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—;
p 1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p 2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p 3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a targeted protein selected from CREBBP, TRIM24, BRPF1, glucocorticoid receptor, estrogen receptor, androgen receptor, DOT1L, BRAF, HER3, Bcl-2, Bel-XL, HDAC, and PPAR-gamma;
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker;
R′ is
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 CREBBP TRIM24, or BRPF1.
3. The compound of claim 1 , wherein the targeted protein is DOT1L, BRAF, or HER3.
4. The compound of claim 1 , wherein the targeted protein is Bcl-2, Bcl-XL, HDAC, or PPAR-gamma.
5. The compound of claim 1 wherein X is C(CH 3 ) 2 .
6. The compound of claim 1 , wherein X is C(CH 2 CH 3 ) 2 .
7. 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.
8. 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.
9. The compound of claim 1 , wherein R 5 is H or deuterium.
10. The compound of claim 1 , wherein each R 1 is independently selected from F, Cl, OH, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.
11. The compound of claim 1 , wherein m is 0.
12. The compound of claim 1 , wherein m is 1.
13. The compound of claim 1 , wherein n is 0.
14. The compound of claim 1 , wherein n is 1.
15. The compound of claim 1 , wherein n is 2.
16. The compound of claim 1 , wherein each R 1 is independently methyl, methoxy, ethoxy, or propoxy.
17. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —O.
18. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NH.
19. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —C(O)NR 2 ′.
20. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NR 2 ′C(O).
21. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NR 2 .
22. The compound of claim 1 selected from:
or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
p1 is selected from 0, 1, 2, 3, 4, and 5.
23. The compound of claim 22 , wherein the Linker has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 chain atoms.
24. The compound of claim 22 , wherein W is independently CH 2 , O, S, NH, or NR 5 .
25. The compound of claim 22 , wherein at least one W is CH 2 .
26. The compound of claim 22 , wherein at least one W is O.
27. The compound of claim 22 , wherein at least one W is S.
28. The compound of claim 22 , wherein at least one W is NH.
29. The compound of claim 22 , wherein at least one W is NR 5 .
30. The compound of claim 22 , wherein Q is absent.
31. The compound of claim 22 , wherein Q is —CH 2 C(O)NH—.
32. The compound of claim 22 , wherein W is absent.
33. The compound of claim 22 , wherein at least one of W is CH 2 and Z is NH or O.
34. The compound of claim 22 , wherein at least one of W is O and Z is NH or O.
35. The compound of claim 22 , wherein at least one of W is S and Z is NH or O.
36. The compound of claim 22 , wherein at least one of W is NH and Z is NH or O.
37. The compound of claim 22 , wherein at least one of W is NR 5 and Z is NH or O.
38. The compound of claim 22 , wherein Z is CH 2 .
39. The compound of claim 22 , wherein Z is O.
40. The compound of claim 22 , wherein at least one of Z is NH.
41. The compound of claim 22 , wherein at least one of Z is NR 5 .
42. The compound of claim 1 , wherein the Linker is of Formula L1 or L2:
43. The compound of claim 1 , wherein the Targeting Ligand is a CREBBP Targeting Ligand selected from:
wherein:
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.
44. The compound of claim 1 , wherein the Targeting Ligand is a TRIM24 or BRPF1 Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker; and
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
45. The compound of claim 1 , wherein the Targeting Ligand is a glucocorticoid receptor Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.
46. The compound of claim 1 , wherein the Targeting Ligand is an estrogen or androgen receptor Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.
47. The compound of claim 1 , wherein the Targeting Ligand is a DOT1L Targeting Ligand selected from:
wherein:
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.
48. The compound of claim 1 , wherein the Targeting Ligand is a BRAF Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.
49. The compound of claim 1 , wherein the Targeting Ligand is a HER3 Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker; and
R′ is
50. The compound of claim 1 , wherein the Bcl-2 or Bcl-XL Targeting Ligand is:
wherein:
R is the attachment point to the Linker.
51. The compound of claim 1 , wherein the HDAC Targeting Ligand is:
wherein:
R is the attachment point to the Linker.
52. The compound of claim 1 , wherein the Targeting Ligand is a PPAR-gamma Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.
53. 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—;
p 1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p 2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p 3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a targeted protein selected from BRD1, BRD2, BRD3, BRD4, BRDS, BRD6, BRD7, BRD8, BRD9, BRD10, and BRDT
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker.
54. The compound of claim 53 , wherein the targeted protein is BRD4.
55. The compound of claim 53 , wherein the Targeting Ligand is a BRD Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker; and
R′ is methyl or ethyl.
56. 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, or 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 ; 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—;
p 1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p 2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p 3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a BET bromodomain-containing protein
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker.