PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING

1 . A compound of formula I:

wherein

A is a carbocycle or heterocycle;

X is alkylene, NR 4 C(O), NR 4 C(S), N(C(O)R 1 )C(O), NR 4 SO, NR 4 SO 2 , NR 4 C(O)NH, NR 4 C(S)NH, C(O)NR 4 , C(S)NR 4 , NR 4 PO or NR 4 PO(OH);

Y is absent, CHR 4 , O, S, SO, SO 2 or NR 4 ;

R 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, 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;

R 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 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 0-3;

and salts and solvates thereof.

2 . The compound of claim 1 , wherein A is a ring selected from the group consisting of A 1 , A 2 , A 3 , A 4 A 5 , A 6 and A 7 :

wherein Z 1 is 0, S or NR 5 wherein R 5 is H or alkyl; Z 2 is CH, CR 2′ or N; R 2 is halogen, hydroxyl, alkyl or alkoxy; R 2′ is H, halogen, hydroxyl, alkyl or alkoxy; and n is 0-3.

3 . The compound of claim 2 , wherein A is ring A 1 wherein Z 1 is S and Z 2 is CH or N.

4 . The compound of claim 2 , wherein A is the ring A 2 .

5 . The compound of claim 2 , wherein R 2 or R 2 ′ is Cl.

6 . The compound of claim 1 , wherein A is A 1a , A 1b , A 2a , A 3a , A 3b , A 4a , A 5a , A 6a , A 7a :

7 . The compound of claim 1 , wherein X is NR 4 C(O).

8 . The compound of claim 1 , wherein X is NR 4 SO 2 .

9 . The compound of claim 7 , wherein R 4 is H or Me.

10 . The compound of claim 9 , wherein R 4 is H.

11 . The compound of claim 1 , wherein R 3 is Me or F.

12 . The compound of claim 1 , wherein R 3 is Me and m is 1 or 2.

13 . The compound of claim 1 , wherein R 3 is F and m is 1 or 2.

14 . The compound of claim 1 , wherein m is 0.

15 .- 31 . (canceled)

32 . A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

33 . A method of treating cancer in a mammal, comprising administering to said mammal an effective amount of a compound of claim 1 .

34 . The method of claim 33 , wherein said cancer is basal cell carcinoma, medullablastoma, pancreatic adenocarcinoma, small-cell lung carcinoma, breast carcinoma, rhabdomyosarcoma, oesophageal cancer, stomach cancer, biliary tract cancer.

35 . A method of inhibiting angiogenesis in a mammal, comprising administering to said mammal an effective amount of a compound of claim 1 .

36 . A method of inhibiting hedgehog pathway signalling in a cell comprising contacting said cell with an effective amount of a compound of claim 1 .

37 . A process for preparing a compound of formula Ib″

wherein

ring B is a carbocycle or heterocycle;

R 3 is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, alkylsulfinyl, alkylsulfonyl, a carbocycle or a heterocycle wherein each alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, alkylsulfinyl, alkylsulfonyl, carbocycle and heterocycle is optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy;

R 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;

o is 0-3; and

m is 0-3;

said process comprising

reacting a compound of formula (a)

wherein Q is Cl, Br or I; with a compound of formula (b)

wherein L is Br, I or OTf; to yield a compound of formula (c);

reducing said compound of formula (c) to give a compound of formula (d)

and reacting said compound of formula (d) with a compound of formula (e)

wherein Q′ is halogen, OH, OR wherein R is an activating group; to yield said compound of formula Ib″.