Methods to induce targeted protein degradation through bifunctional molecules

Patent metadata

Field	Value
Publication number	US-9821068-B2
Application number	US-201615148253-A
Country	US
Kind code	B2
Filing date	May 6, 2016
Priority date	Dec 23, 2014
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

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.

First claim

We claim:

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(O) or C(R 3 ) 2 ;
each R 1 is independently 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;
each R 3 is independently H or C 1 -C 3 alkyl;
each R 3 ′ is methyl;
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 C(O), or a C 3 -C 6 carbocycle;
R 5 is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
m is 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 CREBBP, TRIM24, BRPF1, glucocorticoid receptor, estrogen receptor, androgen receptor, DOT1L, BRAF, HER3, Bcl-2, Bcl-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 a glucocorticoid receptor.

3. The compound of claim 1 , wherein the targeted protein is CREBBP TRIM24, or BRPF1.

4. The compound of claim 1 , wherein the targeted protein is a estrogen receptor or androgen receptor.

5. The compound of claim 1 , wherein the targeted protein is DOT1L, BRAF, or HER3.

6. The compound of claim 1 , wherein the targeted protein is Bcl-2, Bcl-XL, HDAC, or PPAR-gamma.

7. The compound of claim 1 , wherein one R 4 is C 1 -C 3 alkyl.

8. 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.

9. The compound of claim 1 , wherein X is C(O).

10. The compound of claim 1 , wherein X is C(R 3 ) 2 .

11. The compound of claim 1 , wherein R 5 is H or deuterium.

12. The compound of claim 1 , wherein R 3 is H or methyl.

13. The compound of claim 1 , wherein each R 1 is independently selected from methoxy, ethoxy and propoxy.

14. The compound of claim 1 , wherein m is 1.

15. The compound of claim 1 , wherein n is 0.

16. The compound of claim 1 , wherein n is 1.

17. The compound of claim 1 , wherein n is 2.

18. The compound of claim 1 , wherein each R 1 is methoxy.

19. The compound of claim 1 , wherein X is C(CH 3 ) 2 .

20. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —O.

21. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NH.

22. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —C(O)NR 2 ′.

23. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NR 2 ′C(O).

24. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NR 2 .

25. The compound of claim 1 wherein p1 is selected from 0, 1, 2, 3, 4, and 5.

26. The compound of claim 25 , wherein the Linker has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 chain atoms.

27. The compound of claim 25 , wherein W is independently CH 2 , O, S, NH, or NR 5 .

28. The compound of claim 25 , wherein at least one W is CH 2 .

29. The compound of claim 25 , wherein at least one W is O.

30. The compound of claim 25 , wherein at least one W is S.

31. The compound of claim 25 , wherein at least one W is NH.

32. The compound of claim 25 , wherein at least one W is NR 5 .

33. The compound of claim 25 , wherein Q is absent.

34. The compound of claim 25 , wherein Q is —CH 2 C(O)NH—.

35. The compound of claim 25 , wherein W is absent.

36. The compound of claim 25 , wherein at least one W is CH 2 and Z is NH or O.

37. The compound of claim 25 , wherein at least one W is O and Z is NH or O.

38. The compound of claim 25 , wherein at least one W is S and Z is NH or O.

39. The compound of claim 25 , wherein at least one W is NH and Z is NH or O.

40. The compound of claim 25 , wherein at least one W is NR 5 and Z is NH or O.

41. The compound of claim 25 , wherein is CH 2 .

42. The compound of claim 25 , wherein Z is O.

43. The compound of claim 25 , wherein Z is NH.

44. The compound of claim 25 , wherein Z is NR 5 .

45. The compound of claim 25 , wherein the Linker is of Formula L1 or L2:

46. 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(O) or C(R 3 ) 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;
each R 3 is independently H or C 1 -C 3 alkyl;
each R 3 ′ is methyl;
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) or a C 3 -C 6 carbocycle;
R 5 is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
m is 0, 1, 2 or 3;
n is 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 f

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James
• Buckley Dennis
• Winter Georg

Classifications

• C07J43/003 Primary

  not condensed · CPC title

• A61K47/48038

  Human Necessities · mapped topic

• C07D495/14

  Ortho-condensed systems · CPC title

• A61K47/48123

  Human Necessities · mapped topic

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title