Pyridyl inhibitors of hedgehog signalling

• US 9,278,961 B2
• Filed: 12/06/2010
• Issued: 03/08/2016
• 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, Janet L., Sutherlin, Daniel, Stanley, Mark S., Bao, Liang, Castanedo, Georgette M., Lalonde, Rebecca L., Wang, Shumei, Reynolds, Mark E., Savage, Scott J., Malesky, Kimberly, Dina, Michael S., Koehler, Michael F. T.
• Primary Examiner(s): NORTHINGTON DAVI, ZINNA
• Application Number:
  US12/960,609
• Publication Number:
  US 20110092461A1
• Time in Patent Office: 1,919 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 method of treating cancer in a mammal, comprising administering a compound of formula I:

2. The method of claim 1, wherein A is a ring selected from the group consisting of A¹, A², A³, A⁴ A⁵, A⁶ and A⁷:

3. The method of claim 2, wherein A is ring A¹ wherein Z₁ is S and Z₂ is CH or N.

4. The method of claim 2, wherein A is the ring A².

5. The method of claim 2, wherein R₂ or R₂′

is Cl.

6. The method of claim 1, wherein A is A^1a, A^1b, A^2a, A^3a, A^3b, A^4a, A^5a, A^6a, A^7a:

7. The method of claim 1, wherein X is NR₄C(O).

8. The method of claim 1, wherein X is NR₄SO₂.

9. The method of claim 7, wherein R₄ is H or methyl.

10. The method of claim 9, wherein R₄ is H.

11. The method of claim 1, wherein R₃ is methyl or F.

12. The method of claim 1, wherein R₃ is methyl and m is 1 or 2.

13. The method of claim 1, wherein R₃ is F and m is 1 or 2.

14. The method of claim 1, wherein m is 0.

15. The method of claim 1, wherein R₁ is selected from the group consisting of formulae IIa-IIo:

16. The method of claim 15, wherein R₁ is the group of formula IIa.

17. The method of claim 16, wherein R₆ is alkoxy and o is 1 or 2.

18. The method of claim 16, wherein R₁ is selected from the group of formulae IIa¹-IIa²⁸:

19. The method of claim 16, wherein A is

20. The method of claim 16, wherein A is

21. The method of claim 16, wherein R₃ is methyl or F.

22. The method of claim 3, wherein m is 0.

23. The method of claim 3, wherein X is NR₄C(O).

24. The method of claim 15, wherein R₁ is the group of formula IIb.

25. The method of claim 24, wherein R₆ is alkyl or haloalkyl.

26. The method of claim 24, wherein R₁ is the group of the formula

27. The method of claim 24, wherein A is

28. The method of claim 24, wherein A is

29. The method of claim 24, wherein R₃ is H, methyl or F.

30. The method of claim 24, wherein R₃ is H.

31. The method of claim 24, wherein X is NR₄C(O).

32. The method of claim 1 comprising administering said compound in a composition further comprising a pharmaceutically acceptable carrier.

33. The method of claim 1, wherein said cancer is basal cell carcinoma, medullablastoma, pancreatic adenocarcinoma, small-cell lung carcinoma, breast carcinoma, rhabdomyosarcoma, oesophageal cancer, stomach cancer, or biliary tract cancer.

34. The method of claim 33 wherein said cancer is basal cell carcinoma.

35. The method of claim 1 wherein said administration is oral.

36. The method of claim 34 wherein said administration is oral.

37. A method of treating cancer in a mammal, comprising administering a compound of the formula

38. The method of claim 37 comprising administering said compound in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

39. The method of claim 37 wherein R₈ is halogen and R¹ is substituted phenyl or substituted pyridyl.

40. The method of claim 39 wherein R₄ is H, m is 0 and R₈ is Cl.

41. The method of claim 39 wherein said substituted phenyl or pyridyl R¹ group comprises —

SO₂—

.

43. The method of claim 37 wherein said cancer is basal cell carcinoma.

45. The method of claim 37 wherein said administration is oral.

47. The method of claim 43 wherein said administration is oral.

49. The method of claim 39 wherein said compound is

50. The method of claim 49 wherein at least one R₆ is an optionally substituted sulfonyl.

51. The method of claim 49 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.

52. The method of claim 50 wherein m is 0.

53. The method of claim 50 wherein R₈ is Cl.

54. The method of claim 50 wherein o is 2.

55. The method of claim 50 wherein one R₆ is Cl.

56. The method of claim 50 wherein m is 0, o is 2, R₈ is Cl, one R₆ is Cl and one R₆ is an optionally substituted sulfonyl.

57. The method of claim 37 wherein m is 0 or 1.

58. The method of claim 37 wherein R₆ is independently in each instance optionally substituted alkyl, halogen, alkoxy, carbonyl, a heterocycle, alkylamino, arylamino, alkylcarbamoyl, alkylsulfamoyl or sulfonyl.

59. The method of claim 49 wherein R₆ is independently in each instance substituted alkyl, halogen, alkoxy, carbonyl, a heterocycle, alkylamino, arylamino, alkylcarbamoyl, alkylsulfamoyl or sulfonyl.

60. The method of claim 37 wherein R₁ is of formula IIa or IIb:

61. The method of claim 37 wherein R¹ is of formula IIa.

62. The method of claim 60 wherein R₈ is halogen and R¹ is substituted phenyl or substituted pyridyl.

63. The method of claim 62 wherein R₄ is H, m is 0 and R₈ is Cl.

64. The method of claim 62 wherein said substituted phenyl or pyridyl R¹ group comprises —

SO₂—

.

65. The method of claim 60 wherein R₁ is substituted phenyl or substituted pyridyl, R₃ is H or methyl and X is —

NHC(O)—

.

87. The method of claim 49 wherein said compound or a salt thereof is administered.

89. The method of claim 60 wherein said compound or a salt thereof is administered.

92. The method of claim 37 comprising administering said compound in a composition further comprising a pharmaceutically acceptable carrier.

42. A method of treating cancer in a mammal, comprising administering a compound of the formula:

44. The method of claim 42 wherein said cancer is basal cell carcinoma.

46. The method of claim 42 wherein said administration is oral.

48. The method of claim 44 wherein said administration is oral.

90. The method of claim 42 wherein said compound or a salt thereof is administered.

91. The method of claim 42 comprising administering said compound in a composition further comprising a pharmaceutically acceptable carrier.

66. A method of treating cancer in a mammal, comprising administering a compound of the formula:

67. The method of claim 66, wherein R₄ is H or methyl.

68. The method of claim 66, wherein R₄ is H.

69. The method of claim 66, wherein R₁ is substituted.

70. The method of claim 69, wherein R₁ is substituted phenyl or substituted pyridyl.

71. The method of claim 70, wherein R₁ is substituted phenyl.

72. The method of claim 70 wherein R₁ is substituted phenyl or substituted pyridyl, R₃ is H or methyl, ring A is o-chlorophenyl, and X is —

NHC(O)—

.

73. The method of claim 72 wherein R₁ substituted phenyl or pyridyl comprises —

SO₂—

.

74. The method of claim 70 wherein, ring A is o-chlorophenyl, X is —

NHC(O)—

, and R₁ substituted phenyl or substituted pyridyl comprises —

SO₂—

.

75. The method of claim 70 wherein A is

76. The method of claim 70 wherein R₂ is Cl.

77. The method of claim 70 wherein X is NR₄C(O).

78. The method of claim 70 wherein R₃ is methyl or F.

79. The method of claim 70 wherein R₃ is methyl and m is 1 or 2.

80. The method of claim 70 wherein m is 0.

81. The method of claim 66 wherein R₁ is not naphthyl.

82. The method of claim 66 wherein R₁ is of formula IIa or IIb:

83. The method of claim 82 wherein R¹ is of formula IIa.

84. The method of claim 66 wherein said compound or a salt thereof is administered.

85. The method of claim 72 wherein said compound or a salt thereof is administered.

86. The method of claim 70 wherein said compound or a salt thereof is administered.

88. The method of claim 75 wherein said compound or a salt thereof is administered.

93. A method of treating basal cell carcinoma in a human, comprising orally administering an effective amount of a compound of the formula: