Methods to induce targeted protein degradation through bifunctional molecules

Patent metadata

Field	Value
Publication number	US-11059801-B2
Application number	US-202016838656-A
Country	US
Kind code	B2
Filing date	Apr 2, 2020
Priority date	Dec 23, 2014
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

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 cancer. The present application also provides compounds of Formula X0 and X0′:

First claim

We claim:

1. A compound, which is:

or a stereoisomer or pharmaceutically acceptable salt thereof; or

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

wherein Y is a bond, Y 1 , O, NH, NR 2 , C(O)O, OC(O), C(O)NR 2 ′, NR 2 ′C(O), Y 1 —O, Y 1 —NH, Y 1 —NR 2 , Y 1 —C(O), Y 1 —C(O)O, Y 1 —OC(O), Y 1 —C(O)NR 2 ′, or Y 1 —NR 2 ′C(O);
Y 1 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene;
X is C(O) or CH 2 ;
X 1 -X 2 is C(R 3 )═N;
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 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C(O)—C 1 -C 6 alkyl, C(O)—C 2 -C 6 alkenyl, C(O)—C 3 -C 8 cycloalkyl, or C(O)-3- to 8-membered heterocycloalkyl, and R 2 is optionally substituted with one or more of halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each of the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH 2 , CN, nitro, OH, C(O)OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 2 ′ is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; wherein each R 2 ′ other than H is optionally substituted with one or more of halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each of the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH 2 , CN, nitro, OH, C(O)OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
each R 3 is independently H or C 1 -C 3 alkyl optionally substituted with C 6 -C 10 aryl or 5- to 10-membered heteroaryl;
each R 3 ′ is independently C 1 -C 3 alkyl;
two R 4 , together with the carbon atom to which they are attached, form C(O);
R 5 is H, C 1 -C 3 alkyl, F, or Cl;
each R a independently is H or C 1 -C 6 alkyl;
R b is H or tosyl;
t is 0 or 1;
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 wherein
the Targeting Ligand is selected from:

wherein
R is the attachment point to the Linker.

2. The compound of claim 1 , wherein the Linker has the Formula:

wherein:
p1 is an integer selected from 0 to 12;
p2 is an integer selected from 0 to 12;
p3 is an integer selected from 0 to 6;
each W is independently absent, CH 2 , O, S, NH or NR 5 ;
Z is absent, CH 2 , O, NH or N(C 1 -C 3 alkyl); and
Q is absent, —C(O)NH—, —C(O)O—, —CH 2 C(O)NH—, or —CH 2 C(O)O—; wherein
the Linker is covalently bonded to the Y with the

next to Q, and covalently bonded to the Targeting Ligand with the

next to Z.

3. The compound of claim 1 , wherein the compound is Formula (X0):

or a stereoisomer or pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein t is 0.

5. The compound of claim 4 , wherein

6. The compound of claim 4 , wherein n is 0, R 5 is H, and each R 3 is H.

7. The compound of claim 6 , wherein X is C(O).

8. The compound of claim 3 , wherein n is 0, R 5 is H, and each R 3 is H.

9. The compound of claim 3 , wherein

10. The compound of claim 9 , wherein n is 0 and R 5 is H.

11. The compound of claim 10 , wherein X 1 -X 2 is C(CH 3 )═N.

12. The compound of claim 1 , wherein the compound is of Formula (X0′):

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , wherein

14. The compound of claim 13 , wherein n is 0, R 5 is H, and each R 3 is H.

15. The compound of claim 14 , wherein X is C(O).

16. The compound of claim 15 , wherein Y is a bond, O, NH, or NR 2 .

17. The compound of claim 12 , wherein

18. The compound of claim 17 , wherein n is 0, and R 5 is H.

19. The compound of claim 18 , wherein X 1 -X 2 is C(CH 3 )═N.

20. The compound of claim 1 , wherein the targeting ligand is represented by any one of structures:

21. The compound of claim 1 , wherein the targeting ligand is represented by any one of structures:

22. A pharmaceutical composition comprising a therapeutically effective amount of the compound or stereoisomer or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable carrier.

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James
• Buckley Dennis
• Winter Georg

Classifications

• C07D475/00

  Heterocyclic compounds containing pteridine ring systems · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P13/10

  of the bladder · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title