Pyridyl inhibitors of hedgehog signalling

Patent metadata

Field	Value
Publication number	US-9790183-B2
Application number	US-201615015586-A
Country	US
Kind code	B2
Filing date	Feb 4, 2016
Priority date	Sep 2, 2004
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

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 R 1 , R 2 , R 3 , R 4 , m and n are as described herein.

First claim

We claim:

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, *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), wherein * indicates the point of attachment to ring A;
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;
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 1 , A 2 , A 3 , A 4 A 5 , A 6 and A 7 :

wherein Z 1 is O, 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 method according to claim 2 , wherein A is ring A 1 wherein Z 1 is S and Z 2 is CH or N.

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

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

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

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

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

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

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

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

13. The method according to claim 1 , wherein R 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 1 is selected from the group consisting of formulae IIa-IIo:

wherein
W is O, S or NR 7 wherein R 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 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 1 is the group of formula IIa.

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

18. The method according to claim 16 , wherein R 1 is selected from the group of formulae IIa 1 -IIa 28 :

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 R 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 4 C(O).

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

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

26. The method according to claim 24 , wherein R 1 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 *NR 4 C(O).

31. The method according to claim 1 , wherein said compound is of the following formula

wherein
X, R 3 , and m are as defined in claim 1 ;
R 8 is a halogen;
ring B is phenyl or pyridyl,
o is 1-3, and
each R 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 6 independently is methyl, trifluoromethyl, dimethylaminomethyl, piperidinylmethyl, morpholinomethyl, thiomorpholinomethyl, chloro, methoxy, morpholinocarbonyl, acetyl, morpholino, N-methyl-piperazin-4-yl, N-acetyl-piperazin-4-y

Assignees

• Genentech Inc
• Curis Inc

Inventors

• Gunzner-Toste Janet L
• Sutherlin Daniel
• Stanley Mark S
• Bao Liang
• Castanedo Georgette M
• Lalonde Rebecca L
• Wang Shumei
• Reynolds Mark E
• Savage Scott J
• Malesky Kimberly
• Dina Michael S
• Koehler Michael F T

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title