Premature-termination-codons readthrough compounds
Premature termination codons readthrough compounds, composition thereof, and methods of making and using the same are provided.
1. A compound of formula Ia:
where
R 1a is 2-hydroxylphenyl, 2-alkoxyphenyl, 3-hydroxylphenyl, or 3-alkoxyphenyl;
X 1 is S, O, NH, or N(C 1-3 -alkyl);
R 2a is (CH 2 ) m ;
m is 1, 2, or 3;
Y 1 is O, S, or NH;
R 3a is hydroxy or —NR 7 R 7a ;
R 7 is hydrogen or C 1-3 -alkyl;
R 7a is hydroxyalkyl; phenyl substituted with 1, 2, or 3 R 8 groups; phenyl substituted with two independently selected halo;
each R 8 is independently hydroxy or haloalkyl; and
each R 9 , when present, is independently hydroxy, alkoxy, halo, haloalkyl, or C 1-6 -alkyl; and
provided that 1) when X 1 is S, R 2a is —CH 2 —, Y 1 is O, and R 3a is —NR 7 R 7a and R 7 is hydrogen, then R 7a is not 2-methoxyphenyl; and 2) when R 1a is 2-methoxyphenyl, X 1 is S, R 2a is —CH 2 —, Y 1 is O, and R 3a is —NR 7 R 7a and R 7 is hydrogen, then R 7a is not 4-methoxyphenyl; or
a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , where X 1 is S; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , where Y 1 is O; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , where R 2a is —(CH 2 ) m — and m is 1; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , where R 1a is 3-alkoxyphenyl; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , where R 7a is hydroxyalkyl; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , where R 7a is phenyl substituted with two independently selected halo; or R 7a is phenyl substituted with 1 or 2 R 8 groups; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , where R 7a is phenyl substituted with two independently selected halo; or R 7a is phenyl substituted with one hydroxy or haloalkyl; or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , selected from 2-((4-(3-methoxyphenyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid; sodium 2-((4-(3-methoxyphenyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetate; N-(4-hydroxyphenyl)-2-((4-(3-methoxyphenyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide; N-(2,6-difluorophenyl)-2-((4-(3-methoxyphenyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide; 2-((4-(3-methoxyphenyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(4-(trifluoromethyl)phenyl)acetamide; N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-((4-(3-methoxyphenyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide; 2-((4-(3-methoxyphenyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N-phenylacetamide; or a
pharmaceutically acceptable salt thereof.
10. A compound having the following formula:
or a pharmaceutically acceptable salt thereof.