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Publication numberUS20080096928 A9
Publication typeApplication
Application numberUS 11/180,961
Publication dateApr 24, 2008
Filing dateJul 14, 2005
Priority dateJul 14, 2004
Also published asCA2573185A1, EP1771169A1, US8013006, US20060223863, US20120009142, WO2006019831A1
Publication number11180961, 180961, US 2008/0096928 A9, US 2008/096928 A9, US 20080096928 A9, US 20080096928A9, US 2008096928 A9, US 2008096928A9, US-A9-20080096928, US-A9-2008096928, US2008/0096928A9, US2008/096928A9, US20080096928 A9, US20080096928A9, US2008096928 A9, US2008096928A9
InventorsGary Karp, Peter Hwang, James Takasugi, Hongyu Ren, Richard Wilde, Anthony Turpoff, Alexander Arefolov, Guangming Chen, Jeffrey Campbell
Original AssigneeKarp Gary M, Hwang Peter S, James Takasugi, Hongyu Ren, Wilde Richard G, Anthony Turpoff, Alexander Arefolov, Guangming Chen, Campbell Jeffrey A
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Indole compounds that modify translational control of Hepatitis C virus
US 20080096928 A9
Abstract
In accordance with the present invention, compounds that inhibit viral replication, preferably Hepatitis C Virus (HCV) replication, have been identified, and methods for their use provided. In one aspect of the invention, compounds useful in the treatment or prevention of a viral infection are provided. In another aspect of the invention, compounds useful in the treatment or prevention of HCV infection are provided.
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Claims(41)
1. A pharmaceutical composition for the prevention or treatment of Hepatitis C viral (HCV) infection comprising a therapeutically effective amount of at least one compound having the following formula:
wherein:
X is:
hydrogen;
a nitro group;
a cyano group;
a —CORa group, where Ra is:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
a dialkyl-amino;
a —COORx group, where Rx is a C1 to C6 alkyl;
a formyl group;
a C6 to C8 aryl optionally substituted with an alkoxy; or
a 5 or 6-membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
a 5 to 6 membered heteroaryl;
Y is:
a hydrogen;
a haloalkyl;
a halogen;
an amino optionally substituted with one or more C1 to C6 alkyls;
a benzofuran;
a benzothiophene;
a dibenzofuran;
a dibenzothiophene;
a benzothiazole;
a naphthalene;
an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
a —NHCORe group, where Re is:
a C1 to C6 alkyl;
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
an alkoxy,
a cyano group,
a nitro group, or
a halogen;
a —NHCOORx group, where Rx is as defined above;
a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
a C1 to C6 alkyl;
a 5 or 6 membered heteroaryl, optionally substituted with:
a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
an amino group;
a 5 or 6 membered heterocycle optionally substituted with:
a —COORx group, where Rx is as defined above, or
a —NHCOORx group, where Rx is as defined above;
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy, optionally substituted with:
an alkoxy,
a hydroxy,
one or more halogens,
a 5 or 6 membered heterocycle, optionally substituted with:
a C1 to C6 alkyl, or
a hydroxy,
an amino group optionally substituted with one or more C1 to C6 alkyls,
a —NRiSO2Rx group, where Rx is as defined above and Ri is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRjCORk group, where Rk is:
a C1 to C6 alkyl,
a hydrogen, or
an amino optionally substituted with one or more C1 to C6 alkyls,
and Rj is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —N═N+═N group, or
a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
an amino optionally substituted with one or more C1 to C6 alkyls,
a nitro group,
a C1 to C6 alkyl group, optionally substituted with:
a —NHSO2Rx group, where Rx is as defined above, or
a —NRxSO2Rx group, where Rx is as defined above,
a haloalkoxy,
a halogen,
a hydroxy,
a —COORx group, where Rx is as defined above,
a —CORm group, where Rm is:
an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
a hydroxy
a 5 or 6 membered heterocycle,
an amino optionally substituted with one or more C1 to C6 alkyls,
an alkoxy,
a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
a —NHRn group, where Rn is:
a —CH2CONH2, or
a C6 to C8 aryl optionally substituted with:
 an alkyl,
 one or more halogens,
 a nitro group, or
 one or more alkoxys,
a —NRoCORp group, where Rp is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
an alkoxy, or
a C6 to C8 aryl,
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with a halogen,
a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
a hydrogen,
and where Ro is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRqCONRqRr group, where Rq is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
and where Rr is:
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
a haloalkyl,
a —ORs group, where Rs is a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a C1 to C6 alkyl optionally substituted with one or more of the following:
a halogen,
an alkylene,
a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a —COORx group, where Rx is as defined above,
a —NRtCOORu group, where Ru is:
a C1 to C12 alkyl, optionally substituted with:
a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
an alkylene,
an alkoxy,
an alkyne,
a halogen, or
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with:
an alkoxy,
a halogen, or
a C1 to C6 alkyl, or
a 5 or 6 membered heterocycle,
and Rt is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRvSO2Rw group, where Rv is:
a hydrogen,
a —CORx, where Rx is as defined above, or
a C1 to C6 alkyl, optionally substituted with:
a halogen,
a —CORx group, where Rx is as defined above,
a —OCORx group, where Rx is as defined above,
a hydroxyl,
a hydroxyl, or
an alkoxy,
and where Rw is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
a haloalkyl,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle,
a C2 to C6 alkylene,
an alkyl- or dialkyl-amino optionally substituted with a halogen,
a 5 or 6 membered heterocycle, or
a 5 or 6 membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a 5 or 6 membered heterocycle, or
 optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
 where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a —SRx group, where Rx is as defined above,
a —SO2Raa group, where Raa is:
a C1 to C6 alkyl,
an amino group,
an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, or
a —NHRbb group, where Rbb is:
a —C(═S)NH2 group, or
a —PO(ORx)2, where Rx is as defined above;
 group, where Rcc is:
a naphthalene,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy,
an hydroxy,
a halogen,
a C1 to C6 alkyl, optionally substituted with a cyano group,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NHPORxRx, where Rx is as defined above,
a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
a hydrogen,
a haloalkyl,
a haloalkoxy,
a C1 to C6 alkyl, or
a —CORx, where Rx is as defined above,
a —NRggCORhh group, where Rhh is:
a hydrogen,
a C1 to C6 alkyl optionally substituted with:
 an alkoxy,
 a halogen, or
 an amino optionally substituted with one or more C1 to C6 alkyls,
an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
a 5 or 6 membered heterocycle,
a 5 or 6 membered heteroaryl,
and Rgg is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
a haloalkyl,
5 or 6 membered heterocycle groups,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy,
a —CORx group, where Rx is as defined above;
Z is:
a hydrogen;
a C1 to C6 alkyl optionally substituted with:
an alkoxy,
one or more halogens, or
a C6 to C8 aryl;
a C2 to C6 alkylene;
a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
a —COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
R1 is:
a hydrogen;
a hydroxy;
a halogen;
a haloalkyl;
a nitro group;
a 5 or 6 membered heteroaryl;
a 5 or 6 membered heterocycle;
an alkoxy optionally substituted with:
one or more halogens,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle;
a C6 to C8 aryl optionally substituted with an alkoxy;
a —CORx group, where Rx is as defined above;
a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
R1 joins together with R2 to form:
R2 is:
a nitro group;
a hydrogen;
a halogen;
a hydroxy group;
a C1 to C6 alkyl group, optionally substituted with one or more halogens;
an amino group;
an alkoxy group optionally substituted with:
one or more halogens,
an —OCORx group, where Rx is as defined above,
a dialkyl-amino optionally substituted with an alkoxy,
a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
a 5 or 6 membered heteroaryl group, or
a C6 to C8 aryl group;
a —COORx group, where Rx is as defined above;
a haloalkyl;
an amide group optionally substituted with:
a hydroxy group, or
a C6 to C8 aryl;
a 5 or 6 membered heteroaryl;
a —OCORx group, where Rx is as defined above;
a —NHCORjj group, where Rjj is:
an alkoxy, or
an amino optionally substituted with one or more C1 to C6 alkyls;
a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
a —NHSO2Rx group, where Rx is as defined above; or
R2 joins together with R1 to form:
R3 is:
a hydrogen; or
CH2OCORx, and Rx is as defined above;
or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient, and optionally one or more additional anti-HCV agent.
2. The pharmaceutical composition of claim 1, wherein said one or more additional anti-HCV agent is selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a helicase inhibitor, a glycosidase inhibitor, a Toll-like receptor agonist and combinations thereof.
3. The pharmaceutical composition of claim 1, wherein X is selected from the group consisting of -hydrogen; -a cyano group; and -a —CORa group, where Ra is: -a C1 to C6 alkyl, or -a dialkyl-amino.
4. The pharmaceutical composition of claim 3, wherein X is selected from the group consisting of cyano and a —CORa group, where Ra is -a dialkyl-amino.
5. The pharmaceutical composition of claim 4, wherein X is cyano.
6. The pharmaceutical composition of claim 1, wherein Y is selected from the group consisting of the following compounds:
7. The pharmaceutical composition of claim 1, wherein Y is selected from the group consisting of the following compounds:
8. The pharmaceutical composition of claim 1, wherein Z is selected from the group consisting of -a hydrogen; -a C1 to C6 alkyl optionally substituted with: -an alkoxy, -one or more halogens, or -a C6 to C8 aryl; -a C2 to C6 alkylene; and -a C6 to C8 aryl optionally substituted with an alkoxy.
9. The pharmaceutical composition of claim 1, wherein Z is selected from the group consisting of a hydrogen; -a C1 to C6 alkyl optionally substituted with: -a C6 to C8 aryl; -a C2 to C6 alkylene; and -a C6 to C8 aryl optionally substituted with an alkoxy.
10. The pharmaceutical composition of claim 1, wherein R is a hydrogen.
11. The pharmaceutical composition of claim 1, wherein R1 is selected from the group consisting of -a hydrogen; -a halogen; -a nitro group; -a 5 or 6 membered heterocycle; -an alkoxy optionally substituted with: -a C6 to C8 aryl; -a C6 to C8 aryl optionally substituted with an alkoxy.
12. The pharmaceutical composition of claim 1, wherein R2 is selected from the group consisting of -a nitro group; -a hydrogen; -a halogen; -a hydroxy group; -a C1 to C6 alkyl group, optionally substituted with one or more halogens; -an alkoxy group optionally substituted with: -one or more halogens, -an —OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, or -a 5 or 6 membered heteroaryl group; -an amide group; and -a —NHSO2Rx group, where Rx is as defined above.
13. The pharmaceutical composition of claim 1, wherein R2 is selected from the group consisting of -a hydrogen; -a C1 to C6 alkyl group, optionally substituted with one or more halogens; -an alkoxy group optionally substituted with: -one or more halogens, -a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, or -a 5 or 6 membered heteroaryl group.
14. The pharmaceutical composition of claim 1, wherein R3 is a hydrogen.
15. A pharmaceutical composition for the treatment of Hepatitis C viral (HCV) infection comprising a therapeutically effective amount of one or more of the following compounds:
or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
16. The pharmaceutical composition of claim 15, wherein said composition further comprises an additional anti-HCV agent selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a helicase inhibitor, a glycosidase inhibitor, a Toll-like receptor agonist and combinations thereof.
17. A method for treating a subject for a Hepatitis C viral (HCV) infection comprising administering to said subject a pharmaceutical composition comprising an HCV inhibitory amount of one or more compound having the following formula:
wherein:
X is:
hydrogen;
a nitro group;
a cyano group;
a —CORa group, where Ra is:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
a dialkyl-amino;
a —COORx group, where Rx is a C1 to C6 alkyl;
a formyl group;
a C6 to C8 aryl optionally substituted with an alkoxy; or
a 5 or 6-membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
a 5 to 6 membered heteroaryl;
Y is:
a hydrogen;
a haloalkyl;
a halogen;
an amino optionally substituted with one or more C1 to C6 alkyls;
a benzofuran;
a benzothiophene;
a dibenzofuran;
a dibenzothiophene;
a benzothiazole;
a naphthalene;
an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
a —NHCORe group, where Re is:
a C1 to C6 alkyl;
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
an alkoxy,
a cyano group,
a nitro group, or
a halogen;
a —NHCOORx group, where Rx is as defined above;
a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
a C1 to C6 alkyl;
a 5 or 6 membered heteroaryl, optionally substituted with:
a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
an amino group;
a 5 or 6 membered heterocycle optionally substituted with:
a —COORx group, where Rx is as defined above, or
a —NHCOORx group, where Rx is as defined above;
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy, optionally substituted with:
an alkoxy,
a hydroxy,
one or more halogens,
a 5 or 6 membered heterocycle, optionally substituted with:
a C1 to C6 alkyl, or
a hydroxy,
an amino group optionally substituted with one or more C1 to C6 alkyls,
a —NRiSO2Rx group, where Rx is as defined above and Ri is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRjCORk group, where Rk is:
a C1 to C6 alkyl,
a hydrogen, or
an amino optionally substituted with one or more C1 to C6 alkyls,
and Rj is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —N═N+═N group, or
a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
an amino optionally substituted with one or more C1 to C6 alkyls,
a nitro group,
a C1 to C6 alkyl group, optionally substituted with:
a —NHSO2Rx group, where Rx is as defined above, or
a —NRxSO2Rx group, where Rx is as defined above,
a haloalkoxy,
a halogen,
a hydroxy,
a —COORx group, where Rx is as defined above,
a —CORm group, where Rm is:
an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
a hydroxy
a 5 or 6 membered heterocycle,
an amino optionally substituted with one or more C1 to C6 alkyls,
an alkoxy,
a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
a —NHRn group, where Rn is:
a —CH2CONH2, or
a C6 to C8 aryl optionally substituted with:
 an alkyl,
 one or more halogens,
 a nitro group, or
 one or more alkoxys,
a —NRoCORp group, where Rp is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
an alkoxy, or
a C6 to C8 aryl,
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with a halogen,
a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
a hydrogen,
and where Ro is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRqCONRqRr group, where Rq is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
and where Rr is:
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
a haloalkyl,
a —ORs group, where Rs is a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a C1 to C6 alkyl optionally substituted with one or more of the following:
a halogen,
an alkylene,
a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a —COORx group, where Rx is as defined above,
a —NRtCOORu group, where Ru is:
a C1 to C12 alkyl, optionally substituted with:
a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
an alkylene,
an alkoxy,
an alkyne,
a halogen, or
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with:
an alkoxy,
a halogen, or
a C1 to C6 alkyl, or
a 5 or 6 membered heterocycle,
and Rt is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRvSO2Rw group, where Rv is:
a hydrogen,
a —CORx, where Rx is as defined above, or
a C1 to C6 alkyl, optionally substituted with:
a halogen,
a —CORx group, where Rx is as defined above,
a —OCORx group, where Rx is as defined above,
a hydroxyl,
a hydroxyl, or
an alkoxy,
and where Rw is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
a haloalkyl,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle,
a C2 to C6 alkylene,
an alkyl- or dialkyl-amino optionally substituted with a halogen,
a 5 or 6 membered heterocycle, or
a 5 or 6 membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a 5 or 6 membered heterocycle, or
 optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
 where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a —SRx group, where Rx is as defined above,
a —SO2Raa group, where Raa is:
a C1 to C6 alkyl,
an amino group,
an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, or
a —NHRbb group, where Rbb is:
a —C(═S)NH2 group, or
a —PO(ORx)2, where Rx is as defined above;
 group, where Rcc is:
a naphthalene,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy,
an hydroxy,
a halogen,
a C1 to C6 alkyl, optionally substituted with a cyano group,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NHPORxRx, where Rx is as defined above,
a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
a hydrogen,
a haloalkyl,
a haloalkoxy,
a C1 to C6 alkyl, or
a —CORx, where Rx is as defined above,
a —NRggCORhh group, where Rhh is:
a hydrogen,
a C1 to C6 alkyl optionally substituted with:
 an alkoxy,
 a halogen, or
 an amino optionally substituted with one or more C1 to C6 alkyls,
an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
a 5 or 6 membered heterocycle,
a 5 or 6 membered heteroaryl,
and Rgg is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
a haloalkyl,
5 or 6 membered heterocycle groups,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy,
a —CORx group, where Rx is as defined above;
Z is:
a hydrogen;
a C1 to C6 alkyl optionally substituted with:
an alkoxy,
one or more halogens, or
a C6 to C8 aryl;
a C2 to C6 alkylene;
a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
a —COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
R1 is:
a hydrogen;
a hydroxy;
a halogen;
a haloalkyl;
a nitro group;
a 5 or 6 membered heteroaryl;
a 5 or 6 membered heterocycle;
an alkoxy optionally substituted with:
one or more halogens,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle;
a C6 to C8 aryl optionally substituted with an alkoxy;
a —CORx group, where Rx is as defined above;
a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
R1 joins together with R2 to form:
R2 is:
a nitro group;
a hydrogen;
a halogen;
a hydroxy group;
a C1 to C6 alkyl group, optionally substituted with one or more halogens;
an amino group;
an alkoxy group optionally substituted with:
one or more halogens,
an —OCORx group, where Rx is as defined above,
a dialkyl-amino optionally substituted with an alkoxy,
a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
a 5 or 6 membered heteroaryl group, or
a C6 to C8 aryl group;
a —COORx group, where Rx is as defined above;
a haloalkyl;
an amide group optionally substituted with:
a hydroxy group, or
a C6 to C8 aryl;
a 5 or 6 membered heteroaryl;
a —OCORx group, where Rx is as defined above;
a —NHCORjj group, where Rjj is:
an alkoxy, or
an amino optionally substituted with one or more C1 to C6 alkyls;
a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
a —NHSO2Rx group, where Rx is as defined above; or
R2 joins together with R1 to form:
R3 is:
a hydrogen; or
CH2OCORx, and Rx is as defined above;
and/or a pharmaceutically acceptable salt thereof, together with a a pharmaceutically acceptable excipient.
18. The method of claim 17, wherein said method further comprises administering one or more additional anti-HCV agent.
19. The method of claim 18, wherein said one or more additional anti-HCV agent is selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a helicase inhibitor, a glycosidase inhibitor, a Toll-like receptor agonist and combinations thereof.
20. The method of claim 17, wherein X is selected from the group consisting of -hydrogen; -a cyano group; and -a —CORa group, where Ra is: -a C1 to C6 alkyl, or -a dialkyl-amino.
21. The method of claim 17, wherein X is selected from the group consisting of cyano and a —CORa group, where Ra is -a dialkyl-amino.
22. The method of claim 17, wherein X is cyano.
23. The method of claim 17, wherein Y is selected from the group consisting of the following compounds:
24. The method of claim 17, wherein Y is selected from the group consisting of the following compounds:
25. The method of claim 17, wherein Z is selected from the group consisting of -a hydrogen; -a C1 to C6 alkyl optionally substituted with: -an alkoxy, -one or more halogens, or -a C6 to C8 aryl; -a C2 to C6 alkylene; and -a C6 to C8 aryl optionally substituted with an alkoxy.
26. The method of claim 17, wherein Z is selected from the group consisting of -a hydrogen; -a C1 to C6 alkyl optionally substituted with: -a C6 to C8 aryl; -a C2 to C6 alkylene; and -a C6 to C8 aryl optionally substituted with an alkoxy.
27. The method of claim 17, wherein R is a hydrogen.
28. The method of claim 17, wherein R1 is selected from the group consisting of -a hydrogen; -a halogen; -a nitro group; -a 5 or 6 membered heterocycle; -an alkoxy optionally substituted with: -a C6 to C8 aryl; -a C6 to C8 aryl optionally substituted with an alkoxy.
29. The method of claim 17, wherein R2 is selected from the group consisting of -a nitro group; -a hydrogen; -a halogen; -a hydroxy group; -a C1 to C6 alkyl group, optionally substituted with one or more halogens; -an alkoxy group optionally substituted with: -one or more halogens, -an —OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, or -a 5 or 6 membered heteroaryl group; -an amide group; and -a —NHSO2Rx group, where Rx is as defined above.
30. The method of claim 17, wherein R2 is selected from the group consisting of -a hydrogen; -a C1 to C6 alkyl group, optionally substituted with one or more halogens; -an alkoxy group optionally substituted with: -one or more halogens, -a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, or -a 5 or 6 membered heteroaryl group.
31. The method of claim 17, wherein R3 is a hydrogen.
32. The method of claim 17, wherein said compound is selected from the following compounds:
34. A method for treating or preventing infection by a virus in a subject, wherein said virus comprises a internal ribosome entry site (IRES), comprising administering to said subject a pharmaceutical composition comprising a viral inhibitory amount of one or more compound having the following formula:
wherein
X is:
hydrogen;
a nitro group;
a cyano group;
a —CORa group, where Ra is:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
a dialkyl-amino;
a —COORx group, where Rx is a C1 to C6 alkyl;
a formyl group
a C6 to C8 aryl optionally substituted with an alkoxy; or
a 5 or 6-membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
a 5 to 6 membered heteroaryl;
Y is:
a hydrogen;
a haloalkyl;
a halogen;
an amino optionally substituted with one or more C1 to C6 alkyls;
a benzofuran;
a benzothiophene;
a dibenzofuran;
a dibenzothiophene;
a benzothiazole;
a naphthalene;
an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
a —NHCORe group, where Re is:
a C1 to C6 alkyl;
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
an alkoxy,
a cyano group,
a nitro group, or
a halogen;
a —NHCOORx group, where Rx is as defined above;
a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
a C1 to C6 alky;
a 5 or 6 membered heteroaryl, optionally substituted with:
a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
an amino group;
a 5 or 6 membered heterocycle optionally substituted with:
a —COORx group, where Rx is as defined above, or
a —NHCOORx group, where Rx is as defined above;
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy, optionally substituted with:
an alkoxy,
a hydroxy,
one or more halogens,
a 5 or 6 membered heterocycle, optionally substituted with:
a C1 to C6 alkyl, or
a hydroxy,
an amino group optionally substituted with one or more C1 to C6 alkyls,
a —NRiSO2Rx group, where Rx is as defined above and Ri is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRjCORk group, where Rk is:
a C1 to C6 alkyl,
a hydrogen, or
an amino optionally substituted with one or more C1 to C6 alkyls,
and Rj is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —N═N+═N group, or
a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
an amino optionally substituted with one or more C1 to C6 alkyls,
a nitro group,
a C1 to C6 alkyl group, optionally substituted with:
a —NHSO2Rx group, where Rx is as defined above, or
a —NRxSO2Rx group, where Rx is as defined above,
a haloalkoxy,
a halogen,
a hydroxy,
a —COORx group, where Rx is as defined above,
a —CORm group, where Rm is:
an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
a hydroxy
a 5 or 6 membered heterocycle,
an amino optionally substituted with one or more C1 to C6 alkyls,
an alkoxy,
a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
a —NHRn group, where Rn is:
a —CH2CONH2, or
a C6 to C8 aryl optionally substituted with:
 an alkyl,
 one or more halogens,
 a nitro group, or
 one or more alkoxys,
a —NRoCORp group, where Rp is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
an alkoxy, or
a C6 to C8 aryl,
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with a halogen,
a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
a hydrogen,
and where Ro is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRqCONRqRr group, where Rq is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
and where Rr is:
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
a haloalkyl,
a —ORs group, where Rs is a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a C1 to C6 alkyl optionally substituted with one or more of the following:
a halogen,
an alkylene,
a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a —COORx group, where Rx is as defined above,
a —NRtCOORu group, where Ru is:
a C1 to C12 alkyl, optionally substituted with:
a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
an alkylene,
an alkoxy,
an alkyne,
a halogen, or
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with:
an alkoxy,
a halogen, or
a C1 to C6 alkyl, or
a 5 or 6 membered heterocycle,
and Rt is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRvSO2Rw group, where Rv is:
a hydrogen,
a —CORx, where Rx is as defined above, or
a C1 to C6 alkyl, optionally substituted with:
a halogen,
a —CORx group, where Rx is as defined above,
a —OCORx group, where Rx is as defined above,
a hydroxyl,
a hydroxyl, or
an alkoxy,
and where Rw is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
a haloalkyl,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle,
a C2 to C6 alkylene,
an alkyl- or dialkyl-amino optionally substituted with a halogen,
a 5 or 6 membered heterocycle, or
a 5 or 6 membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a 5 or 6 membered heterocycle, or
 optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
 where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a —SRx group, where Rx is as defined above,
a —SO2Raa group, where Raa is:
a C1 to C6 alkyl,
an amino group,
an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, or
a —NHRbb group, where Rbb is:
a —C(═S)NH2 group, or
a —PO(ORx)2, where Rx is as defined above;
 group, where Rcc is:
a naphthalene,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy,
an hydroxy,
a halogen,
a C1 to C6 alkyl, optionally substituted with a cyano group,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NHPORxRx, where Rx is as defined above,
a —NeeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
a hydrogen,
a haloalkyl,
a haloalkoxy,
a C1 to C6 alkyl, or
a —CORx, where Rx is as defined above,
a —NRggCORhh group, where Rhh is:
a hydrogen,
a C1 to C6 alkyl optionally substituted with:
 an alkoxy,
 a halogen, or
 an amino optionally substituted with one or more C1 to C6 alkyls,
an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
a 5 or 6 membered heterocycle,
a 5 or 6 membered heteroaryl,
and Rgg is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
a haloalkyl,
5 or 6 membered heterocycle groups,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy,
a —CORx group, where Rx is as defined above;
Z is:
a hydrogen;
a C1 to C6 alkyl optionally substituted with:
an alkoxy,
one or more halogens, or
a C6 to C8 aryl;
a C2 to C6 alkylene;
a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
a —COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
R1 is:
a hydrogen;
a hydroxy;
a halogen;
a haloalkyl;
a nitro group;
a 5 or 6 membered heteroaryl;
a 5 or 6 membered heterocycle;
an alkoxy optionally substituted with:
one or more halogens,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle;
a C6 to C8 aryl optionally substituted with an alkoxy;
a —CORx group, where Rx is as defined above;
a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
R1 joins together with R2 to form:
R2 is:
a nitro group;
a hydrogen;
a halogen;
a hydroxy group;
a C1 to C6 alkyl group, optionally substituted with one or more halogens;
an amino group;
an alkoxy group optionally substituted with:
one or more halogens,
an —OCORx group, where Rx is as defined above,
a dialkyl-amino optionally substituted with an alkoxy,
a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
a 5 or 6 membered heteroaryl group, or
a C6 to C8 aryl group;
a —COORx group, where Rx is as defined above;
a haloalkyl;
an amide group optionally substituted with:
a hydroxy group, or
a C6 to C8 aryl;
a 5 or 6 membered heteroaryl;
a —OCORx group, where Rx is as defined above;
a —NHCORjj group, where Rjj is:
an alkoxy, or
an amino optionally substituted with one or more C1 to C6 alkyls;
a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
a —NHSO2Rx group, where Rx is as defined above; or
R2 joins together with R1 to form:
R3 is:
a hydrogen; or
CH2OCORx, and Rx is as defined above;
or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
35. The method of claim 34, further comprising administering one or more additional anti-viral agent.
36. The method of claim 35, wherein said one or more additional anti-viral agent is selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a helicase inhibitor, a glycosidase inhibitor, a Toll-like receptor agonist, and combinations thereof.
37. A pharmaceutical composition for affecting viral IRES activity in a subject infected with a virus, comprising one or more compound having the following formula:
wherein:
X is:
hydrogen;
a nitro group;
a cyano group;
a —CORa group, where Ra is:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
a dialkyl-amino;
a —COORx group, where Rx is a C1 to C6 alkyl;
a formyl group;
a C6 to C8 aryl optionally substituted with an alkoxy; or
a 5 or 6-membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
a 5 to 6 membered heteroaryl;
Y is:
a hydrogen;
a haloalkyl;
a halogen;
an amino optionally substituted with one or more C1 to C6 alkyls;
a benzofuran;
a benzothiophene;
a dibenzofuran;
a dibenzothiophene;
a benzothiazole;
a naphthalene;
an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
a —NHCORe group, where Re is:
a C1 to C6 alkyl;
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
an alkoxy,
a cyano group,
a nitro group, or
a halogen;
a —NHCOORx group, where Rx is as defined above;
a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
a C1 to C6 alkyl;
a 5 or 6 membered heteroaryl, optionally substituted with:
a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
an amino group;
a 5 or 6 membered heterocycle optionally substituted with:
a —COORx group, where Rx is as defined above, or
a —NHCOORx group, where Rx is as defined above;
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy, optionally substituted with:
an alkoxy,
a hydroxy,
one or more halogens,
a 5 or 6 membered heterocycle, optionally substituted with:
a C1 to C6 alkyl, or
a hydroxy,
an amino group optionally substituted with one or more C1 to C6 alkyls,
a —NRiSO2Rx group, where Rx is as defined above and Ri is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRjCORk group, where Rk is:
a C1 to C6 alkyl,
a hydrogen, or
an amino optionally substituted with one or more C1 to C6 alkyls,
and Rj is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —N═N+═N group, or
a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
an amino optionally substituted with one or more C1 to C6 alkyls,
a nitro group,
a C1 to C6 alkyl group, optionally substituted with:
a —NHSO2Rx group, where Rx is as defined above, or
a —NRxSO2Rx group, where Rx is as defined above,
a haloalkoxy,
a halogen,
a hydroxy,
a —COORx group, where Rx is as defined above,
a —CORm group, where Rm is:
an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
a hydroxy
a 5 or 6 membered heterocycle,
an amino optionally substituted with one or more C1 to C6 alkyls,
an alkoxy,
a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
a —NHRn group, where Rn is:
a —CH2CONH2, or
a C6 to C8 aryl optionally substituted with:
 an alkyl,
 one or more halogens,
 a nitro group, or
 one or more alkoxys,
a —NRCORp group, where Rp is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
an alkoxy, or
a C6 to C8 aryl,
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with a halogen,
a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
a hydrogen,
and where Ro is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRqCONRqRr group, where Rq is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
and where Rr is:
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
a haloalkyl,
a —ORs group, where Rs is a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a C1 to C6 alkyl optionally substituted with one or more of the following:
a halogen,
an alkylene,
a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a —COORx group, where Rx is as defined above,
a —NRtCOORx group, where R1 is:
a C1 to C12 alkyl, optionally substituted with:
a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
an alkylene,
an alkoxy,
an alkyne,
a halogen, or
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with:
an alkoxy,
a halogen, or
a C1 to C6 alkyl, or
a 5 or 6 membered heterocycle,
and Rt is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRvSO2Rw group, where Rv is:
a hydrogen,
a —CORx, where Rx is as defined above, or
a C1 to C6 alkyl, optionally substituted with:
a halogen,
a —CORx group, where Rx is as defined above,
a —OCORx group, where Rx is as defined above,
a hydroxyl,
a hydroxyl, or
an alkoxy,
and where Rw is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
a haloalkyl,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle,
a C2 to C6 alkylene,
an alkyl- or dialkyl-amino optionally substituted with a halogen,
a 5 or 6 membered heterocycle, or
a 5 or 6 membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a 5 or 6 membered heterocycle, or
 optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
 where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a —SRx group, where Rx is as defined above,
a —SO2Raa group, where Raa is:
a C1 to C6 alkyl,
an amino group,
an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, or
a —NHRbb group, where Rbb is:
a —C(═S)NH2 group, or
a —PO(ORx)2, where Rx is as defined above;
 group, where Rcc is:
a naphthalene,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy,
an hydroxy,
a halogen,
a C1 to C6 alkyl, optionally substituted with a cyano group,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NHPORxRx, where Rx is as defined above,
a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
a hydrogen,
a haloalkyl,
a haloalkoxy,
a C1 to C6 alkyl, or
a —CORx, where Rx is as defined above,
a —NRggCORhh group, where Rhh is:
a hydrogen,
a C1 to C6 alkyl optionally substituted with:
 an alkoxy,
 a halogen, or
 an amino optionally substituted with one or more C1 to C6 alkyls,
an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
a 5 or 6 membered heterocycle,
a 5 or 6 membered heteroaryl,
and Rgg is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
a haloalkyl,
5 or 6 membered heterocycle groups,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy,
a —CORx group, where Rx is as defined above;
Z is:
a hydrogen;
a C1 to C6 alkyl optionally substituted with:
an alkoxy,
one or more halogens, or
a C6 to C8 aryl;
a C2 to C6 alkylene;
a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
a —COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
R1 is:
a hydrogen;
a hydroxy;
a halogen;
a haloalkyl;
a nitro group;
a 5 or 6 membered heteroaryl;
a 5 or 6 membered heterocycle;
an alkoxy optionally substituted with:
one or more halogens,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle;
a C6 to C8 aryl optionally substituted with an alkoxy;
a —CORx group, where Rx is as defined above;
a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
R1 joins together with R2 to form:
R2 is:
a nitro group;
a hydrogen;
a halogen;
a hydroxy group;
a C1 to C6 alkyl group, optionally substituted with one or more halogens;
an amino group;
an alkoxy group optionally substituted with:
one or more halogens,
an —OCORx group, where Rx is as defined above,
a dialkyl-amino optionally substituted with an alkoxy,
a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
a 5 or 6 membered heteroaryl group, or
a C6 to C8 aryl group;
a —COORx group, where Rx is as defined above;
a haloalkyl;
an amide group optionally substituted with:
a hydroxy group, or
a C6 to C8 aryl;
a 5 or 6 membered heteroaryl;
a —OCORx group, where Rx is as defined above;
a —NHCORjj group, where Rjj is:
an alkoxy, or
an amino optionally substituted with one or more C1 to C6 alkyls;
a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
a —NHSO2Rx group, where Rx is as defined above; or
R2 joins together with R1 to form:
R3 is:
a hydrogen; or
CH2OCORx, and Rx is as defined above;
and/or a pharmaceutically acceptable salt thereof, together with a compound known in the art to affect IRES activity and a pharmaceutically acceptable excipient.
38. The pharmaceutical composition of claim 37, wherein said compound known in the art to affect IRES activity affects IRES mediated translation of an ORF encoding the polyprotein.
39. A method for affecting viral IRES activity in a subject infected with a virus, comprising administering to said subject one or more compound having the following formula:
wherein:
X is:
hydrogen;
a nitro group;
a cyano group;
a —CORa group, where Ra is:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
a dialkyl-amino;
a —COORx group, where Rx is a C1 to C6 alkyl;
a formyl group;
a C6 to C8 aryl optionally substituted with an alkoxy; or
a 5 or 6-membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
a 5 to 6 membered heteroaryl;
Y is:
a hydrogen;
a haloalkyl;
a halogen;
an amino optionally substituted with one or more C1 to C6 alkyls;
a benzofuran;
a benzothiophene;
a dibenzofuran;
a dibenzothiophene;
a benzothiazole;
a naphthalene;
an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
a —NHCORe group, where Re is:
a C1 to C6 alkyl;
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
an alkoxy,
a cyano group,
a nitro group, or
a halogen;
a —NHCOORx group, where Rx is as defined above;
a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
a C1 to C6 alkyl;
a 5 or 6 membered heteroaryl, optionally substituted with:
a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
an amino group;
a 5 or 6 membered heterocycle optionally substituted with:
a —COORx group, where Rx is as defined above, or
a —NHCOORx group, where Rx is as defined above;
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy, optionally substituted with:
an alkoxy,
a hydroxy,
one or more halogens,
a 5 or 6 membered heterocycle, optionally substituted with:
a C1 to C6 alkyl, or
a hydroxy,
an amino group optionally substituted with one or more C1 to C6 alkyls,
a —NRiSO2Rx group, where Rx is as defined above and Ri is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRjCORk group, where Rk is:
a C1 to C6 alkyl,
a hydrogen, or
an amino optionally substituted with one or more C1 to C6 alkyls,
and Rj is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —N═N+═N group, or
a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
an amino optionally substituted with one or more C1 to C6 alkyls,
a nitro group,
a C1 to C6 alkyl group, optionally substituted with:
a —NHSO2Rx group, where Rx is as defined above, or
a —NRxSO2Rx group, where Rx is as defined above,
a haloalkoxy,
a halogen,
a hydroxy,
a —COORx group, where Rx is as defined above,
a —CORm group, where Rm is:
an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
a hydroxy
a 5 or 6 membered heterocycle,
an amino optionally substituted with one or more C1 to C6 alkyls,
an alkoxy,
a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
a —NHRn group, where Rn is:
a —CH2CONH2, or
a C6 to C8 aryl optionally substituted with:
 an alkyl,
 one or more halogens,
 a nitro group, or
 one or more alkoxys,
a —NRoCORp group, where Rp is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
an alkoxy, or
a C6 to C8 aryl,
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with a halogen,
a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyls,
a hydrogen,
and where Ro is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRqCONRqRr group, where Rq is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
and where Rr is:
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
a haloalkyl,
a —ORs group, where Rs is a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a C1 to C6 alkyl optionally substituted with one or more of the following:
a halogen,
an alkylene,
a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a —COORx group, where Rx is as defined above,
a —NRtCOORu group, where Ru is:
a C1 to C12 alkyl, optionally substituted with:
a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
an alkylene,
an alkoxy,
an alkyne,
a halogen, or
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with:
an alkoxy,
a halogen, or
a C1 to C6 alkyl, or
a 5 or 6 membered heterocycle,
and Rt is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRvSO2Rw group, where Rv is:
a hydrogen,
a —CORx, where Rx is as defined above, or
a C1 to C6 alkyl, optionally substituted with:
a halogen,
a —CORx group, where Rx is as defined above,
a —OCORx group, where Rx is as defined above,
a hydroxyl,
a hydroxyl, or
an alkoxy,
and where Rw is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
a haloalkyl,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle,
a C2 to C6 alkylene,
an alkyl- or dialkyl-amino optionally substituted with a halogen,
a 5 or 6 membered heterocycle, or
a 5 or 6 membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a 5 or 6 membered heterocycle, or
 optionally substituted with a C1 to C6 alkyl, where Ry to C6 alkyl or hydrogen,
 where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl
a —SRx group, where Rx is as defined above,
a —SO2Raa group, where Raa is:
a C1 to C6 alkyl,
an amino group,
an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, or
a —NHRbb group, where Rbb is:
a —C(═S)NH2 group, or
a —PO(ORx)2, where Rx is as defined above;
 group, where Rcc is:
a naphthalene,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy,
an hydroxy,
a halogen,
a C1 to C6 alkyl, optionally substituted with a cyano group,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NHPORxRx, where Rx is as defined above,
a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
a hydrogen,
a haloalkyl,
a haloalkoxy,
a C1 to C6 alkyl, or
a —CORx, where Rx is as defined above,
a —NRggCORhh group, where Rhh is:
a hydrogen,
a C1 to C6 alkyl optionally substituted with:
 an alkoxy,
 a halogen, or
 an amino optionally substituted with one or more C1 to C6 alkyls,
an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
a 5 or 6 membered heterocycle,
a 5 or 6 membered heteroaryl,
and Rgg is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
a haloalkyl,
5 or 6 membered heterocycle groups,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy,
a —CORx group, where Rx is as defined above;
Z is:
a hydrogen;
a C1 to C6 alkyl optionally substituted with:
an alkoxy,
one or more halogens, or
a C6 to C8 aryl;
a C2 to C6 alkylene;
a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
a —COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
R1 is:
a hydrogen;
a hydroxy;
a halogen;
a haloalkyl;
a nitro group;
a 5 or 6 membered heteroaryl;
a 5 or 6 membered heterocycle;
an alkoxy optionally substituted with:
one or more halogens,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle;
a C6 to C8 aryl optionally substituted with an alkoxy;
a —CORx group, where Rx is as defined above;
a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
R1 joins together with R2 to form:
R2 is:
a nitro group;
a hydrogen;
a halogen;
a hydroxy group;
a C1 to C6 alkyl group, optionally substituted with one or more halogens;
an amino group;
an alkoxy group optionally substituted with:
one or more halogens,
an —OCORx group, where Rx is as defined above
a dialkyl-amino optionally substituted with an alkoxy,
a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
a 5 or 6 membered heteroaryl group, or
a C6 to C8 aryl group;
a —COORx group, where Rx is as defined above;
a haloalkyl;
an amide group optionally substituted with:
a hydroxy group, or
a C6 to C8 aryl;
a 5 or 6 membered heteroaryl;
a —OCORx group, where Rx is as defined above;
a —NHCORjj group, where Rjj is:
an alkoxy, or
an amino optionally substituted with one or more C1 to C6 alkyls;
a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
a —NHSO2Rx group, where Rx is as defined above; or
R2 joins together with R1 to form:
R3 is:
a hydrogen; or
CH2OCORx, and Rx is as defined above;
and/or a pharmaceutically acceptable salt thereof, together with a compound known in the art to affect IRES activity and a pharmaceutically acceptable excipient.
40. The method of claim 39, wherein said compound known in the art to affect IRES activity affects IRES mediated translation of an ORF encoding the polyprotein.
41. A pharmaceutical composition for affecting viral IRES activity in a subject infected with a virus, comprising one or more compound having the following formulas, in an amount effective for affecting viral IRES activity:
wherein:
X is:
hydrogen;
a nitro group;
a cyano group;
a —CORa group, where Ra is:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
a dialkyl-amino;
a —COORx group, where Rx is a C1 to C6 alkyl;
a formyl group;
a C6 to C8 aryl optionally substituted with an alkoxy; or
a 5 or 6-membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
a 5 to 6 membered heteroaryl;
Y is:
a hydrogen;
a haloalkyl;
a halogen;
an amino optionally substituted with one or more C1 to C6 alkyls;
a benzofuran;
a benzothiophene;
a dibenzofuran;
a dibenzothiophene;
a benzothiazole;
a naphthalene;
an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
a —NHCORe group, where Re is:
a C1 to C6 alkyl;
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
an alkoxy,
a cyano group,
a nitro group, or
a halogen;
a —NHCOORx group, where Rx is as defined above;
a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
a C1 to C6 alkyl;
a 5 or 6 membered heteroaryl, optionally substituted with:
a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
an amino group;
a 5 or 6 membered heterocycle optionally substituted with:
a —COORx group, where Rx is as defined above, or
a —NHCOORx group, where Rx is as defined above;
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy, optionally substituted with:
an alkoxy,
a hydroxy,
one or more halogens,
a 5 or 6 membered heterocycle, optionally substituted with:
a C1 to C6 alkyl, or
a hydroxy,
an amino group optionally substituted with one or more C1 to C6 alkyls,
a —NRiSO2Rx group, where Rx is as defined above and Ri is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRjCORk group, where Rk is:
a C1 to C6 alkyl,
a hydrogen, or
an amino optionally substituted with one or more C1 to C6 alkyls,
and Rj is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —N═N+═N group, or
a —CORx, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
an amino optionally substituted with one or more C1 to C6 alkyls,
a nitro group,
a C1 to C6 alkyl group, optionally substituted with:
a —NHSO2Rx group, where Rx is as defined above, or
a —NRxSO2Rx group, where Rx is as defined above,
a haloalkoxy,
a halogen,
a hydroxy,
a —COORx group, where Rx is as defined above,
a —CORm group, where Rm is:
an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
a hydroxy
a 5 or 6 membered heterocycle,
an amino optionally substituted with one or more C1 to C6 alkyls,
an alkoxy,
a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
a —NHRn group, where Rn is:
a —CH2CONH2, or
a C6 to C8 aryl optionally substituted with:
 an alkyl,
 one or more halogens,
 a nitro group, or
 one or more alkoxys,
a —NRoCORp group, where Rp is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
an alkoxy, or
a C6 to C8 aryl,
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with a halogen,
a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
a hydrogen,
and where Ro is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRqCONRqRr group, where Rq is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
and where Rr is:
a C6 to C8 aryl optionally substituted with:
a C1 to C6 alkyl,
a haloalkyl,
a —ORs group, where Rs is a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a C1 to C6 alkyl optionally substituted with one or more of the following:
a halogen,
an alkylene,
a C6 to C8 aryl, or
a —COORx group, where Rx is as defined above,
a —COORx group, where Rx is as defined above,
a —NRtCOORu group, where Ru is:
a C1 to C12 alkyl, optionally substituted with:
a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
an alkylene,
an alkoxy,
an alkyne,
a halogen, or
a 5 or 6 membered heterocycle,
a C6 to C8 aryl, optionally substituted with:
an alkoxy,
a halogen, or
a C1 to C6 alkyl, or
a 5 or 6 membered heterocycle,
and Rt is:
a hydrogen,
a C1 to C6 alkyl,
a —CORx group, where Rx is as defined above,
a haloalkyl, or
a haloalkoxy,
a —NRvSO2Rw group, where Rv is:
a hydrogen,
a —CORx, where Rx is as defined above, or
a C1 to C6 alkyl, optionally substituted with:
a halogen,
a —CORx group, where Rx is as defined above,
a —OCORx group, where Rx is as defined above,
a hydroxyl,
a hydroxyl, or
an alkoxy,
and where Rw is:
a C1 to C6 alkyl optionally substituted with:
a halogen,
a haloalkyl,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle,
a C2 to C6 alkylene,
an alkyl- or dialkyl-amino optionally substituted with a halogen,
a 5 or 6 membered heterocycle, or
a 5 or 6 membered heteroaryl optionally substituted with:
a C1 to C6 alkyl,
a 5 or 6 membered heterocycle, or
 optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
 where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
a —SRx group, where Rx is as defined above,
a —SO2Raa group, where Raa is:
a C1 to C6 alkyl,
an amino group,
an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, or
a —NHRbb group, where Rbb is:
a —C(═S)NH2 group, or
a —PO(ORx)2, where Rx is as defined above;
 group, where Rcc is:
a naphthalene,
a 5 or 6 membered heteroaryl,
a C6 to C8 aryl, optionally substituted with one or more of the following:
an alkoxy,
an hydroxy,
a halogen,
a C1 to C6 alkyl, optionally substituted with a cyano group,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NHPORxRx, where Rx is as defined above,
a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
a hydrogen,
a haloalkyl,
a haloalkoxy,
a C1 to C6 alkyl, or
a —CORx, where Rx is as defined above,
a —NRggCORhh group, where Rhh is:
a hydrogen,
a C1 to C6 alkyl optionally substituted with:
 an alkoxy,
 a halogen, or
 an amino optionally substituted with one or more C1 to C6 alkyls,
an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
a 5 or 6 membered heterocycle,
a 5 or 6 membered heteroaryl,
and Rgg is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy, or
a —CORx group, where Rx is as defined above,
a haloalkyl,
5 or 6 membered heterocycle groups,
an amino optionally substituted with one or more C1 to C6 alkyls,
a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
a hydrogen,
a C1 to C6 alkyl,
a haloalkyl,
a haloalkoxy,
a —CORx group, where Rx is as defined above;
Z is:
a hydrogen;
a C1 to C6 alkyl optionally substituted with:
an alkoxy,
one or more halogens, or
a C6 to C8 aryl;
a C2 to C6 alkylene;
a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
a —COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
R1 is:
a hydrogen;
a hydroxy;
a halogen;
a haloalkyl;
a nitro group;
a 5 or 6 membered heteroaryl;
a 5 or 6 membered heterocycle;
an alkoxy optionally substituted with:
one or more halogens,
a C6 to C8 aryl, or
a 5 or 6 membered heterocycle;
a C6 to C8 aryl optionally substituted with an alkoxy;
a —CORx group, where Rx is as defined above;
a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
R1 joins together with R2 to form:
R2 is:
a nitro group;
a hydrogen;
a halogen;
a hydroxy group;
a C1 to C6 alkyl group, optionally substituted with one or more halogens;
an amino group;
an alkoxy group optionally substituted with:
one or more halogens,
an —OCORx group, where Rx is as defined above
a dialkyl-amino optionally substituted with an alkoxy,
a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
a 5 or 6 membered heteroaryl group, or
a C6 to C8 aryl group;
a —COORx group, where Rx is as defined above;
a haloalkyl;
an amide group optionally substituted with:
a hydroxy group, or
a C6 to C8 aryl;
a 5 or 6 membered heteroaryl;
a —OCORx group, where Rx is as defined above;
a —NHCORjj group, where Rjj is:
an alkoxy, or
an amino optionally substituted with one or more C1 to C6 alkyls;
a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
a —NHSO2Rx group, where Rx is as defined above; or
R2 joins together with R1 to form:
R3 is:
a hydrogen; or
CH2OCORx, and Rx is as defined above;
or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Description
CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 60/587,487, filed Jul. 14, 2004, U.S. Provisional Application No. 60/634,979, filed Dec. 13, 2004, U.S. Provisional Application No. 60/645,586, filed Jan. 24, 2005, U.S. Provisional Application No. 60/665,349, filed Mar. 28, 2005, and U.S. Provisional Application No. 60/675,440, filed Apr. 28, 2005, all of which applications are incorporated herein by reference in their entireties. This application also claims priority to International Application having the title “Methods for Treating Hepatitis C”, attorney docket number 19025.037, filed Jul. 14, 2005, which application is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods for treating Hepatitis C using Indole compounds that modify translational control of Hepatitis C virus.

BACKGROUND OF THE INVENTION

An estimated 170 million people worldwide are reported to be infected with hepatitis C virus (HCV), the causative agent of hepatitis C. Seventy to eighty percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (115).

HCV constitutes the Hepacivirus genus of the family Flaviviridae (106), and contains a positive-stranded 9.6 kb RNA genome. The features of the HCV genome include a 5′-untranslated region (UTR) that encodes an internal ribosome entry site (IRES) that directs the translation of a single long open reading frame (ORF) encoding a polyprotein of 3,010 amino acids. The HCV ORF is followed by a 3′-UTR of variable length, depending on the HCV variant, that encodes the sequences required for the initiation of antigenomic strand synthesis (79).

The HCV IRES and 3′-UTR both encode regions of RNA structures that are required for genome translation and replication. The HCV polyprotein is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), E1 and E2 and the nonstructural (NS) proteins NS2 to NS5B.

Three distinct elements have been shown to be involved in HCV IRES-mediated translation: (1) integrity of the global structure of HCV IRES, (2) the 3′-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV IRES element and assist in translation initiation (35).

The initiation of protein synthesis in eukaryotic cells predominantly follows the 5′ cap-dependent, first AUG rule (61). However, an increasing number of viral (6, 12, 28, 31a, 50, 95, 97, 98, 105, 128) and cellular mRNAs (18, 39, 45, 78, 91, 130) have been shown to use an IRES element to direct translation initiation. In 1992, an IRES element was reported in the 5′ UTR of the HCV RNA genome (129), indicating that synthesis of the viral protein is initiated in a cap-independent fashion.

A bicistronic expression system can be used to define and evaluate the function of IRES elements. This test system harbors two different reporter genes in which the 5′-proximal reporter gene is expressed by a cap dependent translation mechanism while the second reporter is expressed only if an upstream sequence inserted in the intergenic space contains an IRES sequence element. Using this system, a putative IRES in the HCV 5′ UTR was unambiguously demonstrated to function as an IRES involved in translational control of viral proteins (133). In vitro translation, RNA transfection, and mutagenesis studies provided further evidence that the HCV 5′ UTR contains an IRES element (23, 41, 42, 108, 129, 132, 133, 134). Both in vitro and cell-based studies demonstrated that the HCV IRES guides cellular translation initiation factors to an internal site of the viral RNA (56, 58, 120), thus functionally demonstrating the HCV IRES activity. Taken together, these results demonstrate that the HCV 5′-UTR contains an IRES element that plays an active and crucial role in the mechanism of internal initiation for HCV protein translation.

The IRES is one of the most conserved regions of the HCV genome, reflecting its essential nature for viral replication and protein synthesis (13, 118, 122). Although both 5′ and 3′ sequences of the IRES appear to play a role in the control of initiation of translation (42, 109, 110, 113, 136), the minimal sequence requirement for HCV IRES function has been mapped to a region between nucleotides 44-354 (40).

Biochemical probing and computer modeling indicate that the HCV IRES and its 5′ sequence is folded into a distinct structure that consists of four major domains and a pseudoknot (11, 42, 122). Domain I contains a small stem-loop structure that does not appear to be a functional part of the IRES element while domains II, III, and IV contain the HCV IRES activity (43, 111). The relationships between secondary and tertiary structures of the HCV IRES and their function have recently been established (5, 55, 56, 99, 124). Both domains II and III consist of multiple stems, loops, and bulges and are important for IRES activity (23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131, 139). Domain II can induce conformational changes on the ribosome that have been implicated in the decoding process (124). Domain III has the highest degree of structural conservation among the different HCV strains. It comprises the core of the flavivirus IRES and has 6 subdomains (40). Various studies have shown that subdomain IIId forms complex secondary/tertiary structures and is critical for initiation activity (55, 56, 57, 124, 129). Domain IV has one stem-loop that spans the initiation codon and is specific for the HCV IRES (41, 122), but the precise role of domain IV in IRES activity remains controversial (41, 112).

The role of the HCV IRES is to position the translational machinery near an internal initiator codon in the viral mRNA. The translation initiation mechanism of the HCV IRES differs significantly from that of 5′-cap-dependent translation initiation (7, 21, 31, 35, 81, 96, 114, 123). Most cellular capped mRNAs utilize a number of initiation factors (eIFs) that are required for the translation initiation process. The initial steps of the process require proteins that interact with the 5′ cap structure and recruit the 40S ribosomal subunit to the cap-proximal region of mRNA. This complex then scans 3′ of the cap, until reaching an AUG codon at which translation will initiate (21, 114). However, in the case of HCV, the IRES functionally replaces the 5′ cap structure, allowing the 40S ribosomal subunit and eIF3 to bind directly to the RNA. Subdomain IIId of the HCV IRES harbors the binding site for the 40S ribosomal subunit and the only initiation factors required for translation initiation are eIF2, eIF3, and eIF4E (15, 58, 94, 100, 120, 124).

The polypyrimidine track-binding protein (PTB) and La autoantigen are noncanonical translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53). PTB, a 57-kDa protein involved in RNA splicing, is also necessary for efficient IRES-mediated translation initiation of picornavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92). The La autoantigen, a 52 kDa double-stranded RNA unwinding protein, also increases the activity of poliovirus and cellular IRESs (38, 85, 86). Other cellular factors involved in HCV IRES-mediated translation initiation include proteasome α-subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33). However, the role of these RNA-binding proteins in HCV IRES-mediated initiation of translation is unclear. Recently, it was reported that the activity of interferon (IFN) α against HCV replication might target HCV IRES-mediated translation initiation by causing a reduction of La protein levels (117). Thus, an inhibitor that blocks interaction between the IRES and the noncanonical factors might efficiently inhibit HCV replication and lack cytotoxicity.

Currently, only interferon (IFN) α and the nucleoside analogue ribavirin, in combination, are marketed for the treatment of HCV infection. However, these two agents are immunomodulators and have limited efficacy, relatively high toxicity, and high cost (80, 83, 84, 138). Although the treatment outcome is variable among the six major HCV genotypes, only about one-half of all treated patients respond to therapy, suggesting that the virus encodes protein products that may directly or indirectly attenuate the antiviral action of IFN. IFNs are naturally produced in response to virus infection, and cellular exposure to IFN leads to the induced expression of a variety of IFN-stimulated genes (ISGs), many of which have an antiviral function. ISG action can limit virus replication at multiple points within the replicative cycle.

There remains a need for a more effective means of treating patients afflicted with HCV. Specifically, a need exists for novel antiviral drugs that have no cross-resistance with existing treatment modalities, and which demonstrate synergy with other anti-HCV agents. The applicants set out to identify drug candidates that inhibit HCV infection and were successful in identifying Indole compounds that are useful as anti-HCV agents. Without being limited to one theory, it is believed that the compounds of the present invention inhibit IRES-mediated initiation, elongation, and termination, i.e. translation.

The compounds of the present invention are also useful for inhibiting translation of other cap-independent viruses that contain an IRES element. Such viruses include those of the picornavirus genus, such as poliovirus, hepatitis A virus and rhinovirus; those of the coronavirus genus, such as SARS; those of the arbovirus genus; those of the flavivirus genus, such as yellow fever, dengue, and West Nile virus, herpesviruses, such as herpes simplex virus and Kaposi's sarcoma-associated herpesvirus, or any other virus with a similar mode of replication. Furthermore, compounds of the invention are also useful for inhibiting HIV, or any other virus with a similar mode of translation.

All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.

SUMMARY OF THE INVENTION

In accordance with the present invention, compounds that can inhibit HCV replication have been identified. Also in accordance with the present invention, compounds that can inhibit HCV infection have been identified, and methods for their use provided.

In one aspect of the invention, compounds of Formula (I) are provided which are useful in the prevention and/or treatment of HCV infection. Without being limited to one theory, it is believed that the compounds of the present invention inhibit IRES-mediated initation, elongation and termination, i.e., translation. The compounds of Formula (I) may also be useful for inhibiting and/or treating other viral infections where the virus contains an IRES element. Such viruses include those of the picornavirus genus, such as by way of non-limiting example poliovirus, hepatitis A virus and rhinovirus; those of the coronaviridae genus, such as by way of non-limiting example SARS; those of the arbovirus genus; those of the flavivirus genus, such as by way of non-limiting example yellow fever, dengue, and West Nile virus; herpesviruses, such as by way of non-limiting example herpes simplex virus and Kaposi's sarcoma-associated herpesvirus, or any other virus with a similar mode of replication. Furthermore, compounds of the invention are also useful for inhibiting HIV, or any other virus with a similar mode of translation.

In another aspect of the invention, methods are provided for the prevention and/or treatment of HCV infection.

In yet another aspect of the invention, pharmaceutical compositions comprising the compounds of the invention for the prevention and/or treatment of HCV infection are provided.

In one embodiment, the invention is directed to methods for inhibiting HCV IRES-mediated initiation and translation comprising administering an amount of one or more compound of the invention, effective for inhibiting IRES-mediated initiation and translation, to a subject in need thereof.

CERTAIN EMBODIMENTS Embodiment 1

A pharmaceutical composition for the prevention or treatment of Hepatitis C viral (HCV) infection comprising a therapeutically effective amount of at least one compound having the following formula:


wherein:

  • X is:
    • hydrogen;
    • a nitro group;
    • a cyano group;
    • a —CORa group, where Ra is:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
      • a dialkyl-amino;
    • a —COORx group, where Rx is a C1 to C6 alkyl;
    • a formyl group;
    • a C6 to C8 aryl optionally substituted with an alkoxy; or
    • a 5 or 6-membered heteroaryl optionally substituted with:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
      • a 5 to 6 membered heteroaryl;
  • Y is:
    • a hydrogen;
    • a haloalkyl;
    • a halogen;
    • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a benzofuran;
    • a benzothiophene;
    • a dibenzofuran;
    • a dibenzothiophene;
    • a benzothiazole;
    • a naphthalene;
    • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
      where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
      where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
      where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
    • a —NHCORe group, where Re is:
      • a C1 to C6 alkyl;
      • a C6 to C8 aryl optionally substituted with:
        • a C1 to C6 alkyl,
        • an alkoxy,
        • a cyano group,
        • a nitro group, or
        • a halogen;
    • a —NHCOORx group, where Rx is as defined above;
    • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
    • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
    • a C1 to C6 alkyl;
    • a 5 or 6 membered heteroaryl, optionally substituted with:
      • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
      • an amino group;
    • a 5 or 6 membered heterocycle optionally substituted with:
      • a —COORx group, where Rx is as defined above, or
      • a —NHCOORx group, where Rx is as defined above;
    • a C6 to C8 aryl, optionally substituted with one or more of the following:
      • an alkoxy, optionally substituted with:
        • an alkoxy,
        • a hydroxy,
        • one or more halogens,
        • a 5 or 6 membered heterocycle, optionally substituted with:
          • a C1 to C6 alkyl, or
          • a hydroxy,
        • an amino group optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiSO2Rx group, where Rx is as defined above and Ri is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRjCORk group, where Rk is:
          • a C1 to C6 alkyl,
          • a hydrogen, or
          • an amino optionally substituted with one or more C1 to C6 alkyls, and Rj is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —N═N+═N— group, or
        • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
      • an amino optionally substituted with one or more C1 to C6 alkyls,
      • a nitro group,
      • a C1 to C6 alkyl group, optionally substituted with:
        • a —NHSO2Rx group, where Rx is as defined above, or
        • a —NRxSO2Rx group, where Rx is as defined above,
      • a haloalkoxy,
      • a halogen,
      • a hydroxy,
      • a —COORx group, where Rx is as defined above,
      • a —CORm group, where Rm is:
        • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
          • a hydroxy
          • a 5 or 6 membered heterocycle,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • an alkoxy,
        • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
        • a —NHRn group, where Rn is:
          • a —CH2CONH2, or
          • a C6 to C8 aryl optionally substituted with:
          •  an alkyl,
          •  one or more halogens,
          •  a nitro group, or
          •  one or more alkoxys,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with a halogen,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
        • a hydrogen,
      • and where Ro is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRqCONRqRr group, where Rq is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a haloalkyl,
        • a haloalkoxy, or
        • a —CORx group, where Rx is as defined above,
      • and where Rr is:
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a —ORs group, where Rs is a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a halogen,
          • an alkylene,
          • a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a —COORx group, where Rx is as defined above,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with:
          • a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
          • an alkylene,
          • an alkoxy,
          • an alkyne,
          • a halogen, or
          • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with:
          • an alkoxy,
          • a halogen, or
          • a C1 to C6 alkyl, or
        • a 5 or 6 membered heterocycle,
      • and Rt is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRvSO2Rw group, where Rv is:
        • a hydrogen,
        • a —CORx, where Rx is as defined above, or
        • a C1 to C6 alkyl, optionally substituted with:
          • a halogen,
          • a —CORx group, where Rx is as defined above,
          • a —OCORx group, where Rx is as defined above,
          • a hydroxyl,
          • a hydroxyl, or
          • an alkoxy,
      • and where Rw is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • a haloalkyl,
          • a C6 to C8 aryl, or
          • a 5 or 6 membered heterocycle,
        • a C2 to C6 alkylene,
        • an alkyl- or dialkyl-amino optionally substituted with a halogen,
        • a 5 or 6 membered heterocycle, or
        • a 5 or 6 membered heteroaryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a 5 or 6 membered heterocycle, or
      •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
      •  where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a —SRx group, where Rx is as defined above,
      • a —SO2Raa group, where Raa is:
        • a C1 to C6 alkyl,
        • an amino group,
        • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
        • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, or
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
    •  group, where Rcc is:
      • a naphthalene,
      • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an hydroxy,
        • a halogen,
        • a C1 to C6 alkyl, optionally substituted with a cyano group,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NHPORxRx, where Rx is as defined above,
        • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
          • a hydrogen,
          • a haloalkyl,
          • a haloalkoxy,
          • a C1 to C6 alkyl, or
          • a —CORx, where Rx is as defined above,
        • a —NRggCORhh group, where Rhh is:
          • a hydrogen,
          • a C1 to C6 alkyl optionally substituted with:
          •  an alkoxy,
          •  a halogen, or
          •  an amino optionally substituted with one or more C1 to C6 alkyls,
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl,
        • and Rgg is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • a haloalkyl,
        • 5 or 6 membered heterocycle groups,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy,
          • a —CORx group, where Rx is as defined above;
  • Z is:
    • a hydrogen;
    • a C1 to C6 alkyl optionally substituted with:
      • an alkoxy,
      • one or more halogens, or
      • a C6 to C8 aryl;
    • a C2 to C6 alkylene;
    • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
    • a —COORx group, where Rx is as defined above; or
  • R is a hydrogen, a halogen or an alkoxy;
  • R1 is:
    • a hydrogen;
    • a hydroxy;
    • a halogen;
    • a haloalkyl;
    • a nitro group;
    • a 5 or 6 membered heteroaryl;
    • a 5 or 6 membered heterocycle;
    • an alkoxy optionally substituted with:
      • one or more halogens,
      • a C6 to C8 aryl, or
      • a 5 or 6 membered heterocycle;
    • a C6 to C8 aryl optionally substituted with an alkoxy;
    • a —CORx group, where Rx is as defined above;
    • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
  • R1 joins together with R2 to form:
  • R2 is:
    • a nitro group;
    • a hydrogen;
    • a halogen;
    • a hydroxy group;
    • a C1 to C6 alkyl group, optionally substituted with one or more halogens;
    • an amino group;
    • an alkoxy group optionally substituted with:
      • one or more halogens,
      • an —OCORx group, where Rx is as defined above,
      • a dialkyl-amino optionally substituted with an alkoxy,
      • a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
      • a 5 or 6 membered heteroaryl group, or
      • a C6 to C8 aryl group;
    • a —COORx group, where Rx is as defined above;
    • a haloalkyl;
    • an amide group optionally substituted with:
      • a hydroxy group, or
      • a C6 to C8 aryl;
    • a 5 or 6 membered heteroaryl;
    • a —OCORx group, where Rx is as defined above;
    • a —NHCORjj group, where Rjj is:
      • an alkoxy, or
      • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
    • a —NHSO2Rx group, where Rx is as defined above; or
  • R2 joins together with R1 to form:
  • R3 is:
    • a hydrogen; or —CH2OCORx, and Rx is as defined above;
      or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and optionally at least one additional anti-HCV agents.
Embodiment 2

The pharmaceutical composition of Embodiment 1, wherein said optional at least one additional anti-HCV agent is selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidase inhibitor, a helicase inhibitor, a Toll-like receptor agonist, and combinations thereof.

Embodiment 3

The pharmaceutical composition of Embodiment 1, wherein X is selected from the group consisting of -hydrogen; -a cyano group; and -a —CORa group, where Ra is: -a C1 to C6 alkyl, or -a dialkyl-amino.

Embodiment 4

The pharmaceutical composition of Embodiment 1, wherein Y is selected from the group consisting of

Embodiment 5

The pharmaceutical composition of Embodiment 1, wherein Y is selected from the group consisting of

Embodiment 6

The pharmaceutical composition of Embodiment 1, wherein R is a hydrogen.

Embodiment 7

The pharmaceutical composition of Embodiment 1, wherein R1 is selected from the group consisting of a hydrogen, a nitro group, or an alkoxy.

Embodiment 8

The pharmaceutical composition of Embodiment 1, wherein R2 is selected from the group consisting of a hydroxy, a hydrogen, a haloalkyl group, a nitro group, an amide, —COORx or an alkoxy.

Embodiment 9

The pharmaceutical composition of Embodiment 1, wherein R3 is a hydrogen.

Embodiment 10

The pharmaceutical composition of Embodiment 1, wherein said compound is selected from the compounds of Table A.

Embodiment 11

The pharmaceutical composition of Embodiment 1 wherein said compound is selected from the compounds of Table B or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Embodiment 12

The pharmaceutical composition of Embodiment 17, wherein said composition further comprises at least one additional anti-HCV agent selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidase inhibitor, a helicase inhibitor, a Toll-like receptor agonist, and combinations thereof.

Embodiment 13

A method for treating a subject for a Hepatitis C viral (HCV) infection comprising administering to said subject a pharmaceutical composition comprising an HCV inhibitory amount of at least one compound having the following formula:


wherein:

  • X is:
    • hydrogen;
    • a nitro group;
    • a cyano group;
    • a —CORa group, where Ra is:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
      • a dialkyl-amino;
    • a —COORx group, where Rx is a C1 to C6 alkyl;
    • a formyl group;
    • a C6 to C8 aryl optionally substituted with an alkoxy; or
    • a 5 or 6-membered heteroaryl optionally substituted with:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
      • a 5 to 6 membered heteroaryl;
  • Y is:
    • a hydrogen;
    • a haloalkyl;
    • a halogen;
    • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a benzofuran;
    • a benzothiophene;
    • a dibenzofuran;
    • a dibenzothiophene;
    • a benzothiazole;
    • a naphthalene;
    • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
      where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
      where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
      where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
    • a —NHCORe group, where Re is:
      • a C1 to C6 alkyl;
      • a C6 to C8 aryl optionally substituted with:
        • a C1 to C6 alkyl,
        • an alkoxy,
        • a cyano group,
        • a nitro group, or
        • a halogen;
    • a —NHCOORx group, where Rx is as defined above;
    • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
    • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
    • a C1 to C6 alkyl;
    • a 5 or 6 membered heteroaryl, optionally substituted with:
      • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
      • an amino group;
    • a 5 or 6 membered heterocycle optionally substituted with:
      • a —COORx group, where Rx is as defined above, or
      • a —NHCOORx group, where Rx is as defined above;
    • a C6 to C8 aryl, optionally substituted with one or more of the following:
      • an alkoxy, optionally substituted with:
        • an alkoxy,
        • a hydroxy,
        • one or more halogens,
        • a 5 or 6 membered heterocycle, optionally substituted with:
          • a C1 to C6 alkyl, or
          • a hydroxy,
        • an amino group optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiSO2Rx group, where Rx is as defined above and Ri is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRjCORk group, where Rk is:
          • a C1 to C6 alkyl,
          • a hydrogen, or
          • an amino optionally substituted with one or more C1 to C6 alkyls,
        • and Rj is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —N═N+═N group, or
        • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
      • an amino optionally substituted with one or more C1 to C6 alkyls,
      • a nitro group,
      • a C1 to C6 alkyl group, optionally substituted with:
        • a —NHSO2Rx group, where Rx is as defined above, or
        • a —NRxSO2Rx group, where Rx is as defined above,
      • a haloalkoxy,
      • a halogen,
      • a hydroxy,
      • a —COORx group, where Rx is as defined above,
      • a —CORm group, where Rm is:
        • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
          • a hydroxy
          • a 5 or 6 membered heterocycle,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • an alkoxy,
        • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
        • a —NHRn group, where Rn is:
          • a —CH2CONH2, or
          • a C6 to C8 aryl optionally substituted with:
          •  an alkyl,
          •  one or more halogens,
          •  a nitro group, or
          •  one or more alkoxys,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with a halogen,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
        • a hydrogen,
      • and where Ro is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRqCONRqRr group, where Rq is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a haloalkyl,
        • a haloalkoxy, or
        • a —CORx group, where Rx is as defined above,
      • and where Rr is:
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a —ORs group, where Rs is a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a halogen,
          • an alkylene,
          • a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a —COORx group, where Rx is as defined above,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with:
          • a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
          • an alkylene,
          • an alkoxy,
          • an alkyne,
          • a halogen, or
          • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with:
          • an alkoxy,
          • a halogen, or
          • a C1 to C6 alkyl, or
        • a 5 or 6 membered heterocycle,
      • and Rt is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRvSO2Rw group, where Rv is:
        • a hydrogen,
        • a —CORx, where Rx is as defined above, or
        • a C1 to C6 alkyl, optionally substituted with:
          • a halogen,
          • a —CORx group, where Rx is as defined above,
          • a —OCORx group, where Rx is as defined above,
          • a hydroxyl,
          • a hydroxyl, or
          • an alkoxy,
      • and where Rw is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • a haloalkyl,
          • a C6 to C8 aryl, or
          • a 5 or 6 membered heterocycle,
        • a C2 to C6 alkylene,
        • an alkyl- or dialkyl-amino optionally substituted with a halogen,
        • a 5 or 6 membered heterocycle, or
        • a 5 or 6 membered heteroaryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a 5 or 6 membered heterocycle, or
      •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
      • where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a —SRx group, where Rx is as defined above,
      • a —SO2Raa group, where Raa is:
        • a C1 to C6 alkyl,
        • an amino group,
        • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
        • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, or
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
    •  group, where Rcc is:
      • a naphthalene,
      • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an hydroxy,
        • a halogen,
        • a C1 to C6 alkyl, optionally substituted with a cyano group,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NHPORxRx, where Rx is as defined above,
        • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
          • a hydrogen,
          • a haloalkyl,
          • a haloalkoxy,
          • a C1 to C6 alkyl, or
          • a —CORx, where Rx is as defined above,
        • a —NRggCORhh group, where Rhh is:
          • a hydrogen,
          • a C1 to C6 alkyl optionally substituted with:
          •  an alkoxy,
          •  a halogen, or
          •  an amino optionally substituted with one or more C1 to C6 alkyls,
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl,
        • and Rgg is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • a haloalkyl,
        • 5 or 6 membered heterocycle groups,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy,
          • a —CORx group, where Rx is as defined above;
  • Z is:
    • a hydrogen;
    • a C1 to C6 alkyl optionally substituted with:
      • an alkoxy,
      • one or more halogens, or
      • a C6 to C8 aryl;
    • a C2 to C6 alkylene;
    • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
    • a —COORx group, where Rx is as defined above; or
  • R is a hydrogen, a halogen or an alkoxy;
  • R1 is:
    • a hydrogen;
    • a hydroxy;
    • a halogen;
    • a haloalkyl;
    • a nitro group;
    • a 5 or 6 membered heteroaryl;
    • a 5 or 6 membered heterocycle;
    • an alkoxy optionally substituted with:
      • one or more halogens,
      • a C6 to C8 aryl, or
      • a 5 or 6 membered heterocycle;
    • a C6 to C8 aryl optionally substituted with an alkoxy;
    • a —CORx group, where Rx is as defined above;
    • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
  • R1 joins together with R2 to form:
  • R2 is:
    • a nitro group;
    • a hydrogen;
    • a halogen;
    • a hydroxy group;
    • a C1 to C6 alkyl group, optionally substituted with one or more halogens;
    • an amino group;
    • an alkoxy group optionally substituted with:
      • one or more halogens,
      • an —OCORx group, where Rx is as defined above,
      • a dialkyl-amino optionally substituted with an alkoxy,
      • a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
      • a 5 or 6 membered heteroaryl group, or
      • a C6 to C8 aryl group;
    • a —COORx group, where Rx is as defined above;
    • a haloalkyl;
    • an amide group optionally substituted with:
      • a hydroxy group, or
      • a C6 to C8 aryl;
    • a 5 or 6 membered heteroaryl;
    • a —OCORx group, where Rx is as defined above;
    • a —NHCORjj group, where Rjj is:
      • an alkoxy, or
      • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
    • a —NHSO2Rx group, where Rx is as defined above; or
  • R2 joins together with R1 to form:
  • R3 is:
    • a hydrogen; or —CH2OCORx, and Rx is as defined above;
      or a pharmaceutically acceptable salt thereof and a pharamceutically acceptable excipient.
Embodiment 14

The method of Embodiment 13, wherein said pharmaceutical composition further comprises at least one additional anti-HCV agent.

Embodiment 15

The method of Embodiment 14, wherein said at least one additional anti-HCV agent is selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidase inhibitor, a helicase inhibitor, a Toll-like receptor agonist, and combinations thereof.

Embodiment 16

The method of Embodiment 13, wherein X is selected from the group consisting of -hydrogen; -a cyano group; and -a —CORa group, where Ra is: -a C1 to C6 alkyl, or -a dialkyl-amino.

Embodiment 17

The method of Embodiment 13, wherein Y is selected from the group consisting of

Embodiment 18

The method of Embodiment 13, wherein Y is selected from the group consisting of

Embodiment 19

The method of Embodiment 13, wherein R is a hydrogen.

Embodiment 20

The method of Embodiment 13, wherein R1 is selected from the group consisting of a hydrogen; -a halogen; -a nitro group; -a 5 or 6 membered heterocycle; -an alkoxy optionally substituted with: -a C6 to C8 aryl; -a C6 to C8 aryl optionally substituted with an alkoxy

Embodiment 21

The method of Embodiment 13, wherein R2 is selected from the group consisting of -a nitro group; -a hydrogen; -a halogen; -a hydroxy group; -a C1 to C6 alkyl group, optionally substituted with one or more halogens; -an alkoxy group optionally substituted with: -one or more halogens, -an —OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, or -a 5 or 6 membered heteroaryl group; -an amide group; and -a —NHSO2Rx group, where Rx is as defined above

Embodiment 22

The method of Embodiment 13, wherein R3 is a hydrogen.

Embodiment 23

The method of Embodiment 13, wherein said compound is selected from the compounds of Table A.

Embodiment 24

The method of Embodiment 13, wherein said compound is selected from the compounds of Table B.

Embodiment 25

A method for treating or preventing infection by a virus in a subject, wherein said virus comprises a internal ribosome entry site (IRES), comprising administering to said subject a pharmaceutical composition comprising a viral inhibitory amount of one or more compound having the following formula:


wherein:

  • X is:
    • hydrogen;
    • a nitro group;
    • a cyano group;
    • a —CORa group, where Ra is:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
      • a dialkyl-amino;
    • a —COORx group, where Rx is a C1 to C6 alkyl;
    • a formyl group;
    • a C6 to C8 aryl optionally substituted with an alkoxy; or
    • a 5 or 6-membered heteroaryl optionally substituted with:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
      • a 5 to 6 membered heteroaryl;
  • Y is:
    • a hydrogen;
    • a haloalkyl;
    • a halogen;
    • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a benzofuran;
    • a benzothiophene;
    • a dibenzofuran;
    • a dibenzothiophene;
    • a benzothiazole;
    • a naphthalene;
    • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
      where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
      where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
      where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
    • a —NHCORe group, where Re is:
      • a C1 to C6 alkyl;
      • a C6 to C8 aryl optionally substituted with:
        • a C1 to C6 alkyl,
        • an alkoxy,
        • a cyano group,
        • a nitro group, or
        • a halogen;
    • a —NHCOORx group, where Rx is as defined above;
    • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
    • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
    • a C1 to C6 alkyl;
    • a 5 or 6 membered heteroaryl, optionally substituted with:
      • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
      • an amino group;
    • a 5 or 6 membered heterocycle optionally substituted with:
      • a —COORx group, where Rx is as defined above, or
      • a —NHCOORx group, where Rx is as defined above;
    • a C6 to C8 aryl, optionally substituted with one or more of the following:
      • an alkoxy, optionally substituted with:
        • an alkoxy,
        • a hydroxy,
        • one or more halogens,
        • a 5 or 6 membered heterocycle, optionally substituted with:
          • a C1 to C6 alkyl, or
          • a hydroxy,
        • an amino group optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiSO2Rx group, where Rx is as defined above and R1 is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRjCORk group, where Rk is:
          • a C1 to C6 alkyl,
          • a hydrogen, or
          • an amino optionally substituted with one or more C1 to C6 alkyls,
        • and Rj is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —N═N+═N group, or
        • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
      • an amino optionally substituted with one or more C1 to C6 alkyls,
      • a nitro group,
      • a C1 to C6 alkyl group, optionally substituted with:
        • a —NHSO2Rx group, where Rx is as defined above, or
        • a —NRxSO2Rx group, where Rx is as defined above,
      • a haloalkoxy,
      • a halogen,
      • a hydroxy,
      • a —COORx group, where Rx is as defined above,
      • a —CORm group, where Rm is:
        • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
          • a hydroxy
          • a 5 or 6 membered heterocycle,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • an alkoxy,
        • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
        • a —NHRn group, where Rn is:
          • a —CH2CONH2, or
          • a C6 to C8 aryl optionally substituted with:
          •  an alkyl,
          •  one or more halogens,
          •  a nitro group, or
          •  one or more alkoxys,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with a halogen,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
        • a hydrogen,
      • and where Ro is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRqCONRqRr group, where Rq is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a haloalkyl,
        • a haloalkoxy, or
        • a —CORx group, where Rx is as defined above,
      • and where Rr is:
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a —ORs group, where Rs is a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a halogen,
          • an alkylene,
          • a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a —COORx group, where Rx is as defined above,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with:
          • a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
          • an alkylene,
          • an alkoxy,
          • an alkyne,
          • a halogen, or
          • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with:
          • an alkoxy,
          • a halogen, or
          • a C1 to C6 alkyl, or
        • a 5 or 6 membered heterocycle,
      • and Rt is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRvSO2Rw group, where Rv is:
        • a hydrogen,
        • a —CORx, where Rx is as defined above, or
        • a C1 to C6 alkyl, optionally substituted with:
          • a halogen,
          • a —CORx group, where Rx is as defined above,
          • a —OCORx group, where Rx is as defined above,
          • a hydroxyl,
          • a hydroxyl, or
          • an alkoxy,
      • and where Rw is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • a haloalkyl,
          • a C6 to C8 aryl, or
          • a 5 or 6 membered heterocycle,
        • a C2 to C6 alkylene,
        • an alkyl- or dialkyl-amino optionally substituted with a halogen,
        • a 5 or 6 membered heterocycle, or
        • a 5 or 6 membered heteroaryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a 5 or 6 membered heterocycle, or
      •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
      • where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a —SRx group, where Rx is as defined above,
      • a —SO2Raa group, where Raa is:
        • a C1 to C6 alkyl,
        • an amino group,
        • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
        • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, or
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
    •  group, where Rcc is:
      • a naphthalene,
      • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an hydroxy,
        • a halogen,
        • a C1 to C6 alkyl, optionally substituted with a cyano group,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NHPORxRx, where Rx is as defined above,
        • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
          • a hydrogen,
          • a haloalkyl,
          • a haloalkoxy,
          • a C1 to C6 alkyl, or
          • a —CORx, where Rx is as defined above,
        • a —NRggCORhh group, where Rhh is:
          • a hydrogen,
          • a C1 to C6 alkyl optionally substituted with:
          •  an alkoxy,
          •  a halogen, or
          •  an amino optionally substituted with one or more C1 to C6 alkyls,
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl,
        • and Rgg is:
          • a hydrogen,
          • a C1 to C 6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • a haloalkyl,
        • 5 or 6 membered heterocycle groups,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy,
          • a —CORx group, where Rx is as defined above;
  • Z is:
    • a hydrogen;
    • a C1 to C6 alkyl optionally substituted with:
      • an alkoxy,
      • one or more halogens, or
      • a C6 to C8 aryl;
    • a C2 to C6 alkylene;
    • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
    • a —COORx group, where Rx is as defined above; or
  • R is a hydrogen, a halogen or an alkoxy;
  • R1 is:
    • a hydrogen;
    • a hydroxy;
    • a halogen;
    • a haloalkyl;
    • a nitro group;
    • a 5 or 6 membered heteroaryl;
    • a 5 or 6 membered heterocycle;
    • an alkoxy optionally substituted with:
      • one or more halogens,
      • a C6 to C8 aryl, or
      • a 5 or 6 membered heterocycle;
    • a C6 to C8 aryl optionally substituted with an alkoxy;
    • a —CORx group, where Rx is as defined above;
    • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
  • R1 joins together with R2 to form:
  • R2 is:
    • a nitro group;
    • a hydrogen;
    • a halogen;
    • a hydroxy group;
    • a C1 to C6 alkyl group, optionally substituted with one or more halogens;
    • an amino group;
    • an alkoxy group optionally substituted with:
      • one or more halogens,
      • an —OCORx group, where Rx is as defined above,
      • a dialkyl-amino optionally substituted with an alkoxy,
      • a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
      • a 5 or 6 membered heteroaryl group, or
      • a C6 to C8 aryl group;
    • a —COORx group, where Rx is as defined above;
    • a haloalkyl;
    • an amide group optionally substituted with:
      • a hydroxy group, or
      • a C6 to C8 aryl;
    • a 5 or 6 membered heteroaryl;
    • a —OCORx group, where Rx is as defined above;
    • a —NHCORjj group, where Rjj is:
      • an alkoxy, or
      • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
    • a —NHSO2Rx group, where Rx is as defined above; or
  • R2 joins together with R1 to form:
  • R3 is:
    • a hydrogen; or —CH2OCORx, and Rx is as defined above;
      and/or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Embodiment 33

The method of Embodiment 32 wherein said pharmaceutical composition further comprises at least one additional anti-viral agent.

Embodiment 34

The method of Embodiment 33, wherein said at least one additional anti-viral agent is elected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidase inhibitor, a helicase inhibitor, and a Toll-like receptor agonist.

Embodiment 26

A compound selected from the group consisting of the following:

Embodiment 27

A compound selected from the group consisting of the following:

Embodiment 27

A compound selected from the group consisting of the following:

Embodiment 29

A pharmaceutical composition for affecting viral IRES activity in a subject infected with a virus, comprising one or more compound having the following formula:


wherein:

  • X is:
    • hydrogen;
    • a nitro group;
    • a cyano group;
    • a —CORa group, where Ra is:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
      • a dialkyl-amino;
    • a —COORx group, where Rx is a C1 to C6 alkyl;
    • a formyl group;
    • a C6 to C8 aryl optionally substituted with an alkoxy; or
    • a 5 or 6-membered heteroaryl optionally substituted with:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
      • a 5 to 6 membered heteroaryl;
  • Y is:
    • a hydrogen;
    • a haloalkyl;
    • a halogen;
    • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a benzofuran;
    • a benzothiophene;
    • a dibenzofuran;
    • a dibenzothiophene;
    • a benzothiazole;
    • a naphthalene;
    • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
      where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
      where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
      where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
    • a —NHCORe group, where Re is:
      • a C1 to C6 alkyl;
      • a C6 to C8 aryl optionally substituted with:
        • a C1 to C6 alkyl,
        • an alkoxy,
        • a cyano group,
        • a nitro group, or
        • a halogen;
    • a —NHCOORx group, where Rx is as defined above;
    • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
    • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
    • a C1 to C6 alkyl;
    • a 5 or 6 membered heteroaryl, optionally substituted with:
      • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
      • an amino group;
    • a 5 or 6 membered heterocycle optionally substituted with:
      • a —COORx group, where Rx is as defined above, or
      • a —NHCOORx group, where Rx is as defined above;
    • a C6 to C8 aryl, optionally substituted with one or more of the following:
      • an alkoxy, optionally substituted with:
        • an alkoxy,
        • a hydroxy,
        • one or more halogens,
        • a 5 or 6 membered heterocycle, optionally substituted with:
          • a C1 to C6 alkyl, or
          • a hydroxy,
        • an amino group optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiSO2Rx group, where Rx is as defined above and Ri is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRjCORk group, where Rk is:
          • a C1 to C6 alkyl,
          • a hydrogen, or
          • an amino optionally substituted with one or more C1 to C6 alkyls,
        • and Rj is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —N═N+═N group, or
        • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
      • an amino optionally substituted with one or more C1 to C6 alkyls,
      • a nitro group,
      • a C1 to C6 alkyl group, optionally substituted with:
        • a —NHSO2Rx group, where Rx is as defined above, or
        • a —NRxSO2Rx group, where Rx is as defined above,
      • a haloalkoxy,
      • a halogen,
      • a hydroxy,
      • a —COORx group, where Rx is as defined above,
      • a —CORm group, where Rm is:
        • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
          • a hydroxy
          • a 5 or 6 membered heterocycle,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • an alkoxy,
        • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
        • a —NHRn group, where Rn is:
          • a —CH2CONH2, or
          • a C6 to C8 aryl optionally substituted with:
          •  an alkyl,
          •  one or more halogens,
          •  a nitro group, or
          •  one or more alkoxys,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with a halogen,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyls,
        • a hydrogen,
      • and where Ro is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRqCONRqRr group, where Rq is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a haloalkyl,
        • a haloalkoxy, or
        • a —CORx group, where Rx is as defined above,
      • and where Rr is:
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a —ORs group, where Rs is a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a halogen,
          • an alkylene,
          • a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a —COORx group, where Rx is as defined above,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with:
          • a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
          • an alkylene,
          • an alkoxy,
          • an alkyne,
          • a halogen, or
          • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with:
          • an alkoxy,
          • a halogen, or
          • a C1 to C6 alkyl, or
        • a 5 or 6 membered heterocycle,
      • and Rt is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRvSO2Rw group, where Rv is:
        • a hydrogen,
        • a —CORx, where Rx is as defined above, or
        • a C1 to C6 alkyl, optionally substituted with:
          • a halogen,
          • a —CORx group, where Rx is as defined above,
          • a —OCORx group, where Rx is as defined above,
          • a hydroxyl,
          • a hydroxyl, or
          • an alkoxy,
      • and where Rw is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • a haloalkyl,
          • a C6 to C8 aryl, or
          • a 5 or 6 membered heterocycle,
        • a C2 to C6 alkylene,
        • an alkyl- or dialkyl-amino optionally substituted with a halogen,
        • a 5 or 6 membered heterocycle, or
        • a 5 or 6 membered heteroaryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a 5 or 6 membered heterocycle, or
      •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
    •  where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a —SRx group, where Rx is as defined above,
      • a —SO2Raa group, where Raa is:
        • a C1 to C6 alkyl,
        • an amino group,
        • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
        • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, or
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
    •  group, where Rcc is:
      • a naphthalene,
      • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an hydroxy,
        • a halogen,
        • a C1 to C6 alkyl, optionally substituted with a cyano group,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NHPORxRx, where Rx is as defined above,
        • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
          • a hydrogen,
          • a haloalkyl,
          • a haloalkoxy,
          • a C1 to C6 alkyl, or
          • a —CORx, where Rx is as defined above,
        • a —NRggCORhh group, where Rhh is:
          • a hydrogen,
          • a C1 to C6 alkyl optionally substituted with:
          •  an alkoxy,
          •  a halogen, or
          •  an amino optionally substituted with one or more C1 to C6 alkyls,
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl,
        • and Rgg is:
          • a hydrogen,
          • a C1 to C 6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • a haloalkyl,
        • 5 or 6 membered heterocycle groups,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy,
          • a —CORx group, where Rx is as defined above;
  • Z is:
    • a hydrogen;
    • a C1 to C6 alkyl optionally substituted with:
      • an alkoxy,
      • one or more halogens, or
      • a C6 to C8 aryl;
    • a C2 to C6 alkylene;
    • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
    • a —COORx group, where Rx is as defined above; or
  • R is a hydrogen, a halogen or an alkoxy;
  • R1 is:
    • a hydrogen;
    • a hydroxy;
    • a halogen;
    • a haloalkyl;
    • a nitro group;
    • a 5 or 6 membered heteroaryl;
    • a 5 or 6 membered heterocycle;
    • an alkoxy optionally substituted with:
      • one or more halogens,
      • a C6 to C8 aryl, or
      • a 5 or 6 membered heterocycle;
    • a C6 to C8 aryl optionally substituted with an alkoxy;
    • a —CORx group, where Rx is as defined above;
    • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
  • R1 joins together with R2 to form:
  • R2 is:
    • a nitro group;
    • a hydrogen;
    • a halogen;
    • a hydroxy group;
    • a C1 to C6 alkyl group, optionally substituted with one or more halogens;
    • an amino group;
    • an alkoxy group optionally substituted with:
      • one or more halogens,
      • an —OCORx group, where Rx is as defined above,
      • a dialkyl-amino optionally substituted with an alkoxy,
      • a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
      • a 5 or 6 membered heteroaryl group, or
      • a C6 to C8 aryl group;
    • a —COORx group, where Rx is as defined above;
    • a haloalkyl;
    • an amide group optionally substituted with:
      • a hydroxy group, or
      • a C6 to C8 aryl;
    • a 5 or 6 membered heteroaryl;
    • a —OCORx group, where Rx is as defined above;
    • a —NHCORjj group, where Rjj is:
      • an alkoxy, or
      • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
    • a —NHSO2Rx group, where Rx is as defined above; or
  • R2 joins together with R1 to form:
  • R3 is:
    • a hydrogen; or
    • CH2OCORx, and Rx is as defined above;
      or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and optionally one or more compound known in the art to affect IRES activity.
Embodiment 30

The pharmaceutical composition of Embodiment 29, wherein said one or more compound known in the art to affect IRES activity affects IRES mediated translation of the single ORF encoding the polyprotein.

Embodiment 31

A method for affecting viral IRES activity in a subject infected with a virus, comprising administering to said subject one or more compound having the following formula:


wherein:

  • X is:
    • hydrogen;
    • a nitro group;
    • a cyano group;
    • a —CORa group, where Ra is:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
      • a dialkyl-amino;
    • a —COORx group, where Rx is a C1 to C6 alkyl;
    • a formyl group;
    • a C6 to C8 aryl optionally substituted with an alkoxy; or
    • a 5 or 6-membered heteroaryl optionally substituted with:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
      • a 5 to 6 membered heteroaryl;
  • Y is:
    • a hydrogen;
    • a haloalkyl;
    • a halogen;
    • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a benzofuran;
    • a benzothiophene;
    • a dibenzofuran;
    • a dibenzothiophene;
    • a benzothiazole;
    • a naphthalene;
    • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
      where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
      where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
      where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
    • a —NHCORe group, where Re is:
      • a C1 to C6 alkyl;
      • a C6 to C8 aryl optionally substituted with:
        • a C1 to C6 alkyl,
        • an alkoxy,
        • a cyano group,
        • a nitro group, or
        • a halogen;
    • a —NHCOORx group, where Rx is as defined above;
    • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
    • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
    • a C1 to C6 alkyl;
    • a 5 or 6 membered heteroaryl, optionally substituted with:
      • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
      • an amino group;
    • a 5 or 6 membered heterocycle optionally substituted with:
      • a —COORx group, where Rx is as defined above, or
      • a —NHCOORx group, where Rx is as defined above;
    • a C6 to C8 aryl, optionally substituted with one or more of the following:
      • an alkoxy, optionally substituted with:
        • an alkoxy,
        • a hydroxy,
        • one or more halogens,
        • a 5 or 6 membered heterocycle, optionally substituted with:
          • a C1 to C6 alkyl, or
          • a hydroxy,
        • an amino group optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiSO2Rx group, where Rx is as defined above and Ri is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRjCORk group, where Rk is:
          • a C1 to C6 alkyl,
          • a hydrogen, or
          • an amino optionally substituted with one or more C1 to C6 alkyls,
        • and Rj is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —N═N+═N group, or
        • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
      • an amino optionally substituted with one or more C1 to C6 alkyls,
      • a nitro group,
      • a C1 to C6 alkyl group, optionally substituted with:
        • a —NHSO2Rx group, where Rx is as defined above, or
        • a —NRxSO2Rx group, where Rx is as defined above,
      • a haloalkoxy,
      • a halogen,
      • a hydroxy,
      • a —COORx group, where Rx is as defined above,
      • a —CORm group, where Rm is:
        • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
          • a hydroxy
          • a 5 or 6 membered heterocycle,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • an alkoxy,
        • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
        • a —NHRn group, where Rn is:
          • a —CH2CONH2, or
          • a C6 to C8 aryl optionally substituted with:
          •  an alkyl,
          •  one or more halogens,
          •  a nitro group, or
          •  one or more alkoxys,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with a halogen,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
        • a hydrogen,
      • and where Ro is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRqCONRqRr group, where Rq is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a haloalkyl,
        • a haloalkoxy, or
        • a —CORx group, where Rx is as defined above,
      • and where Rr is:
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a —ORs group, where Rs is a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a halogen,
          • an alkylene,
          • a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a —COORx group, where Rx is as defined above,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with:
          • a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
          • an alkylene,
          • an alkoxy,
          • an alkyne,
          • a halogen, or
          • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with:
          • an alkoxy,
          • a halogen, or
          • a C1 to C6 alkyl, or
        • a 5 or 6 membered heterocycle,
      • and Rt is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRvSO2Rw group, where Rv is:
        • a hydrogen,
        • a —CORx, where Rx is as defined above, or
        • a C1 to C6 alkyl, optionally substituted with:
          • a halogen,
          • a —CORx group, where Rx is as defined above,
          • a —OCORx group, where Rx is as defined above,
          • a hydroxyl,
          • a hydroxyl, or
          • an alkoxy,
      • and where Rw is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • a haloalkyl,
          • a C6 to C8 aryl, or
          • a 5 or 6 membered heterocycle,
        • a C2 to C6 alkylene,
        • an alkyl- or dialkyl-amino optionally substituted with a halogen,
        • a 5 or 6 membered heterocycle, or
        • a 5 or 6 membered heteroaryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a 5 or 6 membered heterocycle, or
      •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
    •  where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a —SRx group, where Rx is as defined above,
      • a —SO2Raa group, where Raa is:
        • a C1 to C6 alkyl,
        • an amino group,
        • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
        • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, or
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
    •  group, where Wcc is:
      • a naphthalene,
      • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an hydroxy,
        • a halogen,
        • a C1 to C6 alkyl, optionally substituted with a cyano group,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NHPORxRx, where Rx is as defined above,
        • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
          • a hydrogen,
          • a haloalkyl,
          • a haloalkoxy,
          • a C1 to C6 alkyl, or
          • a —CORx, where Rx is as defined above,
        • a —NRggCORhh group, where Rhh is:
          • a hydrogen,
          • a C1 to C6 alkyl optionally substituted with:
          •  an alkoxy,
          •  a halogen, or
          •  an amino optionally substituted with one or more C1 to C6 alkyls,
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl,
        • and Rgg is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • a haloalkyl,
        • 5 or 6 membered heterocycle groups,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy,
          • a —CORx group, where Rx is as defined above;
  • Z is:
    • a hydrogen;
    • a C1 to C6 alkyl optionally substituted with:
      • an alkoxy,
      • one or more halogens, or
      • a C6 to C8 aryl;
    • a C2 to C6 alkylene;
    • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
    • a —COORx group, where Rx is as defined above; or
  • R is a hydrogen, a halogen or an alkoxy;
  • R1 is:
    • a hydrogen;
    • a hydroxy;
    • a halogen;
    • a haloalkyl;
    • a nitro group;
    • a 5 or 6 membered heteroaryl;
    • a 5 or 6 membered heterocycle;
    • an alkoxy optionally substituted with:
      • one or more halogens,
      • a C6 to C8 aryl, or
      • a 5 or 6 membered heterocycle;
    • a C6 to C8 aryl optionally substituted with an alkoxy;
    • a —CORx group, where Rx is as defined above;
    • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
  • R1 joins together with R2 to form:
  • R2 is:
    • a nitro group;
    • a hydrogen;
    • a halogen;
    • a hydroxy group;
    • a C1 to C6 alkyl group, optionally substituted with one or more halogens;
    • an amino group;
    • an alkoxy group optionally substituted with:
      • one or more halogens,
      • an —OCORx group, where Rx is as defined above,
      • a dialkyl-amino optionally substituted with an alkoxy,
      • a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
      • a 5 or 6 membered heteroaryl group, or
      • a C6 to C8 aryl group;
    • a —COORx group, where Rx is as defined above;
    • a haloalkyl;
    • an amide group optionally substituted with:
      • a hydroxy group, or
      • a C6 to C8 aryl;
    • a 5 or 6 membered heteroaryl;
    • a —OCORx group, where Rx is as defined above;
    • a —NHCORjj group, where Rjj is:
      • an alkoxy, or
      • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
    • a —NHSO2Rx group, where Rx is as defined above; or
  • R2 joins together with R1 to form:
  • R3 is:
    • a hydrogen; or
    • CH2OCORx, and Rx is as defined above;
      or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and optionally one or more compound known in the art to affect IRES activity.
Embodiment 32

The method of Embodiment 31, wherein said compound known in the art to affect IRES activity affects IRES mediated translation of the single ORF encoding the polyprotein.

Embodiment 33

A pharmaceutical composition for affecting viral IRES activity in a subject infected with a virus, comprising one or more compound having the following formula, in an amount effective for affecting viral IRES activity:


wherein:

  • X is:
    • hydrogen;
    • a nitro group;
    • a cyano group;
    • a —CORa group, where Ra is:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
      • a dialkyl-amino;
    • a —COORx group, where Rx is a C1 to C6 alkyl;
    • a formyl group;
    • a C6 to C8 aryl optionally substituted with an alkoxy; or
    • a 5 or 6-membered heteroaryl optionally substituted with:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
      • a 5 to 6 membered heteroaryl;
  • Y is:
    • a hydrogen;
    • a haloalkyl;
    • a halogen;
    • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a benzofuran;
    • a benzothiophene;
    • a dibenzofuran;
    • a dibenzothiophene;
    • a benzothiazole;
    • a naphthalene;
    • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
      where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
      where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
      where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
    • a —NHCORe group, where Re is:
      • a C1 to C6 alkyl;
      • a C6 to C8 aryl optionally substituted with:
        • a C1 to C6 alkyl,
        • an alkoxy,
        • a cyano group,
        • a nitro group, or
        • a halogen;
    • a —NHCOORx group, where Rx is as defined above;
    • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
    • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
    • a C1 to C6 alkyl;
    • a 5 or 6 membered heteroaryl, optionally substituted with:
      • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
      • an amino group;
    • a 5 or 6 membered heterocycle optionally substituted with:
      • a —COORx group, where Rx is as defined above, or
      • a —NHCOORx group, where Rx is as defined above;
    • a C6 to C8 aryl, optionally substituted with one or more of the following:
      • an alkoxy, optionally substituted with:
        • an alkoxy,
        • a hydroxy,
        • one or more halogens,
        • a 5 or 6 membered heterocycle, optionally substituted with:
          • a C1 to C6 alkyl, or
          • a hydroxy,
        • an amino group optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiSO2Rx group, where Rx is as defined above and Ri is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRjCORk group, where Rk is:
          • a C1 to C6 alkyl,
          • a hydrogen, or
          • an amino optionally substituted with one or more C1 to C6 alkyls,
        • and Rj is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —N═N+═N group, or
        • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
      • an amino optionally substituted with one or more C1 to C6 alkyls,
      • a nitro group,
      • a C1 to C6 alkyl group, optionally substituted with:
        • a —NHSO2Rx group, where Rx is as defined above, or
        • a —NRxSO2Rx group, where Rx is as defined above,
      • a haloalkoxy,
      • a halogen,
      • a hydroxy,
      • a —COORx group, where Rx is as defined above,
      • a —CORm group, where Rm is:
        • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
          • a hydroxy
          • a 5 or 6 membered heterocycle,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • an alkoxy,
        • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
        • a —NHRn group, where Rn is:
          • a —CH2CONH2, or
          • a C6 to C8 aryl optionally substituted with:
          •  an alkyl,
          •  one or more halogens,
          •  a nitro group, or
          •  one or more alkoxys,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with a halogen,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
        • a hydrogen,
      • and where Ro is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRqCONRqRr group, where Rq is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a haloalkyl,
        • a haloalkoxy, or
        • a —CORx group, where Rx is as defined above,
      • and where Rr is:
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a —ORs group, where Rs is a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a halogen,
          • an alkylene,
          • a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a —COORx group, where Rx is as defined above,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with:
          • a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
          • an alkylene,
          • an alkoxy,
          • an alkyne,
          • a halogen, or
          • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with:
          • an alkoxy,
          • a halogen, or
          • a C1 to C6 alkyl, or
        • a 5 or 6 membered heterocycle,
      • and Rt is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRvSO2Rw group, where Rv is:
        • a hydrogen,
        • a —CORx, where Rx is as defined above, or
        • a C1 to C6 alkyl, optionally substituted with:
          • a halogen,
          • a —CORx group, where Rx is as defined above,
          • a —OCORx group, where Rx is as defined above,
          • a hydroxyl,
          • a hydroxyl, or
          • an alkoxy,
      • and where Rw is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • a haloalkyl,
          • a C6 to C8 aryl, or
          • a 5 or 6 membered heterocycle,
        • a C2 to C6 alkylene,
        • an alkyl- or dialkyl-amino optionally substituted with a halogen,
        • a 5 or 6 membered heterocycle, or
        • a 5 or 6 membered heteroaryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a 5 or 6 membered heterocycle, or
    •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
    •  where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a —SRx group, where Rx is as defined above,
      • a —SO2Raa group, where Raa is:
        • a C1 to C6 alkyl,
        • an amino group,
        • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
        • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, or
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
    •  group, where Rcc is:
      • a naphthalene,
      • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an hydroxy,
        • a halogen,
        • a C1 to C6 alkyl, optionally substituted with a cyano group,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NHPORxRx, where Rx is as defined above,
        • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
          • a hydrogen,
          • a haloalkyl,
          • a haloalkoxy,
          • a C1 to C6 alkyl, or
          • a —CORx, where Rx is as defined above,
        • a —NRggCORhh group, where Rhh is:
          • a hydrogen,
          • a C1 to C6 alkyl optionally substituted with:
          •  an alkoxy,
          •  a halogen, or
          •  an amino optionally substituted with one or more C1 to C6 alkyls,
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl,
        • and Rgg is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • a haloalkyl,
        • 5 or 6 membered heterocycle groups,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy,
          • a —CORx group, where Rx is as defined above;
  • Z is:
    • a hydrogen;
    • a C1 to C6 alkyl optionally substituted with:
      • an alkoxy,
      • one or more halogens, or
      • a C6 to C8 aryl;
    • a C2 to C6 alkylene;
    • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
    • a —COORx group, where Rx is as defined above; or
  • R is a hydrogen, a halogen or an alkoxy;
  • R1 is:
    • a hydrogen;
    • a hydroxy;
    • a halogen;
    • a haloalkyl;
    • a nitro group;
    • a 5 or 6 membered heteroaryl;
    • a 5 or 6 membered heterocycle;
    • an alkoxy optionally substituted with:
      • one or more halogens,
      • a C6 to C8 aryl, or
      • a 5 or 6 membered heterocycle;
    • a C6 to C8 aryl optionally substituted with an alkoxy;
    • a —CORx group, where Rx is as defined above;
    • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
  • R1 joins together with R2 to form:
  • R2 is:
    • a nitro group;
    • a hydrogen;
    • a halogen;
    • a hydroxy group;
    • a C1 to C6 alkyl group, optionally substituted with one or more halogens;
    • an amino group;
    • an alkoxy group optionally substituted with:
      • one or more halogens,
      • an —OCORx group, where Rx is as defined above,
      • a dialkyl-amino optionally substituted with an alkoxy,
      • a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
      • a 5 or 6 membered heteroaryl group, or
      • a C6 to C8 aryl group;
    • a —COORx group, where Rx is as defined above;
    • a haloalkyl;
    • an amide group optionally substituted with:
      • a hydroxy group, or
      • a C6 to C8 aryl;
    • a 5 or 6 membered heteroaryl;
    • a —OCORx group, where Rx is as defined above;
    • a —NHCORjj group, where Rjj is:
      • an alkoxy, or
      • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
    • a —NHSO2Rx group, where Rx is as defined above; or
  • R2 joins together with R1 to form:
  • R3 is:
    • a hydrogen; or —CH2OCORx, and Rx is as defined above;
      or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the HCV-PV chimera construct. The cloverleaf-like RNA structure of PV, an essential cis-acting replication signal ending with the genome-linked protein VPg, is located at the 5′ end of the genome. The solid (HCV) and open (PV) boxes depict open reading frames encoding viral polypeptides. The position of the HCV core fragment (the first 123 amino acids) gene is denoted by A Core. Overall, the HCV_specific sequence in the HCV-PV spans from nucleotides 18 to 710 (139).

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds that modify HCV translation have been identified and methods of using these compounds for preventing or treating HCV infection are provided. Without being limited to one theory, it is believed that the compounds of the present invention inhibit IRES-mediated initiation and translation. The HCV IRES directs the translation of a single long ORF encoding a polyprotein that is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), E1 and E2 and the nonstructural (NS) proteins NS2 to NS5B.

A. Compounds of the Invention

In one aspect of the invention, compounds of the invention are provided which are useful for preventing or treating HCV infection.

Preferred compounds of the present invention useful for preventing or treating HCV infection include those of Formula (I) as shown below.


wherein:

  • X is:
    • hydrogen;
    • a nitro group;
    • a cyano group;
    • a —CORa group, where Ra is:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or
      • a dialkyl-amino;
    • a —COORx group, where Rx is a C1 to C6 alkyl;
    • a formyl group;
    • a C6 to C8 aryl optionally substituted with an alkoxy; or
    • a 5 or 6-membered heteroaryl optionally substituted with:
      • a C1 to C6 alkyl,
      • a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogens, or
      • a 5 to 6 membered heteroaryl;
  • Y is:
    • a hydrogen;
    • a haloalkyl;
    • a halogen;
    • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a benzofuran;
    • a benzothiophene;
    • a dibenzofuran;
    • a dibenzothiophene;
    • a benzothiazole;
    • a naphthalene;
    • an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
      where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
      where Rc is a hydrogen, a —CONHRx, where Rx is as defined above, or an —SO2Rx, where Rx is as defined above; or
      where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
    • a —NHCORe group, where Re is:
      • a C1 to C6 alkyl;
      • a C6 to C8 aryl optionally substituted with:
        • a C1 to C6 alkyl,
        • an alkoxy,
        • a cyano group,
        • a nitro group, or
        • a halogen;
    • a —NHCOORx group, where Rx is as defined above;
    • a —CH2O—Rf group, where Rf is a C6 to C8 aryl;
    • a —NRgRh group, where Rg is a C1 to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
    • a C1 to C6 alkyl;
    • a 5 or 6 membered heteroaryl, optionally substituted with:
      • a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a C6 to C8 aryl, optionally substituted with —COORx, where Rx is as defined above, or
      • an amino group;
    • a 5 or 6 membered heterocycle optionally substituted with:
      • a —COORx group, where Rx is as defined above, or
      • a —NHCOORx group, where Rx is as defined above;
    • a C6 to C8 aryl, optionally substituted with one or more of the following:
      • an alkoxy, optionally substituted with:
        • an alkoxy,
        • a hydroxy,
        • one or more halogens,
        • a 5 or 6 membered heterocycle, optionally substituted with:
          • a C1 to C6 alkyl, or
          • a hydroxy,
        • an amino group optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiSO2Rx group, where Rx is as defined above and Ri is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —NRjCORk group, where Rk is:
          • a C1 to C6 alkyl,
          • a hydrogen, or
          • an amino optionally substituted with one or more C1 to C6 alkyls,
        • and Rj is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a —CORx group, where Rx is as defined above,
          • a haloalkyl, or
          • a haloalkoxy,
        • a —N═N+═N group, or
        • a —CORl, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
      • an amino optionally substituted with one or more C1 to C6 alkyls,
      • a nitro group,
      • a C1 to C6 alkyl group, optionally substituted with:
        • a —NHSO2Rx group, where Rx is as defined above, or
        • a —NRxSO2Rx group, where Rx is as defined above,
      • a haloalkoxy,
      • a halogen,
      • a hydroxy,
      • a —COORx group, where Rx is as defined above,
      • a —CORm group, where Rm is:
        • an amino optionally substituted with one or more C1 to C6 alkyls, where the C1 to C6 alkyls are optionally substituted with:
          • a hydroxy
          • a 5 or 6 membered heterocycle,
          • an amino optionally substituted with one or more C1 to C6 alkyls,
          • an alkoxy,
        • a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino,
        • a —NHRn group, where Rn is:
          • a —CH2CONH2, or
          • a C6 to C8 aryl optionally substituted with:
          •  an alkyl,
          •  one or more halogens,
          •  a nitro group, or
          •  one or more alkoxys,
      • a —NRoCORp group, where Rp is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • an alkoxy, or
          • a C6 to C8 aryl,
        • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with a halogen,
        • a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls,
        • a hydrogen,
      • and where Ro is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRqCONRqRr group, where Rq is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a haloalkyl,
        • a haloalkoxy, or
        • a —CORx group, where Rx is as defined above,
      • and where Rr is:
        • a C6 to C8 aryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a —ORs group, where Rs is a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a C1 to C6 alkyl optionally substituted with one or more of the following:
          • a halogen,
          • an alkylene,
          • a C6 to C8 aryl, or
          • a —COORx group, where Rx is as defined above,
        • a —COORx group, where Rx is as defined above,
      • a —NRtCOORu group, where Ru is:
        • a C1 to C12 alkyl, optionally substituted with:
          • a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy,
          • an alkylene,
          • an alkoxy,
          • an alkyne,
          • a halogen, or
          • a 5 or 6 membered heterocycle,
        • a C6 to C8 aryl, optionally substituted with:
          • an alkoxy,
          • a halogen, or
          • a C1 to C6 alkyl, or
        • a 5 or 6 membered heterocycle,
      • and Rt is:
        • a hydrogen,
        • a C1 to C6 alkyl,
        • a —CORx group, where Rx is as defined above,
        • a haloalkyl, or
        • a haloalkoxy,
      • a —NRvSO2Rw group, where Rv is:
        • a hydrogen,
        • a —CORx, where Rx is as defined above, or
        • a C1 to C6 alkyl, optionally substituted with:
          • a halogen,
          • a —CORx group, where Rx is as defined above,
          • a —OCORx group, where Rx is as defined above,
          • a hydroxyl,
          • a hydroxyl, or
          • an alkoxy,
      • and where Rw is:
        • a C1 to C6 alkyl optionally substituted with:
          • a halogen,
          • a haloalkyl,
          • a C6 to C8 aryl, or
          • a 5 or 6 membered heterocycle,
        • a C2 to C6 alkylene,
        • an alkyl- or dialkyl-amino optionally substituted with a halogen,
        • a 5 or 6 membered heterocycle, or
        • a 5 or 6 membered heteroaryl optionally substituted with:
          • a C1 to C6 alkyl,
          • a 5 or 6 membered heterocycle, or
    •  optionally substituted with a C1 to C6 alkyl, where Ry is a C1 to C6 alkyl or hydrogen,
    •  where Rz is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl,
      • a —SRx group, where Rx is as defined above,
      • a —SO2Raa group, where Raa is:
        • a C1 to C6 alkyl,
        • an amino group,
        • an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a —COORx group, where Rx is as defined above,
        • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, or
      • a —NHRbb group, where Rbb is:
        • a —C(═S)NH2 group, or
        • a —PO(ORx)2, where Rx is as defined above;
    •  group, where Rcc is:
      • a naphthalene,
      • a 5 or 6 membered heteroaryl,
      • a C6 to C8 aryl, optionally substituted with one or more of the following:
        • an alkoxy,
        • an hydroxy,
        • a halogen,
        • a C1 to C6 alkyl, optionally substituted with a cyano group,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NHPORxRx, where Rx is as defined above,
        • a —NReeCONRffRff group, where Ree is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and Rff is:
          • a hydrogen,
          • a haloalkyl,
          • a haloalkoxy,
          • a C1 to C6 alkyl, or
          • a —CORx, where Rx is as defined above,
        • a —NRggCORhh group, where Rhh is:
          • a hydrogen,
          • a C1 to C6 alkyl optionally substituted with:
          •  an alkoxy,
          •  a halogen, or
          •  an amino optionally substituted with one or more C1 to C6 alkyls,
          • an amino optionally substituted with one or more C1 to C6 alkyls, where the alkyls are optionally substituted with a halogen,
          • a 5 or 6 membered heterocycle,
          • a 5 or 6 membered heteroaryl,
        • and Rgg is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy, or
          • a —CORx group, where Rx is as defined above,
        • a haloalkyl,
        • 5 or 6 membered heterocycle groups,
        • an amino optionally substituted with one or more C1 to C6 alkyls,
        • a —NRiiSO2Rx group, where Rx is as defined above, and Rii is:
          • a hydrogen,
          • a C1 to C6 alkyl,
          • a haloalkyl,
          • a haloalkoxy,
          • a —CORx group, where Rx is as defined above;
  • Z is:
    • a hydrogen;
    • a C1 to C6 alkyl optionally substituted with:
      • an alkoxy,
      • one or more halogens, or
      • a C6 to C8 aryl;
    • a C2 to C6 alkylene;
    • a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyls;
    • a —COORx group, where Rx is as defined above; or
  • R is a hydrogen, a halogen or an alkoxy;
  • R1 is:
    • a hydrogen;
    • a hydroxy;
    • a halogen;
    • a haloalkyl;
    • a nitro group;
    • a 5 or 6 membered heteroaryl;
    • a 5 or 6 membered heterocycle;
    • an alkoxy optionally substituted with:
      • one or more halogens,
      • a C6 to C8 aryl, or
      • a 5 or 6 membered heterocycle;
    • a C6 to C8 aryl optionally substituted with an alkoxy;
    • a —CORx group, where Rx is as defined above;
    • a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
  • R1 joins together with R2 to form:
  • R2 is:
    • a nitro group;
    • a hydrogen;
    • a halogen;
    • a hydroxy group;
    • a C1 to C6 alkyl group, optionally substituted with one or more halogens;
    • an amino group;
    • an alkoxy group optionally substituted with:
      • one or more halogens,
      • an —OCORx group, where Rx is as defined above,
      • a dialkyl-amino optionally substituted with an alkoxy,
      • a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl,
      • a 5 or 6 membered heteroaryl group, or
      • a C6 to C8 aryl group;
    • a —COORx group, where Rx is as defined above;
    • a haloalkyl;
    • an amide group optionally substituted with:
      • a hydroxy group, or
      • a C6 to C8 aryl;
    • a 5 or 6 membered heteroaryl;
    • a —OCORx group, where Rx is as defined above;
    • a —NHCORjj group, where Rjj is:
      • an alkoxy, or
      • an amino optionally substituted with one or more C1 to C6 alkyls;
    • a —ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
    • a —NHSO2Rx group, where Rx is as defined above; or
  • R2 joins together with R1 to form:
  • R3 is:
    • a hydrogen; or
    • CH2OCORx, and Rx is as defined above;
      or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, a compound or a composition of the present invention includes a compound of Formula I, wherein the compound of Formula I is not

As used herein, the term “alkyl” generally refers to saturated hydrocarbyl radicals of straight, branched or cyclic configuration, or combinations of cyclic and branched or straight, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclohexyl, n-heptyl, octyl, n-octyl, and the like. In some embodiments, alkyl substituents may be C1 to C12, or C1 to C8 or C1 to C6 alkyl groups.

As used herein, “alkylene” generally refers to linear, branched or cyclic alkene radicals having one or more carbon-carbon double bonds, such as C2 to C6 alkylene groups including 3-propenyl.

As used herein, “aryl” refers to a carbocyclic aromatic ring structure. Included in the scope of aryl groups are aromatic rings having from five to twenty carbon atoms. Aryl ring structures include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Examples of aryl groups that include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl (i.e., phenanthrene), and napthyl (i.e., napthalene) ring structures. In certain embodiments, the aryl group may be optionally substituted.

As used herein, “heteroaryl” refers to cyclic aromatic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heteroaryl, and independently selectable, are O, N, and S heteroaryl ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. In some embodiments, the heteroaryl groups may be selected from heteroaryl groups that contain two or more heteroatoms, three or more heteroatoms, or four or more heteroatoms. Heteroaryl ring structures may be selected from those that contain five or more atoms, six or more atoms, or eight or more atoms. Examples of heteroaryl ring structures include: acridine, benzimidazole, benzoxazole, benzodioxole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, furan, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.

As used herein, “heterocycle” refers to cyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heterocycle, and independently selectable, are O, N, and S heterocycle ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Example of heterocyclo groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl or tetrahydrothiopyranyl and the like. In certain embodiments, the heterocycle may optionally be substituted.

As used herein, “alkoxy” generally refers to a group with the structure —O—R, where R is an alkyl group as defined above.

For the purposes of this invention, halo substituents may be independently selected from the halogens such as fluorine, chlorine, bromine, iodine, and astatine. A haloalkyl is an alkyl group, as defined above, substituted with one or more halogens. A haloalkoxy is an alkoxy group, as defined above, substituted with one or more halogens.

For the purposes of this invention, where one or more functionalities encompassing X, Y, Z, R, R1, R2, and R3, are incorporated into a molecule of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently substituted. Further, where a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.

By “substituted” or “optionally substituted” it is meant that the particular substituent may be substituted with a chemical group known to one of skill in the art to be appropriate for the referred-to substituent, unless a chemical group is specifically mentioned.

Exemplary X substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Preferred X substituents include -hydrogen; -a cyano group; and -a —CORa group, where Ra is: -a C1 to C6 alkyl, or -a dialkyl-amino.

Preferred X substituents also include the following, where the * indicates the bond of attachment of the scaffold molecule.

More preferred X substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Exemplary Y substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Preferred Y substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.