Pyridyl inhibitors of hedgehog signalling

• US 9,321,761 B2
• Filed: 12/18/2014
• Issued: 04/26/2016
• Est. Priority Date: 09/02/2004
• Status: Active Grant

• Current Assignee: Curis, Inc., Genentech, Inc. (Roche Holding AG)
• Original Assignee: Curis, Inc., Genentech, Inc. (Roche Holding AG)
• Inventors: Gunzner-Toste, Janet L., Stanley, Mark S., Castanedo, Georgette M., Wang, Shumei, Reynolds, Mark E., Savage, Scott J., Dina, Michael S., Koehler, Michael F. T., Sutherlin, Daniel, Bao, Liang, LaLonde, Rebecca L., Malesky, Kimberly
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US14/575,018
• Publication Number:
  US 20150105550A1
• Time in Patent Office: 495 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 213/16 containing only one pyridine ring
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/70 Sulfur atoms
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 9/58 : Pyridine rings

Abstract

The invention provides novel inhibitors of hedgehog signaling that are useful as a therapeutic agents for treating malignancies where the compounds have the general formula I:

wherein A, X, Y R₁, R₂, R₃, R₄, m and n are as described herein.

Claims

1. A process for preparing a compound of formula I

2. The process of claim 1, wherein R₄ is H or methyl.

3. The process of claim 2, wherein R₄ is H.

4. The process of claim 1, wherein R₁ is substituted.

5. The process of claim 4, wherein R₁ is substituted phenyl or substituted pyridyl.

6. The process of claim 5, wherein R₁ is substituted phenyl.

7. A process of claim 1 for preparing a compound of formula Ib

8. A process of claim 7, wherein R₈ is halogen and R₁ is substituted phenyl or substituted pyridyl.

9. A process of claim 8, wherein R₄ is H, m is 0 and R₈ is Cl.

10. A process of claim 8, wherein said substituted phenyl or pyridyl R¹ group comprises —

SO₂—

.

11. A process of claim 1 for preparing a compound of the formula

12. A process of claim 8 for preparing a compound of the formula Ib′

13. A process of claim 12, wherein at least one R₆ is an optionally substituted sulfonyl.

14. A process of claim 5, wherein, ring A is o-chlorophenyl, X is —

NHC(O)—

, and R₁ substituted phenyl or substituted pyridyl comprises —

SO₂—

.

15. A process of claim 12, wherein carbocycle is a mono-, bi-, or tricyclic ring having 3 to 14 carbon atoms which can be saturated or unsaturated aliphatic or aromatic and heterocycle is a mono-, bi-, or tricyclic ring which is saturated or unsaturated, or aromatic, having from 5 to about 14 ring atoms, where the ring atoms are carbon and from 1 to 4 heteroatoms which are nitrogen, sulfur or oxygen.

16. A process of claim 1, wherein R₁ is of formula IIa or IIb:

17. A process of claim 7 wherein R₁ is of formula IIa or IIb:

18. A process of claim 1, wherein said optional salt and said optional solvate formations are omitted.

21. A process of claim 1 further comprising reducing a compound of formula (c)

22. A process of claim 7, wherein said optional salt and said optional solvate formations are omitted.

25. A process of claim 21 further comprising reacting a compound of formula (a)

19. A process for preparing a compound of formula Ib″

20. A process of claim 19, wherein said optional salt and said optional solvate formations are omitted.

23. A process of claim 20 for preparing a compound of the formula

24. A process of claim 20 further comprising reacting a compound of formula (a)

26. A process of claim 23 for preparing a compound of the formula