WO2016057518A1 - Anti-viral compounds, pharmaceutical compositions, and methods of use thereof - Google Patents

Anti-viral compounds, pharmaceutical compositions, and methods of use thereof Download PDF

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Publication number
WO2016057518A1
WO2016057518A1 PCT/US2015/054250 US2015054250W WO2016057518A1 WO 2016057518 A1 WO2016057518 A1 WO 2016057518A1 US 2015054250 W US2015054250 W US 2015054250W WO 2016057518 A1 WO2016057518 A1 WO 2016057518A1
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optionally substituted
compound
group
virus
independently
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PCT/US2015/054250
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French (fr)
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Shawn Iadonato
Kristin Bedard
Kerry Fowler
Shari KAISER
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Kineta, Inc.
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Publication of WO2016057518A1 publication Critical patent/WO2016057518A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the disclosure provides compounds, pharmaceutical compositions, and methods for treating viral infection, among other uses.
  • RNA viruses represent an enormous public health problem in the U.S. and worldwide.
  • Well-known RNA viruses include influenza virus (including the avian and swine isolates; also referred to herein as flu), Hepatitis C virus (HCV), West Nile virus (WNV), SARS-coronavirus (SARS), MERS-coronavirus (MERS), respiratory syncytial virus (RSV), and human immunodeficiency virus (HIV).
  • Flaviviruses, Henipaviruses, Filoviruses, and Arenaviruses are among emerging RNA viruses that pose significant public health and biodefense threats. These viruses collectively place hundreds of millions of people at risk of infection throughout the world.
  • DNV Dengue virus
  • WNV West Nile virus
  • Flaviviruses positive strand RNA virus
  • Arboviruses transmitted through mosquitoes.
  • Each of these viruses represents a potent potential biological threat through their ability to transmit readily among insects or animals and humans, high infectivity, and their potential to be weaponized in bioterror events.
  • DNV is the most prevalent flavivirus in humans, is endemic in most tropical and subtropical countries, and is currently emerging elsewhere including the U.S. and across the Pacific Islands. DNV circulates as 4 serotypes (DNV1 - 4) and following a first infection, re-infection can lead to fatal hemorrhagic fever and shock syndrome. Infection is believed to provide life-long immunity against reinfection by the same serotype, but not against other serotypes. Epidemic outbreaks have been reported in many countries throughout Latin America, South-East Asia, and the Western Pacific Regions. It is estimated that between 50 and 100 million cases of Dengue fever occur globally each year. Dengue Hemorrhagic Fever and Dengue Shock Syndrome represent severe forms of the disease. Currently there is no specific antiviral therapy to treat DNV infection and no approved vaccine.
  • WNV is a related flavivirus that is endemic in regions of Africa and Asia, but is now emerging in the Western hemisphere. WNV is neuroinvasive to cause serious encephalitis disease and is lethal in about 6% of cases. Neuroinvasive WNV can present as meningitis, encephalitis or less frequently a flaccid paralysis referred to as poliomyelitis. WNV was largely absent from North America prior to 1999, but reemerged on the continent following an isolated outbreak of encephalitis in New York. In the subsequent 7 years, WNV infection spread throughout the 48 contiguous United States, and current estimates suggest as many as 2 - 3 million Americans have been infected. Over the past 20 years, outbreaks have been reported in parts of Europe, North Africa, the Middle East, and North America. Currently there is no specific antiviral therapy to treat WNV infection and no approved vaccine.
  • Nipah virus is a paramyxovirus (negative strand RNA virus) distantly related to respiratory syncytial virus (RSV).
  • RSV respiratory syncytial virus
  • NV is a highly dangerous emerging virus responsible for severe encephalitis and respiratory disease.
  • Outbreaks of NV infection have now occurred in East and Central Asia, and are likely attributed to zoonotic transmission to humans from farm animals and wild fruit bats as well as actual human-to-human transmission. NV is fatal in approximately 40% of confirmed patients.
  • Ebola virus At least 4 subtypes of Ebola virus (EV) are infectious to humans (Zaire, Sudan, Bundibugyo, and Cote d'lsian). EV outbreaks have been described in Africa with a fatality rate of up to 90%. Cases of EV infection have been reported in other countries including, very recently, the United States.
  • the natural host for EV is not defined but nonhuman primates (NHP) are susceptible.
  • EV is a negative-strand RNA virus of the Filoviridae and can be spread effectively from person-to-person.
  • Lassa virus is a member of the Old World arenaviruses and chronically infects rodents, the natural host animal, typically without presentation of symptoms. In contrast, infected humans can present with symptoms of severe hemorrhagic fever and can result in shock and/or death.
  • the virus is spread through direct contact with rodent carriers or their secretions, or through direct contact with body fluids from an infected human. Lassa fever is endemic in West Africa and the estimated number of human infections total 100,000 to 500,000 annually. There is a risk of spread of LASV beyond West African countries, primarily due to high rates of worldwide travel and the potential for human to human transmission.
  • RNA viruses listed very few vaccines are currently approved for clinical use.
  • One such vaccine exists for influenza virus, which must be revised and administered annually.
  • Drug therapy is essential to mitigate the significant morbidity and mortality associated with these viruses.
  • the number of antiviral drugs is limited, many are poorly effective, and nearly all are plagued by the rapid evolution of viral resistance and a limited spectrum of action.
  • Ribavirin a guanine nucleoside analog, has been studied in clinical trials of diverse RNA virus infections and is likely the most broadly acting antiviral agent available. Rusnak, J. (201 1 ) AppI Biosaf 16, 67-87; Debing, Y., et al. (2013) Curr Opin Virol 3, 217-224.
  • Ribavirin is approved to treat hepatitis C virus (HCV) and respiratory syncytial virus (RSV) infection, and Lassa virus related mortality was shown to be reduced with intravenous ribavirin treatment. McCormick, J.B., et al. (1986) N Engl J Med 314, 20-26. However, it is weakly effective as a single agent and has significant hematologic toxicity. Both classes of acute influenza antivirals, adamantanes and neuraminidase inhibitors, are only effective within the first 48 hours after infection, thereby limiting the window of opportunity for treatment. High resistance to adamantanes already restricts their use, and massive stockpiling of neuraminidase inhibitors will eventually lead to overuse and the emergence of resistant strains of influenza.
  • HCV hepatitis C virus
  • RSV respiratory syncytial virus
  • RIG- l-like receptor (RLR) pathway of innate antiviral immunity can impose a potent blockade to RNA virus infection through the actions of a variety antiviral defense genes.
  • new antiviral therapy can act directly against viruses.
  • Most drug development efforts target viral proteins.
  • RNA viruses have small genomes, with many encoding less than a dozen proteins, resulting in a very limited number of viral targets for new drugs. This is a large part of the reason that current drugs are narrow in spectrum and subject to the emergence of viral resistance.
  • direct-acting antiviral therapy can work to counteract any infection mechanisms such as viral entry into a host cell.
  • the compounds have the following chemical structure
  • At least one group selected from Y 1 , Y 2 , Y 3 , or Y 4 includes N or NR a and at least another group selected from Y 1 , Y 2 , Y 3 , or Y 4 includes CR a or CR a R b .
  • R a and R b are each independently H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl.
  • R 1 , R 2 , R 3 , and R 4 are each independently R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO 2 , S(O) n R a , or S(O) n NR a R b .
  • m is an integer from 1 through 7 and n is 0, 1 , or 2.
  • the dashed lines represent the presence or absence of a double bond.
  • Example compounds can also have the following structure
  • R 1 is R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • R a is H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfonyl.
  • R 6 and R 7 are each independently R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b , or R 6 and R 7 are optionally fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring.
  • Figure 1 shows results from the influenza focus-forming assay. Decrease in foci is graphed as percent inhibition of viral infection by compound. Compound 1 and Compound 9 demonstrated dose-dependent decrease in viral infection of 293 cells. Compound 10 showed effective inhibition of viral infection of 293 cells.
  • Figures 2A and 2B show the antiviral activity of selected compounds against DNV.
  • Compound 1 -Compound 1 1 All compounds tested (Compound 1 -Compound 1 1 ) showed effective inhibition of DNV serotype 2 when used at a concentration of at least 5 ⁇ .
  • Compound 2, Compound 3, Compound 6, Compound 7, Compound 8, and Compound 10 showed dose-dependent decrease in viral infection.
  • Compound 1 -Compound 1 1 showed effective inhibition of DNV serotype 4. The calculated EC50 and EC90 values are shown.
  • Figure 3 shows Compound 1 and Compound 10 blood and spleen levels after dosing at 10mg/kg via intraperitoneal injection. Compound 1 levels in plasma are shown over time up to 4 hours post injection. Spleen level is shown at 4 hours post injection, when tissue was harvested.
  • the present disclosure provides compounds, pharmaceutical compositions, and methods of small molecule based broad-spectrum antiviral therapies.
  • the disclosed compounds represent a new class of antiviral therapeutics. Although the disclosure is not bound by a specific mechanism of action of the compounds in vivo, the compounds are selected for their inhibition of a variety of viruses. Compounds, pharmaceutical compositions, and methods disclosed herein function to treat subjects, decrease viral protein, decrease viral RNA, and/or decrease infectious virus in laboratory models of viral infection.
  • the compounds described herein are antiviral compounds.
  • the compounds are innate immune modulating compounds. In another embodiment, the compounds are innate immune activating compounds. In another embodiment, the compounds are innate immune agonists.
  • example compounds of the present disclosure can have the structure:
  • W can be CR a or N.
  • R a can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl.
  • R a can be optionally substituted lower alkyl.
  • W can be N.
  • W can be CH.
  • R b can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl.
  • X can be NH.
  • X can be O.
  • X can be S.
  • X can be Chb.
  • At least one group selected from Y 1 , Y 2 , Y 3 , or Y 4 includes N or NRa.
  • at least another group selected from Y 1 , Y 2 , Y 3 , or Y 4 includes CRa or CRaRb.
  • Y 4 can be N.
  • Y 1 , Y 2 , and Y 3 can be CH.
  • Y 4 can be N and Y 1 , Y 2 , and Y 3 can be CH.
  • R 1 can be R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO 2 , S(O) n R a , or S(O) n NR a R b .
  • R 2 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O)nR a , or S(O) n NR a R b .
  • R 3 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O)nR a , or S(O) n NR a R b .
  • R 3 can be OH.
  • R 4 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • m can be an integer from 1 through 7.
  • R 4 can be H and m can be 1 .
  • n can be 0, 1 , or 2.
  • the dashed lines can indicate the presence or absence of a double bond.
  • R 1 can be an unsubstituted aryl group, such as a phenyl group.
  • R 1 can be a substituted aryl group including one or more substituents. Substituents of a substituted aryl group can be located in the para position, the meta position, the ortho position, or combinations thereof.
  • one or more substituents of a substituted aryl group can include an alkyl group.
  • one or more substituents of a substituted aryl group can include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, or a heptyl group.
  • one or more substituents of a substituted aryl group can include one or more ether groups.
  • one or more substituents of a substituted aryl group can include OCH3.
  • one or more substituents of a substituted aryl group can include one or more halogen atoms.
  • one or more substituents of a substituted aryl group can include one or more F atoms, one or more CI atoms, one or more Br atoms, or a combination thereof.
  • one or more substituents of a substituted aryl group can include OCHF2.
  • one or more substituents of a substituted aryl group can include OCF3.
  • one or more substituents of a substituted aryl group can include CF3.
  • example compounds can have a structure
  • R 5 can be R a , OR a , OCHF2, OCF3, CF3, F, or CI. Additionally, o can be an integer from 1 through 7, in some embodiments. In some cases, R 2 , R 3 , R 4 , W, X, Y 1 , Y 2 , Y 3 , Y 4 , and m can be defined as above.
  • R 2 can be R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 3 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 4 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 5 can be R a , OR a , OCHF2, OCFs
  • R 3 can be OH or OCH3.
  • W can be CR a or N;
  • m can be an integer from 1 through 7;
  • n can be 0, 1 , or 2.
  • the dashed lines can indicate the presence or absence of a double bond.
  • R 1 can also include a heteroaryl group.
  • R 1 can include an unsubstituted heteroaryl group.
  • R 1 can include a substituted heteroaryl group.
  • R 1 can include a heteroaryl group having at least one oxygen atom.
  • R 1 can also include a heteroaryl group having at least one sulfur atom.
  • R 1 can include a heteroaryl group having at least one nitrogen atom.
  • R 1 can include a heteroaryl group with a ring structure having 3 members.
  • R 1 can include a heteroaryl group with a ring structure having 4 members.
  • R 1 can include a heteroaryl group with a ring structure having 5 members.
  • R 1 can include a heteroaryl group with a ring structure having 6 members.
  • R 1 can include a furyl group.
  • R 1 can include a 2-furyl group.
  • R 2 can include a 3-furyl group.
  • R 1 can include a thienyl group.
  • R 1 can include a 2-thienyl group.
  • R 1 can include a 3-thienyl group.
  • R 1 can include a pyrrolyl group.
  • R 1 can include a 2-pyrrolyl group.
  • R 1 can include 3-pyrrolyl group.
  • R 1 can include a thiazolyl group.
  • the heteroaryl group when R 1 is a substituted heteroaryl group, can be substituted with a substituted aryl group. In some embodiments when R 1 is a substituted heteroaryl group, the heteroaryl group can be substituted with an unsubstituted aryl group, such as a phenyl group. In particular illustrative embodiments, R 1 can be a thiazolyl group substituted by a phenyl group.
  • R 2 can include at least one aryl group.
  • R 2 can include an unsubstituted aryl group.
  • R 2 can include a substituted aryl group.
  • R 2 can include at least one heteroaryl group.
  • R 2 can include a heteroaryl group having at least one N atom in the ring of the heteroaryl group.
  • R 2 can include a heteroaryl group having at least one S atom in the ring of the heteroaryl group.
  • R 2 can include a heteroaryl group having at least one O atom in the ring of the heteroaryl group.
  • R 2 can include a heteroaryl group with a ring structure having 3 members.
  • R 2 can include a heteroaryl group with a ring structure having 4 members.
  • R 2 can include a heteraryl group with a ring structure having 5 members.
  • R 2 can include a heteroaryl group with a ring structure having 6 members.
  • R 2 can include an azolyl group.
  • R 2 can include a pyrrolyl group.
  • R 2 can include a pyrazolyl group.
  • R 2 can include an imidazolyl group.
  • R 2 can include a triazolyl group.
  • R 2 can include a tetrazolyl group.
  • R 2 can include an oxazolyl group.
  • R 2 can include an isoxazolyl group.
  • R 2 can include a thiazolyl group.
  • R 2 can also include an isothiazolyl group, in some instances.
  • R 2 can include a phenyl group. In other embodiments, R 2 can include a pyridinyl group. In additional embodiments, R 2 can include a piperidinyl group. R 2 can also include a cyclopentyl group. Further, R 2 can include a cyclohexyl group.
  • example compounds can have a structure
  • W, X, Y 1 , Y 2 , Y 3 , Y 4 , R 3 , R 4 , R 5 , m, and o can be defined as above.
  • R 3 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO 2 , S(O) n R a , or S(O) n NR a R b
  • R 4 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 5 can be R a , OR a , OCHF2, OCFs, CFs, F, or CI.
  • R 3 can be OH or OCH3.
  • W can be CR a or N;
  • m can be an integer from 1 through 7;
  • n can be 0, 1 , or 2;
  • o can be an integer from 1 through 7.
  • R 5 can be CH3.
  • o can be 1 and R 5 can be CH3 located in the para position.
  • R 5 can be OCHF2.
  • o can be 1 and R 5 can be OCHF2 located in the para position.
  • R 5 can be F.
  • o can be 1 and R 5 can be F located in the para position.
  • R 5 can also be CI.
  • o can be 1 and R 5 can be CI located in the para position.
  • R 5 can be OCH3.
  • o can be 1 and R 5 can be OCH3 in the para position.
  • R 5 can be OCF3.
  • o can be 1 and R 5 can be OCF3 located in the meta position.
  • R 5 can be CF3.
  • o can be 1 and R 5 can be CF3 located in the meta position.
  • R 2 includes an optionally substituted aryl group or an optionally substituted heteroaryl group
  • example compounds can have a structure
  • Z 1 can be N, NR a , S, O, CR a , or CR a R b .
  • Z 2 can be N, NR a , S, O, CR a , or CR a R b .
  • R 6 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • R 7 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b .
  • R 6 and R 7 can be fused to form a ring having 3 or more members.
  • R 6 and R 7 can be fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring.
  • the dashed lines indicate the presence or absence of a double bond.
  • R 1 , R 3 , R 4 , W, X, Y 1 , Y 2 , Y 3 , Y 4 , and m can be defined as above.
  • R 1 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 3 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 4 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b ,
  • n can be 0, 1 , or 2.
  • R 3 can be OH or OCH3.
  • W can be CR a or N;
  • Z 1 can be N.
  • Z 2 can be S.
  • Z 1 can be N and Z 2 can be S.
  • Z 1 can be S and Z 2 can be N.
  • R 6 can include an alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, or a heptyl group.
  • R 6 can include an optionally substituted aryl group.
  • R 7 can include an optionally substituted aryl group.
  • R 6 and R 7 can be fused to form an optionally substituted aryl ring. In some cases, R 6 and R 7 can be fused to form a phenyl group. Additionally, R 6 and R 7 can be fused to form a phenyl group substituted by H, a lower alkyl group, an ether group, or a combination thereof. For example, R 6 and R 7 can be fused to form a phenyl group substituted by OCH3.
  • example compounds can have a structure where R 1 includes an optionally substituted aryl group and R 2 includes an optionally substituted heteroaryl group or an optionally substituted aryl group, example compounds can have a structure
  • Z 1 can be N, NR a , S, O, CR a , or CR a R b .
  • Z 2 can be N, NR a , S, O, CR a , or CR a R b .
  • R 5 can be R a , OR a , OCHF2, OCFs, CFs, F, or CI.
  • R 6 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b .
  • R 7 can be R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b .
  • R 6 and R 7 can be fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring.
  • o can be an integer from 1 through 7.
  • R 3 , R 4 , W, X, Y 1 , Y 2 , Y 3 , Y 4 , and m can be defined as above.
  • R 3 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 4 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • R 3 can be OH or OCH3.
  • W can be CR a or N;
  • m can be an integer from 1 through 7;
  • n can be 0, 1 , or 2.
  • the dashed lines indicate the presence or absence of a double bond.
  • R 1 includes an optionally substituted aryl group
  • R 2 includes a substituted heteroaryl group
  • R 6 and R 7 are fused to form an optionally substituted aryl ring
  • example compounds can have a structure
  • R 5 can be R a , OR a , OCHF2, OCFs, CFs, F, or CI .
  • R 8 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • o can be an integer from 1 through 7.
  • t can be an integer from 1 through 7.
  • R 3 , R 4 , W, X, Y 1 , Y 2 , Y 3 , Y 4 , Z 1 and Z 2 , and m can be defined as above.
  • R 3 can be R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 4 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • R 3 can be OH or OCH3.
  • W can be CR a or N;
  • Z 1 can be N, NR a , S, O, CR a , or CR a R b ;
  • Z 2 can be N, NR a , S, O, CR a , or CR a R b ;
  • m can be an integer from 1 through 7;
  • n can be 0, 1 , or 2.
  • the dashed lines indicate the presence or absence of a double bond.
  • t can be 1 and R
  • example compounds can have a structure
  • R 1 can be R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • R a can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl.
  • R b can be H, optionally substituted hydrocarbyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl.
  • R 6 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b .
  • R 7 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b .
  • n can be 0, 1 , or 2.
  • at least one of R 6 or R 7 can include an optionally substituted aryl ring.
  • R 1 can include an optionally substituted aryl ring.
  • the substituted aryl ring can have substituents as defined above.
  • example compounds can have a structure
  • R 9 can be R a as defined above.
  • R 1 can be defined as above.
  • R a can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl;
  • R 1 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • n can be 0, 1 , or 2.
  • R 9 can be CH3.
  • Additional embodiments of example compounds can have a structure
  • R 10 can be R a , CHF2, or CF3.
  • the group OR 10 can be located in the para position or the meta position.
  • R 10 can be CH3.
  • a group OCH3 can be located in the para position.
  • R 10 can be CHF2.
  • a group OCHF2 can be located in the para position.
  • R 10 can be CF3.
  • a group OCF3 can be located in a meta position.
  • R a , R 6 , R 7 can be defined as above.
  • R a can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl;
  • R 6 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O)nNR a R b ;
  • R 7 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b .
  • n can be 0, 1
  • At least one group selected from Y 1 , Y 2 , Y 3 , or Y 4 can include N or NR a . Additionally, at least another group selected from Y 1 , Y 2 , Y 3 , or Y 4 can include CR a or CR a R b . In various embodiments, R a , R b , R 3 , R 4 , m, o, and t can be defined as above.
  • R a can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl;
  • R b can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl;
  • R 3 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 5 can be optionally substituted hydrocarbyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl, OR a , OCHF2, OCFs, CFs, F, or CI.
  • R 8 can R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • R 11 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • R 12 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • at least one of R 3 , R 11 , or R 12 is OR a .
  • m can be an integer from 1 through 7.
  • o can be an integer from 1 through 7.
  • t can be an integer from 1 through 7.
  • n can be 0, 1 , or 2.
  • the dashed lines can represent the presence or absence of a double bond.
  • Embodiments of example compounds can also have a structure
  • At least one group selected from Y 1 , Y 2 , Y 3 , or Y 4 can include N or NR a . Additionally, at least another group selected from Y 1 , Y 2 , Y 3 , or Y 4 can include CR a or CR a R b . In various embodiments, R a , R b , R 2 , R 3 , R 4 , R 11 , R 12 , m and o can be defined as above.
  • R a can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl;
  • R b can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl;
  • R 2 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 12 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • m can be an integer from 1 through 7; n can be 0, 1 , or 2; o can be an integer from 1 through 7.
  • at least one of R 3 , R 11 , or R 12 is OR a .
  • the dashed lines can represent the presence or absence of a double bond.
  • R 5 is (O) u C(H) v (F) w .
  • u is 0, 1 , or 2.
  • v can be 0 or 1 .
  • w can be 1 , 2, or 3.
  • u can be 1
  • v can be 1
  • w can be 2.
  • u can be 1
  • v can be 0
  • w can be 3.
  • u can be 0, v can be 0, and w can be 3.
  • At least one group selected from Y 1 , Y 2 , Y 3 , or Y 4 can include N or NR a .
  • at least another group selected from Y 1 , Y 2 , Y 3 , or Y 4 can include CR a or CR a R b .
  • R a , R b , R 2 , R 3 , R 4 , R 11 , R 12 , and m can be defined as above.
  • R a can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl;
  • R b can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl;
  • R 2 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b
  • R 12 can be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • m can be an integer from 1 through 7; n can be 0, 1 , or 2.
  • at least one of R 3 , R 11 , or R 12 is OR a .
  • the dashed lines can represent the presence or absence of a double bond.
  • R 6 or R 7 is optionally substituted hydrocarbyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, alkylsulfonyl; OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b , and the other of R 6 or R 7 is R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • R 6 can be CH3 and R 7 can be an optionally substituted aryl group. In another illustrative embodiment, R 6 can be an optionally substituted aryl group and R 7 can be H.
  • example compounds can have the structure
  • Z 1 can be N, NR a , S, O, CR a , or CR a R b .
  • Z 2 can be N, NR a , S, O, CR a , or CR a R b .
  • Z 3 can be N, NR a , S, O, CR a , or CR a R b .
  • Z 2 can be N, NR a , S, O, CR a , or CR a R b .
  • one of Z 1 or Z 2 can be S and the other one of Z 1 or Z 2 can be N.
  • Z 1 can be S and Z 2 can be N.
  • At least one of Z 3 or Z 4 can be S. In various embodiments, at least one of Z 3 or Z 4 can be O. In an illustrative embodiment, Z 3 can be O and Z 4 can be CH. In another illustrative embodiment, Z 3 can be S and Z 4 can be CH. In an additional illustrative embodiment, Z 3 can be CH and Z 4 can be O. In further illustrative embodiments, Z 3 can be CH and Z 4 can be S.
  • R 13 and R 14 can include R a and r and q can be 0, 1 , 2, 3, 4, or 5. In addition, the dashed lines can indicate the presence or absence of a double bond. In embodiments, R 13 can include a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. In particular illustrative embodiments, R 13 can include a phenyl group.
  • example compounds can have a structure
  • At least one of Z 3 or Z 4 can be S. In various embodiments, at least one of Z 3 or Z 4 can be O. In an illustrative embodiment, Z 3 can be O and Z 4 can be CH. In another illustrative embodiment, Z 3 can be S and Z 4 can be CH. In an additional illustrative embodiment, Z 3 can be CH and Z 4 can be O. In further illustrative embodiments, Z 3 can be CH and Z 4 can be S.
  • R 13 and R 14 can include R a and r and q can be 0, 1 , 2, 3, 4, or 5. In addition, the dashed lines can indicate the presence or absence of a double bond. In embodiments, R 13 can include a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. In particular illustrative embodiments, R 13 can include a phenyl group.
  • R 1 is an optionally substituted heteroaryl group
  • compounds can have a structure
  • Z 3 , Z 4 , R 2 , R 14 , and r can be defined as above.
  • Z 3 can be O, S, CH, or CH 2
  • Z 4 can be O, S, CH, or CH 2
  • R 2 can be R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO 2 , S(O) n R a , or S(O) n NR a R b
  • R 14 can be R a ;
  • n can be 0, 1 , or 2;
  • r can be 0, 1 , 2, 3, 4, or 5.
  • compounds having W is N and X is CH2 can have a structure
  • At least one of Z 5 or Z 6 can be S. In various embodiments, at least one of Z 5 or Z 6 can be N. In an illustrative embodiment, Z 5 can be N and Z 6 can be S. In other embodiments, Z 5 or Z 6 can be CH or CH2.
  • R 15 and R 16 can include R a , OR a , OCFs, OCHF2, OCH2F, COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b . and d and e can be 0, 1 , 2, 3, 4, or 5.
  • R 3 can be defined as above.
  • R 3 can be R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b .
  • n can be 0, 1 , or 2.
  • R 3 can include OH and R 16 can include OCHF2.
  • Embodiments of compounds can also have a structure
  • R 17 and R 18 can include a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group, or an unsubstituted heteroaryl group.
  • R 17 , R 18 , or both can each independently include a substituted aryl group or an unsubstituted aryl group having a ring structure with 3 members, 4 members, 5 members, 6 members, or 7 members.
  • R 17 , R 18 , or both can each independently include a substituted heteroaryl group or an unsubstituted heteroaryl group having a ring structure with 3 members, 4 members, 5, members, 6 members, or 7 members.
  • R 17 can include a dual ring structure comprising a phenyl ring and a pyrrodinyl ring and R 18 can include a substituted heteroaryl group.
  • the phenyl ring can be substituted by a hydroxyl group.
  • R 17 can include H or lower alkyl and R 18 can include a substituted heteroaryl group or an unsubstituted heteroaryl group.
  • R 18 can include a heteroaryl group with a phenyl substituent.
  • R 18 can include a dual ring structure having a thioazolyl group and a phenyl group.
  • R 17 can include H and R 18 can include a thiozaolyl group substituted by a phenyl group.
  • example compounds can have a structure
  • Z 7 and Z 8 can each independently be S, N, O, CH, or CH2. In a particular embodiment Z 7 or Z 8 can be S. In another embodiment, Z 7 or Z 8 can be N. In still other embodiments, Z 7 can be S and Z 8 can be N. In further embodiments, Z 7 can be N and Z 8 can be S.
  • R 19 , R 20 , and R 21 can each independently be R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b , where R a , R b , and n are defined above.
  • R a can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfonyl;
  • R b can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfonyl;
  • n can be 0, 1 , or 2.
  • R 19 and R 20 can be fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring.
  • R 19 and R 20 are fused to form a pyridinyl group.
  • R 22 can be H, lower alkyl, ORa, a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group, or an unsubstituted heteroaryl group and f can be 0, 1 , or 2.
  • R 22 can include a phenyl group.
  • two R 22 groups can be fused to form a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group, or an unsubstituted heteroaryl group.
  • Z 7 can be N
  • Z 8 can be S
  • R 19 and R 20 can be fused to form an unsubstituted pyridinyl group
  • R 21 can be OH
  • two R 22 groups can be fused to form a phenyl group.
  • Example compounds can also have any one of the following structures, as shown in Table 1 .
  • alkyloxy or “alkoxy” refer to a functional group including an alkyl ether group.
  • alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkyl refers to substituted and unsubstituted alkyls, alkenyls, and alkynyls.
  • Hydrocarbyl used alone or in combination refers to a substituted or unsubstituted hydrocarbon based group.
  • hydrocarbyl can, in some cases, include an alkyl group, an alkenyl group, an alkynyl group, a cyclic hydrocarbon group, or an aryl group.
  • alkyl refers to a functional group including a straight-chain or branched-chain hydrocarbon containing from 1 to 20 carbon atoms linked exclusively by single bonds and not having any cyclic structure.
  • “Lower alkyl” refers to a functional group containing from 1 to 6 carbon atoms. An alkyl group may be optionally substituted as defined herein.
  • alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, and the like.
  • alkenyl refers to a functional group including a straight-chain or branched-chain hydrocarbon containing from 2 to 20 carbon atoms and having one or more carbon-carbon double bonds and not having any cyclic structure.
  • An alkenyl group may be optionally substituted as defined herein. Examples of alkenyl groups include ethene, propene, 2-methylpropene, 1 -butene, 2-butene, pentene,
  • alkynyl refers to a functional group including a straight-chain or branched-chain hydrocarbon containing from 2 to 20 carbon atoms and having one or more carbon-carbon triple bonds and not having any cyclic structure.
  • An alkynyl group may be optionally substituted as defined herein.
  • alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butynyl, butyn-1 -yl, butyn-2-yl, 3- methylbutyn-1 -yl, pentynyl, pentyn-1 -yl, hexynyl, hexyn-2-yl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, eicosynyl, and the like.
  • substituted alkyls, alkenyls, and alkynyls refer to alkyls, alkenyls, and alkynyls substituted with one to five substituents from the group including H, lower alkyl, aryl, alkenyl, alkynyl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkoxyalkylaryl, alkylamino, arylamino, Nhb, OH, CN, NO2, OCF3, CF3, F, Cl,1 -amidine,
  • Alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.
  • alkylcarbonyl or “alkanoyl” refer to a functional group including an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylcarbonyl groups include, methylcarbonyl, ethylcarbonyl, and the like.
  • alkynylene refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C:::C-, -C ⁇ C-). Unless otherwise specified, the term “alkynyl” can include “alkynylene” groups.
  • aryl refers to a functional group including a substituted or unsubstituted aromatic hydrocarbon with a conjugated cyclic molecular ring structure of 3 to 12 carbon atoms.
  • An aryl group can be monocyclic, bicyclic, or polycyclic, and can optionally include one to three additional ring structures, such as, e.g., a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, or a heteroaryl.
  • aryl includes phenyl (benzenyl), thiophenyl, indolyl, naphthyl, tolyl, xylyl, anthracenyl, phenanthryl, azulenyl, biphenyl, naphthalenyl, 1 -Methylnaphthalenyl, acenaphthenyl, acenaphthylenyl, anthracenyl, fluorenyl, phenalenyl, phenanthrenyl, benzo[a]anthracenyl, benzo[c]phenanthrenyl, chrysenyl, fluoranthenyl, pyrenyl, tetracenyl (naphthacenyl), triphenylenyl, anthanthrenyl, benzopyrenyl, benzo[a]pyrenyl, benzo[e]fluoranthenyl, benzo[ghi
  • aryl refers to aryls substituted with one to five substituents from the group including H, lower alkyl, aryl, alkenyl, alkynyl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkoxyalkylaryl, alkylamino, arylamino, NH2, OH, CN, NO2, OCF3, CF3, Br, CI, F, 1 -amidino, 2-amidino, alkylcarbonyl, morpholino, piperidinyl, dioxanyl, pyranyl, heteroaryl, furanyl, thiophenyl, tetrazolo, thiazole, isothiazolo, imidazolo, thiadiazole, thiadiazole S-oxide, thiadiazole S,S-dioxide,pyrazolo, oxazole, isoxazole, pyridinyl, pyrimi
  • An "O-carboxyl” group refers to a carboxyl group having the general formula RCOO, wherein R is an organic moiety or group.
  • a “C-carboxyl” group refers to a carboxyl group having the general formula COOR, wherein R is an organic moiety or group.
  • cycloalkyl refers to a functional group including a substituted or unsubstituted non- aromatic hydrocarbon with a non-conjugated cyclic molecular ring structure of 3 to 12 carbon atoms linked exclusively with carbon-carbon single bonds in the carbon ring structure.
  • a cycloalkyl group can be monocyclic, bicyclic, or polycyclic, and may optionally include one to three additional ring structures, such as, e.g., an aryl, a heteroaryl, a cycloalkenyl, a heterocycloalkyl, or a heterocycloalkenyl.
  • lower cycloalkyl refers to a functional group including a monocyclic substituted or unsubstituted non-aromatic hydrocarbon with a non- conjugated cyclic molecular ring structure of 3 to 6 carbon atoms linked exclusively with carbon-carbon single bonds in the carbon ring structure.
  • lower cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heteroalkyl refers to a functional group including a straight-chain or branched-chain hydrocarbon containing from 1 to 20 atoms linked exclusively by single bonds, where at least one atom in the chain is a carbon and at least one atom in the chain is O, S, N, or any combination thereof.
  • the heteroalkyl group can be fully saturated or contain from 1 to 3 degrees of unsaturation.
  • the non-carbon atoms can be at any interior position of the heteroalkyl group, and up to two non-carbon atoms may be consecutive, such as, e.g., -CH2-NH-OCH3.
  • the non-carbon atoms may optionally be oxidized and the nitrogen may optionally be quaternized.
  • heteroaryl refers to a functional group including a substituted or unsubstituted aromatic hydrocarbon with a conjugated cyclic molecular ring structure of 3 to 12 atoms, where at least one atom in the ring structure is a carbon and at least one atom in the ring structure is O, S, N, or any combination thereof.
  • a heteroaryl group can be monocyclic, bicyclic, or polycyclic, and may optionally include one to three additional ring structures, such as, e.g., an aryl, a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, or a heterocycloalkenyl.
  • heteroaryl groups include acridinyl, benzidolyl, benzimidazolyl, benzisoxazolyl, benzodioxinyl, dihydrobenzodioxinyl, benzodioxolyl, 1 ,3-benzodioxolyl, benzofuryl, benzoisoxazolyl, benzopyranyl, benzothiophenyl, benzo[c]thiophenyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, carbazolyl, chromonyl, cinnolinyl, dihydrocinnolinyl, coumarinyl, dibenzofuranyl, furopyridinyl, furyl, indolizinyl, indolyl, dihydroindolyl, imidazolyl, indazolyl, in
  • hydroxy refers to the functional group hydroxyl (-OH).
  • “Functional group” refers to an atom or a group of atoms that have similar chemical properties whenever they occur in different compounds, and as such the functional group defines the characteristic physical and chemical properties of families of organic compounds.
  • the substituent may be an ordinary organic moiety known in the art, which can have a molecular weight (e.g., the sum of the atomic masses of the atoms of the substituent) of 15 g/mol to 50 g/mol , 15 g/mol to 100 g/mol , 15 g/mol to 150 g/mol , 15 g/mol to 200 g/mol , 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol.
  • a molecular weight e.g., the sum of the atomic masses of the atoms of the substituent
  • the substituent includes: 0-30, 0-20, 0-10, or 0-5 C atoms; and/or 0-30, 0-20, 0-10, or 0-5 heteroatoms including N, O, S, Si, F, CI, Br, or I; provided that the substituent includes at least one atom, including C, N, O, S, Si, F, CI, Br, or I, in a substituted compound.
  • substituents include alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N carbamyl, O thiocarbamyl, N thiocarbamyl, C amido, N amido, S-sulfonamido, N sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, amino,
  • molecular weight is used with respect to a moiety or part of a compound to indicate the sum of the atomic masses of the atoms in the moiety or part of a compound, even though it may not be a complete compound.
  • any structure, formula, or name for a compound can refer to any stereoisomer or any mixture of stereoisomers of the compound.
  • Compounds can also be provided as alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • Compounds also include pharmaceutically acceptable salts of the compounds.
  • the term "pharmaceutically acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the pharmaceutically acceptable salt is a sulfate salt.
  • S. M. Berge, et al. describes pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66:1 -19.
  • Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, ⁇ -hydroxybutyric, malonic, galactic, and galacturonic acid.
  • Pharnnaceutically acceptable acidic/anionic salts also include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate,
  • Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine, arginine and procaine. All of these salts can be prepared by conventional means from the corresponding compound represented by the disclosed compounds by treating, for example, the disclosed compounds with the appropriate acid or base.
  • Pharmaceutically acceptable basic/cationic salts also include, the diethanolamine, ammonium, ethanolamine, piperazine and triethanolamine salts.
  • a pharmaceutically acceptable salt includes any salt that retains the activity of the parent compound and is acceptable for pharmaceutical use.
  • a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
  • any structure, formula, or name for a compound can refer to any stereoisomer or any mixture of stereoisomers of the compound.
  • a prodrug includes a compound which is converted to a therapeutically active compound after administration, such as by hydrolysis of an ester group or some other biologically labile group.
  • compositions [0098] According to other embodiments, the present disclosure provides for a pharmaceutical composition including any one or more of the compounds described herein.
  • compositions can be formed by combining a compound disclosed herein, or a pharmaceutically acceptable prodrug or salt thereof, with a pharmaceutically acceptable carrier suitable for delivery to a subject in accordance with known methods of drug delivery.
  • a pharmaceutical composition includes at least one compound disclosed herein together with one or more pharmaceutically acceptable carriers, excipients, or diluents, as appropriate for the chosen mode of administration.
  • the pharmaceutical composition including a compound of the disclosure can be formulated in a variety of forms depending upon the particular indication being treated and will be apparent to one of ordinary skill in the art. Formulating pharmaceutical compositions including one or more compounds of the disclosure can employ straightforward medicinal chemistry processes.
  • the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional adjuvants, such as buffering agents, preservatives, isotonicifiers, stabilizers, wetting agents, emulsifiers, etc.
  • Buffering agents help to maintain the pH in a range which approximates physiological conditions. They are typically present at a concentration ranging from 2 mM to 50 mM of a pharmaceutical composition.
  • Suitable buffering agents include both organic and inorganic acids, and salts thereof, such as citrate buffers (e.g., monosodium citrate- disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid- potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, fumaric acid-d
  • Preservatives can be added to pharmaceutical compositions to retard microbial growth, and are typically added in amounts of 0.2%-1 % (w/v).
  • Suitable preservatives include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides (e.g., benzalkonium chloride, bromide or iodide), hexamethonium chloride, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.
  • Isotonicifiers can be added to pharmaceutical compositions to ensure isotonicity.
  • Appropriate isotonicifiers include polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol.
  • Polyhydric alcohols can be present in an amount between 0.1 % and 25% by weight, typically 1 % to 5%, taking into account the relative amounts of the other ingredients.
  • Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the compound or helps to prevent denaturation or adherence to the container wall.
  • Typical stabilizers can be polyhydric sugar alcohols; amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, and the like, including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur-containing reducing agents, such as urea, gluta
  • Additional miscellaneous excipients can include chelating agents (e.g., EDTA), antioxidants (e.g., ascorbic acid, methionine, and vitamin E) and cosolvents.
  • chelating agents e.g., EDTA
  • antioxidants e.g., ascorbic acid, methionine, and vitamin E
  • cosolvents e.g., ascorbic acid, methionine, and vitamin E
  • Particular embodiments can include one or more of ethanol ( ⁇ 10%), propylene glycol ( ⁇ 40%), polyethylene glycol (PEG) 300 or 400 ( ⁇ 60%), N-N-dimethylacetamide (DMA, ⁇ 30%), N-methyl-2-pyrrolidone (NMP, ⁇ 20%), dimethyl sulfoxide (DMSO, ⁇ 20%) co-solvents or the cyclodextrins ( ⁇ 40%) and have a pH of 3 to 9.
  • the pharmaceutical compositions can be made up in a solid form (including granules, powders, or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions).
  • the compounds can be admixed with adjuvants such as lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • adjuvants such as lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alg
  • the carrier or diluent can include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the pharmaceutical composition can be in solid or liquid form, e.g., in the form of a capsule, tablet, powder, granule, suspension, emulsion, or solution.
  • Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules.
  • the compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms can also include, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms can also include buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • the pharmaceutical compositions can take the form of tablets or lozenges formulated in conventional manners.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such pharmaceutical compositions can also include adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
  • the pharmaceutical compositions can be formulated for parenteral administration by injection, e.g. by bolus injection, or infusion.
  • Formulations for injection can be presented in unit dosage form, e.g. in glass ampoule or multi-dose containers, e.g. glass vials.
  • the pharmaceutical compositions for injection can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as antioxidants, buffers, non-ionic detergents, dispersants, isotonicifiers, suspending agents, stabilizers, preservatives, dispersing agents and/or other miscellaneous additives.
  • Parenteral formulations to be used for in vivo administration generally are sterile. This is readily accomplished, for example, by filtration through sterile filtration membranes.
  • compositions provided in liquid form are appropriate for immediate use, such parenteral formulations can also be provided in frozen or in lyophilized form.
  • the latter form is often used to enhance the stability of the compound contained in the pharmaceutical composition under a wider variety of storage conditions, as it is recognized by those or ordinary skill in the art that lyophilized preparations are generally more stable than their liquid counterparts.
  • Parenterals can be prepared for storage as lyophilized formulations by mixing, as appropriate, the compound having the desired degree of purity with one or more pharmaceutically acceptable carriers, excipients, or stabilizers typically employed in the art (all of which are termed "excipients"), for example, antioxidants, buffers, non-ionic detergents, dispersants, isotonicifiers, suspending agents, stabilizers, preservatives, dispersing agents and/or other miscellaneous additives.
  • excipients for example, antioxidants, buffers, non-ionic detergents, dispersants, isotonicifiers, suspending agents, stabilizers, preservatives, dispersing agents and/or other miscellaneous additives.
  • excipients for example, antioxidants, buffers, non-ionic detergents, dispersants, isotonicifiers, suspending agents, stabilizers, preservatives, dispersing agents and/or other miscellaneous additives.
  • the pharmaceutical compositions can be conveniently delivered in the form of an aerosol spray, from pressurized packs or a nebulizer, and/or with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases or mixture of gases.
  • suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases or mixture of gases.
  • compositions described above can also be formulated as depot preparations. Such long acting formulations can be administered by implantation or by intramuscular injection.
  • the compounds can also be entrapped in microcapsules prepared, for example, by coascervation techniques or by interfacial polymerization, (for example hydroxymethylcellulose, gelatin or poly-(methylmethacylate) microcapsules), in colloidal drug delivery systems (for example liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • coascervation techniques or by interfacial polymerization for example hydroxymethylcellulose, gelatin or poly-(methylmethacylate) microcapsules
  • colloidal drug delivery systems for example liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • macroemulsions for example liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, the matrices having a suitable form such as a film or microcapsules.
  • sustained- release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate) or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the PROLEASE® technology (Alkermes, Inc., Cambridge, MA) or LUPRON DEPOT® (Tap Pharmaceuticals Products, Inc.; Lake Forest, IL; injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such
  • compositions disclosed herein can be used to treat a viral infection in a subject; wherein the viral infection is caused by a virus from one the following families: Arenaviridae, Arterivirus, Astroviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Closteroviridae, Comoviridae, Coronaviridae, Cystoviridae, Flaviviridae, Flexiviridae, Hepadnaviridae, Hepevirus, Herpesviridae, Leviviridae, Luteoviridae, Meson iviridae, Mononegavirales, Mosaic Viruses, Nidovirales, Nodaviridae, Orthomyxoviridae, Papillomaviridae, Paramyxoviridae, Picobirnaviridae, Picobirnavirus, Picornaviridae, Potyviridae, Reovirida
  • the pharmaceutical compositions can be used to treat a viral infection caused by one or more of Alfuy virus, Banzi virus, bovine diarrhea virus, Chikungunya virus, Dengue virus (DNV), Ebola virus, Encephalomyocarditis virus (EMCV), Hepatitis B virus (HBV), HCV, human cytomegalovirus (hCMV), HIV, llheus virus, influenza virus (including avian and swine isolates), Japanese encephalitis virus, Kokobera virus, Kunjin virus, Kyasanur forest disease virus, louping-ill virus, Lassa virus (LASV), measles virus, MERS-coronavirus (MERS), metapneumovirus, any of the Mosaic Viruses, Murray Valley virus, Nipah virus, parainfluenza virus, poliovirus, Powassan virus, respiratory syncytial virus (RSV), Rocio virus, SARS-coronavirus
  • RNA viruses share biochemical, regulatory, and signaling pathways. These viruses include influenza viruses (including avian and swine isolates), DNV, RSV, WNV, HCV, parainfluenza virus, metapneumovirus, Chikungunya virus, SARS, MERS, poliovirus, measles virus, yellow fever virus, tick-borne encephalitis virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley virus, Powassan virus, Rocio virus, louping-ill virus, Banzi virus, llheus virus, Kokobera virus, Kunjin virus, Alfuy virus, bovine diarrhea virus, and the Kyasanur forest disease virus.
  • Methods disclosed herein include treating subjects (humans, mammals, free- range herds, veterinary animals (dogs, cats, reptiles, birds, etc.), farm animals and livestock (horses, cattle, goats, pigs, chickens, etc.), and research animals (monkeys, rats, mice, fish, etc.)) with pharmaceutical compositions disclosed herein. Treating subjects includes delivering therapeutically effective amounts. Therapeutically effective amounts include those that provide effective amounts, prophylactic treatments, and/or therapeutic treatments. [0121] An "effective amount" is the amount of a compound necessary to result in a desired physiological change in the subject. Effective amounts are often administered for research purposes.
  • Effective amounts disclosed herein reduce, control, or eliminate the presence or activity of viral infections and/or reduce, control, or eliminate unwanted side effects of viral infections.
  • an effective amount may result in a reduction in viral protein in a subject or assay, a reduction in viral RNA in a subject or assay, and/or a reduction in virus present in a cell culture.
  • a prophylactic treatment includes a treatment administered to a subject who does not display signs or symptoms of a viral infection or displays only early signs or symptoms of the viral infection such that treatment is administered for the purpose of diminishing, preventing, or decreasing the risk of developing the viral infection further.
  • a prophylactic treatment functions as a preventative treatment against a viral infection.
  • Prophylactic treatment may also include vaccines as described elsewhere herein.
  • Prophylactic treatment may result in a lack of increase in viral proteins or RNA in a subject, and/or a lack of increase in clinical indicators of viral infection, such as: loss of appetite, fatigue, fever, muscle aches, nausea, and/or abdominal pain in the case of HCV; fever and/or headache in the case of WNV; and cough, congestion, fever, sore throat, and/or headache in the case of RSV.
  • Prophylactic treatments can be administered to any subject regardless of whether signs of viral infection are present. In some embodiments, prophylactic treatments can be administered before travel.
  • a "therapeutic treatment” includes a treatment administered to a subject who displays symptoms or signs of a viral infection and is administered to the subject for the purpose of diminishing or eliminating the signs or symptoms of the viral infection.
  • the therapeutic treatment can reduce, control, or eliminate the presence or activity of viruses and/or reduce, control, or eliminate side effects of viruses.
  • Therapeutic treatment may result in a decrease in viral proteins or RNA in a subject, and/or a decrease in clinical indicators of viral infection, such as: loss of appetite, fatigue, fever, muscle aches, nausea, and/or abdominal pain in the case of HCV; fever and/or headache in the case of WNV; and cough, congestion, fever, cyanosis, sore throat, and/or headache in the case of RSV.
  • therapeutically effective amounts can be initially estimated based on results from in vitro assays and/or animal model studies.
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes an IC50 as determined in cell culture against a particular target. Such information can be used to more accurately determine useful doses in subjects of interest.
  • the actual dose amount administered to a particular subject can be determined by a physician, veterinarian, or researcher taking into account parameters such as physical and physiological factors including target, body weight, severity of condition, type of viral infection, previous or concurrent therapeutic interventions, idiopathy of the subject, and route of administration.
  • compositions can be administered intravenously to a subject for treatment of viral infections in a clinically safe and effective manner, including one or more separate administrations of the composition.
  • 0.05 mg/kg to 5.0 mg/kg can be administered to a subject per day in one or more doses (e.g., doses of 0.05 mg/kg once-daily (QD), 0.10 mg/kg QD, 0.50 mg/kg QD, 1 .0 mg/kg QD, 1 .5 mg/kg QD, 2.0 mg/kg QD, 2.5 mg/kg QD, 3.0 mg/kg QD, 0.75 mg/kg twice-daily (BID), 1 .5 mg/kg BID or 2.0 mg/kg BID).
  • QD 0.05 mg/kg once-daily
  • BID twice-daily
  • the total daily dose of a compound can be 0.05 mg/kg to 3.0 mg/kg administered intravenously to a subject one to three times a day, including administration of total daily doses of 0.05-3.0, 0.1 -3.0, 0.5-3.0, 1 .0-3.0, 1 .5-3.0, 2.0-3.0, 2.5-3.0, and 0.5-3.0 mg/kg/day of compounds of Figure 1 using 60-minute QD, BID, or three times daily (TID) intravenous infusion dosing.
  • TID three times daily
  • antiviral pharmaceutical compositions can be intravenously administered QD or BID to a subject with, e.g., total daily doses of 1 .5 mg/kg, 3.0 mg/kg, 4.0 mg/kg of a composition with up to 92-98% wt/wt of a compound of Figure 1 .
  • Additional useful doses can often range from 0.1 to 5 pg/kg or from 0.5 to 1 g /kg.
  • a dose can include 1 g /kg, 5 g /kg, 10 g /kg, 15 g /kg, 20 g /kg, 25 ig /kg, 30 pg /kg, 35 pg/kg, 40 pg/kg, 45 pg/kg, 50 pg/kg, 55 pg/kg, 60 pg/kg, 65 Mg/kg, 70 pg/kg, 75 pg/kg, 80 pg/kg, 85 pg/kg, 90 pg/kg, 95 pg/kg, 100 pg/kg, 150 pg/kg, 200 Mg/kg, 250 pg/kg, 350 pg/kg, 400 pg/kg, 450 pg/kg, 500 pg/kg, 550 pg/kg, 600 pg/kg,
  • a dose can include 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, 1000 mg/kg, or more.
  • Therapeutically effective amounts can be achieved by administering single or multiple doses during the course of a treatment regimen (e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 1 1 months, or yearly.
  • a treatment regimen e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 1 1 months, or yearly.
  • compositions of the present disclosure can be performed in a variety of ways, including orally, subcutaneously, intravenously, intracerebrally, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, intrathecally, vaginally, rectally, intraocularly, or in any other acceptable manner.
  • the pharmaceutical compositions can be administered continuously by infusion, although bolus injection is acceptable, using techniques well known in the art, such as pumps (e.g., subcutaneous osmotic pumps) or implantation.
  • the pharmaceutical compositions can be directly applied as a solution or spray.
  • compositions disclosed herein can be additive or synergistic with other therapies currently in development or use.
  • ribavirin and interferon-a provide an effective treatment for HCV infection when used in combination.
  • Another non-limiting example is the combination of the compounds disclosed herein with the compounds disclosed in PCT/US13/026173. Their efficacy in combination can exceed the efficacy of either drug product when used alone.
  • compositions of the disclosure can be administered alone or in combination or conjunction with interferon, ribavirin, and/or a variety of small molecules that are being developed against both viral targets (viral proteases, viral polymerase, and/or assembly of viral replication complexes) and host targets (host proteases required for viral processing, host kinases required for phosphorylation of viral targets such as NS5A, and inhibitors of host factors required to efficiently utilize the viral internal ribosome entry site, or IRES).
  • viral targets viral proteases, viral polymerase, and/or assembly of viral replication complexes
  • host targets host proteases required for viral processing, host kinases required for phosphorylation of viral targets such as NS5A, and inhibitors of host factors required to efficiently utilize the viral internal ribosome entry site, or IRES).
  • compositions disclosed herein could be used in combination or conjunction with adamantane inhibitors, neuraminidase inhibitors, alpha interferons, non-nucleoside or nucleoside polymerase inhibitors, NS5A inhibitors, antihistamines, protease inhibitors, helicase inhibitors, P7 inhibitors, entry inhibitors, IRES inhibitors, immune stimulators, HCV replication inhibitors, cyclophilin A inhibitors, A3 adenosine agonists, and/or microRNA suppressors.
  • Cytokines that could be administered in combination or conjunction with the pharmaceutical compositions disclosed herein include interleukin (IL)-2, IL-12, IL-23, IL- 27, or IFN-y.
  • IL interleukin
  • the compounds or pharmaceutical compositions can be additive or synergistic with other compounds or pharmaceutical compositions to enable vaccine development. By virtue of their antiviral and immune enhancing properties, the compounds can be used to affect a prophylactic or therapeutic vaccination.
  • the compounds need not be administered simultaneously or in combination with other vaccine components to be effective.
  • the vaccine applications of the compounds are not limited to the treatment of viral infection but can encompass all therapeutic and prophylactic vaccine applications due to the general nature of the immune response elicited by the compounds.
  • a "vaccine” is an immunogenic preparation that is used to induce an immune response in an individual.
  • a vaccine can have more than one constituent that is immunogenic.
  • a vaccine can be used for prophylactic and/or therapeutic purposes.
  • a vaccine does not necessarily have to prevent viral infections.
  • the vaccines of the disclosure can affect an individual's immune response in a manner such that viral infection occurs in a lesser amount (including not at all) or such that biological or physiological effects of the viral infection are ameliorated when the vaccine is administered as described herein.
  • vaccines include preparations including pharmaceutical compositions including the compounds, alone or in combination with an antigen, for the purpose of treating a viral infection in a subject including a vertebrate animal.
  • the disclosure provides for the use of the compounds and pharmaceutical compositions as adjuvants.
  • An adjuvant enhances, potentiates, and/or accelerates the beneficial effects of another administered therapeutic agent.
  • the term "adjuvant” refers to compounds that modify the effect of other agents on the immune system. Adjuvants that possess this function may also be inorganic or organic chemicals, macromolecules, or entire cells of certain killed bacteria, which enhance the immune response to an antigen. They may be included in a vaccine to enhance the recipient's immune response to the supplied antigen.
  • vaccines can be against viruses, bacterial infections, cancers, etc. and can include one or more of a live attenuated vaccine (LAIV), an inactivated vaccine (I IV; killed virus vaccine), a subunit (split vaccine); a sub-virion vaccine; a purified protein vaccine; or a DNA vaccine.
  • LAIV live attenuated vaccine
  • I IV inactivated vaccine
  • split vaccine a subunit vaccine
  • purified protein vaccine or a DNA vaccine.
  • Appropriate adjuvants include one or more of water/oil emulsions, non-ionic copolymer adjuvants, e.g., CRL 1005 (Optivax; Vaxcel Inc., Norcross, Ga.), aluminum phosphate, aluminum hydroxide, aqueous suspensions of aluminum and magnesium hydroxides, bacterial endotoxins, polynucleotides, polyelectrolytes, lipophilic adjuvants and synthetic muramyl dipeptide (norMDP) analogs such as N-acetyl-nor-muranyl-L-alanyl-D-isoglutamine, N-acetyl- muranyl-(6-O-stearoyl)-L-alanyl-D-isoglutamine, or N-Glycol-muranyl-LalphaAbu-D- isoglutamine (Ciba-Geigy Ltd.).
  • CRL 1005 Optivax; Vaxcel Inc., Nor
  • the present disclosure further includes the use and application of the compounds and pharmaceutical compositions in vitro in a number of applications including developing therapies and vaccines against viral infections, research in modulation of the innate immune response in eukaryotic cells, etc.
  • the compounds and pharmaceutical compositions disclosure can also be used in animal models.
  • the results of such in vitro and animal in vivo uses of the compounds and pharmaceutical compositions can, for example, inform their in vivo use in humans, or they can be valuable independent of any human therapeutic or prophylactic use.
  • Embodiment 1 A compound having a structure
  • W is CR a or N
  • At least one group selected from Y 1 , Y 2 , Y 3 , or Y 4 includes N or NR a ;
  • At least another group selected from Y 1 , Y 2 , Y 3 , or Y 4 includes CR a or CR a R b ;
  • R a and R b are each independently H, optionally substituted lower alkyl; optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl;
  • R 1 , R 2 , R 3 , and R 4 are each independently R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b ,
  • n is an integer from 1 through 7;
  • n 0, 1 , or 2;
  • the dashed lines represent the presence or absence of a double bond.
  • Embodiment 2 The compound of Embodiment 1 having a structure
  • R 5 is R a , OR a , OCHF2, OCFs, CFs, F, or CI;
  • o is an integer from 1 through 7.
  • Embodiment 3 The compound of Embodiment 1 having a structure
  • Z 1 and Z 2 are each independently N, NR a , S, O, CR a , or CR a R b ;
  • R 6 and R 7 are each independently R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO 2 , S(O) n R a , S(O) n NR a R b , or R 6 and R 7 are fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring.
  • Embodiment 4 The compound of any one of Embodiments 1 -3, having a structure
  • Z 1 and Z 2 are each independently N, NR a , S, O, CR a , or CR a R b ;
  • R 5 is R a , OR a , OCHF2, OCFs, CFs, F, or CI;
  • R 6 and R 7 are each independently R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b , or R 6 and R 7 are fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring; and
  • o is an integer from 1 through 7.
  • Embodiment s The compound of any one of Embodiments 1 -4, having a structure
  • R 5 is R a , OR a , OCHF2, OCFs, CFs, F, or CI;
  • R 8 is R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , or S(O) n NR a R b ; and o and t are each independently an integer from 1 through 7.
  • Embodiment 6 The compound of any one of Embodiments 1 -5, wherein R 3 is OH.
  • Embodiment 7 The compound of any one of Embodiments 1 -6, wherein Y 1 , Y 2 , and Y 3 are CH and Y 4 is N.
  • Embodiment 8 The compound of any one of Embodiments 1 -7, wherein W is CH and X is NH.
  • Embodiment 9 The compound of any one of Embodiments 1 -8 having a structure
  • Embodiment 10 The compound of Embodiment 1 having a structure
  • Z 1 and Z 2 can each independently be S or N
  • Z 3 and Z 4 can each independently be S or O
  • R 13 and R 14 can each independently be Ra
  • r and q can be 0, 1 , 2, 3, 4, or 5, and the dashed lines can indicate the presence or absence of a double bond.
  • Embodiment 12 A compound having a structure
  • R 1 is R a , OR a , COR a , CO 2 R a , CONR a R b , CN, NR a R b , NO 2 , S(O) n R a , or S(O) n NR a R b ;
  • R a and R b are each independently H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl;
  • R 6 and R 7 are each independently R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b , or R 6 and R
  • Embodiment 13 The compound of Embodiment 12, wherein at least one of R 6 or R 7 are an optionally substituted aryl ring.
  • Embodiment 14 The compound of Embodiment 12, having a structure
  • R 9 is R a .
  • Embodiment 15 The compound of Embodiment 12, having a structure
  • R 10 is R a , CHF 2 , or CFs.
  • Embodiment 16 A compound having a structure
  • At least one group selected from Y 1 , Y 2 , Y 3 , or Y 4 includes N or NR a ; at least another group selected from Y 1 , Y 2 , Y 3 , or Y 4 includes CR a or CR a R b ;
  • R a and R b are each independently H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl;
  • R 3 , R 4 , R 11 , and R 12 are each independently R a , OR a , COR a , CO2R a , CONR a R b , CN,
  • n is an integer from 1 through 7;
  • n 0, 1 , or 2;
  • u is 0 or 1 ;
  • v 0, 1 , or 2;
  • w is 1 , 2, or 3;
  • the dashed lines represent the presence or absence of a double bond.
  • Embodiment 17 A compound having a structure
  • R 17 and R 18 are each independently R a , OR a , COR a , CO2R a , CONR a R b , CN, NR a R b , NO2, S(O) n R a , S(O) n NR a R b ;
  • R a is H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfony; and n is 0, 1 , or 2.
  • Embodiment 18 The composition of Embodiment 17 having the structure
  • Embodiment 19 A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 18.
  • Embodiment 20 A pharmaceutical composition of Embodiment 19, for use in therapy.
  • Embodiment 21 A method of treating a viral infection in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of Embodiment 20 thereby treating the viral infection in the subject.
  • Embodiment 22 A method of treating a viral infection in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of Embodiment 19 thereby treating the viral infection in the subject wherein the viral infection is caused by at least one of influenza; RSV; Dengue; Ebola; West Nile Virus; and LASV.
  • Embodiment 23 The method of Embodiment 22 wherein said viral infection is caused by Ebola virus.
  • GBV-C virus other RNA viruses such as RSV, SARS, and the HCV replicon systems.
  • any appropriate cultured cell competent for viral replication can be utilized in the antiviral assays.
  • Antiviral activity against influenza virus in vitro was measured for Compound 1 , Compound 9, and Compound 10.
  • Cultured human 293 cells were seeded in 6-well tissue- culture plates at a density of 3x105 cells per well for the flu focus-forming assay and grown for 24 hours. Cells were infected with influenza virus A Udorn/72 H3N2 strain at MOI of 0.1 for 2 hours and then removed. Compound dilutions were prepared in 0.5% DMSO and used to treat cells at final concentrations of compound ranging 0.6 to 10 ⁇ per well. Vehicle control wells contained 0.5% DMSO and were used to compare to drug treated cells. Replication was then allowed to proceed for 24 hours.
  • Virus supernatants were then harvested and used to infect new monolayer of permissive MDCK cells that were seeded 24 hours prior in 96-well tissue-culture plates at density of 1 .5x104 cells per well. The newly infected cells were incubated overnight (18-24 hours) and used to measure the level of infectious virus in the original supernatants by immunofluorescent staining of viral protein. The cells were fixed with ice-cold 1 :1 methanol and acetone solution and stained for influenza nucleoprotein (NP). Primary mouse anti-NP monoclonal antibody (Chemicon) was used at 1 :3000 dilution.
  • NP nucleoprotein
  • Figure 1 shows results from the influenza focus-forming assay. Decrease in foci is graphed as percent inhibition of viral infection by compound. Compound 1 and Compound 9 demonstrated dose-dependent decrease in viral infection of 293 cells. Compound 10 showed effective inhibition of viral infection of 293 cells.
  • Antiviral activity against DNV in vitro was measured for Compound 9, Compound 10, and other selected analog compounds.
  • Cultured human Huh7 cells were seeded in 6-well tissue-culture plates at a density of 4x10 5 cells per well for the DNV focus-forming assay and grown for 24 hours. Cells were infected with one of the DNV type 2 or type 4 strain at MOI of 0.1 for 2 hours and then removed. Connpound dilutions were prepared in 0.5% DMSO and used to treat cells at final concentrations of connpound ranging 0.6 to 10 ⁇ per well. Vehicle control wells contained 0.5% DMSO and were used to compare to drug treated cells. Replication was then allowed to proceed for 48 hours.
  • Virus supernatants were then harvested and used to infect new monolayer of permissive Vera cells that were seeded 24 hours prior in 96-well tissue-culture plates at density of 8x10 3 cells per well. The newly infected cells were incubated for 24 hours and used to measure the level of infectious virus in the original supernatants by immunofluorescent staining of viral protein. The cells were fixed with ice-cold 1 :1 methanol and acetone solution and stained for DNV fusion protein. Primary mouse monoclonal antibody against DNV fusion protein (Millipore) was used at 1 :2000 dilution.
  • Figures 2A and 2B show the antiviral activity of selected compounds against DNV.
  • All compounds tested (Compound 1 -Compound 1 1 ) showed effective inhibition of DNV serotype 2 when used at a concentration of at least 5 ⁇ .
  • Compound 2, Compound 3, Compound 6, Compound 7, Compound 8, and Compound 10 showed dose-dependent decrease in viral infection.
  • Compound 1 -Compouond 1 1 showed effective inhibition of DNV serotype 4. The calculated EC50 and EC90 values are shown.
  • Example 5 In vivo bioavailability of Compound 1 and Compound 10
  • FIG. 3 shows Compound 1 and Compound 10 blood and spleen levels after dosing at 10mg/kg via intraperitoneal injection.
  • Compound 1 levels in plasma are shown over time up to 4 hours post injection.
  • Spleen level is shown at 4 hours post injection, when tissue was harvested. Both Compound 1 and Compound 10 were present in detectable amounts in both serum and spleen samples taken up to 4 hours post dosing of compound.
  • This Example describes analog compound design using QSAR approach of the compounds described herein for antiviral action.
  • the QSAR studies are designed to provide lead compounds with picomolar to nanomolar potency. Optimization of the compounds focuses on creating structural diversity and evaluating core variants and group modifications.
  • Structural derivatives are tested for antiviral activity against several viruses including the virus assay models described herein. Furthermore, derivatives are tested for cytotoxicity in one or more cell lines or peripheral blood mononuclear cells. Optimized molecules that show improved efficacy and low cytotoxicity are further characterized by additional measures of in vitro and in vivo toxicology and absorption, distribution, metabolism, and elimination (ADME). Their mechanism of action and breadth of antiviral activity are also studied.
  • ADME in vitro and in vivo toxicology and absorption, distribution, metabolism, and elimination
  • a (high-performance liquid chromatography) HPLC- and/or HPLC-mass spectrometry-based analytical method is used to evaluate drug and metabolite concentrations in various test systems.
  • reverse-phase chromatography can be used alone or in combination with quadrupole mass spectrometry to characterize the identity and purity of several of the lead molecules.
  • drug stability over time in increasing concentrations of serum, plasma, and whole blood from mammalian species such as mouse, cynomolgus macaque, and human
  • HPLC drug stability over time in increasing concentrations of serum, plasma, and whole blood from mammalian species (such as mouse, cynomolgus macaque, and human) will be evaluated by HPLC, and a half-life will be determined.
  • prominent metabolites are characterized by mass spectrometry.
  • Compounds described herein, including some of the compounds listed in Table 1 are tested for biological activities including: activation of target pathways including immune response pathways, antiviral activity against a variety of viruses, low cytotoxicity, and a therapeutic index greater than 10.
  • Innate immune signaling pathway activation by compounds is the measurement of downstream gene expression by RT-qPCR in cells treated with compound.
  • the transcription factor IRF-3 is activated through RIG-I signaling and the increased expression of IRF-3 dependent genes indicate activation of the RIG-I innate immune antiviral response pathway.
  • Other genes that are associated with the host innate immune antiviral response are also measured as indicators of compound activity.
  • RNA isolation, reverse transcription, and qPCR are performed using well known techniques. PCR reactions are performed using commercially available, validated TaqMan gene expression assays (Applied Biosystems/Life Technologies) according to manufacturer instructions. Gene expression levels are measured using a relative expression analysis (AACt).
  • Gene expression can be similarly assayed in cell types that include: primary blood mononuclear cells, human macrophages, THP-1 cells, Huh7 cells, A549 cells, MRC5 cells, rat splenocytes, rat thymocytes, mouse macrophages, mouse splenocytes, and mouse thymocytes. Expression of other genes of interest can be assayed as described herein. In addition, gene expression can be assayed in the presence of virus in order to determine compound activity in the context of active viral infection.
  • Innate immune response induction by compounds can be assayed in primary immune cells to determine whether compound treatment stimulates immune response pathways.
  • One example is to assay cytokine expression in cultured human primary blood cells, for example dendritic cells. Cells are seeded in tissue culture dishes and treated with compound ranging 0.001-10 ⁇ of compound.
  • supernatants from treated wells are isolated 24-48 hours after compound treatment and tested for levels of cytokine protein.
  • Cytokines are detected using specific antibodies conjugated to magnetic beads and a secondary antibody that reacts with Streptavidin/Phycoerythrin to produce a fluorescent signal.
  • the bound beads are detected and quantified using the MAGPIX® (Luminex Corp.) instrument, although similar techniques as are known in the art may be used to measure fluorescent protein production, such as for example an ELISA.
  • cytokine secretion include, for example human peripheral blood mononuclear cells, human macrophages, mouse macrophages, mouse splenocytes, rat thymocytes, and rat splenocytes.
  • Cytotoxicity is evaluated using standard in vitro assays including MTS assay and caspase assay. Protocols to perform these assays are known to those skilled in the art and there are several commercially available kits to measure assay readout, such as a colorimetric based assay to measure conversion of MTS to formazan (Cell Titer One, Promega) and a sandwich ELISA based assay to measure levels of activated caspase-3 (PathScan® Cleaved Caspase-3 (Asp175) Sandwich ELISA Kit #7190, Cell Signaling). Cultured human cells are treated with increasing amounts of compound from 0 up to at least 50 ⁇ or equivalent amounts of DMSO diluted in media to see their effect on cell viability. Cultured human cell lines that are used in this assay include Huh7, PH5CH8, A549, or HeLa cells.
  • In vitro pharmacology and toxicology This description of toxicological assays is exemplary. In vitro studies are performed to measure performance of the most promising analogs in one or more assays of intestinal permeability, metabolic stability, and toxicity. These studies can include plasma protein binding; serum, plasma, and whole-blood stability in human and model organisms; intestinal permeability; intrinsic clearance; human Ether-a-go-go (hERG) channel inhibition to test potential cardiac toxicity; and genotoxicity using for example a reversion mutation assay (Ames test) and/or a micronucleus formation assay. Human plasma protein binding will be evaluated by partition analysis using equilibrium dialysis.
  • apical- to-basolateral flux is assessed in a human epithelial cell line such as Caco-2 or TC7.
  • Hepatic clearance is estimated for a subset of the most promising analogs by measuring the rate of disappearance of the parent compound during incubation in human liver microsomes. Specific metabolites may be isolated and characterized.
  • Example 8 Assays of Antiviral Activity Using In Vitro Models
  • the compounds disclosed herein have efficient activity against several viruses in vitro. To further characterize the breadth of antiviral activity of optimized molecules, cell culture infection models are used to analyze different viruses as well as different strains of the same virus. Assays to measure the antiviral activity of compounds against several of these viruses is described herein.
  • the studies include treating cells with compound 2-24 hours prior to infection and/or treating cells 2-24 hours after infection.
  • Compound is administered at different concentrations ranging from 0.001 -10 ⁇ .
  • Positive control treatments used include interferon, ribavirin, oseltamivir, or other known treatment to inhibit the infection of the specific virus.
  • Virus production and cellular ISG expression are assessed over a time course to analyze antiviral activity of each compound. Virus production is measured by focus-forming or plaque assay.
  • An immunofluorescent based focus-forming assay is done in cultured human HeLa cells to measure antiviral activity against RSV.
  • Cells are seeded in 6-well tissue- culture plates at a density of 4x105 cells per well for the RSV focus-forming assay and grown for 24 hours.
  • Cells are infected with RSV A2 Long strain (ATCC VR-26) at MOI of 0.1 for 2 hours and then removed.
  • Compound dilutions are prepared in 0.5% DMSO and used to treat cells at final concentrations of compound ranging 0.001 to 10 ⁇ per well.
  • Vehicle control wells contain 0.5% DMSO and are used to compare to drug treated cells.
  • RSV infections after drug treatment are allowed to proceed for 48 hours.
  • Virus supernatants are then harvested and used to infect new monolayer of HeLa cells seeded in 96-well tissue-culture plates at density of 8x103 cells per well.
  • the newly infected cells are incubated overnight (18 - 24 hours) and used to measure the level of infectious virus in the original supernatants by immunofluorescent staining of viral protein.
  • the cells are fixed with ice-cold 1 :1 methanol and acetone solution and stained for RSV F protein.
  • Primary mouse anti-RSV monoclonal antibody (EMD Millipore) is used at 1 :2000 dilution.
  • Antiviral activity against WNV, Nipah Virus, Lassa Fever Virus, and Ebola Virus in vitro is measured by focus-forming assay.
  • Virus strains that are used in these assays include WNV-TX (WNV), WNV-MAD (WNV), NiV-Malaysia (Nipah), LASV-Josiah (Lassa Fever), and ZEBOV- Mayinga (Ebola).
  • Cultured human cells including human umbilical vein cells (HUVEC) are seeded in tissue-culture plates and infected with virus at MOI of 0.01 to 0.5 for a duration including but not limited to 2 hours and then removed.
  • Compound dilutions are prepared in 0.5% DMSO and used to treat cells at final concentrations of compound ranging 0.001 to 10 ⁇ per well. Vehicle control wells contain 0.5% DMSO and are used to compare to drug treated cells. Virus infections after drug treatment are allowed to proceed for 48 to 96 hours. Virus supernatants are then harvested and used to infect new monolayer of permissive cells. The newly infected cells are incubated overnight (18-24 hours) and used to measure the level of infectious virus in the original supernatants by focus-forming assay using methods generally known in the art.
  • Antiviral activity against influenza virus in vitro is measured by immunofluorescent based focus-forming assay.
  • Influenza A virus strains that are used in this assay include A Udorn/72 H3N2 strain and A/California/04/09 H1 N1 strain. Experimental conditions are as or substantially similar to those described in Example 4.
  • Antiviral activity against DNVs in vitro is measured by immunofluorescent based focus-forming assay. Experimental conditions are as or substantially similar to those described in Example 4.
  • viral RNA and cellular ISG expression are measured by qPCR and immunoblot analyses. These experiments are designed to validate compound signaling actions during virus infection, and assess compound actions to direct innate immune antiviral programs against various strains of viruses and in the setting of virus countermeasures. Detailed dose-response analyses of each compound are conducted in each virus infection system to determine the effective dose that suppresses virus production by 50% (IC50) and 90% (IC90) as compared with control cells for both the pre- treatment and post-treatment infection models.
  • Additional virus infection models that can be assayed by in vitro assays include but are not limited to SARS-like coronaviruses, human cytomegalovirus, Japanese Encephalitis Virus, hepatitis C virus, and hepatitis B virus. Experimental methods are substantially similar to those described herein.
  • Table 2 shows calculated EC50 values in ⁇ of selected compounds.
  • Example 9 In vivo pharmacokinetic and toxicological profiles of selected compounds in preclinical animal models
  • PK pharmacokinetic
  • tolerability profiling The in vivo PK profile and tolerability/toxicity of optimized compounds are evaluated in order to conduct further characterization of their antiviral activity in animal models of virus infection.
  • Mouse and rat are the chosen test species for these studies because there are several established virus models in the mouse and models of PK, toxicology, and immunology in the rat.
  • Reverse-phase, HPLC-MS/MS detection methods are used to detect and quantify the concentration of each compound in biological samples including plasma and target tissue samples.
  • PK profiling an initial oral and injectable formulation for each compound is developed using a limited formulation component screen that is largely focused on maximizing aqueous solubility and stability over a small number of storage conditions.
  • Existing analytical methods known in the art are used to measure formulation performance.
  • a formulation is developed for each compound following a three tiered strategy.
  • Tier 1 pH (pH 3 to 9), buffer, and osmolality adjustment
  • Tier 2 addition of ethanol ( ⁇ 10%), propylene glycol ( ⁇ 40%), or polyethylene glycol (PEG) 300 or 400 ( ⁇ 60%) co-solvents to enhance solubility
  • Tier 3 addition of N-N-dimethylacetamide (DMA, ⁇ 30%), N-methyl-2-pyrrolidone (NMP, ⁇ 20%), and/or dimethyl sulfoxide (DMSO, ⁇ 20%) co-solvents or the cyclodextrins ( ⁇ 40%) as needed to further improve solubility.
  • DMA N-N-dimethylacetamide
  • NMP N-methyl-2-pyrrolidone
  • DMSO dimethyl sulfoxide
  • mice PK studies the following criteria are evaluated after compound has been administrated by at least 2 routes of administration including orally and i.v.: bioavailability at time points 0-24 hours and 0- ⁇ , AUC0-24,0- ⁇ ; maximum concentration, Cmax; half-life t1 ⁇ 2; volume of distribution; and confidence interval CI .
  • routes of administration including orally and i.v.: bioavailability at time points 0-24 hours and 0- ⁇ , AUC0-24,0- ⁇ ; maximum concentration, Cmax; half-life t1 ⁇ 2; volume of distribution; and confidence interval CI .
  • Each compound is administered as a single dose to animals by oral gavage (up to 10 mg/kg) or intravenous bolus injection (up to 5 mg/kg) after an overnight fast. Multiple animals are dosed for each dosing group such that 3 animals can be sampled at each time point.
  • Blood samples are collected by retro-orbital sinus prior to dosing and at 5, 15, and 30 min, and 1 , 2, 4, 8, and 24 hours post dosing.
  • Target tissues including lung, liver, and lymph nodes, are also collected at the time point of final blood collection.
  • Drug concentrations are measured according to the previously developed bioanalytical method specifically for the compound, as described in Example 5.
  • PK parameters are evaluated using the WinNonlin software.
  • Tolerability studies are performed in two stages: an initial dose escalation stage that consists of ascending doses up to 5 doses, each separated by a 5-day washout period, to determine the maximum tolerable dose (MTD; Stage 1 ); this is followed by seven daily administrations of the MTD to evaluate acute toxicity (Stage 2).
  • MTD maximum tolerable dose
  • Stage 2 seven daily administrations of the MTD to evaluate acute toxicity
  • Stage 2 seven daily administrations of the MTD to evaluate acute toxicity
  • all doses are administered by oral gavage.
  • five animals of each sex are placed on-study in stage 1 and 15 animals per sex per dosing group in Stage 2.
  • Study endpoints include a determination of the MTD, examination for acute toxicity, physical examination, clinical observations, hematology, serum chemistry, and animal bodyweights. Gross pathology is performed on all animals whether found dead, euthanized in extremis, or at the intended conclusion of the experiment. The toxicology studies are intended to identify early toxicological endpoints, and drive selection of lead candidates for antiviral animal models.
  • Example 10 In vivo antiviral properties of selected compounds in preclinical animal models.
  • This Example describes the evaluation of antiviral properties and immune protection using mouse infection models.
  • Selected compounds show favorable PK, antiviral, and innate immune activity and can be further evaluated in preclinical mouse models of infection. Innate immune actions of the compounds are measured, and their ability to protect mice from WNV and influenza virus challenge is assessed.
  • WNV infection model subcutaneous footpad infection of wild-type C57BI/6 mice with the virulent lineage 1 strain of WNV (WNV-TX) are performed (Suthar, M. S., et al. (2010) IPS-1 is essential for the control of WNV infection and immunity, PLoS Pathog 6, e1000757).
  • Non-surgical tracheal instillation is performed for influenza virus strains A/PR/8/34, A/WSN/33, and A/Udorn/72.
  • influenza virus strains in these experiments include at least two different subtypes (for example, H1 N1 and H3N2) and exhibit varying pathogenic properties and clinical presentations in C57BI/6 mice (Barnard, D. L. (2009) Animal models for the study of influenza pathogenesis and therapy, Antiviral Res 82, A1 10-122). Mice are monitored for morbidity and mortality over a range of challenge doses (such as, 10 to 1 ,000 pfu of virus) either alone or in combination with compound treatment beginning up to 24 hours before or up to 24 hours after infection and continuing daily subject to the determined plasma half-life of the drug.
  • challenge doses such as, 10 to 1 ,000 pfu of virus
  • Compound dose-response analysis and infection time course studies are conducted to evaluate compound efficacy to: 1 ) limit serum viral load; 2) limit virus replication and spread in target organs; and 3) protect against viral pathogenesis.
  • WNV for WNV, in addition to serum, viral burden is assessed in lymph nodes, spleen, and brain; for influenza virus, viral burden is assessed in heart, lung, kidney, liver, and brain.
  • ED50 and ED90 serum viral load
  • Serum viral loads are determined by qPCR of viral RNA at 24 hour intervals following compound treatment. The compound actions are tested at the ED50 and ED90 toward limiting WNV pathogenesis in the cerebral nervous system using a WNV neuroinvasion model of infection (Daffis, S., et al.
  • Toll-like receptor 3 has a protective role against West Nile virus infection, J Virol 82, 10349-10358). Mice are monitored for morbidity and mortality after standard intracranial challenge of 1 pfu of WNV-MAD, either alone or in combination with compound treatment beginning 24 hours after infection.
  • the drug can be administered via routes including oral, nasal, mucosal, intravenous, intraperitoneal, subcutaneous, or intramuscular.
  • routes including oral, nasal, mucosal, intravenous, intraperitoneal, subcutaneous, or intramuscular.
  • Other in vivo virus infection models that can used to evaluate compound antiviral activity include SARS, DNV, MCMV, or EMCV.
  • each embodiment disclosed herein can comprise, consist essentially of or consist of its particular stated element, step, ingredient or component.
  • the terms “include” or “including” should be interpreted to recite: “comprise, consist of, or consist essentially of.”
  • the transition term “comprise” or “comprises” means includes, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts.
  • the transition phrase “consisting essentially of limits the scope of the embodiment to the specified elements, steps, ingredients or components and to those that do not materially affect the embodiment.
  • a material effect would cause a statistically significant reduction in a disclosed compound's or pharmaceutical composition's ability to treat a viral infection in a subject; reduce viral protein in a subject or assay; reduce viral RNA in a subject or assay or reduce virus in a cell culture.

Abstract

Disclosed herein are compounds, pharmaceutical compositions, and methods for the treatment of viral infection, including RNA viral infection, as well as compounds, pharmaceutical compositions, and methods for modulating innate immunity in a subject and/or in cells.

Description

ANTI-VIRAL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS,
AND METHODS OF USE THEREOF
STATEMENT OF GOVERNMENT INTEREST
[0001] This invention was made with government support under National Institutes of Health Grant No. AI098943. The government has certain rights in the invention.
PRIORITY CLAIM AND CROSS REFERENCES TO RELATED APPLICATIONS
[0002] This Application claims priority to US Provisional Patent Application No. 62/071 ,981 filed October 6, 2014, and to US Provisional Patent Application No. 62/177,890 filed March 25, 2015, the entire contents of both of which are incorporated by reference herein.
FIELD OF THE DISCLOSURE
[0003] The disclosure provides compounds, pharmaceutical compositions, and methods for treating viral infection, among other uses.
BACKGROUND OF THE DISCLOSURE
[0004] As a group, RNA viruses represent an enormous public health problem in the U.S. and worldwide. Well-known RNA viruses include influenza virus (including the avian and swine isolates; also referred to herein as flu), Hepatitis C virus (HCV), West Nile virus (WNV), SARS-coronavirus (SARS), MERS-coronavirus (MERS), respiratory syncytial virus (RSV), and human immunodeficiency virus (HIV). Flaviviruses, Henipaviruses, Filoviruses, and Arenaviruses are among emerging RNA viruses that pose significant public health and biodefense threats. These viruses collectively place hundreds of millions of people at risk of infection throughout the world. Many of these viruses cause viral hemorrhagic fever and can result in significant morbidity and mortality. Dengue virus (DNV) and West Nile virus (WNV) are both Flaviviruses (positive strand RNA virus) and Arboviruses, transmitted through mosquitoes. Each of these viruses represents a potent potential biological threat through their ability to transmit readily among insects or animals and humans, high infectivity, and their potential to be weaponized in bioterror events.
[0005] Seasonal flu infects 5 - 20% of the population annually, resulting in 200,000 hospitalizations and 36,000 deaths. Influenza can precipitate viral or secondary bacterial pneumonia, and complicated disease in those at the extremes of age or with weakened immune systems. Coronaviruses are common throughout the world and typically cause mild to moderate respiratory illness, although certain coronaviruses cause severe respiratory illness and death. A 2003 multi-country outbreak of SARS-coronavirus infection resulted in approximately 8,000 infections and nearly 800 deaths. Recently there have been reported cases of Middle East Respiratory Syndrome caused by MERS- coronavirus.
[0006] DNV is the most prevalent flavivirus in humans, is endemic in most tropical and subtropical countries, and is currently emerging elsewhere including the U.S. and across the Pacific Islands. DNV circulates as 4 serotypes (DNV1 - 4) and following a first infection, re-infection can lead to fatal hemorrhagic fever and shock syndrome. Infection is believed to provide life-long immunity against reinfection by the same serotype, but not against other serotypes. Epidemic outbreaks have been reported in many countries throughout Latin America, South-East Asia, and the Western Pacific Regions. It is estimated that between 50 and 100 million cases of Dengue fever occur globally each year. Dengue Hemorrhagic Fever and Dengue Shock Syndrome represent severe forms of the disease. Currently there is no specific antiviral therapy to treat DNV infection and no approved vaccine.
[0007] WNV is a related flavivirus that is endemic in regions of Africa and Asia, but is now emerging in the Western hemisphere. WNV is neuroinvasive to cause serious encephalitis disease and is lethal in about 6% of cases. Neuroinvasive WNV can present as meningitis, encephalitis or less frequently a flaccid paralysis referred to as poliomyelitis. WNV was largely absent from North America prior to 1999, but reemerged on the continent following an isolated outbreak of encephalitis in New York. In the subsequent 7 years, WNV infection spread throughout the 48 contiguous United States, and current estimates suggest as many as 2 - 3 million Americans have been infected. Over the past 20 years, outbreaks have been reported in parts of Europe, North Africa, the Middle East, and North America. Currently there is no specific antiviral therapy to treat WNV infection and no approved vaccine.
[0008] Nipah virus (NV) is a paramyxovirus (negative strand RNA virus) distantly related to respiratory syncytial virus (RSV). However, while RSV is a mild and endemic human pathogen, NV is a highly dangerous emerging virus responsible for severe encephalitis and respiratory disease. Outbreaks of NV infection have now occurred in East and Central Asia, and are likely attributed to zoonotic transmission to humans from farm animals and wild fruit bats as well as actual human-to-human transmission. NV is fatal in approximately 40% of confirmed patients.
[0009] At least 4 subtypes of Ebola virus (EV) are infectious to humans (Zaire, Sudan, Bundibugyo, and Cote d'lvoire). EV outbreaks have been described in Africa with a fatality rate of up to 90%. Cases of EV infection have been reported in other countries including, very recently, the United States. The natural host for EV is not defined but nonhuman primates (NHP) are susceptible. EV is a negative-strand RNA virus of the Filoviridae and can be spread effectively from person-to-person.
[0010] Lassa virus (LASV) is a member of the Old World arenaviruses and chronically infects rodents, the natural host animal, typically without presentation of symptoms. In contrast, infected humans can present with symptoms of severe hemorrhagic fever and can result in shock and/or death. The virus is spread through direct contact with rodent carriers or their secretions, or through direct contact with body fluids from an infected human. Lassa fever is endemic in West Africa and the estimated number of human infections total 100,000 to 500,000 annually. There is a risk of spread of LASV beyond West African countries, primarily due to high rates of worldwide travel and the potential for human to human transmission.
[0011] Among the RNA viruses listed, very few vaccines are currently approved for clinical use. One such vaccine exists for influenza virus, which must be revised and administered annually. Drug therapy is essential to mitigate the significant morbidity and mortality associated with these viruses. Unfortunately, the number of antiviral drugs is limited, many are poorly effective, and nearly all are plagued by the rapid evolution of viral resistance and a limited spectrum of action. Ribavirin, a guanine nucleoside analog, has been studied in clinical trials of diverse RNA virus infections and is likely the most broadly acting antiviral agent available. Rusnak, J. (201 1 ) AppI Biosaf 16, 67-87; Debing, Y., et al. (2013) Curr Opin Virol 3, 217-224. Ribavirin is approved to treat hepatitis C virus (HCV) and respiratory syncytial virus (RSV) infection, and Lassa virus related mortality was shown to be reduced with intravenous ribavirin treatment. McCormick, J.B., et al. (1986) N Engl J Med 314, 20-26. However, it is weakly effective as a single agent and has significant hematologic toxicity. Both classes of acute influenza antivirals, adamantanes and neuraminidase inhibitors, are only effective within the first 48 hours after infection, thereby limiting the window of opportunity for treatment. High resistance to adamantanes already restricts their use, and massive stockpiling of neuraminidase inhibitors will eventually lead to overuse and the emergence of resistant strains of influenza.
[0012] Based on the foregoing, there is an immense and unmet need for effective treatments against viral infections. In one example, new antiviral therapy can exploit the fact that these viruses are susceptible to control by innate intracellular immune defenses that function to suppress virus replication and spread. Daffis, S., et al. (2009) J Innate Immun 1 , 435-445; Klein, R.S., et al. (2008), Trends Mol Med 14, 286-294; Navarro- Sanches, E., et al. (2005) Arch Med Res 36, 425-435; Levroney, E.L., et al. (2005) J Immunol 175, 413-420; Zampieri, C.A., et al. (2007) Nat Immunol 8, 1 159-1 164. Compounds that act on cellular targets are likely to be more effective, be less susceptible to the emergence of viral resistance, cause fewer side effects, and be effective against a range of different viruses. Tan, S. L, et al. (2007) Nat Biotechnol 25, 1383-1389. An effective broad-spectrum antiviral, whether used on its own or in combination with other therapies, would be an enormous benefit to current clinical practice. While interferon is in principal host-mediated and broad spectrum, many viruses have evolved the ability to disrupt interferon signaling downstream of drug action at the receptor. An important criterion is the development of drugs that activate innate immune signaling below specific virus countermeasures and are a unique addition to conventional antiviral compounds in development or on the market. As one such innate immune antiviral response, the RIG- l-like receptor (RLR) pathway of innate antiviral immunity can impose a potent blockade to RNA virus infection through the actions of a variety antiviral defense genes. Li, K., et al. (2005) J Biol Chem 280, 16739-16747; Loo, Y. M., et al. (2008) J Virol 82, 335-345; Loo, Y. M., et al. (2006) Proc Natl Acad Sci U.S.A. 103, 6001 -6006; Saito, T., et al. (2007) Proc Natl Acad Sci U.S.A. 104, 582-587.
[0013] In another example, new antiviral therapy can act directly against viruses. Most drug development efforts target viral proteins. RNA viruses have small genomes, with many encoding less than a dozen proteins, resulting in a very limited number of viral targets for new drugs. This is a large part of the reason that current drugs are narrow in spectrum and subject to the emergence of viral resistance. However, there is benefit to discovery of new viral targets for inhibition. Alternatively, direct-acting antiviral therapy can work to counteract any infection mechanisms such as viral entry into a host cell.
SUMMARY OF THE DISCLOSURE
[0014] The compounds, pharmaceutical compositions, and methods disclosed herein describe broad-spectrum antiviral therapies.
[0015] In some embodiments, the compounds have the following chemical structure
Figure imgf000006_0001
where W is CRa or N and X is O, S, C=O, CRaRb, or NRa. At least one group selected from Y1, Y2, Y3, or Y4 includes N or NRa and at least another group selected from Y1, Y2, Y3, or Y4 includes CRa or CRaRb. Ra and Rb are each independently H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl. R1 , R2, R3, and R4 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. In addition, m is an integer from 1 through 7 and n is 0, 1 , or 2. The dashed lines represent the presence or absence of a double bond.
[0016] Example compounds can also have the following structure
Figure imgf000007_0001
where one of Z1 or Z2 is N and the other one of Z1 or Z2 is S, R1 is Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Ra is H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfonyl. R6 and R7 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb, or R6 and R7 are optionally fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring.
[0017] Compounds according to embodiments of the disclosure are described more fully in the Detailed Description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 shows results from the influenza focus-forming assay. Decrease in foci is graphed as percent inhibition of viral infection by compound. Compound 1 and Compound 9 demonstrated dose-dependent decrease in viral infection of 293 cells. Compound 10 showed effective inhibition of viral infection of 293 cells.
[0019] Figures 2A and 2B show the antiviral activity of selected compounds against DNV. (A) All compounds tested (Compound 1 -Compound 1 1 ) showed effective inhibition of DNV serotype 2 when used at a concentration of at least 5μΜ. Compound 2, Compound 3, Compound 6, Compound 7, Compound 8, and Compound 10 showed dose-dependent decrease in viral infection. (B) Compound 1 -Compound 1 1 showed effective inhibition of DNV serotype 4. The calculated EC50 and EC90 values are shown. [0020] Figure 3 shows Compound 1 and Compound 10 blood and spleen levels after dosing at 10mg/kg via intraperitoneal injection. Compound 1 levels in plasma are shown over time up to 4 hours post injection. Spleen level is shown at 4 hours post injection, when tissue was harvested.
DETAILED DESCRIPTION
[0021] The present disclosure provides compounds, pharmaceutical compositions, and methods of small molecule based broad-spectrum antiviral therapies.
[0022] The disclosed compounds represent a new class of antiviral therapeutics. Although the disclosure is not bound by a specific mechanism of action of the compounds in vivo, the compounds are selected for their inhibition of a variety of viruses. Compounds, pharmaceutical compositions, and methods disclosed herein function to treat subjects, decrease viral protein, decrease viral RNA, and/or decrease infectious virus in laboratory models of viral infection.
[0023] Compounds
[0024] In one embodiment, the compounds described herein are antiviral compounds.
In another embodiment, the compounds are innate immune modulating compounds. In another embodiment, the compounds are innate immune activating compounds. In another embodiment, the compounds are innate immune agonists.
[0025] In one embodiment, example compounds of the present disclosure can have the structure:
Figure imgf000008_0001
According to certain embodiments the compound may have a substitution pattern wherein the groups are as defined herein. As will be understood by one of skill in the art, while various combinations of substituents are possible, only those combinations that are chemically compatible are within the scope of the various embodiments of the compounds of the present disclosure. [0026] In some embodiments, W can be CRa or N. Ra can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl. In particular embodiments, Ra can be optionally substituted lower alkyl. In an illustrative embodiment, W can be N. In another illustrative embodiment, W can be CH.
[0027] Additionally, X can be O, S, C=O, CRaRb, or NRa. In an embodiment, Rb can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl. In a particular embodiment, X can be NH. In another embodiment, X can be O. In still other embodiments, X can be S. In additional embodiments, X can be Chb. In further embodiments, X can be C=O.
[0028] In various embodiments, at least one group selected from Y1 , Y2, Y3, or Y4 includes N or NRa. In addition, at least another group selected from Y1 , Y2, Y3, or Y4 includes CRa or CRaRb. In some cases, Y4 can be N. Further, Y1, Y2, and Y3 can be CH. In an illustrative embodiment, Y4 can be N and Y1, Y2, and Y3 can be CH.
[0029] In an embodiment, R1 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Additionally, R2 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Further, R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. In an illustrative embodiment, R3 can be OH. Also, R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. In some instances, m can be an integer from 1 through 7. In some illustrative embodiments, R4 can be H and m can be 1 . Additionally, n can be 0, 1 , or 2. Furthermore, the dashed lines can indicate the presence or absence of a double bond.
[0030] In a particular embodiment, R1 can be an unsubstituted aryl group, such as a phenyl group. In another embodiment, R1 can be a substituted aryl group including one or more substituents. Substituents of a substituted aryl group can be located in the para position, the meta position, the ortho position, or combinations thereof.
[0031] In an illustrative embodiment, one or more substituents of a substituted aryl group can include an alkyl group. For example, one or more substituents of a substituted aryl group can include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, or a heptyl group.
[0032] In an illustrative embodiment, one or more substituents of a substituted aryl group can include one or more ether groups. To illustrate, one or more substituents of a substituted aryl group can include OCH3.
[0033] In another illustrative embodiment, one or more substituents of a substituted aryl group can include one or more halogen atoms. For example, one or more substituents of a substituted aryl group can include one or more F atoms, one or more CI atoms, one or more Br atoms, or a combination thereof. In particular illustrative embodiments, one or more substituents of a substituted aryl group can include OCHF2. In additional illustrative embodiments, one or more substituents of a substituted aryl group can include OCF3. In further illustrative embodiments, one or more substituents of a substituted aryl group can include CF3.
[0034] In various embodiments where R1 includes an aryl group, example compounds can have a structure
Figure imgf000010_0001
R5 can be Ra, ORa, OCHF2, OCF3, CF3, F, or CI. Additionally, o can be an integer from 1 through 7, in some embodiments. In some cases, R2, R3, R4, W, X, Y1, Y2, Y3, Y4, and m can be defined as above. For example, R2 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R5 can be Ra, ORa, OCHF2, OCFs, CFs, F, or CI. In illustrative embodiments, R3 can be OH or OCH3. Further, W can be CRa or N; X can be O, S, C=O, CRaRb, or NRa ; at least one group selected from Y1, Y2, Y3, or Y4 includes N or NRa; at least another group selected from Y1 , Y2, Y3, or Y4 includes CRa or CRaRb Also, m can be an integer from 1 through 7; n can be 0, 1 , or 2. The dashed lines can indicate the presence or absence of a double bond.
[0035] R1 can also include a heteroaryl group. For example, R1 can include an unsubstituted heteroaryl group. In another example, R1 can include a substituted heteroaryl group. In some embodiments, R1 can include a heteroaryl group having at least one oxygen atom. R1 can also include a heteroaryl group having at least one sulfur atom. Additionally, R1 can include a heteroaryl group having at least one nitrogen atom. In various embodiments, R1 can include a heteroaryl group with a ring structure having 3 members. In other embodiments, R1 can include a heteroaryl group with a ring structure having 4 members. In additional embodiments, R1 can include a heteroaryl group with a ring structure having 5 members. In further embodiments, R1 can include a heteroaryl group with a ring structure having 6 members.
[0036] In particular embodiments, R1 can include a furyl group. To illustrate, R1 can include a 2-furyl group. In other illustrative embodiments, R2 can include a 3-furyl group. Also, R1 can include a thienyl group. In some examples, R1 can include a 2-thienyl group. In other examples, R1 can include a 3-thienyl group. Further, R1 can include a pyrrolyl group. In some cases, R1 can include a 2-pyrrolyl group. In other cases, R1 can include 3-pyrrolyl group. Additionally, R1 can include a thiazolyl group.
[0037] In embodiments when R1 is a substituted heteroaryl group, the heteroaryl group can be substituted with a substituted aryl group. In some embodiments when R1 is a substituted heteroaryl group, the heteroaryl group can be substituted with an unsubstituted aryl group, such as a phenyl group. In particular illustrative embodiments, R1 can be a thiazolyl group substituted by a phenyl group.
[0038] In illustrative embodiments, R2 can include at least one aryl group. In an embodiment, R2 can include an unsubstituted aryl group. In other embodiments, R2 can include a substituted aryl group.
[0039] In some cases, R2 can include at least one heteroaryl group. For example, R2 can include a heteroaryl group having at least one N atom in the ring of the heteroaryl group. In another example, R2 can include a heteroaryl group having at least one S atom in the ring of the heteroaryl group. In still another example, R2 can include a heteroaryl group having at least one O atom in the ring of the heteroaryl group. In some embodiments, R2 can include a heteroaryl group with a ring structure having 3 members. In other embodiments, R2 can include a heteroaryl group with a ring structure having 4 members. In additional embodiments, R2 can include a heteraryl group with a ring structure having 5 members. In further embodiments, R2 can include a heteroaryl group with a ring structure having 6 members.
[0040] In a particular illustrative embodiment, R2 can include an azolyl group. For example, R2 can include a pyrrolyl group. In another example, R2 can include a pyrazolyl group. In an additional example, R2 can include an imidazolyl group. In a further example, R2 can include a triazolyl group. In still another example, R2 can include a tetrazolyl group. Additionally, R2 can include an oxazolyl group. In various illustrative embodiments, R2 can include an isoxazolyl group. Further, R2 can include a thiazolyl group. R2 can also include an isothiazolyl group, in some instances.
[0041] In some embodiments, R2 can include a phenyl group. In other embodiments, R2 can include a pyridinyl group. In additional embodiments, R2 can include a piperidinyl group. R2 can also include a cyclopentyl group. Further, R2 can include a cyclohexyl group.
[0042] In particular embodiments when R2 is a heteroaryl group, example compounds can have a structure
Figure imgf000012_0001
In particular embodiments, W, X, Y1 , Y2, Y3, Y4, R3, R4, R5, m, and o can be defined as above. For example, R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R5 can be Ra, ORa, OCHF2, OCFs, CFs, F, or CI. In illustrative embodiments, R3 can be OH or OCH3. Further, W can be CRa or N; X can be O, S, C=O, CRaRb, or NRa ; at least one group selected from Y1 , Y2, Y3, or Y4 includes N or NRa; at least another group selected from Y1, Y2, Y3, or Y4 includes CRa or CRaRb. Also, m can be an integer from 1 through 7; n can be 0, 1 , or 2; o can be an integer from 1 through 7.
[0043] In some embodiments, R5 can be CH3. For example, o can be 1 and R5 can be CH3 located in the para position. In addition, R5 can be OCHF2. In some cases, o can be 1 and R5 can be OCHF2 located in the para position. Further, R5 can be F. In particular, o can be 1 and R5 can be F located in the para position. R5 can also be CI. To illustrate, o can be 1 and R5 can be CI located in the para position. In various embodiments, R5 can be OCH3. In an example embodiment, o can be 1 and R5 can be OCH3 in the para position. In an embodiment, R5 can be OCF3. For instance, o can be 1 and R5 can be OCF3 located in the meta position. In certain embodiments, R5 can be CF3. In an illustrative example, o can be 1 and R5 can be CF3 located in the meta position.
[0044] In embodiments where R2 includes an optionally substituted aryl group or an optionally substituted heteroaryl group, example compounds can have a structure
Figure imgf000013_0001
In an embodiment, Z1 can be N, NRa, S, O, CRa, or CRaRb. Z2 can be N, NRa, S, O, CRa, or CRaRb. R6 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. In addition, R7 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb. In some cases, R6 and R7 can be fused to form a ring having 3 or more members. For example, R6 and R7 can be fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring. In particular embodiments, the dashed lines indicate the presence or absence of a double bond. In some cases, R1 , R3, R4, W, X, Y1 , Y2, Y3, Y4, and m can be defined as above. For example, R1 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Also, n can be 0, 1 , or 2. In illustrative embodiments, R3 can be OH or OCH3. Further, W can be CRa or N; X can be O, S, C=O, CRaRb, or NRa ; at least one group selected from Y1 , Y2, Y3, or Y4 includes N or NRa; at least another group selected from Y1 , Y2, Y3, or Y4 includes CRa or CRaRb.
[0045] In an illustrative embodiment, Z1 can be N. In another illustrative embodiment, Z2 can be S. Additionally, in some illustrative embodiments, Z1 can be N and Z2 can be S. Alternatively, Z1 can be S and Z2 can be N. In additional illustrative embodiments, R6 can include an alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, or a heptyl group. Further, R6 can include an optionally substituted aryl group. In particular illustrative embodiments, R7 can include an optionally substituted aryl group. In various illustrative embodiments, R6 and R7 can be fused to form an optionally substituted aryl ring. In some cases, R6 and R7 can be fused to form a phenyl group. Additionally, R6 and R7 can be fused to form a phenyl group substituted by H, a lower alkyl group, an ether group, or a combination thereof. For example, R6 and R7 can be fused to form a phenyl group substituted by OCH3.
[0046] In embodiments where R1 includes an optionally substituted aryl group and R2 includes an optionally substituted heteroaryl group or an optionally substituted aryl group, example compounds can have a structure
Figure imgf000015_0001
In an embodiment, Z1 can be N, NRa, S, O, CRa, or CRaRb. Additionally, Z2 can be N, NRa, S, O, CRa, or CRaRb. In some embodiments, R5 can be Ra, ORa, OCHF2, OCFs, CFs, F, or CI. Further, R6 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb. In various embodiments, R7 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb. In particular embodiments, R6 and R7 can be fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring. In certain embodiments, o can be an integer from 1 through 7. Also, in some cases, R3, R4, W, X, Y1 , Y2, Y3, Y4, and m can be defined as above. For example, R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. In illustrative embodiments, R3 can be OH or OCH3. Further, W can be CRa or N; X can be O, S, C=O, CRaRb, or NRa ; at least one group selected from Y1, Y2, Y3, or Y4 includes N or NRa; at least another group selected from Y1 , Y2, Y3, or Y4 includes CRa or CRaRb. Also, m can be an integer from 1 through 7; n can be 0, 1 , or 2. In particular embodiments, the dashed lines indicate the presence or absence of a double bond.
[0047] In embodiments where R1 includes an optionally substituted aryl group, R2 includes a substituted heteroaryl group, and R6 and R7 are fused to form an optionally substituted aryl ring, example compounds can have a structure
Figure imgf000016_0001
R5 can be Ra, ORa, OCHF2, OCFs, CFs, F, or CI . Additionally, R8 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. In an embodiment, o can be an integer from 1 through 7. Further, t can be an integer from 1 through 7. Also, in some cases, R3, R4, W, X, Y1 , Y2, Y3, Y4, Z1 and Z2, and m can be defined as above. For example, R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. In illustrative embodiments, R3 can be OH or OCH3. Further, W can be CRa or N; X can be O, S, C=O, CRaRb, or NRa ; at least one group selected from Y1 , Y2, Y3, or Y4 includes N or NRa; at least another group selected from Y1 , Y2, Y3, or Y4 includes CRa or CRaRb; Z1 can be N, NRa, S, O, CRa, or CRaRb; Z2 can be N, NRa, S, O, CRa, or CRaRb; m can be an integer from 1 through 7; n can be 0, 1 , or 2. In particular embodiments, the dashed lines indicate the presence or absence of a double bond. In an illustrative embodiment, t can be 1 and R8 can be OCH3.
[0048] In an embodiment, example compounds can have a structure
Figure imgf000016_0002
In some cases, R1 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Ra can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl. Additionally, Rb can be H, optionally substituted hydrocarbyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl. In particular embodiments, R6 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb. Also, R7 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb. Also, n can be 0, 1 , or 2. In an illustrative embodiment, at least one of R6 or R7 can include an optionally substituted aryl ring. In a particular illustrative embodiment, R1 can include an optionally substituted aryl ring. In embodiments where R1 is a substituted aryl ring, the substituted aryl ring can have substituents as defined above.
0049] In a particular embodiment, example compounds can have a structure
Figure imgf000017_0001
R9 can be Ra as defined above. Furthermore, R1 can be defined as above. For example, Ra can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl; R1 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Also, n can be 0, 1 , or 2. In an illustrative example, R9 can be CH3.
[0050] Additional embodiments of example compounds can have a structure
Figure imgf000018_0001
R10 can be Ra, CHF2, or CF3. In some embodiments, the group OR10 can be located in the para position or the meta position. In an illustrative embodiment, R10 can be CH3. For example, a group OCH3 can be located in the para position. In another illustrative embodiment, R10 can be CHF2. To illustrate, a group OCHF2 can be located in the para position. In additional illustrative embodiments, R10 can be CF3. For instance, a group OCF3 can be located in a meta position. Further, Ra, R6, R7 can be defined as above. To illustrate, Ra can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl; R6 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb; R7 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb. Also, n can be 0, 1 , or 2.
[0051] Further embodiments of example compounds can have a structure
Figure imgf000018_0002
In some embodiments, at least one group selected from Y1 , Y2, Y3, or Y4 can include N or NRa. Additionally, at least another group selected from Y1 , Y2, Y3, or Y4 can include CRa or CRaRb. In various embodiments, Ra, Rb, R3, R4, m, o, and t can be defined as above. For example, Ra can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl; Rb can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl; R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb.
[0052] In an embodiment, R5 can be optionally substituted hydrocarbyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl, ORa, OCHF2, OCFs, CFs, F, or CI.
[0053] In particular embodiments, R8 can Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. R11 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Further, R12 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. In an illustrative embodiment, at least one of R3, R11 , or R12 is ORa.
[0054] In some cases, m can be an integer from 1 through 7. Also, o can be an integer from 1 through 7. In addition, t can be an integer from 1 through 7. Furthermore, n can be 0, 1 , or 2. The dashed lines can represent the presence or absence of a double bond.
[0055] Embodiments of example compounds can also have a structure
Figure imgf000019_0001
In some embodiments, at least one group selected from Y1, Y2, Y3, or Y4 can include N or NRa. Additionally, at least another group selected from Y1 , Y2, Y3, or Y4 can include CRa or CRaRb. In various embodiments, Ra, Rb, R2, R3, R4, R11 , R12, m and o can be defined as above. For example, Ra can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl; Rb can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl; R2 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R11 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Further, R12 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Also, m can be an integer from 1 through 7; n can be 0, 1 , or 2; o can be an integer from 1 through 7. In an illustrative embodiment, at least one of R3, R11 , or R12 is ORa. The dashed lines can represent the presence or absence of a double bond.
[0056] In an embodiment, R5 is (O)uC(H)v(F)w. Additionally, u is 0, 1 , or 2. Also, v can be 0 or 1 . Further, w can be 1 , 2, or 3. In an illustrative embodiment, u can be 1 , v can be 1 , and w can be 2. In another illustrative embodiment, u can be 1 , v can be 0 and w can be 3. In other illustrative embodiments, u can be 0, v can be 0, and w can be 3.
[0057] Further embodiments of example compounds can have a structure
Figure imgf000020_0001
In particular embodiments, at least one group selected from Y1 , Y2, Y3, or Y4 can include N or NRa. Additionally, at least another group selected from Y1 , Y2, Y3, or Y4 can include CRa or CRaRb. In various embodiments, Ra, Rb, R2, R3, R4, R11 , R12, and m can be defined as above. For example, Ra can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl; Rb can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, akiylsulfoxide, or alkylsulfonyl; R2 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R4 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R11 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Further, R12 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Also, m can be an integer from 1 through 7; n can be 0, 1 , or 2. In an illustrative embodiment, at least one of R3, R11 , or R12 is ORa. The dashed lines can represent the presence or absence of a double bond.
[0058] In an embodiment, at least one of R6 or R7 is optionally substituted hydrocarbyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, alkylsulfonyl; ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb, and the other of R6 or R7 is Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb.
[0059] In an illustrative embodiment, R6 can be CH3 and R7 can be an optionally substituted aryl group. In another illustrative embodiment, R6 can be an optionally substituted aryl group and R7 can be H.
[0060] In embodiments where R1 includes an optionally substituted heteroaryl group and R2 includes an optionally substituted heteroaryl group, example compounds can have the structure
Figure imgf000022_0001
In some embodiments, Z1 can be N, NRa, S, O, CRa, or CRaRb. Additionally, Z2 can be N, NRa, S, O, CRa, or CRaRb. Also, Z3 can be N, NRa, S, O, CRa, or CRaRb. Furthermore, Z2 can be N, NRa, S, O, CRa, or CRaRb. In particular embodiments one of Z1 or Z2 can be S and the other one of Z1 or Z2 can be N. For example, Z1 can be S and Z2 can be N. Additionally, at least one of Z3 or Z4 can be S. In various embodiments, at least one of Z3 or Z4 can be O. In an illustrative embodiment, Z3 can be O and Z4 can be CH. In another illustrative embodiment, Z3 can be S and Z4 can be CH. In an additional illustrative embodiment, Z3 can be CH and Z4 can be O. In further illustrative embodiments, Z3 can be CH and Z4 can be S. In various embodiments, R13 and R14 can include Ra and r and q can be 0, 1 , 2, 3, 4, or 5. In addition, the dashed lines can indicate the presence or absence of a double bond. In embodiments, R13 can include a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. In particular illustrative embodiments, R13 can include a phenyl group.
[0061] In some embodiments, example compounds can have a structure
Figure imgf000022_0002
At least one of Z3 or Z4 can be S. In various embodiments, at least one of Z3 or Z4 can be O. In an illustrative embodiment, Z3 can be O and Z4 can be CH. In another illustrative embodiment, Z3 can be S and Z4 can be CH. In an additional illustrative embodiment, Z3 can be CH and Z4 can be O. In further illustrative embodiments, Z3 can be CH and Z4 can be S. In various embodiments, R13 and R14 can include Ra and r and q can be 0, 1 , 2, 3, 4, or 5. In addition, the dashed lines can indicate the presence or absence of a double bond. In embodiments, R13 can include a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. In particular illustrative embodiments, R13 can include a phenyl group.
[0062] Additionally, in embodiments where R1 is an optionally substituted heteroaryl group, compounds can have a structure
Figure imgf000023_0001
In some embodiments, Z3, Z4, R2, R14, and r can be defined as above. For example, Z3 can be O, S, CH, or CH2; Z4 can be O, S, CH, or CH2; R2 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; R14 can be Ra; n can be 0, 1 , or 2; r can be 0, 1 , 2, 3, 4, or 5.
[0063] In various embodiments, compounds having W is N and X is CH2 can have a structure
Figure imgf000024_0001
(R16)e
In embodiments, at least one of Z5 or Z6 can be S. In various embodiments, at least one of Z5 or Z6 can be N. In an illustrative embodiment, Z5 can be N and Z6 can be S. In other embodiments, Z5 or Z6 can be CH or CH2. In particular embodiments, R15 and R16 can include Ra, ORa, OCFs, OCHF2, OCH2F, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. and d and e can be 0, 1 , 2, 3, 4, or 5. In addition, the dashed lines can indicate the presence or absence of a double bond. In embodiments, R3 can be defined as above. For example, R3 can be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb. Also, n can be 0, 1 , or 2. In illustrative embodiments, R3 can include OH and R16 can include OCHF2.
[0064] Embodiments of compounds can also have a structure
Figure imgf000025_0001
In some embodiments, R17 and R18 can include a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group, or an unsubstituted heteroaryl group. In particular embodiments, R17, R18, or both can each independently include a substituted aryl group or an unsubstituted aryl group having a ring structure with 3 members, 4 members, 5 members, 6 members, or 7 members. Additionally, R17, R18, or both can each independently include a substituted heteroaryl group or an unsubstituted heteroaryl group having a ring structure with 3 members, 4 members, 5, members, 6 members, or 7 members. In an illustrative embodiment, R17 can include a dual ring structure comprising a phenyl ring and a pyrrodinyl ring and R18 can include a substituted heteroaryl group. In some instances, the phenyl ring can be substituted by a hydroxyl group. In other embodiments, R17 can include H or lower alkyl and R18 can include a substituted heteroaryl group or an unsubstituted heteroaryl group. In some illustrative embodiments, R18 can include a heteroaryl group with a phenyl substituent. In additional illustrative embodiments, R18 can include a dual ring structure having a thioazolyl group and a phenyl group. In further illustrative embodiments, R17 can include H and R18 can include a thiozaolyl group substituted by a phenyl group.
[0065] In particular embodiments, example compounds can have a structure
Figure imgf000026_0001
In some embodiments, Z7 and Z8 can each independently be S, N, O, CH, or CH2. In a particular embodiment Z7 or Z8 can be S. In another embodiment, Z7 or Z8 can be N. In still other embodiments, Z7 can be S and Z8 can be N. In further embodiments, Z7 can be N and Z8 can be S. In various embodiments, R19, R20, and R21 can each independently be Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb, where Ra, Rb, and n are defined above. For example, Ra can be H, optionally substituted hydrocarbyl, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfonyl; Rb can be H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfonyl; n can be 0, 1 , or 2. In particular embodiments, R19 and R20 can be fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring. In example embodiments, R19 and R20 are fused to form a pyridinyl group. Additionally, R22 can be H, lower alkyl, ORa, a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group, or an unsubstituted heteroaryl group and f can be 0, 1 , or 2. In a particular illustrative example, R22 can include a phenyl group. Also, two R22 groups can be fused to form a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group, or an unsubstituted heteroaryl group. In some illustrative embodiments, Z7 can be N, Z8 can be S, R19 and R20 can be fused to form an unsubstituted pyridinyl group, R21 can be OH, and two R22 groups can be fused to form a phenyl group.
[0066] Example compounds can also have any one of the following structures, as shown in Table 1 .
Table 1.
Figure imgf000027_0001
Connpound 4
Figure imgf000028_0001
Connpound 5
Figure imgf000028_0002
Connpound 6
Figure imgf000028_0003
Connpound 7
Figure imgf000028_0004
Figure imgf000029_0001
F
Compound 12
Connpound 13
Figure imgf000030_0001
Connpound 14 1
Connpound 15
Figure imgf000030_0002
Compound 16
Figure imgf000031_0001
Connpound 17
Figure imgf000031_0002
Connpound 18
Figure imgf000031_0003
Connpound 19
Figure imgf000031_0004
Compound 20
Figure imgf000032_0001
Compound 21
Figure imgf000032_0002
[0067] The following definitions are applicable to the description of the compounds:
[0068] Either alone or in combination, "alkyloxy" or "alkoxy" refer to a functional group including an alkyl ether group. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
[0069] "Alkyl", "alkenyl", and "alkynyl" refer to substituted and unsubstituted alkyls, alkenyls, and alkynyls. "Hydrocarbyl" used alone or in combination refers to a substituted or unsubstituted hydrocarbon based group. For example, hydrocarbyl can, in some cases, include an alkyl group, an alkenyl group, an alkynyl group, a cyclic hydrocarbon group, or an aryl group.
[0070] Either alone or in combination, the term "alkyl" refers to a functional group including a straight-chain or branched-chain hydrocarbon containing from 1 to 20 carbon atoms linked exclusively by single bonds and not having any cyclic structure. "Lower alkyl" refers to a functional group containing from 1 to 6 carbon atoms. An alkyl group may be optionally substituted as defined herein. Examples of alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, and the like. [0071] Either alone or in combination, the term "alkenyl" refers to a functional group including a straight-chain or branched-chain hydrocarbon containing from 2 to 20 carbon atoms and having one or more carbon-carbon double bonds and not having any cyclic structure. An alkenyl group may be optionally substituted as defined herein. Examples of alkenyl groups include ethene, propene, 2-methylpropene, 1 -butene, 2-butene, pentene,
1 - pentene, 2-pentene, hexene, heptene, octene, nonene, decene, undecene, dodecene, tridecene, tetradecene, pentadecene, hexadecene, heptadecene, octadecenel, nonadecene, eicosene, and the like
[0072] Either alone or in combination, "alkynyl" refers to a functional group including a straight-chain or branched-chain hydrocarbon containing from 2 to 20 carbon atoms and having one or more carbon-carbon triple bonds and not having any cyclic structure. An alkynyl group may be optionally substituted as defined herein. Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butynyl, butyn-1 -yl, butyn-2-yl, 3- methylbutyn-1 -yl, pentynyl, pentyn-1 -yl, hexynyl, hexyn-2-yl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, eicosynyl, and the like.
[0073] Either alone or in combination, substituted alkyls, alkenyls, and alkynyls refer to alkyls, alkenyls, and alkynyls substituted with one to five substituents from the group including H, lower alkyl, aryl, alkenyl, alkynyl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkoxyalkylaryl, alkylamino, arylamino, Nhb, OH, CN, NO2, OCF3, CF3, F, Cl,1 -amidine,
2- amidine, alkylcarbonyl, morpholinyl, piperidinyl, dioxanyl, pyranyl, heteroaryl, furanyl, thiophenyl, tetrazolo, thiazolyl, isothiazolyl, imidazolyl, thiadiazolyl, thiadiazole S-oxide, thiadiazole S,S-dioxide, pyrazolo, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, SR, SOR, SO2R, CO2R, COR, CONR'R", CSNR'R", or SOnNR'R" where R' and R" may independently be, for example, Ra and Rb.
[0074] "Alkylene," alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.
[0075] Either alone or in combination, "alkylcarbonyl" or "alkanoyl" refer to a functional group including an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of alkylcarbonyl groups include, methylcarbonyl, ethylcarbonyl, and the like.
[0076] Either alone or in combination, "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C:::C-, -C≡C-). Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.
[0077] Either alone or in combination, "aryl", "hydrocarbyl aryl", or "aryl hydrocarbon" refer to a functional group including a substituted or unsubstituted aromatic hydrocarbon with a conjugated cyclic molecular ring structure of 3 to 12 carbon atoms. An aryl group can be monocyclic, bicyclic, or polycyclic, and can optionally include one to three additional ring structures, such as, e.g., a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, or a heteroaryl. The term "aryl" includes phenyl (benzenyl), thiophenyl, indolyl, naphthyl, tolyl, xylyl, anthracenyl, phenanthryl, azulenyl, biphenyl, naphthalenyl, 1 -Methylnaphthalenyl, acenaphthenyl, acenaphthylenyl, anthracenyl, fluorenyl, phenalenyl, phenanthrenyl, benzo[a]anthracenyl, benzo[c]phenanthrenyl, chrysenyl, fluoranthenyl, pyrenyl, tetracenyl (naphthacenyl), triphenylenyl, anthanthrenyl, benzopyrenyl, benzo[a]pyrenyl, benzo[e]fluoranthenyl, benzo[ghi]perylenyl, benzo[j]fluoranthenyl, benzo[k]fluoranthenyl, corannulenyl, coronenyl, dicoronylenyl, helicenyl, heptacenyl, hexacenyl, ovalenyl, pentacenyl, picenyl, perylenyl, and tetraphenylenyl. Substituted aryl refers to aryls substituted with one to five substituents from the group including H, lower alkyl, aryl, alkenyl, alkynyl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkoxyalkylaryl, alkylamino, arylamino, NH2, OH, CN, NO2, OCF3, CF3, Br, CI, F, 1 -amidino, 2-amidino, alkylcarbonyl, morpholino, piperidinyl, dioxanyl, pyranyl, heteroaryl, furanyl, thiophenyl, tetrazolo, thiazole, isothiazolo, imidazolo, thiadiazole, thiadiazole S-oxide, thiadiazole S,S-dioxide,pyrazolo, oxazole, isoxazole, pyridinyl, pyrimidinyl, quinoline, isoquinoline, SR, SOR, SO2R, CO2R, COR, CONRR, CSNRR, and SOnNRR, where each R may independently be, for example, selected from Ra or Rb.
[0078] Either alone or in combination, "carboxyl" or "carboxy" refers to the functional group -C(=O)OH or the corresponding "carboxylate" anion C(=O)O-. Examples include formic acid, acetic acid, oxalic acid, and benzoic acid. An "O-carboxyl" group refers to a carboxyl group having the general formula RCOO, wherein R is an organic moiety or group. A "C-carboxyl" group refers to a carboxyl group having the general formula COOR, wherein R is an organic moiety or group.
[0079] Either alone or in combination, "cycloalkyl", "carbocyclicalkyl", and "carbocyclealkyl" refer to a functional group including a substituted or unsubstituted non- aromatic hydrocarbon with a non-conjugated cyclic molecular ring structure of 3 to 12 carbon atoms linked exclusively with carbon-carbon single bonds in the carbon ring structure. A cycloalkyl group can be monocyclic, bicyclic, or polycyclic, and may optionally include one to three additional ring structures, such as, e.g., an aryl, a heteroaryl, a cycloalkenyl, a heterocycloalkyl, or a heterocycloalkenyl.
[0080] Either alone or in combination, "lower cycloalkyl" refers to a functional group including a monocyclic substituted or unsubstituted non-aromatic hydrocarbon with a non- conjugated cyclic molecular ring structure of 3 to 6 carbon atoms linked exclusively with carbon-carbon single bonds in the carbon ring structure. Examples of lower cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0081] Either alone or in combination, "heteroalkyl" refers to a functional group including a straight-chain or branched-chain hydrocarbon containing from 1 to 20 atoms linked exclusively by single bonds, where at least one atom in the chain is a carbon and at least one atom in the chain is O, S, N, or any combination thereof. The heteroalkyl group can be fully saturated or contain from 1 to 3 degrees of unsaturation. The non-carbon atoms can be at any interior position of the heteroalkyl group, and up to two non-carbon atoms may be consecutive, such as, e.g., -CH2-NH-OCH3. In addition, the non-carbon atoms may optionally be oxidized and the nitrogen may optionally be quaternized.
[0082] Either alone or in combination, "heteroaryl" refers to a functional group including a substituted or unsubstituted aromatic hydrocarbon with a conjugated cyclic molecular ring structure of 3 to 12 atoms, where at least one atom in the ring structure is a carbon and at least one atom in the ring structure is O, S, N, or any combination thereof. A heteroaryl group can be monocyclic, bicyclic, or polycyclic, and may optionally include one to three additional ring structures, such as, e.g., an aryl, a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, or a heterocycloalkenyl. Examples of heteroaryl groups include acridinyl, benzidolyl, benzimidazolyl, benzisoxazolyl, benzodioxinyl, dihydrobenzodioxinyl, benzodioxolyl, 1 ,3-benzodioxolyl, benzofuryl, benzoisoxazolyl, benzopyranyl, benzothiophenyl, benzo[c]thiophenyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, carbazolyl, chromonyl, cinnolinyl, dihydrocinnolinyl, coumarinyl, dibenzofuranyl, furopyridinyl, furyl, indolizinyl, indolyl, dihydroindolyl, imidazolyl, indazolyl, isobenzofuryl, isoindolyl, isoindolinyl, dihydroisoindolyl, isoquinolyl, dihydroisoquinolinyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, phenanthrolinyl, phenanthridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolinyl, pyrrolyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thiophenyl, thiazolyl, thiadiazolyl, thienopyridinyl, thienyl, thiophenyl, triazolyl, xanthenyl, and the like.
[0083] Either alone or in combination, "hydroxy" refers to the functional group hydroxyl (-OH).
[0084] Either alone or in combination, "oxo" refers to the functional group =O.
[0085] "Functional group" refers to an atom or a group of atoms that have similar chemical properties whenever they occur in different compounds, and as such the functional group defines the characteristic physical and chemical properties of families of organic compounds.
[0086] Unless otherwise indicated, when any compound or chemical structural feature, such as, for example, alkyl, aryl, etc., is referred to as being "optionally substituted," that compound can have no substituents (in which case it is "unsubstituted"), or it can include one or more substituents (in which case it is "substituted"). The term "substituent" has the ordinary meaning known to one of ordinary skill in the art. In some embodiments, the substituent may be an ordinary organic moiety known in the art, which can have a molecular weight (e.g., the sum of the atomic masses of the atoms of the substituent) of 15 g/mol to 50 g/mol , 15 g/mol to 100 g/mol , 15 g/mol to 150 g/mol , 15 g/mol to 200 g/mol , 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol. In some embodiments, the substituent includes: 0-30, 0-20, 0-10, or 0-5 C atoms; and/or 0-30, 0-20, 0-10, or 0-5 heteroatoms including N, O, S, Si, F, CI, Br, or I; provided that the substituent includes at least one atom, including C, N, O, S, Si, F, CI, Br, or I, in a substituted compound. Examples of substituents include alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N carbamyl, O thiocarbamyl, N thiocarbamyl, C amido, N amido, S-sulfonamido, N sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, etc.
[0087] For convenience, the term "molecular weight" is used with respect to a moiety or part of a compound to indicate the sum of the atomic masses of the atoms in the moiety or part of a compound, even though it may not be a complete compound.
[0088] Specific embodiments of the compounds disclosed herein have the structures shown in Table. 1 .
[0089] Unless stereochemistry is unambiguously depicted, any structure, formula, or name for a compound can refer to any stereoisomer or any mixture of stereoisomers of the compound.
[0090] Compounds can also be provided as alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein. Compounds also include pharmaceutically acceptable salts of the compounds.
[0091] As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. In one embodiment, the pharmaceutically acceptable salt is a sulfate salt. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66:1 -19.
[0092] Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, malonic, galactic, and galacturonic acid. Pharnnaceutically acceptable acidic/anionic salts also include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.
[0093] Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine, arginine and procaine. All of these salts can be prepared by conventional means from the corresponding compound represented by the disclosed compounds by treating, for example, the disclosed compounds with the appropriate acid or base. Pharmaceutically acceptable basic/cationic salts also include, the diethanolamine, ammonium, ethanolamine, piperazine and triethanolamine salts.
[0094] A pharmaceutically acceptable salt includes any salt that retains the activity of the parent compound and is acceptable for pharmaceutical use. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
[0095] Unless stereochemistry is unambiguously depicted, any structure, formula, or name for a compound can refer to any stereoisomer or any mixture of stereoisomers of the compound.
[0096] Compounds disclosed herein also include prodrugs. A prodrug includes a compound which is converted to a therapeutically active compound after administration, such as by hydrolysis of an ester group or some other biologically labile group.
[0097] Pharmaceutical Compositions [0098] According to other embodiments, the present disclosure provides for a pharmaceutical composition including any one or more of the compounds described herein.
[0099] Pharmaceutical compositions can be formed by combining a compound disclosed herein, or a pharmaceutically acceptable prodrug or salt thereof, with a pharmaceutically acceptable carrier suitable for delivery to a subject in accordance with known methods of drug delivery. Accordingly, a "pharmaceutical composition" includes at least one compound disclosed herein together with one or more pharmaceutically acceptable carriers, excipients, or diluents, as appropriate for the chosen mode of administration.
[0100] The pharmaceutical composition including a compound of the disclosure can be formulated in a variety of forms depending upon the particular indication being treated and will be apparent to one of ordinary skill in the art. Formulating pharmaceutical compositions including one or more compounds of the disclosure can employ straightforward medicinal chemistry processes. The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional adjuvants, such as buffering agents, preservatives, isotonicifiers, stabilizers, wetting agents, emulsifiers, etc.
[0101] Buffering agents help to maintain the pH in a range which approximates physiological conditions. They are typically present at a concentration ranging from 2 mM to 50 mM of a pharmaceutical composition. Suitable buffering agents include both organic and inorganic acids, and salts thereof, such as citrate buffers (e.g., monosodium citrate- disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid- potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, fumaric acid-disodium fumarate mixture, monosodium fumarate-disodium fumarate mixture, etc.), gluconate buffers (e.g., gluconic acid-sodium gluconate mixture, gluconic acid-sodium hydroxide mixture, gluconic acid-potassium gluconate mixture, etc.), oxalate buffer (e.g., oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture, oxalic acid-potassium oxalate mixture, etc.), lactate buffers (e.g., lactic acid-sodium lactate mixture, lactic acid-sodium hydroxide mixture, lactic acid-potassium lactate mixture, etc.), and acetate buffers (e.g., acetic acid-sodium acetate mixture, acetic acid-sodium hydroxide mixture, etc.). Additional possibilities are phosphate buffers, histidine buffers, and trimethylamine salts such as Tris.
[0102] Preservatives can be added to pharmaceutical compositions to retard microbial growth, and are typically added in amounts of 0.2%-1 % (w/v). Suitable preservatives include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides (e.g., benzalkonium chloride, bromide or iodide), hexamethonium chloride, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.
[0103] Isotonicifiers can be added to pharmaceutical compositions to ensure isotonicity. Appropriate isotonicifiers include polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol. Polyhydric alcohols can be present in an amount between 0.1 % and 25% by weight, typically 1 % to 5%, taking into account the relative amounts of the other ingredients.
[0104] Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the compound or helps to prevent denaturation or adherence to the container wall. Typical stabilizers can be polyhydric sugar alcohols; amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, and the like, including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur-containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, alpha- monothioglycerol and sodium thiosulfate; low molecular weight polypeptides (i.e., <10 residues); proteins such as human serum albumin, bovine serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides such as xylose, mannose, fructose and glucose; disaccharides such as lactose, maltose and sucrose; trisaccharides such as raffinose, and polysaccharides such as dextran. Stabilizers are typically present in the range of from 0.1 to 10,000 parts by weight based on compound weight.
[0105] Additional miscellaneous excipients can include chelating agents (e.g., EDTA), antioxidants (e.g., ascorbic acid, methionine, and vitamin E) and cosolvents.
[0106] Particular embodiments can include one or more of ethanol (<10%), propylene glycol (<40%), polyethylene glycol (PEG) 300 or 400 (<60%), N-N-dimethylacetamide (DMA, <30%), N-methyl-2-pyrrolidone (NMP, <20%), dimethyl sulfoxide (DMSO, <20%) co-solvents or the cyclodextrins (<40%) and have a pH of 3 to 9.
[0107] Generally, the pharmaceutical compositions can be made up in a solid form (including granules, powders, or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). The compounds can be admixed with adjuvants such as lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, they can be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, oils (such as corn oil, peanut oil, cottonseed oil, or sesame oil), tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent can include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
[0108] Oral administration of the pharmaceutical compositions is one intended practice of the disclosure. For oral administration, the pharmaceutical composition can be in solid or liquid form, e.g., in the form of a capsule, tablet, powder, granule, suspension, emulsion, or solution.
[0109] Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms can also include, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms can also include buffering agents. Tablets and pills can additionally be prepared with enteric coatings. For buccal administration the pharmaceutical compositions can take the form of tablets or lozenges formulated in conventional manners.
[0110] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such pharmaceutical compositions can also include adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
[0111] The pharmaceutical compositions can be formulated for parenteral administration by injection, e.g. by bolus injection, or infusion. Formulations for injection can be presented in unit dosage form, e.g. in glass ampoule or multi-dose containers, e.g. glass vials. The pharmaceutical compositions for injection can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as antioxidants, buffers, non-ionic detergents, dispersants, isotonicifiers, suspending agents, stabilizers, preservatives, dispersing agents and/or other miscellaneous additives. Parenteral formulations to be used for in vivo administration generally are sterile. This is readily accomplished, for example, by filtration through sterile filtration membranes.
[0112] Although in many cases pharmaceutical compositions provided in liquid form are appropriate for immediate use, such parenteral formulations can also be provided in frozen or in lyophilized form. The latter form is often used to enhance the stability of the compound contained in the pharmaceutical composition under a wider variety of storage conditions, as it is recognized by those or ordinary skill in the art that lyophilized preparations are generally more stable than their liquid counterparts. Parenterals can be prepared for storage as lyophilized formulations by mixing, as appropriate, the compound having the desired degree of purity with one or more pharmaceutically acceptable carriers, excipients, or stabilizers typically employed in the art (all of which are termed "excipients"), for example, antioxidants, buffers, non-ionic detergents, dispersants, isotonicifiers, suspending agents, stabilizers, preservatives, dispersing agents and/or other miscellaneous additives. Such lyophilized preparations are reconstituted prior to use by the addition of one or more suitable pharmaceutically acceptable diluents such as sterile pyrogen-free water for injection or sterile physiological saline solution. [0113] For administration by inhalation (e.g., nasal or pulmonary), the pharmaceutical compositions can be conveniently delivered in the form of an aerosol spray, from pressurized packs or a nebulizer, and/or with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases or mixture of gases.
[0114] In addition to the formulations described above, the pharmaceutical compositions can also be formulated as depot preparations. Such long acting formulations can be administered by implantation or by intramuscular injection.
[0115] The compounds can also be entrapped in microcapsules prepared, for example, by coascervation techniques or by interfacial polymerization, (for example hydroxymethylcellulose, gelatin or poly-(methylmethacylate) microcapsules), in colloidal drug delivery systems (for example liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 21 st Ed., published by Lippincott Williams & Wilkins, A Wolters Kluwer Company, 2005.
[0116] Additional suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, the matrices having a suitable form such as a film or microcapsules. Examples of sustained- release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate) or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the PROLEASE® technology (Alkermes, Inc., Cambridge, MA) or LUPRON DEPOT® (Tap Pharmaceuticals Products, Inc.; Lake Forest, IL; injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for long periods such as up to or over 100 days, certain hydrogels release compounds for shorter time periods.
I. Methods of Use
[0117] The pharmaceutical compositions disclosed herein can be used to treat a viral infection in a subject; wherein the viral infection is caused by a virus from one the following families: Arenaviridae, Arterivirus, Astroviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Closteroviridae, Comoviridae, Coronaviridae, Cystoviridae, Flaviviridae, Flexiviridae, Hepadnaviridae, Hepevirus, Herpesviridae, Leviviridae, Luteoviridae, Meson iviridae, Mononegavirales, Mosaic Viruses, Nidovirales, Nodaviridae, Orthomyxoviridae, Papillomaviridae, Paramyxoviridae, Picobirnaviridae, Picobirnavirus, Picornaviridae, Potyviridae, Reoviridae, Retroviridae, Roniviridae, Sequiviridae, Tenuivirus, Togaviridae, Tombusviridae, Totiviridae, and Tymoviridae.
[0118] According to more specific embodiments, the pharmaceutical compositions can be used to treat a viral infection caused by one or more of Alfuy virus, Banzi virus, bovine diarrhea virus, Chikungunya virus, Dengue virus (DNV), Ebola virus, Encephalomyocarditis virus (EMCV), Hepatitis B virus (HBV), HCV, human cytomegalovirus (hCMV), HIV, llheus virus, influenza virus (including avian and swine isolates), Japanese encephalitis virus, Kokobera virus, Kunjin virus, Kyasanur forest disease virus, louping-ill virus, Lassa virus (LASV), measles virus, MERS-coronavirus (MERS), metapneumovirus, any of the Mosaic Viruses, Murray Valley virus, Nipah virus, parainfluenza virus, poliovirus, Powassan virus, respiratory syncytial virus (RSV), Rocio virus, SARS-coronavirus (SARS), St. Louis encephalitis virus, tick-borne encephalitis virus, WNV, and yellow fever virus.
[0119] Many RNA viruses share biochemical, regulatory, and signaling pathways. These viruses include influenza viruses (including avian and swine isolates), DNV, RSV, WNV, HCV, parainfluenza virus, metapneumovirus, Chikungunya virus, SARS, MERS, poliovirus, measles virus, yellow fever virus, tick-borne encephalitis virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley virus, Powassan virus, Rocio virus, louping-ill virus, Banzi virus, llheus virus, Kokobera virus, Kunjin virus, Alfuy virus, bovine diarrhea virus, and the Kyasanur forest disease virus.
[0120] Methods disclosed herein include treating subjects (humans, mammals, free- range herds, veterinary animals (dogs, cats, reptiles, birds, etc.), farm animals and livestock (horses, cattle, goats, pigs, chickens, etc.), and research animals (monkeys, rats, mice, fish, etc.)) with pharmaceutical compositions disclosed herein. Treating subjects includes delivering therapeutically effective amounts. Therapeutically effective amounts include those that provide effective amounts, prophylactic treatments, and/or therapeutic treatments. [0121] An "effective amount" is the amount of a compound necessary to result in a desired physiological change in the subject. Effective amounts are often administered for research purposes. Effective amounts disclosed herein reduce, control, or eliminate the presence or activity of viral infections and/or reduce, control, or eliminate unwanted side effects of viral infections. For example, an effective amount may result in a reduction in viral protein in a subject or assay, a reduction in viral RNA in a subject or assay, and/or a reduction in virus present in a cell culture.
[0122] A "prophylactic treatment" includes a treatment administered to a subject who does not display signs or symptoms of a viral infection or displays only early signs or symptoms of the viral infection such that treatment is administered for the purpose of diminishing, preventing, or decreasing the risk of developing the viral infection further. Thus, a prophylactic treatment functions as a preventative treatment against a viral infection. Prophylactic treatment may also include vaccines as described elsewhere herein. Prophylactic treatment may result in a lack of increase in viral proteins or RNA in a subject, and/or a lack of increase in clinical indicators of viral infection, such as: loss of appetite, fatigue, fever, muscle aches, nausea, and/or abdominal pain in the case of HCV; fever and/or headache in the case of WNV; and cough, congestion, fever, sore throat, and/or headache in the case of RSV. Prophylactic treatments can be administered to any subject regardless of whether signs of viral infection are present. In some embodiments, prophylactic treatments can be administered before travel.
[0123] A "therapeutic treatment" includes a treatment administered to a subject who displays symptoms or signs of a viral infection and is administered to the subject for the purpose of diminishing or eliminating the signs or symptoms of the viral infection. The therapeutic treatment can reduce, control, or eliminate the presence or activity of viruses and/or reduce, control, or eliminate side effects of viruses. Therapeutic treatment may result in a decrease in viral proteins or RNA in a subject, and/or a decrease in clinical indicators of viral infection, such as: loss of appetite, fatigue, fever, muscle aches, nausea, and/or abdominal pain in the case of HCV; fever and/or headache in the case of WNV; and cough, congestion, fever, cyanosis, sore throat, and/or headache in the case of RSV. [0124] For administration, therapeutically effective amounts (also referred to herein as doses) can be initially estimated based on results from in vitro assays and/or animal model studies. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes an IC50 as determined in cell culture against a particular target. Such information can be used to more accurately determine useful doses in subjects of interest.
[0125] The actual dose amount administered to a particular subject can be determined by a physician, veterinarian, or researcher taking into account parameters such as physical and physiological factors including target, body weight, severity of condition, type of viral infection, previous or concurrent therapeutic interventions, idiopathy of the subject, and route of administration.
[0126] Pharmaceutical compositions can be administered intravenously to a subject for treatment of viral infections in a clinically safe and effective manner, including one or more separate administrations of the composition. For example, 0.05 mg/kg to 5.0 mg/kg can be administered to a subject per day in one or more doses (e.g., doses of 0.05 mg/kg once-daily (QD), 0.10 mg/kg QD, 0.50 mg/kg QD, 1 .0 mg/kg QD, 1 .5 mg/kg QD, 2.0 mg/kg QD, 2.5 mg/kg QD, 3.0 mg/kg QD, 0.75 mg/kg twice-daily (BID), 1 .5 mg/kg BID or 2.0 mg/kg BID). For certain antiviral indications, the total daily dose of a compound can be 0.05 mg/kg to 3.0 mg/kg administered intravenously to a subject one to three times a day, including administration of total daily doses of 0.05-3.0, 0.1 -3.0, 0.5-3.0, 1 .0-3.0, 1 .5-3.0, 2.0-3.0, 2.5-3.0, and 0.5-3.0 mg/kg/day of compounds of Figure 1 using 60-minute QD, BID, or three times daily (TID) intravenous infusion dosing. In one particular example, antiviral pharmaceutical compositions can be intravenously administered QD or BID to a subject with, e.g., total daily doses of 1 .5 mg/kg, 3.0 mg/kg, 4.0 mg/kg of a composition with up to 92-98% wt/wt of a compound of Figure 1 .
[0127] Additional useful doses can often range from 0.1 to 5 pg/kg or from 0.5 to 1 g /kg. In other examples, a dose can include 1 g /kg, 5 g /kg, 10 g /kg, 15 g /kg, 20 g /kg, 25 ig /kg, 30 pg /kg, 35 pg/kg, 40 pg/kg, 45 pg/kg, 50 pg/kg, 55 pg/kg, 60 pg/kg, 65 Mg/kg, 70 pg/kg, 75 pg/kg, 80 pg/kg, 85 pg/kg, 90 pg/kg, 95 pg/kg, 100 pg/kg, 150 pg/kg, 200 Mg/kg, 250 pg/kg, 350 pg/kg, 400 pg/kg, 450 pg/kg, 500 pg/kg, 550 pg/kg, 600 pg/kg, 650 Mg/kg, 700 pg/kg, 750 pg/kg, 800 pg/kg, 850 pg/kg, 900 pg/kg, 950 pg/kg, 1000 pg/kg, 0.1 to 5 mg/kg, or from 0.5 to 1 mg/kg. In other examples, a dose can include 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, 1000 mg/kg, or more.
[0128] Therapeutically effective amounts can be achieved by administering single or multiple doses during the course of a treatment regimen (e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 1 1 months, or yearly.
[0129] The administration of the pharmaceutical compositions of the present disclosure can be performed in a variety of ways, including orally, subcutaneously, intravenously, intracerebrally, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, intrathecally, vaginally, rectally, intraocularly, or in any other acceptable manner. The pharmaceutical compositions can be administered continuously by infusion, although bolus injection is acceptable, using techniques well known in the art, such as pumps (e.g., subcutaneous osmotic pumps) or implantation. In some instances the pharmaceutical compositions can be directly applied as a solution or spray.
[0130] The pharmaceutical compositions disclosed herein can be additive or synergistic with other therapies currently in development or use. For example, ribavirin and interferon-a provide an effective treatment for HCV infection when used in combination. Another non-limiting example is the combination of the compounds disclosed herein with the compounds disclosed in PCT/US13/026173. Their efficacy in combination can exceed the efficacy of either drug product when used alone. The pharmaceutical compositions of the disclosure can be administered alone or in combination or conjunction with interferon, ribavirin, and/or a variety of small molecules that are being developed against both viral targets (viral proteases, viral polymerase, and/or assembly of viral replication complexes) and host targets (host proteases required for viral processing, host kinases required for phosphorylation of viral targets such as NS5A, and inhibitors of host factors required to efficiently utilize the viral internal ribosome entry site, or IRES).
[0131] The pharmaceutical compositions disclosed herein could be used in combination or conjunction with adamantane inhibitors, neuraminidase inhibitors, alpha interferons, non-nucleoside or nucleoside polymerase inhibitors, NS5A inhibitors, antihistamines, protease inhibitors, helicase inhibitors, P7 inhibitors, entry inhibitors, IRES inhibitors, immune stimulators, HCV replication inhibitors, cyclophilin A inhibitors, A3 adenosine agonists, and/or microRNA suppressors.
[0132] Cytokines that could be administered in combination or conjunction with the pharmaceutical compositions disclosed herein include interleukin (IL)-2, IL-12, IL-23, IL- 27, or IFN-y.
[0133] The compounds or pharmaceutical compositions can be additive or synergistic with other compounds or pharmaceutical compositions to enable vaccine development. By virtue of their antiviral and immune enhancing properties, the compounds can be used to affect a prophylactic or therapeutic vaccination. The compounds need not be administered simultaneously or in combination with other vaccine components to be effective. The vaccine applications of the compounds are not limited to the treatment of viral infection but can encompass all therapeutic and prophylactic vaccine applications due to the general nature of the immune response elicited by the compounds.
[0134] A "vaccine" is an immunogenic preparation that is used to induce an immune response in an individual. A vaccine can have more than one constituent that is immunogenic. A vaccine can be used for prophylactic and/or therapeutic purposes. A vaccine does not necessarily have to prevent viral infections. Without being bound by theory, the vaccines of the disclosure can affect an individual's immune response in a manner such that viral infection occurs in a lesser amount (including not at all) or such that biological or physiological effects of the viral infection are ameliorated when the vaccine is administered as described herein. As used herein, vaccines include preparations including pharmaceutical compositions including the compounds, alone or in combination with an antigen, for the purpose of treating a viral infection in a subject including a vertebrate animal. [0135] The disclosure provides for the use of the compounds and pharmaceutical compositions as adjuvants. An adjuvant enhances, potentiates, and/or accelerates the beneficial effects of another administered therapeutic agent. In particular embodiments, the term "adjuvant" refers to compounds that modify the effect of other agents on the immune system. Adjuvants that possess this function may also be inorganic or organic chemicals, macromolecules, or entire cells of certain killed bacteria, which enhance the immune response to an antigen. They may be included in a vaccine to enhance the recipient's immune response to the supplied antigen.
[0136] As is understood by one of ordinary skill in the art, vaccines can be against viruses, bacterial infections, cancers, etc. and can include one or more of a live attenuated vaccine (LAIV), an inactivated vaccine (I IV; killed virus vaccine), a subunit (split vaccine); a sub-virion vaccine; a purified protein vaccine; or a DNA vaccine. Appropriate adjuvants include one or more of water/oil emulsions, non-ionic copolymer adjuvants, e.g., CRL 1005 (Optivax; Vaxcel Inc., Norcross, Ga.), aluminum phosphate, aluminum hydroxide, aqueous suspensions of aluminum and magnesium hydroxides, bacterial endotoxins, polynucleotides, polyelectrolytes, lipophilic adjuvants and synthetic muramyl dipeptide (norMDP) analogs such as N-acetyl-nor-muranyl-L-alanyl-D-isoglutamine, N-acetyl- muranyl-(6-O-stearoyl)-L-alanyl-D-isoglutamine, or N-Glycol-muranyl-LalphaAbu-D- isoglutamine (Ciba-Geigy Ltd.).
[8137J The present disclosure further includes the use and application of the compounds and pharmaceutical compositions in vitro in a number of applications including developing therapies and vaccines against viral infections, research in modulation of the innate immune response in eukaryotic cells, etc. The compounds and pharmaceutical compositions disclosure can also be used in animal models. The results of such in vitro and animal in vivo uses of the compounds and pharmaceutical compositions can, for example, inform their in vivo use in humans, or they can be valuable independent of any human therapeutic or prophylactic use.
[0138] EXAMPLE EMBODIMENTS
[0139] Embodiment 1 . A compound having a structure
Figure imgf000050_0001
wherein
W is CRa or N;
X is O, S, C=O, CRaRb, or NRa;
at least one group selected from Y1, Y2, Y3, or Y4 includes N or NRa;
at least another group selected from Y1, Y2, Y3, or Y4 includes CRa or CRaRb;
Ra and Rb are each independently H, optionally substituted lower alkyl; optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl;
R1 , R2, R3, and R4 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb,
NO2, S(O)nRa, or S(O)nNRaRb;
m is an integer from 1 through 7;
n is 0, 1 , or 2; and
the dashed lines represent the presence or absence of a double bond.
0140] Embodiment 2. The compound of Embodiment 1 having a structure
Figure imgf000050_0002
wherein
R5 is Ra, ORa, OCHF2, OCFs, CFs, F, or CI; and
o is an integer from 1 through 7.
[0141] Embodiment 3. The compound of Embodiment 1 having a structure
Figure imgf000051_0001
wherein
Z1 and Z2 are each independently N, NRa, S, O, CRa, or CRaRb;
R6 and R7 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb, or R6 and R7 are fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring.
[0142] Embodiment 4. The compound of any one of Embodiments 1 -3, having a structure
Figure imgf000051_0002
wherein Z1 and Z2 are each independently N, NRa, S, O, CRa, or CRaRb;
R5 is Ra, ORa, OCHF2, OCFs, CFs, F, or CI;
R6 and R7 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb, or R6 and R7 are fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring; and
o is an integer from 1 through 7.
[0143] Embodiment s. The compound of any one of Embodiments 1 -4, having a structure
Figure imgf000052_0001
wherein
R5 is Ra, ORa, OCHF2, OCFs, CFs, F, or CI;
R8 is Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; and o and t are each independently an integer from 1 through 7.
[0144] Embodiment 6. The compound of any one of Embodiments 1 -5, wherein R3 is OH.
[0145] Embodiment 7. The compound of any one of Embodiments 1 -6, wherein Y1 , Y2, and Y3 are CH and Y4 is N.
[0146] Embodiment 8. The compound of any one of Embodiments 1 -7, wherein W is CH and X is NH.
[0147] Embodiment 9. The compound of any one of Embodiments 1 -8 having a structure
Figure imgf000053_0001
52
Figure imgf000054_0001
53
Figure imgf000055_0001
54
Figure imgf000056_0001
55
Figure imgf000057_0001

Figure imgf000058_0001
Embodiment 10. The compound of Embodiment 1 having a structure
wherein Z1 and Z2 can each independently be S or N, Z3 and Z4 can each independently be S or O, R13 and R14 can each independently be Ra; r and q can be 0, 1 , 2, 3, 4, or 5, and the dashed lines can indicate the presence or absence of a double bond.
[0148] Embodiment 1 1 . The compound of Embodiment 10, wherein r=0 and R13 is a phenyl group.
0149] Embodiment 12. A compound having a structure
Figure imgf000059_0002
wherein
R1 is Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; Ra and Rb are each independently H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl; R6 and R7 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb, or R6 and R7 are fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyi ring; and
n is 0, 1 , or 2. [0150] Embodiment 13. The compound of Embodiment 12, wherein at least one of R6 or R7 are an optionally substituted aryl ring.
0151] Embodiment 14. The compound of Embodiment 12, having a structure
Figure imgf000060_0001
wherein R9 is Ra.
[0152] Embodiment 15. The compound of Embodiment 12, having a structure
Figure imgf000060_0002
wherein R10 is Ra, CHF2, or CFs.
[0153] Embodiment 16. A compound having a structure
Figure imgf000060_0003
wherein
at least one group selected from Y1, Y2, Y3, or Y4 includes N or NRa; at least another group selected from Y1, Y2, Y3, or Y4 includes CRa or CRaRb;
Ra and Rb are each independently H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl;
R3, R4, R11 , and R12 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN,
NRaRb, NO2, S(O)nRa, or S(O)nNRaRb;
Figure imgf000061_0001
m is an integer from 1 through 7;
n is 0, 1 , or 2;
u is 0 or 1 ;
v is 0, 1 , or 2;
w is 1 , 2, or 3; and
the dashed lines represent the presence or absence of a double bond.
[0154] Embodiment 17. A compound having a structure
Figure imgf000061_0002
wherein
R17 and R18 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb;
Ra is H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfony; and n is 0, 1 , or 2.
[0155] Embodiment 18. The composition of Embodiment 17 having the structure
Figure imgf000062_0001
[0156] Embodiment 19. A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 18.
[0157] Embodiment 20. A pharmaceutical composition of Embodiment 19, for use in therapy.
[0158] Embodiment 21 . A method of treating a viral infection in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of Embodiment 20 thereby treating the viral infection in the subject.
[0159] Embodiment 22. A method of treating a viral infection in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of Embodiment 19 thereby treating the viral infection in the subject wherein the viral infection is caused by at least one of influenza; RSV; Dengue; Ebola; West Nile Virus; and LASV.
[0160] Embodiment 23. The method of Embodiment 22 wherein said viral infection is caused by Ebola virus.
[0161] The experimental Examples below are included to demonstrate particular embodiments of the disclosure. Those of ordinary skill in the art should recognize in light of the present disclosure that many changes can be made to the specific embodiments disclosed herein and still obtain a like or similar result without departing from the spirit and scope of the disclosure. For example, the experimental Examples below provide in vitro methods for testing the compounds of the disclosure. Other in vitro and/or in vivo virus infection models include flaviviruses such as DNV, bovine diarrheal virus, WNV, and
GBV-C virus, other RNA viruses such as RSV, SARS, and the HCV replicon systems.
Furthermore, any appropriate cultured cell competent for viral replication can be utilized in the antiviral assays.
[0162] EXPERIMENTAL EXAMPLES
[0163] Example 1 . Synthesis of Compounds of the Disclosure
[0164] General synthetic scheme. The compounds of the disclosure may be prepared by the methods described below, together with synthetic methods familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or can be prepared by routine methods known in the art, such as for example those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-lnterscience). Preferred methods include those described below.
[0165] During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 , and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999.
[0166] Compounds of the disclosure, or their pharmaceutically acceptable salts, can be prepared according to the reaction schemes discussed below. These methods can be modified or adapted in ways known to chemists of ordinary skill in order to achieve synthesis of additional compounds within the scope of the present disclosure. Such modification was done to synthesize an exemplary compound of the disclosure as described in Examples 2 and 3. Unless otherwise indicated, the substituents in the schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.
[0167] It will be understood by one skilled in the art that the various symbols, superscripts, and subscripts used in the schemes, methods, and examples are used for convenience of representation and/or to reflect the order in which they are introduced in the schemes, and are not intended to necessarily correspond to the symbols, superscripts, or subscripts in the appended claims. The schemes are representative of methods useful in synthesizing the compounds of the present disclosure. They are not to constrain the scope of the disclosure in any way.
[0168] Example 2. Synthesis of Compound 9
[0169] One mmol each of aromatic alcohol (e.g. 8-quinolinol), aromatic amine 5- methoxy-1 ,3-benzothiazole-2-amine, and aromatic aldehyde (4- difluoromethoxybenzaldehyde) were mixed thoroughly as a solution/suspension in CH2CI2 (1 mL). The CH2CI2 was evaporated and the solid residue was heated at 60 °C for 12-18h. Reaction progress was monitored by removing an aliquot and analyzing by RP-HPLC on an analytical C18 chromatography column using a gradient elution of A) water (+0.05% TFA) and B) Acetonitrile (+0.05% TFA); the gradient was from 10-100% B over 10 min. Starting materials and authentic product standards were used to establish their retention times on the HPLC method and heating was stopped when >95% of the 8- quinolinol was consumed. The product was purified by silica gel column chromatography with a 1 :0 to 1 :1 gradient of CH2Cl2:ethyl acetate with subsequent solvent removal. Additional purification by recrystallization using ethyl acetate afforded products with >95% purity as judged by the UV254 signal on RPHPLC. Isolated yields of pure products were 20-30%.
[0170] Example 3. Synthesis of Compound 10
[0171] One mmol each of aromatic alcohol (e.g. 8-quinolinol), aromatic amine 4-methyl- 5-phenyl-1 ,3-thiazole-2-amine, and aromatic aldehyde (4-difluoromethoxybenzaldehyde) were mixed thoroughly as a solution/suspension in CH2CI2 (1 mL). The CH2CI2 was evaporated and the solid residue was heated at 60 °C for 12-18h. Reaction progress was monitored by removing an aliquot and analyzing by RP-HPLC on an analytical C18 chromatography column using a gradient elution of A) water (+0.05% TFA) and B) Acetonitrile (+0.05% TFA); the gradient was from 10-100% B over 10 min. Starting materials and authentic product standards were used to establish their retention times on the HPLC method and heating was stopped when >95% of the 8-quinolinol was consumed. The product was purified by silica gel column chromatography with a 1 :0 to 1 :1 gradient of Ch C !ethyl acetate with subsequent solvent removal. Additional purification by recrystallization using ethyl acetate afforded products with >95% purity as judged by the UV254 signal on RPHPLC. Isolated yields of pure products were 20-30%.
[0172] Example 4. In vitro antiviral activity of Compound 1 -Compound 1 1
[0173] Antiviral activity against influenza virus in vitro was measured for Compound 1 , Compound 9, and Compound 10. Cultured human 293 cells were seeded in 6-well tissue- culture plates at a density of 3x105 cells per well for the flu focus-forming assay and grown for 24 hours. Cells were infected with influenza virus A Udorn/72 H3N2 strain at MOI of 0.1 for 2 hours and then removed. Compound dilutions were prepared in 0.5% DMSO and used to treat cells at final concentrations of compound ranging 0.6 to 10 μΜ per well. Vehicle control wells contained 0.5% DMSO and were used to compare to drug treated cells. Replication was then allowed to proceed for 24 hours. Virus supernatants were then harvested and used to infect new monolayer of permissive MDCK cells that were seeded 24 hours prior in 96-well tissue-culture plates at density of 1 .5x104 cells per well. The newly infected cells were incubated overnight (18-24 hours) and used to measure the level of infectious virus in the original supernatants by immunofluorescent staining of viral protein. The cells were fixed with ice-cold 1 :1 methanol and acetone solution and stained for influenza nucleoprotein (NP). Primary mouse anti-NP monoclonal antibody (Chemicon) was used at 1 :3000 dilution. Secondary goat anti-mouse antibody conjugated to Alexa Fluor 488 dye (Invitrogen) and Hoescht Dye (nuclear staining) were used at 1 :3000 to detect RSV protein and cell nuclei. Following secondary antibody incubation, the monolayers were washed and left in 100μΙ_ PBS for imaging and quantitation using a Cellomics ArrayScan HCS instrument.
[0174] Figure 1 shows results from the influenza focus-forming assay. Decrease in foci is graphed as percent inhibition of viral infection by compound. Compound 1 and Compound 9 demonstrated dose-dependent decrease in viral infection of 293 cells. Compound 10 showed effective inhibition of viral infection of 293 cells.
[0175] Antiviral activity against DNV in vitro was measured for Compound 9, Compound 10, and other selected analog compounds. Cultured human Huh7 cells were seeded in 6-well tissue-culture plates at a density of 4x105 cells per well for the DNV focus-forming assay and grown for 24 hours. Cells were infected with one of the DNV type 2 or type 4 strain at MOI of 0.1 for 2 hours and then removed. Connpound dilutions were prepared in 0.5% DMSO and used to treat cells at final concentrations of connpound ranging 0.6 to 10 μΜ per well. Vehicle control wells contained 0.5% DMSO and were used to compare to drug treated cells. Replication was then allowed to proceed for 48 hours. Virus supernatants were then harvested and used to infect new monolayer of permissive Vera cells that were seeded 24 hours prior in 96-well tissue-culture plates at density of 8x103 cells per well. The newly infected cells were incubated for 24 hours and used to measure the level of infectious virus in the original supernatants by immunofluorescent staining of viral protein. The cells were fixed with ice-cold 1 :1 methanol and acetone solution and stained for DNV fusion protein. Primary mouse monoclonal antibody against DNV fusion protein (Millipore) was used at 1 :2000 dilution. Secondary goat anti-mouse antibody conjugated to Alexa Fluor 488 dye (Invitrogen) and Hoescht Dye (nuclear staining) were used at 1 :3000 to detect DNV protein and cell nuclei. Following secondary antibody incubation, the monolayers were washed and left in 100μΙ_ PBS for imaging and quantitation using a Cellomics ArrayScan HCS instrument.
[0176] Figures 2A and 2B show the antiviral activity of selected compounds against DNV. (A) All compounds tested (Compound 1 -Compound 1 1 ) showed effective inhibition of DNV serotype 2 when used at a concentration of at least 5μΜ. Compound 2, Compound 3, Compound 6, Compound 7, Compound 8, and Compound 10 showed dose-dependent decrease in viral infection. (B) Compound 1 -Compouond 1 1 showed effective inhibition of DNV serotype 4. The calculated EC50 and EC90 values are shown.
[0177] Example 5. In vivo bioavailability of Compound 1 and Compound 10
[0178] In a mouse PK study, 10 mg/kg Compound 1 and Compound 10 in 30% hydroxypropyl-betacyclodextrin (HPBCD) was administrated by an intraperitoneal route of administration. Blood samples were collected by retro-orbital sinus prior to dosing and at time points up to 4 hours post dosing. Spleen tissue was harvested at 4 hours and compound concentration in tissue was measured. Compound concentrations were measured according to a bioanalytical method developed specifically to each compound.
[0179] Figure. 3 shows Compound 1 and Compound 10 blood and spleen levels after dosing at 10mg/kg via intraperitoneal injection. Compound 1 levels in plasma are shown over time up to 4 hours post injection. Spleen level is shown at 4 hours post injection, when tissue was harvested. Both Compound 1 and Compound 10 were present in detectable amounts in both serum and spleen samples taken up to 4 hours post dosing of compound.
[0180] Example 6. Antiviral activity and pharmacological properties using Quantitative Structure-Activity Relationship (QSAR) studies
[0181] This Example describes analog compound design using QSAR approach of the compounds described herein for antiviral action. The QSAR studies are designed to provide lead compounds with picomolar to nanomolar potency. Optimization of the compounds focuses on creating structural diversity and evaluating core variants and group modifications. Structural derivatives are tested for antiviral activity against several viruses including the virus assay models described herein. Furthermore, derivatives are tested for cytotoxicity in one or more cell lines or peripheral blood mononuclear cells. Optimized molecules that show improved efficacy and low cytotoxicity are further characterized by additional measures of in vitro and in vivo toxicology and absorption, distribution, metabolism, and elimination (ADME). Their mechanism of action and breadth of antiviral activity are also studied.
[0182] Chemical design in QSAR studies. Analysis of drug-like properties, metabolic lability, and toxic potential is done in order to drive analog compound design. Drug-like properties, as measured by Lipinski's Rules (Lipinski, C. A., et al. (2001 ) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv Drug Deliv Rev 46, 3-26), and related physiochemical properties are primary indicators of bioavailability. Structural features that suggest metabolic and toxicological liabilities may indicate limited stability, reduced half-life, reactive intermediates, or idiosyncratic toxicity and will therefore be removed.
[0183] For each analog, a (high-performance liquid chromatography) HPLC- and/or HPLC-mass spectrometry-based analytical method is used to evaluate drug and metabolite concentrations in various test systems. Although the specific analytical method is optimized for each molecule, reverse-phase chromatography can be used alone or in combination with quadrupole mass spectrometry to characterize the identity and purity of several of the lead molecules. Initially, drug stability over time in increasing concentrations of serum, plasma, and whole blood from mammalian species (such as mouse, cynomolgus macaque, and human) will be evaluated by HPLC, and a half-life will be determined. In some instances, prominent metabolites are characterized by mass spectrometry.
[0184] Example 7. In vitro biological activity
[0185] Compounds described herein, including some of the compounds listed in Table 1 , are tested for biological activities including: activation of target pathways including immune response pathways, antiviral activity against a variety of viruses, low cytotoxicity, and a therapeutic index greater than 10.
[0186] Innate immune signaling pathway activation by compounds. One example of an assay to measure innate immune pathway activation is the measurement of downstream gene expression by RT-qPCR in cells treated with compound. In one example, the transcription factor IRF-3 is activated through RIG-I signaling and the increased expression of IRF-3 dependent genes indicate activation of the RIG-I innate immune antiviral response pathway. Other genes that are associated with the host innate immune antiviral response are also measured as indicators of compound activity.
[0187] Cultured human cells are treated with 0.001-10 μΜ of compound or a DMSO vehicle control and incubated for up to 24 hours. Cells are harvested at time points from 4-24 hours after treatment. RNA isolation, reverse transcription, and qPCR are performed using well known techniques. PCR reactions are performed using commercially available, validated TaqMan gene expression assays (Applied Biosystems/Life Technologies) according to manufacturer instructions. Gene expression levels are measured using a relative expression analysis (AACt).
[0188] Gene expression can be similarly assayed in cell types that include: primary blood mononuclear cells, human macrophages, THP-1 cells, Huh7 cells, A549 cells, MRC5 cells, rat splenocytes, rat thymocytes, mouse macrophages, mouse splenocytes, and mouse thymocytes. Expression of other genes of interest can be assayed as described herein. In addition, gene expression can be assayed in the presence of virus in order to determine compound activity in the context of active viral infection.
[0189] Innate immune response induction by compounds. The activity of compounds can be assayed in primary immune cells to determine whether compound treatment stimulates immune response pathways. One example is to assay cytokine expression in cultured human primary blood cells, for example dendritic cells. Cells are seeded in tissue culture dishes and treated with compound ranging 0.001-10 μΜ of compound. For assay of cytokine production, supernatants from treated wells are isolated 24-48 hours after compound treatment and tested for levels of cytokine protein. Cytokines are detected using specific antibodies conjugated to magnetic beads and a secondary antibody that reacts with Streptavidin/Phycoerythrin to produce a fluorescent signal. The bound beads are detected and quantified using the MAGPIX® (Luminex Corp.) instrument, although similar techniques as are known in the art may be used to measure fluorescent protein production, such as for example an ELISA.
[0190] Other cells from which cytokine secretion can be measured include, for example human peripheral blood mononuclear cells, human macrophages, mouse macrophages, mouse splenocytes, rat thymocytes, and rat splenocytes.
[0191] Cytotoxicity is evaluated using standard in vitro assays including MTS assay and caspase assay. Protocols to perform these assays are known to those skilled in the art and there are several commercially available kits to measure assay readout, such as a colorimetric based assay to measure conversion of MTS to formazan (Cell Titer One, Promega) and a sandwich ELISA based assay to measure levels of activated caspase-3 (PathScan® Cleaved Caspase-3 (Asp175) Sandwich ELISA Kit #7190, Cell Signaling). Cultured human cells are treated with increasing amounts of compound from 0 up to at least 50 μΜ or equivalent amounts of DMSO diluted in media to see their effect on cell viability. Cultured human cell lines that are used in this assay include Huh7, PH5CH8, A549, or HeLa cells.
[0192] In vitro pharmacology and toxicology. This description of toxicological assays is exemplary. In vitro studies are performed to measure performance of the most promising analogs in one or more assays of intestinal permeability, metabolic stability, and toxicity. These studies can include plasma protein binding; serum, plasma, and whole-blood stability in human and model organisms; intestinal permeability; intrinsic clearance; human Ether-a-go-go (hERG) channel inhibition to test potential cardiac toxicity; and genotoxicity using for example a reversion mutation assay (Ames test) and/or a micronucleus formation assay. Human plasma protein binding will be evaluated by partition analysis using equilibrium dialysis. For intestinal permeability modeling, apical- to-basolateral flux is assessed in a human epithelial cell line such as Caco-2 or TC7. Hepatic clearance is estimated for a subset of the most promising analogs by measuring the rate of disappearance of the parent compound during incubation in human liver microsomes. Specific metabolites may be isolated and characterized.
[0193] Example 8. Assays of Antiviral Activity Using In Vitro Models
[0194] The compounds disclosed herein have efficient activity against several viruses in vitro. To further characterize the breadth of antiviral activity of optimized molecules, cell culture infection models are used to analyze different viruses as well as different strains of the same virus. Assays to measure the antiviral activity of compounds against several of these viruses is described herein.
[0195] The studies include treating cells with compound 2-24 hours prior to infection and/or treating cells 2-24 hours after infection. Compound is administered at different concentrations ranging from 0.001 -10μΜ. Positive control treatments used include interferon, ribavirin, oseltamivir, or other known treatment to inhibit the infection of the specific virus. Virus production and cellular ISG expression are assessed over a time course to analyze antiviral activity of each compound. Virus production is measured by focus-forming or plaque assay.
[0196] An immunofluorescent based focus-forming assay is done in cultured human HeLa cells to measure antiviral activity against RSV. Cells are seeded in 6-well tissue- culture plates at a density of 4x105 cells per well for the RSV focus-forming assay and grown for 24 hours. Cells are infected with RSV A2 Long strain (ATCC VR-26) at MOI of 0.1 for 2 hours and then removed. Compound dilutions are prepared in 0.5% DMSO and used to treat cells at final concentrations of compound ranging 0.001 to 10 μΜ per well. Vehicle control wells contain 0.5% DMSO and are used to compare to drug treated cells. RSV infections after drug treatment are allowed to proceed for 48 hours. Virus supernatants are then harvested and used to infect new monolayer of HeLa cells seeded in 96-well tissue-culture plates at density of 8x103 cells per well. The newly infected cells are incubated overnight (18 - 24 hours) and used to measure the level of infectious virus in the original supernatants by immunofluorescent staining of viral protein. The cells are fixed with ice-cold 1 :1 methanol and acetone solution and stained for RSV F protein. Primary mouse anti-RSV monoclonal antibody (EMD Millipore) is used at 1 :2000 dilution. Secondary goat anti-mouse antibody conjugated to Alexa Fluor 488 dye (Invitrogen) and Hoescht Dye (nuclear staining) are used at 1 :3000 to detect RSV protein and cell nuclei. Following secondary antibody incubation, the monolayers are washed and left in 100μΙ_ PBS for imaging and quantitation using a Cellomics ArrayScan HCS instrument.
[0197] Antiviral activity against WNV, Nipah Virus, Lassa Fever Virus, and Ebola Virus in vitro is measured by focus-forming assay. Virus strains that are used in these assays include WNV-TX (WNV), WNV-MAD (WNV), NiV-Malaysia (Nipah), LASV-Josiah (Lassa Fever), and ZEBOV-Mayinga (Ebola). Cultured human cells including human umbilical vein cells (HUVEC) are seeded in tissue-culture plates and infected with virus at MOI of 0.01 to 0.5 for a duration including but not limited to 2 hours and then removed. Compound dilutions are prepared in 0.5% DMSO and used to treat cells at final concentrations of compound ranging 0.001 to 10 μΜ per well. Vehicle control wells contain 0.5% DMSO and are used to compare to drug treated cells. Virus infections after drug treatment are allowed to proceed for 48 to 96 hours. Virus supernatants are then harvested and used to infect new monolayer of permissive cells. The newly infected cells are incubated overnight (18-24 hours) and used to measure the level of infectious virus in the original supernatants by focus-forming assay using methods generally known in the art.
[0198] Antiviral activity against influenza virus in vitro is measured by immunofluorescent based focus-forming assay. Influenza A virus strains that are used in this assay include A Udorn/72 H3N2 strain and A/California/04/09 H1 N1 strain. Experimental conditions are as or substantially similar to those described in Example 4.
[0199] Antiviral activity against DNVs in vitro is measured by immunofluorescent based focus-forming assay. Experimental conditions are as or substantially similar to those described in Example 4.
[0200] In parallel experiments, viral RNA and cellular ISG expression are measured by qPCR and immunoblot analyses. These experiments are designed to validate compound signaling actions during virus infection, and assess compound actions to direct innate immune antiviral programs against various strains of viruses and in the setting of virus countermeasures. Detailed dose-response analyses of each compound are conducted in each virus infection system to determine the effective dose that suppresses virus production by 50% (IC50) and 90% (IC90) as compared with control cells for both the pre- treatment and post-treatment infection models.
[0201] Additional virus infection models that can be assayed by in vitro assays include but are not limited to SARS-like coronaviruses, human cytomegalovirus, Japanese Encephalitis Virus, hepatitis C virus, and hepatitis B virus. Experimental methods are substantially similar to those described herein.
[0202] Table 2 shows calculated EC50 values in μΜ of selected compounds.
Table 2.
Figure imgf000072_0001
ND = EC50 was not determined
[0203] Example 9. In vivo pharmacokinetic and toxicological profiles of selected compounds in preclinical animal models
[0204] Preclinical pharmacokinetic (PK) and tolerability profiling. The in vivo PK profile and tolerability/toxicity of optimized compounds are evaluated in order to conduct further characterization of their antiviral activity in animal models of virus infection. Mouse and rat are the chosen test species for these studies because there are several established virus models in the mouse and models of PK, toxicology, and immunology in the rat.
[0205] Reverse-phase, HPLC-MS/MS detection methods are used to detect and quantify the concentration of each compound in biological samples including plasma and target tissue samples. Prior to PK profiling, an initial oral and injectable formulation for each compound is developed using a limited formulation component screen that is largely focused on maximizing aqueous solubility and stability over a small number of storage conditions. Existing analytical methods known in the art are used to measure formulation performance. A formulation is developed for each compound following a three tiered strategy. Tier 1 : pH (pH 3 to 9), buffer, and osmolality adjustment; Tier 2: addition of ethanol (<10%), propylene glycol (<40%), or polyethylene glycol (PEG) 300 or 400 (<60%) co-solvents to enhance solubility; Tier 3: addition of N-N-dimethylacetamide (DMA, <30%), N-methyl-2-pyrrolidone (NMP, <20%), and/or dimethyl sulfoxide (DMSO, <20%) co-solvents or the cyclodextrins (<40%) as needed to further improve solubility.
[0206] In mouse PK studies, the following criteria are evaluated after compound has been administrated by at least 2 routes of administration including orally and i.v.: bioavailability at time points 0-24 hours and 0-∞, AUC0-24,0-∞; maximum concentration, Cmax; half-life t½; volume of distribution; and confidence interval CI . Each compound is administered as a single dose to animals by oral gavage (up to 10 mg/kg) or intravenous bolus injection (up to 5 mg/kg) after an overnight fast. Multiple animals are dosed for each dosing group such that 3 animals can be sampled at each time point. Blood samples are collected by retro-orbital sinus prior to dosing and at 5, 15, and 30 min, and 1 , 2, 4, 8, and 24 hours post dosing. Target tissues, including lung, liver, and lymph nodes, are also collected at the time point of final blood collection. Drug concentrations are measured according to the previously developed bioanalytical method specifically for the compound, as described in Example 5. PK parameters are evaluated using the WinNonlin software.
[0207] Based upon performance in PK studies, compounds are further evaluated for tolerability and toxicity in mice prior to their characterization in antiviral models. Tolerability studies are performed in two stages: an initial dose escalation stage that consists of ascending doses up to 5 doses, each separated by a 5-day washout period, to determine the maximum tolerable dose (MTD; Stage 1 ); this is followed by seven daily administrations of the MTD to evaluate acute toxicity (Stage 2). In the tolerability study, all doses are administered by oral gavage. In such an experiment, five animals of each sex are placed on-study in stage 1 and 15 animals per sex per dosing group in Stage 2. Study endpoints include a determination of the MTD, examination for acute toxicity, physical examination, clinical observations, hematology, serum chemistry, and animal bodyweights. Gross pathology is performed on all animals whether found dead, euthanized in extremis, or at the intended conclusion of the experiment. The toxicology studies are intended to identify early toxicological endpoints, and drive selection of lead candidates for antiviral animal models.
[0208] Example 10. In vivo antiviral properties of selected compounds in preclinical animal models.
[0209] This Example describes the evaluation of antiviral properties and immune protection using mouse infection models. Selected compounds show favorable PK, antiviral, and innate immune activity and can be further evaluated in preclinical mouse models of infection. Innate immune actions of the compounds are measured, and their ability to protect mice from WNV and influenza virus challenge is assessed. For the WNV infection model, subcutaneous footpad infection of wild-type C57BI/6 mice with the virulent lineage 1 strain of WNV (WNV-TX) are performed (Suthar, M. S., et al. (2010) IPS-1 is essential for the control of WNV infection and immunity, PLoS Pathog 6, e1000757). Non-surgical tracheal instillation is performed for influenza virus strains A/PR/8/34, A/WSN/33, and A/Udorn/72.
[0210] The influenza virus strains in these experiments include at least two different subtypes (for example, H1 N1 and H3N2) and exhibit varying pathogenic properties and clinical presentations in C57BI/6 mice (Barnard, D. L. (2009) Animal models for the study of influenza pathogenesis and therapy, Antiviral Res 82, A1 10-122). Mice are monitored for morbidity and mortality over a range of challenge doses (such as, 10 to 1 ,000 pfu of virus) either alone or in combination with compound treatment beginning up to 24 hours before or up to 24 hours after infection and continuing daily subject to the determined plasma half-life of the drug. Compound dose-response analysis and infection time course studies are conducted to evaluate compound efficacy to: 1 ) limit serum viral load; 2) limit virus replication and spread in target organs; and 3) protect against viral pathogenesis.
[0211] For WNV, in addition to serum, viral burden is assessed in lymph nodes, spleen, and brain; for influenza virus, viral burden is assessed in heart, lung, kidney, liver, and brain. Incorporated in the design of these experiments is the determination of an effective dose for 50% and 90% suppression of serum viral load (ED50 and ED90) by each compound after a standard challenge of 100 pfu of WNV-TX or 1 ,000 pfu of influenza virus. Serum viral loads are determined by qPCR of viral RNA at 24 hour intervals following compound treatment. The compound actions are tested at the ED50 and ED90 toward limiting WNV pathogenesis in the cerebral nervous system using a WNV neuroinvasion model of infection (Daffis, S., et al. (2008) Toll-like receptor 3 has a protective role against West Nile virus infection, J Virol 82, 10349-10358). Mice are monitored for morbidity and mortality after standard intracranial challenge of 1 pfu of WNV-MAD, either alone or in combination with compound treatment beginning 24 hours after infection.
[0212] For these and other in vivo virus infection models, the drug can be administered via routes including oral, nasal, mucosal, intravenous, intraperitoneal, subcutaneous, or intramuscular. Other in vivo virus infection models that can used to evaluate compound antiviral activity include SARS, DNV, MCMV, or EMCV.
[0213] Example 10. Antiviral activity of Compound 9.
[0214] The table below shows that Compound 9 exhibited potent broad spectrum antiviral activity against influenza according to techniques described previously herein, specifically FLU A (strain A/Udorn/72); RSV (strain A2); DENV-2 (strain NGC); DENV-4 (strain H241 ); EBOV (strain Zaire); NiV (strain Malaysia); and LASV (strain Josiah).
Figure imgf000075_0001
[0215] As will be understood by one of ordinary skill in the art, each embodiment disclosed herein can comprise, consist essentially of or consist of its particular stated element, step, ingredient or component. Thus, the terms "include" or "including" should be interpreted to recite: "comprise, consist of, or consist essentially of." The transition term "comprise" or "comprises" means includes, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts. The transitional phrase "consisting of excludes any element, step, ingredient or component not specified. The transition phrase "consisting essentially of limits the scope of the embodiment to the specified elements, steps, ingredients or components and to those that do not materially affect the embodiment. As used herein, a material effect would cause a statistically significant reduction in a disclosed compound's or pharmaceutical composition's ability to treat a viral infection in a subject; reduce viral protein in a subject or assay; reduce viral RNA in a subject or assay or reduce virus in a cell culture.
[0216] Unless otherwise indicated, all numbers used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. When further clarity is required, the term "about" has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±1 1 % of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1 % of the stated value.
[0217] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0218] The terms "a," "an," "the" and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0219] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
[0220] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the embodiments of the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the embodiments of the invention to be practiced otherwise than specifically described herein. Accordingly, the embodiments of the invention include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the embodiments of the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
[0221] Furthermore, numerous references have been made to publications, patents and/or patent applications (collectively "references") throughout this specification. Each of the cited references is individually incorporated herein by reference for their particular cited teachings.
[0222] The particulars shown herein are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of various embodiments of the invention. In this regard, no attempt is made to show structural details of the embodiments of the invention in more detail than is necessary for the fundamental understanding of the invention, the description taken with the drawings and/or examples making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.
[0223] Definitions and explanations used in the present disclosure are meant and intended to be controlling in any future construction unless clearly and unambiguously modified in the examples or when application of the meaning renders any construction meaningless or essentially meaningless. In cases where the construction of the term would render it meaningless or essentially meaningless, the definition should be taken from Webster's Dictionary, 3rd Edition or a dictionary known to those of ordinary skill in the art, such as the Oxford Dictionary of Biochemistry and Molecular Biology (Ed. Anthony Smith, Oxford University Press, Oxford, 2004).
[0224] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

A compound having a structure
Figure imgf000079_0001
wherein
W is CRa or N;
X is O, S, C=O, CRaRb, or NRa;
at least one group selected from Y1, Y2, Y3, or Y4 includes N or NRa;
at least another group selected from Y1, Y2, Y3, or Y4 includes CRa or CRaRb;
Ra and Rb are each independently H, optionally substituted alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl;
R1 , R2, R3, and R4 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb,
NO2, S(O)nRa, or S(O)nNRaRb;
m is an integer from 1 through 7;
n is 0, 1 , or 2; and
the dashed lines represent the presence or absence of a double bond.
2. The com ound of claim 1 having a structure
Figure imgf000079_0002
wherein
R5 is Ra, ORa, OCHF2, OCFs, CFs, F, or CI; and
o is an integer from 1 through 7.
3. The compound of claim 1 having a structure
Figure imgf000080_0001
wherein
Z1 and Z2 are each independently N, NRa, S, O, CRa, or CRaRb;
R6 and R7 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb, or R6 and R7 are fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring.
4. The compound of any one of claims 1 -3, having a structure
Figure imgf000081_0001
wherein
Z1 and Z2 are each independently N, NRa, S, O, CRa, or CRaRb;
R5 is Ra, ORa, OCHF2, OCFs, CFs, F, or CI;
R6 and R7 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb, or R6 and R7 are fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring; and
o is an integer from 1 through 7.
5. The com ound of any one of claims 1 -4, having a structure
Figure imgf000081_0002
wherein R5 is Ra, ORa, OCHF2, OCFs, CFs, F, or CI;
R8 is Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; and o and t are each independently an integer from 1 through 7.
6. The compound of any one of claims 1 -5, wherein R3 is OH.
7. The compound of any one of claims 1 -6, wherein Y1, Y2, and Y3 are CH and Y4 is N.
8. The compound of any one of claims 1 -7, wherein W is CH and X is NH.
9. The compound of any one of claims 1 -8 having a structure
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000083_0003
Figure imgf000083_0004
82
Figure imgf000084_0001
Figure imgf000084_0002
Figure imgf000084_0003
83
Figure imgf000085_0001
Figure imgf000085_0002
Figure imgf000085_0003
84
Figure imgf000086_0001
Figure imgf000086_0002
85
Figure imgf000087_0001
Figure imgf000087_0002
86
Figure imgf000088_0001
10. The compound of claim 1 having a structure
Figure imgf000088_0002
wherein Z1 and Z2 can each independently be S or N, Z3 and Z4 can each independently be S or O, R13 and R14 can each independently be Ra, r and q can be 0, 1 , 2, 3, 4, or 5, and the dashed lines can indicate the presence or absence of a double bond.
1 1 . The compound of claim 10, wherein r=0 and R13 is a phenyl group.
12. A com ound having a structure
Figure imgf000089_0001
wherein
R1 is Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, or S(O)nNRaRb; Ra and Rb are each independently H, optionally substituted alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl;
R6 and R7 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb, or R6 and R7 are fused to form an optionally substituted heterocyclic ring, an optionally substituted heteroaryl ring, an optionally substituted aryl ring, or an optionally substituted cycloalkyl ring; and
n is 0, 1 , or 2.
13. The compound of claim 12, wherein at least one of R6 or R7 are an optionally substituted aryl ring.
14. The com ound of claim 12, having a structure
Figure imgf000089_0002
wherein R9 is Ra.
5. The compound of claim 12, having a structure
Figure imgf000090_0001
wherein R10 is Ra, CHF2, or CFs.
16. A compound having a structure
Figure imgf000090_0002
wherein
at least one group selected from Y1, Y2, Y3, or Y4 includes N or NRa;
at least another group selected from Y1, Y2, Y3, or Y4 includes CRa or CRaRb;
Ra and Rb are each independently H, optionally substituted alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, alkylsulfoxide, or alkylsulfonyl;
R3, R4, R11 , and R12 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN,
NRaRb, NO2, S(O)nRa, or S(O)nNRaRb;
Figure imgf000090_0003
m is an integer from 1 through 7;
n is 0, 1 , or 2;
u is 0 or 1 ;
v is 0, 1 , or 2; w is 1 , 2, or 3; and
the dashed lines represent the presence or absence of a double bond.
17. A compound having a structure
Figure imgf000091_0001
wherein
R17 and R18 are each independently Ra, ORa, CORa, CO2Ra, CONRaRb, CN, NRaRb, NO2, S(O)nRa, S(O)nNRaRb;
Ra is H, optionally substituted lower alkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyi, alkylamino, alkylcarbonyl, aklylsulfoxide, or alkylsulfony; and
n is 0, 1 , or 2.
18. The composition of claim 17 having the structure
Figure imgf000092_0001
19. A pharmaceutical composition comprising a compound of any one of claims 1 to 18.
20. A pharmaceutical composition of claim 19, for use in therapy.
21 . A method of treating a viral infection in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 20 thereby treating the viral infection in the subject.
22. A method of treating a viral infection in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 19 thereby treating the viral infection in the subject wherein the viral infection is caused by at least one of influenza; RSV; Dengue; Ebola; West Nile Virus; and LASV.
23. The method of claim 22 wherein said viral infection is caused by Ebola virus.
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