Claims for Patent: 9,790,183

Summary for Patent: 9,790,183

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-Toste, 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
Application Number:	US15/015,586
Patent Claims:	1. A method of inhibiting hedgehog pathway signaling in a cell comprising contacting said cell with an effective amount of 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), wherein * indicates the point of attachment to ring A; 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, 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, haloalkyl, 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 according to 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 according to claim 2, wherein A is ring A1 wherein Z1 is S and Z2 is CH or N. 4. The method according to claim 2, wherein A is the ring A2. 5. The method according to claim 2, wherein R2 or R2′ is Cl. 6. The method according to claim 1, wherein A is A1a, A1b, A2a, A3a, A3b, A4a, A5a, A6a, A7a: 7. The method according to claim 1, wherein X is *NR4C(O). 8. The method according to claim 1, wherein X is *NR4SO2. 9. The method according to claim 7, wherein R4 is H or Me. 10. The method according to claim 9, wherein R4 is H. 11. The method according to claim 1, wherein R3 is Me or F. 12. The method according to claim 1, wherein R3 is Me and m is 1 or 2. 13. The method according to claim 1, wherein R3 is F and m is 1 or 2. 14. The method according to claim 1, wherein m is 0. 15. The method according to 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 according to claim 15, wherein R1 is the group of formula IIa. 17. The method according to claim 16, wherein R6 is alkoxy and o is 1 or 2. 18. The method according to claim 16, wherein R1 is selected from the group of formulae IIa1-IIa28: 19. The method according to claim 16, wherein A is 20. The method according to claim 16, wherein A is 21. The method according to claim 16, wherein R3 is methyl or F. 22. The method according to claim 3, wherein m is 0. 23. The method according to claim 3, wherein X is *NR4C(O). 24. The method according to claim 15, wherein R1 is the group of formula IIb. 25. The method according to claim 24, wherein R6 is alkyl or haloalkyl. 26. The method according to claim 24, wherein R1 is the group of the formula 27. The method according to claim 24, wherein A is 28. The method according to claim 24, wherein A is 29. The method according to claim 24, wherein m is 0. 30. The method according to claim 24, wherein X is *NR4C(O). 31. The method according to claim 1, wherein said compound is of the following formula wherein X, R3, and m are as defined in claim 1; R8 is a halogen; ring B is phenyl or pyridyl, o is 1-3, and each R6 independently is optionally substituted alkyl, halogen, alkoxy, carbonyl, heterocycle, alkylamino, arylamino, alkylcarbamoyl, alkylsulfamoyl, or sulfonyl. 32. The method according to claim 31, wherein each R6 independently is methyl, trifluoromethyl, dimethylaminomethyl, piperidinylmethyl, morpholinomethyl, thiomorpholinomethyl, chloro, methoxy, morpholinocarbonyl, acetyl, morpholino, N-methyl-piperazin-4-yl, N-acetyl-piperazin-4-yl, 1H-1,2,4-triazole, i-butylamino, benzylamino, hydroxyethylamino, methoxyethylamino, dimethylaminoethylamino, morpholinoethylamino, morpholinopropylamino, pyrrolidin-2-one-substituted propylamino, imidazole-ethylamino, imidazole-propylamino, phenylamino, dimethylcarbamoyl, i-butylaminocarbonyl, propylaminosulfonyl, i-butylaminosulfonyl, dimethylaminosulfonyl, dimethylaminoethyl hydroxyethylaminosulfonyl, methoxyethylaminosulfonyl, methoxypropylaminosulfonyl, methylsulfonylethylaminosulfonyl, imidazole-substituted propylaminosulfonyl, hydroxypropylaminosulfonyl, 2-hydroxypropylaminosulfonyl, methylsulfonyl, ethylsulfonyl, aminosulfonyl, dimethylaminopropylsulfonyl, N-methyl-piperazin-4-yl-sulfonyl, morpholino-4-yl-sulfonyl, or trifluoromethylsulfonyl. 33. The method according to claim 31, wherein m is 0. 34. The method according to claim 31, wherein R8 is Cl. 35. The method according to claim 31, wherein o is 2. 36. The method according to claim 31, wherein one R6 is Cl. 37. The method according to claim 31, wherein m is 0, o is 2, R8 is Cl, one R6 is Cl and one R6 is an optionally substituted sulfonyl. 38. The method according to claim 1, 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; and R2 is halogen, or alkyl substituted with halogen and an R2 is in the o-position on said A benzene relative to pyridyl. 39. The method according to claim 38, wherein R4 is H or methyl. 40. The method according to claim 39, wherein R4 is H. 41. The method according to claim 38, wherein R1 is substituted. 42. The method according to claim 41, wherein R1 is substituted phenyl or substituted pyridyl. 43. The method according to claim 42, wherein R1 is substituted phenyl. 44. The method according to claim 38, wherein said compound is a compound of formula Ib wherein R3 is absent or is methyl, R8 is 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. 45. The method according to claim 44, wherein R1 is substituted phenyl or substituted pyridyl. 46. The method according to claim 45, wherein R4 is H, m is 0 and R8 is Cl. 47. The method according to claim 45, wherein said substituted phenyl or pyridyl R1 group comprises —SO2—. 48. A method of inhibiting hedgehog pathway signaling in a cell comprising contacting said cell with an effective amount of a compound of the formula: or a salt or solvate thereof. 49. The method according to claim 38, wherein said compound is of the formula