Benzenesulfonamide derivatives of quinoxaline, pharmaceutical compositions thereof, and their use in methods for treating cancer

• US 9,572,808 B2
• Filed: 12/17/2015
• Issued: 02/21/2017
• Est. Priority Date: 08/26/2011
• Status: Active Grant

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: Zhu, Yong-Liang, Qian, Xiangping
• Primary Examiner(s): Kosack, Joseph
• Assistant Examiner(s): Aguirre, Amanda L
• Application Number:
  US14/973,492
• Publication Number:
  US 20160303118A1
• Time in Patent Office: 432 Days
• US Class Current: 1/1
• 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. A method of treating a BRAF-mediated disorder by inhibiting BRAF in a subject suffering from said disorder, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of Formula I:

2. The method of claim 1, wherein the subject expresses mutant BRAF.

3. The method of claim 1, wherein the BRAF has a mutation in codon 600.

4. The method of claim 1, wherein the BRAF is a BRAF-V600E mutant.

5. The method of claim 1, further comprising administering an additional anti-cancer and/or cytotoxic agent.

6. The method of claim 1, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

7. The method of claim 1, wherein R₆ and R₁₀ are independently fluoro or chloro.

8. The method of claim 1, wherein R₉ is optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

9. The method of claim 1, wherein R₁₁ is hydrogen or optionally substituted lower alkyl.

10. The method of claim 1, wherein the subject expresses a BRAF V600E mutation.

11. The method of claim 1, wherein the disorder is selected from the group consisting of melanoma, non-small cell lung cancer, colon cancer, thyroid cancer and ovarian cancer.