Pyridyl inhibitors of hedgehog signalling

• US 9,790,183 B2
• Filed: 02/04/2016
• Issued: 10/17/2017
• Est. Priority Date: 09/02/2004
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• 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.
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US15/015,586
• Publication Number:
  US 20160152569A1
• Time in Patent Office: 621 Days
• Field of Search: None
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 213/16 containing only one pyridine ring
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/70 Sulfur atoms
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 9/58 : Pyridine rings

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 R₁, R₂, R₃, R₄, m and n are as described herein.

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:

2. The method according to claim 1, wherein A is a ring selected from the group consisting of A¹, A², A³, A⁴ A⁵, A⁶ and A⁷:

3. The method according to claim 2, wherein A is ring A¹ wherein Z₁ is S and Z₂ is CH or N.

4. The method according to claim 2, wherein A is the ring A².

5. The method according to claim 2, wherein R₂ or R₂′

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 *NR₄C(O).

8. The method according to claim 1, wherein X is *NR₄SO₂.

9. The method according to claim 7, wherein R₄ is H or Me.

10. The method according to claim 9, wherein R₄ is H.

11. The method according to claim 1, wherein R₃ is Me or F.

12. The method according to claim 1, wherein R₃ is Me and m is 1 or 2.

13. The method according to claim 1, wherein R₃ 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 R₁ is selected from the group consisting of formulae IIa-IIo:

16. The method according to claim 15, wherein R₁ is the group of formula IIa.

17. The method according to claim 16, wherein R₆ is alkoxy and o is 1 or 2.

18. The method according to claim 16, wherein R₁ is selected from the group of formulae IIa¹-IIa²⁸:

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 R₃ 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 *NR₄C(O).

24. The method according to claim 15, wherein R₁ is the group of formula IIb.

25. The method according to claim 24, wherein R₆ is alkyl or haloalkyl.

26. The method according to claim 24, wherein R₁ 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 *NR₄C(O).

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

32. The method according to claim 31, wherein each R₆ 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 R₈ is Cl.

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

36. The method according to claim 31, wherein one R₆ is Cl.

37. The method according to claim 31, wherein m is 0, o is 2, R₈ is Cl, one R₆ is Cl and one R₆ is an optionally substituted sulfonyl.

38. The method according to claim 1, wherein

A is substituted benzene;

X is *NR₄C(O) or *NR₄C(S);

Y is absent;

R₁ is aryl or heteroaryl, each of which is optionally substituted; and

R₂ is halogen, or alkyl substituted with halogen and an R₂ is in the o-position on said A benzene relative to pyridyl.

39. The method according to claim 38, wherein R₄ is H or methyl.

40. The method according to claim 39, wherein R₄ is H.

41. The method according to claim 38, wherein R₁ is substituted.

42. The method according to claim 41, wherein R₁ is substituted phenyl or substituted pyridyl.

43. The method according to claim 42, wherein R₁ is substituted phenyl.

44. The method according to claim 38, wherein said compound is a compound of formula Ib

45. The method according to claim 44, wherein R₁ is substituted phenyl or substituted pyridyl.

46. The method according to claim 45, wherein R₄ is H, m is 0 and R₈ is Cl.

47. The method according to claim 45, wherein said substituted phenyl or pyridyl R¹ group comprises —

SO₂—

.

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

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: