2-BENZOYLAMINOBENZAMIDE DERIVATIVES AS BCL-3 INHIBITORS

• US 20160185740A1
• Filed: 07/31/2014
• Published: 06/30/2016
• Est. Priority Date: 07/31/2013
• Status: Active Grant

• Current Assignee: University College Cardiff Consultants Ltd (Cardiff University)
• Original Assignee: University College Cardiff Consultants Ltd (Cardiff University)
• Inventors: Westwell, Andrew David, Brancale, Andrea, Clarkson, Richard William Ernest, Soukupova, Jitka
• Granted Patent: US 10,450,285 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain

Abstract

The invention relates to a compound of general formula (I):

wherein R¹, R², R³, R⁴, Q, m and n are as defined herein. The compounds are inhibitors of Bcl3 and are useful for the treatment of cancer, particularly metastatic cancer.

Claims

1-38. -38. (canceled)

39. A compound of general formula (Ia):

40. The compound of claim 39, wherein R¹ is halo, nitro, C_1-4 alkyl, C_1-4 haloalkyl or OR⁵.

41. The compound of claim 39, wherein R⁵ is hydrogen, methyl or ethyl, or methyl or ethyl substituted with one or more halo substituents.

42. The compound of claim 39, wherein R¹ is halo, nitro, methyl, trifluoromethyl, OH, methoxy or trifluoromethoxy.

43. The compound of claim 39, wherein m is 1 or 2.

44. The compound of claim 39, wherein at least one R¹ is fluoro.

45. The compound of claim 44, wherein R¹ is 2-fluoro.

46. The compound of claim 39, wherein at least one R¹ is OR⁵.

47. The compound of claim 46, wherein R⁵ is C_1-6 alkyl.

48. The compound of claim 47, wherein R⁵ is methyl.

49. The compound of claim 39, wherein R³ is morpholinyl.

50. The compound of claim 39, wherein p is 2 or 3.

51. The compound of claim 39, wherein R⁴ is C_1-4 alkyl or OR⁹.

52. The compound of claim 51, wherein R⁴ is methyl or methoxy.

53. The compound of claim 39, wherein n is 0 or 1.

54. The compound of claim 39, selected from:

2-[(3-fluorobenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-[(4-fluorobenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-[(2-methoxybenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-[(3-methoxybenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-[(4-methoxybenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-[(2-nitrobenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-[(3-nitrobenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-[(4-nitrobenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-[(2-methylbenzoyl)amino]-N-(2-morpholin-4-ylethyl)benzamide;

2-benzamido-N-(2-morpholin-4-ylethyl)benzamide;

3,4-dimethoxy-N-(2-[(2-morpholin-4-ylethyl)carbamoyl]phenyl)benzamide;

3,5-dimethoxy-N-(2-[(2-morpholin-4-ylethyl)carbamoyl]phenyl) benzamide;

3,5-difluoro-N-(2-[(2-morpholin-4-ylethyl)carbamoyl]phenyl)benzamide;

2,6-difluoro-N-(2-[(2-morpholin-4-ylethyl) carbamoyl]phenyl)benzamide;

2,4-difluoro-N-(2-[(2-morpholin-4-ylethyl)carbamoyl]phenyl)benzamide;

2-[(2-fluorobenzoyl)amino]-N-(2-morpholin-4-ylpropyl)benzamide;

2-[(4-fluorobenzoyl)amino]-N-(pyridin-3-ylmethyl)benzamide;

2-[(4-fluorobenzoyl)amino]-N-(pyrrolidin-3-ylmethyl)benzamide;

2-[(4-fluorobenzoyl)amino]-N-(piperidin-3-ylmethyl)benzamide;

2-[(4-fluorobenzoyl)amino]-N-(piperazin-3-ylmethyl)benzamide;

N-(2-aminoethyl)-2-(2-fluorobenzamido) benzamide;

2-[(2-fluorobenzoyl)amino]-3-methyl-N-(2-morpholin-4-ylethyl)benzamide;

2-[(2-fluorobenzoyl)amino]-3-methoxy-N-(2-morpholin-4-ylethyl)benzamide; and

2-fluoro-N-(2-((2-morpholinoethyl)carbamoyl)phenyl)benzamide;

or a pharmaceutically or veterinarily acceptable salt thereof.

55. A process for the preparation of a compound of claim 39, comprising reacting a compound of formula (IIa):