SUBSTITUTED QUINOXALINES AS B-RAF KINASE INHIBITORS

• US 20170050938A1
• Filed: 08/02/2016
• Published: 02/23/2017
• Est. Priority Date: 09/30/2011
• Status: Abandoned Application

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: Qian, Xiangping, Zhu, Yong-Liang
• Application Number:
  US15/226,669
• Publication Number:
  US 20170050938A1
• 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 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• 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 241/44 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond

Abstract

Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.

Claims

1-52. -52. (canceled)

53. A compound of Formula I:

54. The compound or pharmaceutically acceptable salt of claim 53, wherein R₁ is hydrogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted amino, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted oxazolyl, optionally substituted tetrazolyl, optionally substituted pyridazinyl, or optionally substituted triazolyl.

55. The compound or pharmaceutically acceptable salt of claim 54, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted oxazolyl, optionally substituted tetrazolyl, or optionally substituted triazolyl.

56. The compound or pharmaceutically acceptable salt of claim 53, wherein R₂, R₃, R₄, and R₅ are independently hydrogen, halo, cyano, optionally substituted alkoxy, or optionally substituted alkyl.

57. The compound or pharmaceutically acceptable salt of claim 56, wherein R₂, R₃, R₄, and R₅ are independently hydrogen or halo.

58. The compound or pharmaceutically acceptable salt of claim 53, wherein R₆ is hydrogen, cyano, or optionally substituted alkyl.

59. The compound or pharmaceutically acceptable salt of claim 53, wherein R₇, R₈, and R₁₀ are independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl and R₆ is independently cyano, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl.

60. The compound or pharmaceutically acceptable salt of claim 59, wherein R₇, R₈, and R₁₀ are independently hydrogen, methyl, cyano, or halo and R₆ is hydrogen, methyl or cyano.

61. The compound or pharmaceutically acceptable salt of claim 53, wherein R₇ is hydrogen or halo.

62. The compound or pharmaceutically acceptable salt of claim 53, wherein R₈ is hydrogen.

63. The compound or pharmaceutically acceptable salt of claim 53, wherein R₁₀ is hydrogen, halo or methyl.

64. The compound or pharmaceutically acceptable salt of claim 53, wherein R₉ is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

65. The compound or pharmaceutically acceptable salt of claim 64, wherein R₉ is hydrogen or optionally substituted lower alkyl.

66. The compound or pharmaceutically acceptable salt of claim 64, wherein R₉ is optionally substituted benzyl.

67. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or pharmaceutically acceptable salt of claim 53.

68. A method of inhibiting B-raf kinase activity in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 53.

69. A method of inhibiting B-raf kinase activity in a subject in need thereof, comprising:

a. determining the presence or absence of a B-raf mutation in a biological sample isolated from the subject; and

b. if a B-raf mutation is determined to be present in the subject, administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 53.

70. The method of claim 69, wherein the B-raf mutation is in codon 600.

71. The method of claim 68, further comprising administering an additional anti-cancer agent.

72. The method of claim 69, further comprising administering an additional anti-cancer agent.