Pyridyl inhibitors of hedgehog signalling
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 R 1 , R 2 , R 3 , R 4 , m and n are as described herein.
1. A compound of formula I:
wherein
A is substituted benzene;
X is NR 4 C(O) or NR 4 C(S);
Y is absent;
R 1 is aryl or heteroaryl, each of which is optionally substituted;
R 2 is halogen, or alkyl substituted with halogen and an R 2 is in the o-position on said A benzene relative to pyridyl;
R 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 4 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 R 4 is H or methyl.
3. The compound of claim 2 , wherein R 4 is H.
4. The compound claim 1 , wherein R 1 is substituted.
5. The compound of claim 4 , wherein R 1 is substituted phenyl or substituted pyridyl.
6. The compound of claim 5 , wherein R 1 is substituted phenyl.
7. A compound of formula Ib
wherein R 3 is H or methyl,
R 8 is halogen or alkyl substituted with halogen;
X is NR 4 C(O),
m is 0-3,
R 4 is H or alkyl, and
R 1 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 R 8 is halogen and R 1 is substituted phenyl or substituted pyridyl.
10. A compound of claim 9 wherein R 4 is H, m is 0 and R 8 is Cl.
11. A compound of claim 9 wherein said substituted phenyl or pyridyl R 1 group comprises —SO 2 —.
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 R 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.
14. A compound of claim 13 wherein at least one R 6 is an optionally substituted sulfonyl.
15. A compound of claim 5 wherein R 1 is substituted phenyl or substituted pyridyl, R 3 is H or methyl, ring A is o-chlorophenyl, and X is —NHC(O)—.
16. A compound of claim 15 wherein R 1 substituted phenyl or pyridyl comprises —SO 2 —.
17. A compound of claim 5 wherein, ring A is o-chlorophenyl, X is —NHC(O)—, and R 1 substituted phenyl or substituted pyridyl comprises —SO 2 —.
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 R 1 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 R 8 is Cl.
22. A compound of claim 14 wherein o is 2.
23. A compound of claim 14 wherein one R 6 is Cl.
24. A compound of claim 14 wherein m is 0, o is 2, R 8 is Cl, one R 6 is Cl and one R 6 is an optionally substituted sulfonyl.
25. The compound of claim 5 , wherein A is
26. The compound of claim 5 , wherein R 2 is Cl.
27. The compound of claim 5 , wherein X is NR 4 C(O).
28. The compound of claim 5 , wherein R 3 is methyl or F.
29. The compound of claim 5 , wherein R 3 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 R 6 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 R 6 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 R 1 is not naphthyl.
35. A compound of claim 1 wherein R 1 is of formula IIa or IIb:
wherein R 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.
36. A compound of claim 7 wherein R 1 is of formula IIa or IIb:
wherein R 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.
37. A compound of claim 35 wherein R 1 is of formula IIa.
38. A compound of claim 36 wherein R 1 is of formula IIa.
39. A compound of claim 36 wherein R 8 is halogen and R 1 is substituted phenyl or substituted pyridyl.
40. A compound of claim 39 wherein R 4 is H, m is 0 and R 8 is Cl.
41. A compound of claim 39 wherein said substituted phenyl or pyridyl R 1 group comprises —SO 2 —.
42. A compound of claim 36 wherein R 1 is substituted phenyl or substituted pyridyl, R 3 is H or methyl, ring A is o-chlorophenyl, and X is —NHC(O)—.
43. A compound of claim 36 wherein each R 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; R 8 is halogen; R 1 is substituted phenyl or substituted pyridyl; at least one R 6 is an optionally substituted sulfonyl; and m is 0.
44. A compound of claim 36 wherein each R 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; R 8 is Cl; R 1 is substituted phenyl or substituted pyridyl; at least one R 6 is an optionally substituted sulfonyl; and R 8 is Cl.
45. A compound of claim 36 wherein each R 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; R 8 is halogen; R 1 is substituted phenyl or substituted pyridyl; at least one R 6 is an optionally substituted sulfonyl; and o is 2.
46. A compound of claim 36 wherein each R 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; R 8 is halogen; R 1 is substituted phenyl or substituted pyridyl; at least one R 6 is an optionally substituted sulfonyl; and one R 6 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.