Compounds for the treatment of paramoxyvirus viral infections
Disclosed herein are new antiviral compounds, together with pharmaceutical compositions that include one or more antiviral compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection with one or more small molecule compounds. Examples of paramyxovirus infection include an infection caused by human respiratory syncytial virus (RSV).
1. A compound of Formula (Id), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
A is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl and an optionally substituted aryl(C 1-2 alkyl);
Y is an optionally substituted benzothiophene;
R 1 is hydrogen or an unsubstituted C 1-4 alkyl;
R 2 and R 2a1 are each independently selected from the group consisting of hydrogen, an optionally substituted C 1-4 alkyl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, hydroxy and an optionally substituted aryl(C 1-6 alkyl);
R 9a , R 10a and R 11a are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted C 1-8 alkyl, an optionally substituted C 2-8 alkenyl, an optionally substituted C 2-8 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl, an optionally substituted C 1-8 alkoxy, an optionally substituted alkoxyalkyl, amino, a mono-substituted amino, a di-substituted amino, halo(C 1-8 alkyl), haloalkyl and an optionally substituted C-carboxy; and
wherein, when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acylalkyl, alkoxyalkyl, aminoalkyl, amino acid, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxyalkyl, acyl, cyano, hydroxy, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, azido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
2. The compound of claim 1 , wherein R 1 is hydrogen.
3. The compound of claim 1 , wherein R 1 is an unsubstituted C 1-4 alkyl.
4. The compound of claim 1 , wherein both R 2 and R 2a1 are hydrogen.
5. The compound of claim 1 , wherein R 2 is hydrogen and R 2a1 is a substituted or an unsubstituted C 1-4 alkyl, an optionally substituted aryl(C 1-6 alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl or hydroxy.
6. The compound of claim 1 , wherein: R 9a , R 10a and R 11a are each independently selected from the group consisting of hydrogen and C 1-8 alkoxy.
7. The compound of claim 1 , wherein A is an optionally substituted aryl.
8. The compound of claim 7 , wherein A is an optionally substituted phenyl.
9. The compound of claim 1 , wherein A is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
10. The compound of claim 1 , wherein Y is an optionally substituted
11. The compound of claim 1 , wherein Y is benzothiophene substituted with one or more R B , wherein each R B is independently selected from the group consisting of: cyano, halogen, an optionally substituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 2-4 alkynyl, an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 5 or 6 membered heterocyclyl, hydroxy, C 1-4 alkoxy, alkoxyalkyl, C 1-4 haloalkyl, haloalkoxy, an unsubstituted acyl, an optionally substituted —C-carboxy, an optionally substituted —C-amido, sulfonyl, carbonyl, amino, a mono-substituted amine, a di-substituted amine and
12. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
14. The compound of claim 1 , wherein at least one of R 9a , R 10a and R 11a is a C 1-4 alkoxy.
15. The compound of claim 1 , wherein R 9a is selected from the group consisting of hydrogen, hydroxy, an optionally substituted C 1-8 alkyl, an optionally substituted C 1-8 alkoxy, an optionally substituted alkoxyalkyl, a mono-substituted amino and a di-substituted amino.
16. The compound of claim 1 , wherein R 10a is selected from the group consisting of hydrogen, hydroxy, halogen, an optionally substituted C 1-8 alkyl, an optionally substituted C 2-8 alkenyl, an optionally substituted C 2-8 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted hydroxyalkyl, an optionally substituted C 1-8 alkoxy, a mono-substituted amino, a di-substituted amino, halo(C 1-8 alkyl) and an optionally substituted C-carboxy.
17. The compound of claim 1 , wherein R 11a is selected from the group consisting of hydrogen, hydroxy and an optionally substituted C 1-8 alkoxy.
18. The compound of claim 8 , wherein A is a di-substituted phenyl.
19. The compound of claim 1 , wherein A is substituted with one or more R A groups selected from the group consisting of an optionally substituted C 1-4 alkyl, cycloalkyl, hydroxy, an optionally substituted C 1-4 alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, a mono-substituted amine, a di-substituted amine, sulfenyl, alkyoxyalkyl, aryl, mono-cyclic heteroaryl, mono-cyclic heterocyclyl and aminoalkyl.
20. The compound of claim 1 , wherein A is substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, phenoxy, bromo, chloro, fluoro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, N,N-di-methyl-amine, N,N-di-ethyl-amine, N-methyl-N-ethyl-amine, N-methyl-amino, N-ethyl-amino, amino, alkylthio, phenyl, imidazole, morpholinyl, pyrazole, pyrrolidinyl, pyridinyl, piperidinyl, pyrrolidinone, pyrimidine, pyrazine, 1,2,4-oxadiazole, —(CH 2 ) 1-2 —NH(CH 3 ), —O(CH 2 ) 2 —NH 2 , —O(CH 2 ) 2 —NH(CH 3 ), —O(CH 2 ) 2 —N(CH 3 ) 2 , —O—(CH 2 ) 2-4 OH, —O(CH 2 ) 2 OCH 3 , —O(CH 2 ) 1-2 -morpholinyl, —O(CH 2 ) 1-2 -triazole, —O(CH 2 ) 1,2 -imidazole,
21. The compound of claim 20 , wherein A is substituted with one or more substituents selected from the group consisting of methyl, hydroxy, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, difluoromethoxy, N,N-di-methyl-amine, N,N-di-ethyl-amine, imidazole, pyrazole, pyridinyl, pyrrolidinone, pyrimidine, 1,2,4-oxadiazole, —O(CH 2 ) 2 —NH 2 , —O(CH 2 ) 2 —NH(CH 3 ), —O(CH 2 ) 2 —N(CH 3 ) 2 , —O—(CH 2 ) 2-4 OH, —O(CH 2 ) 2 OCH 3 , —O(CH 2 ) 1-2 -morpholinyl, —O(CH 2 ) 1-2 -triazole, —O(CH 2 ) 1-2 -imidazole,
22. The compound of claim 1 , wherein Y is substituted by one or more substituents selected from the group consisting of halogen, carbonyl, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, NH 2 and a mono-substituted amine.
23. The compound of claim 1 , wherein Y substituted by one or more halogens.
24. The compound of claim 20 , wherein Y is