3-arylindazoles as selective MEK4 inhibitors

Patent metadata

Field	Value
Publication number	US-11370770-B2
Application number	US-202016910433-A
Country	US
Kind code	B2
Filing date	Jun 24, 2020
Priority date	Jun 24, 2019
Publication date	Jun 28, 2022
Grant date	Jun 28, 2022

Abstract

Disclosed are indazole compounds and derivatives thereof for use as modulators of the activity of mitogen-activated protein kinase 4 (MEK4). The disclosed compounds include 3-Arylindazoles which may be formulated in pharmaceutical composition for treating cell proliferative diseases and disorders associated with MEK4 activity, including cancer.

First claim

We claim:

1. A compound of the following formula or a salt or hydrate thereof:

where:
R 4 , R 5 , and R 6 are independently selected from hydrogen, alkyl, halogen, and haloalkyl;
R 3′ is selected from hydrogen, carboxyl, hydroxymethyl, and carboxamido; and
R 4′ is selected from hydrogen, hydroxyl, carboxamido, hydroxymethyl, 2-hydroxy-2-propyl, carboxyl, and methyl carboxyl ester;
wherein at least one of R 3′ and R 4′ is not hydrogen.

2. The compound of claim 1 , wherein R 6 is halogen.

3. The compound of claim 1 , wherein R 4′ is carboxyl.

4. The compound of claim 1 , wherein the compound is:

5. The compound of claim 1 of a formula selected from:

6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutical carrier, excipient, or diluent.

7. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutical carrier, excipient, or diluent.

8. A method for treating a cancer characterized by increased disease or disorder associated with mitogen-activated protein kinase 4 (MEK4) activity in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 6 and delivering an effective amount of the compound to inhibit MEK4 activity in the subject.

9. The method of claim 8 , wherein the cancer is prostate cancer.

10. The method of claim 8 , wherein the cancer is breast cancer.

11. The method of claim 8 , wherein the cancer is pancreatic cancer.

12. The method of claim 8 , wherein the cancer is colon cancer.

13. The compound of claim 1 , wherein at least one of R 4 , R 5 , and R 6 is not hydrogen.

14. A compound of the following formula or a salt or hydrate thereof:

wherein:
R 3′ is hydrogen, and R 4 is selected from carboxyl and methyl carboxyl ester; or R 3′ and R 4 are linked together and are —O—CH 2 —O—.

15. The compound of claim 14 , wherein R 3′ is hydrogen and R 4′ is carboxyl.

16. The compound of claim 14 , wherein R 3′ and R 4 are linked together and are —O—CH 2 —O—.

17. The compound of claim 14 , wherein the compound is:

18. The compound of claim 14 , wherein the compound is:

19. The compound of claim 14 , wherein the compound is:

20. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutical carrier, excipient, or diluent.

21. A method for treating a cancer characterized by increased mitogen-activated protein kinase 4 (MEK4) activity in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 20 and delivering an effective amount of the compound to inhibit MEK4 activity in the subject.

22. The method of claim 21 , wherein the cancer is prostate cancer.

23. The method of claim 21 , wherein the cancer is breast cancer.

24. The method of claim 21 , wherein the cancer is pancreatic cancer.

25. The method of claim 21 , wherein the cancer is colon cancer.

Assignees

• Univ Northwestern

Inventors

• Scheidt Karl A
• Schiltz Gary E
• Clutter Matthew R
• Kwong Ada J

Classifications

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D231/56 Primary

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title