BENZOPIPERAZINE COMPOSITIONS AS BET BROMODOMAIN INHIBITORS

• US 20190330233A1
• Filed: 06/18/2019
• Published: 10/31/2019
• Est. Priority Date: 11/18/2013
• Status: Active Grant

• Current Assignee: Forma Therapeutics, Inc. (Novo Nordisk A/S)
• Original Assignee: Forma Therapeutics, Inc. (Novo Nordisk A/S)
• Inventors: Bair, Kenneth W., Herbertz, Torsten, Kauffman, Goss S., Kayser-Bricker, Katherine J., Luke, George P., Martin, Matthew W., Millan, David S., Schiller, Shawn E.R., Talbot, Adam C., Tebbe, Mark J.
• Granted Patent: US 10,703,764 B2
• Time in Patent Office: Days
• 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 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 241/42 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 241/50 with hetero atoms directly attached to ring nitrogen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• 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 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 451/04 : with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems

Abstract

The present invention relates to inhibitors of bromo and extra terminal (BET) bromodomains that are useful for the treatment of cancer, inflammatory diseases, diabetes, and obesity, having Formula (I):

wherein X, Y, Z, R₁, R₂, R₄ and R₇ are defined herein.

Claims

1-34. -34. (canceled)

35. A process of preparing a compound of Formula (VI):

36. The process of claim 35, further comprising a step of contacting a first amine compound:

37. The process of claim 36, further comprising a step of contacting a tosylated amine compound:

38. The process of claim 37, further comprising a step of contacting a second amine compound:

39. The process of claim 38, further comprising a step of contacting an alcohol compound:

40. The process of claim 39, further comprising a step of contacting an aniline compound:

41. The process of claim 40, further comprising a step of reducing a nitroarene compound:

42. The process of claim 41, further comprising a step of contacting 4-bromo-1-fluoro-2-nitrobenzene:

43. The process of claim 35, wherein R^d is cyclopropyl or cyclobutyl.

44. The process of claim 43, wherein R₁₀ is —

(CR^kR^l)_nRⁱ, and n is 0.

45. The process of claim 43, wherein Rⁱ is —

(CR^kR^l)_mheterocycloalkyl, and m is 0.

46. The process of claim 45, wherein Rⁱ is tetrahydro-2H-thiopyran-1,1-dioxide.

47. The process of claim 35, wherein the aryl bromide compound:

48. The process of claim 47, wherein the boronic ester compound is:

49. The process of claim 48, further comprising a step of contacting a heteroaryl iodide compound:

50. The process of claim 49, further comprising a step of contacting 4-iodo-1H-pyrazole with a mesylate compound:

51. The process of claim 50, further comprising a step of contacting a hydroxyl compound:

52. The process of claim 47, wherein the boronic ester is:

53. The process of claim 35, wherein the compound of Formula (VI) is selected from:

cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1λ

⁶-thian-4-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate;

cyclobutyl (3S)-4-acetyl-7-{1-[(3R)-1,1-dioxo-1λ

⁶-thian-3-yl]-1H-pyrazol-4-yl}-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate; and

cyclobutyl (3S)-4-acetyl-7-{1-[(3S)-1,1-dioxo-1λ

⁶-thian-3-yl]-1H-pyrazol-4-yl}-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate.