Compounds targeting proteins, compositions, methods, and uses thereof
The present invention provides modulators of protein function, to restore protein homeostasis, including GSPT1 activity. The invention provides methods of modulating protein-mediated diseases, such as GSPT1-mediated diseases, disorders, conditions, or responses. Compositions are also provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions, such as GSPT1-mediated diseases, disorders, and conditions, including cancer and astrogliosis.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 , R 2 , R 3 , and R 4 , are each independently selected from the group consisting of H, deuterium, halogen, cyano, nitro, —NH 2 , an unsubstituted C 1 to C 6 alkoxy, and an unsubstituted C 1 to C 6 alkyl,
wherein one of R 1 and R 2 is
R 5 is selected from the group consisting of H, deuterium, fluoro, and an unsubstituted C 1 to C 6 alkyl;
R 6 is selected from the group consisting of H, deuterium, and an unsubstituted C 1 to C 6 alkyl;
X is selected from the group consisting of CH 2 and C═O;
X 2 is selected from the group consisting of (CH 2 ) n , (CD 2 ) n , (CF 2 ) n , C═O, NH, N-(an optionally substituted C 1 to C 6 alkyl), [(CH 2 ) p —NH—(CH 2 ) q ] t and [(CH 2 ) p —O—(CH 2 ) q ] t ;
X 3 is selected from the group consisting of NH, O, and S;
wherein, when any of R 1 , R 2 , R 3 , or R 4 is
X 2 is selected from the group consisting of (CH 2 ) n , (CD 2 ) n , C═O, [(CH 2 ) p —NH—(CH 2 ) q ]t, and [(CH 2 ) p —O—(CH 2 ) q ] t ;
m is 1, 2, 3, 4, or 5;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p and q are independently 0, 1, 2, 3, 4, 5, or 6;
t is 0, 1, 2, 3, or 4; and
R 7 is selected from the group consisting of an optionally substituted C 3 to C 10 cycloalkyl, an optionally substituted C 6 to C 10 aryl, an optionally substituted 5 to 10-membered heteroaryl, an optionally substituted 3 to 10-membered heterocyclyl, and an optionally substituted C 1 to C 10 alkyl.
2. The compound of claim 1 , wherein R 1 is H.
3. The compound of claim 1 , wherein R 2 is
4. The compound of claim 2 , wherein R 2 is
5. The compound of claim 1 , wherein m is 1.
6. The compound of claim 1 , wherein X 3 is O.
7. The compound of claim 1 , wherein X 2 is NH or (CH 2 ) n .
8. The compound of claim 1 , wherein X 2 is selected from the group consisting of (CH 2 ) n and [(CH 2 ) p —NH—(CH 2 ) q ]t.
9. The compound of claim 1 , wherein n is 0.
10. The compound of claim 1 , wherein t is 0.
11. The compound of claim 1 , wherein X 2 is N-(an unsubstituted C 1 to C 6 alkyl).
12. The compound of claim 1 , wherein X 2 is NH.
13. The compound of claim 1 , wherein R 3 and R 4 , are each independently selected from the group consisting of H and halogen.
14. The compound of claim 1 , wherein R 5 is H.
15. The compound of claim 1 , wherein R 6 is H.
16. The compound of claim 1 , wherein R 7 is selected from the group consisting of an optionally substituted C 3 to C 10 cycloalkyl, an optionally substituted C 6 to C 10 aryl, an optionally substituted 5 to 10-membered heteroaryl, and an optionally substituted 3 to 10-membered heterocyclyl.
17. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is an optionally substituted phenyl group.
18. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a di-substituted phenyl group.
19. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group independently di-substituted with halogen and an unsubstituted C 1 to C 6 alkyl.
20. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group independently di-substituted with an unsubstituted C 1 to C 6 alkyl, halogen, an unsubstituted (heterocyclyl)alkyl, and an unsubstituted alkyl(amino).
21. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group substituted with one or two groups selected from: CH 3 , —Cl, N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 ,
22. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group substituted with 1, 2, or 3 substituents independently selected from halogen, unsubstituted C 1 to C 6 alkyl, —N(unsubstituted C 1 to C 6 alkyl)(unsubstituted C 1 to C 6 alkyl), and unsubstituted C 1 to C 6 alkoxy.
23. The compound of claim 16 , wherein the optionally substituted C 6 to C 10 aryl is a phenyl group substituted with 1 or 2 unsubstituted C 1 to C 6 alkyl groups and 1 or 2 halogens; or wherein the optionally substituted C 6 to C 10 aryl is a phenyl group substituted with 1 unsubstituted C 1 to C 6 alkyl group and 1 halogen.
24. The compound of claim 16 , wherein R 1 is H; R 2 is
R 3 and R 4 are both hydrogen; m is 1; X 2 is NH; and X 3 is O or S.
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure: