Compounds targeting proteins, compositions, methods, and uses thereof

Patent metadata

Field	Value
Publication number	US-10889593-B2
Application number	US-201916457409-A
Country	US
Kind code	B2
Filing date	Jun 28, 2019
Priority date	Dec 21, 2016
Publication date	Jan 12, 2021
Grant date	Jan 12, 2021

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 method of treating cancer associated with a cytokine, aiolos, ikaros, helios, CKla, or GSPT1, comprising administering a compound of Formula (II a ) or a pharmaceutically acceptable salt thereof to a subject in need 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 - C8 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10-membered heterocyclyl, or optionally substituted 5 to 10-membered heteroaryl; or
one of R1 and R 2 is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 - C6 alkyl, optionally substituted C 2 - C6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 - C10 aryl, optionally substituted 3 to 10-membered

heterocyclyl, optionally substituted 5 to 10-membered heteroaryl, or L-Y; and
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;

provided that when one of R 1 and R2 is then the other R 1 and R2 is not L-Y;
R 5 is H, deuterium, or optionally substituted C 1 -C 6 alkyl;
n is 2 or 3;
each of Qa and Qb is independently C═O, C=S, or CH 2 ;
X is CH 2 or C(═O);
X 1 is H, deuterium, halogen, or optionally substituted C 1 -C 6 alkyl;
m is 1, 2, 3, 4, or 5;
X 2 is (CH 2 ) a , C═O, NH, or N—(optionally substituted C 1 - C6 alkyl);
X 3 is 0, NI- 2 or S;
a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R 8 is 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 - C6 alkyl), optionally substituted 5 to 10 membered heteroaryl(C 1 -C 6 alkyl), or optionally substituted 3 to 10 membered heterocyclyl(C 1 -C 6 alkyl);

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

wherein * represents the point of attachment to L.

2. The method of claim 1 , wherein n is 2; X 1 is H; R 5 is H; and Qa and Qb are each C═O.

3. The method of claim 2 , 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 method of claim 2 , wherein one of R 1 and R2 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. The method of claim 1 , wherein the cancer is leukemia, lymphoma, multiple myeloma, breast cancer, or lung cancer.

6. A method of treating cancer associated with a cytokine, aiolos, ikaros, helios, CK1α, or GSPT1, comprising administering a compound of Formula (II b ), or a pharmaceutically acceptable salt thereof to a subject in need 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; and
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;

provided that when one of R 1 and R 2 is then the other R 1 and R 2 is not L-Y;
R 5 is H, deuterium, or optionally substituted C 1 -C 6 alkyl;
n is 2 or 3;
each of Qa and Qb is independently C═O, C=S, or CH 2 ;
X is CH 2 or C(═O);
X 1 is H, deuterium, halogen, or optionally substituted C 1 -C 6 alkyl;
m is 1, 2, 3, 4, or 5;
X 2 is (CH 2 )α, C═O, NH, or N—(optionally substituted C 1 -C 6 alkyl);
X 3 is O, NH, or S;
a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R 8 is 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), or optionally substituted 3 to 10 membered heterocyclyl(C 1 -C 6 alkyl);

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

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

7. The method of claim 6 , wherein n is 2; X 1 is H; R 5 is H; and Qa and Qb are each C═O.

8. The method of claim 7 , wherein one of R 1 and R 2 is

hydrogen and the other R 1 and R 2 is or L-Y.

9. The method of claim 7 , wherein R 1 is

and R 2 is H.

10. The method of claim 9 , wherein R 1 is and X2 is NH.

11. The method of claim 10 , wherein R 8 is a phenyl group substi

Assignees

• Biotheryx Inc

Inventors

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

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P29/00

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

• A61P19/02

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