Macrocyclic kinase inhibitors and uses thereof

• US 8,975,232 B2
• Filed: 07/29/2011
• Issued: 03/10/2015
• Est. Priority Date: 07/29/2010
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Liu, David R., Kleiner, Ralph E.
• Primary Examiner(s): Alstrum Acevedo, James H
• Assistant Examiner(s): REYNOLDS, FRED H
• Application Number:
  US13/812,431
• Publication Number:
  US 20130178429A1
• Time in Patent Office: 1,320 Days
• Field of Search: None
• US Class Current: 514/19.2
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 5/02 containing at least one abnormal peptide link
• CPC Class Codes: C07K 5/1016 and aromatic or cycloaliphatic

Abstract

The present invention provides macrocyclic compounds of Formula (I): pharmaceutically acceptable salts thereof; and pharmaceutical compositions thereof, wherein R₁, R₂, R₃, R₄, R^E, R^F, R^G, R^H, R^I, f, g, h, n, and m are as defined herein. The present invention further provides methods of synthesizing these macrocyclic compounds, and methods of their use and treatment. Certain aspects of the present invention relate to modulation of kinase activity, and in the treatment of kinase-associated diseases or disorders.

Claims

1. A compound of Formula (XV):

2. The compound of claim 1, wherein R₄ is —

N(R_D)₂.

3. The compound of claim 1, wherein each occurrence of R_E, R_F, R_G, R_H, and R_I is hydrogen.

4. The compound of claim 1, wherein n is 3.

5. The compound of claim 1, wherein the compound is selected from the group consisting of:

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

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

8. The compound of claim 1, wherein q is 1;

and R^AA is halogen, perhaloalkyl, —

C(═

O)N(R^A2)₂, —

CN, —

SCN, or —

NO₂ located at the para position relative to the point of attachment.

9. The compound of claim 8, wherein R^AA is —

NO₂.

10. The compound of claim 1, wherein b is 1;

and R^BB is halogen located in the para position relative to the point of attachment.

11. The compound of claim 10, wherein R^BB is —

F.

12. The compound of claim 1, wherein t is 0.

13. The compound of claim 5, wherein R₄ is —

NH₂, n is 3, and represents a double bond in the trans configuration.

14. The compound of claim 5, wherein R₄ is —

NH₂, n is 3, and represents a double bond in the cis configuration.

15. The compound of claim 5, wherein R₄ is —

NH₂, n is 2, and represents a double bond in the trans configuration.

16. The compound of claim 5, wherein R₄ is —

NH₂, n is 2, and represents a double bond in the cis configuration.