BENZENESULFONAMIDE DERIVATIVES OF QUINOXALINE, PHARMACEUTICAL COMPOSITIONS THEREOF, AND THEIR USE IN METHODS FOR TREATING CANCER

• US 20170340630A1
• Filed: 01/06/2017
• Published: 11/30/2017
• Est. Priority Date: 08/26/2011
• Status: Active Grant

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: Zhu, Yong-Liang, Qian, Xiangping
• Granted Patent: US 10,137,125 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• 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 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• 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: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• 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
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 : Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/118 : Prognosis of disease development
• CPC Class Codes: C12Q 2600/156 : Polymorphic or mutational markers
• CPC Class Codes: G01N 2333/47 : Assays involving proteins of known structure or function as defined in the subgroups
• CPC Class Codes: G01N 33/5748 : involving oncogenic proteins

Abstract

Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of using these chemical entities, e.g., for treatment of cancer are described.

Claims

1-63. -63. (canceled)

64. A compound of Formula I:

65. The compound or pharmaceutically acceptable salt of claim 64, wherein R₁ is hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbamimidoyl, or optionally substituted alkynyl.

66. The compound or pharmaceutically acceptable salt of claim 64, wherein R₁ is hydrogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted amino, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

67. The compound or pharmaceutically acceptable salt of claim 64, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

68. The compound or pharmaceutically acceptable salt of claim 64, wherein R₂, R₃, R₄, and R₅ are independently hydrogen, halo, optionally substituted alkoxy, or optionally substituted alkyl.

69. The compound or pharmaceutically acceptable salt of claim 64, wherein R₆, 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.

70. The compound or pharmaceutically acceptable salt of claim 69, wherein R₆, R₈, and R₁₀ are independently hydrogen, cyano, or halo.

71. The compound or pharmaceutically acceptable salt of claim 64, wherein R₆ and R₁₀ are independently halo.

72. The compound or pharmaceutically acceptable salt of claim 64, wherein R₇ is fluoro or chloro.

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

74. The compound or pharmaceutically acceptable salt of claim 73, wherein R₉ is optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

75. The compound or pharmaceutically acceptable salt of claim 74, wherein R₉ is optionally substituted lower alkyl.

76. The compound or pharmaceutically acceptable salt of claim 64, wherein R₁₁ is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

77. The compound or pharmaceutically acceptable salt of claim 76, wherein R₁₁ is hydrogen or optionally substituted lower alkyl.

78. The compound or pharmaceutically acceptable salt of claim 77, wherein R₁₁ is hydrogen.

79. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or pharmaceutically acceptable salt of claim 64.

80. A method of treating a BRAF-mediated disorder, the method comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 64.

81. The method of claim 80, further comprising:

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

b. if the BRAF mutation is determined to be present in the subject, then administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt.

82. The method of claim 81, wherein the BRAF mutation is V600E.

83. The method of claim 81, wherein determining the presence or absence of the BRAF mutation comprises amplifying BRAF nucleic acid from the biological sample and sequencing the amplified nucleic acid.

84. The method of claim 81, wherein determining the presence or absence of the BRAF mutation comprises detecting a mutant BRAF polypeptide in the biological sample using a binding agent to a mutant BRAF polypeptide.

85. The method of claim 84, wherein the binding agent is an antibody.

86. The method of claim 84, wherein the biological sample is isolated from a tumor of the subject.

87. The method of claim 80, wherein the disorder is a cancer.

88. The method of claim 87, wherein the cancer is selected from the group consisting of melanoma, non-small cell lung cancer, colon cancer, and ovarian cancer.

89. The method of claim 80, further comprising administering to the subject an additional anti-cancer and/or cytotoxic agent.