Compounds targeting proteins, compositions, methods, and uses thereof

Patent metadata

Field	Value
Publication number	US-10336771-B2
Application number	US-201816011090-A
Country	US
Kind code	B2
Filing date	Jun 18, 2018
Priority date	Dec 21, 2016
Publication date	Jul 2, 2019
Grant date	Jul 2, 2019

Abstract

The present invention provides compounds that modulate protein function, to restore protein homeostasis, including cytokine, CK1α, GSPT1, aiolos, and/or ikaros 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 diseases, disorders, or conditions associated with a protein, such as diseases, disorders, and conditions associated with cytokines, 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, and cancer, are provided.

First claim

What is claimed is:

1. A compound of Formula (IId):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10-membered heterocyclyl, or optionally substituted 5 to 10-membered heteroaryl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each hydrogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is hydrogen and the other of R 1 and R 2 is optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 8 cycloalkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is optionally substituted C 1 -C 6 alkyl or H; and the other of R 1 and R 2 is chloro, bromo, nitro, cyano, or optionally substituted amino.

5. A method of inhibiting protein activity, comprising contacting a cell with a compound of claim 1 , or a pharmaceutically acceptable salt of the foregoing, wherein the protein is aiolos, ikaros, helios, CK1α, GSPT1, a cytokine, or a combination of any of the foregoing.

6. A compound of Formula (IIe):

or a pharmaceutically acceptable salt thereof, wherein:
one of R 1 and R 2 is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted 5 to 10-membered heteroaryl;

the other of R 1 and R 2 is optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted 5 to 10-membered heteroaryl,

or L-Y,
wherein when one of R 1 and R 2 is

 then the other R 1 and R 2 is not L-Y, wherein:
m is 2, 3, 4, or 5;
X 2 is selected from the group consisting of (CH 2 ) a , C═O, NH, and N-(optionally substituted C 1 -C 6 alkyl);
a is 0, 1, 2, 3, 4, 6, 7, 8, 9, or 10;
R 8 is selected from the group consisting of optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10-membered heteroaryl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted C 3 -C 10 cycloalkyl(C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl(C 1 -C 6 alkyl), optionally substituted 5 to 10 membered heteroaryl(C 1 -C 6 alkyl), and optionally substituted 3 to 10 membered heterocyclyl(C 1 -C 6 alkyl);

Z 1 and Z 2 are each —CH 2 —;
each R 6 is absent or independently C 1 -C 6 alkyl; and
Y is selected from a group consisting of

wherein * represents the point of attachment to the L group.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is hydrogen and the other R 1 and R 2 is

or L-Y.

8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is hydrogen and the other of R 1 and R 2 is optionally substituted C 3 -C 8 cycloalkyl.

9. A method of inhibiting protein activity, comprising contacting a cell with a compound of claim 6 , or a pharmaceutically acceptable salt of the foregoing, wherein the protein is aiolos, ikaros, helios, CK1α, GSPT1, a cytokine, or a combination of any of the foregoing.

10. A compound of Formula (IIf):

or a pharmaceutically acceptable salt thereof, wherein:
one of R 1 and R 2 is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted 5 to 10-membered heteroaryl,

or L-Y,
the other of R 1 and R 2 is optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted 5 to 10-membered heteroaryl,

or L-Y;
wherein when one of R 1 and R 2 is

 then the other R 1 and R 2 is not L-Y, wherein:
m is 1, 2, 3, 4 or 5;
X 2 is selected from the group consisting of (CH 2 ) a , C═O, NH, and N-(optionally substituted C 1 -C 6 alkyl);
a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R 8 is selected from the group consisting of optionally substituted C 3 -C 10 cycloalkyl optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10-membered heteroaryl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted C 3 -C 10 cycloalkyl(C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl(C 1 -C 6 alkyl), optionally substituted 5 to 10 membered heteroaryl(C 1 -C 6 alkyl), and optionally substituted 3 to 10 membered heterocyclyl(C 1 -C 6 alkyl);

Z 1 and Z 2 are each —CH 2 —;
each R 6 is absent or independently C 1 -C 6 alkyl; and
Y is selected from a group consisting of

wherein * represents the point of attachment to the L group.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is hydrogen, and the other R 1

Assignees

• Biotheryx Inc

Inventors

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

Classifications

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P1/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P17/06

  Antipsoriatics · CPC title