Substituted tetrahydrobenzothiophene and tetrahydropyridothiophene derivatives as potential antiviral agents

Abstract

The present disclosure is concerned with substituted tetrahydrobenzothiophene and tetrahydropyridothiophene compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds in the treatment of viral infections due to a Flavi virus (e.g, yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus (WNV), zika (ZIKV), tick-bome encephalitis virus. Kunjin virus. Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Hepatitis C virus) or an Alphavirus (e.g., Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, Sindbis virus). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

SUBSTITUTED TETRAHYDROBENZOTHIOPHENE AND TETRAHYDROPYRIDOTHIOPHENE DERIVATIVES AS POTENTIAL ANTIVIRAL AGENTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No. 63 / 554,746, filed onFebruary 16, 2024, the contents of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grants numbers AI109680and AI142759, awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0003] Arthropod borne viruses have developed a complex life cycle adapted to alternatebetween insect and vertebrate hosts. These arthropod-borne viruses belong mainly to the families Togaviridae, Flaviviridae, and Bunyaviridae. Exemplary genera within these families include Flaviviruses (e.g., West Nile virus (WNV), dengue virus (DENV), Tick- borne Encephalitis virus, yellow fever virus, zika virus (ZIKV)) and Alphaviruses (e.g., chikungunya virus (CHIKV), Venezuelan Equine Encephalitis virus (VEEZ), Western Equine Encephalitis virus (WEEV), Eastern Equine Encephalitis virus (EEEV)).

[0004] Among the most prevalent of the Flaviruses is DENV. Presently, dengue is endemicin 100 tropical and subtropical countries in Southeast Asia, Africa, the Americas, and certain European regions (Kraemer et al. (2015) eLife 4: e08347). An estimated 390 million dengue infections and 25,000 deaths are reported annually, with 96 million cases exhibiting clinical manifestations (Bhatt et al. (2013) Nature 496: 504-507; Obi et al. (2021) Trop. Med. Infect. Dis.6: 180). DENV has four antigenically distinct serotypes, namely DENV-1 to 4. A primary infection with one serotype generates long-term immunity against that particular serotype and short-term immunity against the other three serotypes, which lasts for about six months (Montoya et al. (2013) PLoS Negl. Trop. Dis 7: e2357; Snow et al. (2014) Am. J.Trop. Med. Hyg.91: 1203-1217). However, secondary infection with another DENV serotype might cause severe disease with complications leading to dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) due to antibody-dependent enhancement (ADE) or original antigenic sin (Flipse et al. (2016) Sci. Rep.6: 29201; Midgley et al. (2011) J. Virol. 85: 410-421; Zompi et al. (2013) Proc. Natl. Acad. Sci. USA 110: 8761-8762).

[0005] To date, there are no clinically approved antivirals for the treatment of Alphavirusesand Flaviviruses, and treatment remains relying on supportive care such as fluid replacement and the use of analgesics (see, e.g., Bhatt et al. (2013) Nature 496: 504-507). Although a variety of antiviral drugs have arisen as potential candidates for treating these viruses, these have not succeeded in reaching clinical trials due to poor physicochemical and pharmacokinetic properties (Lim et al. (2013) Antivir. Res.100: 500-519). For example, anti- DENV drug candidates such as chloroquine, prednisolone, lovastatin, and celgosivir have undergone clinical trials but failed to reduce viremia significantly enough to provide any noteworthy beneficial effects (Low et al. (2014) Lancet Infect. Dis.14: 706-715; Tam et al. (2012) Clin. Infect. Dis.55: 1216-1224; Tricou et al. (2010) PLoS Negl. Trop. Dis.4: e785; Whitehorn et al. (2015) Clin. Infect. Dis.62: 468-476). Accordingly, there remains a need for antiviral agents capable of effectively targeting these viruses and methods of making and using same. SUMMARY

[0006] In accordance with the purpose(s) of the invention, as embodied and broadlydescribed herein, the invention, in one aspect, relates to substituted tetrahydrobenzothiopheneand tetrahydropyridothiophene compounds, pharmaceutical compositions comprising thecompounds, and methods of using the compounds in the treatment of viral infections due to a Flavivirus (e.g., yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus (WNV), Zika (ZIKV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Hepatitis C virus) or an Alphavirus (e.g., Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, Sindbis virus).

[0007] Disclosed are compounds having a structure represented by a formula:, wherein n is selected from 0, 1, Z1a2nd Z is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b; wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and provided that the compound is not:., wherein n is selected from 0, 1, a1and Z2is independently selectedfrom NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b; wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen andC1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and provided that the compound is not: , .of acompound having a structure represented by a formula: , wherein n is selected from 0, 1,Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen,‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and a pharmaceutically acceptable carrier.

[0010] Also disclosed are pharmaceutical compositions comprising an effective amount of acompound having a structure represented by a formula: , wherein n is selected from 0, 1,Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and a pharmaceutically acceptable carrier.

[0011] Also disclosed are methods for treating a viral infection in a subject in need thereof,the method comprising administering to the subject a compound having a structure represented by a formula: , wherein n is selected from 0, 1,Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, wherein the viral infection is due to a Flavivirus or due to an Alphavirus.

[0012] Also disclosed are methods for treating a viral infection in a subject in need thereof,the method comprising administering to the subject a compound having a structure represented by a formula: ,wherein n is selected from 0, 1, Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, wherein the viral infection is due to a Flavivirus or due to an Alphavirus.

[0013] Also disclosed are kits comprising a compound having a structure represented by aformula: ,wherein n is selected from 0, 1, Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and one or more selected from: (a) at least one antiviral agent; (b) instructions for administering the compound in connection with treating a viral infection; (c) instructions for administering the compound in connection with reducing the risk of a viral infection; and (d) instructions for treating a viral infection, wherein the viral infection is due to a Flavivirus or an Alphavirus.

[0014] Also disclosed are kits comprising a compound having a structure represented by aformula: ,wherein n is selected from 0, 1, Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10isselected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and one or more selected from: (a) at least one antiviral agent; (b) instructions for administering the compound in connection with treating a viral infection; (c) instructions for administering the compound in connection with reducing the risk of a viral infection; and (d) instructions for treating a viral infection, wherein the viral infection is due to a Flavivirus or an Alphavirus.

[0015] Also disclosed are compounds selected from:, , , or

[0016] Also disclosed are compounds selected from:, , or

[0017] Also disclosed are pharmaceutical compositions comprising a disclosed compound ora pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0018] Also disclosed are methods for treating a viral infection in a subject in need thereof,the method comprising administering to the subject a disclosed compound or a pharmaceutically acceptable salt thereof.

[0019] Also disclosed are kits comprising a disclosed compound or a pharmaceuticallyacceptable salt theref, and one or more selected from: (a) at least one antiviral agent; (b) instructions for administering the compound in connection with treating a viral infection; (c) instructions for administering the compound in connection with reducing the risk of a viral infection; and (d) instructions for treating a viral infection, wherein the viral infection is dueto a Flavivirus or an Alphavirus.

[0020] While aspects of the present invention can be described and claimed in a particularstatutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. DETAILED DESCRIPTION

[0021] The present invention can be understood more readily by reference to the followingdetailed description of the invention and the Examples included therein.

[0022] Before the present compounds, compositions, articles, systems, devices, and / ormethods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0023] While aspects of the present invention can be described and claimed in a particularstatutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps oroperational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0024] Throughout this application, various publications are referenced. The disclosures ofthese publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.A. DEFINITIONS

[0025] As used in the specification and the appended claims, the singular forms “a,” “an” and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0026] As used in the specification and in the claims, the term “comprising” can include theaspects “consisting of” and “consisting essentially of.”

[0027] Ranges can be expressed herein as from “about” one particular value, and / or to“about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0028] As used herein, the terms “about” and “at or about” mean that the amount or value inquestion can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variationunless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0029] References in the specification and concluding claims to parts by weight of aparticular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0030] A weight percent (wt. %) of a component, unless specifically stated to the contrary, isbased on the total weight of the formulation or composition in which the component is included.

[0031] As used herein, “EC50” is intended to refer to the concentration of a substance (e.g., acompound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein.

[0032] As used herein, “EC90” is intended to refer to the concentration of a substance (e.g., acompound or a drug) that is required for 90% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC90can refer to the concentration of a substance that is required for 90% agonism in vivo, as further defined elsewhere herein.

[0033] As used herein, “CC50” is intended to refer to the effective concentration of acytotoxic compound, which produces 50% of the maximum possible cell death for that compound.

[0034] As used herein, the terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance can or cannot occur, and that the description includesinstances where said event or circumstance occurs and instances where it does not.

[0035] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, abird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0036] As used herein, the term “treatment” refers to the medical management of a patientwith the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0037] As used herein, the term “prevent” or “preventing” refers to precluding, averting,obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0038] As used herein, the term “diagnosed” means having been subjected to a physicalexamination by a person of skill, for example, a physician, and found to have a condition thatcan be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0039] As used herein, the terms “administering” and “administration” refer to any method ofproviding a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0040] As used herein, the terms “effective amount” and “amount effective” refer to anamount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective forprevention of a disease or condition.

[0041] As used herein, “dosage form” means a pharmacologically active material in amedium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0042] As used herein, “kit” means a collection of at least two components constituting thekit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0043] As used herein, “instruction(s)” means documents describing relevant materials ormethodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be suppliedwith the kit or as a separate member component, either as a paper form or an electronic form, which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0044] As used herein, the terms “therapeutic agent” include any synthetic or naturallyoccurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expressionvectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0045] The term “pharmaceutically acceptable” describes a material that is not biologicallyor otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0046] As used herein, the term “derivative” refers to a compound having a structure derivedfrom the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, and amides, salts of esters or amides, and N-oxides of a parent compound.

[0047] As used herein, the term “pharmaceutically acceptable carrier” refers to sterileaqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, whichdelay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0048] As used herein, the term “substituted” is contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0049] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as genericsymbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0050] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbonmoiety that may be straight chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one ormore units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0051] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbongroup of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0052] Throughout the specification “alkyl” is generally used to refer to both unsubstitutedalkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0053] This practice is also used for other groups described herein. That is, while a termsuch as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0054] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composedof at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a non-aromatic carbon-based ring type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0055] The term “polyalkylene group” as used herein is a group having two or more CH2groups linked to one another. The polyalkylene group can be represented by the formula — (CH2)a—, where “a” is an integer of from 2 to 500.

[0056] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkylgroup bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or — OA1—(OA2)a—OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0057] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbonatoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

[0058] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0059] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atomswith a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0060] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ringcomposed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0061] The term “aromatic group” as used herein refers to a ring structure having cyclicclouds of delocalized π electrons above and below the plane of the molecule, where the πclouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0062] The term “aryl” as used herein is a group that contains any carbon-based aromaticgroup including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0063] The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0064] The terms “amine” or “amino” as used herein are represented by the formula —NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.

[0065] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl)where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0066] The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)2where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0067] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0068] The term “ester” as used herein is represented by the formula —OC(O)A1 or —C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula —(A1O(O)C-A2-C(O)O)a— or —(A1O(O)C-A2-OC(O))a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0069] The term “ether” as used herein is represented by the formula A1OA2, where A1 andA2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula —(A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0070] The terms “halo,” “halogen,” or “halide,” as used herein can be used interchangeablyand refer to F, Cl, Br, or I.

[0071] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as used herein can beused interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0072] The term “heteroalkyl,” as used herein refers to an alkyl group containing at least oneheteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0073] The term “heteroaryl,” as used herein refers to an aromatic group that has at least oneheteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or moregroups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0074] The terms “heterocycle” or “heterocyclyl,” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group that has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0075] The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein refers to aring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.

[0076] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturatedor fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0077] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula —OH.

[0078] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0079] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0080] The term “nitro” as used herein is represented by the formula —NO2.

[0081] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0082] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1,A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0083] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, —S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0084] The term “thiol” as used herein is represented by the formula —SH.

[0085] “R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently,possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0086] As described herein, compounds of the invention may contain “optionally substituted”moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0087] The term “stable,” as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0088] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, – O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; – (CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; –N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; –C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; –OC(O)(CH2)0– 4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; -(CH2)0–4OC(O)NR^2; -C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; –P(O)2R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; SiR^3; –(C1–4 straight or branched alkylene)O–N(R^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, - CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0089] Suitable monovalent substituents on R^ (or the ring formed by taking two independentoccurrences of R^ together with their intervening atoms), are independently halogen, – (CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =Oand =S.

[0090] Suitable divalent substituents on a saturated carbon atom of an “optionallysubstituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0091] Suitable substituents on the aliphatic group of R* include halogen, –R^, -(haloR^),-OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] Suitable substituents on a substitutable nitrogen of an “optionally substituted” groupinclude –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0093] Suitable substituents on the aliphatic group of R† are independently halogen, –R^,-(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

[0094] The term “leaving group” refers to an atom (or a group of atoms) with electronwithdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0095] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functionalgroup capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0096] The term “organic residue” defines a carbon-containing residue, i.e., a residuecomprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0097] A very close synonym of the term “residue” is the term “radical,” which as used in thespecification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure: ,regardless of whether the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0098] “Organic radicals,” as the term is defined and used herein, contain one or more carbonatoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1- 12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0099] Compounds described herein can contain one or more double bonds and, thus,potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0100] Unless stated to the contrary, a formula with chemical bonds shown only assolid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0101] Many organic compounds exist in optically active forms having the ability torotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0102] When the disclosed compounds contain one chiral center, the compounds existin two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0103] Designation of a specific absolute configuration at a chiral carbon in adisclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[0104] When a disclosed compound has two or more chiral carbons, it can have morethan two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S) / (R,R) and (R,S) / (S,R)). The pairs of enantiomers (e.g., (S,S) / (R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[0105] The compounds according to this disclosure may form prodrugs at hydroxyl oramino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem.1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p.30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[0106] “Derivatives” of the compounds disclosed herein are pharmaceuticallyacceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context are refer toderivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, and solvates. Examples of radioactively labeled forms include compounds labeled with tritium, phosphorous-32, iodine- 129, carbon-11, fluorine-18, and the like.

[0107] Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can be isotopically labeled or isotopically substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0108] The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0109] The term “co-crystal” means a physical association of two or more moleculesthat owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances,the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[0110] It is also appreciated that certain compounds described herein can be presentas an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

[0111] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amideform and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N1-unsubstituted, 3-A3and N1-unsubstituted, 5-A3as shown below. Unless stated to thetautomers.

[0112] It is known that chemical substances form solids that are present in differentstates of order that are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0113] In some aspects, a structure of a compound can be represented by a formula:,which is understood to be equivalent to a, wherein n is typically an integer.to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0114] Certain materials, compounds, compositions, and components disclosed hereincan be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0115] Unless otherwise expressly stated, it is in no way intended that any method setforth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0116] Disclosed are the components to be used to prepare the compositions of theinvention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0117] It is understood that the compositions disclosed herein have certain functions.Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.B. COMPOUNDS

[0118] In one aspect, disclosed are to compounds useful in treating viral infectionsdue to a Flavivirus (e.g., yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus (WNV), zika (ZIKV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Hepatitis C virus) or an Alphavirus (e.g., Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, Sindbis virus).

[0119] In one aspect, the disclosed compounds exhibit antiviral activity.

[0120] In one aspect, the compounds of the invention are useful in inhibiting viralactivity in a mammal.

[0121] In one aspect, the compounds of the invention are useful in the treatment ofviral infections, as further described herein.

[0122] It is contemplated that each disclosed derivative can be optionally furthersubstituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1. STRUCTURE

[0123] In one aspect, disclosed are compounds having a structure represented by aformula: , wherein n is selected from 0, 1,Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b; wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and provided that the compound is not: , .by aformula: ,wherein n is selected from 0, 1, Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b; wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and provided that the compound is not: , .by aformula:, wherein n is selected from 0, 1, Z1an2d Z is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole.

[0126] In one aspect, disclosed are compounds having a structure represented by aformula: , wherein n is selected from 0, 1,Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole.

[0127] In one aspect, disclosed are compounds selected from:, , , or

[0128] In one aspect, disclosed are compounds selected from:, , or

[0129] In various aspects, the compound has a structure represented by a formula:R1b OAr1,or a pharmaceutically acceptable

[0130] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable

[0131] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically

[0132] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically

[0133] In various aspects, the compound has a structure represented by a formula:R20a NR20b, wherein each of R20a, R20b,from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR22C(O)(C1-C4 alkyl), and ‒C(O)NR23aR23b; wherein R22is selected from hydrogen and C1-C4 alkyl; and wherein each of R23aand R23bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0134] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically

[0135] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically

[0136] In various aspects, the compound is not:, or a pharmaceutically

[0137] In various aspects, the compound is selected from:,, or

[0138] In one aspect, n is selected from 0, 1, and 2. In a further aspect, n is selectedfrom 0 and 1. In a still further aspect, n is selected from 1 and 2. In a yet further aspect, n is selected from 0 and 2. In an even further aspect, n is 0. In an even still further aspect, n is 1. In an even yet further aspect, n is 2. a. Z1 AND Z2 GROUPS

[0139] In one aspect, each of Z1 and Z2 is independently selected from NR10 andCR11aR11b, provided that at least one of Z1and Z2is CR11aR11b. In a further aspect, each of Z1and Z2is CR11aR11b.

[0140] In various aspects, Z1 is NR10 and Z2 is CR11aR11b. In a further aspect, R10 ishydrogen. In a still further aspect, R10is C1-C4 alkyl. In yet a further aspect, R10is selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In an even further aspect, R10is selected from n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In a still further aspect, R10is selected from n-butyl, isobutyl, and tert-butyl. In yet a further aspect, R10is tert-butyl. In an even further aspect, each of R11aand R11bis hydrogen.

[0141] In various aspects, Z2 is NR10 and Z2 is CR11aR11b. In a further aspect, R10 ishydrogen. In a still further aspect, R10is C1-C4 alkyl. In yet a further aspect, R10is selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In an even further aspect, R10is selected from n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In a still further aspect, R10is selected from n-butyl, isobutyl, and tert-butyl. In yet a further aspect, R10is tert-butyl. In an even further aspect, each of R11aand R11bis hydrogen. b. R1A AND R1B GROUPS

[0142] In one aspect, each of R1a and R1b is independently selected from hydrogen,halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, methyl, ethyl, n-propyl, i- propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, – NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), CH2NH2, CH2CH2NH2, and CH2CH2CH2NH2. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, – NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), CH2NH2, and CH2CH2NH2. In yet a further aspect, each of R1aand R1bis independently selected fromhydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, – OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –NHCH3, –N(CH3)2and CH2NH2.

[0143] In various aspects, each of R1a and R1b is independently selected fromhydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, – CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, – CH2CH2CH2CN, and –CH(CH3)CH2CN. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN, and – CH2CH2CN. In yet a further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, and –CH2CN.

[0144] In various aspects, each of R1a and R1b is independently selected fromhydrogen, halogen, ‒CN, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2CH2CH2CN, and –CH(CH3)CH2CN. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN, and –CH2CH2CN. In yet a further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, and –CH2CN.

[0145] In various aspects, each of R1a and R1b is independently selected fromhydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n- propyl, i-propyl, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCH3, – OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, – OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, – OCH(CH3)CH2F, and –OCH(CH3)CH2Cl. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In yet a further aspect, each of R1aandR1bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, – CH2OH, –OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0146] In various aspects, each of R1a and R1b is independently selected fromhydrogen, ‒OH, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R1aand R1bis independently selected from hydrogen, –OH, –CH2OH,– CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCH3, –OCH2CH3, –OCH2CH2CH3, – OCH(CH3)CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and – OCH(CH3)CH2Cl. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, –OH, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, –OCHF2, – OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In yet a further aspect, each of R1aand R1bis independently selected from hydrogen, –OH, –CH2OH, –OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0147] In various aspects, each of R1a and R1b is independently selected fromhydrogen, ‒NH2, ‒NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R1aand R1bis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), CH2NH2, CH2CH2NH2, and CH2CH2CH2NH2. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –NHCH2CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH3)(CH2CH3), CH2NH2, and CH2CH2NH2. In yet a further aspect, each of R1aand R1bis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –N(CH3)2and CH2NH2.

[0148] In various aspects, each of R1a and R1b is independently selected fromhydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R1aand R1bis independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, and i-propenyl. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, each of R1aand R1bis independently selected from hydrogen and methyl.

[0149] In various aspects, each of R1a and R1b is independently selected fromhydrogen and halogen. In a further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, and ‒Br. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, –F, and –Cl. In yet a further aspect, each of R1aand R1bis independently selected from hydrogen and –Cl. In an even further aspect, each of R1aand R1bis independently selected from hydrogen and –F.

[0150] In various aspects, each of R1a and R1b is independently selected fromhydrogen, halogen, and C1-C4 alkyl. In a further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, methyl, ethyl, n-propyl, and i-propyl. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, –F, –Cl, methyl, and ethyl. In yet a further aspect, each of R1aand R1bis independently selected from hydrogen, – F, –Cl, and methyl.

[0151] In various aspects, each of R1a and R1b is hydrogen.c. R2 GROUPS

[0152] In one aspect, R2 is selected from hydrogen and C1-C4 alkyl. In a furtheraspect, R2is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R2is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R2is selected from hydrogen and methyl.

[0153] In various aspects, R2 is C1-C4 alkyl. In a further aspect, R2 is selected frommethyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R2is selected from methyl, and ethyl. In yet a further aspect, R2is methyl.

[0154] In various aspects, R2 is hydrogen.d. R10 GROUPS

[0155] In one aspect, R10 is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH,‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, ethenyl, n- propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, – CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, – CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, – NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), CH2NH2, CH2CH2NH2, and CH2CH2CH2NH2. In astill further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN,– CH2CH2CN, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, –OCHF2, –OCF3, – OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –NHCH3, –NHCH2CH3, – N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), CH2NH2, and CH2CH2NH2. In yet a further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, – CH2Cl, –CH2CN, –CH2OH, –OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, – OCCl3, –NHCH3, –N(CH3)2, and CH2NH2.

[0156] In various aspects, R10 is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH,‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n- propyl, i-propyl, n-butyl, tert-butyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2CH2CH2CN, and –CH(CH3)CH2CN. In a still further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN, and – CH2CH2CN. In yet a further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, – OH, ‒NO2, methyl, –CH2F, –CH2Cl, and –CH2CN.

[0157] In various aspects, R10 is selected from hydrogen, halogen, ‒CN, C1-C4haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, R10is selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2CH2CH2CN, and – CH(CH3)CH2CN. In a still further aspect, R10is selected from hydrogen, –F, –Cl, –CH2F, – CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN, and –CH2CH2CN. In yet a further aspect, R10is selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, and –CH2CN.

[0158] In various aspects, R10 is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH,‒NO2, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n- propyl, i-propyl, n-butyl, tert-butyl, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –OCH2F, – OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, – OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and –OCH(CH3)CH2Cl. In a still further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In yet a further aspect, R10is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2OH, –OCH3, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0159] In various aspects, R10 is selected from hydrogen, ‒OH, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, R10is selected from hydrogen, – OH, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCH3, –OCH2CH3, – OCH2CH2CH3, –OCH(CH3)CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and – OCH(CH3)CH2Cl. In a still further aspect, R10is selected from hydrogen, –OH, –CH2OH, – CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In yet a further aspect, R10is selected from hydrogen, – OH, –CH2OH, –OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0160] In various aspects, R10 is selected from hydrogen, ‒NH2, ‒NO2, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, R10is selected from hydrogen, –NH2, –NO2, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, – NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, – N(CH3)(CH2CH3) and CH2NH2, CH2CH2NH2, and CH2CH2CH2NH2. In a still further aspect, R10is selected from hydrogen, –NH2, –NO2, –NHCH3, –NHCH2CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH3)(CH2CH3), CH2NH2, and CH2CH2NH2. In yet a further aspect, R10is selected from hydrogen, –NH2, –NO2, –NHCH3, –N(CH3)2, and CH2NH2.

[0161] In various aspects, R10 is selected from hydrogen, C1-C4 alkyl, and C2-C4alkenyl. In a further aspect, R10is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, ethenyl, n-propenyl, and i-propenyl. In a still further aspect, R10is selected from hydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, R10is selected from hydrogen and methyl.

[0162] In various aspects, R10 is selected from hydrogen and halogen. In a furtheraspect, R10is selected from hydrogen, –F, –Cl, and ‒Br. In a still further aspect, R10is selected from hydrogen, –F, and –Cl. In yet a further aspect, R10is selected from hydrogen and –Cl. In an even further aspect, R10is selected from hydrogen and –F.

[0163] In various aspects, R10 is C1-C4 alkyl. In a further aspect, R10 is selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, and tert-butyl. In a still further aspect, R10is selected from methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, R10is selected from methyl and ethyl.

[0164] In various aspects, R10 is tert-butyl.

[0165] In various apects, R10 is hydrogen.e. R11A AND R11B GROUPS

[0166] In one aspect, each of R11a and R11b is independently selected from hydrogen,halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, – NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), CH2NH2, CH2CH2NH2, and CH2CH2CH2NH2. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, – NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), CH2NH2, and CH2CH2NH2. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, – OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –NHCH3, –N(CH3)2,and CH2NH2.

[0167] In various aspects, each of R11a and R11b is independently selected fromhydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, – CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, – CH2CH2CH2CN, and –CH(CH3)CH2CN. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl,ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN, and – CH2CH2CN. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, and –CH2CN.

[0168] In various aspects, each of R11a and R11b is independently selected fromhydrogen, halogen, ‒CN, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2CH2CH2CN, and –CH(CH3)CH2CN. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, – CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN, and –CH2CH2CN. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, – CH2F, –CH2Cl, and –CH2CN.

[0169] In various aspects, each of R11a and R11b is independently selected fromhydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –OCH2F, –OCHF2, –OCF3, – OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, – OCH2CH2CH2Cl, –OCH(CH3)CH2F, and –OCH(CH3)CH2Cl. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, –OCHF2, – OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, –NH2, –CN, – OH, ‒NO2, methyl, –CH2OH, –OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0170] In various aspects, each of R11a and R11b is independently selected fromhydrogen, ‒OH, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R11aand R11bis independently selected from hydrogen, –OH, –CH2OH,– CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCH3, –OCH2CH3, –OCH2CH2CH3, – OCH(CH3)CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and – OCH(CH3)CH2Cl. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, –OH, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen, –OH, –CH2OH, – OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0171] In various aspects, each of R11a and R11b is independently selected fromhydrogen, ‒NH2, ‒NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R11aand R11bis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, – N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), CH2NH2, CH2CH2NH2, and CH2CH2CH2NH2.. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –NHCH2CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH3)(CH2CH3), CH2NH2, and CH2CH2NH2. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –N(CH3)2, and CH2NH2.

[0172] In various aspects, each of R11a and R11b is independently selected fromhydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R11aand R11bis independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, and i-propenyl. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen and methyl.

[0173] In various aspects, each of R11a and R11b is independently selected fromhydrogen and halogen. In a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, and ‒Br. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, –F, and –Cl. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen and –Cl. In an even further aspect, each of R11aand R11bis independently selected from hydrogen and –F.

[0174] In various aspects, each of R11a and R11b is independently selected fromhydrogen, halogen, and C1-C4 alkyl. In a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, methyl, ethyl, n-propyl, and i-propyl. In a still further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, methyl, and ethyl. In yet a further aspect, each of R11aand R11bis independently selected from hydrogen, –F, –Cl, and methyl.

[0175] In various aspects, each of R11a and R11b is hydrogen.f. R12 GROUPS

[0176] In one aspect, R12 is selected from hydrogen and C1-C4 alkyl. In a furtheraspect, R12is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R12is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R12is selected from hydrogen and methyl.

[0177] In various aspects, R12 is C1-C4 alkyl. In a further aspect, R12 is selected frommethyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R12is selected from methyl and ethyl. In yet a further aspect, R12is methyl.

[0178] In various aspects, R12 is hydrogen.g. R13A AND R13B GROUPS

[0179] In one aspect, each of R13a and R13b is independently selected from hydrogen,C1-C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring.

[0180] In one aspect, each of R13a and R13b is independently selected from hydrogenand C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

[0181] In various aspects, each of R13a and R13b is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl. In a further aspect, each of R13aand R13bis independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, ‒CH2CH2OH, ‒CH2CH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetadine, pyran, and piperidine. In a still further aspect, each of R13aand R13bis independently selectedfrom hydrogen, methyl, ethyl, ‒CH2CH2OH, cyclopropyl, cyclobutyl, aziridine, and azetadine. In yet a further aspect, each of R13aand R13bis independently selected from hydrogen and methyl.

[0182] In various aspects, each of R13a and R13b is independently selected fromhydrogen, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl. In a further aspect, each of R13aand R13bis independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetadine, pyrrolidine, and piperidine. In a still further aspect, each of R13aand R13bis independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentane, aziridine, azetadine, and pyrrolidine. In yet a further aspect, each of R13aand R13bis independently selected from hydrogen, cyclopropyl, cyclobutyl, aziridine, and azetadine. In yet a further aspect, each of R13aand R13bis independently selected from hydrogen, cyclopropyl and aziridine.

[0183] In various aspects, each of R13a and R13b is independently selected fromhydrogen and C2-C4 hydroxyalkyl. In a further aspect, each of R13aand R13bis independently selected from hydrogen, ‒CH2CH2OH, and ‒CH2CH2CH2OH. In a still further aspect, each of R13aand R13bis independently selected from hydrogen and ‒CH2CH2OH.

[0184] In various aspects, each of R13a and R13b is independently selected fromhydrogen and C1-C4 alkyl. In a further aspect, each of R13aand R13bis independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R13aand R13bis independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R13aand R13bis independently selected from hydrogen and methyl.

[0185] In various aspects, each of R13a and R13b is independently C1-C4 alkyl. In afurther aspect, each of R13aand R13bis independently selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R13aand R13bis independently selected from methyl and ethyl. In yet a further aspect, each of R13aand R13bis methyl.

[0186] In various aspects, each of R13a and R13b is hydrogen.

[0187] In various aspects, each of R13a and R13b are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring. In a further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle,and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring. In a yet further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring. In a still further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6- membered heterocycle, and is unsubstituted.

[0188] In various aspects, each of R13a and R13b are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring. In a further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring. In a yet further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is unsubstituted.

[0189] In various aspects, each of R13a and R13b are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is unsubstituted.

[0190] In various aspects, each of R13a and R13b are covalently bonded and, togetherwith the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, 2, or 3groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3- dioxolane ring. In a further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring. In a yet further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle.

[0191] In various aspects, each of R13a and R13b are covalently bonded and, togetherwith the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0 or 1 group selected fromhalogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- membered heterocycle monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 5- membered heterocycle.

[0192] In various aspects, each of R13a and R13b are covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered heterocycle substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3- dioxolane ring. In a further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 6-membered heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring. In a yet further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 6-membered heterocycle substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 6-membered heterocycle monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 6-membered heterocycle.

[0193] In various aspects, each of R13a and R13b are covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered heterocycle substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 6-membered heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspects, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 6-membered heterocycle substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 6- membered heterocycle monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 6- membered heterocycle. h. R20A, R20B, AND R20C GROUPS

[0194] In one aspect, each of R20a, R20b, and R20c is independently selected fromhydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR22C(O)(C1-C4 alkyl), and ‒C(O)NR23aR23b. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, – CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, – CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, – NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), CH2NH2, CH2CH2NH2, and CH2CH2CH2NH2. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, – Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, – CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH, –CH2CH2OH, –OCH3, – OCH2CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), CH2NH2, and CH2CH2NH2. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, – CH2Cl, –CH2CN, –CH2OH, –OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –NHCH3, –N(CH3)2, and CH2NH2.

[0195] In various aspects, each of R20a, R20b, and R20c is independently selected fromhydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, – CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, – CH2CH2CH2CN, and –CH(CH3)CH2CN. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN, and – CH2CH2CN. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, and –CH2CN.

[0196] In various aspects, each of R20a, R20b, and R20c is independently selected fromhydrogen, halogen, ‒CN, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2CH2CH2CN, and –CH(CH3)CH2CN. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH(CH3)CH2Cl, –CH2CN, and –CH2CH2CN. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –CH2F, –CH2Cl, and –CH2CN.

[0197] In various aspects, each of R20a, R20b, and R20c is independently selected fromhydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –OCH2F, –OCHF2, –OCF3, – OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, – OCH2CH2CH2Cl, –OCH(CH3)CH2F, and –OCH(CH3)CH2Cl. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, – OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2OH, –OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, – OCHCl2, and –OCCl3.

[0198] In various aspects, each of R20a, R20b, and R20c is independently selected fromhydrogen, ‒OH, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –OH, – CH2OH,–CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCH3, –OCH2CH3, – OCH2CH2CH3, –OCH(CH3)CH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and – OCH(CH3)CH2Cl. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –OH, –CH2OH, –CH2CH2OH, –OCH3, –OCH2CH3, –OCH2F, – OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –OH, – CH2OH, –OCH3, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0199] In various aspects, each of R20a, R20b, and R20c is independently selected fromhydrogen, ‒NH2, ‒NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, – N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), CH2NH2, CH2CH2NH2, and CH2CH2CH2NH2.. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –NHCH2CH3, – N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), CH2NH2, and CH2CH2NH2. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –NH2, –NO2, –NHCH3, –N(CH3)2, and CH2NH2.

[0200] In various aspects, each of R20a, R20b, and R20c is independently selected fromhydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, and i-propenyl. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen and methyl.

[0201] In various aspects, each of R20a, R20b, and R20c is independently selected fromhydrogen and halogen. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, and ‒Br. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, and –Cl. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen and –Cl. In an even further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen and –F.

[0202] In various aspects, each of R20a, R20b, and R20c is independently selected fromhydrogen, halogen, and C1-C4 alkyl. In a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, methyl, ethyl, n-propyl, and i-propyl. In a still further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, – Cl, methyl, and ethyl. In yet a further aspect, each of R20a, R20b, and R20cis independently selected from hydrogen, –F, –Cl, and methyl.

[0203] In various aspects, each of R20a, R20b, and R20c is hydrogen.i. R22 GROUPS

[0204] In one aspect, R22 is selected from hydrogen and C1-C4 alkyl. In a furtheraspect, R12is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R22is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R22is selected from hydrogen and methyl.

[0205] In various aspects, R22 is C1-C4 alkyl. In a further aspect, R22 is selected frommethyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R22is selected from methyl and ethyl. In yet a further aspect, R22is methyl.

[0206] In various aspects, R22 is hydrogen.j. R23A AND R23B GROUPS

[0207] In one aspect, each of R23a and R23b is independently selected from hydrogenand C1-C4 alkyl, or each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

[0208] In various aspects, each of R23a and R23b is independently selected fromhydrogen and C1-C4 alkyl. In a further aspect, each of R23aand R23bis independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R23aand R23bis independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R23aand R23bis independently selected from hydrogen and methyl.

[0209] In various aspects, each of R23a and R23b is independently C1-C4 alkyl. In afurther aspect, each of R23aand R23bis independently selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R23aand R23bis independently selected from methyl and ethyl. In yet a further aspect, each of R23aand R23bis methyl.

[0210] In various aspects, each of R23a and R23b is hydrogen.

[0211] In various aspects, each of R23a and R23b are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspects, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspects, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is unsubstituted.

[0212] In various aspects, each of R23a and R23b are covalently bonded and, togetherwith the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspects, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspects, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5- membered heterocycle monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 5- membered heterocycle.

[0213] In various aspects, each of R23a and R23b are covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered heterocycle substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspects, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 6-membered heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspects, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 6-membered heterocycle substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 6- membered heterocycle monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 6- membered heterocycle. k. AR1 GROUPS

[0214] In one aspect, Ar1 is a 5-membered, N-linked heteroaryl substituted with 0, 1,2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole. Examples of 5-membered, N-linked heteroaryls include, but are not limited to, pyrrolyl, imidazolyl, and triazolyl. In a further aspect, Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In a yet further aspect, Ar1is a 5-membered, N-linked heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In a still further aspect, Ar1is a 5-membered, N-linked heteroaryl monosubstituted with a groupselected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In an even further aspect, Ar1is an unsubstituted 5-membered, N- linked heteroaryl.

[0215] In various aspects, Ar1 is selected from pyrrolyl, imidazolyl, and triazolyl, andis substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In a further aspect, Ar1is selected from pyrrolyl, imidazolyl, and triazolyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In a yet further aspect, Ar1is selected from pyrrolyl, imidazolyl, and triazolyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In a still further aspect, Ar1is selected from pyrrolyl, imidazolyl, and triazolyl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In an even further aspect, Ar1is selected from pyrrolyl, imidazolyl, and triazolyl, and is unsubstituted.

[0216] In various aspects, Ar1 is imidazolyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In a further aspect, Ar1is imidazolyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In a yet further aspect, Ar1is imidazolylsubstituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In a still further aspect, Ar1is imidazolyl monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b. In an even further aspect, Ar1is unsubstituted imidazolyl.

[0217] In various aspects, Ar1 is selected from pyrrolyl, imidazolyl, and triazolyl, andis substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl). In a further aspect, Ar1is selected from pyrrolyl, imidazolyl, and triazolyl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl). In a still further aspect, Ar1is selected from pyrrolyl, imidazolyl, and triazolyl, and is substituted with 0 or 1 group selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl). In a yet further aspect, Ar1is selected from pyrrolyl, imidazolyl, and triazolyl, and is monosubstituted with a group selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl).

[0218] In various aspects, Ar1 is imidazolyl substituted with 0, 1, 2, or 3 groupsindependently selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl). In a further aspect, Ar1is imidazolyl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl). In a further aspect, Ar1is imidazolyl substituted with 0 or 1 group selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl). In a yet further aspect, Ar1is imidazolyl monosubstituted with a group selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl). 2. EXAMPLE COMPOUNDS

[0219] In one aspect, a compound can be present as one or more of the followingstructures:, , ,, ,

[0220] In one aspect, a compound can be present as one or more of the followingstructures: , ,, , ,or a pharmaceutically acceptable salt thereof.

[0221] In one aspect, a compound can be present as one or more of the followingstructures:, , ,or a pharmaceutically acceptable salt thereof.C. PHARMACEUTICAL COMPOSITIONS

[0222] In one aspect, disclosed are pharmaceutical compositions comprising aneffective amount of a compound having a structure represented by a formula:, wherein n is selected from 0, 1, Z1and2Z is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and a pharmaceutically acceptable carrier.

[0223] In one aspect, disclosed are pharmaceutical compositions comprising adisclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1,Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and a pharmaceutically acceptable carrier.

[0224] In one aspect, disclosed are pharmaceutical compositions comprising acompound selected from: , , , or

[0225] In one aspect, disclosed are pharmaceutical compositions comprising acompound selected from:, , or

[0226] In various aspects, the compound is selected from:, , ,, or a pharmaceutically

[0227] In various aspects, the compounds and compositions of the invention can beadministered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration.

[0228] The nature of the pharmaceutical compositions for administration is dependenton the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0229] In various aspects, the disclosed pharmaceutical compositions comprise thedisclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeuticingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0230] In various aspects, the pharmaceutical compositions of this invention caninclude a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0231] The pharmaceutical carrier employed can be, for example, a solid, liquid, orgas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0232] In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0233] A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0234] The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof) as an activeingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0235] Pharmaceutical compositions of the present invention suitable for parenteraladministration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0236] Pharmaceutical compositions of the present invention suitable for injectableuse include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0237] Pharmaceutical compositions of the present invention can be in a form suitablefor topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouthwashes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0238] Pharmaceutical compositions of this invention can be in a form suitable forrectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly usedin the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0239] In addition to the aforementioned carrier ingredients, the pharmaceuticalformulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0240] In a further aspect, an effective amount is a therapeutically effective amount.In a still further aspect, an effective amount is a prophylactically effective amount.

[0241] In a further aspect, the pharmaceutical composition is administered to amammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[0242] In a further aspect, the pharmaceutical composition is used to treat a viralinfection such as, for example, a viral infection due to a Flavivirus (e.g., yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus (WNV), zika (ZIKV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Hepatitis C virus) or an Alphavirus (e.g., Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, Sindbis virus).

[0243] It is understood that the disclosed compositions can be prepared from thedisclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.D. METHODS OF MAKING A COMPOUND

[0244] The compounds of this invention can be prepared by employing reactions asshown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0245] Reactions used to generate the compounds of this invention are prepared byemploying reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-IV, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1. ROUTE 1

[0246] In one aspect, substituted tetrahydrobenzothiophene andtetrahydropyridothiophene compounds can be prepared as shown below.SCHEME 1A.compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 1B.according to reaction Scheme 1B above. Thus, compounds of type 1.6 can be prepared by a cyclization reaction between an appropriate cyclohexanone, e.g., 1.5 as show above, and an appropriate nitrile, e.g., malonitrile as shown above. Appropriate cyclohexanones and appropriate nitriles are commercially available or prepared by methods known to a person of ordinary skill in the art. The cyclization is carried out in the presence of sulfur and an appropriate base, e.g., morpholine, in an appropriate solvent, e.g., methanol, at an appropriatetemperature, e.g., room temperature, for an appropriate period of time, e.g., 1 hour. Compounds of type 1.8 can be prepared by amidation of an appropriate amine, e.g., 1.6 as shown above, using an appropriate carboxylic acid, e.g., 1.7 as shown above. Appropiate carboxylic acids are commercially available or prepared by methods known to person of ordinary skill in the art. The amidation can be carried out in the presence of an appropriate coupling reagent, e.g., hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), and an appropriate base, triethylamine (TEA), in an appropriate solvent, e.g., dichloromethane, at an appropriate temperature, e.g., 39 °C, for an appropriate period of time, e.g., 18 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specificreactants above (compounds similar to compounds of type 1.1, 1.2, and 1.3), can besubstituted in the reaction to provide substituted tetrahydrobenzothiophene andtetrahydropyridothiophene analogs similar to Formula 1.4.2. ROUTE 2

[0249] In one aspect, substituted tetrahydrobenzothiophene andtetrahydropyridothiophene compounds can be prepared as shown below.SCHEME 2A.independently halogen and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME 2B.prepared according to reaction Scheme 2B above. Thus, compounds of type 2.8 can be prepared by a coupling reaction between an appropriate amine, e.g., 2.6 as show above, and an appropriate 2-haloacetyl halide, e.g., 2.7 as shown above. Appropriate amines and appropriate 2-haloacetyl halides are commercially available or prepared by methods known to a person of ordinary skill in the art. The coupling reaction is carried out in the presence of an appropriate base, e.g., pyridine, in an appropriate solvent, e.g., dichloromethane (DCM), at an appropriate temperature, e.g., room temperature, for an appropriate period of time, e.g., 1 hour. Compounds of type 2.10 can be prepared by a coupling reaction between an appropriate halide, e.g., 2.8 as shown above, and an appropriate heteroaryl, e.g., 2.9 as shown above. Appropiate heteroaryls are commercially available or prepared by methods known to one of ordinary skill in the art. The coupling reaction can be carried out in the presence of an appropriate base, e.g., sodium hydride, in an appropriate solvent, e.g., dimethylformamide, at an appropriate temperature, e.g., 50 °C, for an appropriate period of time, e.g., 2 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above(compounds similar to compounds of type 2.1, 2.2, 2.3, and 2.4), can be substituted in thereaction to provide substituted tetrahydrobenzothiophene and tetrahydropyridothiophene analogs similar to Formula 2.5. 3. ROUTE3

[0252] In one aspect, substituted tetrahydrobenzothiophene andtetrahydropyridothiophene compounds can be prepared as shown below.SCHEME 3A.isindependently C1-C4 alkyl and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 3B.

[0254] In one aspect, compounds of type 3.8, and similar compounds, can be preparedaccording to reaction Scheme 3B above. Thus, compounds of type 3.6 can be prepared by reduction of an appropriate alkyl ester, e.g., 3.5 as show above. The reduction is carried out in the presence of an appropriate base, e.g., aqueous lithium hydroxide, in an appropriate solvent system, e.g., tetrahydrofuran (THF) and water, at an appropriate temperature, e.g., 50 °C, for an appropriate period of time, e.g., 14 hours. Compounds of type 3.8 can be prepared by a coupling reaction between an appropriate carboxylic acid, e.g., 3.6 as shown above, and an appropriate amine, e.g., 3.7 as shown above. Appropiate amines are commercially available or prepared by methods known to one of ordinary skill in the art. The coupling reaction can be carried out in the presence of an appropriate coupling agent, e.g.,hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), and an appropriatebase, e.g., diisopropylethylamine (DIPEA), in an appropriate solvent, e.g.,dimethylformamide (DMF), at an appropriate temperature, e.g., room temperature, for an appropriate period of time, e.g., 12 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1, 3.2, and 3.3), can be substituted in the reaction to provide substituted tetrahydrobenzothiopheneand tetrahydropyridothiophene analogs similar to Formula 3.4.4. ROUTE 4

[0255] In one aspect, substituted tetrahydrobenzothiophene andtetrahydropyridothiophene compounds can be prepared as shown below.SCHEME4A. O Randwith other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME4B.

[0257] In one aspect, compounds of type 4.6, and similar compounds, can be preparedaccording to reaction Scheme 4B above. Thus, compounds of type 4.6 can be prepared by reductive acylation of an appropriate nitroarene, e.g., 4.4 as show above, using an appropriatealkanoic acid, e.g., 4.5 as shown above. Appropiate alkanoic acids are commercially available or prepared by methods known to one of ordinary skill in the art. The reductive acylation is carried out in the presence of an appropriate reducing agent, e.g., iron, and an appropriate acid or acid anhydride, e.g., acetic anhydride, at an appropriate temperature, e.g., 80 °C, for an appropriate period of time, e.g., 2 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 4.1 and 4.2), can be substituted in the reaction to provide substitutedtetrahydrobenzothiophene and tetrahydropyridothiophene analogs similar to Formula 4.3.5. ROUTE 5

[0258] In one aspect, substituted tetrahydrobenzothiophene andtetrahydropyridothiophene compounds can be prepared as shown below.SCHEME 5A.

[0259] X2 isindependently halogen and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 5B.according to reaction Scheme 5B above. Thus, compounds of type 5.8 can be prepared by protection of an appropriate aminothiophene, e.g., 5.5 as show above. See also WO 2005 / 044008 A2. Appropriate aminothiophenes are commercially available or prepared bymethods known to a person of ordinary skill in the art. The protection is carried out in the presence of an appropriate protecting agent, e.g., di-tert-butyl dicarbonate, and an appropriate base, e.g., 4-dimethylaminopyridine (DMAP), in an appropriate solvent, e.g., acetonitrile, at an appropriate temperature, e.g., room temperature. Compounds of type 5.8 can be prepared by alkylation of an appropriate amine, e.g., 5.6 as shown above, using an appropriate alkyl halide, e.g., 5.7 as shown above, followed by deprotection. Appropiate alkyl halides are commercially available or prepared by methods known to one of ordinary skill in the art. The alkylation can be carried out in the presence of an appropriate base, e.g., sodium hydride, in an appropriate solvent, e.g., tetrahydrofuran, at an appropriate temperature, e.g., room temperature. The deprotection can then be carried out in the presence of an appropriate acid, e.g., trifluoroacetic acid (TFA), in an appropriate solvent, e.g., dichloromethane (DCM). As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 5.1, 5.2, and 5.3), can be substituted in the reactionto provide substituted tetrahydrobenzothiophene and tetrahydropyridothiophene analogssimilar to Formula 5.4.E. METHODS OF USING THE COMPOUNDS

[0261] The compounds and pharmaceutical compositions of the invention are usefulin treating or controlling disorders associated with a viral infection. To treat or control the disorder, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a viral infection, such as, for example, a viral infection due to a Flavivirus (e.g., yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus (WNV), zika (ZIKV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Hepatitis C virus) or an Alphavirus (e.g., Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, Sindbis virus).

[0262] The compounds or compositions can be administered to the subject accordingto any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of a viral infection, such as, for example, a viral infection due to a Flavivirus (e.g., yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus (WNV), zika (ZIKV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Hepatitis C virus) or an Alphavirus (e.g., Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, Sindbis virus).

[0263] The therapeutically effective amount or dosage of the compound can varywithin wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. 1. TREATMENT METHODS

[0264] The compounds disclosed herein are useful for treating or controllingdisorders associated with a viral infection such as, for example, a viral infection due to a Flavivirus (e.g., yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus(WNV), zika (ZIKV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Hepatitis C virus) or an Alphavirus (e.g., Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, Sindbis virus). In a further aspect, the viral infection is due to a Flavivirus. In a still further aspect, the Flavivirus is selected from yellow fever, Japanese encephalitis, dengue (DENV), influenza, West Nile virus (WNV), and zika (ZIKV). In yet a further aspect, the Flavivirus is DENV. Thus, provided is a method comprising administering a therapeutically effective amount of a disclosed compound to a subject. In a further aspect, the method can be a method for treating a viral infection. a. TREATING A VIRAL INFECTION IN A SUBJECT

[0265] In one aspect, disclosed are methods for treating a viral infection in a subjectin need thereof, the method comprising administering to the subject a compound having a structure represented by a formula: , wherein n is selected from 0, 1,Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, wherein the viral infection is due to a Flavivirus or due to an Alphavirus.

[0266] In one aspect, disclosed are methods of treating a viral infection in a subjecthaving the viral infection, the method comprising the step of administering to the subject a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof. Thus, in one aspect, disclosed are methods of treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: wherein n is selected from 0, 1,and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen,‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, wherein the viral infection is due to a Flavivirus or due to an Alphavirus.

[0267] In one aspect, disclosed are methods for treating a viral infection in a subjectin need thereof, the method comprising administering to the subject a compound selected from:, , , or

[0268] In one aspect, disclosed are methods for treating a viral infection in a subjectin need thereof, the method comprising administering to the subject a compound selected from:, , or

[0269] In various aspects, the compound is selected from :, , ,, or a pharmaceutically

[0270] In various aspects, the viral infection is due to a Flavivirus. Examples of viralinfections due to a Flavivirus include, but are not limited to, yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus (WNV), zika (ZIKV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, and Hepatitis C virus. In a further aspect, the Flavivirus is selected from yellow fever, Japanese encephalitis, dengue (DENV), influenza, West Nile virus (WNV), and zika (ZIKV). In a yet further aspect, the Flavivirus is DENV.

[0271] In various aspects, the viral infection is due to an Alphavirus. Examples ofAlphaviruses include, but are not limited to, Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, and Sindbis virus.

[0272] In a further aspect, the subject is a mammal. In a still further aspect, themammal is a human.

[0273] In a further aspect, the subject has been diagnosed with a need for treatment ofthe viral infection prior to the administering step.

[0274] In a further aspect, the method further comprises the step of identifying asubject in need of treatment of the viral infection.

[0275] In a further aspect, the effective amount is a therapeutically effective amount.In a still further aspect, the effective amount is a prophylactically effective amount.

[0276] In a further aspect, the method further comprises the step of administering atherapeutically effective amount of at least one antiviral agent. In a still further aspect, the at least one agent is selected from acemannan, acyclovir, acyclovir sodium, adamantanamine, adefovir, adenine arabinoside, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate, avridine, cidofovir, cipamfylline, cytarabine hydrochloride, BMS 806, C31G, carrageenan, cellulose sulfate, cyclodextrins, dapivirine, delavirdine mesylate, desciclovir, dextrin 2-sulfate, didanosine, disoxaril, dolutegravir, edoxudine, enviradene, envirozime, etravirine, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet sodium, fosfonet sodium, FTC, ganciclovir,ganciclovir sodium, GSK 1265744, 9-2-hydroxy-ethoxy methylguanine, ibalizumab, idoxuridine, interferon, 5-iodo-2′-deoxyuridine, IQP-0528, kethoxal, lamivudine, lobucavir, maraviroc, memotine pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statolon, stavudine, T20, tilorone hydrochloride, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxyl fumarate, prodrugs of tenofovir, UC-781, UK-427, UK-857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabene, zidovudine, and zinviroxime.

[0277] In a further aspect, the at least one compound and the at least one agent areadministered sequentially. In a still further aspect, the at least one compound and the at least one agent are administered simultaneously.

[0278] In a further aspect, the at least one compound and the at least one agent are co-formulated. In a still further aspect, the at least one compound and the at least one agent are co-packaged. 2. USE OF COMPOUNDS

[0279] In one aspect, the invention relates to the use of a disclosed compound or aproduct of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for the treatment of a viral infection in a subject.

[0280] Also provided are the uses of the disclosed compounds and products. In oneaspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0281] In a further aspect, the use relates to a process for preparing a pharmaceuticalcomposition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[0282] In a further aspect, the use relates to a process for preparing a pharmaceuticalcomposition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of the compound or the product of a disclosed method of making.

[0283] In various aspects, the use relates to a treatment of a viral infection in asubject. Also disclosed is the use of a compound for antagonism or inhibition of a viral infection. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the viral infection is due to a Flavivirus. In one aspect, the use is characterized in that the viral infection is due to an Alphavirus.

[0284] In a further aspect, the use relates to the manufacture of a medicament for thetreatment of a viral infection in a subject.

[0285] In a further aspect, the use relates to antagonism or inhibition of a viralinfection in a subject. In a further aspect, the use relates to modulating viral activity in a subject. In a still further aspect, the use relates to modulating viral activity in a cell. In yet a further aspect, the subject is a human.

[0286] It is understood that the disclosed uses can be employed in connection with thedisclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a viral infection in a mammal. In a further aspect, the viral infection is due to a Flavivirus (e.g., yellow fever, Japanese encephalitis, dengue (DENV), West Nile virus (WNV), zika (ZIKV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Hepatitis C virus) or an Alphavirus (e.g., Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, Sindbis virus). In a further aspect, the viral infection is due to a Flavivirus. In a still further aspect, the Flavirus is DENV. 3. MANUFACTURE OF A MEDICAMENT

[0287] In one aspect, the invention relates to a method for the manufacture of amedicament for treating a viral infection in a subject having the viral infection, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[0288] As regards these applications, the present method includes the administrationto an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the inhibition of a viral infection. The doseadministered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.

[0289] The total amount of the compound of the present disclosure administered in atypical treatment is preferably between about 10 mg / kg and about 1000 mg / kg of body weight for mice, and between about 100 mg / kg and about 500 mg / kg of body weight, and more preferably between 200 mg / kg and about 400 mg / kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[0290] The size of the dose also will be determined by the route, timing andfrequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

[0291] Thus, in one aspect, the invention relates to the manufacture of a medicamentcomprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent. 4. KITS

[0292] In one aspect, disclosed are kits comprising a compound having a structurerepresented by a formula: ,wherein n is selected from 0, 1, Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and one or more selected from: (a) at least one antiviral agent; (b) instructions for administering the compound in connection with treating a viral infection; (c) instructions for administering the compound in connection with reducing the risk of a viral infection; and (d) instructions for treating a viral infection, wherein the viral infection is due to a Flavivirus or an Alphavirus.

[0293] In one aspect, disclosed are kits comprising at least one disclosed compoundand one or more of: (a) at least one antiviral agent; (b) instructions for administering the compound in connection with treating a viral infection; (c) instructions for administering the compound in connection with reducing the risk of viral infection; and (d) instructions fortreating a viral infection. Thus, in one aspect, disclosed are kits comprising a compound having a structure represented by a formula: , wherein n is selected from 0, 1,1 2Z and Z is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert- butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and one or more selected from: (a) at least one antiviral agent; (b) instructions for administering the compound in connection with treating a viral infection; (c) instructions for administering the compound inconnection with reducing the risk of a viral infection; and (d) instructions for treating a viral infection, wherein the viral infection is due to a Flavivirus or an Alphavirus.

[0294] In one aspect, disclosed are kits comprising a compound selected from:, , , orone antiviral agent; (b) instructions for administering the compound in connection with treating a viral infection; (c) instructions for administering the compound in connection with reducingthe risk of a viral infection; and (d) instructions for treating a viral infection, wherein the viral infection is due to a Flavivirus or an Alphavirus.

[0295] In one aspect, disclosed are kits comprising a compound selected from:, ,or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) at least one antiviral agent; (b) instructions for administering the compound in connection with treating a viral infection; (c) instructions for administering the compound in connection with reducing the risk of a viral infection; and (d) instructions for treating a viral infection, wherein the viral infection is due to a Flavivirus or an Alphavirus.

[0296] In various aspects, the viral infection is due to a Flavivirus. Examples of aFlaviviruses include, but are not limited to, dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valleyencephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and Hepatitis C virus. In a further aspect, the Flavivirus is DENV.

[0297] In various aspects, the viral infection is due to an Alphavirus. Examples ofAlphaviruses include, but are not limited to, Venezeulan equine encephalitis virus, chikungunya virus (CHIKV), Ross River virus, Mayaro virus, and Sindbis virus.

[0298] In a still further aspect, the antiviral agent is selected from selected fromacemannan, acyclovir, acyclovir sodium, adamantanamine, adefovir, adenine arabinoside, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate, avridine, cidofovir, cipamfylline, cytarabine hydrochloride, BMS 806, C31G, carrageenan, cellulose sulfate, cyclodextrins, dapivirine, delavirdine mesylate, desciclovir, dextrin 2-sulfate, didanosine, disoxaril, dolutegravir, edoxudine, enviradene, envirozime, etravirine, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet sodium, fosfonet sodium, FTC, ganciclovir, ganciclovir sodium, GSK 1265744, 9-2-hydroxy- ethoxy methylguanine, ibalizumab, idoxuridine, interferon, 5-iodo-2′-deoxyuridine, IQP- 0528, kethoxal, lamivudine, lobucavir, maraviroc, memotine pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statolon, stavudine, T20, tilorone hydrochloride, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxyl fumarate, prodrugs of tenofovir, UC-781, UK-427, UK- 857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabene, zidovudine, and zinviroxime.

[0299] In a further aspect, the at least one compound and the at least one agent are co-formulated. In a further aspect, the at least one compound and the at least one agent are co- packaged.

[0300] The kits can also comprise compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0301] It is understood that the disclosed kits can be prepared from the disclosedcompounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.

[0302] The foregoing description illustrates and describes the disclosure.Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations,modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[0303] All publications and patent applications cited in this specification are hereinincorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.F. EXAMPLES

[0304] The following examples are put forth so as to provide those of ordinary skill inthe art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0305] The Examples are provided herein to illustrate the invention, and should notbe construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. CHEMISTRY EXPERIMENTALS a. GENERAL EXPERIMENTAL METHODS

[0306] The reactions were performed under a dry argon atmosphere and reactiontemperatures were measured externally. Anhydrous solvents over molecular sieves were purchased from Aldrich and used as such in reactions. The reactions were monitored by thin-layer chromatography (TLC) on pre-coated silica gel (6OF254) aluminum plates (0.25 mm) from E. Merck and visualized using UV light (254 nm). Purification of compounds was performed on an Isco Teledyne Combiflash Rf200. Universal RediSep solid sample loading pre-packed cartridges (5.0 g silica) were used to absorb crude product and purified on silica RediSep Rf Gold Silica (20- 40 pm spherical silica) columns using appropriate solvent gradients. Pure samples were dried overnight under high vacuum before analyses. The high- resolution electrospray ionization mass spectral data (HR-ESIMS) were obtained on an Agilent LC-MSTOF.1H,13C,19F, and31P NMR spectra were recorded at 400, 101, 376 and 162 MHz respectively on an Agilent / Varian MR-400 spectrometer. The chemical shifts (δ) are in ppm downfield from standard tetramethyl silane (TMS). HPLC of final compounds were run on an Agilent 1100 LC equipped with a diode array UV detector and were monitored at 254 nm by using one of the following methods Method A: Sunfire C18 column (5gm, 4.6 χ 150 mm) using H2O-CH3CN (both containing 0.1% formic acid) 5-95% in 20 min with flow rate 1.0 mL / min.; Method B: Phenomenex Kinetex 2.6μ Phenyl-hexyl 100 A 50 X 4.6 mm column using Solvent A: 95:5 H2O-MeCN with 1% HCO2H, Solvent B: MeCN with 0.1% HCO2H, flow rate 2.0 mL / min; 4 min linear gradient from 5-95% B. b. GENERAL PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 1-10i. SYNTHESIS OF COMPOUND 1

[0307] Step 1:6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (Int-1A). A solution of sulfur (416 mg, 12.97 mmol),triethylamine (5.4216 mL, 38.9 mmol), malononitrile (0.86 g, 12.97 mmol) and 4-tert- butylcyclohexanone (SM-A) (2 g, 12.97 mmol) in anhydrous methanol (30 mL) was stirred at 70oC for 2 hrs. The solvent was evaporated, the residue was diluted with DCM (50 mL) and washed with H2O (2 x 30 mL) and brine (30 mL). The organic layer was collected, dried over anhydrous Na2SO4. The excess solvent was removed under vacuum, and the residue was purified by a flash column chromatography (ISCO, 24 g RediSep silica column, 1-2% MeOH in DCM) to yield the product 2-amino-6-tert-butyl-4,5,6,7-tetrahydrobenzothiophene-3- carbonitrile (Int-1A) (2.457g, 81% yield) as a light brown solid. LCMS (ESI): [M+H]+= 235.1.1H NMR (400 MHz, DMSO-d6) δ 6.91 (s, 2H), 2.43 (d, J = 15.9 Hz, 3H), 2.34 – 2.09 (m, 2H), 1.98 – 1.82 (m, 1H), 1.40 (tt, J = 11.3, 5.5 Hz, 1H), 1.21 (tt, J = 12.4, 6.0 Hz, 1H), 0.87 (s, 9H).

[0308] Step 2: Synthesis of N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (1). HATU (1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (243 mg, 0.64 mmol) and triethylamine (0.18 mL, 1.28 mmol) were added to a solution of (2-methyl-imidazol-1-yl)-acetic acid (SM-1) (598 mg, 0.43 mmol) in anhydrous DCM (8 mL). After stirring for 10 min at rt, 2-amino-6-tert-butyl-4,5,6,7- tetrahydro-1-benzothiophene -3-carbonitrile (Int-1A) (100 mg, 0.43 mmol) was added. The reaction mixture was then stirred at 39oC for 18 hrs. After cooling to rt, the reaction mixture was treated with ice cold H2O (10 mL) and extracted with DCM (3 x 10mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to obtained the product N-(6-(tert- butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (1) (79 mg, 52%) as an orange solid. 1H NMR (400 MHz, CD3OD) δ 7.41(d, J = 1.9 Hz, 1H), 6.13 (d, J = 1.6 Hz, 1H), 5.11 (s, 2H), 2.80 – 2.64 (m, 2H), 2.52 – 2.35 (m, 2H), 2.31 (s, 3H), 2.10 (d, J = 13.0 Hz, 1H), 1.51 (td, J = 11.5, 4.3 Hz, 1H), 1.41 – 1.28 (m, 1H), 0.96 (s, 9H). HRMS [M+H]+calculated = 357.1749, found = 357.1754. ii. SYNTHESIS OF COMPOUND 2

[0309] Step 2:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(5-methyl-1H-pyrazol-1-yl)acetamide (2). BOP-Cl (273 mg, 1.07 mmol) and triethylamine (0.30 mL, 2.14 mmol) were added to a solution of 2-(5- methyl-1H-pyrazol-1-yl)acetic acid (SM-2) (100 mg, 0.71 mmol) in anhydrous DCM (7 mL) at rt. After stirring for 10 min, 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carbonitrile (Int-1A) (167 mg, 0.71 mmol) was added and the reaction mixture was then stirred at 39oC for 18 hrs. The reaction mixture was basified with 2 N NaOH and extracted with DCM (3 x 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(5-methyl-1H-pyrazol-1-yl)acetamide (2) (81 mg, 31%) as a light yellow solid. HRMS[M+H]+calculated = 357.1749, found = 357.1752.1H NMR (400 MHz, CD3OD) δ 7.41 (d, J = 1.9 Hz, 1H), 6.13 (d, J = 1.6 Hz, 1H), 5.11 (s, 2H), 2.80 – 2.64 (m, 2H), 2.52 – 2.35 (m, 2H), 2.31 (s, 3H), 2.10 (d, J = 13.0 Hz, 1H), 1.51 (td, J = 11.5, 4.3 Hz, 1H), 1.41 – 1.28 (m, 1H), 0.96 (s, 9H). iii. SYNTHESIS OF COMPOUND 3

[0310] Step 2: Synthesis of N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-pyrrol-1-yl)acetamide (3). BOP-Cl (82 mg, 0.32 mmol) and triethylamine (0.09 mL, 0.64 mmol) were added to a solution of 2-(2- methylpyrrol-1-yl)acetic acid (SM-3) (30 mg, 0.21 mmol) in anhydrous DCM (2 mL) at rt. After stirring for 10 min, 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carbonitrile (Int-1A) (50 mg, 0.21 mmol) was added and the reaction mixture was thenstirred at 39 oC for 18 hrs. The reaction mixture was basified with 2 N NaOH and extractedwith DCM (3 x 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 12 g RediSep silica column, 1-30% EtOAc in hexane) to yield the product N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-pyrrol-1-yl)acetamide (3) (20 mg, 26%) to yield the product as a whitesolid. HRMS [M+H]+calculated = 356.1800, found = 356.1795.1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 6.63 (t, J = 2.4 Hz, 1H), 5.85 (t, J = 3.1 Hz, 1H), 5.78 – 5.69 (m, 1H), 4.86 (s, 2H), 3.40 (s, 1H), 2.63 (d, J = 15.6 Hz, 2H), 2.33 (d, J = 13.9 Hz, 1H), 2.07 (s, 3H), 1.98 (d, J = 12.4 Hz, 1H), 1.48 – 1.39 (m, 1H), 1.26 (td, J = 12.6, 5.4 Hz, 1H), 0.89 (s, 9H). iv. SYNTHESIS OF COMPOUND 4

[0311] Step 2:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(5-chloropyridin-2-yl)acetamide (4). HATU (266 mg, 0.70 mmol) and triethylamine (0.20 mL, 1.4 mmol) were added to a solution of 2-(5- chloropyridin-2-yl)acetic acid (SM-4) (80 mg, 0.47 mmol) in anhydrous DCM (9 mL). After stirring for 10 min at rt, 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carbonitrile (Int-1A) (109 mg, 0.47 mmol) was added. The reaction mixture was then stirred at 39oC for 18 hrs. After cooling to rt, the reaction mixture was treated with ice cold H2O (10 mL) and extracted with DCM (3 x 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silicacolumn, 1-30% EtOAc in hexane) to yield the product N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(5-chloropyridin-2-yl)acetamide (4) (91 mg, 50%) as alight-yellow solid. HRMS [M+H]+calculated = 388.1250, found = 388.1257.1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.3, 2.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 4.04 (s, 2H), 2.70 – 2.56 (m, 3H), 2.34 – 2.26 (m, 1H), 1.98 (d, J = 11.6 Hz, 1H), 1.47 – 1.36 (m, 1H), 1.24 (dd, J = 12.4, 5.1 Hz, 1H), 0.89 (s, 9H). v. SYNTHESIS OF COMPOUND 5Cl N

[0312] Step 2:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(5-chloropyrimidin-2-yl)acetamide (5). BOP-Cl (66 mg, 0.26 mmol) and triethylamine (0.07 mL, 0.52 mmol) were added to a solution of (5- chloropyrimidin-2-yl)acetic acid (SM-5) (30 mg, 0.17 mmol) in anhydrous DCM (2 mL) at rt. After stirring for 10 min, 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carbonitrile (Int-1A) (41 mg, 0.17 mmol) was added and the reaction mixture was then stirred at 39oC for 18 hrs. The reaction mixture was basified with 2 N NaOH and extracted with DCM (3 x 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-30% EtOAc in hexane) to yield the product N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(5-chloropyrimidin-2-yl)acetamide (5) (28 mg, 41%) as a yellow solid. HRMS[M+H]+calculated = 389.1203, found = 389.1213.1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.89 (s, 2H), 4.19 (s, 2H), 2.75 – 2.53 (m, 3H), 2.31 (t, J = 14.2 Hz, 1H), 2.05 – 1.93 (m, 1H), 1.48 – 1.40 (m, 1H), 1.31 – 1.20 (m, 1H), 0.89 (s, 9H). vi. SYNTHESIS OF COMPOUND 6

[0313] Step 2:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(4-methylthiazol-2-yl)acetamide (6). HATU (109 mg, 0.29 mmol) and triethylamine (0.08 mL, 0.57 mmol) were added to a solution of 2-(4- methylthiazol-2-yl)acetic acid (SM-6) (30 mg, 0.19 mmol) in anhydrous DCM (4 mL). After stirring for 10 min at rt, 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carbonitrile (Int-1A) (45 mg, 0.19 mmol) was added. The reaction mixture was then stirred at 39oC for 18 hrs. After cooling to rt, the reaction mixture was treated with ice cold H2O (10 mL) and extracted with DCM (3 x 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 4 g RediSep silica column, 1- 9% MeOH in DCM) to obtain the product N-(6-(tert-butyl)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)-2-(4-methylthiazol-2-yl)acetamide (6) (15 mg, 21%) as a light yellow solid. HRMS [M+H]+calculated = 374.1361, found = 374.1371.1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.18 (s, 1H), 4.25 (s, 2H), 2.75 – 2.55 (m, 3H), 2.44 – 2.38 (m, 1H), 2.32 (s, 3H), 1.98 (d, J = 12.4 Hz, 1H), 1.49 – 1.39 (m, 1H), 1.31 – 1.21 (m, 1H), 0.89 (s, 9H). vii. SYNTHESIS OF COMPOUND 7

[0314] Step 2:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-1-methyl-1H-imidazole-4-carboxamide (7). BOP-Cl (49mg, 0.19 mmol) and triethylamine (0.05 mL, 0.38 mmol) were added to a solution of 1- methyl-1H-imidazole-4-carboxylic acid (0.0161g, 0.1300mmol) in anhydrous DCM (1 mL) at rt. After stirring for 10 min, 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carbonitrile (Int-1A) (30 mg, 0.13 mmol) was added and the reaction mixture was thenstirred at 39oC for 18 hrs. The reaction mixture was basified with NaOH (2N) and extracted with DCM (3 x 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-1-methyl-1H-imidazole-4-carboxamide (10 mg, 23%) as a beige solid. HRMS [M+H]+calculated = 343.1592, found = 343.1601.1H NMR (400 MHz, CD3OD) δ 7.84 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 3.80 (s, 3H), 2.83 – 2.76 (m, 1H), 2.75 – 2.72 (m, 1H), 2.56 – 2.37 (m, 2H), 2.16 – 2.06 (m, 1H), 1.58 – 1.49 (m, 1H), 1.44 – 1.32 (m, 1H), 0.97 (s, 9H). viii. SYNTHESIS OF COMPOUND 8

[0315] Step 2: Synthesis[b]thiophen-2-yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (8). HATU (224 mg, 0.59 mmol) and triethylamine (0.16 mL, 1.18 mmol) were added to a solution of (2-methyl-imidazol-1-yl)-acetic acid (SM- 8) (55 mg, 0.39 mmol) in anhydrous DCM (8 mL). After stirring for 10 min at rt, 2-amino- 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (Int-1B, prepared by the procedure similar to that for the preparation of Int-1A) (70 mg, 0.39 mmol) was added. The reaction mixture was then stirred at 39 °C for 18 hrs. After cooling to rt, the reaction mixture was treated with ice cold H2O (10 mL) and extracted with DCM (3 × 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (8) (37mg, 31%) as a white solid. HRMS [M+H]+calculated = 301.1123, found = 301.1122.1H NMR (400 MHz, CD3OD) δ 7.02 (d, J = 1.5 Hz, 1H), 6.85 (d, J = 1.5 Hz, 1H), 4.99 (s, 2H), 4.57 (s, 1H), 2.64 – 2.56 (m, 4H), 2.33 (s, 3H), 1.88 – 1.81 (m, 4H). ix. SYNTHESIS OF COMPOUND 9

[0316] Step 2: tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (9). HATU (138 mg, 0.36 mmol) andtriethylamine (0.10 mL, 0.73 mmol) were added to a solution of (2-methyl-imidazol-1-yl)- acetic acid (SM-9) (34 mg, 0.24 mmol) in anhydrous DCM (5 mL). After stirring for 10 minat rt, 2-amino-6-ethyl-4,5,6,7-tetrahydrobenzothiophene-3-carbonitrile (Int-1C, prepared bythe procedure similar to that for the preparation of Int-1A) (50 mg, 0.24 mmol) was added. The reaction mixture was then stirred at 39 °C for 18 hrs. After cooling to rt, the reaction mixture was treated with ice cold H2O (10 mL) and extracted with DCM (3 × 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product N-(3-cyano-6-ethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (9) (24 mg, 30%) as a beige solid. HRMS [M+H]+ calculated =329.1436, found = 329.1442.1H NMR (400 MHz, CD3OD) δ 7.02 (d, J = 1.5 Hz, 1H), 6.85 (d, J = 1.5 Hz, 1H), 4.98 (s, 2H), 2.80 – 2.63 (m, 2H), 2.59 – 2.47 (m, 1H), 2.33 (s, 3H), 2.29 – 2.18 (m, 1H), 2.01 (d, J = 9.5 Hz, 1H), 1.72 – 1.63 (m, 1H), 1.50 – 1.37 (m, 3H), 0.99 (t, J = 7.4 Hz, 3H). x. SYNTHESIS OF COMPOUND 10

[0317] Step 2: Synthesis4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (10). HATU (277 mg, 0.73 mmol) and triethylamine (0.20 mL, 1.45 mmol) were added to a solution of (2- methyl-imidazol-1-yl)-acetic acid (SM-10) (68 mg, 0.48 mmol) in anhydrous DCM (9 mL). After stirring for 10 min at rt, 2-amino-6,6-dimethyl-5,7-dihydro-4H-benzothiophene-3-carbonitrile (Int-1D, prepared by the procedure similar to that for the preparation of Int-1A) (100 mg, 0.48 mmol) was added. The reaction mixture was then stirred at 39 °C for 18 hrs. After cooling to rt, the reaction mixture was treated with ice cold H2O (10 mL) and extracted with DCM (3 × 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product N-(3-cyano-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (10) (85 mg, 51%) as a light yellow solid. HRMS [M+H]+calculated = 329.1436, found = 329.1443.1H NMR (400 MHz, CD3OD) δ 7.20 (s, 1H), 7.07 (s, 1H), 5.09 (s, 2H), 2.60 (t, J = 6.5 Hz, 2H), 2.43 (s, 3H), 2.41 (t, J = 1.6 Hz, 2H), 1.60 (t, J = 6.5 Hz, 2H), 1.01 (s, 6H). c. GENERAL PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 11-19

[0318] Step 2’: Synthesis of N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetamide (11). BOP-Cl (891 mg, 3.5 mmol) and triethylamine (1 mL, 7 mmol) were added to a solution of 2- (2-methyl-5-nitro-imidazol-1-yl)acetic acid (SM-11) (432 mg, 2.33 mmol) in anhydrous DCM (23 mL) at rt. After stirring for 10 min, 2-amino-6-tert-butyl-4,5,6,7- tetrahydro-1-benzothiophene-3-carbonitrile (Int-1A) (547 mg, 2.33 mmol) was added and the reaction mixture was then stirred at 39oC for 18 hrs. The reaction mixture was basified with 2 N NaOH and extracted with DCM (3 x 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 12 g RediSep silica column, 1-9% MeOH in DCM ) as N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetamide (11), asa tan solid (378 mg, 40%).1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.30 (s, 1H), 5.14 (s, 2H), 2.64 (d, J =16.2 Hz, 2H), 2.45 – 2.37 (m, 1H), 2.36 – 2.30 (m, 1H), 2.27 (s, 3H), 2.04 – 1.94 (m, 1H), 1.49 – 1.38 (m, 1H), 1.29 – 1.21 (m, 1H), 0.89 (s, 9H). ii. SYNTHESIS OF COMPOUND 12

[0319] Step 3’:1H-imidazol-1-yl)-N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (12). Iron (49 mg, 0.87 mmol) was added to a solution of N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetamide (11) (100mg, 0.25 mmol) and acetic anhydride (0.09 mL, 1 mmol) in AcOH (1 mL) at rt. The reaction mixture was then stirred at 80 °C for 2 hrs. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate was washed with NaHCO3(saturated solution in H2O). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM ) to yield the product 2-(5-acetamido-2-methyl-1H-imidazol-1-yl)-N-(6-(tert-butyl)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)acetamide (12) (77 mg, 74%) as a light yellow solid.HRMS [M+H]+calculated = 414.1964, found = 414.1971.1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.10 (s, 1H), 7.08 (s, 1H), 4.90 (s, 2H), 2.63 (d, J = 16.4 Hz, 2H), 2.44 – 2.36 (m, 1H), 2.35 – 2.26 (m, 1H), 2.15 (s, 3H), 2.01 – 1.95 (m, 1H), 1.93 (s, 3H), 1.48 – 1.38 (m, 1H), 1.24 (dd, J = 12.4, 5.1 Hz, 1H), 0.89 (s, 9H). iii. SYNTHESIS OF COMPOUND 13

[0320] Step 2’:6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetamide (Int-2E). BOP-Cl (173 mg, 0.68 mmol) and triethylamine (0.19 mL, 1.36 mmol) were added to a solution of 2-(2-methyl-5-nitro-imidazol-1-yl)acetic acid (SM-11) (84 mg, 0.45 mmol) in anhydrous DCM (4 mL) at rt. After stirring for 10 min, 2-amino-6-isopropyl-4,5,6,7-tetrahydrobenzothiophene-3-carbonitrile (Int-1E) (100 mg, 0.45 mmol) was added and thereaction mixture was then stirred at 39oC for 18 hrs. The reaction mixture was basifiedwith 2 N NaOH and extracted with DCM (3 x 10 mL). The organic layer was collected andevaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 12 g RediSep silica column, 1-9% MeOH in DCM) to yield the product N-(3-cyano-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(2-methyl-5- nitro-1H-imidazol-1-yl)acetamide (Int-2E) an orange solid (40 mg, 23%).1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 5.13 (s, 2H), 2.75 – 2.67 (m, 2H), 2.56 – 2.46 (m, 1H), 2.37 (s, 3H), 2.05 – 1.99 (m, 1H), 1.67 – 1.56 (m, 2H), 1.49 – 1.39 (m, 1H), 1.32 – 1.24 (m, 1H), 0.99 – 0.96 (m, 6H).

[0321] Step 3’: Synthesis of 2-(5-acetamido-2-methyl-1H-imidazol-1-yl)-N-(3-cyano-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (13). Iron (20 mg, 0.36mmol) was added to a solution of N-(3-cyano-6-isopropyl-4,5,6,7-tetrahydrobenzothiophen- 2-yl)-2-(2-methyl-5-nitro-imidazol-1-yl)acetamide (Int-2E) (40 mg, 0.10 mmol) and acetic anhydride (0.04 mL, 0.41 mmol) in AcOH (1 mL) at rt. The reaction mixture was then stirred at 80oC for 1 hr. After cooling to rt, the reaction mixture was filtered through celite and washed with EtOAc. The filtrate was neutralized with NaHCO3 (saturated solution in H2O). The organic layer was collected and evaporated to dryness under reduced pressure to give aresidue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product 2-(5-acetamido-2-methyl-1H-imidazol-1- yl)-N-(3-cyano-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (13) (30 mg, 73%) as a yellow solid. HRMS [M+H]+calculated = 400.1807, found = 400.1808.1H NMR (400 MHz, CD3OD) δ 7.15 (s, 1H), 4.93 (s, 2H), 2.75 – 2.65 (m, 2H), 2.57 – 2.46 (m, 1H), 2.41 – 2.32 (m, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 2.05 – 1.99 (m, 1H), 1.72 – 1.53 (m, 2H), 1.50 – 1.39 (m, 1H), 1.00 – 0.94 (m, 6H). iv. SYNTHESIS OF COMPOUND 14

[0322] Step 3’:1H-imidazol-1-yl)-N-(3-cyano-6-methoxy-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (14). Iron (17 mg, 0.30 mmol)was added to a solution of N-(3-cyano-6-methoxy-4,5,6,7-tetrahydrobenzothiophen-2-yl)-2- (2-methyl-5-nitro-imidazol-1-yl)acetamide (Int-2F, prepared by the procedure similar to that for the preparation of Int-2E) (32 mg, 0.09 mmol) and acetic anhydride (0.03 mL, 0.34 mmol) in AcOH (1 mL) at rt. The reaction mixture was then stirred at 80oC for 3 hrs. After cooling to rt, the reaction mixture was filtered through celite and washed with EtOAc. The filtrate was neutralized with NaHCO3(saturated solution in H2O). The aqueous layer was collected and evaporated to dryness under reduced pressure to give a residue, which was purified by flash column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product 2-(5-acetamido-2-methyl-1H-imidazol-1-yl)-N-(3-cyano-6- methoxy-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (14) (16 mg, 48%) as a white solid. HRMS [M+H]+calculated = 388.1443, found = 388.1442.1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 10.10 (s, 1H), 7.08 (s, 1H), 4.90 (s, 2H), 3.70 – 3.62 (m, 1H), 3.26 (s, 3H), 2.93 – 2.82 (m, 1H), 2.72 – 2.57 (m, 1H), 2.56 – 2.51 (m, 2H), 2.15 (s, 3H), 1.93 (s, 3H), 1.90 – 1.73 (m, 2H). v. SYNTHESIS OF COMPOUND 15

[0323] Step 3’:imidazol-1-yl)-N-(3-cyano-6-isopropoxy-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (15). Iron (20 mg, 0.36mmol) was added to a solution of N-(3-cyano-6-isopropoxy-4,5,6,7-tetrahydrobenzothiophen- 2-yl)-2-(2-methyl-5-nitro-imidazol-1-yl)acetamide (Int-2G, prepared by the procedure similar to that for the preparation of Int-2E) (41 mg, 0.10 mmol) and acetic anhydride (0.04 mL, 0.41 mmol) in AcOH (1 mL) at rt. The reaction mixture was then stirred at 80oC for 2 hrs. After cooling to rt, the reaction mixture was filtered through celite and washed with EtOAc. The filtrate was neutralized with NaHCO3 (saturated solution in H2O). The aqueous layer was collected and evaporated to dryness under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product 2-(5-acetamido-2-methyl-1H-imidazol-1-yl)-N-(3- cyano-6-isopropoxy-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (15) (20 mg, 47%) as a white solid. HRMS [M+H]+calculated = 416.1756, found = 416.1758.1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 10.10 (s, 1H), 7.08 (s, 1H), 4.90 (s, 2H), 3.88 – 3.80 (m, 1H), 3.73 (p, J = 6.0 Hz, 1H), 2.91 – 2.81 (m, 1H), 2.60 – 2.50 (m, 3H), 2.15 (s, 3H), 1.93 (s, 3H), 1.90 – 1.83 (m, 1H), 1.79 – 1.67 (m, 1H), 1.06 (t, J = 6.7 Hz, 6H). vi. SYNTHESIS OF COMPOUND 16FFO

[0324] Step 3’:1H-imidazol-1-yl)-N-(3-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (16). Iron (100 mg,1.80 mmol) was added to a solution of N-[3-cyano-6-(trifluoromethyl)-4,5,6,7- tetrahydrobenzothiophen-2-yl]-2-(2-methyl-5-nitro-imidazol-1-yl)acetamide (Int-2H, prepared by the procedure similar to that for the preparation of Int-2E) (212 mg, 0.51 mmol)and Acetic anhydride (0.2 mL) in AcOH (2 mL) at rt. The reaction mixture was then stirred at 80 °C for 2 hrs. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate was washed with NaHCO3 (saturated solution in H2O). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product 2-(5-acetamido-2-methyl- 1H-imidazol-1-yl)-N-(3-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)acetamide (16) (146 mg, 66%) as a white solid. HRMS [M+H]+calculated = 426.1212, found = 426.1215.1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.11 (s, 1H), 7.09 (s, 1H), 4.93 (s, 2H), 2.91 (d, J = 16.0 Hz, 1H), 2.82 – 2.73 (m, 1H), 2.67 – 2.55 (m, 3H), 2.15 (s, 3H), 2.14 – 2.03 (m, 1H), 1.93 (s, 3H), 1.71 – 1.57 (m, 1H). vii. SYNTHESIS OF COMPOUND 17

[0325] Step 3’:1H-imidazol-1-yl)-N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (17). Iron (32.5 mg,0.58 mmol) was added to a solution of N-(6-tert-butyl-3-cyano-5,7-dihydro-4H-thieno[2,3- c]pyridin-2-yl)-2-(2-methyl-5-nitro-imidazol-1-yl)acetamide (Int-2J, prepared by the procedure similar to that for the preparation of Int-2E) (67 mg, 0.17 mmol) and acetic anhydride (0.06 mL, 0.67 mmol) in AcOH (1 mL) at rt. The reaction mixture was then stirred at 80 °C for 2 hrs. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate was neutralized with NaHCO3(saturated solution in H2O). The aqueous layer was collected and evaporated to dryness under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product 2-(5-acetamido-2-methyl-1H-imidazol-1-yl)-N-(6-(tert-butyl)-3- cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (17) (35 mg, 43%) as an yellow solid of acetic acid salt. HRMS [M+H]+calculated = 415.1916, found = 415.1918.1H NMR (400 MHz, CD3OD) δ 7.15 (s, 1H), 4.94 (s, 2H), 3.93 (s, 2H), 3.12 (t, J = 5.8 Hz, 2H), 2.84 – 2.75 (m, 2H), 2.29 (s, 3H), 2.09 (s, 3H), 1.96 (s, 3H), 1.27 (s, 9H).viii. SYNTHESIS OF COMPOUND 18

[0326] Step 3’:imidazol-1-yl)-N-(3-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (18). Iron (26 mg,0.4100 mmol) was added to a solution of 3-cyano-2-[[2-(2-methyl-5-nitro-imidazol-1- yl)acetyl]amino]-4,5,6,7-tetrahydrobenzothiophene-6-carboxylic acid (Int-2K, prepared by the procedure similar to that for the preparation of Int-2E, the intermediate Int-2K’ formed in this reaction was further treated with 2N NaOH to obtain the desired intermediate Int-2K) (46 mg, 0.12 mmol) and acetic anhydride (0.04 mL, 0.47 mmol) in AcOH (1 mL) at rt. The reaction mixture was then stirred at 80oC for 2 hrs. After cooling to rt, the reaction mixture was filtered through celite and washed with EtOAc. The filtrate was neutralized with NaHCO3 (saturated solution in H2O). The aqueous layer was collected and evaporated to dryness under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product 2-(2-(5-acetamido-2-methyl-1H-imidazol-1-yl)acetamido)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophene-6-carboxylic acid (18) (23 mg, 47%) as a light yellow solid. HRMS [M+H]+calculated = 402.1236, found = 402.1237.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.07 (s, 1H), 4.87 (s, 2H), 2.85 – 2.77 (m, 1H), 2.71 – 2.64 (m, 2H), 2.58 – 2.52 (m, 2H), 2.15 (s, 3H), 2.12 – 2.05 (m, 1H), 1.93 (s, 3H), 1.79 – 1.69 (m, 1H). ix. SYNTHESIS OF COMPOUND 19N

[0327] Step 2’: Synthesis of 2-(5-acetamido-2-methyl-1H-imidazol-1-yl)-N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (19). HATU (262 mg,0.69 mmol) and triethylamine (0.192 mL, 1.38 mmol) were added to a solution of (2-methyl- imidazol-1-yl)-acetic acid (SM-19)(64 mg, 0.4600 mmol) in anhydrous DCM (9 mL). After stirring for 10 min at rt, 2-aminobenzo[b]thiophene-3-carbonitrile (Int-1L, prepared by the procedure similar to that for the preparation of Int-2E) (80 mg, 0.46 mmol) was added. The reaction mixture was then stirred at 39oC for 18 hrs. After cooling to rt, the reaction mixture was treated with ice cold H2O (10 mL) and extracted with DCM (3 x 10 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 4 g RediSep silica column, 1-9% MeOH in DCM) to yield the product N-(3- cyanobenzo[b]thiophen-2-yl)-2-(2-methyl-1H-imidazol-1-yl)acetamide (19) (44 mg, 32%) as a beige solid. HRMS [M+H]+calculated = 297.0810, found = 297.0802.1H NMR (400 MHz, acetone-d6) δ 7.95 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.24 (d, J = 1.7 Hz, 1H), 5.42 (s, 2H), 2.58 (s, 3H). d. GENERAL PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 20-45O HArylONO ClOR O S Cl S O Cl SM (20-23, 45) SN ArylNH NH Br (45) O

[0328] Step 1:butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-chloroacetamide (Int-3A). To a stirred solution of 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (Int-1A) (6.7 g, 28.58 mmol) and pyridine (4.58 g, 57.17 mmol) in DCM (100 mL) was added chloroacetyl chloride (6.46 g, 57.17 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (200 mL), extracted with CH2Cl2(3 x 200 mL). The combined organic layers were washed with water (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the product N-(6-tert-butyl-3- cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)-2-chloroacetamide (Int-3A) (5.5 g, 61.8%) as a white solid. LCMS (ESI): [M+H]+= 311.1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 4.27 (s, 2H), 2.74 (ddd, J = 22.6, 16.1, 4.7 Hz, 2H), 2.45 (dt, J = 45.0, 14.2 Hz, 2H), 2.05 (d, J = 1.8 Hz, 1H), 1.56 – 1.45 (m, 1H), 1.34 (qd, J = 12.3, 5.1 Hz, 1H), 0.94 (s, 9H).

[0329] Step 2: Synthesis of the intermediate ethyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (Int-4A (20)). To a solution of ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate(SM-20) (541.1 mg, 3.21 mmol) in DMF (5 mL) was added NaH (128.6 mg, 3.21 mmol) at 0oC. The mixture was stirred for 30 min. N-(6-tert-butyl-3-cyano-4,5,6,7-tetrahydro-1- benzothiophen-2-yl)-2-chloroacetamide (Int-3A) (500 mg, 1.60 mmol) was added and the mixture was allowed to warm to RT and then stirred for 3 h at 50 °C. The reaction was quenched with sat. NH4Cl (aq.) and the precipitated solids were collected by filtration and washed with water (2 x 2 mL). This resulted in ethyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (Int-4A (20)) (650 mg, 91.3%) as a light yellow solid. LCMS (ESI): [M+H]+ =443.

[0330] Step 3: Synthesis of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylicacid (18). A mixture of ethyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (Int-4A (20)) (100 mg, 0.22 mmol) and LiOH.H2O (28.4 mg, 0.67 mmol) in THF(1.5 mL) and H2O (0.5 mL) was stirred overnight at 50 °C. The mixture neutralized to pH = 7 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30 * 150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 42% B in 9 min; Wave Length: 254nm / 220nm; RT(min): 9.5) to afford 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (20) (22.6 mg, 23.7%) as a off-white solid. LCMS (ESI): [M+H]+=415.1H NMR (400 MHz, DMSO-d6) δ 12.09 (d, J = 63.4 Hz, 2H), 5.15 (s, 2H), 2.71 – 2.61 (m, 2H), 2.46 – 2.39 (m, 4H), 2.38 – 2.23 (m, 4H), 2.04 – 1.96 (m, 1H), 1.51 – 1.41 (m, 1H), 1.32 – 1.25 (m, 1H), 0.91 (s, 9H). ii. SYNTHESIS OF COMPOUND 21

[0331] Step 2:((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxylate(Int-4A (21)). To a solution of methyl 1H-imidazole-4-carboxylate (SM-21) (811 mg, 6.43mmol) in DMF (10 mL) was added NaH (257 mg, 6.43 mmol, 60%) at 0oC. The mixture was stirred for 30 min. N-(6-tert-butyl-3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)-2- chloroacetamide (Int-3A) (1 g, 3.21 mmol) was added and the mixture was allowed to warm to rt and then stirred for 2 h at 50 °C. The resulting mixture was diluted with water (100 mL), extracted with CH2Cl2(3 x 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by trituration with MeOH (30 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 1 mL). This resulted in methyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxylate (Int-4A (21)) (900 mg, 69.8%) as a white solid. Thefiltrate was concentrated under reduced pressure. The residue was purified by silica gelcolumn chromatography, eluted with CH2Cl2 / MeOH = 96 / 4 to afford methyl 1-(2-((6-(tert- butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole- 5-carboxylate (Int-4A (22) (70 mg, 5.4%) as a white solid. LCMS (ESI): [M+H]+=401.

[0332] Step 3: Synthesis of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxylic acid (21). A solution of methyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxylate (Int-4A (21)) (60 mg, 0.15 mmol) and LiOH.H2O (19 mg, 0.45 mmol) in MeOH (0.9 mL) and H2O (0.3 mL) was stirred for 2 h at 50 °C. The mixture was neutralized to pH = 7 with HCl (aq.). The resulting mixture was filtered, the filter cake was washed with water (2 x 1 mL). The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30 * 150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 60 mL / min mL / min; Gradient: 17% B to 42% B in 9 min; Wave Length: 254nm / 220nm nm; RT(min): 9.5) to afford 1-(2-((6-(tert-butyl)-3-cyano- 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxylic acid (21) (11.6 mg, 20%) as a white solid. LCMS (ESI): [M+H]+=387.1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 1.3 Hz, 1H), 5.15 (s, 2H), 2.72 – 2.60 (m, 2H), 2.46 – 2.25 (m, 2H), 2.06 – 1.95 (m, 1H), 1.53 – 1.40 (m, 1H), 1.35 – 1.21 (m, 1H), 0.91 (s, 9H). iii. SYNTHESIS OF COMPOUND 22

[0333] Step 3:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-5-carboxylic acid (22). Amixture of methyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-5-carboxylate (Int-4A (22), the minor isomer obtainedfrom the step 2 for the synthesis of compound 21), (70 mg, 0.17 mmol), and LiOH.H2O (22.0 mg, 0.52 mmol) in THF (1.5 mL) and H2O (0.5 mL) was stirred for 2 hours at room temperature. The mixture was neutralized to pH = 7 with HCl (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silicagel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)amino)-2-oxoethyl)-1H-imidazole-5-carboxylic acid (22) (34.6 mg, 51%) as a white solid. LCMS (ESI): [M+H]+=387.1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 12.07 (s, 1H), 7.90 (d, J = 1.0 Hz, 1H), 7.60 (d, J = 1.1 Hz, 1H), 5.32 (s, 2H), 2.71 – 2.60 (m, 2H), 2.49 – 2.40 (m, 1H), 2.38 – 2.27 (m, 1H), 2.05 – 1.95 (m, 1H), 1.50 – 1.41 (m, 1H), 1.33 – 1.20 (m, 1H), 0.91 (s, 9H). iv. SYNTHESIS OF COMPOUND 23

[0334] Step 2:(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-imidazole-4- carboxylate (Int-4A (23)). To a solution of ethyl 5-methyl-1H-imidazole-4-carboxylate (SM- 23) (992 mg, 6.43 mmol) in DMF (10 mL) was added NaH (257 mg, 6.43 mmol) at 0oC. The mixture was stirred for 30 min. N-(6-tert-butyl-3-cyano-4,5,6,7-tetrahydro-1-benzothiophen- 2-yl)-2-chloroacetamide (Int-3A) (1 g, 3.21 mmol) was added and the mixture was allowed to warm to RT and then stirred for 2 h at 50 °C. The reaction was quenched with sat. NH4Cl (aq.) and the precipitated solids were collected by filtration and washed with water (2 x 2 mL). The residue was purified by trituration with MeOH (10 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (2x1 mL). This resulted in ethyl 1-(2-((6- (tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl- 1H-imidazole-4-carboxylate ((Int-4A (23)) (950 mg, 68.9%) as a white solid. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH = 10 / 1 to afford ethyl 1-(2-((6-(tert-butyl)-3- cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-4-methyl-1H-imidazole- 5-carboxylate (Int-4A (23)). (100 mg, 7.2%) as a yellow oil. LCMS (ESI): [M+H]+=429.

[0335] Step 3: Synthesis of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-imidazole-4-carboxylicacid (23). A solution of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-imidazole-4-carboxylate (Int-4A (23)) (70 mg, 0.16mmol) and LiOH.H2O (20.5 mg, 0.48 mmol) in THF (1.5 mL) and H2O (0.5 mL) was stirred for 1 hours at room temperature. The mixture was neutralized to pH = 7 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column, 30 * 150mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 60 mL / min; Gradient: 28% B to 56% B in 8 min; Wave Length: 254nm / 220nm) to afford 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)amino)-2-oxoethyl)-5-methyl-1H-imidazole-4-carboxylic acid (23) (20.5 mg, 31%) as a white solid. LCMS (ESI): [M+H]+=401.1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.66 (s, 1H), 5.08 (s, 2H), 2.71 – 2.59 (m, 2H), 2.45 – 2.27 (m, 5H), 2.06 – 1.95 (m, 1H), 1.54 – 1.40 (m, 1H), 1.36 – 1.25 (m, 1H), 0.91 (s, 9H). v. SYNTHESIS OF COMPOUND 24

[0336] Step 3:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-4-methyl-1H-imidazole-5-carboxylicacid (24). A solution of ethyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-4-methyl-1H-imidazole-5-carboxylate(Int-4A (24), the minor isomer obtained from the step 2 for the synthesis of compound 23)(100 mg, 0.23 mmol) and LiOH.H2O (29 mg, 0.69 mmol) in THF (1.5 mL) and H2O (0.5 mL) was stirred overnight at 50 °C. The mixture was neutralized to pH = 7 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column, 30 * 150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 56% B in 8 min; Wave Length: 254nm / 220nm) to afford 1-(2- ((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-4-methyl-1H-imidazole-5-carboxylic acid (24) (11.6 mg, 12.2%) as a white solid. LCMS (ESI):[M+H]+=401.1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 11.96 (s, 1H), 7.75 (s, 1H), 5.25 (s, 2H), 2.70 – 2.62 (m, 2H), 2.46 – 2.40 (m, 1H), 2.36 (s, 3H), 2.34 – 2.27 (m, 1H), 2.03 – 1.98 (m, 1H), 1.50 – 1.40 (m, 1H), 1.33 – 1.26 (m, 1H), 0.91 (s, 9H).vi. SYNTHESIS OF COMPOUND 25

[0337] Step 2:(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (Int-4A (25)). A mixture of N-(6-tert-butyl-3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)-2-chloroacetamide (Int-3A) (500 mg, 1.60 mmol), ethyl 5-methyl-1H- 1,2,4-triazole-3-carboxylate (SM-25) (499 mg, 3.21 mmol) and Cs2CO3(786.1 mg, 2.41 mmol) in DMF (5 mL) was stirred for 3 h at 50 °C. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH = 98 / 2 to afford ethyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)- 2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (Int-4A (25)) (360 mg, 52%) as a white solid. LCMS (ESI): [M+H]+= 430. In addition to that, a minor isomer, ethyl 1-(2-((6- (tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-3-methyl- 1H-1,2,4-triazole-5-carboxylate (Int-4A (26)) (50 mg, 7%) was isolated in CH2Cl2 / MeOH = 99 / 1, as a light yellow oil.

[0338] Step 3: Synthesis of the intermediate 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3- carboxylic acid (23). A solution of ethyl 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7 tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3- carboxylate (Int-4A (25)) (100 mg, 0.23 mmol) and LiOH.H2O (29.3 mg, 0.69 mmol) in THF (1.5 mL) and H2O (0.5 mL) was stirred for 1 hour at room temperature. The mixture was neutralized to pH = 7 with HCl (aq.). The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5- methyl-1H-1,2,4-triazole-3-carboxylic acid (25) (50 mg, 54%) as a white solid. LCMS (ESI):[M+H]+=402.1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 12.12 (s, 1H), 5.36 (s, 2H), 2.73 – 2.62 (m, 2H), 2.47 – 2.39 (m, 4H), 2.39 – 2.29 (m, 1H), 2.05 – 1.96 (m, 1H), 1.50 – 1.40 (m, 1H), 1.32 – 1.21 (m, 1H), 0.90 (s, 9H). vii. SYNTHESIS OF COMPOUND 26

[0339] Step 3: N-(6- [b]thiophen-2-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)acetamide (26). A A solution of ethyl 1-(2-((6-(tert-butyl)-3- cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-3-methyl-1H-1,2,4-triazole-5-carboxylate (Int-4A (26), ), the minor isomer obtained from the step 2 for thesynthesis of compound 25) and LiOH.H2O (14.65 mg, 0.348 mmol) in THF (0.75 mL) and H2O (0.25 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The mixture was neutralized to pH 7 with HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 42% B to 64% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 9) to afford N-(6-(tert- butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)acetamide (26) (6.5 mg, 15%) as a white solid. LCMS (ESI): [M+H] + =358. 1H NMR(300 MHz, DMSO-d6) δ 8.37 (s, 1H), 5.16 (s, 2H), 2.64 (d, J = 16.5 Hz, 2H), 2.35 (d, J = 13.7 Hz, 2H), 2.25 (s, 3H), 2.00 (d, J = 13.2 Hz, 1H), 1.46 (s, 1H), 1.30 – 1.24 (m, 1H), 0.91 (s, 9H). viii. SYNTHESIS OF COMPOUND 27O NNH2

[0340] Step 4: 4,5,6,7-tetrahydrobenzo[b] - - 1H-pyrazole-4- carboxamide (27). A mixture of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (20) (100 mg, 0.24 mmol), NH4Cl (64.5 mg, 1.20 mmol), HATU (183.4 mg, 0.48 mmol) and DIPEA (62.3 mg, 0.48 mmol) in DMF (1 mL) was stirred overnight at room temperature. The resulting mixture was diluted with brine (20 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH = 10 / 1 to afford the crude.The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30 * 150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 58% B in 8 min; Wave Length: 254nm / 220nm; RT(min): 7.79) to afford 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)- 3,5-dimethyl-1H-pyrazole-4-carboxamide (27) (13.0 mg, 13%) as a white solid. LCMS (ESI): [M+H]+=414.1H NMR (300 MHz, DMSO-d6) δ 11.96 (s, 1H), 6.97 (s, 2H), 5.10 (s, 2H), 2.72 – 2.59 (m, 2H), 2.47 – 2.28 (m, 5H), 2.24 (s, 3H), 2.07 – 1.95 (m, 1H), 1.53 – 1.41 (m, 1H), 1.35 – 1.22 (m, 1H), 0.91 (s, 9H). ix. SYNTHESIS OF COMPOUND 28

[0341] Step 4:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxamide (28). Amixture of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2- oxoethyl)-1H-imidazole-4-carboxylic acid (21) (140 mg, 0.36 mmol), NH4Cl (96.8 mg, 1.81 mmol), HATU (275.4 mg, 0.72 mmol) and DIPEA (93.6 mg, 0.72 mmol) in DMF (2 mL) was stirred overnight at room temperature. The resulting mixture was diluted with brine (30 mL), extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30 * 150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 42% B in 9 min; Wave Length: 254nm / 220nm; RT(min): 8.0) to afford 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2- oxoethyl)-1H-imidazole-4-carboxamide (28) (11.4 mg, 8.0%) as a off-white solid. LCMS (ESI): [M+H]+=386.1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.74 – 7.60 (m, 2H), 7.18 (d, J = 64.0 Hz, 2H), 5.11 (s, 2H), 2.71 – 2.59 (m, 2H), 2.44 – 2.26 (m, 2H), 2.06 – 1.95 (m, 1H), 1.53 – 1.39 (m, 1H), 1.35 – 1.21 (m, 1H), 0.91 (s, 9H). x. SYNTHESIS OF COMPOUND 29

[0342] Step 4: Synthesis4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-imidazole-4-carboxamide(29). A mixture of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-imidazole-4-carboxylic acid (23) (100 mg, 0.25 mmol), NH4Cl (66.7 mg, 1.25 mmol), HATU (190 mg, 0.50 mmol) and DIPEA (64.5 mg, 0.50 mmol) in DMF (2 mL) was stirred overnight at room temperature. The resulting mixture was diluted with brine (20 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30 * 150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 42% B in 9 min; Wave Length: 254nm / 220nm; RT(min):8.5) to afford the product 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)amino)-2-oxoethyl)-5-methyl-1H-imidazole-4-carboxamide (29) (30 mg, 30%) as a white solid. LCMS (ESI): [M+H]+=400.1H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.62 (s, 1H), 7.19 (s, 1H), 6.95 (s, 1H), 5.06 (s, 2H), 2.72 – 2.60 (m, 2H), 2.47 – 2.24 (m, 5H), 2.08 – 1.95 (m, 1H), 1.54 – 1.39 (m, 1H), 1.34 – 1.23 (m, 1H), 0.91 (s, 9H). xi. SYNTHESIS OF COMPOUND 30

[0343] Step 4:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3-carboxamide (30). A mixture of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3- carboxylic acid (25) (100 mg, 0.24 mmol), NH4Cl (66.6 mg, 1.24 mmol), HATU (189.4 mg, 0.49 mmol) and DIPEA (96.5 mg, 0.74 mmol) in DMF (1 mL) was stirred for 2 hours at room temperature. The resulting mixture was diluted with brine (20 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30 * 150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 55% B in 10 min; Wave Length: 254nm / 220nm; RT(min): 10) to afford 1-(2-((6-(tert-butyl)-3- cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-5-methyl-1H-1,2,4- triazole-3-carboxamide (30) (37.5 mg, 37%) as a white solid. LCMS (ESI): [M+H]+=401.1H NMR (300 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.74 (s, 1H), 7.51 (s, 1H), 5.34 (s, 2H), 2.74 – 2.60 (m, 2H), 2.47 – 2.38 (m, 4H), 2.37 – 2.26 (m, 1H), 2.06 – 1.96 (m, 1H), 1.53 – 1.39 (m, 1H), 1.36 – 1.19 (m, 1H), 0.91 (s, 9H). xii. SYNTHESIS OF COMPOUND 31

[0344] Step 4: N- [b]thiophen-2-yl)-2-(4-(morpholine-4--. a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]imidazole-4- carboxylic acid (21), (50 mg, 0.13 mmol), PyBOP; (Benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.16 mmol), Morpholine (0.013 mL, 0.16 mmol) in DMF (3 mL) was added DIPEA (0.08 mL, 0.45 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was isolated and removed the solvent under reduced pressure and the product N-(6-(tert-butyl)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)-2-(4-(morpholine-4-carbonyl)-1H-imidazol-1-yl)acetamide (31) (18 mg, 31%) was precipitated from the crude (DCM and hexane) as a white solid. HRMS [M+H]+calculated = 456.2069, found = 456.2068.1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.69 (s, 2H), 5.11 (d, J = 1.8 Hz, 2H), 3.59 (s, 5H), 2.64 (d, J = 15.8 Hz, 2H), 1.97 (s, 1H), 1.43 (s, 1H), 1.23 (s, 2H), 0.89 (d, J = 2.7 Hz, 9H). xiii. SYNTHESIS OF COMPOUND 32

[0345] Step 4:tetrahydrobenzo[b]thiophen-2-yl)-2-(4-(4-methylpiperazine-1-carbonyl)-1H-imidazol-1- yl)acetamide (32). To a mixture of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7- tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]imidazole-4-carboxylic acid (21) (50 mg, 0.13 mmol PyBOP; (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.16 mmol), Piperazine, 1-methyl (0.015 mL, 0.16 mmol) in DMF (3 mL) wasadded DIPEA (0.08 mL, 0.45 mmol) and stirred for 12 hours at room temperature. Reaction was quenched by the addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was isolated and removed the solvent under reduced pressure and the crude was subjected to a flash column chromatography (ISCO silica 4g column, 1-10% MeOH in DCM to obtain the product N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)-2-(4-(4-methylpiperazine-1-carbonyl)-1H-imidazol-1-yl)acetamide (32) (30 mg, 49% yield) as off-white solid. HRMS [M+H]+calculated = 469.2386, found = 469.2383.1H NMR (400 MHz, DMSO-d6) δ 11.96 (1H, s), 7.67 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 5.10 (s, 2H), 4.07 (d, J = 5.3 Hz, 1H), 3.56 (s, 1H), 2.63 (d, J = 16.4 Hz, 2H), 2.34 (s, 6H), 2.20 (s, 4H), 1.98 (d, J = 12.7 Hz, 1H), 1.43 (s, 1H), 1.25 (dt, J = 12.6, 6.2 Hz, 1H), 0.89 (d, J = 1.5 Hz, 10H). xiv. SYNTHESIS OF COMPOUND 33

[0346] Step 4:tetrahydrobenzo[b]thiophen-2-yl)-2-(4-(3-hydroxyazetidine-1-carbonyl)-1H-imidazol-1- yl)acetamide (33). To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7- tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]imidazole-4-carboxylic acid (21) (50 mg, 0.13 mmol), PyBOP; (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.16 mmol), 3-Hydroxyazetidine hydrochloride (17 mg, 0.16 mmol) in DMF (3 mL) was added DIPEA (0.08 mL, 0.45 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was isolated and removed the solvent under reduced pressure and the crude was subjected to a flash column chromatography (ISCO silica 4g column, MeOH in DCM 1-10%) to obtain the product N-(6-(tert-butyl)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)-2-(4-(3-hydroxyazetidine-1-carbonyl)-1H-imidazol-1- yl)acetamide (33) (18 mg, 31% yield) as white solid. HRMS [M+H]+calculated = 442.1913, found = 442.1913.1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 7.66 (s, 2H), 5.63 (d, J = 6.3 Hz, 1H), 5.10 (s, 2H), 4.67 (s, 1H), 4.46 (d, J = 5.3 Hz, 1H), 4.15 (s, 2H), 3.68 (s, 1H),2.64 (d, J = 16.2 Hz, 2H), 2.45 – 2.22 (m, 2H), 2.06 – 1.92 (m, 1H), 1.43 (s, 1H), 1.24 (dt, J = 12.0, 5.9 Hz, 1H), 0.89 (s, 9H). xv. SYNTHESIS OF COMPOUND 34

[0347] Step 4: 4,5,6,7-tetrahydrobenzo[b] - - N-methyl-1H-imidazole- 4-carboxamide (34). To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7- tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]imidazole-4-carboxylic acid (21) (50 mg, 0.13 mmol) was added PyBOP; (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.16 mmol), N-Methylcyclohexylamine (0.02 mL, 0.16 mmol) in DMF (2 mL) was then added DIPEA (0.08 mL, 0.45 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was isolated and removed the solvent under reduced pressure and the crude was subjected to a flash column chromatography (ISCO silica 4g column, MeOH in DCM 1-10%) to obtain the product 1-(2-((6-(tert-butyl)-3-cyano- 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-N-cyclohexyl-N-methyl-1H- imidazole-4-carboxamide (34) (31 mg, 50% yield) as white solid. HRMS [M+H]+calculated = 482.2590, found = 482.2589.1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.73 – 7.63 (m, 1H), 7.59 (s, 1H), 5.10 (s, 2H), 4.55 (d, J = 207.1 Hz, 1H), 3.20 (s, 1H), 2.78 (s, 2H), 2.70 – 2.56 (m, 2H), 2.44 – 2.25 (m, 2H), 1.98 (d, J = 12.6 Hz, 1H), 1.74 (d, J = 12.5 Hz, 2H), 1.69 – 1.37 (m, 6H), 1.25 (dt, J = 12.6, 6.3 Hz, 3H), 1.09 (t, = 12.9 Hz, 1H), 0.89 (s, 9H). xvi. SYNTHESIS OF COMPOUND 35

[0348] Step 4: Synthesis of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-N-(2-hydroxyethyl)-1H-imidazole-4- carboxamide (35). To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7- tetrahydrobenzothiophen-2-yl)amino]-2-oxoethyl] imidazole-4-carboxylic acid (21) (30 mg, 0.08 mmol), PyBOP; (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.16 mmol), 2-aminoethanol (0.006 mL, 0.09 mmol) in DMF (3 mL) was added DIPEA (0.08 mL, 0.45 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was isolated and removed the solvent under reduced pressure and the crude was subjected to a flash column chromatography (ISCO silica 4g column, MeOH in DCM 10-20%,) to obtain the product 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-N-(2-hydroxyethyl)-1H-imidazole-4- carboxamide (35) (14 mg, 42% yield) as off-white solid. HRMS [M+H]+calculated = 430.0913, found = 430.1919.1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.80 (t, J = 5.9 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 5.10 (s, 2H), 4.74 (t, J = 5.4 Hz, 1H), 3.45 (q, J = 5.9 Hz, 2H), 3.27 (d, J = 6.1 Hz, 2H), 2.64 (d, J = 16.4 Hz, 2H), 2.46 – 2.25 (m, 2H), 1.98 (d, J = 12.9 Hz, 1H), 1.52 – 1.12 (m, 3H), 0.89 (s, 9H). xvii. SYNTHESIS OF COMPOUND 36

[0349] Step 4:tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]-N,N-dimethyl-imidazole-4-carboxamide(36). To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]imidazole-4-carboxylic acid (21) (50 mg, 0.13 mmol), PyBOP; (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (80.7913mg, 0.16 mmol), dimethylamine solution (0.08 mL, 0.16 mmol) in DMF (3 mL) was added DIPEA (0.08 mL, 0.45 mmol). The reaction mixture was stirred for 12 hours at room temperature. The reaction was quenched by the addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was isolated and removed the solvent under reduced pressure and theproduct 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo- ethyl]-N,N-dimethyl-imidazole-4-carboxamide (36) (39 mg, 73% yield) was precipitated from the crude (DCM and hexane) as off white solid. HRMS [M+H]+calculated = 414.1964, found = 414.1958.1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 5.11 (s, 2H), 3.39 (s, 3H), 2.91 (s, 3H), 2.64 (d, J = 16.3 Hz, 2H), 2.44 – 2.25 (m, 2H), 1.98 (d, J = 12.7 Hz, 1H), 1.52 – 1.36 (m, 1H), 1.25 (dt, J = 12.5, 6.5 Hz, 1H), 0.89 (s, 9H). xviii. SYNTHESIS OF COMPOUND 37

[0350] Step 4:tetrahydrobenzothiophen-2-yl)-2-[4-(3,3-difluoropyrrolidine-1-carbonyl)imidazol-1-yl]acetamide (37). To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo- ethyl]imidazole-4-carboxylic acid (21) (50 mg, 0.13 mmol), PyBOP; (Benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.16 mmol), 3,3- difluoropyrrolidine;hydrochloride (22 mg, 0.16 mmol) in DMF (3 mL) was added 0.08 mL, 0.45 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15ml x 3). The organic layer was isolated and removed the solvent under reduced pressure and the product N-(6-tert-butyl-3- cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)-2-[4-(3,3-difluoropyrrolidine-1- carbonyl)imidazol-1-yl]acetamide (37) (40 mg, 65% yield) was precipitated from the crude (DCM and hexane) as a white solid. HRMS [M+H]+calculated = 476.1930, found = 476.1925.1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 5.13 (s, 2H), 4.38 (t, J = 13.2 Hz, 1H), 4.21 (s, 1H), 3.84 (t, J = 13.6 Hz, 1H), 3.67 (s, 1H), 2.64 (d, J = 16.3 Hz, 2H), 2.46 – 2.24 (m, 4H), 1.98 (d, J = 12.1 Hz, 1H), 1.42 (d, J = 12.5 Hz, 1H), 1.36 – 1.15 (m, 1H), 0.89 (s, 9H).19F NMR (376 MHz, DMSO-d6) δ -100.92 – -101.09 (m), - 101.67 (t, J = 13.8 Hz). xix. SYNTHESIS OF COMPOUND 38

[0351] Step 4: tetrahydrobenzothiophen-2-yl)-2-[4-[4-yl]acetamide (38). To asolution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo- ethyl]imidazole-4-carboxylic acid (21) (50 mg, 0.13 mmol), PyBOP; (Benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.16 mmol), 4- (trifluoromethyl)- (24 mg, 0.16 mmol), in DMF (3 mL) was added DIPEA (0.08 mL, 0.45 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was isolated and removed the solvent under reduced pressure and the crude was subjected to flash column chromatography to obtain the product N-(6-tert-butyl-3-cyano-4,5,6,7- tetrahydrobenzothiophen-2-yl)-2-[4-[4-(trifluoromethyl)piperidine-1-carbonyl]imidazol-1- yl]acetamide (38) (34 mg, 50% yield) as white solid. HRMS [M+H]+calculated = 522.2150, found = 522.2141.1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.73 – 7.63 (m, 1H), 7.59 (s, 1H), 5.10 (s, 2H), 4.55 (d, J = 207.1 Hz, 1H), 3.20 (s, 1H), 2.78 (s, 2H), 2.70 – 2.56 (m, 2H), 2.44 – 2.25 (m, 2H), 1.98 (d, J = 12.6 Hz, 1H), 1.74 (d, J = 12.5 Hz, 2H), 1.69 – 1.37 (m, 6H), 1.25 (dt, J = 12.6, 6.3, 1.09 (t, J = 12.9 Hz, 1H), 0.89 (s, 9H).19F NMR (376 MHz, DMSO-d6) δ -72.6. xx. SYNTHESIS OF COMPOUND 39

[0352] Step 4:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-N-methyl-1H-imidazole-4-carboxamide(39). A mixture of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxylic acid (21) (150 mg, 0.38 mmol), methylamine (0.78 mL, 0.77 mmol), HATU (295 mg, 0.77 mmol) and DIPEA (100 mg, 0.77mmol) in DMF (2 mL) was stirred overnight at room temperature. The resulting mixture was diluted with brine (30 mL), extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30 * 150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 42% B in 9 min; Wave Length: 254nm / 220nm; RT(min): 8.5) to afford 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)amino)-2-oxoethyl)-N-methyl-1H-imidazole-4-carboxamide (39) (13.5 mg, 8%) as a white solid. LCMS (ESI): [M+H]+= 400.1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 7.93 – 7.86 (m, 1H), 7.68 (d, J = 1.3 Hz, 1H), 7.62 (d, J = 1.3 Hz, 1H), 5.08 (s, 2H), 2.73 (d, J = 4.8 Hz, 3H), 2.69 – 2.60 (m, 2H), 2.48 – 2.39 (m, 1H), 2.38 – 2.27 (m, 1H), 2.04 – 1.95 (m, 1H), 1.50 – 1.41 (m, 1H), 1.32 – 1.21 (m, 1H), 0.90 (s, 9H). xxi. SYNTHESIS OF COMPOUND 40

[0353] Step 4:4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-N-(piperidin-4-yl)-1H-imidazole-4-carboxamide (40). To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]imidazole-4-carboxylic acid (21) (100 mg, 0.2600 mmol), PyBOP; (Benzotriazol1yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.1600 mmol), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (62 mg, 0.3100 mmol) in DMF (5 mL) was added DIPEA (0.16 mL, 0.9100 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15 mL x 3). The precipitated solid was dissolved in DCM (3 mL) and treated added trifluoroacetic acid (0.07 mL, 0.8500 mmol) and stirred at room temperature for 14 hours. The reaction mixture was washed with sodium bicarbonate (50 mL x 3) and the crude was subjected to a column flash chromatography (ISCO silica 4g column, MeOH in DCM 1-25%) to obtain the product 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-N-(piperidin-4-yl)-1H-imidazole-4- carboxamide (40) (16 mg, 61% yield) as an off-white solid. HRMS [M+H]+= 469.2386 (calculated) 469.2390 (found)1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.41 (d, J = 114.3 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.12 (s, 2H), 4.00 (d, J = 9.9 Hz, 1H), 3.00 (d, J = 13.4 Hz, 2H), 2.64 (d, J = 16.0 Hz, 2H), 2.45 – 2.25 (m, 2H), 1.99 (d, J = 12.7 Hz, 1H), 1.89 (d, J = 13.5 Hz, 2H), 1.75 (q, J = 11.8 Hz, 2H), 1.52 – 1.33 (m, 1H), 1.30 – 1.17 (m, 1H), 0.89 (s, 9H). xxii. SYNTHESIS OF COMPOUND 41

[0354] Step 4:decane-8-carbonyl)-1H-imidazol-1-yl)-N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide(41). To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]imidazole-4-carboxylic acid (21) (50 mg, 0.1300 mmol), PyBOP; (Benzotriazol1yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.1600 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (22 mg, 0.1600 mmol) in DMF (3mL) was added DIPEA (0.08 mL, 0.4500 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was concentrated under reduced pressure and the crude was subjected to a flash column chromatography (ISCO silica 12g column, MeOH in DCM 1-20%) to obtain the product (41) 2-(4-(1,4-dioxa-8-azaspiro[4.5]decane-8-carbonyl)-1H-imidazol-1- yl)-N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (28 mg, 42% yield) as a white solid. HRMS [M+H]+= calculated 512.2331, found 512.2328.1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.70 – 7.67 (m, 1H), 7.65 (d, J = 1.3 Hz, 1H), 5.10 (s, 2H), 4.19 (s, 2H), 3.90 (s, 4H), 3.63 (s, 2H), 2.64 (d, J = 16.3 Hz, 2H), 2.44 – 2.25 (m, 2H), 1.98 (d, J = 11.8 Hz, 1H), 1.61 (t, J = 5.9 Hz, 4H), 1.44 (s, 1H), 1.25 (dd, J = 12.4, 5.0 Hz, 1H), 0.89 (s, 9H). xxiii. SYNTHESIS OF COMPOUND 42

[0355] Step 4:tetrahydrobenzo[b]thiophen-2-yl)-2-(4-(4-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-1-yl)acetamide (42). To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]imidazole-4-carboxylic acid (21) (50 mg, 0.13 mmol) was added PyBOP; (Benzotriazol1yloxy)tripyrrolidinophosphonium hexafluorophosphate (81 mg, 0.16 mmol), and 1-methylpiperazine-2-one (18 mg, 0.16 mmol) was added DIPEA (0.08 mL, 0.4500 mmol). The reaction mixture was stirred for 12 hours at room temperature and quenched by addition of 15 mL water and extracted with DCM (15 mL x 3). The organic layer was concentrated under reduced pressure and the crude was subjected to a flash column chromatography (ISCO silica 4g column, MeOH in DCM 1-20%, Fractions 44-52) to obtain the product N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl)-2-(4-(4-methyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-1-yl)acetamide (28 mg, 42% yield) as an off-white solid. HRMS [M+H]+= Calculated = 483.2178, found = 483.2181.1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.84 – 7.56 (m, 2H), 5.13 (s, 2H), 4.67 (d, J = 148.5 Hz, 2H), 3.96 (d, J = 119.2 Hz, 2H), 3.36 (s, 2H), 2.85 (s, 3H), 2.64 (d, J = 16.8 Hz, 2H), 2.46 – 2.23 (m, 2H), 1.98 (d, J = 12.6 Hz, 1H), 1.50 – 1.36 (m, 1H), 1.28 – 1.20 (m, 1H), 0.89 (s, 9H). xxiv. SYNTHESIS OF COMPOUND 43

[0356] Step 4:- tetrahydrobenzo[b]thiophen-2-yl)-2-(3,5-dimethyl-4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)acetamide (43). A To a solution of 1-[2-[(6-tert-butyl-3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxo-ethyl]-2,5-dimethyl-imidazole-4-carboxylic acid (20) (50 mg, 0.12 mmol) was mixed in with HATU (55 mg, 0.14 mmol) and piperidine (12.3 mg, 0.14 mmol) in Acetonitrile (3 mL) was added DIPEA (0.06 mL, 0.36 mmol) and stirred at room temperature for an overnight. The reaction was quenched by the addition of 15 mL water and extracted with EtOAc (15 mL x 3). The organic layer was isolated and removed the solvent under vacuum and the crude was subjected to a column flash chromatography (ISCO, 4 g, RediSep column, 0-40% EtOAc / Hexanes) to obtain the product (43) N-(6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-2-(3,5-dimethyl-4- (piperidine-1-carbonyl)-1H-pyrazol-1-yl)acetamide (28 mg, 47% yield) as a white solid. HRMS [M+H]+= Calculated = 482.2590, found = 482.2585.1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 5.05 (s, 2H), 3.39 (s, 3H), 2.61 (s, 1H), 2.42 (s, 1H), 2.31 (d, J = 27.8 Hz, 1H), 2.13 (s, 3H), 2.04 (s, 3H), 1.98 (d, J = 10.4 Hz, 1H), 1.58 (d, J = 6.7 Hz, 2H), 1.45 (s, 5H), 1.25 (dd, J = 12.2, 5.2 Hz, 1H), 0.89 (s, 9H). xxv. SYNTHESIS OF COMPOUND 44

[0357] Step 4:((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1H-imidazole-4carboxamido)propanoate (Int-44). A mixture of 1-(2-((6-(tert-butyl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-y...

Claims

CLAIMS What is claimed is:

1. A compound having a structure represented by a formula:, wherein n is selected from 0,wherein each of Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b; wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or wherein each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and provided that the compound is not: , .

2. The compound of claim 1, wherein n is 0.

3. The compound of claim 1, wherein n is 1.

4. The compound of claim 1, wherein n is 2.

5. The compound of any one of claims 1 to 4, wherein Z1 is NR10 and Z2 is CR11aR11b.

6. The compound of any one of claims 1 to 5, wherein R10 is hydrogen.

7. The compound of any one of claims 1 to 5, wherein R10 is C1-C4 alkyl.

8. The compound of any one of claims 1 to 5, wherein R10 is tert-butyl.

9. The compound of any one of claims 1 to 5, wherein each of R11a and R11b is hydrogen.

10. The compound of any one of claims 1 to 4, wherein Z2 is NR10 and Z1 is CR11aR11b.

11. The compound of any one of claims 1 to 10, wherein each of R1a and R1b is hydrogen.

12. The compound of any one of claims 1 to 11, wherein R2 is hydrogen.

13. The compound of any one of claims 1 to 12, wherein Ar1 is selected from pyrrolyl,imidazolyl, and triazolyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b.

14. The compound of any one of claims 1 to 12, wherein Ar1 is imidazolyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR12C(O)(C1-C4 alkyl), and ‒C(O)NR13aR13b.

15. The compound of any one of claims 1 to 12, wherein Ar1 is selected from pyrrolyl,imidazolyl, and triazolyl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl).

16. The compound of claim 1, wherein Ar1 is imidazolyl substituted with 0, 1, or 2 groupsindependently selected from C1-C4 alkyl and ‒NR12C(O)(C1-C4 alkyl).

17. The compound of claim 1, wherein the compound has a structure represented by aformula: R1b OAr1Z1S , or a pharmaceutically18. The compound of claim 1, wherein the compound has a structure represented by aformula: , or a pharmaceutically19. The compound of claim 1, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound has a structure represented by aformula: R20a NR20bR1b ON, wherein each of R20a, R20b,from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒NR22C(O)(C1-C4 alkyl), and ‒C(O)NR23aR23b; wherein R22is selected from hydrogen and C1-C4 alkyl; and wherein each of R23aand R23bis independently selected from hydrogen and C1-C4 alkyl, or wherein each of R23aand R23bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

23. The compound of claim 21, wherein the compound has a structure represented by aformula: , or a pharmaceutically24. The compound of claim 1, wherein the compound is not:,or a pharmaceutically25. The compound of claim 1, wherein the compound is selected from:,, , ,or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising an effective amount of a compound havinga structure represented by a formula:, wherein n is selected from 0,wherein each of Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; andwherein each of R13aand R13bis independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and a pharmaceutically acceptable carrier.

27. The pharmaceutical composition of claim 26, wherein the compound is selected from:,, , , ,, or a pharmaceutically28. A method for treating a viral infection in a subject in need thereof, the methodcomprising administering to the subject a compound having a structure represented by a formula: , wherein n is selected from 0,wherein each of Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; andwherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; and wherein each of R13aand R13bis independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, wherein the viral infection is due to a Flavivirus or due to an Alphavirus.

29. The method of claim 28, wherein the viral infection is due to a Flavivirus.

30. The method of claim 29, wherein the Flavivirus is selected from yellow fever,Japanese encephalitis, dengue (DENV), influenza, West Nile virus (WNV), and Zika (ZIKV).

31. The method of claim 29, wherein the Flavivirus is DENV.

32. The method of any one of claims 28 to 31, wherein the subject is a mammal.

33. The method of any one of claims 28 to 31, wherein the subject is a human.

34. The method of any one of claims 28 to 33, wherein the subject has been diagnosedwith a need for treatment of the viral infection prior to the administering step.

35. The method of any one of claims 28 to 34, further comprising the step of identifying asubject in need of treatment of the viral infection.

36. The method of any one of claims 28 to 35, wherein the effective amount is atherapeutically effective amount.

37. The method of any one of claims 28 to 35, wherein the effective amount is aprophylactically effective amount.

38. The method of claim 28, wherein the compound is selected from:, ,, , ,or a pharmaceutically acceptable salt thereof.

39. A kit comprising a compound having a structure represented by a formula:, wherein n is selected from 0,wherein each of Z1and Z2is independently selected from NR10and CR11aR11b, provided that at least one of Z1and Z2is CR11aR11b; wherein R10is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R11aand R11bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R1aand R1bis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is a 5-membered, N-linked heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NR13aR13b, and ‒NR12C(O)(C1-C4 alkyl); wherein R12is selected from hydrogen and C1-C4 alkyl; andwherein each of R13aand R13bis independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, unsubstituted C3-C6 cycloalkyl, and unsubstituted C2-C5 heterocycloalkyl, or each of R13aand R13bare covalently bonded and, together with the intermediate atoms, comprise a 5- or 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein 2 adjacent groups are covalently bonded and together comprise an unsubstituted 1,3-dioxolane ring, or a pharmaceutically acceptable salt thereof, provided that when n is 1 or 2, then Z1is CH(tert-butyl), each of R1aand R1bis hydrogen, and Ar1is not pyrazole, and one or more selected from: (a) at least one antiviral agent;(b) instructions for administering the compound in connection with treating a viralinfection; (c) instructions for administering the compound in connection with reducing therisk of a viral infection; and (d) instructions for treating a viral infection,wherein the viral infection is due to a Flavivirus or an Alphavirus.

40. The kit of claim 39, wherein the viral infection is due to a Flavivirus.

41. The kit of claim 40, wherein the Flavivirus is DENV.

42. The kit of any one of claims 39 to 41, wherein the antiviral agent is selected fromacemannan, acyclovir, acyclovir sodium, adamantanamine, adefovir, adenine arabinoside, alovudine, alvircept sudotox, amantadine hydrochloride, aranotin, arildone, atevirdine mesylate, avridine, cidofovir, cipamfylline, cytarabine hydrochloride, BMS 806, C31G, carrageenan, cellulose sulfate, cyclodextrins, dapivirine, delavirdine mesylate, desciclovir, dextrin 2-sulfate, didanosine, disoxaril, dolutegravir, edoxudine, enviradene, envirozime,etravirine, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet sodium, fosfonet sodium, FTC, ganciclovir, ganciclovir sodium, GSK 1265744, 9-2-hydroxy- ethoxy methylguanine, ibalizumab, idoxuridine, interferon, 5-iodo-2′-deoxyuridine, IQP- 0528, kethoxal, lamivudine, lobucavir, maraviroc, memotine pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statolon, stavudine, T20, tilorone hydrochloride, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxyl fumarate, prodrugs of tenofovir, UC-781, UK-427, UK- 857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabene, zidovudine, and zinviroxime.

43. The kit of any one of claims 39 to 42, wherein the compound and the agent are co-packaged.

44. The kit of any one of claims 39 to 42, wherein the compound and the agent are co-formulated.

45. A compound selected from:, ,,46. A pharmaceutical composition comprising the compound of claim 45 or apharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

47. A method for treating a viral infection in a subject in need thereof, the methodcomprising administering to the subject the compound of claim 45 or a pharmaceutically acceptable salt thereof.

48. A kit comprising the compound of claim 45 or a pharmaceutically acceptable salttheref, and one or more selected from: (a) at least one antiviral agent;(b) instructions for administering the compound in connection with treating a viralinfection; (c) instructions for administering the compound in connection with reducing the riskof a viral infection; and (d) instructions for treating a viral infection,wherein the viral infection is due to a Flavivirus or an Alphavirus.

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