Aza-pyridone compounds and uses thereof
Disclosed herein are aza-pyridone compounds, pharmaceutical compositions that include one or more aza-pyridone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an orthomyxovirus infection, with an aza-pyridone compounds. Examples of an orthomyxovirus viral infection include an influenza infection.
1. A method for ameliorating or treating an influenza virus infection comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject suffering from the influenza virus infection, wherein the compound of Formula (I) has the structure:
wherein:
is a single bond or double bond;
R 1 is selected from the group consisting of hydrogen, an unsubstituted C 1-4 alkyl, —C(═O)Y 1 , —C(═O)—O—Y 1 , —(CH 2 )—O—C(═O)—Y 1 , —(CH 2 )—O—C(═O)—O—Y 1 , —(CHCH 3 )—O—C(═O)—Y 1 and —(CHCH 3 )—O—C(═O)—O—Y 1 ;
R 2 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C 1-6 alkyl), an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl(C 1-6 alkyl) and an optionally substituted heterocyclyl(C 1-6 alkyl);
R 3a and R 3b are independently hydrogen or an optionally substituted C 1-4 alkyl;
R 4 and R 5 are independently selected from the group consisting of hydrogen, an optionally substituted aryl, an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl and an optionally substituted heteroaryl(C 1-6 alkyl), provided that at least one of R 4 and R 5 is not hydrogen; or
R 4 and R 5 are taken together with the carbon to which they are attached to form an optionally substituted tricyclic cycloalkenyl or an optionally substituted tricyclic heterocyclyl;
R 6 is selected from the group consisting of hydrogen, halogen, —CN, an optionally substituted C 1-6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —CH 2 OH, —CH(Y 2 )(OH) and —C(O)Y 2 ; and
Y 1 and Y 2 are independently selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, a mono-substituted amino group, and a di-substituted amino group.
2. A method for ameliorating or treating an influenza virus infection comprising contacting a cell infected with the influenza virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:
wherein:
is a single bond or double bond;
R 1 is selected from the group consisting of hydrogen, an unsubstituted C 1-4 alkyl, —C(═O)Y 1 , —C(═O)—O—Y 1 , —(CH 2 )—O—C(═O)—Y 1 , —(CH 2 )—O—C(═O)—O—Y 1 , —(CHCH 3 )—O—C(═O)—Y 1 and —(CHCH 3 )—O—C(═O)—O—Y 1 ;
R 2 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C 1-6 alkyl), an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl(C 1-6 alkyl) and an optionally substituted heterocyclyl(C 1-6 alkyl);
R 3a and R 3b are independently hydrogen or an optionally substituted C 1-4 alkyl;
R 4 and R 5 are independently selected from the group consisting of hydrogen, an optionally substituted aryl, an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl and an optionally substituted heteroaryl(C 1-6 alkyl), provided that at least one of R 4 and R 5 is not hydrogen; or
R 4 and R 5 are taken together with the carbon to which they are attached to form an optionally substituted tricyclic cycloalkenyl or an optionally substituted tricyclic heterocyclyl;
R 6 is selected from the group consisting of hydrogen, halogen, —CN, an optionally substituted C 1-6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —CH 2 OH, —CH(Y 2 )(OH) and —C(O)Y 2 ; and
Y 1 and Y 2 are independently selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, a mono-substituted amino group, and a di-substituted amino group.
3. The method of claim 2 , further comprising contacting the cell with one or more anti-influenza agents.
4. The method of claim 3 , wherein the one or more anti-influenza agents is selected from the group consisting of a neuraminidase inhibitor, a M2 protein inhibitor, a polymerase inhibitor, a PB2 inhibitor, amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir, laninamivir octanoate, favipiravir, fludase, ADS-8902, an immuno-modulator, ribavirin, (R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid, and (2S, 3S)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylic acid (VX-787).
5. The method of claim 2 , wherein the influenza virus is influenza A virus.
6. The method of claim 2 , wherein the influenza virus is influenza B virus.
7. The method of claim 1 , wherein R 4 is an optionally substituted aryl; and R 5 is an optionally substituted aryl.
8. The method of claim 7 , wherein R 4 is an optionally substituted phenyl; and R 5 is an optionally substituted phenyl.
9. The method of claim 1 , wherein R 2 is an optionally substituted C 1-6 alkyl.
10. The method of claim 1 , wherein R 1 is hydrogen.
11. The method of claim 1 , wherein R 1 is —C(═O)Y 1 , —C(═O)—O—Y 1 , —(CH 2 )—O—C(═O)—Y 1 , —(CH 2 )—O—C(═O)—O—Y 1 , —(CHCH 3 )—O—C(═O)—Y 1 and —(CHCH 3 )—O—C(═O)—O—Y 1 .
12. The method of claim 11 , wherein R 1 is —C(═O)Y 1 .
13. The method of claim 12 , wherein Y 1 is an optionally substituted C 1-6 alkyl.
14. The method of claim 1 , wherein R 6 is hydrogen.
15. The method of claim 1 , wherein is a single bond.
16. The method of claim 1 , wherein R 3a is hydrogen; and R 3b is hydrogen.
17. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
18. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
19. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
23. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
24. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
25. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
26. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt of any of the foregoing.
27. The method of claim 1 , wherein R 4 and R 5 are taken together with the carbon to which they are attached to form an optionally substituted tricyclic heterocyclyl.
28. The method of claim 1 , wherein the influenza virus is influenza A virus.
29. The method of claim 1 , wherein the influenza virus is influenza B virus.
30. A method for ameliorating or treating an influenza virus infection comprising administering an effective amount of a compound selected from the group consisting
of or a pharmaceutically acceptable salt of any of the foregoing, to a subject suffering from the influenza virus infection.
31. The method of claim 1 , further comprising administering one or more additional agents.
32. The method of claim 31 , wherein the one or more additional agents is selected from the group consisting of a neuraminidase inhibitor, a M2 protein inhibitor, a polymerase inhibitor, a PB2 inhibitor, amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir, laninamivir octanoate, favipiravir, fludase, ADS-8902, an immuno-modulator, ribavirin, (R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid, and (2S, 3S)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylic acid (VX-787).
33. A method for ameliorating or treating an influenza virus infection comprising contacting a cell infected with the influenza virus with an effective amount of a compound selected from the group consisting of
a pharmaceutically acceptable salt of any of the foregoing.