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

Patent metadata

Field	Value
Publication number	US-9938302-B2
Application number	US-201715599401-A
Country	US
Kind code	B2
Filing date	May 18, 2017
Priority date	May 18, 2016
Publication date	Apr 10, 2018
Grant date	Apr 10, 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 compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 is 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 3 to C 8 carbocyclyl, or optionally substituted C 3 to C 8 heterocyclyl;
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 3 to C 8 carbocyclyl, or optionally substituted C 3 to C 8 heterocyclyl; or,
R 1 is H and R 2 is 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 3 to C 8 carbocyclyl, or optionally substituted C 3 to C 8 heterocyclyl;
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 or SO 2 ; and
n is or 2.

2. The compound of claim 1 , wherein Q is C═O.

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

4. The compound of claim 2 , wherein X is C═O.

5. The compound of claim 2 , wherein X is CH 2 .

6. The compound of claim 2 , wherein R 5 is H.

7. The compound of claim 2 , wherein R 2 , R 3 , and R 4 , are each independently H, hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, optionally substituted amino, optionally substituted C 3 to C 8 heterocyclyl, unsubstituted C 1 to C 6 alkyl, unsubstituted C 3 to C 6 cycloalkyl, or CF 3 ; or R 1 is H and R 2 , R 3 , and R 4 , are each independently hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, optionally substituted amino, optionally substituted C 3 to C 8 heterocyclyl, unsubstituted C 1 to C 6 alkyl, unsubstituted C 3 to C 6 cycloalkyl, or —CF 3 .

8. The compound of claim 7 , wherein R 2 , R 3 , and R 4 , are each independently H, hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, unsubstituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 heterocyclyl, or —CF 3 .

9. The compound of claim 2 , wherein R 3 , and R 4 are each H.

10. The compound of claim 9 , wherein R 1 is hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, optionally substituted amino, optionally substituted C 3 to C 8 heterocyclyl, unsubstituted C 1 to C 6 alkyl, unsubstituted C 3 to C 6 cycloalkyl, or —CF 3 ; and R 2 is H, hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, optionally substituted amino, optionally substituted C 3 to C 8 heterocyclyl, unsubstituted C 1 to C 6 alkyl, unsubstituted C 3 to C 6 cycloalkyl, or —CF 3 ; or R 1 is H and R 2 is hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, optionally substituted amino, optionally substituted C 3 to C 8 heterocyclyl, unsubstituted C 1 to C 6 alkyl, unsubstituted-C 3 to C 6 cycloalkyl, or —CF 3 .

11. The compound of claim 10 , wherein R 1 is hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, unsubstituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 heterocyclyl, or —CF 3 ; and R 2 is H, hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, unsubstituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 heterocyclyl, or —CF 3 .

12. The compound of claim 2 , wherein the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing.

13. A compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of R 1 and R 2 is L-Y and the other of R 1 and R 2 is H, deuterium, hydroxyl, halogen, cyano, 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, or optionally substituted C 3 to C 6 cycloalkyl;
R 3 and R 4 are each independently H, deuterium, hydroxyl, halogen, cyano, 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, or optionally substituted C 3 to C 6 cycloalkyl;
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 or SO 2 ;
n is 1 or 2;
L is —Z 1 —(R 6 —O—R 6 ) t —Z 2 —; —Z 1 (R 6 —NH—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(NHCO)—R 6 ) t —Z 2 —; or —Z 1 —(R 6 —(CONH)—R 6 ) t —Z 2 —;
Z 1 is —NH—; —O—; —CH 2 —; —NH(CO)—;
Z 2 is —NH—; —O—; —CH 2 —; —NH(CO)—; or —(CO)NH—;
each R 6 is independently C 1 to C 6 alkyl;
t is 1; and
Y is

wherein Y is derivatized to attach to L.

14. The compound of claim 13 , wherein Q is C═O.

15. The compound of claim 13 , wherein n is 1.

16. The compound of claim 13 , wherein X is C═O.

17. The compound of claim 13 , wherein X is CH 2 .

18. The compound of claim 13 , wherein R 5 is H.

19. The compound of claim 13 , wherein R 1 is L-Y.

20. The compound of claim 19 , wherein R 2 , R 3 , and R 4 , are each independently H, hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, optionally substituted amino, optionally substituted C 3 to C 8 heterocyclyl, unsubstituted C 1 to C 6 alkyl, unsubstituted C 3 to C 6 cycloalkyl, or —CF 3 .

21. The compound of claim 20 , wherein R 2 , R 3 , and R 4 , are each independently H, hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, unsubstituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 heterocyclyl, or —CF 3 .

22. The compound of claim 13 , wherein R 3 and R 4 are each H.

23. The compound of claim 22 , wherein R 1 and R 2 are each independently L-Y, H, hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, optionally substituted amino, optionally substituted C 3 to C 8 heterocyclyl, unsubstituted C 1 to C 6 alkyl, unsubstituted C 3 to C 6 cycloalkyl, or —CF 3 .

24. The compound of claim 23 , wherein R 1 and R 2 are each independently L-Y, H, hydroxyl, halogen, unsubstituted C 1 to C 6 alkoxy, unsubstituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 heterocyclyl, or —CF 3 .

25. The compound of claim 13 , wherein Y is

26. The compound of claim 13 selected from:

Assignees

• Bio Theryx Inc
• Biotheryx Inc

Inventors

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

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P1/00

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