Small molecule inhibitors of fibrosis
Described herein are compounds and compositions for the treatment of a fibrotic disease.
1. A compound of Formula (II), 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, -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 compound of claim 1 wherein A 1 is phenyl and s is 0 or 1.
3. The compound of claim 2 , wherein A 2 is phenyl and t is 0.
4. The compound of claim 3 , wherein C is
and R 7 is alkyl.
5. The compound of claim 3 wherein C is
and R 7 is alkyl.
6. The compound of claim 4 , wherein E is alkyl.
7. The compound of claim 4 , wherein E is cycloalkyl.
8. The compound of claim 7 , wherein E is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
9. The compound of claim 4 , wherein E is heterocyclyl.
10. The compound of claim 4 , wherein E is
and u is 0, 1, or 2.
11. The compound of claim 4 , wherein E is heteroaryl.
12. The compound of claim 11 , wherein
E is selected from:
W 1 , W 2 , W 3 , W 5 , W 6 , and W 7 are independently selected from N and CR 9 ;
Z 1 is NR 12 , S, or O;
Z 2 is N or CR 9 ;
each R 9 is independently selected from H, halogen, CN, NO 2 , alkyl, —SR 10 , —OR 10 , —NR 10 R 11 , NR 10 C(O)(alkyl), —NR 10 C(O)(cycloalkyl), —NR 10 C(O)(heterocycloalkyl), —NR 10 C(O)(aryl), —NR 10 C(O)(heteroaryl), —C(O)NR 10 R 11 , —C(O)NR 10 (cycloalkyl), —C(O)NR 10 (heterocycloalkyl), —C(O)NR 10 (aryl), —C(O)NR 10 (heteroaryl), —NR 10 C(O)NR 10 R 11 , —NR 10 C(O)NR 11 (cycloalkyl), —NR 10 C(O)NR 11 (heterocycloalkyl), —NR 10 C(O)NR 11 (aryl), —NR 10 C(O)NR 11 (heteroaryl), —NR 10 C(O)O(alkyl), —NR 10 C(O)O(cycloalkyl), —NR 10 C(O)O(heterocycloalkyl), —NR 10 C(O)O(aryl), —NR 10 C(O)O(heteroaryl), —NR 10 SO 2 (alkyl), —NR 10 SO 2 (cycloalkyl), —NR 10 SO 2 (heterocycloalkyl), —NR 10 SO 2 (aryl), —NR 10 SO 2 (heteroaryl), —SO 2 NR 10 R 11 , —SO 2 NR 10 (cycloalkyl), —SO 2 NR 10 (heterocycloalkyl), —SO 2 NR 10 (aryl), —SO 2 NR 10 (heteroaryl), haloalkyl, aryl, and heteroaryl;
each R 10 and R 11 is independently selected from H and alkyl; or R 10 and R 11 taken together form a heterocycle with the nitrogen to which they are attached; and
R 12 is H, alkyl, or haloalkyl.
13. The compound of claim 10 , wherein D is
14. The compound of claim 13 , wherein D is
15. The compound of claim 13 , wherein D is
16. The compound of claim 13 , wherein v is 0.
17. The compound of claim 16 , wherein p is 1.
18. The compound of claim 17 , wherein R 1 , R 2 , R 3 , and R 4 are hydrogen.
19. The compound of claim 1 , wherein the compound is selected from:
20. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, N oxide, stereoisomer, or isomer thereof, and a pharmaceutically acceptable excipient.