Methods to induce targeted protein degradation through bifunctional molecules

Patent metadata

Field	Value
Publication number	US-2016243247-A1
Application number	US-201615148253-A
Country	US
Kind code	A1
Filing date	May 6, 2016
Priority date	Dec 23, 2014
Publication date	Aug 25, 2016
Grant date	—

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

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 a group that covalently binds to the Targeting Ligand and Y; and
the Targeting Ligand binds to a targeted protein selected from FKBP, CREBBP, TRIM24/BRPF1, glucocorticoid receptors, estrogen/androgen receptors, DOT1L, BRAF, HER3, Bcl-2/Bcl-XL, HDAC, and PPAR-gamma.

2 . The compound of claim 1 , wherein the targeted protein is FKBP.

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

4 . The compound of claim 1 , wherein the targeted protein is a glucocorticoid receptor or an estrogen/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 7 , wherein one R 4 is methyl or ethyl.

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

10 . 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.

11 . 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.

12 . The compound of claim 11 , wherein the heterocycle is selected from azetidine, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, and oxetane.

13 . The compound of claim 11 , wherein the heterocycle is oxetane.

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

15 . The compound of claim 11 , wherein the heterocycle is tetrahydrofuran.

16 . The compound of claim 11 , wherein the heterocycle is pyrrolidine.

17 . The compound of claim 11 , wherein the heterocycle is piperidine.

18 . The compound of claim 11 , wherein the heterocycle is piperazine.

19 . The compound of claim 11 , wherein the heterocycle is morpholine.

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

21 . The compound of claim 20 , wherein X is C(O).

22 . The compound of claim 20 , wherein X is C(R 3 ) 2 .

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

39 . The compound of claim 1 of the following formula:

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 Targeting Ligand binds to a targeted protein selected from FKBP, CREBBP, TRIM24/BRPF1, glucocorticoid receptor, estrogen/androgen receptor, DOT1L, BRAF, HER3, Bcl-2/Bcl-XL, HDAC, and PPAR-gamma;
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; and
p3 is selected from 1, 2, 3, 4, and 5.

40 . The compound of claim 39 , wherein the Linker has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 chain atoms.

41 . The compound of claim 39 , wherein each W is independently CH 2 , O, S, NH, or NR 5 .

42 . The compound of claim 39 , wherein at least one W is CH 2 .

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

44 . The compound of claim 39 , wherein at least one W is S.

45 . The compound of claim 39 , wherein at least one W is NH.

46 . The compound of claim 39 , wherein at least one W is NR 5 .

47 . The compound of claim 39 , wherein Q is absent.

48 . The compound of claim 39 , wherein Q is —CH 2 C(O)NH—.

49 . The compound of claim 39 , wherein W is absent.

50 . The compound of claim 39 , wherein at least one W is CH 2 and Z is NH or 0.

51 . The compound of claim 39 , wherein at least one W is 0 and Z is NH or 0.

52 . The compound of claim 39 , wherei

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

• A61K47/48023

  Human Necessities · mapped topic

• A61K31/454

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

• A61K47/542 Primary

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title