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

• US 9,295,671 B2
• Filed: 08/24/2012
• Issued: 03/29/2016
• 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): Grazier, Nyeemah A
• Assistant Examiner(s): Aguirre, Amanda L
• Application Number:
  US13/594,634
• Publication Number:
  US 20130053384A1
• Time in Patent Office: 1,313 Days
• Field of Search: 514/234.8, 514/249, 544/353, 544/119, 544/356, 544/354, 435/6.11, 435/7.4
• 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 benzenesulfonamide derivatives of quinoxaline, pharmaceutical compositions and methods of treatment of cancer are described.

Claims

1. A compound of Formula I:

2. The compound or pharmaceutically acceptable salt of claim 1, wherein R₇ and R₈ are hydrogen.

3. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

4. The compound or pharmaceutically acceptable salt of claim 3, wherein R₁ is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted pyridyl.

5. The compound or pharmaceutically acceptable salt of claim 1, wherein R₆ and R₁₀ are independently halo.

6. The compound or pharmaceutically acceptable salt of claim 5, wherein R₆ and R₁₀ are independently fluoro or chloro.

7. The compound or pharmaceutically acceptable salt of claim 6, wherein R₆ is fluoro.

8. The compound or pharmaceutically acceptable salt of claim 6, wherein R₁₀ is chloro.

9. The compound or pharmaceutically acceptable salt of claim 1, wherein R₉ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

10. The compound or pharmaceutically acceptable salt of claim 9, wherein R₉ is optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

11. The compound or pharmaceutically acceptable salt of claim 10, wherein R₉ is optionally substituted lower alkyl.

12. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁₁ is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

13. The compound or pharmaceutically acceptable salt of claim 12, wherein R₁₁ is hydrogen or optionally substituted lower alkyl.

14. The compound or pharmaceutically acceptable salt of claim 13, wherein R₁₁ is hydrogen.

15. The compound or pharmaceutically acceptable salt of claim 1, provided that when R₁₀ is fluoro, then R₇ is not hydrogen, or R₈ is not hydrogen, or R₆ is not hydrogen or halo.

16. The compound or pharmaceutically acceptable salt of claim 15, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

17. The compound or pharmaceutically acceptable salt of claim 16, wherein R₁ is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted pyridyl.

18. The compound or pharmaceutically acceptable salt of claim 1, wherein R₇ is halo.

19. The compound or pharmaceutically acceptable salt of claim 18, wherein R₇ is fluoro.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of claim 1.

21. A pharmaceutical composition of claim 20 wherein the composition is formulated in a form which is a tablet, capsule, powder, liquid, suspension, suppository, or aerosol.

22. A packaged pharmaceutical composition comprising a pharmaceutical composition of claim 20 and instructions for administering said composition to a subject.

23. A compound chosen from the group consisting of:

N-(2-chloro-4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2-chloro-4-fluoro-3-(3-methylquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2-chloro-3-(3-cyanoquinoxaline-6-carbonyl)-4-fluorophenyl)propane-1-sulfonamide,

N-(2-chloro-4-fluoro-3-(3-methoxyquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2-chloro-4-fluoro-3-(3-phenylquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2-chloro-3-(3-(4-chlorophenyl)quinoxaline-6-carbonyl)-4-fluorophenyl)propane-1-sulfonamide,

N-(2-chloro-4-fluoro-3-(3-(4-fluorophenyl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(3-(3-(1H-imidazol-1-yl)quinoxaline-6-carbonyl)-2-chloro-4-fluorophenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(2,4-difluoro-3-(3-methylquinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(3-(3-cyanoquinoxaline-6-carbonyl)-2,4-difluorophenyl)benzenesulfonamide,

N-(2,4-difluoro-3-(3-methoxyquinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(2,4-difluoro-3-(3-methylquinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(3-(3-cyanoquinoxaline-6-carbonyl)-2,4-difluorophenyl)-3-fluorobenzenesulfonamide,

N-(2,4-difluoro-3-(3-methoxyquinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(2,4-difluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(2,4-difluoro-3-(3-(piperazin-l-yl)quinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(2,4-difluoro-3-(3-(2-hydroxyethoxy)quinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(2,4-difluoro-3-(3-(2-methoxyethoxy)quinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(3-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)-2,4-difluorophenyl)-3-fluorobenzenesulfonamide,

N-(2,4-difluoro-3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-methylquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(3-(3-cyanoquinoxaline-6-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-methoxyquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(2-methoxyethoxy)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(2-hydroxyethoxy)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-phenylquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(3-(3-(4-chlorophenyl)quinoxaline-6-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(4-fluorophenyl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(3-(3-(1H-imidazol-1-yl)quinoxaline-6-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(2-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(5-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(4-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(3-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

N-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide, and

N-(2,4-difluoro-3-(3-(pyridin-4-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide, and pharmaceutically acceptable salts thereof.

24. A compound or chosen from the group consisting of: