Compounds targeting proteins, compositions, methods, and uses thereof

Patent metadata

Field	Value
Publication number	US-10406165-B2
Application number	US-201815916752-A
Country	US
Kind code	B2
Filing date	Mar 9, 2018
Priority date	Mar 14, 2017
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

The present invention provides modulators of protein function, to restore protein homeostasis, including GSPT1 activity. The invention provides methods of modulating protein-mediated diseases, such as GSPT1-mediated diseases, disorders, conditions, or responses. Compositions are also provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions, such as GSPT1-mediated diseases, disorders, and conditions, including cancer and astrogliosis.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 , R 2 , R 3 , and R 4 , are each independently selected from the group consisting of H, deuterium, halogen, cyano, nitro, —NH 2 , an unsubstituted C 1 to C 6 alkoxy, and an unsubstituted C 1 to C 6 alkyl,

wherein one of R 1 and R 2 is

R 5 is selected from the group consisting of H, deuterium, fluoro, and an unsubstituted C 1 to C 6 alkyl;
R 6 is selected from the group consisting of H, deuterium, and an unsubstituted C 1 to C 6 alkyl;
X is selected from the group consisting of CH 2 and C═O;
X 2 is selected from the group consisting of (CH 2 ) n , (CD 2 ) n , (CF 2 ) n , C═O, NH, N-(an optionally substituted C 1 to C 6 alkyl), [(CH 2 ) p —NH—(CH 2 ) q ] t and [(CH 2 ) p —O—(CH 2 ) q ] t ;
X 3 is selected from the group consisting of NH, O, and S;
wherein, when any of R 1 , R 2 , R 3 , or R 4 is

X 2 is selected from the group consisting of (CH 2 ) n , (CD 2 ) n , C═O, [(CH 2 ) p —NH—(CH 2 ) q ]t, and [(CH 2 ) p —O—(CH 2 ) q ] t ;
m is 1, 2, 3, 4, or 5;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p and q are independently 0, 1, 2, 3, 4, 5, or 6;
t is 0, 1, 2, 3, or 4; and
R 7 is selected from the group consisting of an optionally substituted C 3 to C 10 cycloalkyl, an optionally substituted C 6 to C 10 aryl, an optionally substituted 5 to 10-membered heteroaryl, an optionally substituted 3 to 10-membered heterocyclyl, and an optionally substituted C 1 to C 10 alkyl.

2. The compound of claim 1 , wherein R 1 is H.

3. The compound of claim 1 , wherein R 2 is

4. The compound of claim 2 , wherein R 2 is

5. The compound of claim 1 , wherein m is 1.

6. The compound of claim 1 , wherein X 3 is O.

7. The compound of claim 1 , wherein X 2 is NH or (CH 2 ) n .

8. The compound of claim 1 , wherein X 2 is selected from the group consisting of (CH 2 ) n and [(CH 2 ) p —NH—(CH 2 ) q ]t.

9. The compound of claim 1 , wherein n is 0.

10. The compound of claim 1 , wherein t is 0.

11. The compound of claim 1 , wherein X 2 is N-(an unsubstituted C 1 to C 6 alkyl).

12. The compound of claim 1 , wherein X 2 is NH.

13. The compound of claim 1 , wherein R 3 and R 4 , are each independently selected from the group consisting of H and halogen.

14. The compound of claim 1 , wherein R 5 is H.

15. The compound of claim 1 , wherein R 6 is H.

16. The compound of claim 1 , wherein R 7 is selected from the group consisting of an optionally substituted C 3 to C 10 cycloalkyl, an optionally substituted C 6 to C 10 aryl, an optionally substituted 5 to 10-membered heteroaryl, and an optionally substituted 3 to 10-membered heterocyclyl.

17. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is an optionally substituted phenyl group.

18. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a di-substituted phenyl group.

19. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group independently di-substituted with halogen and an unsubstituted C 1 to C 6 alkyl.

20. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group independently di-substituted with an unsubstituted C 1 to C 6 alkyl, halogen, an unsubstituted (heterocyclyl)alkyl, and an unsubstituted alkyl(amino).

21. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group substituted with one or two groups selected from: CH 3 , —Cl, N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 ,

22. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group substituted with 1, 2, or 3 substituents independently selected from halogen, unsubstituted C 1 to C 6 alkyl, —N(unsubstituted C 1 to C 6 alkyl)(unsubstituted C 1 to C 6 alkyl), and unsubstituted C 1 to C 6 alkoxy.

23. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group substituted with 1 or 2 unsubstituted C 1 to C 6 alkyl groups and 1 or 2 halogens; or wherein the optionally substituted C 6 to C 10 aryl is a phenyl group substituted with 1 unsubstituted C 1 to C 6 alkyl group and 1 halogen.

24. The compound of claim 16 , wherein R 1 is H; R 2 is

R 3 and R 4 are both hydrogen; m is 1; X 2 is NH; and X 3 is O or S.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure:

Assignees

• Biotheryx Inc

Inventors

• Chan Kyle W H
• Erdman Paul E
• Fung Leah
• Mercurio Frank
• Sullivan Robert

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/04

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

• A61P35/02

  specific for leukemia · CPC title

• A61K31/55 Primary

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title