Details for Patent: 9,321,761

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-Toste; Janet L. (Piedmont, CA), Sutherlin; Daniel (Burlingame, CA), Stanley; Mark S. (Pacifica, CA), Bao; Liang (Freemont, CA), Castanedo; Georgette M. (Redwood City, CA), LaLonde; Rebecca L. (Portland, OR), Wang; Shumei (Foster City, CA), Reynolds; Mark E. (Millbrae, CA), Savage; Scott J. (Burlingame, CA), Malesky; Kimberly (Boston, MA), Dina; Michael S. (Daly City, CA), Koehler; Michael F. T. (Palo Alto, CA)
Assignee:	CURIS, INC. (Lexington, MA) GENENTECH, INC. (South San Francisco, CA)
Filing Date:	Dec 18, 2014
Application Number:	14/575,018
Claims:	1. A process for preparing a compound of formula I ##STR00460## 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, comprising, reacting a compound of formula (d) ##STR00461## with a compound of formula (e) ##STR00462## wherein R.sub.14, m and n are as defined above; Z is O or S, and Q' is halogen, OH or OR wherein R is an activating group, to yield said compound of formula I, and, optionally, forming a salt or solvate thereof. 2. The process of claim 1, wherein R.sub.4 is H or methyl. 3. The process of claim 2, wherein R.sub.4 is H. 4. The process of claim 1, wherein R.sub.1 is substituted. 5. The process of claim 4, wherein R.sub.1 is substituted phenyl or substituted pyridyl. 6. The process of claim 5, wherein R.sub.1 is substituted phenyl. 7. A process of claim 1 for preparing a compound of formula Ib ##STR00463## 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.sub.1 is aryl or heteroaryl, each of which is optionally substituted. 8. A process of claim 7, wherein R.sub.8 is halogen and R.sub.1 is substituted phenyl or substituted pyridyl. 9. A process of claim 8, wherein R.sub.4 is H, m is 0 and R.sub.8 is Cl. 10. A process of claim 8, wherein said substituted phenyl or pyridyl R.sup.1 group comprises --SO.sub.2--. 11. A process of claim 1 for preparing a compound of the formula ##STR00464## 12. A process of claim 8 for preparing a compound of the formula Ib' ##STR00465## 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. 13. A process of claim 12, wherein at least one R.sub.6 is an optionally substituted sulfonyl. 14. A process of claim 5, wherein, ring A is o-chlorophenyl, X is --NHC(O)--, and R.sub.1 substituted phenyl or substituted pyridyl comprises --SO.sub.2--. 15. A process of claim 12, 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. 16. A process of claim 1, wherein R.sub.1 is of formula IIa or IIb: ##STR00466## 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. 17. A process of claim 7 wherein R.sub.1 is of formula IIa or IIb: ##STR00467## 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. 18. A process of claim 1, wherein said optional salt and said optional solvate formations are omitted. 19. A process for preparing a compound of formula Ib'' ##STR00468## wherein ring B is a carbocycle or heterocycle; R.sub.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.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; o is 0-3; and m is 0-3; comprising reacting a compound of formula (d') ##STR00469## with a compound of formula (e') ##STR00470## wherein Q' is halogen, OH or OR wherein R is an activating group, to yield said compound of formula Ib'', and, optionally, forming a salt or solvate thereof. 20. A process of claim 19, wherein said optional salt and said optional solvate formations are omitted. 21. A process of claim 1 further comprising reducing a compound of formula (c) ##STR00471## to give a compound of formula (d) wherein R.sub.4 is H. 22. A process of claim 7, wherein said optional salt and said optional solvate formations are omitted. 23. A process of claim 20 for preparing a compound of the formula ##STR00472## 24. A process of claim 20 further comprising reacting a compound of formula (a) ##STR00473## wherein Q is Cl, Br or I; with a compound of formula (b) ##STR00474## wherein L is Br, I or O--SO.sub.2--CF.sub.3; to yield a compound of formula (c'); ##STR00475## 25. A process of claim 21 further comprising reacting a compound of formula (a) ##STR00476## wherein Q is Cl, Br or I; with a compound of formula (b) ##STR00477## wherein L is Br, I or O--SO.sub.2--CF.sub.3; to yield a compound of formula (c') ##STR00478## 26. A process of claim 23 for preparing a compound of the formula ##STR00479##