Hydrophobically tagged small molecules as inducers of protein degradation

• US 9,758,522 B2
• Filed: 10/18/2013
• Issued: 09/12/2017
• Est. Priority Date: 10/19/2012
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, Yale University
• Original Assignee: Dana-Farber Cancer Institute, Yale University
• Inventors: Gray, Nathanael, Xie, Ting, Lim, Sang Min, Janne, Pasi A., Crews, Craig M.
• Primary Examiner(s): MCDOWELL, BRIAN E
• Application Number:
  US14/436,657
• Publication Number:
  US 20150274738A1
• Time in Patent Office: 1,425 Days
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Provided are bifunctional small molecules of Formula (I): or pharmaceutically acceptable salts thereof, wherein M represents a small organic molecule which binds, covalently or non-covalently, a kinase, such as Her3 protein kinase; L¹ represents a linker; and R^H represents a hydrophobic group. An example of a compound of Formula (I) is a compound of Formula (II): Also provided are pharmaceutical compositions comprising a compound of Formula (I) or (II) and methods of using such compounds for treating proliferative diseases.

Claims

1. A compound of Formula (II):

2. The compound of claim 1, wherein Ring A is substituted or unsubstituted phenyl.

3. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 5- to 6-membered heteroaryl ring.

4. The compound of claim 1, wherein Ring A is a substituted or unsubstituted C_3-8carbocyclyl ring.

5. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 3- to 8-membered heterocyclyl ring.

6. The compound of claim 1 of Formula (II-g):

7. The compound of claim 1 of Formula (II-e4):

8. The compound of claim 1, wherein R^H is a hydrophobic substituted or unsubstituted aryl, or a hydrophobic substituted or unsubstituted aralkyl.

9. The compound of claim 8, wherein R^H is a group of formula:

10. The compound of claim 1, wherein R^H is a hydrophobic substituted or unsubstituted carbocyclyl, or a hydrophobic substituted or unsubstituted carbocyclylalkyl.

11. The compound of claim 10, wherein R^H is a group of formula:

12. The compound of claim 1, wherein R^H is a hydrophobic substituted or unsubstituted heterocyclyl, or a hydrophobic substituted or unsubstituted heterocyclylalkyl.

13. The compound of claim 12, wherein R^H is a group of formula:

14. The compound of claim 1, wherein L¹ represents a linker consisting of one group, or a combination of 2 to 20 consecutive covalently bonded groups, of the formula:

15. The compound of claim 14, wherein -L¹-R^H represents a group of the formula:

16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A method of treating breast cancer, ovarian cancer, or lung cancer, the method comprising administering a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof in an amount sufficient to treat the breast cancer, ovarian cancer, or lung cancer.

18. The compound of claim 1 selected from the group consisting of:

21. The compound of claim 1, wherein L¹ represents a linker of 5 to 15, inclusive, consecutive, covalently bonded atoms in length.

22. The compound of claim 1, wherein L¹ represents a linker of 5 to 11, inclusive, consecutive, covalently bonded atoms in length.

19. A compound selected from the group consisting of:

20. A compound selected from the group consisting of: