Details 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: ##STR00001## wherein A, X, Y R.sub.1, R.sub.2, R.sub.3, R.sub.4, m and n are as described herein.
Inventor(s):	Gunzner; Janet L. (Berkeley, CA), Sutherlin; Daniel (South San Francisco, CA), Stanley; Mark S. (Pacifica, CA), Bao; Liang (San Mateo, CA), Castanedo; Georgette M. (Redwood City, CA), Lalonde; Rebecca L. (Berkeley, CA), Wang; Shumei (Foster City, CA), Reynolds; Mark E. (Millbrae, CA), Savage; Scott J. (Burlingame, CA), Malesky; Kimberly (San Francisco, CA), Dina; Michael S. (Daly City, CA), Koehler; Michael F. T. (Palo Alto, CA)
Assignee:	GENENTECH, INC. (South San Francisco, CA) CURIS, INC. (Lexington, MA)
Filing Date:	Dec 06, 2010
Application Number:	12/960,609
Claims:	1. A method of treating cancer in a mammal, comprising administering a compound of formula I: ##STR00453## wherein A is a carbocycle or heterocycle; X is alkylene, NR.sub.4C(O), NR.sub.4C(S), N(C(O)R.sub.1)C(O), NR.sub.4SO, NR.sub.4SO.sub.2, NR.sub.4C(O)NH, NR.sub.4C(S)NH, C(O)NR.sub.4, C(S)NR.sub.4, NR.sub.4PO or NR.sub.4PO(OH); Y is absent, CHR.sub.4, O, S, SO, SO.sub.2 or NR.sub.4; R.sub.1 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; R.sub.2 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; R.sub.3 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; R.sub.4 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 A.sup.1, A.sup.2, A.sup.3, A.sup.4 A.sup.5, A.sup.6 and A.sup.7: ##STR00454## wherein Z.sub.1 is O, S or NR.sub.5 wherein R.sub.5 is H or alkyl; Z.sub.2 is CH, CR.sub.2, or N; R.sub.2 is halogen, hydroxyl, alkyl or alkoxy; R.sub.2' is H, halogen, hydroxyl, alkyl or alkoxy; and n is 0-3. 3. The method of claim 2, wherein A is ring A.sup.1 wherein Z.sub.1 is S and Z.sub.2 is CH or N. 4. The method of claim 2, wherein A is the ring A.sup.2. 5. The method of claim 2, wherein R.sub.2 or R.sub.2' is Cl. 6. The method of claim 1, wherein A is A.sup.1a, A.sup.1b, A.sup.2a, A.sup.3a, A.sup.3b, A.sup.4a, A.sup.5a, A.sup.6a, A.sup.7a: ##STR00455## 7. The method of claim 1, wherein X is NR.sub.4C(O). 8. The method of claim 1, wherein X is NR.sub.4SO.sub.2. 9. The method of claim 7, wherein R.sub.4 is H or methyl. 10. The method of claim 9, wherein R.sub.4 is H. 11. The method of claim 1, wherein R.sub.3 is methyl or F. 12. The method of claim 1, wherein R.sub.3 is methyl and m is 1 or 2. 13. The method of claim 1, wherein R.sub.3 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 R.sub.1 is selected from the group consisting of formulae IIa-IIo: ##STR00456## ##STR00457## wherein W is O, S or NR.sub.7 wherein R.sub.7 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; R.sub.6 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 R.sub.1 is the group of formula IIa. 17. The method of claim 16, wherein R.sub.6 is alkoxy and o is 1 or 2. 18. The method of claim 16, wherein R.sub.1 is selected from the group of formulae IIa.sup.1-IIa.sup.28: ##STR00458## ##STR00459## ##STR00460## 19. The method of claim 16, wherein A is ##STR00461## 20. The method of claim 16, wherein A is ##STR00462## 21. The method of claim 16, wherein R.sub.3 is methyl or F. 22. The method of claim 3, wherein m is 0. 23. The method of claim 3, wherein X is NR.sub.4C(O). 24. The method of claim 15, wherein R.sub.1 is the group of formula IIb. 25. The method of claim 24, wherein R.sub.6 is alkyl or haloalkyl. 26. The method of claim 24, wherein R.sub.1 is the group of the formula ##STR00463## 27. The method of claim 24, wherein A is ##STR00464## 28. The method of claim 24, wherein A is ##STR00465## 29. The method of claim 24, wherein R.sub.3 is H, methyl or F. 30. The method of claim 24, wherein R.sub.3 is H. 31. The method of claim 24, wherein X is NR.sub.4C(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 ##STR00466## wherein R.sub.3 is H or methyl, R.sub.8 is halogen or alkyl substituted with halogen; X is NR.sub.4C(O), m is 0-3, R.sub.4 is H or alkyl, and R.sup.1 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 R.sub.8 is halogen and R.sup.1 is substituted phenyl or substituted pyridyl. 40. The method of claim 39 wherein R.sub.4 is H, m is 0 and R.sub.8 is Cl. 41. The method of claim 39 wherein said substituted phenyl or pyridyl R.sup.1 group comprises --SO.sub.2--. 42. A method of treating cancer in a mammal, comprising administering a compound of the formula: ##STR00467## 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 ##STR00468## wherein ring B is phenyl or pyridyl, o is 1-3, and each R.sub.6 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 R.sub.6 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 R.sub.8 is Cl. 54. The method of claim 50 wherein o is 2. 55. The method of claim 50 wherein one R.sub.6 is Cl. 56. The method of claim 50 wherein m is 0, o is 2, R.sub.8 is Cl, one R.sub.6 is Cl and one R.sub.6 is an optionally substituted sulfonyl. 57. The method of claim 37 wherein m is 0 or 1. 58. The method of claim 37 wherein R.sub.6 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 R.sub.6 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 R.sub.1 is of formula IIa or IIb: ##STR00469## wherein R.sub.6 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 R.sup.1 is of formula IIa. 62. The method of claim 60 wherein R.sub.8 is halogen and R.sup.1 is substituted phenyl or substituted pyridyl. 63. The method of claim 62 wherein R.sub.4 is H, m is 0 and R.sub.8 is Cl. 64. The method of claim 62 wherein said substituted phenyl or pyridyl R.sup.1 group comprises --SO.sub.2--. 65. The method of claim 60 wherein R.sub.1 is substituted phenyl or substituted pyridyl, R.sub.3 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: ##STR00470## wherein A is substituted benzene; X is NR.sub.4C(O) or NR.sub.4C(S); Y is absent; R.sub.1 is aryl or heteroaryl, each of which is optionally substituted; R.sub.2 is halogen, or alkyl substituted with halogen and an R.sub.2 is in the o-position on said A benzene relative to pyridyl; R.sub.3 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; R.sub.4 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 R.sub.4 is H or methyl. 68. The method of claim 66, wherein R.sub.4 is H. 69. The method of claim 66, wherein R.sub.1 is substituted. 70. The method of claim 69, wherein R.sub.1 is substituted phenyl or substituted pyridyl. 71. The method of claim 70, wherein R.sub.1 is substituted phenyl. 72. The method of claim 70 wherein R.sub.1 is substituted phenyl or substituted pyridyl, R.sub.3 is H or methyl, ring A is o-chlorophenyl, and X is --NHC(O)--. 73. The method of claim 72 wherein R.sub.1 substituted phenyl or pyridyl comprises --SO.sub.2--. 74. The method of claim 70 wherein, ring A is o-chlorophenyl, X is --NHC(O)--, and R.sub.1 substituted phenyl or substituted pyridyl comprises --SO.sub.2--. 75. The method of claim 70 wherein A is ##STR00471## 76. The method of claim 70 wherein R.sub.2 is Cl. 77. The method of claim 70 wherein X is NR.sub.4C(O). 78. The method of claim 70 wherein R.sub.3 is methyl or F. 79. The method of claim 70 wherein R.sub.3 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 R.sub.1 is not naphthyl. 82. The method of claim 66 wherein R.sub.1 is of formula IIa or IIb: ##STR00472## wherein R.sub.6 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 R.sup.1 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: ##STR00473## or a salt or solvate thereof.