Degradation of protein kinases by conjugation of protein kinase inhibitors with E3 ligase ligand and methods of use

Patent metadata

Field	Value
Publication number	US-10925868-B2
Application number	US-201716343973-A
Country	US
Kind code	B2
Filing date	Nov 10, 2017
Priority date	Nov 10, 2016
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

The present application provides bifunctional compounds of Formula (I):

or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases (e.g., Bcr-Abl). The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.

First claim

The invention claimed is:

1. A bifunctional compound
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the bifunctional compound is of Formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-10, I-11, or I-12:

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

3. A method of inhibiting the activity of at least protein kinase Bcr-Abl, comprising administering to a subject in need thereof an effective amount of the compound or a stereoisomer or pharmaceutically acceptable salt thereof of claim 1 .

4. A method of treating a cancer in which at least protein kinase Bcr-Abl plays a role, wherein the cancer is leukemia, rhabdomyosarcoma or lymphoma, comprising administering to a subject in need thereof an effective amount of the compound or a stereoisomer or pharmaceutically acceptable salt thereof of claim 1 .

5. The method of claim 4 , wherein the cancer is leukemia.

6. The method of claim 5 , wherein the leukemia is adult T-cell leukemia/lymphoma (ATLL), acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute-myeloid leukemia (AML), or chronic myeloid leukemia (CML).

7. The method of claim 4 , wherein the cancer is rhabdomyosarcoma.

8. The method of claim 4 , wherein the cancer is lymphoma.

9. The bifunctional compound of claim 1 , wherein the structure is of Formula I-1:

(I-1), or a stereoisomer or pharmaceutically acceptable salt thereof.

10. The bifunctional compound of claim 1 , wherein the structure is of Formula I-2:

stereoisomer or pharmaceutically acceptable salt thereof.

11. The bifunctional compound of claim 1 , wherein the structure is of Formula I-3:

(I-3), or a stereoisomer or pharmaceutically acceptable salt thereof.

12. The bifunctional compound of claim 1 , wherein the structure is of Formula I-4:

(I-4), or a stereoisomer or pharmaceutically acceptable salt thereof.

13. The bifunctional compound of claim 1 , wherein the structure is of Formula I-5:

(I-5), or a stereoisomer or pharmaceutically acceptable salt thereof.

14. The bifunctional compound of claim 1 , wherein the structure is of Formula I-6:

(I-6), or a stereoisomer or pharmaceutically acceptable salt thereof.

15. The bifunctional compound of claim 1 , wherein the structure is of Formula I-7:

(I-7), or a stereoisomer or pharmaceutically acceptable salt thereof.

16. The bifunctional compound of claim 1 , wherein the structure is of Formula I-8:

(I-8), or a stereoisomer or pharmaceutically acceptable salt thereof.

17. The bifunctional compound of claim 1 , wherein the structure is of Formula I-10:

(I-10), or a stereoisomer or pharmaceutically acceptable salt thereof.

18. The bifunctional compound of claim 1 , wherein the structure is of Formula I-11:

(I-11), or a stereoisomer or pharmaceutically acceptable salt thereof.

19. The bifunctional compound of claim 1 , wherein the structure is of Formula I-12:

(I-12), or a stereoisomer or pharmaceutically acceptable salt thereof.

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Gray Nathanael S
• Bradner James
• Tan Li
• Huang Hai-Tsang
• Buckley Dennis
• Winter Georg
• Rosenbaum Mette Ishoey

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/454 Primary

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

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D241/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title