Pyridyl inhibitors of hedgehog signalling

• US 7,888,364 B2
• Filed: 09/02/2005
• Issued: 02/15/2011
• Est. Priority Date: 09/02/2004
• Status: Active Grant

• Current Assignee: Curis, Inc., Genentech, Inc. (Roche Holding AG)
• Original Assignee: Curis, Inc.
• Inventors: Bao, Liang, Sutherlin, Daniel, Lalonde, Rebecca L., Dina, Michael S., Reynolds, Mark E., Savage, Scott J., Malesky, Kimberly, Castanedo, Georgette M., Stanley, Mark S., Wang, Shumei, Gunzner, Janet L.
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US11/217,663
• Publication Number:
  US 20060063779A1
• Time in Patent Office: 1,992 Days
• Field of Search: None
• US Class Current: 514/255.05
• 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 compound of formula I:

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

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

4. The compound claim 1, wherein R₁ is substituted.

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

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

15. A compound of claim 5 wherein R₁ is substituted phenyl or substituted pyridyl, R₃ is H or methyl, ring A is o-chlorophenyl, and X is —

NHC(O)—

.

16. A compound of claim 15 wherein R₁ substituted phenyl or pyridyl comprises —

SO₂—

.

17. A compound of claim 5 wherein, ring A is o-chlorophenyl, X is —

NHC(O)—

, and R₁ substituted phenyl or substituted pyridyl comprises —

SO₂—

.

19. A compound of claim 1 wherein R₁ is thiophene, isoxazole, benzothiadiazole, pyrimidine, pyrazole, phenyl or pyridine.

25. The compound of claim 5, wherein A is

26. The compound of claim 5, wherein R₂ is Cl.

27. The compound of claim 5, wherein X is NR₄C(O).

28. The compound of claim 5, wherein R₃ is methyl or F.

29. The compound of claim 5, wherein R₃ is methyl and m is 1 or 2.

30. The compound of claim 5, wherein m is 0.

34. A compound of claim 1 where R₁ is not naphthyl.

35. A compound of claim 1 wherein R₁ is of formula IIa or IIb:

37. A compound of claim 35 wherein R¹ is of formula IIa.

47. A compound of claim 1 or a salt thereof.

48. A compound of claim 5 or a salt thereof.

51. A compound of claim 25 or a salt thereof.

54. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

55. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.

7. A compound of formula Ib

8. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier.

9. A compound of claim 7 wherein R₈ is halogen and R¹ is substituted phenyl or substituted pyridyl.

10. A compound of claim 9 wherein R₄ is H, m is 0 and R₈ is Cl.

11. A compound of claim 9 wherein said substituted phenyl or pyridyl R¹ group comprises —

SO₂—

.

13. A compound of claim 9 of the formula Ib′

14. A compound of claim 13 wherein at least one R₆ is an optionally substituted sulfonyl.

18. A compound of claim 13 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.

20. A compound of claim 14 wherein m is 0.

21. A compound of claim 14 wherein R₈ is Cl.

22. A compound of claim 14 wherein o is 2.

23. A compound of claim 14 wherein one R₆ is Cl.

24. A compound of claim 14 wherein m is 0, o is 2, R₈ is Cl, one R₆ is Cl and one R₆ is an optionally substituted sulfonyl.

31. A compound of claim 7 wherein m is 0 or 1.

32. A compound of claim 13 wherein R₆ is independently in each instance optionally substituted alkyl, halogen, alkoxy, carbonyl, a heterocycle, alkylamino, arylamino, alkylcarbamoyl, alkylsulfamoyl or sulfonyl.

33. A compound of claim 14, wherein R₆ is independently in each instance optionally substituted alkyl, halogen, alkoxy, carbonyl, a heterocycle, alkylamino, arylamino, alkylcarbamoyl, alkylsulfamoyl or sulfonyl.

36. A compound of claim 7 wherein R₁ is of formula IIa or IIb:

38. A compound of claim 36 wherein R¹ is of formula IIa.

39. A compound of claim 36 wherein R₈ is halogen and R¹ is substituted phenyl or substituted pyridyl.

40. A compound of claim 39 wherein R₄ is H, m is 0 and R₈ is Cl.

41. A compound of claim 39 wherein said substituted phenyl or pyridyl R¹ group comprises —

SO₂—

.

42. A compound of claim 36 wherein R₁ is substituted phenyl or substituted pyridyl, R₃ is H or methyl, ring A is o-chlorophenyl, and X is —

NHC(O)—

.

43. A compound of claim 36 wherein each R₆ independently is hydroxyl, halogen, amino, carboxyl, amidino, guanidino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, akylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, a carbocycle or a heterocycle;

wherein said amino, amidino, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, alkylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, carbocycle and heterocycle substituent is optionally substituted with, halogen, haloakyl, hydroxyl, carboxyl, carbonyl, or an amino, alkyl, alkoxy, acyl, sulfonyl, sulfinyl, phosphinate, carbocycle or heterocycle that is optionally substituted with hydroxyl, carboxyl, carbonyl, amino, halogen, haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl, sulfinyl, acyl, a carbocycle or a heterocycle;

R₈ is halogen;

R¹ is substituted phenyl or substituted pyridyl;

at least one R₆ is an optionally substituted sulfonyl; and

m is 0.

44. A compound of claim 36 wherein each R₆ independently is hydroxyl, halogen, amino, carboxyl, amidino, guanidino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, akylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, a carbocycle or a heterocycle;

wherein said amino, amidino, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, alkylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, carbocycle and heterocycle substituent is optionally substituted with, halogen, haloakyl, hydroxyl, carboxyl, carbonyl, or an amino, alkyl, alkoxy, acyl, sulfonyl, sulfinyl, phosphinate, carbocycle or heterocycle that is optionally substituted with hydroxyl, carboxyl, carbonyl, amino, halogen, haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl, sulfinyl, acyl, a carbocycle or a heterocycle;

R₈ is Cl;

R¹ is substituted phenyl or substituted pyridyl;

at least one R₆ is an optionally substituted sulfonyl; and

R₈ is Cl.

45. A compound of claim 36 wherein each R₆ independently is hydroxyl, halogen, amino, carboxyl, amidino, guanidino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, akylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, a carbocycle or a heterocycle;

wherein said amino, amidino, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, alkylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, carbocycle and heterocycle substituent is optionally substituted with, halogen, haloakyl, hydroxyl, carboxyl, carbonyl, or an amino, alkyl, alkoxy, acyl, sulfonyl, sulfinyl, phosphinate, carbocycle or heterocycle that is optionally substituted with hydroxyl, carboxyl, carbonyl, amino, halogen, haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl, sulfinyl, acyl, a carbocycle or a heterocycle;

R₈ is halogen;

R¹ is substituted phenyl or substituted pyridyl;

at least one R₆ is an optionally substituted sulfonyl; and

o is 2.

46. A compound of claim 36 wherein each R₆ independently is hydroxyl, halogen, amino, carboxyl, amidino, guanidino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, akylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, a carbocycle or a heterocycle;

wherein said amino, amidino, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, alkylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, carbocycle and heterocycle substituent is optionally substituted with, halogen, haloakyl, hydroxyl, carboxyl, carbonyl, or an amino, alkyl, alkoxy, acyl, sulfonyl, sulfinyl, phosphinate, carbocycle or heterocycle that is optionally substituted with hydroxyl, carboxyl, carbonyl, amino, halogen, haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl, sulfinyl, acyl, a carbocycle or a heterocycle;

R₈ is halogen;

R¹ is substituted phenyl or substituted pyridyl;

at least one R₆ is an optionally substituted sulfonyl; and

one R₆ is Cl.

49. A compound of claim 7 or a salt thereof.

50. A compound of claim 13 or a salt thereof.

52. A compound of claim 36 or a salt thereof.

12. The compound of the formula

53. A composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier.