Claims for Patent: 9,278,961

Summary for Patent: 9,278,961

Title:	Pyridyl inhibitors of hedgehog signalling
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.
Inventor(s):	Janet L. Gunzner, Daniel Sutherlin, Mark S. Stanley, Liang Bao, Georgette M. Castanedo, Rebecca L. LaLonde, Shumei Wang, Mark E. Reynolds, Scott J. Savage, Kimberly Malesky, Michael S. Dina, Michael F. T. Koehler
Assignee:	Genentech Inc, Curis Inc
Application Number:	US12/960,609
Patent Claims:	1. A method of treating cancer in a mammal, comprising administering a compound of formula I: wherein A is a carbocycle or heterocycle; X is alkylene, NR4C(O), NR4C(S), N(C(O)R1)C(O), NR4SO, NR4SO2, NR4C(O)NH, NR4C(S)NH, C(O)NR4, C(S)NR4, NR4PO or NR4PO(OH); Y is absent, CHR4, O, S, SO, SO2 or NR4; R1 is selected from the group consisting of alkyl, a carbocycle or a heterocycle each of which is optionally substituted with hydroxyl, halogen, amino, carboxyl, amidino, guanidino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, alkylthio, 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; R2 is halogen, hydroxyl, alkyl, acyl or alkoxy, wherein each alkyl, acyl and alkoxy is optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; R3 is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, sulfinyl, sulfonyl, a carbocycle or a heterocycle wherein each alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, sulfinyl, sulfonyl, carbocycle and heterocycle is optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, sulfonyl or alkoxy; R4 is H or alkyl; m is 0-3; n is 0-3; or a salt or solvate thereof. 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: wherein Z1 is O, S or NR5 wherein R5 is H or alkyl; Z2 is CH, CR2, or N; R2 is halogen, hydroxyl, alkyl or alkoxy; R2′ is H, halogen, hydroxyl, alkyl or alkoxy; and n is 0-3. 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 A1a, A1b, A2a, A3a, A3b, A4a, A5a, A6a, A7a: 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: wherein W is O, S or NR7 wherein R7 is H, alkyl, acyl, a carbocycle or a heterocycle wherein said alkyl, carbocycle and heterocycle are each optionally substituted with 1-3 amino, halogen, hydroxyl and haloalkyl; R6 in each instance is independently hydroxyl, halogen, amino, carbonyl, nitro, cyano, acyl, alkyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine, alkylsulfamoyl, alkylsulfonamide, a carbocycle or a heterocycle; wherein said amino, alkyl, carbonyl, acyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine, alkylsulfamoyl, alkylsulfonamide, carbocycle and heterocycle substituent is optionally substituted with amino, halogen, hydroxyl, carbonyl, or a carbocycle or heterocycle that is optionally substituted with hydroxyl, amino, halogen, haloalkyl, alkyl, alkoxy or acyl; and o is 0-3. 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 wherein R3 is H or methyl, R8 is halogen or alkyl substituted with halogen; X is NR4C(O), m is 0-3, R4 is H or alkyl, and R1 is aryl or heteroaryl, each of which is optionally substituted with hydroxyl, halogen, amino, carboxyl, amidino, guanidino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, alkylthio, 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, or a salt or solvate thereof. 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—. 42. A method of treating cancer in a mammal, comprising administering a compound of the formula: or a salt or solvate thereof. 43. The method of claim 37 wherein said cancer is basal cell carcinoma. 44. The method of claim 42 wherein said cancer is basal cell carcinoma. 45. The method of claim 37 wherein said administration is oral. 46. The method of claim 42 wherein said administration is oral. 47. The method of claim 43 wherein said administration is oral. 48. The method of claim 44 wherein said administration is oral. 49. The method of claim 39 wherein said compound is wherein ring B is phenyl or pyridyl, o is 1-3, and 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. 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: wherein R6 is independently in each instance optionally substituted alkyl, halogen, alkoxy, carbonyl, a heterocycle, alkylamino, arylamino, alkylcarbamoyl, alkylsulfamoyl or sulfonyl; and o is 1-3. 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)—. 66. A method of treating cancer in a mammal, comprising administering a compound of the formula: wherein A is substituted benzene; X is NR4C(O) or NR4C(S); Y is absent; R1 is aryl or heteroaryl, each of which is optionally substituted; R2 is halogen, or alkyl substituted with halogen and an R2 is in the o-position on said A benzene relative to pyridyl; R3 is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, sulfinyl, sulfonyl, a carbocycle or a heterocycle wherein each alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, sulfinyl, sulfonyl, carbocycle and heterocycle is optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, sulfonyl or alkoxy; R4 is H or alkyl; m is 0-3; n is 1-3; or a salt or solvate thereof. 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: wherein R6 is independently in each instance optionally substituted alkyl, halogen, alkoxy, carbonyl, a heterocycle, alkylamino, arylamino, alkylcarbamoyl, alkylsulfamoyl or sulfonyl; and o is 1-3. 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. 87. The method of claim 49 wherein said compound or a salt thereof is administered. 88. The method of claim 75 wherein said compound or a salt thereof is administered. 89. The method of claim 60 wherein said compound or a salt thereof is administered. 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. 92. The method of claim 37 comprising administering said compound in a composition further comprising a pharmaceutically acceptable carrier. 93. A method of treating basal cell carcinoma in a human, comprising orally administering an effective amount of a compound of the formula: or a salt or solvate thereof.