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Generated: August 20, 2018

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Details for Patent: 9,790,183

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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: GENENTECH, INC. (Lexington, MA)
Filing Date:Feb 04, 2016
Application Number:15/015,586
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: ##STR00462## wherein A is a carbocycle or heterocycle; X is alkylene, *NR.sub.4C(O), *NR.sub.4C(S), *N(C(O)R.sub.1)C(O), *NR.sub.4SO, *NR.sub.4SO.sub.2, *NR.sub.4C(O)NH, *NR.sub.4C(S)NH, *C(O)NR.sub.4, *C(S)NR.sub.4, *NR.sub.4PO or *NR.sub.4PO(OH), wherein * indicates the point of attachment to ring A; Y is absent, CHR.sub.4, O, S, SO, SO.sub.2 or NR.sub.4; R.sub.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.sub.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.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 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 A.sup.1, A.sup.2, A.sup.3, A.sup.4 A.sup.5, A.sup.6 and A.sup.7: ##STR00463## wherein Z.sub.1 is O, S or NR.sub.5 wherein R.sub.5 is H or alkyl; Z.sub.2 is CH, CR.sub.2' or N; R.sub.2 is halogen, hydroxyl, alkyl or alkoxy; R.sub.2' is H, halogen, hydroxyl, alkyl or alkoxy; and n is 0-3.

3. The method according to claim 2, wherein A is ring A.sup.1 wherein Z.sub.1 is S and Z.sub.2 is CH or N.

4. The method according to claim 2, wherein A is the ring A.sup.2.

5. The method according to claim 2, wherein R.sub.2 or R.sub.2' is Cl.

6. The method according to claim 1, wherein A is A.sup.1a, A.sup.1b, A.sup.2a, A.sup.3a, A.sup.3b, A.sup.4a, A.sup.5a, A.sup.6a, A.sup.7a: ##STR00464##

7. The method according to claim 1, wherein X is *NR.sub.4C(O).

8. The method according to claim 1, wherein X is *NR.sub.4SO.sub.2.

9. The method according to claim 7, wherein R.sub.4 is H or Me.

10. The method according to claim 9, wherein R.sub.4 is H.

11. The method according to claim 1, wherein R.sub.3 is Me or F.

12. The method according to claim 1, wherein R.sub.3 is Me and m is 1 or 2.

13. The method according to claim 1, wherein R.sub.3 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 R.sub.1 is selected from the group consisting of formulae IIa-IIo: ##STR00465## ##STR00466## wherein W is O, S or NR.sub.7 wherein R.sub.7 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; 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; and o is 0-3.

16. The method according to claim 15, wherein R.sub.1 is the group of formula IIa.

17. The method according to claim 16, wherein R.sub.6 is alkoxy and o is 1 or 2.

18. The method according to claim 16, wherein R.sub.1 is selected from the group of formulae IIa.sup.1-IIa.sup.28: ##STR00467## ##STR00468## ##STR00469##

19. The method according to claim 16, wherein A is ##STR00470##

20. The method according to claim 16, wherein A is ##STR00471##

21. The method according to claim 16, wherein R.sub.3 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 *NR.sub.4C(O).

24. The method according to claim 15, wherein R.sub.1 is the group of formula IIb.

25. The method according to claim 24, wherein R.sub.6 is alkyl or haloalkyl.

26. The method according to claim 24, wherein R.sub.1 is the group of the formula ##STR00472##

27. The method according to claim 24, wherein A is ##STR00473##

28. The method according to claim 24, wherein A is ##STR00474##

29. The method according to claim 24, wherein m is 0.

30. The method according to claim 24, wherein X is *NR.sub.4C(O).

31. The method according to claim 1, wherein said compound is of the following formula ##STR00475## wherein X, R.sub.3, and m are as defined in claim 1; R.sub.8 is a halogen; ring B is phenyl or pyridyl, o is 1-3, and each R.sub.6 independently is optionally substituted alkyl, halogen, alkoxy, carbonyl, heterocycle, alkylamino, arylamino, alkylcarbamoyl, alkylsulfamoyl, or sulfonyl.

32. The method according to claim 31, wherein each R.sub.6 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 R.sub.8 is Cl.

35. The method according to claim 31, wherein o is 2.

36. The method according to claim 31, wherein one R.sub.6 is Cl.

37. The method according to claim 31, wherein m is 0, o is 2, R.sub.8 is Cl, one R.sub.6 is Cl and one R.sub.6 is an optionally substituted sulfonyl.

38. The method according to claim 1, 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; and 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.

39. The method according to claim 38, wherein R.sub.4 is H or methyl.

40. The method according to claim 39, wherein R.sub.4 is H.

41. The method according to claim 38, wherein R.sub.1 is substituted.

42. The method according to claim 41, wherein R.sub.1 is substituted phenyl or substituted pyridyl.

43. The method according to claim 42, wherein R.sub.1 is substituted phenyl.

44. The method according to claim 38, wherein said compound is a compound of formula Ib ##STR00476## wherein R.sub.3 is absent or is methyl, R.sub.8 is 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.

45. The method according to claim 44, wherein R.sub.1 is substituted phenyl or substituted pyridyl.

46. The method according to claim 45, wherein R.sub.4 is H, m is 0 and R.sub.8 is Cl.

47. The method according to claim 45, wherein said substituted phenyl or pyridyl R.sup.1 group comprises --SO.sub.2--.

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: ##STR00477## or a salt or solvate thereof.

49. The method according to claim 38, wherein said compound is of the formula ##STR00478##

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