Compounds targeting proteins, compositions, methods, and uses thereof

Patent metadata

Field	Value
Publication number	US-10857155-B2
Application number	US-201916539933-A
Country	US
Kind code	B2
Filing date	Aug 13, 2019
Priority date	Mar 14, 2017
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

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 method of inhibiting GSPT1 activity, comprising contacting a cell with a compound of Formula (I), or a pharmaceutically acceptable salt 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 , —NHR 7 , NR 7 R 7 , an optionally substituted C 1 to C 6 alkoxy, an optionally substituted C 1 to C 6 alkyl,

wherein at least one of R 1 , R 2 , R 3 , and R 4 is

R 5 is selected from the group consisting of H, deuterium, fluoro, and an optionally substituted C 1 to C 6 alkyl;
R 6 is selected from the group consisting of H, deuterium, and an optionally substituted C 1 to C 6 alkyl;
X is selected from the group consisting of CH 2 and C═O;
each X 2 is independently 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 ;
each X 3 is independently 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 ;
each m is independently 1, 2, 3, 4, or 5;
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
each p and q is independently 0, 1, 2, 3, 4, 5, or 6;
each t is independently 0, 1, 2, 3, or 4; and
each R 7 is independently 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 method of claim 1 , wherein R 1 is H and R 2 is

3. The method of claim 2 , wherein X 2 is selected from the group consisting of NH, (CH 2 ) n , [(CH 2 ) p —NH—(CH 2 ) q ] t , and N—(an optionally substituted C 1 to C 6 alkyl).

4. The method of claim 2 , wherein R 3 and R 4 are each independently selected from the group consisting of H and halogen.

5. The method of claim 2 , wherein each R 5 and R 6 is H.

6. The method of claim 2 , 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.

7. The method compound of claim 6 , wherein the phenyl group is substituted with 1 or 2 unsubstituted C 1 to C 6 alkyl groups and 1 or 2 halogens; or wherein the phenyl group is substituted with 1 unsubstituted C 1 to C 6 alkyl groups and 1 halogen.

8. The method of claim 2 , wherein R 3 and R4 are both hydrogen; m is 1; X 2 is NH; and X 3 is O or S.

9. The method of claim 1 , wherein the compound is selected form the group consisting of:

and pharmaceutically acceptable salts thereof.

Assignees

• Biotheryx Inc

Inventors

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

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/55 Primary

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

• C07D403/04

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