Small molecule inhibition of transcription factor SALL4 and uses thereof
View Patent ↗Provided herein are compounds that interrupt the function of SALL4. Also described are pharmaceutical compositions and medical uses of these compounds.
1. A compound having a structure of Formula I or a pharmaceutically acceptable salt thereof:
wherein
Z is CR 3 ;
R 1 is
optionally
substituted cycloalkyl, heterocyclyl, aryl, oxazolyl, indolyl, benzoisoxazolyl, indazolyl, azaindolyl, benzothiazolyl, imidazo[1,2-a]pyridine, or thiazolyl, wherein the optionally substituted aryl is optionally substituted phenanthrenyl or naphthalenyl substituted with one or more groups selected from hydroxyl and nitro;
R 2 is optionally substituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
R 3 is H or optionally substituted alkyl, carboxy or ester, provided when R 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl and R 2 is optionally substituted alkyl, R 3 is not alkyl.
2. The compound of claim 1 , wherein R 3 is
3. The compound of claim 1 , wherein R 1 is naphthalenyl substituted with one or more groups selected from hydroxyl and nitro.
4. The compound of claim 3 , wherein R 1 is selected from
5. The compound of claim 1 , wherein R 1 is selected from
6. The compound of claim 1 , wherein the oxazolyl, indolyl, benzoisoxazolyl, indazolyl, azaindolyl, benzothiazolyl, imidazo[1,2-a]pyridine, and thiazolyl is substituted with one or more groups selected from halo, oxy, nitro, sulfonate, and optionally substituted alkyl.
7. The compound of claim 1 , wherein R 1 is selected from
8. The compound of claim 1 , wherein R 2 is alkyl substituted with alkoxy, amino or optionally substituted aryl.
9. The compound of claim 1 , wherein R 2 is selected from
10. The compound of claim 1 , wherein R 2 is selected from
11. The compound of claim 1 , wherein R 2 is optionally substituted phenyl.
12. The compound of claim 11 , wherein the phenyl is substituted with one more groups selected from halo, hydroxyl, cyano, optionally substituted alkyl, optionally substituted alkoxy, carboxy, and ester.
13. The compound of claim 1 , wherein R 2 is selected from
14. A compound selected from
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.
16. A method of treating acute myeloid leukemia, liver cancer, lung cancer, or myelodysplastic syndrome (MDS) comprising administering to a subject the compound or a pharmaceutically acceptable salt thereof of claim 1 .
17. The compound of claim 14 , which is
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof of claim 17 and a pharmaceutically acceptable carrier.
19. The method of claim 16 , wherein the cancer is acute myeloid leukemia.
20. The method of claim 16 , wherein the cancer is liver cancer.
21. The method of claim 16 , wherein the cancer is lung cancer.
22. The method of claim 16 , wherein the cancer is myelodysplastic syndrome.