Small molecule inhibition of transcription factor SALL4 and uses thereof

Patent metadata

Field	Value
Publication number	US-11530209-B2
Application number	US-201816753536-A
Country	US
Kind code	B2
Filing date	Oct 4, 2018
Priority date	Oct 4, 2017
Publication date	Dec 20, 2022
Grant date	Dec 20, 2022

Abstract

Provided herein are compounds that interrupt the function of SALL4. Also described are pharmaceutical compositions and medical uses of these compounds.

First claim

The invention claimed is:

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.

Assignees

• Dana Farber Cancer Inst Inc
• Brigham & Womens Hospital Inc

Inventors

• Qi Jun
• Varca Anthony
• Chai Li

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title