Methods to induce targeted protein degradation through bifunctional molecules
The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.
1. A compound selected from:
or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
Y is a bond, (CH 2 ) 1-6 , (CH 2 ) 0-6 —O, (CH 2 ) 0-6 —C(O)NR 2 ′, (CH 2 ) 0-6 —NR 2 ′C(O), (CH 2 ) 0-6 —NH, or (CH 2 ) 0-6 —NR 2 ;
X is C(C 1 -C 3 alkyl) 2 ;
each R 1 is independently halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 is C 1 -C 6 alkyl, C(O)—C 1 -C 6 alkyl, or C(O)—C 3 -C 6 cycloalkyl;
R 2 ′ is H or C 1 -C 6 alkyl;
R 3 is H or C 1 -C 3 alkyl;
each R 3 ′ is independently C 1 -C 3 alkyl;
each R 4 is independently H or C 1 -C 3 alkyl; or two R 4 , together with the carbon atom to which they are attached, form a C(O), a C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R 5 is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
m is 0, 1, 2 or 3;
n is 0, 1 or 2;
the Linker is
each W is independently absent, CH 2 , O, S, NH or NR 5 ;
Z is absent, CH 2 , O, NH or NR 5 ;
Q is absent or —CH 2 C(O)NH—;
p1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a targeted protein selected from SMARCA2, and Ras;
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker;
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.
2. The compound of claim 1 , wherein the targeted protein is SMARCA2.
3. The compound of claim 1 , wherein the targeted protein is Ras.
4. The compound of claim 1 wherein X is C(CH 3 ) 2 .
5. The compound of claim 1 , wherein X is C(CH 2 CH 3 ) 2 .
6. The compound of claim 1 , wherein two R 4 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
7. The compound of claim 1 , wherein two R 4 , together with the carbon to which they are attached, form a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O.
8. The compound of claim 1 , wherein R 5 is H or deuterium.
9. The compound of claim 1 , wherein each R 1 is independently selected from F, Cl, OH, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.
10. The compound of claim 1 , wherein m is 0.
11. The compound of claim 1 , wherein m is 1.
12. The compound of claim 1 , wherein n is 0.
13. The compound of claim 1 , wherein n is 1.
14. The compound of claim 1 , wherein n is 2.
15. The compound of claim 1 , wherein each R 1 is independently methyl, methoxy, ethoxy, or propoxy.
16. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —O.
17. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NH.
18. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —C(O)NR 2 ′.
19. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NR 2 ′C(O).
20. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NR 2 .
21. The compound of claim 1 , wherein the Linker has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 chain atoms.
22. The compound of claim 1 , wherein W is independently CH 2 , O, S, NH, or NR 5 .
23. The compound of claim 1 , wherein at least one W is CH 2 .
24. The compound of claim 1 , wherein at least one W is O.
25. The compound of claim 1 , wherein at least one W is S.
26. The compound of claim 1 , wherein at least one W is NH.
27. The compound of claim 1 , wherein at least one W is NR 5 .
28. The compound of claim 1 , wherein Q is absent.
29. The compound of claim 1 , wherein Q is CH 2 C(O)NH—.
30. The compound of claim 1 , wherein W is absent.
31. The compound of claim 1 , wherein at least one of W is CH 2 and Z is NH or O.
32. The compound of claim 1 , wherein at least one of W is O and Z is NH or O.
33. The compound of claim 1 , wherein at least one of W is S and Z is NH or O.
34. The compound of claim 1 , wherein at least one of W is NH and Z is NH or O.
35. The compound of claim 1 , wherein at least one of W is NR 5 and Z is NH or O.
36. The compound of claim 1 , wherein Z is CH 2 .
37. The compound of claim 1 , wherein Z is O.
38. The compound of claim 1 , wherein Z is NH.
39. The compound of claim 1 , wherein Z is NR 5 .
40. The compound of claim 1 , wherein the Targeting Ligand is a SMARCA2 Targeting Ligand selected from:
41. The compound of claim 1 , wherein the Targeting Ligand is a Ras Targeting Ligand selected from:
42. The compound of claim 1 , wherein the Targeting Ligand is a RasG12C Targeting Ligand selected from: