Methods to induce targeted protein degradation through bifunctional molecules

Patent metadata

Field	Value
Publication number	US-9694084-B2
Application number	US-201514707930-A
Country	US
Kind code	B2
Filing date	May 8, 2015
Priority date	Dec 23, 2014
Publication date	Jul 4, 2017
Grant date	Jul 4, 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

The invention claimed is:

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 ;
X 1 -X 2 is C(R 3 )═N or C(R 3 ) 2 —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 independently C 1 —C 3 alkyl;
each R 4 is independently H or C 1 —C 3 alkyl and at least one R 4 is C 1 —C 3 alkyl; or two R 4 , together with the carbon atom to which they are attached, form 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 one R 4 is C 1 -C 3 alkyl.

5. The compound of claim 4 , wherein one R 4 is methyl or ethyl.

6. The compound of claim 1 , wherein each R 4 is independently methyl or ethyl.

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 8 , wherein the heterocycle is selected from azetidine, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, and oxetane.

10. The compound of claim 8 , wherein the heterocycle is oxetane.

11. The compound of claim 8 , wherein the heterocycle is azetidine.

12. The compound of claim 8 , wherein the heterocycle is tetrahydrofuran.

13. The compound of claim 8 , wherein the heterocycle is pyrrolidine.

14. The compound of claim 8 , wherein the heterocycle is piperidine.

15. The compound of claim 8 , wherein the heterocycle is piperazine.

16. The compound of claim 8 , wherein the heterocycle is morpholine.

17. The compound of claim 1 , wherein the compound is Formula I.

18. The compound of claim 17 , wherein X is C(O).

19. The compound of claim 17 , wherein X is C(R 3 ) 2 .

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

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

22. The compound of claim 1 , wherein each R 1 is independently selected from F, Cl, OH, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.

23. The compound of claim 1 , wherein m is 0.

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

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

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

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

28. The compound of claim 1 , wherein the compound is Formula II.

29. The compound of claim 1 , wherein each R 1 is independently methyl, methoxy, ethoxy or propoxy.

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

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

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

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

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

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

36. The compound of claim 1 , wherein the Linker has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 chain atoms.

37. The compound of claim 1 , wherein W is independently CH 2 , O, S, NH, or NR 5 .

38. The compound of claim 1 , wherein at least one W is CH 2 .

39. The compound of claim 1 , wherein at least one W is O.

40. The compound of claim 1 , wherein at least one W is S.

41. The compound of claim 1 , wherein at least one W is NH.

42. The compound of claim 1 , wherein at least one W is NR 5 .

43. The compound of claim 42 , wherein R 5 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.

44. The compound of claim 1 , wherein Q is absent.

45. The compound of claim 1 , wherein Q is —CH 2 C(O)NH—.

46. The compound of claim 1 , wherein W is absent.

47. The compound of claim 1 , wherein at least one of W is CH 2 and Z is NH or O.

48. The compound of claim 1 , wherein at least one of W is O and Z is NH or O.

49. The compound of claim 1 , wherein at least one of W is S and Z is NH or O.

50. The compound of claim 1 , wherein at least one of W is NH and Z is NH or O.

51. The compound of claim 1 , wherein at least one of W is NR 5 and Z is NH or O.

52. The compound of claim 1 , wherein Z is CH 2.

53. The compound of claim 1 , wherein Z is O.

54. The compound of claim 1 , wherein at least one of Z is NH.

55. The compound of claim 1 , wherein at least one of Z is NR 5 .

56. The compound of claim 1 , wherein the Linker is of Formula L1 or L2:

57. 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 ;
X 1 -X 2 is C(R 3 )═N or C(R 3 ) 2 —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 al

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James
• Buckley Dennis
• Winter Georg

Classifications

• C07J43/003 Primary

  not condensed · CPC title

• A61K47/48061 Primary

  Human Necessities · mapped topic

• C07J3/005

  the carbon atom being part of a carboxylic function · CPC title

• A61K31/454

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

• C07D471/04

  Ortho-condensed systems · CPC title