Claims for Patent: 7,888,364

Summary for Patent: 7,888,364

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
Assignee:	Genentech Inc, Curis Inc
Application Number:	US11/217,663
Patent Claims:	1. A compound of formula I: 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. 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. 7. A compound of formula Ib 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. 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—. 12. The compound of the formula 13. A compound of claim 9 of the formula Ib′ 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. 14. A compound of claim 13 wherein at least one R6 is an optionally substituted sulfonyl. 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—. 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. 19. A compound of claim 1 wherein R1 is thiophene, isoxazole, benzothiadiazole, pyrimidine, pyrazole, phenyl or pyridine. 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. 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. 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. 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: 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. 36. A compound of claim 7 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. 37. A compound of claim 35 wherein R1 is of formula IIa. 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. 47. A compound of claim 1 or a salt thereof. 48. A compound of claim 5 or a salt thereof. 49. A compound of claim 7 or a salt thereof. 50. A compound of claim 13 or a salt thereof. 51. A compound of claim 25 or a salt thereof. 52. A compound of claim 36 or a salt thereof. 53. A composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier. 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.