Small molecule inhibitors of fibrosis
Described herein are compounds and compositions for the treatment of a fibrotic disease.
1. A compound of Formula (I) or Formula (Ia):
wherein:
R 1 is —CH(CH 3 )CH 2 CH 2 CH 3 or —CH(CH 2 CH 3 ) 2 ;
R 5 is H, —CN, halogen, haloalkyl, alkyl, —NR 13 R 14 , -alkylene(NR 13 R 14 ), and —SO 2 R 13 ;
each R 8 is independently selected from halogen, —OH, —NO 2 , —N 3 , —CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR 13 R 14 ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, —SR 13 , —SOR 13 , —SO 2 R 13 , —SO 2 NR 13 R 14 , —NR 13 R 14 , —NR 13 SO 2 R 14 , —NR 13 C(O)R 14, —NR 13 C(O)OR 14 , —NR 13 C(O)NR 13 R 14 , —C(O)R 14 , —C(O)OR 14 , and —C(O)NR 13 R 14 ; or two adjacent R 8 form a heterocyclyl ring;
each R 13 and each R 14 is each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R 13 and R 14 taken together form a heterocycle with the atoms to which they are attached; and
n is selected from 0, 1, 2, 3, and 4;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
2. The compound of claim 1 , wherein R 1 is —CH(CH 2 CH 3 ) 2 .
3. The compound of claim 1 , wherein R 1 is —CH(CH 3 ) 2 —.
4. The compound of claim 1 , wherein n is 0.
5. The compound of claim 1 , wherein n is 1 or 2.
6. The compound of claim 5 , wherein each R 8 is independently selected from halogen, —CN, alkyl, alkoxy, haloalkoxy, and haloalkyl.
7. The compound of claim 6 , wherein each R 8 is halogen.
8. The compound of claim 7 , wherein each R 8 is Cl.
9. The compound of claim 1 , wherein R 5 is H.
10. The compound of claim 1 , wherein R 5 is halogen.
11. The compound of claim 10 , wherein R 5 is F.
12. The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.
14. A method of treating fibrosis in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
15. The method of claim 14 wherein the fibrosis is liver fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis, or cardiac fibrosis.