Chimeric compounds targeting proteins, compositions, methods, and uses thereof

Patent metadata

Field	Value
Publication number	US-10144745-B2
Application number	US-201715597671-A
Country	US
Kind code	B2
Filing date	May 17, 2017
Priority date	May 18, 2016
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

The present invention provides chimeric compounds that modulate protein function, to restore protein homeostasis, including cytokine, aiolos, and/or ikaros activity, TNF-alpha activity, CK1-alpha activity and cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions, including in combination with other cytokine and inflammatory mediators, are provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions, such as cytokine-mediated diseases, disorders, and conditions, including inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant rejection, and cancer, are provided.

First claim

What is claimed is:

1. A method of inhibiting TNF-alpha activity, comprising contacting a cell with a compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 , R 2 , R 3 , and R 4 , are each independently H, deuterium, hydroxyl, halogen, nitro, optionally substituted amino, optionally substituted C 1 to C 6 alkoxy, optionally substituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 carbocyclyl, optionally substituted C 6 to C 10 aryl, optionally substituted C 3 to C 8 heterocyclyl, or optionally substituted C 6 to C 10 heteroaryl;
each R 5 is independently H, deuterium, or optionally substituted C 1 to C 6 alkyl;
X is CH 2 or C═O;
Q is C═O, C═S; S═O, or SO 2 ;
n is 1 or 2; and
wherein at least one of R 1 , R 2 , R 3 , and R 4 is not H.

2. The method of claim 1 , wherein n is 1.

3. The method of claim 1 , wherein R 5 is H.

4. The method of claim 1 , wherein X is CH 2 .

5. The method of claim 1 , wherein X is C═O.

6. The method of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 , are each independently H, hydroxyl, halogen, nitro, unsubstituted C 1 to C 6 alkoxy, or unsubstituted C 1 to C 6 alkyl.

7. A method of inhibiting CK1-alpha activity, comprising contacting a cell with a compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 , R 2 , R 3 , and R 4 , are each independently H, deuterium, hydroxyl, halogen, nitro, optionally substituted amino, optionally substituted C 1 to C 6 alkoxy, optionally substituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 carbocyclyl, optionally substituted C 6 to C 10 aryl, optionally substituted C 3 to C 8 heterocyclyl, or optionally substituted C 6 to C 10 heteroaryl;
each R 5 is independently H, deuterium, or optionally substituted C 1 to C 6 alkyl;
X is CH 2 or C═O;
Q is C═O, C═S; S═O, or SO 2 ;
n is 1 or 2; and
wherein at least one of R 1 , R 2 , R 3 , and R 4 is not H.

8. The method of claim 7 , wherein n is 1.

9. The method of claim 7 , wherein each R 5 is H.

10. The method of claim 7 , wherein R 1 , R 2 , R 3 , and R 4 , are each independently H, hydroxyl, halogen, nitro, unsubstituted C 1 to C 6 alkoxy, or unsubstituted C 1 to C 6 alkyl.

11. The method of claim 7 , wherein X is CH 2 .

12. The method of claim 7 , wherein X is C═O.

13. A method of inducing IL-2 activity, comprising contacting a cell with a compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 , R 2 , R 3 , and R 4 , are each independently H, deuterium, hydroxyl, halogen, nitro, optionally substituted amino, optionally substituted C 1 to C 6 alkoxy, optionally substituted C 1 to C 6 alkyl, optionally substituted C 2 to C 6 alkenyl, optionally substituted C 2 to C 6 alkynyl, optionally substituted C 3 to C 8 carbocyclyl, optionally substituted C 6 to C 10 aryl, optionally substituted C 3 to C 8 heterocyclyl, or optionally substituted C 6 to C 10 heteroaryl;
each R 5 is independently H, deuterium, or optionally substituted C 1 to C 6 alkyl;
X is CH 2 or C═O;
Q is C═O, C═S; S═O, or SO 2 ;
n is 1 or 2; and
wherein at least one of R 1 , R 2 , R 3 , and R 4 is not H.

14. The method of claim 13 , wherein n is 1.

15. The method of claim 13 , wherein each R 5 is H.

16. The method of claim 13 , wherein X is CH 2 .

17. The method of claim 13 , wherein X is C═O.

18. The method of claim 13 , wherein R 1 , R 2 , R 3 , and R 4 , are each independently H, hydroxyl, halogen, nitro, unsubstituted C 1 to C 6 alkoxy, or unsubstituted C 1 to C 6 alkyl.

Assignees

• Biotheryx Inc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title