporator to provide 138 mg of the title compound as an off white solid. LC/MS m/z: 498.28 (M+H)⁺, 995.55 (2M+H)⁺

General Procedure C For formation of Examples B-163 to B-167

To (S)-3-((2-benzyl-4-(5-methoxy-1 H-indole-2-carbonyl)-6-oxopiperazin-1 -yl)methyl)benzoic acid (20 mg, 0.04 mmol) was added 1 mL dichloroethane. Carbonyldiimidazole (8 mg, 0.048mmol) was then added in one portion and the mixture was stirred for 45 minutes, or until the mixture appears homogenous. Next, the appropriate amine (0.12 mmol, 3 equivalents) was added via micropipettor, and the mixture was stirred for one hour. After completion, the mixture was diluted with DCM, washed 3X with water, dried with brine and Na₂S0₄, and the organics were evaporated under reduced pressure. The crude residue was tpurified by flash chromatography on silica gel with 100% ethyl acetate as eluent to provide the product as a viscous oil.

cyclopropyl benzamide

Examples B-168 to B-197

Step 1 : fe/f-butyl 2-{[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl]amino}acetate

>r I °m o ^πr M Ni-IHBOC

To a solution of fe/f-butyl 2-{/V-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl](2-nitrobenzene) sulfonamido} acetate (2.04 g, 3.7 mmol) in DMF (25 mL), under N₂ was added K₂C0₃ (1 .79 g, 13 mmol), followed by thiophenol (1 .23 g, 1 1 .1 mmol). The reaction mixture was stirred at rt overnight, and then concentrated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHC0₃ solution. The organic phase was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography using a 5:1 to 1 :2 hexanes / ethyl acetate gradient, then pure EtOAc as eluent to provide the title compound as a viscous oil (1 .1 1 g, 82% yield). H NMR (300 MHz, Chloroform-d) δ 1 .40 (s, 9H), 1 .44 (s, 9H), 2.63 (d, 2H), 2.75 (dd, 1 H), 2.82 - 2.92 (m, 1 H), 3.23 (d, 1 H), 3.33 (d, 1 H), 3.81 - 3.91 (m, 1 H), 4.82 - 4.92 (m, 1 H), 7.16 - 7.23 (m, 3H), 7.24 - 7.31 (m, 2H). LC/MS m/z: 209.34 (M - fe/f-butyl - Boc+H)⁺, 253.21 (M - 2 fe/f-butyl+H)⁺, 309.24 (M - fe/f-butyl+H)⁺, 365.3 (M+H)⁺.

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

To a solution of fe/f-butyl 2-{[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl]amino}acetate (1 .1 1 g, 3 mmol) in DMF (30 ml_) were added 5-methoxy-1 /-/-indole-2-carboxylic acid (0.58 g, 3 mmol), 2,6- lutidine (1 g, 9 mmol), and HOAt (0.54 g, 3.96 mmol). The EDCI hydrochloride (0.88 g, 4.5 mmol) was then added and the reaction mixture was stirred at rt overnight. The reaction mixture was

concentrated, the residue was dissolved in EtOAc and washed with saturated aqueous NaHC0₃ solution. The organic phase was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography using a 7:3 to 1 .5:1 hexanes / ethyl acetate gradient to provide the title compound as a white solid (1 .28 g, 78% yield). H NMR (300 MHz, Chloroform-d) δ 1 .33 (s, 9H), 1 .44 (s, 9H), 2.78 - 2.88 (m, 1 H), 2.91 - 3.04 (m, 1 H), 3.83 (s, 3H), 3.98 - 4.14 (m, 3H), 4.36 - 4.48 (m, 1 H), 4.97 - 5.14 (m, 1 H), 6.56 - 6.64 (m, 1 H), 6.92 - 7.02 (m, 2H), 7.21 - 7.32 (m, 7H), 9.19 (br. s, 1 H). LC/MS m/z: 382.24 (M - fe/f-butyl - Boc+H)⁺, 438.36 (M - Boc+H)⁺, 482.3 (M - fe/f-butyl+H)⁺, 538.41 (M+H)⁺.

Step 3: 2-{/V-[(2S)-2-{[(fe/f-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methoxy-1 H-indol-2-yl) formamido} acetic acid

To a solution of fe/f-butyl 2-{/V-[(2S)-2-{[(fe t-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methoxy- 1 H-indol-2-yl)formamido}acetate (1 g, 1 .86 mmol) in 2:2:1 fBuOH/H₂0/THF (20 mL) was added LiOH (0.22 g, 9.3 mmol). The reaction mixture was stirred at rt for 1 h and concentrated. The residue was acidified with 1 N aq. HCI and extracted with ethyl acetate. The organic phase was dried over Na₂S0₄, and concentrated to provide the title compound as a white solid (0.81 g, 91 % yield), which was used in the next step without further purification. LC/MS m/z: 382.28 (M - Boc+H)⁺, 426.25 (M - tert- butyl+H)⁺, 482.25 (M+H)⁺, 963.53 (2M+H)⁺.

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

To a solution of 2-{/V-[(2S)-2-{[(fe/ -butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methoxy-1 H-indol-2- yl)formamido} acetic acid (0.81 g, 1 .68 mmol) in DMF (20 mL) were added HOAt (0.3 g, 2.2 mmol) and 2,6-lutidine (0.54 g, 5 mmol). The EDCI hydrochloride (0.48 g, 2.5 mmol) was then added and the reaction mixture was stirred at rt for 2 h, and then concentrated. The residue was dissolved in ethyl acetate and washed with saturated aq. NaHC0₃ solution. The organic phase was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography using a 3:1 to 1 :1 hexanes / ethyl acetate gradient, then pure EtOAc to provide the title compound as a light yellow solid (0.61 g, 78% yield). H NMR (300 MHz, Chloroform-d) δ 1 .23 (s, 9H), 2.78 (dd, 1 H), 2.99 (dd, 1 H), 3.86 (s, 3H), 4.05 - 4.23 (m, 3H), 4.63 (d, 1 H), 4.78 (d, 1 H), 7.07 - 7.1 1 (m, 2H), 7.20 - 7.24 (m, 3H), 7.28 - 7.35 (m, 3H), 8.29 (d, 1 H). LC/MS m/z: 364.24 (M - Boc+H)⁺, 408.17 (M - fe/ -butyl+H)⁺, 464.21 (M+H)⁺, 927.43 (2M+H)⁺.

Step 5: 2-[(2S)-2-amino-3-phenylpropyl]-1 H,2H,3H,4H-pyrazino[1 ,2-a]indole-1 ,4-dione

To a solution of fe/ -butyl A/-[(2S)-1 -{1 ,4-dioxo-1 H,2H,3H,4H-pyrazino[1 ,2-a]indol-2-yl}-3- phenylpropan-2-yl]carbamate (0.34 g, 0.73 mmol) in CH₂CI₂ (5 mL) was added dropwise

trifluoroacetic acid (0.6 mL). The mixture was stirred at rt for 3 h, then concentrated in vacuo. The residue was dissolved in methanol and filtered through an Agilent Stratopheres PL-HC0₃ ion exchange resin. The filtrate was concentrated to provide the title compound as a light yellow solid (0.26 g, 100% yield). H NMR (300 MHz, Methanol-d₄) δ 2.72 (dd, 1 H), 2.84 (dd, 1 H), 3.45 - 3.54 (m, 1 H), 3.55 - 3.59 (m, 2H), 3.78 - 3.84 (m, 2H), 3.85 (s, 3H), 7.10 (dd, 1 H), 7.15 - 7.23 (m, 3H), 7.25 - 7.30 (m, 3H), 7.33 (s, 1 H), 8.24 (d, 1 H). LC/MS m/z: 364.18 (M+H)⁺.

Step 6: General Procedure D for formation of intermediates 1-1 to 1-31

To a suspension of 2-[(2S)-2-amino-3-phenylpropyl]-1 /-/,2/-/,3/-/,4/-/-pyrazino[1 ,2-a]indole-1 ,4-dione (27 mg, 0.074 mmol) in DCE (0.8 ml_) was added the appropriate aldehyde (0.089 mmol), followed by AcOH (0.089 mmol). The reaction mixture was stirred at rt for 0.5 h. Then NaBH₃CN (7 mg, 0.1 1 mmol) was added, followed by MeOH (0.08 ml_). The reaction mixture was stirred overnight, then diluted with EtOAc, washed with saturated aqueous NaHC0₃ solution and brine. The organic phase was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography using hexanes / ethyl acetate or CH₂CI₂ / MeOH as eluent.

Preparation of Aldehydes

3-[3-(Diethoxymethyl)phenyl]oxetan-3-ol

To a solution of 1 -bromo-3-(diethoxymethyl)benzene (0.25 g, 0.96 mmol) in dry THF (3 ml_) was added a solution of n-BuLi (2.5 M in hexxanes, 0.4 ml_, 0.96 mmol) at -78 °C. After stirring for 20 min at this temperature, a solution of oxetan-3-one (0.056 g, 0.77 mmol) in dry THF (0.75 ml_) was added dropwise. The reaction mixture was stirred at -78 °C for 10 min and allowed to warm to room temperature. Water was added and the reaction mixture was extracted with EtOAc. The organic phase was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography using a 3:1 to 1 :2 hexanes / ethyl acetate gradient to provide the title compound as a colorless oil (0.14 g, 58% yield). H NMR (500 MHz, Chloroform-d) δ 1 .23 (t, 6H), 3.70 (q, 4H), 4.90 (d, 2H), 4.94 (d, 2H), 7.60 (t, 1 H), 7.85 (dt, 1 H), 7.93 (dt, 1 H), 8.15 (t, 1 H), 10.05 (s, 1 H).

3-(3-hydroxyoxetan-3-yl)benzaldehyde

To a solution of 3-[3-(diethoxymethyl)phenyl]oxetan-3-ol (57 mg, 0.22 mmol) in CH₂CI₂ (0.5 ml_) was added dropwise trifluoroacetic acid (0.35 ml_). The mixture was stirred at rt for 0.5 h, then

concentrated in vacuo. The residue was dissolved in CH₂CI₂, washed with saturated aqueous NaHC0₃ solution. The organic phase was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography using a 7:3 to 1 :2 hexanes / ethyl acetate gradient, then pure EtOAc to provide the title compound as a colorless oil (20 mg, 40% yield). H NMR (500 MHz, Chloroform-d) δ 4.90 (d, 2H), 4.94 (d, 2H), 7.60 (t, 1 H), 7.86 (dt, 1 H), 7.93 (dt, 1 H), 8.15 (t, 1 H), 10.06 (s, 1 H).

3-(3-fluorooxetan-3-yl)benzaldehyde

To a solution of 3-[3-(diethoxymethyl)phenyl]oxetan-3-ol (0.21 g, 0.83 mmol) in dry CH₂CI₂ (12 mL) was added DAST (0.28 g, 1 .25 mmol) at -78 °C. The mixture was allowed to warm to 0 °C, and then 1 M aqueous NaOH solution was added at -5 °C. The reaction mixture was extracted with EtOAc. The organic phase was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography using a 4:1 to 7:3 hexanes / ethyl acetate gradient to provide the title compound as a colorless oil (36 mg, 24% yield).

1 -(Propan-2-yl)-1 /-/-indole-6-carbaldehyde

The title compound was obtained from 1 /-/-indole-6-carbaldehyde and isopropyl bromide using the procedure described in WO 2014/073904.

1 -Cyclopropyl-1 /-/-indole-6-carbaldehyde

The title compound was obtained from 1 /-/-indole-6-carbaldehyde and cyclopropylboronic acid according to the procedure described for 7-methyl-1 -(cyclopropyl)-1 H-indole-3-carboxaldehyde in WO 201 1 /146324. H NMR (500 MHz, Chloroform-d) δ 1 .03 - 1 .06 (m, 2H), 1 .13 - 1 .17 (m, 2H), 3.40 - 3.44 (m, 1 H), 6.49 (d, 1 H), 7.34 (d, 1 H), 7.63 (dd, 1 H), 7.68 (d, 1 H), 8.1 1 (s, 1 H), 10.08 (s, 1 H)

3-Cyclopropylbenzaldehyde

The title compound was obtained from 3-cyclopropylbromobenzene and DMF using the procedure described in US 2014/0329797.

3-(Oxetan-3-yloxy)benzaldehyde

To a solution of 3-hydroxybenzaldehyde (0.16 g, 1 .31 mmol) in DMF (4 mL) was added Cs₂C0₃ (0.64 g, 1 .97 mmol). The mixture is stirred 10 minutes, and 3-tosyloxyoxetane (0.45g, 1 .97 mmol) was added in one portion, followed by heating to 100°C overnight. The reaction mixture was then cooled, filtered through a pad of celite and the filter pad was rinsed with ethyl acetate. The organics were then diluted with ethyl acetate, washed 3X with water, dried with brine and Na₂S0₄, and evaporated. The crude residue was purified by flash chromatography on silica using 7:3 hexanes:ethyl acetate as eluent, providing 1 18 mg of the title compound as a pale green liquid.

3-(Oxetan-3-yl)benzaldehyde

The title compound was prepared as decribed by Duncton, M.A.J. ; Kelly, M.G. Preparation of Aryloxetanes and Arylazetidines by Use of an Alkyl-Aryl Suzuki Coupling Org. Lett. 2008, 10, 3259- 3262.

The following intermediates were prepared using General Procedure D and the appropriate aldehyde.

Aldehyde Structure/Name Analytical Data

1-1 3-ethoxy LC/MS m/z: 498.32

benzaldehyde (M+H)⁺ o

2- [(2S)-2-{[(3-ethoxyphenyl)methyl] amino}-

3- phenylpropyl]-8-methoxy-1 H,2H,3H,4H- pyrazino[1 ,2-a]indole-1 ,4-dione

Step 6: General Procedure E for formation of examples B-168 to B-196 and intermediate J-1 .

To a solution of the intermediate (0.029 mmol) in a mixture of MeOH (1 mL) and H₂0 (0.5 mL) was added LiOH (3.5 mg, 0.14 mmol). The reaction mixture was stirred at rt for 1 h, then concentrated. 1 N aqueous HCI was adeed to the residue and the resulting mixture was extracted with EtOAc. The organic phase was dried over Na₂S0₄ and concentrated. The crude product (0.02 mmol) was dissolved in DMF (0.5 mL) and 2,6-lutidine (6.5 mg, 0.06 mmol) was added, followed by the EDCI hydrochloride (5 mg, 0.026 mmol). The reaction mixture was stirred at rt for 2 h, and then concentrated. The residue was dissolved in ethyl acetate and washed with saturated aq. NaHC0₃ solution. The organic phase was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography using hexanes / ethyl acetate, pure EtOAc or CH₂CI₂ / MeOH as eluent.

carbamate

Example B-198: (6S)-1 -{[3-(Aminomethyl)phenyl]methyl}-6-benzyl-4-[(5-methoxy-1 H-indol-2-yl) carbonyl]piperazin-2-one

Crude tert-Jbt/fy/ (S)-(3-((2-benzyl-4-(5-methoxy-1 H-indole-2-carbonyl)-6-oxopiperazin-1 -yl)methyl) benzyl)carbamate (10 mg) was added to a flask containing 0.5 mL DCM and 0.5 mL TFA. The mixture was stirred until LC/MS indicates completion, at which time all volatiles were evaporated. The residue was resuspended in 10 mL DCM and washed with saturated NaHC0₃, then brine. The organic portion was dried over Na₂S0₄ and evaporated to give the crude product. Purification with flash

chromatography on silica gel using a mixture of 5% methanol and 0.1 % NH₄OH in DCM as eluent gave 5 mg of product as a viscous oil. LC/MS m/z: 483.34 (M+H)⁺, 524.34 (M+H+CH₃CN)⁺

Examples B-199 to B-207

Step 1 : fe/ -Butyl 2-{/V-[(2S)-2-{[(fe/ -butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methyl-1 H-indol-2- yl) formamido}acetate

The title compound was prepared in the same manner for fe/f-butyl 2-{N-[(2S)-2-{[(fert- butoxy)carbonyl] amino}-3-phenylpropyl]-1 -(5-methoxy-1 /-/-indol-2-yl)formamido}acetate in step 2 for examples B-168 to B-197 using 4-methyl-1 /-/-indole-2-carboxylic acid instead of 4-methoxy-1 /-/-indole- 2-carboxylic acid. LC/MS m/z: 522.38 (M+H)⁺, 422.32 (M+H-BOC)⁺

Step 2: 2-{/V-[(2S)-2-{[(fe/ -butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methyl-1 H-indol-2- yl)formamido} acetic acid

The title compound was prepared as decribed in Step 3 for examples B-168 to B-197 from fe/f-butyl 2- {/V-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methyl-1 H-indol-2-yl)formamido} acetate. LC/MS m/z: 466.35 (M+H)⁺, 366.32 (M+H-BOC)⁺

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

The title compound was prepared as decribed in Step 4 for examples B-168 to B-197 from 2-{/V-[(2S)- 2-{[(fe/f-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methyl-1 /-/-indol-2-yl)formamido}acetic acid. LC/MS m/z: 448.24 (M+H)⁺, 348.20 (M+H-BOC)⁺

Step 4: 2-[(2S)-2-amino-3-phenylpropyl]-8-methyl-1 H,2H,3H,4H-pyrazino[1 ,2-a]indole-1 ,4-dione

The title compound was prepared as decribed in Step 6 for examples B-168 to B-197 from 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. LC/MS m/z: 348.27 (M+H)⁺, 695.39 (2M+H)⁺

Preparation of Intermediates I-32 to I-40. The intermediates were prepared from 2-[(2S)-2-amino-3- phenylpropyl]-8-methyl-1 /-/,2/-/,3/-/,4/-/-pyrazino[1 ,2-a]indole-1 ,4-dione and the appropriate aldehyde using General Procedure D.

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.

yl)carbonyl]piperazin-2-one

Examples B-208 to B-226

Step 1 : fe/f-butyl 2-{N-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-cyclopropyl-1 /-/- indol-2-yl)formamido}acetate

The title compound was prepared in the same manner as for the preparation fe/f-butyl 2-{N-[(2S)-2- {[(fe t-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methoxy-1 H-indol-2-yl)formamido}acetate in step 2 for examples B-168 to B-197 using 4-cyclopropyl-1 /-/-indole-2-carboxylic acid instead of 4-methoxy- 1 H-indole-2-carboxylic acid. LC/MS m/z: 548.40 (M+H)⁺, 448.32 (M+H-BOC)⁺

Step 2: 2-{N-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-methyl-1 H-indol-2- yl)formamido} acetic acid

The title compound was prepared as decribed in Step 3 for examples B-168 to B-197 from fe/f-butyl 2- {N-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-cyclopropyl-1 /-/-indol-2- yl)formamido}acetate. LC/MS m/z: 492.29 (M+H)⁺, 392.27 (M+H-BOC)⁺ Step 3: fe/f-butyl A/-[(2S)-1 -{8-cyclopropyl-1 ,4-dioxo-1 H,2H,3H,4H-pyrazino[1 ,2-a]indol-2-yl}-3-phenyl propan-2-yl]carbamate.

The title compound was prepared as decribed in Step 4 for examples B-168 to B-197 from 2-{N-[(2S)- 2-{[(tert-butoxy)carbonyl]amino}-3-phenylpropyl]-1 -(5-cyclopropyl-1 /-/-indol-2-yl)formamido}acetic acid. LC/MS m/z: 474.28 (M+H)⁺, 374.26 (M+H-BOC)⁺

The title compound was prepared as decribed in Step 6 for examples B-168 to B-197 from fe/f-butyl A/-[(2S)-1 -{8-cyclopropyl-1 ,4-dioxo-1 H,2H,3H,4H-pyrazino[1 ,2-a]indol-2-yl}-3-phenylpropan-2- yl]carbamate LC/MS m/z: 374.18 (M+H)⁺, 415.35 (M+H+CH3CN)⁺

Preparation of intermediates 1-41 to I-49. The intermediates were prepared from 2-[(2S)-2-amino-3- phenylpropyl]-8-cyclopropyl-1 H,2H,3/-/,4/-/-pyrazino[1 ,2-a]indole-1 ,4-dione and the appropriate aldehyde using General Procedure D.

ID Aldehyde Structure/Name Analytical Data

1-41 3- (2- hydroxy LC/MS m/z: 524.28 ethoxy) (M+H)⁺

benzaldehyde ?,

0

8-cyclopropyl-2-[(2S)-2-({[3-(2-hydroxyl

ethoxy)phenyl]methyl}amino)-3-phenylpropyl]- 1 H,2H,3H,4H-pyrazino[1 ,2-a]indole-1 ,4-dione

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.

ylmethyl)piperazin-2-one

Examples B-215 to B-254 Step 1 : A/-benzoyl-0-(tert-butyl)-L-serine

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). Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave the title compound as a white solid. Used as such in the next step without further purification. Yield : 8.2 g (99%). H NMR (300 MHz, DMSO-d₆) δ ppm 12.76 (brs, 1 H), 8.42 (d, 1 H), 7.87 (d, 2H), 7.45-7.56 (m, 2H), 4.47-4.54 (m, 1 H), 3.72 (d, 2H), 1 .14 (s, 9H). %), LCMS m/z: 266.23 (M+H)⁺.

Step 2: (R)-2-(benzylamino)-3-(fe/ -butoxy)propan-1 -ol

To a suspension of LAH (2.46 g, 64.90 mmol) in THF (30 mL) cooled to 0°C was added /V-benzoyl- 0-(fe/ -butyl)-L-serine (8.6 g, 32.45 mmol) in THF (69 mL) drop wise. The reaction mixture was refluxed over night. It was cooled to 0°C, quenched by slow addition of saturated aqueous Na₂S0₄ (8 mL) stirred for 1 h, and filtered. Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave the title compound as pale yellow oil. Used as such in the next step without further purification. Yield : 6.1 g (79%). H NMR (300 MHz, DMSO-d₆) δ ppm 7.21 -7.33 (m, 5H), 4.42 (t, 1 H), 3.77 (s, 2H), 3.35-3.44 (m, 2H), 3.24-3.32 (m, 2H), 2.53-2.64 (m, 1 H), 1 .85 (brs, 1 H), 1 .13 (s, 9H). LCMS m/z: 238.27 (M+H)⁺.

Step 3: (R)-/V-benzyl-/V-(1 -(fe/ -butoxy)-3-hydroxypropan

nitrophenyl)sulfonamido)acetamide

To a solution of (R)-2-(benzylamino)-3-(fe/?-butoxy)propan-1 -ol (6.1 g, 25.73 mmol) in THF (140 ml_) was added water (35 mL) followed by MgO (5.18 g, 128.65 mmol). The resulting white suspension was stirred at room temperature for 30 min. Then Nosyl glycine chloride (8.46 g, 30.88 mmol) in THF (100 mL) was added drop wise at room temperature over a period of 30 min. Resulting reaction mixture was stirred at room temperature for 4 h, and filtered. Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave the crude residue which was purified on Si0₂ column chromatography to give the title compound as pale yellow syrup. Yield : 9.2 g (74%). H NMR (300 MHz, DMSO-d₆) δ ppm 7.72-8.21 (m, 4H), 7.23-7-41 (m, 5H), 4.51 (d, 1 H), 4.17 (s, 2H), 3.74-3.82 (m, 1 H), 3.38-3.46 (m, 2H), 3.26-3.32 (m, 4H), 0.92 (s, 9H). LC/MS m/z: 480.26 (M+H)⁺.

Step 4: (R)-1 -benzyl-6-(fe/ -butoxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one

To a solution of (R)-N-benzyl-N-(1 -(fe/ -butoxy)-3-hydroxypropan-2-yl)-2-((2-nitrophenyl)sulfonamido) acetamide (9.2 g, 19.2 mmol) in THF (200 mL) was added Ph₃P (7.55 g, 28.8 mmol) followed by DIAD (7.765 g, 38.4 mmol) under N₂ atmosphere. Resulting reaction mixture was stirred at room temperature over night. Evaporation of solvent under vacuum gave crude residue which was purified on Si0₂ column chromatography to provide the title compound as pale yellow syrup. Yield : 8.1 g (91 %). H NMR (300 MHz, DMSO-d₆) δ ppm 8.03-8.1 1 (m, 2H), 7.85-7.96 (m, 2H), 7.20-7.35 (m, 5H), 4.98 (d, 1 H), 4.77 (t, 1 H), 4.29 (d, 1 H), 4.04 (d, 1 H), 3.80-3.88 (m, 1 H), 3.35-3.41 (m, 2H), 3.23-3.31 (m, 2H), 1 .05 (s, 9H). LC/MS m/z: 503.26 (M+H+CH₃CN)⁺.

Step 5: (R)-1 -benzyl-6-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one

To (R)-1 -benzyl-6-(tert-butoxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one (2 g, 4.34 mmol) was added 4N HCI/1 ,4-dioxane (5 mL, 20 mmol). The resulting reaction mixture was stirred at 70 °C for 4 h. Evaporation of solvent under vacuum gave crude residue which was treated with saturated aqueous NaHC0₃ solution (10 mL), then extracted with ethyl acetate (2 x 100 mL). Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave the crude residue which was purified on Si0₂ column chromatography to give the title compound as pale yellow syrup. Yield : 0.984 g (56%). H NMR (300 MHz, DMSO-d₆) δ ppm 8.02-8.12 (m, 2H), 7.85-8.00 (m, 2H), 7.16-7.35 (m, 5H), 5.05 (d, 1 H), 5.01 (t, 1 H), 4.21 (d, 1 H), 4.03 (d, 1 H), 3.88 (t, 1 H), 3.85 (d, 1 H), 3.52-3.61 (m, 1 H), 3.38-3.46 (m, 1 H), 3.25-3.38 (m, 2H). LC/MS m/z: 406.14 (M+H)⁺.

Step 6: (R)-(1 -benzyl-4-((2-nitrophenyl)sulfonyl)-6-oxopiperazin-2-yl)methyl trifluoromethanesulfonate

To a solution (R)-1 -benzyl-6-(hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one (0.2 g, 0.5 mmol) in DCM (5 mL) was added Et₃N (0.101 g, 1 mmol) and cooled to 0 °C. Then triflic anhydride (0.225 g, 0.8 mmol) was added under N₂ atmosphere. The resulting reaction mixture was stirred at 0 °C for i h, then at room temperature for additional 3 h, and washed with water (1 x 2 mL). Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave the title compound as pale yellow syrup. Used as such in the next step. Yield : 0.260 g (97%), H NMR (300 MHz, DMSO-d₆) δ ppm 8.02-8.12 (m, 2H), 7.85-8.00 (m, 2H), 7.16-7.35 (m, 5H), 5.05 (d, 1 H), 5.01 (t, 1 H), 4.21 (d, 1 H), 4.03 (d, 1 H), 3.88 (t, 1 H), 3.85 (d, 1 H), 3.52-3.61 (m, 1 H), 3.38-3.46 (m, 1 H), 3.25-3.38 (m, 2H). LC/MS m/z: 579.20 (M+CH₃CN+H)⁺.

Step 7: General Procedure F for formation of Intermediates I-58 to I-79.

To a solution of (R)-(1 -benzyl-4-((2-nitrophenyl)sulfonyl)-6-oxopiperazin-2-yl)methyl trifluoromethane sulfonate (0.053 g, 0.1 mmol) in THF (1 mL) was added the appropriate amine (0.1 1 mmol) followed by Et₃N (0.021 g, 0.2 mmol). Resulting reaction mixture was stirred at room temperature over night. Evaporation of solvent under vacuum gave crude residue which was extracted with ethyl acetate (2 mL), washed with water (1 x 1 mL). Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave the residue which was purified on Si0₂ column chromatography to give the pure desired product.

1-79 1-(2,2,2-tri LC/MS m/z: 556.25 fluoroethyl) (M+H)⁺

piperazine

(6S)-1-benzyl-4-[(2-nitrobenzene)sulfonyl]-6-{[1- (2,2,2-trifluoroethyl)piperidin-4-yl]methyl} piperazin-2- one

Step 8: General Procedure G for preparation Examples B-215 to B-254

To a solution of 1-benzyl-6-((dialkylamino)methyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one

(intermediates I-50 to 1-81) (0.1 mmol) in DMF (1 mL) was added K₂C0₃ (0.048 g, 0.35 mmol) followed by PhSH (0.033 g, 0.3 mmol). Resulting reaction mixture was stirred at room temperature over night. Evaporation of solvent under vacuum gave crude residue which was extracted with ethyl acetate (2 mL), washed with water (1 x 1 mL). Ethyl acetate layer was extracted with aqueousI M HCI (0.2 mL), then HCI layer was basified with 2M NaOH and extracted with DCM (2 mL). Dried

(Na₂S0₄), filtered and evaporation of solvent under vacuum gave almost pure product which was used without purification as such in the next step.

To a solution of (R)-1-benzyl-6-((dialkylamino)methyl)piperazin-2-one (0.1 mmol) and suitable carboxylic acid (0.1 mmol) in DMF (1 mL) was added 2,6-lutidine (0.032g, 0.3 mmol) followed by EDCI. HCI (0.025 g, 0.13 mmol). Resulting reaction mixture was stirred at room temperature for 4h. Evaporation of solvent under vacuum gave crude residue which was extracted with ethyl acetate (2 mL), washed with water (1 x 1 mL). Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave the residue which was purified on Si0₂ column chromatography to give the pure product.

s

1 H) H) 1 .52

(s, (br. -

methyl)piperazin-2-one

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.

The title compound was prepared as described for example B-237 starting from 0-(ferf-butyl)-D- serine. LC/MS m/z: 487.36 (M+H)⁺

Example B-256: (6R)-1 -benzyl-4-(5-methoxy-1 /-/-indole-2-carbonyl)-6-(piperidin-1 -ylmethyl)piperazin- 2-one.

The title compound was prepared as described for examples B-225 starting from 0-(tert-butyl)-D- serine. LC/MS m/z: 461 .28 (M+H)⁺

Examples B-257 to B-264

Step 1 : (2S)-3-(fe/ -butoxy)-2-{[3-(difluoromethoxy)phenyl]formamido}propanoic acid

To a solution of 3-(difluoromethoxy)benzoic acid (2.82 g, 15 mmol) in DCM (30 mL) was added Et₃N (3.34 g, 33 mmol) followed by EDC (3.43 g, 18 mmol) and HOBt (0.27 g, 2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. Then 0-(tert-butyl)-L- serine methyl ester hydrochloride (3.17 g, 15 mmol) was added and reaction mixture was stirred at room temperature for 12h. Evaporation of solvent under vacuum gave crude residue which was treated with saturated aqueous NaHC0₃ solution (10 mL), then extracted with ethyl acetate (2 x 100 mL). Dried (Na₂S0₄), filtered and evaporation of solvent under vacuum gave almost pure product as pale yellow syrup which was used as such in the next. Yield : 4.33 g (83%), LCMS m/z: 346.32 (M+H)⁺.

Step 2: (2R)-3-(fe/ -butoxy)-2-({[3-(difluoromethoxy)phenyl]methyl}amino)propan-1 -ol

The title compound was prepared as described for (R)-2-(benzylamino)-3-(fe/?-butoxy)propan-1 -ol using (2S)-3-(fe/ -butoxy)-2-{[3-(difluoromethoxy)phenyl]formamido}propanoic acid instead of N- benzoyl-0-(fe/ -butyl)-L-serine. LC/MS m/z: 304.25 (M+H)⁺

Step 3: A/-[(2f?)-1 -(fe/ -butoxy)-3-hydroxypropan-2-yl]-/V-{[3-(difluoromethoxy)phenyl]methyl}-2-[(2- nitrobenzene)sulfonamido]acetamide

The title compound was prepared as described for (R)-/V-benzyl-/V-(1 -(fe/ -butoxy)-3-hydroxypropan- 2-yl)-2-((2-nitrophenyl)sulfonamido)acetamide using (2R)-3-(fe/ -butoxy)-2-({[3- (difluoromethoxy)phenyl]methyl} amino)propan-1 -ol instead of (R)-2-(benzylamino)-3-(fe/f- butoxy)propan-1 -ol. LC/MS m/z: 546.24 (M+H)⁺

Step 4: (6R)-6-[(tert-butoxy)methyl]-1 -{[3-(difluoromethoxy)phenyl]methyl}-4-[(2-nitrobenzene)sulfonyl] piperazin-2-one

The title compound was prepared as described for (R)-1 -benzyl-6-(fe/ -butoxymethyl)-4-((2- nitrophenyl) sulfonyl)piperazin-2-one using A/-[(2R)-1 -(fe/ -butoxy)-3-hydroxypropan-2-yl]-/V-{[3- (difluoromethoxy) phenyl]methyl}-2-[(2-nitrobenzene)sulfonamido]acetamide instead of(R)-N-benzyl- N-(1 -(fe/ -butoxy)-3-hydroxypropan-2-yl)-2-((2-nitrophenyl)sulfonamido) acetamide. LC/MS m/z: 569.19 (M+H+CH₃CN)⁺

Step 5: (6R)-1 -{[3-(difluoromethoxy)phenyl]methyl}-6-(hydroxymethyl)-4-[(2-nitrobenzene)sulfonyl] piperazin-2-one

The title compound was prepared as described for (R)-1 -benzyl-6-(hydroxymethyl)-4-((2-nitrophenyl) sulfonyl)piperazin-2-one using (6R)-6-[(tert-butoxy)methyl]-1 -{[3-(difluoromethoxy)phenyl]methyl}-4- [(2-nitrobenzene)sulfonyl] piperazin-2-one instead of (R)-1 -benzyl-6-(tert-butoxymethyl)-4-((2- nitrophenyl) sulfonyl)piperazin-2-one. LC/MS m/z: 513.20 (M+H+CH₃CN)⁺

Step 6: [(2R)-1 -{[3-(difluoromethoxy)phenyl]methyl}-4-[(2-nitrobenzene)sulfonyl]-6-oxopiperazin-2-yl] methyl trifluoromethanesulfonate

The title compound was prepared as described for (R)-(1 -benzyl-4-((2-nitrophenyl)sulfonyl)-6- oxopiperazin-2-yl)methyl trifluoromethanesulfonate using (6R)-1 -{[3-(difluoromethoxy)phenyl]methyl}- 6-(hydroxymethyl)-4-[(2-nitrobenzene)sulfonyl] piperazin-2-one instead of (R)-1 -benzyl-6- (hydroxymethyl)-4-((2-nitrophenyl)sulfonyl)piperazin-2-one. LC/MS m/z: 645.15 (M+H+CH₃CN)⁺

Step 7: Intermediates I-82 to I-89.

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.

piperazin-2-one

Step 8: Preparation Examples B-257 to B-264.

The title compounds were prepared from Intermediates 1-82 to 1-89 using General Procedure G.

B-264 1-87 LC/MS m/z: 563.29 (M+H)^÷

(6S)-1 -(3-(difluoromethoxy)benzyl)- 6-((3,3-difluoropiperidin-1 -yl)methyl)- 4-(5-methoxy-1 /-/-indole-2-carbonyl)

piperazin-2-one

Protocol A : Arenavirus GP Pseudotype Assay.

Utilizing a VSV pseudotype system expressing the LASV glycoprotein and the Renilla luciferase reporter gene a library collection of small molecule compounds was screened to identify individual compounds that inhibit infectivity of the LASV pseudotyped VSV virus. 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% C0₂, 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 μg/mL G418 antibiotic. When cells reached approximately 80% confluency, they were transfected with a mixture of 15 μg of the pCAGGS plasmid encoding the desired glycoprotein and 45 μΙ of PEI (polyethylenimine) transfection reagent. The cells were incubated with the solution for 5 hours at 37°C at 5% C0₂. The cells were then washed and the mixture replaced with supplemented DMEM and incubated at 37°C at 5% C0₂ for approximately 16- 18 hours. Subsequently cells were infected with approximately 50 μΙ 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. 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% C0₂. The compound-virus mixture was aspirated off the cells 24 hours post-infection and washed 1X with PBS. Cells were then lysed using 20 μΙ of lysis buffer from a Luciferase kit diluted according to manufacturer's instructions. After incubating for approximately 20 minutes, 5 μΙ of cell lysate was transferred to an opaque white plate, and mixed with 12.5 μΙ of Coelenterazine diluted in buffer. This mixture was incubated at room temperature for 10 minutes on a plate shaker, and then the luminescence was read using a plate reader (Beckman Coulter DTX 880 multimode detector with an emission of 535 nm) 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. As shown in 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% C0₂. 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 %. For positive and negative control wells, 1 % DMSO was mixed with media or virus solution. For compound testing, cells were treated with 200ul of virus/compound mixtures in replicates of 4- 5 wells. For control wells, cells were treated with DMSO with and without virus, in replicates of 6-8 wells. The plates were incubated at 37C for 7 days, and then dead cells were washed off using 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. The absorbance was read at 540nm and 690 nm using Spectramax Plus 384 spectrophotometer. Data was calculated as 540nm- 690nm subtraction and compound activity was calculated by comparing compound wells to positive (100% activity / 0% CPE) and negative (0% activity / 100% CPE) control wells.

Protocol C: Cytotoxicity Screening

Active compounds in the pseudotype assays were also evaluated for cytotoxicity. Because the 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. Aborsorbances were read at 540 nm and 690 nm on a Spectramax Plus 384 spectrophotometer. Data were analyzed as (540 nm - 690 nm) and then compared to untreated controls to obtain % cell survival.

Table 1. Examples. Example compounds and their observed inhibitory activities against the indicated pseudotype viruses (LASV, MACV, JUNV, GTOV) or in cellular cytotoxicity assays; shown is % Inh. at 25 nM for LASV, MACV, JUNV, % Inh. for VSV at 1 uM; EC₅₀ for TCRV, CC₅₀ for cytotoxicity.

Example LASV MACV JUNV VSV Control Cytoxoxicity

A-1 82.1 48.9 21 0 CC₅₀ »5 uM

A-2 66.1 28.3 4.7 0 CC₅₀ = 17.6 uM

A-3 30.7 27.7 52.7 12.0 nd

A-4 55.6 19.3 0 15.0 CC₅₀ » 5 uM

A-5 0 14.4 0 2.4 nd

A-6 27.8 22 25.5 10.0 nd

A-7 9.3 33.1 30.1 5.5 nd

A-8 44.3 59.7 56.6 15.4 nd

A-9 44.2 59 72.7 0 nd

A-10 61 .8 0 0 0 CC₅₀ » 5 uM

A-1 1 12.5 10.6 14.1 6.8 nd

A-12 23.9 44.8 27.9 0 nd

A-13 36.5 44 34.5 6.8 nd

A-14 13.6 25.8 1 1 .9 16.6 nd

A-15 24.8 19.9 20.3 0.58 nd

A-16 2 0 18.3 3.9 nd

A-17 15.8 16.7 0 0 nd

A-18 0 27.9 0 0 nd

A-19 22.3 61 .7 3.2 0 nd

A-20 40.8 35.7 10.9 0 nd

A-21 40.6 43.7 21 .9 0 nd

A-22 4.1 19 0 0.7 nd

A-23 55.2 85.8 70.9 0 CC₅₀ » 5 uM

A-24 10.4 17.2 0 0 nd

A-25 0 0 4.8 0 nd

A-26 30.9 32.9 0 0 nd

A-27 35.9 21 .5 15 0 nd

A-28 25.7 16.6 0 0 nd

A-29 1 1 .6 20.9 0 0.1 nd

A-30 10.9 7.5 47.3 0 nd

A-31 19.9 9.2 1 1 .3 9.7 nd A-32 37.7 48.3 45.4 0 nd

A-33 38.5 48.7 18.9 17.3 nd

A-34 14.1 1 1 .9 0 34.7 nd

A-35 30.6 26.2 36.9 0 nd

A-36 30.7 48.4 0 8.4 nd

A-37 0 18 0 0 nd

A-38 0 7 1 .9 18.2 nd

A-39 26.9 40.7 36.2 0 nd

A-40 30.2 44.5 0 0 nd

A-41 0 5.3 0 19.4 nd

A-42 27 17.7 1 .9 0 nd

A-43 1 19 0 34.8 nd

A-44 10.9 24.5 0 21 .3 nd

A-45 6.2 0 0 0 nd

A-46 37.3 39.3 9.9 0 nd

A-47 18.1 28.1 9.7 0 nd

A-48 4.6 21 .1 0 17.2 nd

A-49 16.7 23.9 14.1 10.0 nd

Table 2. Examples. Example compounds and their observed inhibitory activities against the indicated pseudotype viruses (LASV, MACV, JUNV), VSV control, or in cellular cytotoxicity assays;

shown is % Inh. at 100 nM for LASV, MACV, JUNV; % Inh. for VSV at 1 uM; CC₅₀ for cytotoxicity.

Example LASV MACV JUNV VSV Control Cytoxoxicity

A-32 37.7 48.3 45.4 0 nd

A-33 38.5 48.7 18.9 17.3 nd

A-34 14.1 1 1 .9 0 34.7 nd

A-35 30.6 26.2 36.9 0 nd

A-36 30.7 48.4 0 8.4 nd

A-37 0 18 0 0 nd

A-38 0 7 1 .9 18.2 nd

A-39 26.9 40.7 36.2 0 nd

A-40 30.2 44.5 0 0 nd

A-41 0 5.3 0 19.4 nd

A-42 27 17.7 1 .9 0 nd

A-43 1 19 0 34.8 nd

A-44 10.9 24.5 0 21 .3 nd

A-45 6.2 0 0 0 nd

A-46 37.3 39.3 9.9 0 nd A-47 18.1 28.1 9.7 0 nd

A-59 81 .6 29.2 nd 23.5 CC₅₀ = 44 uM

A-60 34 23.7 nd 10.2 nd

A-61 63.9 69.3 nd 0 nd

A-62 61 .4 15.9 nd 0 CC₅₀ » 5 uM

A-63 58 45.6 nd 24.4 CC₅₀ » 5 uM

A-64 85.3 62.9 nd 18.8 CC₅₀ » 5 uM

A-65 71 44.1 nd 0.3 CC₅₀ » 5 uM

A-66 48.1 62.6 nd 0 nd

A-67 6.3 0 nd 1 1 .0 nd

A-68 55.2 5.8 nd 0 CC₅₀ » 5 uM

A-69 44.9 75.6 nd 0 nd

A-70 25.7 38.5 nd 4.3 nd

A-71 50.3 21 .1 nd 0 CC₅₀ » 5 uM

A-72 0 0 nd 0 nd

A-73 0 1 1 .2 nd 20.8 nd

A-74 32.5 9.6 nd 0 nd

A-75 22.1 6 nd 0 nd

A-76 0 27.7 nd 0 nd

A-77 0 20.7 nd 0 nd

A-78 28.4 26.1 nd 3.6 nd

A-79 58 0 nd 38.7 CC₅₀ » 5 uM

A-80 0 0 nd 0 nd

A-81 0 9.9 nd 0 nd

A-82 0.9 14.4 nd 0 nd

A-83 17 0 nd 20.5 nd

A-84 31 .1 0 nd 0 nd

A-85 39 19.5 nd 0 nd

A-86 0 2.7 nd 0 nd

A-87 14.5 0 nd 0 nd

A-88 23 14.1 nd 16.5 nd

A-89 12.8 67.1 nd 0 nd

A-90 27.7 32.1 nd 0 nd

A-91 26.6 15.6 nd 0.3 nd

A-92 45 17.6 nd 0 nd

A-93 54.7 17.2 nd 13.0 CC₅₀ » 5 uM

A-94 0 0.7 nd 0 nd

A-95 30 25.5 nd 0 nd

A-96 2.5 10.1 nd 0 nd A-97 0 0 nd 0 nd

A-98 0 5.9 nd 0 nd

A-99 0.5 18.9 nd 0 nd

A- 100 0 0 nd 0 nd

A-101 5.9 0 nd 20.6 nd

A- 102 8.7 0 nd 0 nd

A- 103 0 0 nd 0 nd

A- 104 13.4 19.2 nd 13.7 nd

A- 105 0 8.2 nd 12.0 nd

A- 106 2.8 7.8 nd 0 nd

A- 107 5.8 15.9 nd 0 nd

A- 108 27.1 13 nd 0 nd

A- 109 17.6 12.6 nd 0 nd

A-1 10 37.2 40.9 nd 0 nd

A-1 1 1 15.9 0 nd 0 nd

A-1 12 4.2 20.3 nd 3.0 nd

A-1 13 29.6 0 nd 0 nd

A-1 14 14.6 42.9 nd 0 nd

A-1 15 22.5 13.7 nd 0 nd

A-1 16 0 16.6 nd 0 nd

A-1 17 43.4 43.1 nd 0 nd

A-1 18 0 0.1 nd 15.4 nd

A-1 19 0 22 nd 0 nd

A- 120 2.7 18.6 nd 0 nd

A-121 29.4 0 nd 0 nd

A- 122 0 0 nd 1 .9 nd

A- 123 8.9 0 nd 0.6 nd

A- 124 29 1 .4 nd 0 nd

A- 125 1 0 nd 4.6 nd

A- 126 0 22.6 nd 17.7 nd

A- 127 0 31 .8 nd nd nd

A- 128 24.5 0 nd nd nd

A- 129 0.7 0 nd nd nd

A- 130 20.7 0 nd nd nd

A-131 0 0 nd nd nd

A- 132 53.3 0.6 nd 0 CC₅₀ » 5 uM

A- 133 9.1 0 nd 22.2 nd

A- 134 14.6 0.1 nd 4.0 nd

A- 135 3.2 0 nd 0 nd A- 136 12.5 0 nd 15.8 nd

A- 137 0 0 nd 0.5 nd

A- 138 0 54.8 nd nd nd

A- 139 3.7 38.7 nd nd nd

A- 140 0 0 nd 0 nd

A-141 0 38.7 nd nd nd

A- 142 0 20.6 nd nd nd

A- 143 0 0 nd nd nd

Table 3. Examples. 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 ; EC₅₀ for TCRV, CC₅₀ for cytotoxicity.

Example LASV MACV JUNV VSV Control TCRV Cytoxoxicity

A-50 25.4 33.8 0 0 nd CC₅₀ » 5 uM

A-51 25.1 6.3 19.1 0 nd CC₅₀ » 5 uM

A-52 32.2 27.4 26.2 0 nd CC₅₀ » 5 uM

A-53 7.7 45.9 0 15.0 nd CC₅₀ » 5 uM

A-54 33.5 46.1 16.1 23.5 nd CC₅₀ » 5 uM

A-55 48.9 0 0 0 nd CC₅₀ » 5 uM

A-56 36.6 19.1 2.2 5.3 nd CC₅₀ » 5 uM

A-57 32.3 25.3 7.4 0 nd CC₅₀ » 5 uM

A-58 19.0 5.7 0 0 nd nd

A- 144 36.1 48.5 0 0 nd nd

A- 145 36.5 26.4 22.1 0 nd nd

A- 146 67 20.7 0 0 nd CC₅₀ = 6.7 uM

A- 147 87.3 75.9 57.8 0 nd CC₅₀ » 5 uM

A- 148 54.5 24.8 0 0 nd CC₅₀ » 5 uM

A- 149 47.1 40.8 0 0 nd CC₅₀ > 5 uM

A- 150 69.6 83.5 57.1 0 nd CC₅₀ » 5 uM

A-151 86.4 73.8 49.7 1 .3 nd CC₅₀ » 5 uM

A- 152 90.4 35.4 3.5 0 nd CC₅₀ » 5 uM

A- 153 93.2 90.7 91 .7 4.0 nd CC₅₀ » 5 uM

A- 154 82.6 73.3 81 .8 0 nd CC₅₀ » 5 uM

A- 155 67.5 74.2 39.9 0 nd CC₅₀ » 5 uM

A- 156 66 53.7 43.6 0 nd CC₅₀ >10 uM

A- 157 59.6 49.8 43.2 0 nd CC₅₀ » 5 uM

A- 158 46.4 55.2 1 1 .5 0 nd nd Table 4. Examples. Example compounds and their observed inhibitory activities against the indicated pseudotype viruses (LASV, MACV, JUNV, GTOV, TCRV), TCRV live virus (TCRVIv), or in cellular cytotoxicity assays; shown is EC₅₀ for LASV, MACV, GTOV, TCRV, TCRVIv; CC₅₀ for cytotoxicity

LASV MACV JUNV GTOV TCRV TCRVIv CC50

Ex. EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) (μΜ)

B-1 6.5 4.7 1 .1 nd nd 120 2.7

B-2 1 .4 25 1 .7 nd nd nd nd

B-3 2.3 3.0 2.7 2.0 2.8 8.8 4.5

B-4 3.8 3.8 1 .02 nd nd nd >10

B-5 >25 20.7 8.69 nd nd nd 52.8

B-6 7.6 16.3 23.7 nd nd 15.7 >10

B-7 5.5 1 1 2.44 nd nd nd 8.5

B-8 >25 >25 >25 nd nd nd nd

B-9 >25 >25 >25 nd nd nd nd

B-10 >25 >25 >25 nd nd nd nd

B-1 1 >25 >25 >25 nd nd nd nd

B-12 2.83 2.75 <1 nd nd 35.1 0.45

B-13 2.03 12.5 3.21 4.55 nd nd >10

B-14 9.3 1 1 .5 1 .33 nd nd nd >10

B-15 25 >25 24.5 nd nd nd >10

B-16 >25 >25 >25 nd nd nd nd

B-17 >25 >25 >25 nd nd nd nd

B-18 >25 >25 >25 nd nd nd nd

B-19 >25 >25 >25 nd nd nd nd

B-20 >25 >25 >25 nd nd nd nd

B-21 >25 >25 >25 nd nd nd nd

B-22 >25 >25 >25 nd nd nd nd

B-23 >25 >25 >25 nd nd nd nd

B-24 16.4 14 6.69 nd nd nd >10

B-25 3.07 8.81 1 .26 nd nd 61 .2 >30

B-26 >25 >25 >25 nd nd nd nd

B-27 >25 >25 >25 nd nd nd nd

B-28 >25 >25 >25 nd nd nd nd

B-29 23.4 1 .04 2.88 nd nd nd >10

B-30 5.58 16.53 10.39 nd nd 235 >10

B-31 6.02 3.57 3.57 nd nd 12.1 3.3 B-32 >25 >25 >25 nd nd nd nd

B-33 3.8 7.7 4.6 nd nd nd >10

B-34 1 1 .7 18.0 5.0 nd >25 nd nd

B-35 0.82 0.9 1 .39 nd nd 3.94 >10

B-36 1 .64 3.38 1 .27 nd nd nd >10

B-37 6.75 4.18 6.25 nd nd nd >10

B-38 15.1 23.3 2.15 nd nd 148 >10

B-39 3.3 1 .42 6.29 nd nd 255 >30

B-40 6.23 3.84 4.78 nd nd 412 9.4

B-41 1 1 .9 13.0 1 1 .1 7.1 nd 301 9.3

B-42 5.53 20.7 5.66 5.9 nd 74 >10

B-43 >25 >25 >25 nd nd nd >30

B-44 4.2 >25 8.7 nd nd nd >30

B-45 6 4.01 4.69 nd nd 26.5 78.2

B-46 >25 >25 13.3 nd nd nd >30

B-47 >25 >25 25 nd nd nd >30

B-48 10.2 5.4 1 .5 nd nd nd 33.2

B-49 10.9 18.7 3.33 4.84 nd nd 31 .4

B-50 2.85 2.08 3.05 nd 1 .97 6.35 >10

B-51 14.9 >25 19.7 nd nd nd 94.6

B-52 >25 >25 >25 nd nd nd nd

B-53 >25 >25 >25 nd nd nd nd

B-54 >25 >25 >25 nd nd nd nd

B-55 >25 >25 >25 nd nd nd nd

B-56 >25 >25 >25 nd nd nd nd

B-57 20.6 >25 12.3 nd nd nd >30

B-58 20.6 1 .38 1 .65 nd nd nd >30

B-59 >25 1 .3 2.3 nd nd nd >30

B-60 >25 <25 <25 nd nd nd 1 1

B-61 >25 <25 <25 nd nd nd nd

B-62 >25 5.71 3.27 nd nd nd nd

B-63 >25 >25 >25 nd nd nd nd

B-64 >25 >25 >25 nd nd nd nd

B-65 >25 >25 >25 nd nd nd >30

B-66 >25 >25 >25 nd nd nd >30

B-67 >25 5.4 1 .8 nd nd nd >30

B-68 >25 <25 10.3 nd nd nd 102.4

B-69 >25 >25 ND >25 nd nd nd

B-70 6.26 1 .74 7.66 2.42 >25 >300 >30 B-71 >25 >25 >25 nd nd nd >30

B-72 23.1 >25 23.2 nd >25 nd nd

B-73 16.2 23.1 17.3 nd >25 nd nd

B-74 >25 >25 >25 nd nd nd nd

B-75 5.91 5.78 8.34 nd nd nd >10

B-76 3.39 3.49 3.55 nd 2.58 nd >100

B-77 5.71 18.7 9.54 nd ND nd 27.9

B-78 9.5 1 1 .9 5.79 nd 1 1 .15 62.9 >10

B-79 25.4 >25 >25 nd nd nd >10

B-80 8.48 8.3 3.02 nd nd 16.3 >30

B-81 17 8.66 13.9 nd nd nd >30

B-82 >25 >25 >25 nd nd nd 16

B-83 9.38 >25 25 25 nd nd >30

B-84 >25 >25 >25 nd nd nd >30

B-85 >25 >25 >25 nd nd nd >30

B-86 >25 >25 >25 nd nd nd nd

B-87 >25 >25 4.23 nd nd nd nd

B-88 >25 17.28 10.46 nd nd nd 33.1

B-89 >25 20.1 nd nd nd nd 17.2

B-90 >25 15.8 nd nd nd nd nd

B-91 >25 >25 nd nd nd nd nd

B-92 >25 >25 >25 nd nd nd nd

B-93 4.76 24.4 18.1 >25 nd nd 15.8

B-94 1 .95 21 .5 2.68 >25 34.4 nd 1 1 .2

B-95 >25 >25 >25 5.5 nd nd >100

B-96 16.2 >25 >25 nd nd nd 46.1

B-97 14.7 19.4 >25 nd nd nd 23.8

B-98 9.49 >25 >25 nd >25 nd >100

B-99 14.3 >25 >25 nd nd nd 24.5

B-100 29.4 >25 >25 nd nd nd >100

B-101 26.7 >25 >25 nd nd nd 96.3

B-102 >25 >25 nd nd nd nd nd

B-103 >25 >25 nd nd nd nd nd

B-104 >25 19.4 nd nd nd nd nd

B-105 >25 >25 >25 nd >25 nd nd

B-106 >25 >25 >25 nd >25 nd nd

B-107 >25 >25 >25 nd >25 nd nd

B-108 >25 >25 >25 nd >25 nd nd

B-109 4.41 8.57 3.03 nd 21 .3 nd nd B-110 22.5 17.3 >25 nd >25 nd nd

B-111 2.17 1.87 5.83 nd nd nd >30

B-112 4.13 3 2.74 4.95 nd nd >30

B-113 17.5 4.49 8.95 nd nd nd >30

B-114 6.28 2.98 6.12 nd nd nd >30

B-115 3.3 2.13 5.81 2.4 nd nd >30

B-116 3.0 4.31 6.48 3.0 nd nd >30

B-117 8.7 15.4 nd 19.4 nd nd 23.5

B-118 3.35 27.5 11.0 >25 nd nd 30.5

B-119 19.2 >25 2.84 nd nd nd >10

B-120 10.2 4.8 nd nd nd nd >10

B-121 20.6 13.1 nd nd nd nd >10

B-122 >25 20.2 nd nd nd nd nd

B-123 >25 >25 nd >25 nd nd nd

B-124 9.11 18.9 nd 23.2 nd nd >30

B-125 4.1 1.81 5.07 4.22 nd nd nd

B-126 >25 >25 nd >25 nd nd nd

B-127 >25 >25 nd >25 nd nd nd

B-128 >25 >25 nd >25 nd nd nd

B-129 3.65 5.61 2.4 13.7 nd nd 20

B-130 >25 >25 nd >25 nd nd nd

B-131 >25 >25 nd >25 nd nd nd

B-132 >25 >25 nd >25 nd nd nd

B-133 >25 >25 nd >25 nd nd nd

B-134 1.24 1.23 1.83 1.37 nd 1.75 >30

B-135 1.52 3.17 nd 1.73 nd nd 26.7

B-136 >25 >25 nd nd nd nd nd

B-137 4.27 7.73 9.85 7.98 nd nd 28.7

B-138 6.02 21.6 4.66 9.37 nd nd 25.8

B-139 18 26.6 20.7 nd nd nd 9.4

B-140 17.2 9.44 2.51 5.99 5.04 nd 4.2

B-141 2.95 4.35 1.49 1.71 2.35 nd 7.6

B-142 2.77 3.77 2.6 3.54 nd nd 34.7

B-143 >25 >25 >25 nd >25 nd nd

B-144 2.53 23.53 3.4 nd 19.26 39.2 >100

B-145 1.3 3.67 6.35 nd nd 23.2 >100

B-146 >25 >25 >25 nd nd nd nd

B-147 4.68 3.98 8.92 nd nd 7.4 46.7

B-148 2.77 20.6 13.4 13.3 nd nd nd B-149 2.31 3.58 4.78 2.71 nd 13.0 >100

B-150 1 .87 10.38 3.18 12.8 >25 61 .7 22.4

B-151 2.12 6.81 5.05 nd 7.49 6.27 10.4

B-152 >25 >25 25.2 nd nd nd 3.1

B-153 5.6 19.71 12.7 nd nd nd 32

B-154 13.9 25.73 22.5 nd nd nd >100

B-155 2.29 2.98 0.52 2.43 nd nd 29.7

B-156 >25 >25 >25 nd nd nd nd

B-157 2.27 4.28 4.29 nd nd 62.6 >30

B-158 1 .83 3.82 2.77 nd nd nd >30

B-159 7.8 >25 5.6 nd nd nd 21 .7

B-160 1 .61 2.03 4.75 nd nd 36.4 >100

B-161 1 .34 1 .6 3.5 nd nd 7.57 1 1 .7

B-162 >25 >25 >25 nd nd nd >30

B-163 >25 >25 >25 nd nd nd nd

B-164 >25 >25 >25 nd nd nd nd

B-165 >25 >25 >25 nd nd nd nd

B-166 >25 >25 >25 nd nd nd nd

B-167 >25 >25 >25 nd nd nd nd

B-168 1 .33 1 .54 1 .91 nd nd 3.4 41

B-169 21 .4 >25 9.87 nd nd nd 27

B-170 2.37 2.88 3.78 nd nd 4.6 49

B-171 18.6 21 .3 1 .19 nd nd 100 15.2

B-172 4.26 2.18 1 .81 3.44 nd 34.6 >30

B-173 5.44 2.84 1 .55 3.98 2.22 17.5 >30

B-174 0.73 2.1 4.35 2.36 2 1 .77 5

B-175 >25 4.1 1 6.5 4.2 5.96 nd >30

B-176 0.94 1 .85 0.75 3.57 nd 8.5 >30

B-177 12.3 >25 1 1 .3 19.0 5.64 nd >30

B-178 2.42 2.5 5.38 nd nd 7.43 10.2

B-179 >25 1 .5 nd nd nd nd >30

B-180 >25 >25 nd 18.3 nd nd >30

B-181 >25 9.5 nd 5.4 nd nd >30

B-182 16.8 3.2 nd 3.6 nd nd 26.1

B-183 0.68 0.63 >25 0.45 nd nd >30

B-184 >25 >25 nd >25 nd nd nd

B-185 2.81 3.17 6.91 8.6 nd 5.82 79.5

B-186 5.65 0.99 2.69 ND nd nd >30

B-187 12.81 2.32 nd 3.75 nd nd >30 B-188 >25 12.7 nd nd nd nd nd

B-189 >25 2.4 nd nd nd nd nd

B-190 20.27 4.42 9.24 3.09 6.59 nd 7.2

B-191 15.4 >25 13.7 >25 nd nd >30

B-192 3.7 2.88 nd 4.03 nd nd >30

B-193 >25 <25.00 nd <25.00 nd nd nd

B-194 <25 >25 nd >25 nd nd nd

B-195 2.7 2.03 2.6 nd nd nd >100

B-196 4.09 1 .01 1 .85 1 .78 4.3 nd 39

B-197 8.34 6.26 1 1 .16 3.6 5.37 27.1 >100

B-198 25 >25 nd nd nd nd nd

B-199 15.6 4.38 3.47 nd 5.93 nd 86.0

B-200 6.41 3.97 3.52 nd 13.52 nd 8.17

B-201 7.06 4.54 3.76 nd 7.84 nd 23.9

B-202 >25 28.68 10.02 nd >25 nd nd

B-203 4.49 14.64 5.49 nd 21 .35 nd 3.96

B-204 16.09 5.07 5.17 nd 21 .93 nd 9.47

B-205 >25 >25 6.06 nd >25 nd 129

B-206 >25 >25 >25 nd >25 nd 8.43

B-207 >25 >25 >25 nd >25 nd 13.6

B-208 7.73 1 .09 9.56 nd nd 6.33 4.13

B-209 0.94 1 .38 1 .61 nd 2.85 9.17 9.77

B-210 2.16 1 .62 1 .06 nd 3.41 23.4 >100

B-21 1 22.9 6.52 4.1 1 nd 8.52 nd nd

B-212 3.58 3.06 1 .53 nd 3.77 nd nd

B-213 3.15 1 .14 0.77 nd 1 .96 nd nd

B-214 2.42 1 .30 1 .73 nd 4.29 nd nd

B-215 1 1 .2 >25 3.15 nd nd 125 50.6

B-216 >25 >25 >25 nd nd nd nd

B-217 >25 >25 >25 nd nd nd nd

B-218 8.65 13.67 2.41 nd nd nd >10

B-219 >25 14 14.8 nd nd nd 26.4

B-220 >25 14.6 7.66 nd nd nd nd

B-221 16.7 >25 8.5 nd nd nd 38.1

B-222 >25 >25 9.5 nd nd nd >30

B-223 1 1 .3 14.3 23.6 >25 nd nd 95.3

B-224 >25 >25 nd nd nd nd nd

B-225 >25 >25 nd nd nd nd nd

B-226 4.75 4.75 5.34 28 nd 18.1 76.9 B-227 >25 >25 nd >25 nd nd nd

B-228 3.37 2.76 2.54 5.15 8.6 7.18 >30

B-229 4.21 10.48 5.75 6.22 nd 22.2 >30

B-230 3.47 8.92 3.92 28.9 18.5 nd 17.3

B-231 >25 >25 nd nd nd nd nd

B-232 20.4 15.1 nd nd nd nd >30

B-233 >25 >25 nd nd nd nd nd

B-234 >25 >25 9.5 >25 nd nd nd

B-235 21 .1 >25 16.2 17.9 nd nd nd

B-236 2.4 4.5 1 .4 4 nd nd 14

B-237 4.13 5.32 2.19 nd nd nd 3.03

B-238 2.45 4.71 1 .27 nd 4.61 7.56 7.56

B-239 7.5 15.9 3.73 nd 4.4 32.9 3.4

B-240 5.4 5.32 5.58 nd nd 1 1 .2 8.3

B-241 1 1 .73 4.5 3.77 nd nd 22.6 88.8

B-242 13.8 24.2 17.89 nd nd nd 52.7

B-243 12.6 1 1 .2 12.62 nd nd nd 4.9

B-244 1 1 .9 17.2 26.05 nd nd nd 7.8

B-245 9.66 13.9 7.63 nd nd nd 10.6

B-246 7.1 23.9 5.67 nd nd nd 4.9

B-247 5.18 20.6 5.1 nd nd nd 13.8

B-248 6.67 4.66 5.99 nd nd nd 26.2

B-249 13.4 5.55 4.34 nd nd nd 3.6

B-250 10.3 23.0 22.7 nd nd nd >100

B-251 0.96 3.67 1 .23 5.25 1 1 .3 38.5 51 .8

B-252 2.25 5.5 6.21 1 1 .6 >25 139 >100

B-253 1 .01 2.15 1 .03 2.94 nd nd >100

B-254 3.45 6.2 5.43 21 .1 12.5 nd 94.4

B-255 29.3 23.3 21 .5 nd nd nd nd

B-256 24.0 >25 25.1 nd nd nd nd

B-257 4.4 5.67 7.3 nd nd nd 12.1

B-258 10.8 8.57 20.23 nd nd nd 26.9

B-259 1 1 .45 13.3 22.8 nd nd nd >100

B-260 20.7 23.2 >25 nd nd nd nd

B-261 19.7 21 .4 >25 nd nd nd nd

B-262 12.7 17.2 >25 nd nd nd >100

B-263 21 .4 10.3 14.32 nd nd nd nd

B-264 20.2 25.5 32.67 nd nd nd >100

Claims

WHAT IS CLAIMED IS:

1 . A compound represented by Formula I

or a pharmaceutically acceptable salt thereof, wherein

R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Cs to Cio) cycloalkyi, (Cs to Cio) cycloalkenyl, and (C2 to C9) cycloheteroalkyi, (Ce 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 C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁵ group;

R² 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 C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (Ce to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁶ group;

R³ 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)R⁷,-C(0)NR^8aR^8b, -(CH₂)nC(0)OR⁷, and - (CH₂)nC(0)N(R^8aR^8b), wherein

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

R⁶ 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 Co) cycloheteroalkyi, (Ce to C10) aryl, (C2 to Co) heteroaryl, -C(0)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C^ to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

each of the R⁷ is independently selected from hydrogen, (C^o C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C₃ to C ₀) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

each of the said (C to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

each of the R ⁰ is independently selected from hydrogen, (C^ to C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C₃ to C ₀) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

each of the said (C to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ 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 C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉)

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

or 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

R ² is independently selected from hydrogen, halogen, cyano, OH, CF3, (Ci to Ce) alkyl, (Ci to C6) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, and (C2 to C9) heteroaryl,

with the proviso that

and with the proviso that

2 is not selected from the group consisting of

and with the proviso that

4 is not selected from the group consisting of optionally substituted

■ wherein

A is selected from a bond, alkylidene, heterocyclylene, arylene, heteroarylene, -0-,

-SO-, and -S0₂-,

and with the proviso when

R is benzyl or 2-phenylethyl, and

2 is selected from the group consisting of

4 is not selected from the group consisting of

2. A c

n or a pharmaceutically acceptable salt thereof, wherein:

R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Csto C10) cycloalkyi, (Csto Cio) cycloalkenyl, and (C2 to C9) cycloheteroalkyi, (Ceto C10) aryl, (C2 to C9) heteroaryl, wherein each of the said (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ceto C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁵ group;

R² is (Ci to C6) alkyl substituted with a group selected from (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Csto C10) cycloalkenyl, (Ceto C10) aryl, and (C2 to C9) heteroaryl, wherei

each of the said (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (Ceto C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁶ group;

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁵ group;

R⁴ is selected from (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkenyl, (Ceto C10) aryl, and (C2 to C9) heteroaryl, wherein

each of the said (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkenyl, (Ceto C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁵ group;

R⁵ 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, (Csto C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ceto C10) aryl, (C2 to C9) heteroaryl, -C(0)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, aryloxy, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

R⁶ 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) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ceto C10) aryl, (C2 to C9) heteroaryl, -C(0)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Csto C10) cycloalkyi, (Csto C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group; each of the R⁷ is independently selected from hydrogen, (C^ to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to C6) alkynyl, (C₃ to C ₀) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

each of the said (C^ to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to Cio) cydoalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

each of the R^8a, R^8b, and R^8c are independently selected from hydrogen, (C^ to C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cydoalkenyl, (C₂ to C₉)

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

R⁹ 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) cydoalkenyl, (C2 to Co) cycloheteroalkyi, (Ce to C10) aryl, (C2 to Co) heteroaryl, -C(0)R¹⁰, -C(0)NR ^aR ^b, -NR ^aR ^b -S(0)mR¹⁰, -S(0)mNR ^aR ^b, -NR ^aS(O)mR ⁰, -(CH2)nC(O)OR¹⁰, -(CH₂)nC(0)N(R ^aR ^b), -OC(0)R¹⁰, -NR ^aC(0)R¹⁰, and -NR ^acC(0)N(R ^aR ^b), wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Csto C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R ² group;

each of the R ⁰ is independently selected from hydrogen, (C^ to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (C₃ to C ₀) cycloalkyi, (Csto C10) cydoalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

each of the said (C^ to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ 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 C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

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 C6) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, and (C2 to C9) heteroaryl,

with the proviso that

and with the proviso that

R² is not selected from the group consisting of

and with the proviso that

4 is not selected from the group consisting of optionally substituted

^■ wherein

A is selected from a bond, alkylidene, heterocyclylene, arylene, heteroarylene, -0-, -S-, -NR- -CO-, -SO-, and -S0₂-,

and with the proviso that the following compound is excluded: (6S)-4-[(1 -benzofuran-2- yl)carbonyl]-6-benzyl-[(4-methylphenyl)methyl]piperazin-2-one

3. A compound represented by Formula III

III

or a pharmaceutically acceptable salt thereof, wherein:

R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Csto C10) cycloalkyi, (Cs to C10) cycloalkenyl, and (C2 to C9) cycloheteroalkyi, (Ce 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 C10) cycloalkenyl, (C2to C9) cycloheteroalkyi, (Ce to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁵ group;

R² is (Ci to Ce) alkyl substituted with a group selected from (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkenyl, (Ceto 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 R⁶ group;

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

with the proviso that

and with the proviso that

2 is not selected from the group consisting of

■ wherein

-CO-, -SO-, and -S0₂-,

4. A compound according to claim 3, wherein

R² is (Ci to C6) alkyl substituted with a group selected from (C6 to Cio) aryl and (C2 to C9) heteroaryl, wherein

R³ is hydrogen or methyl;

R⁴ is selected from (C6to C10) aryl and (C2 to C9) heteroaryl, wherein

5. A compound according to claim 4, wherein

R² is methyl substituted with a group selected from (C6to 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 R⁶ group.

6. A compound according to claim 5, wherein

R is selected from benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, aryloxymethyl, and CH₂NR^8aR^8b wherein

each of the said benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, aryloxymethyl and is optionally substituted with at least one R⁵ group.

7. A compound according to claim 5, wherein

, wherein each of the said C6 to C10) aryl and (C2 to C9) heteroaryl aryl group is optionally substituted with at least one R ³ group;

8. A compound according to claim 5, wherein

4 is selected from the group consisting of

, 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, Ν,Ν-dimethylamino, 1 -pyrrolidinyl, and 1 - piperidinyl.

9. A compound according to claim 5, wherein

each of the said benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, aryloxymethyl and is optionally substituted with at least one R⁵ group;

R² is methyl substituted with a (C6 to C10) aryl or (C2 to C9) heteroaryl aryl group selected from the group consisting of

R⁴ 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, /V,/V-dimethylamino, and 1 H-pyrazol-1 -yl;

10. A compound selected from the group consisting of

282

287

288

1 1 . The compound according to claim 1 , wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

12. The compound according to claim 2, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

13. The compound according to claim 3, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

14. The compound according to claim 4, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

15. The compound according to claim 5, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

16. The compound according to claim 6, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

17. The compound according to claim 7, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

18. The compound according to claim 8, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

19. The compound according to claim 9, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

20. The compound according to claim 10, wherein said compound is incorporated into a composition comprising a therapeutically effective amount of said compound, and a pharmaceutically acceptable carrier, diluent, or vehicle.

21 . A method of treating Arena virus infection comprising administration of a therapeutically effective amount of a compound of formul

or a pharmaceutically acceptable salt thereof, wherein

R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Cs to Cio) cycloalkyl, (Cs 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) cycloalkyl, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁵ group;

each of the said (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyl, (Cs to C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁶ group;

R³ is independently selected from hydrogen, halogen, CF3, cyano, (Ci to C6) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyl, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyl, (Ce to C10) aryl, (C2 .0 C9) heteroaryl, -C(0)R⁷,-C(0)NR^8aR^8b, -(CH₂)nC(0)OR⁷, and - (CH₂)nC(0)N(R^8aR^8b), wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyl, (Cs to C10) cycloalkenyl, (C₂ to C₉) cycloheteroalkyl, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁵ group;

R⁴ is selected from (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl, wherein each of the said (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Csto C10) cycloalkenyl, (C6 to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁵ group;

R⁵ 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, (Cs to C10) cycloalkenyl, (C2 to Co) cycloheteroalkyi, (Ceto C10) aryl, (C2 to Co) heteroaryl, -C(0)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C^ to C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Ci to C6) alkoxy, aryloxy, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

R⁶ 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 Co) cycloheteroalkyi, (Ce to C10) aryl, (C2 to Co) heteroaryl, -C(0)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Csto C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

each of the R⁷ is independently selected from hydrogen, (C^o C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C₃ to C ₀) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl; wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

each of the R^8a, R^8b, and R^8c are independently selected from hydrogen, (d to C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Csto C10) cycloalkenyl, (C₂ to C₉)

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

R⁹ 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 Co) cycloheteroalkyi, (Ce to C10) aryl, (C2 to Co) heteroaryl, -C(0)R¹⁰, -C(0)NR ^aR ^b, -NR ^aR ^b -S(0)mR¹⁰, -S(0)mNR ^aR ^b, -NR ^aS(O)mR ⁰, -(CH2)nC(O)OR¹⁰, -(CH₂)nC(0)N(R ^aR ^b), -OC(0)R¹⁰, -NR ^aC(0)R¹⁰, and -NR ^acC(0)N(R ^aR ^b), wherein each of the said (C^ to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, (Cs to Cio) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R ² group;

each of the said (C to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to Cio) cydoalkenyl, (C₂ to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ 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 C₆) alkyl, (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cydoalkenyl, (C₂ to C₉)

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

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,

with the proviso that

R is not selected from the group consisting of methyl, ethyl, CF₃, CHF₂, CH₂F, cyclopropyl, isopropyl, and hydroxymethyl,

and with the proviso that

2 is not selected from the group consisting of

and with the proviso that

and with the proviso when

R is benzyl or 2-phenylethyl, and

2 is selected from the group consisting of

4 is not selected from the group consisting of

22. A method of treating Arena virus infection comprising administration of a therapeutically effective amount of a compound of formula II

n

or a pharmaceutically acceptable salt thereof, wherein:

R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Csto Cio) cycloalkyi, (Cs to Cio) cycloalkenyl, and (C2 to C9) cycloheteroalkyi, (Ce 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 C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (Ce to C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁵ group;

R² is (Ci to C6) alkyl substituted with a group selected from (Ci to C6) alkenyl, (Ci to C6) alkynyl, (Cs to C10) cycloalkenyl, (Ceto C10) aryl, and (C2 to C9) heteroaryl, wherei

each of the said (Ci to C6) alkenyl, (Ci to C6) alkynyl, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (Ceto C10) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R⁶ group;

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁵ group;

R⁴ is selected from (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Cs to C10) cycloalkenyl, (Ceto C10) aryl, and (C2 to C9) heteroaryl, wherein

R⁵ 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, (Ceto C10) aryl, (C2 to C9) heteroaryl, -C(0)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

each of the said (C-, to C₆) alkyl, (Ci to Ce) alkenyl, (Ci to Ce) alkynyl, (Ci to Ce) alkoxy, aryloxy, (C3 to C10) cycloalkyi, (Cs to C10) cycloalkenyl, (C₂to C₉) cycloheteroalkyi, (C₂to C₉) heteroaryl, and (C₆ to C ₀) aryl is optionally substituted with at least one R⁹ group;

R⁶ 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) cycloalkenyl, (C2 to Co) cycloheteroalkyi, (Ce to C10) aryl, (C2 to Co) heteroaryl, -C(0)R⁷, -C(0)NR^8aR^8b, -NR^8aR^8b, -S(0)mR⁷, -S(0)mNR^8aR^8b, -NR^8aS(0)mR⁷, -(CH₂)nC(0)OR⁷, -(CH₂)nC(0)NR^8aR^8b, -OC(0)R⁷,

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

R ² is independently selected from hydrogen, halogen, cyano, OH, CF3, (Ci to Ce>) alkyl, (Ci to C6) alkenyl, (Ci to Ce>) alkynyl, (Ci to Ce>) alkoxy, (C3 to C10) cycloalkyl, (Cs to C10) cycloalkenyl, (C2 to C9) cycloheteroalkyi, (C6 to C10) aryl, and (C2 to C9) heteroaryl,

with the proviso that

and with the proviso that

2 is not selected from the group consisting of

and with the proviso that the following compound is excluded: (6S)-4-[(1 -benzofuran-2-yl)carbonyl]-6- benzyl-[(4-methylphenyl)methyl]piperazin-2-one

23. A method of treating Arena virus infection comprising administration of a therapeutically effective amount of a compound of formula II I

III

or a pharmaceutically acceptable salt thereof, wherein:

R is selected from (Ci to Ce) alkyl, (Ci to Ce) alkenyl, (Ci toCe) alkynyl, (Cs to C10) cycloalkyl, (Cs to C10) 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 R⁵ group;

-NR^8aC(0)R⁷, and -NR^8cC(0)NR^8aR^8b, wherein

cycloheteroalkyi, (C₂ to C₉) heteroaryl, and (C₆ to C ₀) aryl,

with the proviso that

R is not selected from the group consisting of methyl, ethyl, CF₃, CHF₂, CH₂F, cyclopropyl, isopropyl, and hydroxymethyl

and with the proviso that

R² is not selected from the group consisting of

24. The method of claim 23, wherein

R³ is hydrogen or methyl;

R⁴ is selected from (C6 to C10) aryl and (C2 to C9) heteroaryl, wherein

25. The method of claim 24, wherein

26. The method of claim 25, wherein

each of the said benzyl, 2-phenylethyl, 3-indolylmethyl, cyclohexylmethyl, alkoxymethyl, and aryloxymethyl is optionally substituted with at least one R⁵ group.

27. The method of claim 25, wherein

, wherein

each of the said C6 to C10) aryl or (C2 to C9) heteroaryl group aryl is optionally substituted with at least one R ³ group;

28. The method of claim 25, wherein

4 is selected from the group consisting of

, wherein

29. The method of claim 25, wherein

R² is methyl substituted with an C6 to C10) aryl or (C2 to C9) heteroaryl group selected from the group consisting of

, wherein

each of the said C6 to C10) aryl or (C2 to C9) heteroaryl 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, Ν,Ν-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, Ν,Ν-dimethylamino, 1 -pyrrolidinyl, 1 -piperidinyl.

30. A method of treating Arena virus infection comprising administration of a therapeutically effective amount of a compound selected from the group consisting of

307

312

31 . The method of claim 21 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.

32. The method of claim 22 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.

33. The method of claim 23 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.

34. The method of claim 24 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.

35. The method of claim 25 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.

36. The method of claim 26 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.

37. The method of claim 27 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.

38. The method of claim 28 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.

39. The method of claim 29 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and immunomodulators.

40. The method of claim 30 including administrating a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and

immunomodulators.