Sonic hedgehog modulators

• US 8,530,456 B2
• Filed: 04/21/2009
• Issued: 09/10/2013
• Est. Priority Date: 04/21/2008
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation), Massachusetts Institute of Technology, The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation), Massachusetts Institute of Technology, The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Peng, Lee F., Lamenzo, Julia, Maloof, Nicole, Stanton, Benjamin, MacPherson, Lawrence, Weiwer, Michel, Schreiber, Stuart L., Nakai, Kazuo, Buhrlage, Sara Jean
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US12/988,755
• Publication Number:
  US 20110172233A1
• Time in Patent Office: 1,603 Days
• Field of Search: 540/454, 514/183
• US Class Current: 514/183
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 267/00 Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
• CPC Class Codes: C07D 269/02 having the hetero atoms in positions 1 and 3
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to macrocyclic small molecule inhibitors of the Sonic Hedgehog signaling pathway, syntheses thereof, and intermediates thereto. Such small molecule modulators of the Sonic Hedgehog signaling pathway are useful in the treatment of proliferative diseases (e.g., basal cell carcinoma, Gorlin syndrome, medulloblastoma, or pancreatic cancer), pulmonary diseases (e.g., interstitial pnuemonitis or interstitial pulmonary fibrosis), and developmental disorders (e.g., phocomelia or cyclopia). Novel non-natural macrocycles are provided that inhibit Sonic Hedgehog induced-protein transcription.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein T is —

CH₂—

.

3. The compound according to claim 1, wherein R¹ is hydrogen.

4. The compound according to claim 1, wherein R² is optionally substituted 6-10-membered aryl.

5. The compound according to claim 4, wherein R² is phenyl.

6. The compound according to claim 1, wherein R³ is hydrogen.

7. The compound according to claim 1, wherein Z is —

NR⁴R⁵.

8. The compound according to claim 1, wherein R⁵ is —

C(R⁶)₃.

9. The compound according to claim 8, wherein:

each occurrence of R⁶ is independently hydrogen or an optionally substituted group selected from the group consisting of C_1-12 aliphatic, C_1-12 heteroaliphatic, C_7-15 arylalkyl, 6-10-membered aryl;

or

two occurrences of R⁶ may be taken together with their intervening atoms to form a 3-8-membered ring.

10. The compound according to claim 9, wherein each occurrence of R⁶ is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic and 6-10-membered aryl.

11. The compound according to claim 10, wherein one occurrence of R⁶ is optionally substituted 6-membered aryl.

12. The compound according to claim 11, wherein one occurrence of R⁶ is 4-chlorophenyl.

13. The compound according to claim 1, wherein designates a double bond.

14. The compound according to claim 13, wherein designates a trans double bond.

15. The compound according to claim 1, wherein the compound is of the formula:

16. The compound according to claim 15, wherein the compound is of the formula:

17. The compound according to claim 16, wherein the compound is of the formula:

18. The compound according to claim 15, wherein the compound is selected from:

19. The compound according to claim 15, wherein the compound is of the formula:

20. The compound according to claim 16, wherein the compound is of the formula:

21. The compound according to claim 20, wherein the compound is of the formula:

22. The compound according to claim 1, wherein the compound is selected from:

23. The compound according to claim 1, wherein the compound is:

24. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

26. The compound according to claim 1, wherein R² is hydrogen.

27. The compound according to claim 1, wherein Z is —

OR⁵.

28. The compound according to claim 1, wherein R⁵ is hydrogen.

29. The compound according to claim 8, wherein two occurrences of R⁶ are hydrogen.

30. The compound according to claim 8, wherein one occurrence of R⁶ is an optionally substituted group selected from the group consisting of C_1-6 aliphatic group, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

25. A method of treating Gorlin syndrome, medulloblastoma, basal cell carcinoma, or pancreatic cancer in a subject suffering therefrom, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I: