Small molecule inhibitors of fibrosis
Described herein are compounds and compositions for the treatment of a fibrotic disease.
1. A method to treat fibrosis, a disorder characterized by fibrosis, or a disease characterized by fibrosis, the method comprising administering a composition comprising a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, N-oxide, stereoisomer, or isomer thereof:
wherein:
A 1 is phenyl;
A 2 is phenyl, or pyridine;
B is
C is
D is
E is
heteroaryl, cycloalkyl, heterocyclyl, or alkyl;
each R 1 , R 2 , R 3 , and R 4 is independently selected from H and alkyl;
R 7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -alkylene(NR 13 R 14 );
each R 8 is independently selected from alkyl, halo, nitrile, alkoxy, haloalkyl and —SO 2 R 13 ;
each R 13 and R 14 is independently selected from H and alkyl;
Y 1 and Y 2 are O;
n is 1;
m is 1;
p is 1, 2, 3, or 4;
s is 0, 1, or 2;
t is 0, 1, or 2;
u is 0, 1, 2, or 3; and
v is 0, 1, or 2.
2. The method of claim 1 , wherein A 1 is phenyl and s is 0 or 1.
3. The method of claim 2 , wherein A 2 is phenyl and t is 0.
4. The method of claim 3 , wherein C is
and R 7 is alkyl.
5. The method of claim 4 , wherein E is
and u is 0, 1, or 2.
6. The method of claim 5 , wherein D is
7. The method of claim 6 , wherein D is
8. The method of claim 7 , wherein v is 0.
9. The method of claim 8 , wherein p is 1.
10. The method of claim 9 , wherein R 1 , R 2 , R 3 , and R 4 are hydrogen.
11. The method of claim 1 , wherein the compound is selected from:
12. The method of claim 1 , wherein the fibrosis is liver fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis, or cardiac fibrosis.
13. The method of claim 1 , wherein the fibrosis is idiopathic pulmonary fibrosis.
14. The method of claim 1 , wherein the disease characterized by fibrosis or the disorder characterized by fibrosis is a chronic autoimmune disease.
15. The method of claim 14 , wherein the chronic autoimmune disease is scleroderma.