Compounds targeting proteins, compositions, methods, and uses thereof
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.
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 and R 2 is
or L-Y.
12. The compound of claim 10 , 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.
13. A method of inhibiting protein activity, comprising contacting a cell with a compound of claim 10 , 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.
14. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
and R 2 is H.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein in is 1, and X 2 is NH, C═O, or (CH 2 ) a , wherein a is 2 or 3.
16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
and X 2 is NH.
17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 8 is a phenyl group substituted with one or more substituents selected from the group consisting of halogen, unsubstituted C 1 -C 6 alkyl, C 1 -C 3 alkoxy, and unsubstituted di(C 1 -C 3 alkyl)amino, or a 5-6 membered heteroaryl group substituted with one or more substituents selected from the group consisting of halogen, unsubstituted C 1 -C 6 alkyl, C 1 -C 3 alkoxy, and unsubstituted di(C 1 -C 3 alkyl)amino.
18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 8 is a phenyl group substituted with an unsubstituted C 1 -C 6 alkyl and halogen, a phenyl group substituted with an unsubstituted C 1 -C 6 alkyl and an unsubstituted C 1 -C 3 alkoxy, a phenyl group substituted with an unsubstituted C 1 -C 3 alkoxy and halogen, a phenyl group substituted with an unsubstituted C 1 -C 6 alkyl and an unsubstituted di(C 1 -C 3 alkyl)amino, or a phenyl group substituted with an unsubstituted di(C 1 -C 3 alkyl)amino and halogen.
19. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is L-Y and R 2 is H.
20. The compound of claim 10 , or a pharmaceutically acceptable salt thereof wherein R 1 is H and R 2 is
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein m is 1, and X 2 is NH, C═O, or (CH 2 ) a , wherein a is 2 or 3.
22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 8 is a phenyl group substituted with one or more substituents selected from the group consisting of halogen, unsubstituted C 1 -C 6 alkyl, C 1 -C 3 alkoxy, and unsubstituted di(C 1 -C 3 alkyl)amino, or a 5-6 membered heteroaryl group substituted with one or more substituents selected from the group consisting of halogen, unsubstituted C 1 -C 6 alkyl, C 1 -C 3 alkoxy, and unsubstituted di(C 1 -C 3 alkyl)amino.
23. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H and R 2 is L-Y.
24. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein L is