Anti-fibrotic compounds
Provided herein are anti-fibrotic compounds, in particular those of Formula (I), that inhibit the TGF-beta signaling pathway. Also provided are pharmaceutical compositions comprising the anti-fibrotic compounds, and methods of treating diseases or conditions associated with fibrosis, inflammation, and benign or malignant neoplastic diseases in a subject by administering a compound or composition described herein. (Formula (I))
1. A compound of Formula I-i:
or a pharmaceutically acceptable salt thereof; wherein
X is O or NR 10 ;
Y is O or NR 10 ; provided that at least one of X and Y is NR 10 ;
each occurrence of R g and R h is, independently, hydrogen or alkyl, or R g and R h together with the carbon atom to which they are attached form a carbonyl;
t is 1 or 2;
each occurrence of R 10 is, independently, hydrogen or C 1-4 alkyl optionally substituted with oxo.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 10 is, independently, hydrogen or C 1-4 alkyl.
3. The compound of claim 2 , wherein R 10 is methyl.
4. The compound of claim 2 , wherein R 10 is hydrogen.
5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
X is O;
Y is NR 10 ; and
R 10 is C 1-4 alkyl.
6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
X is NR 10 ;
Y is O; and
R 10 is C 1-4 alkyl.
7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein t is 2.
8. The compound of claim 7 , wherein each occurrence of R g and R h is hydrogen.
9. The compound of claim 7 , wherein one occurrence of R g and R h is hydrogen, and the other occurrence of R g and R h is that R g and R h together with the carbon atom to which they are attached form a carbonyl.
10. The compound of claim 2 , wherein the compound is of Formula I-j:
or a pharmaceutically acceptable salt thereof, wherein:
X is O;
Y is NR 10 ; and
R 10 is C 1-4 alkyl.
11. The compound of claim 2 , wherein the compound is of Formula I-j:
or a pharmaceutically acceptable salt thereof, wherein:
X is NR 10 ;
Y is O; and
R 10 is C 1-4 alkyl.
12. A compound selected from the group consisting of:
2-[[(E)-3-(4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)prop-2-enoyl]amino]benzoic acid (107);
(E)-2-(3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)acrylamido)benzoic acid (109);
(E)-2-(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)acrylamido)benzoic acid (110);
(E)-2-(3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acrylamido)benzoic acid (111);
(E)-2-(3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acrylamido)benzoic acid (112);
and pharmaceutically acceptable salts thereof.
13. The compound of claim 12 , wherein the compound is:
2-[[(E)-3-(4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)prop-2-enoyl]amino]benzoic acid (107);
(E)-2-(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)acrylamido)benzoic acid (110); or
(E)-2-(3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acrylamido)benzoic acid (112);
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 , wherein the compound is:
(E)-2-(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)acrylamido)benzoic acid (110); or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising the compound of claim 12 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.